Treatment of chronic obstructive pulmonary disease with anti-interleukin-33 antibodies

Abstract

The present disclosure relates to methods of treating COPD, in particular by administering an anti-IL-33 antibody or an antibody variant thereof at a specified dosing regimen.

Description

[0001] This application is a divisional application of the patent application with the application date of August 26, 2022, application number 202280051952.9, and invention title "Treatment of Chronic Obstructive Pulmonary Disease with Anti-Interleukin-33 Antibodies". Technical Field

[0002] This disclosure relates to methods for treating COPD, particularly by administering anti-IL-33 antibodies or antibody variants thereof. Background Art

[0003] Chronic obstructive pulmonary disease (COPD) is the fourth leading cause of death worldwide and is projected to become the third leading cause of death globally by 2030 (Adeloye et al. 2015). COPD is characterized by persistent respiratory symptoms and airflow limitation (forced expiratory volume in the first second [FEV1] / forced vital capacity [FVC] < 0.70 after bronchodilator [BD]), which is caused by airway and / or alveolar abnormalities, typically due to substantial exposure to toxic particles or gases, and is influenced by host factors including abnormal lung development. Severe comorbidities can impact morbidity and mortality (GOLD [Global Initiative for Chronic Obstructive Lung Disease] 2020). COPD is a life-threatening respiratory condition, and the course of the disease is characterized by long-term disability, which results in a significant loss of health-related quality of life (van Manen et al. 2003).

[0004] COPD is not fully reversible, is typically progressive, and is associated with an enhanced chronic inflammatory response in the lung. Increasing evidence demonstrates that the overall symptomatic burden has a substantial adverse impact on health-related quality of life and also leads to an increased risk of exacerbations and worsening disease prognosis (Miravitlles and Ribera 2017).

[0005] An acute exacerbation of COPD is a worsening of symptoms that has significant adverse consequences for patients (Wedzicha and Seemungal 2007). Higher exacerbation frequencies are associated with accelerated decline in lung function, impaired health-related quality of life, and increased mortality (Donaldson et al. 2002, Seemungal et al. 1998, Soler-Cataluna et al. 2005). In addition, as the incidence of COPD increases, exacerbations impose a greater burden on the healthcare system, resulting in over 10 million unplanned visits per year in the United States (Mannino and Braman 2007). In the United States, the direct costs of treating COPD exceed $32 billion per year, and exacerbations are estimated to account for 50% to 75% of these healthcare costs (Celli et al. 2004, Guarascio et al. 2013, Toy et al. 2010). Exacerbations are also an important outcome measure in COPD, with the goal of acute treatment being to accelerate recovery, while long-term maintenance inhaled therapies are aimed at preventing and reducing their frequency and severity (Ritchie and Wedzicha 2020).

[0006] Despite adequate treatment with optimized maintenance inhaled therapies, approximately 30% to 40% of patients continue to experience moderate or severe exacerbations (Müllerová et al. 2017, Vestbo et al. 2017). Even the maximum triple therapy (LABA + LAMA + ICS) may still be insufficient (Rabe et al. 2020); thus, there remains a large unmet medical need. Summary of the Invention

[0007] The present disclosure provides methods for treating COPD. The methods disclosed herein include administering an anti-IL-33 antibody or an antibody variant thereof.

[0008] Interleukin-33 expression is increased in COPD (Byers et al. 2013), and is negatively correlated with lung function (Byers et al. 2013, Kearley et al. 2015). Neutralizing IL-33 activity with MEDI3506 has the potential to disrupt the cycle of inflammatory structural damage in the lungs of patients with COPD, and thereby provide a therapeutic benefit to patients with COPD.

[0009] In one aspect, the present disclosure provides a method of treating a subject having chronic obstructive pulmonary disease (COPD), the method comprising administering a therapeutically effective amount of an anti-IL-33 antibody or an antibody variant thereof at an interval of once every 4 weeks (Q4W) or once every 8 weeks (Q8W), at a dose ranging from about 300 mg to about 600 mg, wherein the anti-IL-33 antibody comprises: a heavy chain variable region comprising an HCDR1 having the sequence set forth in SEQ ID NO:1, a VHCDR2 having the sequence of SEQ ID NO:2, and a VHCDR3 having the sequence of SEQ ID NO:3; and a light chain variable region comprising a VLCDR1 having the sequence of SEQ ID NO:5, a VLCDR2 having the sequence of SEQ ID NO:6, and a VLCDR3 having the sequence of SEQ ID NO:7.

[0010] In another aspect, the present disclosure provides a method of treating a subject having chronic obstructive pulmonary disease (COPD), the method comprising administering a therapeutically effective amount of an anti-IL-33 antibody or an antibody variant thereof at an interval of once every 4 weeks (Q4W) at a dose of about 150 mg, wherein the anti-IL-33 antibody comprises: a heavy chain variable region comprising an HCDR1 having the sequence set forth in SEQ ID NO:1, a VHCDR2 having the sequence of SEQ ID NO:2, and a VHCDR3 having the sequence of SEQ ID NO:3; and a light chain variable region comprising a VLCDR1 having the sequence of SEQ ID NO:5, a VLCDR2 having the sequence of SEQ ID NO:6, and a VLCDR3 having the sequence of SEQ ID NO:7.

[0011] In another aspect, the present disclosure provides a method of treating a subject's COPD, the method comprising administering a therapeutically effective amount of an anti-IL-33 antibody or an antibody variant thereof at a dose effective to achieve at least 80% inhibition of IL-33 in the lung or epithelial lining fluid (ELF), wherein the anti-IL-33 antibody comprises: a heavy chain variable region comprising an HCDR1 having the sequence set forth in SEQ ID NO:1, a VHCDR2 having the sequence of SEQ ID NO:2, and a VHCDR3 having the sequence of SEQ ID NO:3; and a light chain variable region comprising a VLCDR1 having the sequence of SEQ ID NO:5, a VLCDR2 having the sequence of SEQ ID NO:6, and a VLCDR3 having the sequence of SEQ ID NO:7.

[0012] In some cases, the dose is effective to achieve at least about 90%, optionally at least 95%, inhibition of IL-33 in the lung.

[0013] In some cases, the dose is from about 300 mg to about 600 mg, administered at intervals of once every 4 weeks (Q4W) or once every 8 weeks (Q8W). In some cases, the dose is about 300 mg Q8W. In some cases, the dose is about 300 mg Q4W. In some cases, the dose is about 150 mg Q4W.

[0014] In some cases, the COPD is associated with the subject's chronic bronchitis.

[0015] In some cases, the COPD is moderate COPD, moderate to severe COPD, or severe COPD.

[0016] In some cases, the subject to be treated has a history of at least one, optionally at least two moderate, or at least one severe chronic obstructive pulmonary disease exacerbation (aeCOPD) within 12 months prior to treatment.

[0017] In some cases, prior to treatment, the ratio of forced expiratory volume in the first second (FEV1) to forced vital capacity (FVC) after bronchodilator administration (FEV1 / FVC after BD) in the subject is less than (<) 0.70. In some cases, prior to treatment, the subject's FEV1 after BD is > 20% of the predicted normal value.

[0018] In some cases, the subject is a current smoker or a former smoker. In some cases, the subject is a former smoker. In some cases, the subject has a smoking history of at least 10 pack - years.

[0019] In some cases, the subject to be treated is receiving COPD inhaled maintenance therapy, including a long - acting β2 - agonist (LABA), a long - acting muscarinic receptor antagonist (LAMA), and / or an inhaled corticosteroid (ICS). In some cases, the inhaled maintenance therapy includes LABA and LAMA, ICS and LABA, or ICS, LABA, and LAMA.

[0020] In some cases, the anti - IL - 33 antibody or its antibody variant is selected from: human antibody, humanized antibody, chimeric antibody, monoclonal antibody, recombinant antibody, antigen - binding antibody fragment, single - chain antibody, monomeric antibody, dimeric antibody, trimeric antibody, tetrameric antibody, Fab fragment, IgG1 antibody, IgG2 antibody, IgG3 antibody, and IgG4 antibody.

[0021] In some cases, the anti - IL - 33 antibody or its antibody variant is IgG1.

[0022] In some cases, the anti - IL - 33 antibody or its antibody variant is a human antibody.

[0023] In some cases, the anti-IL-33 antibody or antibody variant thereof comprises a VH domain having at least 95%, 90% or 85% identity to the sequence listed in SEQ ID NO:4 and a VL domain having at least 95%, 90% or 85% identity to the sequence listed in SEQ ID NO:8.

[0024] In some cases, the anti-IL-33 antibody comprises the VH domain sequence listed in SEQ ID NO:4 and the VL domain sequence listed in SEQ ID NO:8.

[0025] In some cases, the anti-IL-33 antibody comprises the light chain sequence listed in SEQ ID NO:9 and the heavy chain sequence listed in SEQ ID NO:10.

[0026] In some cases, the anti-IL-33 antibody variant has the same pharmacokinetic (pK) profile in humans as 33_670087_7B (MEDI3506 / tozorakimab).

[0027] In some cases, the anti-IL-33 antibody is tozorakimab.

[0028] In some cases, the administration is subcutaneous administration.

[0029] In another aspect, the present disclosure provides a method of improving a biomarker of chronic obstructive pulmonary disease (COPD) in a subject, the method comprising: administering a therapeutically effective amount of an anti-IL-33 antibody or antibody variant thereof at an interval of once every 4 weeks (Q4W) or once every 8 weeks (Q8W), in a dose ranging from about 300 mg to about 600 mg, wherein the anti-IL-33 antibody comprises: a heavy chain variable region comprising HCDR1 having the sequence listed in SEQ ID NO:1, VHCDR2 having the sequence of SEQ ID NO:2, VHCDR3 having the sequence of SEQ ID NO:3; and a light chain variable region comprising VLCDR1 having the sequence of SEQ ID NO:5, VLCDR2 having the sequence of SEQ ID NO:6, and VLCDR3 having the sequence of SEQ ID NO:7. The biomarker is selected from: annualized rate of moderate to severe COPD exacerbation, time to first moderate to severe COPD exacerbation, FEV1, forced expiratory volume in one second (FEV1), ratio of FEV1 to forced vital capacity (FEV1 / FVC), or breathlessness, cough and sputum scale (BCSS) score, COPD assessment test (CAT) score, and St. George's Respiratory Questionnaire (SGRQ) score.

[0030] In some cases, for any of the foregoing aspects, the anti-IL-33 antibody or an antibody variant thereof is administered for a period of at least 12 weeks. In some cases, for any of the foregoing aspects, the anti-IL-33 antibody or an antibody variant thereof is administered for a period of at least 24 weeks. In some cases, for any of the foregoing aspects, the anti-IL-33 antibody or an antibody variant thereof is administered for a period of at least 52 weeks.

[0031] In another aspect, the present disclosure provides a method of reducing the annualized moderate to severe COPD exacerbation rate in a subject, the method comprising administering a therapeutically effective amount of an anti-IL-33 antibody or an antibody variant thereof at intervals of once every 4 weeks (Q4W) or once every 8 weeks (Q8W), at a dose of from about 300 mg to about 600 mg, wherein the anti-IL-33 antibody comprises: a heavy chain variable region comprising an HCDR1 having the sequence set forth in SEQ ID NO:1, a VHCDR2 having the sequence of SEQ ID NO:2, and a VHCDR3 having the sequence of SEQ ID NO:3; and a light chain variable region comprising a VLCDR1 having the sequence of SEQ ID NO:5, a VLCDR2 having the sequence of SEQ ID NO:6, and a VLCDR3 having the sequence of SEQ ID NO:7.

[0032] In another aspect, the present disclosure provides a method of improving pre-bronchodilator FEV1 in a subject with COPD, the method comprising administering a therapeutically effective amount of an anti-IL-33 antibody or an antibody variant thereof at intervals of once every 4 weeks (Q4W) or once every 8 weeks (Q8W), at a dose of from about 300 mg to about 600 mg, wherein the anti-IL-33 antibody comprises: a heavy chain variable region comprising an HCDR1 having the sequence set forth in SEQ ID NO:1, a VHCDR2 having the sequence of SEQ ID NO:2, and a VHCDR3 having the sequence of SEQ ID NO:3; and a light chain variable region comprising a VLCDR1 having the sequence of SEQ ID NO:5, a VLCDR2 having the sequence of SEQ ID NO:6, and a VLCDR3 having the sequence of SEQ ID NO:7.

[0033] In another aspect, the present disclosure provides a method of improving the E-RS:COPD score in a subject with COPD, the method comprising administering a therapeutically effective amount of an anti-IL-33 antibody or an antibody variant thereof at an interval of once every 4 weeks (Q4W) or once every 8 weeks (Q8W), at a dose from about 300 mg to about 600 mg, wherein the anti-IL-33 antibody comprises: a heavy chain variable region comprising HCDR1 having the sequence listed in SEQ ID NO:1, VHCDR2 having the sequence of SEQ ID NO:2, and VHCDR3 having the sequence of SEQ ID NO:3; and a light chain variable region comprising VLCDR1 having the sequence of SEQ ID NO:5, VLCDR2 having the sequence of SEQ ID NO:6, and VLCDR3 having the sequence of SEQ ID NO:7.

[0034] In another aspect, the present disclosure provides a method of improving the SGRQ score in a subject with COPD, the method comprising administering a therapeutically effective amount of an anti-IL-33 antibody or an antibody variant thereof at an interval of once every 4 weeks (Q4W) or once every 8 weeks (Q8W), at a dose from about 300 mg to about 600 mg, wherein the anti-IL-33 antibody comprises: a heavy chain variable region comprising HCDR1 having the sequence listed in SEQ ID NO:1, VHCDR2 having the sequence of SEQ ID NO:2, and VHCDR3 having the sequence of SEQ ID NO:3; and a light chain variable region comprising VLCDR1 having the sequence of SEQ ID NO:5, VLCDR2 having the sequence of SEQ ID NO:6, and VLCDR3 having the sequence of SEQ ID NO:7.

[0035] In another aspect, the present disclosure provides a method of improving the CAT score in a subject with COPD, the method comprising administering a therapeutically effective amount of an anti-IL-33 antibody or an antibody variant thereof at an interval of once every 4 weeks (Q4W) or once every 8 weeks (Q8W), at a dose from about 300 mg to about 600 mg, wherein the anti-IL-33 antibody comprises: a heavy chain variable region comprising HCDR1 having the sequence listed in SEQ ID NO:1, VHCDR2 having the sequence of SEQ ID NO:2, and VHCDR3 having the sequence of SEQ ID NO:3; and a light chain variable region comprising VLCDR1 having the sequence of SEQ ID NO:5, VLCDR2 having the sequence of SEQ ID NO:6, and VLCDR3 having the sequence of SEQ ID NO:7.

[0036] In summary, the present disclosure provides specific embodiments of the following items:

[0037] 1. A method of treating a subject with chronic obstructive pulmonary disease (COPD), the method comprising administering a therapeutically effective amount of an anti-IL-33 antibody or an antibody variant thereof at intervals of once every 4 weeks (Q4W) or once every 8 weeks (Q8W), in a dose ranging from about 300 mg to about 600 mg, wherein the anti-IL-33 antibody comprises:

[0038] a. A heavy chain variable region that comprises an HCDR1 having the sequence set forth in SEQ ID NO:1, a VHCDR2 having the sequence of SEQ ID NO:2, and a VHCDR3 having the sequence of SEQ ID NO:3; and

[0039] b. A light chain variable region that comprises a VLCDR1 having the sequence of SEQ ID NO:5, a VLCDR2 having the sequence of SEQ ID NO:6, and a VLCDR3 having the sequence of SEQ ID NO:7.

[0040] 2. A method of treating a subject's COPD, the method comprising administering a therapeutically effective amount of an anti-IL-33 antibody or an antibody variant thereof in a dose effective to achieve at least 80% inhibition of IL-33 in the lung or epithelial lining fluid (ELF), wherein the anti-IL-33 antibody comprises:

[0041] a. A heavy chain variable region that comprises an HCDR1 having the sequence set forth in SEQ ID NO:1, a VHCDR2 having the sequence of SEQ ID NO:2, and a VHCDR3 having the sequence of SEQ ID NO:3; and

[0042] b. A light chain variable region that comprises a VLCDR1 having the sequence of SEQ ID NO:5, a VLCDR2 having the sequence of SEQ ID NO:6, and a VLCDR3 having the sequence of SEQ ID NO:7.

[0043] 3. The method according to item 2, wherein the dose is effective to achieve at least about 90%, optionally at least 95%, inhibition of IL-33 in the lung.

[0044] 4. The method according to item 2 or 3, wherein the dose is from about 300 mg to about 600 mg, at intervals of once every 4 weeks (Q4W) or once every 8 weeks (Q8W).

[0045] 5. The method according to any one of the preceding items, wherein the dose is about 300 mg Q8W.

[0046] 6. The method according to any one of items 1 to 4, wherein the dose is about 300 mg Q4W.

[0047] 7. The method according to any one of items 1 to 4, wherein the dose is about 600 mg Q4W.

[0048] 8. The method according to any one of the preceding items, wherein the COPD is associated with the subject's chronic bronchitis.

[0049] 9. The method according to any one of the preceding items, wherein the COPD is moderate COPD, moderate-to-severe COPD, or severe COPD.

[0050] 10. The method according to any one of the preceding items, wherein the subject has a history of at least one, optionally at least two moderate, or at least one severe COPD acute exacerbation (aeCOPD) within 12 months before treatment.

[0051] 11. The method according to any one of the preceding items, wherein before treatment, the ratio of the forced expiratory volume in the first second (FEV1) to the forced vital capacity (FVC) after bronchodilator in the subject (post-bronchodilator (BD post)-FEV1 / FVC) is less than (<) 0.70.

[0052] 12. The method according to any one of the preceding items, wherein before treatment, the subject's BD post FEV1 > 20% of the predicted normal value.

[0053] 13. The method according to any one of the preceding items, wherein the subject is a current smoker or a former smoker.

[0054] 14. The method according to item 13, wherein the subject has a smoking history of at least 10 pack-years.

[0055] 15. The method according to any one of the preceding items, wherein the subject is receiving COPD inhaled maintenance therapy, including long-acting β2-agonist (LABA), long-acting muscarinic receptor antagonist (LAMA), and / or inhaled corticosteroid (ICS).

[0056] 16. The method according to item 15, wherein the inhaled maintenance therapy includes LABA and LAMA, ICS and LABA, or ICS, LABA, and LAMA.

[0057] 17. The method according to any one of the preceding items, wherein the annualized moderate-to-severe COPD exacerbation rate is reduced in the subject.

[0058] 18. The method according to any one of the preceding items, wherein the time to the first moderate-to-severe COPD exacerbation is increased.

[0059] 19. The method according to any one of the preceding items, wherein the time to the first severe COPD exacerbation is increased.

[0060] 20. The method according to any one of the preceding items, wherein the annualized rate of severe COPD exacerbations is reduced in the subject.

[0061] 21. The method according to any one of the preceding items, wherein the post - bronchodilator FEV1 is improved in the subject.

[0062] 22. The method according to any one of the preceding items, wherein the score of one or more of the following questionnaires is improved in the subject: COPD Evaluation of Respiratory Symptoms (E - RS), St. George's Respiratory Questionnaire (SGRQ), COPD Assessment Test (CAT), Exacerbations of Chronic Pulmonary Disease Tool - Patient Reported Outcomes (EXACT - PRO), Breathlessness, Cough, and Sputum Scale (BCSS), Five - Level Five - Dimension Health Scale (EQ - 5D - 5L), Work Productivity and Activity Impairment Questionnaire (WPAI - GH), Patient Global Impression of Severity Scale (PGIS), and Patient Global Impression of Change Scale (PGIC).

[0063] 23. The method according to any one of the preceding items, wherein the dose effectively achieves a C of from about 10 to 35 μg / ml during the dosing period. max.ss .

[0064] 24. The method according to any one of the preceding items, wherein the anti - IL - 33 antibody or its antibody variant is selected from: human antibody, humanized antibody, chimeric antibody, monoclonal antibody, recombinant antibody, antigen - binding antibody fragment, single - chain antibody, monomeric antibody, dimeric antibody, trimeric antibody, tetrameric antibody, Fab fragment, IgG1 antibody, IgG2 antibody, IgG3 antibody, and IgG4 antibody.

[0065] 25. The method according to any one of the preceding items, wherein the anti - IL - 33 antibody or its antibody variant is IgG1.

[0066] 26. The method according to any one of the preceding items, wherein the anti - IL - 33 antibody or its antibody variant is a human antibody.

[0067] 27. The method according to any one of the preceding items, wherein the anti - IL - 33 antibody or its antibody variant comprises a VH domain having at least 95%, 90% or 85% identity to the sequence listed in SEQ ID NO:4 and a VL domain having at least 95%, 90% or 85% identity to the sequence listed in SEQ ID NO:8.

[0068] 28. A method according to any one of the preceding items, wherein the anti-IL-33 antibody comprises a VH domain sequence as set forth in SEQ ID NO:4 and a VL domain sequence as set forth in SEQ ID NO:8.

[0069] 29. A method according to any one of the preceding items, wherein the anti-IL-33 antibody comprises a light chain sequence as set forth in SEQ ID NO:9 and a heavy chain sequence as set forth in SEQ ID NO:10.

[0070] 30. A method according to any one of the preceding items, wherein the anti-IL-33 antibody variant has the same pharmacokinetic (pK) profile as 33_670087_7B in humans.

[0071] 31. A method according to any one of the preceding items, wherein the anti-IL-33 antibody is 33-670087_7B (MEDI3506).

[0072] 32. A method according to any one of the preceding items, wherein the administration is subcutaneous administration.

[0073] 33. A method of improving a biomarker of chronic obstructive pulmonary disease (COPD) in a subject, the method comprising: administering a therapeutically effective amount of an anti-IL-33 antibody or an antibody variant thereof at intervals of once every 4 weeks (Q4W) or once every 8 weeks (Q8W), at a dose of from about 300 mg to about 600 mg, wherein the anti-IL-33 antibody comprises:

[0074] a. a heavy chain variable region that comprises an HCDR1 having a sequence as set forth in SEQ ID NO:1, a VHCDR2 having the sequence of SEQ ID NO:2, and a VHCDR3 having the sequence of SEQ ID NO:3; and

[0075] b. a light chain variable region that comprises a VLCDR1 having the sequence of SEQ ID NO:5, a VLCDR2 having the sequence of SEQ ID NO:6, and a VLCDR3 having the sequence of SEQ ID NO:7,

[0076] wherein the biomarker is selected from: annualized moderate to severe or severe COPD exacerbation rate, time to first moderate to severe or severe COPD exacerbation, FEV1, forced expiratory volume in the first second (FEV1), ratio of FEV1 to forced vital capacity (FVC) (FEV1 / FVC), or breathlessness, cough, and sputum scale (BCSS) score, COPD assessment test (CAT) score, and St. George's Respiratory Questionnaire (SGRQ) score.

[0077] 34. The method according to item 33, wherein the improvement of the biomarker is related to the baseline.

[0078] 35. The method according to any one of the preceding items, wherein the anti-IL-33 antibody or an antibody variant thereof is administered for a period of at least 12 weeks.

[0079] 36. The method according to any one of the preceding items, wherein the anti-IL-33 antibody or an antibody variant thereof is administered for a period of at least 24 weeks.

[0080] 37. The method according to any one of the preceding items, wherein the anti-IL-33 antibody or an antibody variant thereof is administered for a period of at least 52 weeks.

[0081] 38. The anti-IL-33 antibody or an antibody variant thereof according to any one of the preceding items, wherein the antibody or an antibody variant thereof is for use in a method of treating COPD, wherein the method is the method according to any one of the preceding items.

[0082] 39. Use of the anti-IL-33 antibody or an antibody variant thereof according to any one of items 1 to 38 for the manufacture of a medicament for use in a method of treating COPD according to any one of items 1 to 38.

[0083] 40. A method of reducing the annualized moderate to severe or severe COPD exacerbation rate in a subject, the method comprising administering a therapeutically effective amount of an anti-IL-33 antibody or an antibody variant thereof at intervals of once every 4 weeks (Q4W) or once every 8 weeks (Q8W), at a dose of from about 300 mg to about 600 mg, wherein the anti-IL-33 antibody comprises:

[0084] a. A heavy chain variable region comprising an HCDR1 having the sequence listed in SEQ ID NO: 1, a VHCDR2 having the sequence of SEQ ID NO: 2, and a VHCDR3 having the sequence of SEQ ID NO: 3; and

[0085] b. A light chain variable region comprising a VLCDR1 having the sequence of SEQ ID NO: 5, a VLCDR2 having the sequence of SEQ ID NO: 6, and a VLCDR3 having the sequence of SEQ ID NO: 7.

[0086] 41. A method of improving pre-bronchodilator FEV1 in a subject with COPD, the method comprising administering a therapeutically effective amount of an anti-IL-33 antibody or an antibody variant thereof at intervals of once every 4 weeks (Q4W) or once every 8 weeks (Q8W), at a dose of from about 300 mg to about 600 mg, wherein the anti-IL-33 antibody comprises:

[0087] a. A heavy chain variable region that includes HCDR1 having the sequence listed in SEQ ID NO:1, VHCDR2 having the sequence of SEQ ID NO:2, and VHCDR3 having the sequence of SEQ ID NO:3; and

[0088] b. A light chain variable region that includes VLCDR1 having the sequence of SEQ ID NO:5, VLCDR2 having the sequence of SEQ ID NO:6, and VLCDR3 having the sequence of SEQ ID NO:7.

[0089] 42. A method of improving the E-RS:COPD score in a subject with COPD, the method comprising administering a therapeutically effective amount of an anti-IL-33 antibody or an antibody variant thereof at intervals of once every 4 weeks (Q4W) or once every 8 weeks (Q8W), at a dose ranging from about 300 mg to about 600 mg, wherein the anti-IL-33 antibody comprises:

[0090] a. A heavy chain variable region that includes HCDR1 having the sequence listed in SEQ ID NO:1, VHCDR2 having the sequence of SEQ ID NO:2, and VHCDR3 having the sequence of SEQ ID NO:3; and

[0091] b. A light chain variable region that includes VLCDR1 having the sequence of SEQ ID NO:5, VLCDR2 having the sequence of SEQ ID NO:6, and VLCDR3 having the sequence of SEQ ID NO:7.

[0092] 43. The method according to item 42, wherein the method achieves the minimal clinically important difference in the E-RS:COPD score.

[0093] 44. A method of improving the SGRQ score in a subject with COPD, the method comprising administering a therapeutically effective amount of an anti-IL-33 antibody or an antibody variant thereof at intervals of once every 4 weeks (Q4W) or once every 8 weeks (Q8W), at a dose ranging from about 300 mg to about 600 mg, wherein the anti-IL-33 antibody comprises:

[0094] a. A heavy chain variable region that includes HCDR1 having the sequence listed in SEQ ID NO:1, VHCDR2 having the sequence of SEQ ID NO:2, and VHCDR3 having the sequence of SEQ ID NO:3; and

[0095] b. A light chain variable region comprising a VLCDR1 having the sequence of SEQ ID NO:5, a VLCDR2 having the sequence of SEQ ID NO:6, and a VLCDR3 having the sequence of SEQ ID NO:7.

[0096] 45. The method according to item 44, wherein the method achieves the minimal clinically important difference in the SGRQ score.

[0097] 46. A method for improving the CAT score in a subject with COPD, the method comprising administering a therapeutically effective amount of an anti-IL-33 antibody or an antibody variant thereof at intervals of once every 4 weeks (Q4W) or once every 8 weeks (Q8W), at a dose ranging from about 300 mg to about 600 mg, wherein the anti-IL-33 antibody comprises:

[0098] a. A heavy chain variable region comprising an HCDR1 having the sequence listed in SEQ ID NO:1, a VHCDR2 having the sequence of SEQ ID NO:2, and a VHCDR3 having the sequence of SEQ ID NO:3; and

[0099] b. A light chain variable region comprising a VLCDR1 having the sequence of SEQ ID NO:5, a VLCDR2 having the sequence of SEQ ID NO:6, and a VLCDR3 having the sequence of SEQ ID NO:7.

[0100] 47. The method according to item 46, wherein the method achieves the minimal clinically important difference in the CAT score.

[0101] 48. The method according to any one of items 40 - 47, wherein the dose is about 300 mg Q8W.

[0102] 49. The method according to any one of items 40 - 47, wherein the dose is about 300 mg Q4W.

[0103] 50. The method according to any one of items 40 - 47, wherein the dose is about 600 mg Q4W and comprises a VLCDR1 having the sequence of SEQ ID NO:5, a VLCDR2 having the sequence of SEQ ID NO:6, and a VLCDR3 having the sequence of SEQ ID NO:7. BRIEF DESCRIPTION OF THE DRAWINGS

[0104] Figure 1A Shows the amount of IL-33 / tezepelumab complex measured in the sera of healthy participants in Part I of NCT03096795

[0105] Figure 1BShown is the amount of IL-33 / sST2 complex measured in the serum of healthy participants from Part I of NCT03096795

[0106] Figure 1C Shown is the amount of IL-33 / tozolin complex measured in the serum of participants with COPD from Part II of NCT03096795

[0107] Figure 1D Shown is the amount of IL-33 / sST2 complex measured in the serum of participants with COPD from Part II of NCT03096795

[0108] Figure 2A Free IL-33 measured on day 29 in the 300 mg MAD cohort is shown. red Add IL-33 red Nasal mucosal fluid levels of tozolanimab

[0109] Figure 2B Free IL-33 measured on day 29 in the 300 mg MAD cohort is shown. red Levels of nasal mucosal fluid

[0110] Figure 2C Free IL-33 measured on day 29 in the 300 mg MAD cohort is shown. ox Levels of nasal mucosal fluid

[0111] Figure 3 Tozolinumab was shown to inhibit ex vivo IL-33 challenge in whole blood from healthy participants

[0112] Figure 4A Serum levels of IL-5 for participants in the 300 mg MAD cohort on days 1, 14, and 28 are shown (placebo, n=6; tozolanimab (n=6)). The graph shows the mean ± SEM. A mixed-effects longitudinal model was used to generate a p-value comparing the trajectory of the biomarker between tozolanimab and placebo. (p=0.0037)

[0113] Figure 4B Serum levels of IL-13 are shown for participants in the 300 mg MAD cohort on days 1, 14, and 28 (placebo, n=6; tozolumab (n=6)). The graph shows the mean ± SEM. A mixed-effects longitudinal model was used to generate a p-value comparing the trajectory of the biomarker between tozolumab and placebo. (p=0.034)

[0114] Figure 4CShows the serum levels of eosinophils in participants in the 300 mg MAD cohort on days 1, 14, and 28 (placebo, n = 6; tozakinumab (n = 6)). The figure shows the mean ± SEM. A mixed-effects longitudinal model was used to generate p-values to compare the trajectories of the biomarker between tozakinumab and placebo. (p = 0.0023)

[0115] Figure 5 Shows that Alternaria alternata induces rapid IL-33 release in bronchoalveolar lavage fluid (BALF) of humanized IL-33 mice

[0116] Figure 6 Shows that tozakinumab inhibits ALT-induced BALF IL-5 in humanized IL-33 mice. The test substance was administered intranasally 24 hours before the ALT challenge. BALF was harvested 24 hours after the ALT challenge and analyzed for the presence of IL-5. The significant effect of the test substance was determined using one-way ANOVA with Bonferroni multiple comparison test. ***p < 0.001, **p < 0.01 (n = 4)

[0117] Figure 7A Shows the scratch wound repair of normal human bronchial epithelial cells after treatment with wild-type IL-33 (IL-33), oxIL-33, and oxIL-33 + anti-ST2 antibody

[0118] Figure 7B Shows Figure 7A Quantification of wound closure % of the scratch wound assay described in

[0119] Figure 8 Shows that scratch wound impairment was also seen in bronchial epithelial cells obtained from COPD subjects

[0120] Figure 9 Shows the % scratch closure in A549 cells with increasing concentrations of tozakinumab and anti-TSLP antibody

[0121] Figure 10 Is the PK / PD target engagement model description

[0122] Figure 11 Shows the predicted values of tozakinumab systemic concentrations from the Ph1 dose cohort relative to the observed tozakinumab systemic concentrations

[0123] Figure 12 Shows the predicted values of tozakinumab:IL-33 complex formulations from the Ph1 dose cohort relative to the observed tozakinumab:IL-33 complex formulations

[0124] Figure 13 Shows the predicted values of the reduction in the IL-33:sST2 complex from the Ph1 dose cohort relative to the observed reduction in the IL-33:sST2 complex

[0125] Figure 14 Shows the predicted IL-33 inhibition (Q2W - top row; Q4W - middle row; Q6W - bottom row) predicted by the dose response inhibited by the IL33 / sST2 complex in the blood

[0126] Figure 15 Shows the predicted IL-33 inhibition at the trough by tocilizumab in the lung (Q4W - top row; Q8W - bottom row)

[0127] Figure 16 Shows the predicted tocilizumab serum concentrations according to 300 mg Q4W (top row) and 300 mg Q8W (bottom row). The serum concentrations required for 60%, 80%, and 90% identified by the Alternaria murine model are indicated by the dashed lines

[0128] Figure 17 Shows the predicted tocilizumab serum concentrations according to 300 mg Q4W (top row) and 150 mg Q4W (bottom row). The serum concentration thresholds for the response in the scratch wound closure assay are shown as dashed lines

[0129] Figure 18 Also shows the predicted values of the tocilizumab systemic concentration from the Ph1 dose cohort relative to the observed tocilizumab systemic concentration

[0130] Figure 19 Also shows the predicted values of the reduction in the IL-33:sST2 complex from the Ph1 dose cohort relative to the observed reduction in the IL-33:sST2 complex Detailed Description

[0131] The term "about" or "approximately" means an acceptable error of a particular value as determined by a person of ordinary skill in the art, which depends in part on how the value is measured or determined. In certain embodiments, the term "about" or "approximately" means within 1, 2, 3, or 4 standard deviations. In certain embodiments, the term "about" or "approximately" means within 30%, 25%, 20%, 15%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.5%, or 0.05% of a given value or range. Whenever the term "about" or "approximately" precedes the first of a series of two or more numerical values, it is understood that the term "about" or "approximately" applies to each value in the series

[0132] Treatment of COPD

[0133] Chronic obstructive pulmonary disease (COPD) is a chronic inflammatory lung disease that causes airflow obstruction in the lungs. Symptoms include shortness of breath, coughing, mucus (sputum) production, and wheezing.

[0134] COPD is characterized by persistent respiratory symptoms and airflow limitation, as reported by spirometry, preferably post - bronchodilator (post - BD) spirometry. As used herein, "post - bronchodilator (post - BD) spirometry" refers to spirometry performed after administration of a bronchodilator (typically administered via inhaler or nebulizer). In some embodiments, the bronchodilator is selected from albuterol or salbutamol. Post - BD spirometry results can be expressed as forced expiratory volume in the first second (FEV1) or forced vital capacity (FVC).

[0135] This disclosure provides treatment for COPD. In some cases, the COPD is moderate to severe COPD. Moderate to severe COPD is typically characterized by a post - BD forced expiratory volume in the first second (FEV1) of a subject < 80% of the predicted normal value (i.e., the normal value predicted for a healthy patient). In some cases, the post - BD FEV1 of the subject is < 80%, < 75%, < 70%, < 65%, < 60%, < 55%, < 50%, < 45%, < 40%, or < 35% of the predicted normal value. In some cases, the post - BD FEV1 of the subject is < 70% and > 30% of the predicted normal value. In some cases, the post - BD FEV1 of the subject is < 80% and > 30%, < 75% and > 30%, < 70% and > 30%, < 65% and > 30%, < 60% and > 30%, < 55% and > 30%, < 50% and > 30%, < 45% and > 30%, < 40% and > 30% of the predicted normal value. In some cases, the post - BD FEV1 of the subject is < 80% and > 35%, < 75% and > 35%, < 70% and > 35%, < 65% and > 35%, < 60% and > 35%, < 55% and > 35%, < 50% and > 35%, < 45% and > 35%, or < 40% and > 35% of the predicted normal value. In some cases, the post - BD FEV1 of the subject is < 60% and > 40%, < 55% and > 40%, < 50% and > 40%, or < 45% and > 40% of the predicted normal value.

[0136] In some cases, the post - bronchodilator FEV1 of the subject is > 20% of the predicted normal value. In some cases, the post - bronchodilator FEV1 of the subject is > 21%, > 22%, > 23%, > 24%, > 25%, > 26%, > 27%, > 28%, > 29% or > 30% of the predicted normal value. In some cases, the post - bronchodilator FEV1 of the subject is > 30% of the predicted normal value.

[0137] In some cases, COPD is characterized by a post - bronchodilator FEV1 / forced vital capacity (FVC) of < 0.70, < 0.65, < 0.60, < 0.55, < 0.50, < 0.45, < 0.40, < 0.35 or < 0.30. In some cases, COPD is characterized by a post - bronchodilator FEV1 / FVC of < 0.70.

[0138] COPD is a chronic condition, the severity of which may fluctuate. Thus, a subject with COPD may experience one or more acute exacerbations of COPD (AECOPD, also referred to herein as "COPD exacerbation"), which may be separated by periods of relatively fewer symptoms.

[0139] As used herein, "AECOPD" or "aeCOPD" is a change in the subject's usual COPD symptoms that lasts for 2 days or more, exceeds normal daily variations, is acute at onset, and may require a change in regular medication therapy. The change in symptoms can include at least one major or minor COPD symptom from the following list:

[0140] · Major COPD symptoms: dyspnea, increased sputum volume, and change in sputum color

[0141] · Minor COPD symptoms: cough, wheeze, sore throat, cold symptoms (runny or stuffy nose), and fever without other cause.

[0142] In some cases, the change in symptoms includes at least two COPD symptoms from the above list. In some cases, the change in symptoms includes at least one major COPD symptom from the above list. In some cases, the change in symptoms includes at least one major COPD symptom and at least one other major or minor symptom from the above list.

[0143] AECOPD can be classified as mild, moderate, or severe. As used herein, "severe AECOPD" is a disease that results in COPD-related hospitalization of inpatients (e.g., a subject is hospitalized for treatment of a COPD exacerbation or admitted to an observation area, emergency department, or other equivalent healthcare facility for ≥ 24 hours, depending on the country and healthcare system). Severe AECOPD may lead to COPD-related death. "Moderate AECOPD" refers to a disease that does not meet the "severe" criteria (i.e., hospitalization). Moderate and severe AECOPD result in the use of systemic corticosteroids and / or antibiotics, or a single depot injection dose of corticosteroids. In some cases, it is confirmed that AECOPD occurs during a subject's ongoing stable dual or triple maintenance therapy for COPD and is not due to an interval or decline in treatment. Finally, "mild AECOPD" refers to an exacerbation that does not meet the "severe" or "moderate" criteria.

[0144] The start date of AECOPD can be the date of hospitalization (for severe AECOPD) or the start date of systemic corticosteroid or antibiotic treatment (for moderate AECOPD), whichever is earlier, and the end date can be the end date of systemic corticosteroid or antibiotic treatment or the date of discharge, whichever is later.

[0145] In some cases, the subject to be treated may have a history of at least one moderate or severe AECOPD within 12 months prior to treatment (i.e., before the first dose is administered). In some cases, the subject may have a history of at least one, optionally at least two, moderate or at least one severe AECOPD within 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 month(s) prior to treatment. In some cases, the subject may have a history of at least two moderate AECOPD within 12 months prior to treatment. In some cases, the subject may have a history of at least two moderate AECOPD within 52 weeks prior to treatment. In some cases, the subject may have a history of at least one severe AECOPD within 12 months prior to treatment. In some cases, the subject may have a history of at least one severe AECOPD within 52 weeks prior to treatment.

[0146] Another method of classifying AECOPD is the COPD Composite Exacerbation (COPDCompEx) algorithm, as outlined in "COPDCompEx: A novel composite endpoint for COPD exacerbations to enable faster clinical development" (Vogelmeier et al., Respiratory Medicine, Volume 173, November 2020, 106175). COPDCompEx is a composite endpoint for COPD exacerbations that combines acute exacerbations with events defined by a participant's electronic diary and PEF. The definitions of the two types of exacerbations are as follows: COPDCompEx-defined exacerbation: A situation that results in one or more of the following: hospitalization, emergency department visit, treatment with OCS, or treatment with antibiotics. Diary event: Defined by threshold and slope criteria, using the following diary and home spirometry variables: overall symptom score, nocturnal awakening due to symptoms, treatment with rescue medication, PEF. Advantageously, compared to the AECOPD events described above, COPDCompEx events tend to be more frequent and provide diagnostic ability for the severity of COPD over a shorter time frame.

[0147] In some cases, a subject to be treated may have a history of at least one COPDCompEx event within 12 months prior to treatment (i.e., prior to administration of the first dose). A subject to be treated may have a history of at least one COPDCompEx event within 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 month prior to treatment (i.e., prior to administration of the first dose).

[0148] COPD can also be classified by the breathlessness, cough, and sputum scale (BCSS) score relative to baseline. As used herein, "baseline", with respect to any COPD biomarker disclosed herein (such as the BCSS score), means the value of the parameter for a patient prior to or at the time of first administration of an IL-33 therapy.

[0149] The BCSS is a 3-item daily diary (Leidy et al. 2003) that assesses the severity of 3 symptoms: shortness of breath, sputum, and cough, each with a 5-point scale. The item scores can be reported as domain scores and summed to produce a total score. In some cases, the subject had a BCSS total score of 4 or greater, 5 or greater, 6 or greater, 7 or greater, 8 or greater, 9 or greater, 10 or greater, 11 or greater, 12 or greater, 13 or greater, or 14 or greater before treatment with an anti-IL33 antibody or fragment thereof. In some cases, the subject had a score of 2 or greater, 3 or greater, 4 or greater, or 5 in the cough domain before treatment with an anti-IL33 antibody or fragment thereof. In some embodiments, the subject had a score of 2 or greater, 3 or greater, 4 or greater, or 5 in the sputum domain before treatment with an anti-IL33 antibody or fragment thereof. In some cases, the BSCC score "before treatment" is the mean of the daily scores recorded within 4 weeks before treatment with an anti-IL33 antibody or fragment thereof as described herein.

[0150] In some cases, COPD is classified using the Exacerbations of Chronic Pulmonary Disease Tool - Patient Reported Outcomes (EXACT-PRO) score. The EXACT-PRO is a 14-item ePRO tool (Jones et al. 2011; Leidy et al. 2011) that was developed to assess the frequency, severity, and duration of COPD exacerbations. The tool was developed for daily home administration using a handheld electronic device. Respondents are instructed to complete the diary just before going to bed each night and to answer the questions considering their "today" experience. The daily EXACT-PRO total score has a range of 0 to 100, where a higher score indicates greater severity. Total score changes are used to identify the onset and recovery of exacerbation events as defined by the EXACT-PRO. In identifying the onset and recovery of events, the EXACT-PRO can provide information on event frequency and duration as well as event severity. In some cases, the subject to be treated had an EXACT-PRO score of at least 50, at least 60, at least 70, or at least 80 before treatment with an anti-IL33 antibody or fragment thereof as described herein.

[0151] In some cases, COPD can be classified using the St. George's Respiratory Questionnaire (SGRQ). The SGRQ is a 50-item questionnaire developed to measure the health status (quality of life) of patients with airway obstructive diseases. The overall score ranges from 0 to 100. Scores for three domains are calculated by dimension: symptoms, activity, and impact (psycho-social), as well as the total score. A lower score indicates a better quality of life (QoL). The first part ("symptoms") assesses symptomatology, including the frequency of cough, sputum production, wheezing, shortness of breath, and the duration and frequency of episodes of shortness of breath or wheezing. The second part has two components: "activity" and "impact". The "activity" section addresses activities that cause or are limited by shortness of breath. The "impact" section covers a range of factors, including the impact on employment, control of health, panic, scarring, need for medication, side effects of prescribed therapies, expectations for health, and disruption of daily life. The recall period for the questionnaire is within the past 4 weeks. Psychometric testing has demonstrated its reproducibility, reliability, and validity. Sensitivity has been demonstrated in clinical trials. After testing in patients and clinicians, a minimum change of 4 units ("minimal clinically important difference") was determined to be clinically relevant (Jones COPD 2005 2(1):75-9).

[0152] In some cases, COPD can be classified by the COPD Assessment Test (CAT) score. The CAT is a questionnaire designed for patients with COPD that is used to measure the impact of the disease on their quality of life. The CAT is an 8-item questionnaire completed by the patient that generally assesses the impact of COPD (cough, sputum, dyspnea, chest tightness) on health status. The range of the CAT is from 0 to 40. The higher the score, the more severe the impact of COPD on the subject's life. In some cases, subjects to be treated have a CAT score of at least 10 before therapy.

[0153] In some cases, COPD can be classified by the E-RS TM :COPD, an 11-item ePRO developed to evaluate the severity of respiratory symptoms in COPD (Leidy et al. 2014a; Leidy et al. 2014b). The E-RS TM :COPD is a subset of items from EXACT-PRO. The E-RS TM :COPD is designed to be obtained as part of a daily EXACT-PRO assessment. For the E-RS TM: The COPD item responses are summed to produce a total score in the range from 0 to 40, where a higher score indicates greater severity. In addition to this total score, symptom domain scores can be calculated for dyspnea (5 items; score range: 0 to 17), cough and sputum (3 items; score range: 0 to 11), and chest symptoms (3 items; score range: 0 to 12) by summing the item responses within the corresponding domains. In some cases, the subject to be treated has an E-RS of at least 20, at least 25, at least 30, or at least 35. TM : COPD score. In some cases, the subject to be treated has an E-RS of at least 6, at least 7, at least 8, at least 9, at least 10, or 11 in the cough and sputum domain. TM : COPD score. In some cases, the subject to be treated has an E-RS of at least 7, at least 8, at least 9, at least 10, at least 11, or 12 in the chest symptoms domain. TM : COPD score. In some cases, the subject to be treated has an E-RS of at least 9, at least 10, at least 11, at least 12, at least 13, at least 14, at least 15, at least 16, or 17 in the dyspnea domain. TM : COPD score.

[0154] In some cases, COPD is associated with the subject's chronic bronchitis. Subjects with chronic bronchitis may have symptoms of bronchitis (cough, mucus / sputum production, fatigue, shortness of breath, fever, chills, and / or chest discomfort) for a period of more than 8 weeks, more than 16 weeks, more than 32 weeks, or more than 52 weeks.

[0155] In some cases, the subject to be treated is a current smoker or a former smoker. In some cases, the subject to be treated has a smoking history of 10 or more pack-years. Pack-years are calculated as the average number of cigarettes per day × number of years / 20. For example, 1 pack-year = smoking 20 cigarettes per day for 1 year or 10 cigarettes per day for 2 years.

[0156] In some cases, the subject is a current smoker.

[0157] In some cases, the subject is a former smoker. "Former smoker" can be defined as a subject who does not smoke at the start of the therapy and has quit smoking for at least 6 months before the start of the therapy and intends to quit permanently.

[0158] In some embodiments, the subject has a history of insufficient response or intolerance to other drug therapies for COPD, such as inhaled corticosteroids (ICS), long-acting beta agonists (LABA), and / or long-acting muscarinic antagonists (LAMA), or these other drug therapies for COPD may be otherwise medically undesirable. As used herein, "insufficient response" to a therapy means that administration of the therapy does not result in short-term and / or long-term improvement of one or more symptoms of COPD as described herein. Alternatively, insufficient response may result in the condition reverting to a moderate to severe level after discontinuation of the therapy. In some embodiments, COPD has previously been treated with ICS and LABA, ICS and LAMA, LABA and LAMA, or ICS, LABA, and LAMA and has been shown to have no response to the therapy. COPD may be classified as having an insufficient response to therapy if it remains moderate to severe despite treatment, or if the subject experiences a moderate or severe AECOPD event during or after the course of treatment is discontinued or completed.

[0159] In some cases, the subject to be treated has received or is receiving a course of ICS, LAMA, and / or LABA (e.g., ICS-LAMA, ICS-LABA, LAMA-LABA, or ICS-LAMA-LABA therapy, collectively referred to as "COPD inhaled maintenance therapy") prior to treatment with an anti-IL-33 antibody or an antibody variant thereof as described herein. In some cases, the course begins at least 3 months prior to administration of the first dose of the anti-IL-33 antibody or an antibody variant thereof as described herein and may be at least 3 months in duration. In some cases, the course begins at least 3 months prior to administration of the first dose of the anti-IL-33 antibody or an antibody variant thereof as described herein and is ongoing at the start of treatment with the anti-IL-33 antibody or an antibody variant thereof and continues during the treatment window.

[0160] As used herein, "inhaled corticosteroid (ICS)" refers to corticosteroid therapy for the treatment of COPD administered by use of a nebulizer, inhaler, or nebulizer. ICS may be selected from fluticasone propionate, budesonide, and / or beclomethasone dipropionate.

[0161] As used herein, "long-acting β2-adrenergic agonist (LABA)" refers to any β-adrenergic receptor agonist having a duration of action of about 12 hours or longer. This is in contrast to short-acting β-agonists (SABA) such as albuterol, which have a duration of action of about 4 - 6 hours. Exemplary LABAs include amobuterol, bambuterol, clenbuterol, formoterol, salmeterol, protokylol. A LABA can be a "ultra-LABA" having a duration of action of 24 hours or longer, such as indacaterol, olodaterol, or vilanterol. A LABA can be administered by any suitable route, such as by use of a nebulizer, inhaler, or nebulizer spray.

[0162] As used herein, a long-acting muscarinic antagonist (LAMA) is an anticholinergic agent that blocks the activity of muscarinic acetylcholine receptors. Exemplary LAMAs include tiotropium, glycopyrronium, and aclidinium. A LAMA can be administered by any suitable route, such as by use of a nebulizer, inhaler, or nebulizer spray.

[0163] A subject "intolerant" to treatment is a subject for whom treatment causes one or more side effects that make continued treatment inadvisable. For example, an allergic reaction to treatment can indicate intolerance.

[0164] In some cases, the COPD to be treated is moderate to severe COPD. In some cases, moderate to severe COPD is characterized by:

[0165] · being associated with the subject's chronic bronchitis,

[0166] · having a history of at least one, optionally at least two, moderate or at least one severe COPD exacerbation within 12 months prior to treatment,

[0167] · a ratio of forced expiratory volume in the first second (FEV1) to forced vital capacity (FVC) after bronchodilator (FEV1 / FVC after BD) < 0.70, and / or FEV1 after BD > 30% and < 80% of predicted normal value.

[0168] · an average breathlessness, cough, and sputum scale (BCSS) score > 2 in the cough domain and / or > 2 in the sputum domain.

[0169] In some cases, the COPD to be treated is characterized by:

[0170] · having a history of at least two moderate or at least one severe COPD exacerbation within 52 weeks prior to treatment,

[0171] · a ratio of forced expiratory volume in the first second (FEV1) to forced vital capacity (FVC) after bronchodilator (FEV1 / FVC after BD) < 0.70

[0172] · The post - BD FEV1 > 20% of the predicted normal value.

[0173] · Before treatment, the CAT score is greater than or equal to 10, and each of the items of sputum and cough is greater than or equal to 2.

[0174] In some cases, the subject has a blood eosinophil count of greater than or equal to about 300 cells / μl or less than 300 cells / μl before treatment. In some cases, the subject has a blood eosinophil count of greater than or equal to 300 cells / μl before treatment.

[0175] Dosing regimen

[0176] This disclosure relates to a dosing regimen of an anti - IL - 33 antibody or antibody variant, which is particularly effective in the treatment of COPD. The dosing regimen consists of one or more doses that are size - controlled and administered throughout the treatment window. In the presence of more than one dose, the doses are separated by a dosing interval. The anti - IL - 33 antibody or antibody variant is administered in a therapeutically effective amount. As used herein, an "effective amount" or "therapeutically effective amount" of an agent (e.g., a pharmaceutical formulation) containing an IL - 33 antibody is an amount that effectively achieves the desired therapeutic or prophylactic outcome at the required dose and for the required period of time.

[0177] The dose size of the anti - IL - 33 antibody or its antibody variant can be expressed in terms of the weight of the anti - IL - 33 antibody or antibody variant. In some cases, the anti - IL - 33 antibody or its antibody variant is administered in a dose of about 400 to about 800 mg, about 450 to about 750 mg, about 500 to about 700 mg, about 510 to about 690 mg, about 520 to about 680 mg, about 530 to about 670 mg, about 540 to about 660 mg, about 550 to about 650 mg, about 560 to about 640 mg, about 570 to about 630 mg, about 580 to about 620 mg, about 590 to about 630 mg, or about 600 mg.

[0178] In some cases, the dose is 600 mg. In some cases, the anti - IL - 33 antibody or its antibody variant is formulated for subcutaneous injection at 150 mg / mL, such that a 600 mg dose is administered as a 4 mL treatment. The 600 mg dose of the anti - IL - 33 antibody or its antibody variant can be administered as two parallel 300 mg doses. As used herein, "parallel" doses refer to doses that are administered simultaneously or sequentially, with no interval or only a minimal time period (e.g., less than 1 hour, less than 30 minutes, less than 15 minutes, less than 5 minutes) separating them.

[0179] In some cases, the anti-IL-33 antibody or an antibody variant thereof is administered at a dose of about 200 to about 400 mg, about 250 to about 350 mg, about 260 to about 340 mg, about 270 to about 330 mg, about 280 to about 320 mg, about 290 to about 310 mg, about 295 to about 305 mg, or about 300 mg.

[0180] In some cases, the dose is 300 mg. In some cases, the anti-IL-33 antibody or an antibody variant thereof is formulated for subcutaneous injection at 150 mg / mL such that a 300 mg dose is administered as a 2 mL treatment. In some cases, a 300 mg dose of the anti-IL-33 antibody or an antibody variant thereof can be administered as two parallel 150 mg doses. As used herein, "parallel" doses are doses administered simultaneously or sequentially with no interval or only a minimal time period (e.g., less than 1 hour, less than 30 minutes, less than 15 minutes, less than 5 minutes) separating them.

[0181] In some cases, the dose is 150 mg. In some cases, the anti-IL-33 antibody or an antibody variant thereof is formulated for subcutaneous injection at 150 mg / mL such that a 150 mg dose is administered as a 1 mL treatment.

[0182] The dose size of the anti-IL-33 antibody or an antibody variant thereof can be expressed as the amount of active compound manipulated to provide a certain level of plasma drug concentration by the plasma drug concentration provided by the dose. By varying the amount of antibody or variant administered, bioavailability, or time / frequency, one of ordinary skill in the art can control the plasma concentration of a subject. Since plasma concentrations vary over time according to drug uptake and clearance, they may be expressed in various standardized ways - such as maximum, minimum (trough), or over time.

[0183] In some cases, the dose is selected to provide a Cmax,ss (maximum concentration observed at steady state) between about 20 and about 50 μg / mL, between about 25 and about 45 μg / mL, between about 30 and about 40 μg / mL, between about 35 and about 40 μg / mL, or about 37 μg / mL. In some cases, C maz.ss is the maximum concentration observed during the dosing period. In this context, the "dosing period" refers to the time between two consecutive doses.

[0184] Examples show that the 300 mg Q4W or Q8W dosing regimens of MEDI3506 are predicted to achieve the serum concentrations required to inhibit both the redIL-33:ST2 and oxIL-33:RAGE / EGFR signaling axes, thereby achieving sustained dual pathway inhibition ( Figure 16 and Figure 17)。The serum concentration of the anti-drug antibody reagent MEDI3506 can be measured in a suitable assay format (and thus used to determine C max.ss ) to capture and detect MEDI3506 from a biological sample (e.g., blood). In some cases, the assay can use an anti-IgG1 capture mAb and a stabilized MEDI3506 antigen labeled with a detectable marker. The detectable marker can be quantified to determine the concentration of MEDI3506. In some cases, the MEDI3506 antigen (IL-33) can be stabilized in a reduced form, e.g., by mutating one or more cysteine residues to serine, to prevent the conversion of redIL-33 to the oxidized form (oxIL-33) via disulfide bond formation. Assays and platforms suitable for detecting serum biomarkers are well known to those skilled in the art.

[0185] In some cases, the dose is selected to provide a Cmax,ss between about 10 and about 35 μg / mL, between about 15 and about 30 μg / mL, between about 15 and about 30 μg / mL, between about 15 and about 25 μg / mL, about 15 to about 20 μg / mL, or about 18.6 μg / mL.

[0186] In some cases, the anti-IL-33 antibody or an antibody variant thereof is administered in a dose selected to provide an area under the plasma concentration-time curve over the entire dosing period (AUC).

[0187] In some cases, the dose is selected to provide an AUC between about 400 and about 800 μg-day / mL, between about 500 and about 750 μg-day / mL, between about 600 and about 700 μg-day / mL, between about 600 and about 650 μg-day / mL, between about 600 and about 620 μg-day / mL, between about 610 and about 620 μg-day / mL, or about 616 μg-day / mL over the dosing period.

[0188] In some cases, the dose is selected to provide an AUC between about 200 and about 515 μg-day / mL, between about 250 and about 500 μg-day / mL, between about 300 and about 450 μg-day / mL, between about 300 and about 350 μg-day / mL, or about 323 μg-day / mL over the dosing period.

[0189] In some cases, the dose is selected to provide an AUC between about 100 and about 300 μg-day / mL, between about 100 and about 250 μg-day / mL, between about 100 and about 200 μg-day / mL, between about 150 and about 200 μg-day / mL, or about 161.5 μg-day / mL over the dosing period.

[0190] Administration of an anti-IL-33 antibody or an antibody variant thereof is performed as multiple doses separated by a dosing interval. In some cases, the dosing interval is 2 weeks (14 days), 3 weeks (21 days), 4 weeks (28 days), or 5 weeks (35 days). In some embodiments, the dosing interval is 4 weeks (28 days). In some cases, the dosing interval is about 4 weeks (i.e., 28 ± 4 days). In some cases, the dosing interval is about 8 weeks (i.e., 56 ± 4 days).

[0191] In some cases, a dose can be administered, for example, as two or more sub-doses over multiple days. As used herein, a "sub-dose" is a fraction of a dose of a therapeutic agent such that the total amount of the therapeutic agent administered as sub-doses equals the total amount of that dose. Any fraction can be used, such that two, three, four, five, or more sub-doses constitute a single dose. In some cases, a dose can be administered as two or more sub-doses separated by a period of 1, 2, 3, 4, 5, or 6 days. In some cases, a dose can be administered as two or more sub-doses separated by a period of 1, 2, or 3 weeks. Sub-doses can be administered for two, three, four, or more consecutive days. The sub-doses that make up a dose can be of equal size or can be of different sizes, so long as their total amount equals the dose.

[0192] Thus, as used herein, a 600 mg dose with a 4-week dosing window (Q4W) can be replaced by administering 150 mg once a week (Q1W), 300 mg once every 2 weeks (Q2W), or 450 mg once every 3 weeks (Q3W), all of which provide a dosing regimen equivalent to 600 mg once every 4 weeks. A 300 mg dose with a 4-week dosing window (Q4W) can be replaced by administering 150 mg once every 2 weeks (Q2W) or 75 mg once a week (Q1W). A 300 mg dose with an 8-week dosing window (Q8W) can be replaced by administering 150 mg once every 4 weeks (Q4W), 75 mg once every 2 weeks (Q2W), or 37.5 mg once a week (Q1W).

[0193] When the dosing interval is expressed in weeks, a certain margin of error is allowed such that one week can be represented as 7 days ± 1 day. In some embodiments, one week can be represented as 7 days ± 0.5 days, 7 days ± 0.25 days, or exactly 7 days. When the dosing interval is several weeks, the margin of error per week can be combined. For example, in some cases, the dosing interval is 4 weeks ± 4 days. In some cases, the dosing interval is 4 weeks ± 3 days. In some embodiments, the dosing interval is 4 weeks ± 2 days. In some embodiments, the dosing cycle is 4 weeks ± 1 day. In some cases, the dosing interval is exactly 4 weeks. In some cases, the dosing interval is 8 weeks ± 4 days. In some cases, the dosing interval is 8 weeks ± 3 days. In some cases, the dosing interval is 8 weeks ± 2 days. In some cases, the dosing interval is 8 weeks ± 1 day. In some cases, the dosing interval is exactly 8 weeks.

[0194] In some cases, the anti-IL-33 antibody or its antibody variant is administered during a "treatment window", as used herein, the treatment window refers to the time period that starts at the administration of the first dose and runs until the administration of the final dose of the anti-IL-33 antibody or its antibody variant. The date of administration of the first dose is referred to as "Day 1" of "Week 0", Week 1 starts 7 days later, Week 2 starts 7 days after that, and so on. In some embodiments, the treatment window length is 12 weeks (i.e., runs from Week 0 to Week 12). In some embodiments, the treatment window length is 16 weeks (i.e., runs from Week 0 to Week 15), and the dosing interval is 4 weeks, such that a total of 4 doses are administered (at Weeks 0, 4, 8, and 12 respectively). In some embodiments, the treatment window length is 12 weeks, and the dosing interval is 4 weeks, such that doses are administered on Day 1 (Week 0), Day 29 ± 4 days (Week 4), Day 57 ± 4 days (Week 8), and Day 85 ± 4 days (Week 12).

[0195] In some cases, the treatment window is 12 weeks, 14 weeks, 16 weeks, 18 weeks, 20 weeks, 22 weeks, 24 weeks, 26 weeks, 28 weeks, 30 weeks, 32 weeks, 34 weeks, 36 weeks, 38 weeks, 40 weeks, 42 weeks, 44 weeks, 46 weeks, 48 weeks, 50 weeks, 52 weeks or longer. In some cases, the treatment window is 52 weeks or longer. In some cases, the treatment window is 48 weeks or longer.

[0196] In some cases, an anti-IL-33 antibody or an antibody variant thereof is administered at about 300 mg Q4W. Examples show that administration of predicted MEDI3506 at 300 mg Q4W will achieve approximately 94% depletion (target engagement) in the lung. This level of target engagement is potentially greater than that achieved with the predicted anti-IL-33 antibody itepekimab, where a recent Phase II study in COPD in former smokers resulted in a significant reduction in COPD exacerbations and a significant improvement in FEV1 (Rabe et al. 2021). Compared to MEDI3506, itepekimab has a significantly longer reported half-life (itepekimab t 1 / 2 (which is also known as SAR440340 and REGN3500) was reported in US2021 / 0000949 to be 30 days - see

[411] therein).

[0197] In some cases, an anti-IL-33 antibody or an antibody variant thereof is administered at about 300 mg Q8W. Examples show that administration of predicted MEDI3506 at 300 mg Q8W (i.e., twice the dosing window) will provide approximately 83% inhibition of IL33 at the trough in lung tissue; thus, it can provide sufficient efficacy in COPD and is more convenient for patients in terms of dosing frequency compared to Q4W.

[0198] Thus, in some cases, an IL-33 antibody or an antibody variant thereof is administered at a dose that achieves at least 80%, 85%, or 90% target engagement in the lung. In some cases, the dose achieves at least 90% target engagement in the lung. In some cases, the dose achieves at least 91%, 92%, 93%, or 94% target engagement in the lung. In some cases, % target engagement is achieved at trough concentration.

[0199] Markers of COPD

[0200] In some cases, the methods disclosed herein improve one or more markers of COPD (also referred to as "COPD markers").

[0201] COPD markers include: annualized rate of moderate to severe COPD exacerbations, time to first moderate to severe COPD exacerbation, time to first severe COPD exacerbation, FEV1, FVC, E-RS COPD total score, SGRQ score, CAT score.

[0202] In some cases, an improvement in the E-RS COPD score means that the CAT score of the subject is reduced by more than or equal to 2 ("minimal clinically important difference" or "MCID") compared to baseline.

[0203] In some cases, an improvement in the CAT score means that the subject's CAT score has decreased by more than or equal to 2 compared to baseline (“minimal clinically important difference” or “MCID”).

[0204] In some cases, an improvement in the SGRQ score means that the total SGRQ score of the subject has decreased by more than or equal to 4 compared to baseline (“minimal clinically important difference” or “MCID”).

[0205] In some cases, a change in the biomarker is observed after the treatment window. In some cases, the observation is made immediately after the treatment window. In some cases, the observation is made after an additional period of time that runs immediately from the treatment window. The additional period of time can be 1, 2, 3, 4, 5, 6, or more days. The additional period of time can be 1, 2, 3, 4, or more weeks. The additional period of time can be 1, 2, 3, 4, or more months. The additional period of time can be the same length as the dosing interval such that the additional period of time starts after the final dose and runs until the point at which another dose is due. The treatment window plus any additional period of time can be referred to as the “intervention window”. Certain treatment outcomes can be measured after the intervention window, such as changes in FEV1 or FEV1i / FVC before or after BD.

[0206] In some cases, the additional period of time is 4 weeks and the treatment window is 8 weeks such that the total length of the treatment window plus the additional period of time is 12 weeks. In some embodiments, the additional period of time is 4 weeks and the treatment window is 12 weeks such that the total length of the treatment window plus the additional period of time is 16 weeks. In other embodiments, the additional period of time is 4 weeks and the treatment window is 24 weeks such that the total length of the treatment window plus the additional period of time is 28 weeks.

[0207] Alternatively or additionally, changes in the biomarker can be observed during the treatment window. The biomarker can be observed at the end of an administration period, such as the first, second, third, fourth, fifth, sixth, seventh, or additional administration periods. Alternatively, the biomarker can be observed or measured one day after the end of an administration period, such as the first, second, third, fourth, fifth, sixth, seventh, or additional administration periods. The biomarker can be observed or measured one day before the end of an administration period, such as the first, second, third, fourth, fifth, sixth, seventh, or additional administration periods. The biomarker can be observed two days after the end of an administration period, such as the first, second, third, fourth, fifth, sixth, seventh, or additional administration periods. The biomarker can be observed two days before the end of an administration period, such as the first, second, third, fourth, fifth, sixth, seventh, or additional administration periods. The biomarker can be observed three days after the end of an administration period, such as the first, second, third, fourth, fifth, sixth, seventh, or additional administration periods. The biomarker can be observed three days before the end of an administration period, such as the first, second, third, fourth, fifth, sixth, seventh, or additional administration periods. The biomarker can be observed four days after the end of an administration period, such as the first, second, third, fourth, fifth, sixth, seventh, or additional administration periods. The biomarker can be observed four days before the end of an administration period, such as the first, second, third, fourth, fifth, sixth, seventh, or additional administration periods. In some embodiments, the treatment window is 24 weeks, and changes in symptoms are observed during week 12.

[0208] Certain treatment outcomes, such as changes in FEV1 before BD or FEV1 i / FVC fraction, can be measured at the 4, 12, 24, or 28, 36, or 52 week time points.

[0209] As described herein, treatment with an anti-IL-33 antibody or variant thereof can result in an increase in forced expiratory volume in one second (FEV1) as defined herein, particularly an increase relative to baseline observed after the treatment window (and any additional periods as defined herein). In some cases, an increase in FEV1 relative to baseline is observed at weeks 2, 4, 8, 12, 16, 20, 24, 28, 32, 36, or 52. In some cases, an increase in FEV1 relative to baseline is observed at weeks 4, 12, 24, 36, or 52. In some cases, the increase in FEV1 is 5%, 10%, 15%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, or more than 100% of the FEV1 observed before treatment. In some cases, the increase in FEV1 is >70%, >75%, or >80% of the predicted normal value.

[0210] In some cases, as described herein, treatment with an anti-IL-33 antibody or variant thereof results in an increase in FEV1 / FVC relative to baseline. In some cases, the increase in FEV1 / FVC is an increase in FEV1 / FVC relative to baseline of 5%, 10%, 15%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, or more than 100% after BD. In some cases, the increase in FEV1 / FVC is an increase of at least 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, or 0.7. In some cases, the increase in FEV1 / FVC is an increase to >0.70. In some cases, the increase in FEV1 / FVC is an increase to >0.75, >0.80, >0.85, >0.90, >0.95, or >0.99.

[0211] In some cases, the frequency, duration, or severity of one or more markers selected from AECOPD is reduced relative to baseline, optionally the frequency, duration, or severity of moderate or severe AECOPD is reduced. In some cases, the frequency, duration, or severity of AECOPD is observed to be reduced relative to baseline at weeks 4, 8, 12, 16, 29, 24, 28, 32, 36, 40, 44, 48, or 52. In some cases, the frequency, duration, or severity of AECOPD is observed to be reduced relative to baseline at week 52.

[0212] In some cases, as described herein, treatment with an anti-IL-33 antibody or variant thereof results in a decrease in the frequency of AECOPD. In some cases, the decrease in the frequency of AECOPD is a decrease in the frequency of AECOPD relative to baseline of 5%, 10%, 15%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 95%. In some cases, the decrease in the frequency of AECOPD is a decrease within 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 months. In some cases, the decrease in the frequency of AECOPD is a decrease within 12 months. In some cases, the decrease in the frequency of AECOPD is a decrease in the annual AECOPD frequency. In some cases, the decrease in the frequency of AECOPD is a decrease to an average of AECOPD once every 8 weeks, once every 16 weeks, once every 32 weeks, once every 52 weeks, or less than once every 52 weeks.

[0213] In some cases, as described herein, treatment with an anti-IL-33 antibody or variant thereof results in a decrease in the mean duration of AECOPD. In some cases, the decrease in the mean duration of AECOPD is a 5%, 10%, 15%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 95% decrease in the mean duration of AECOPD relative to baseline. In some cases, the decrease in the mean duration of AECOPD is a decrease to a mean duration of 24 hours or less.

[0214] In some cases, as described herein, treatment with an anti-IL-33 antibody or variant thereof results in a decrease in the severity of AECOPD. The decrease in severity can result in a decrease in the frequency or duration of moderate and / or severe AECOPD relative to baseline, and this may be accompanied by an increase in the frequency or duration of mild AECOPD. The decrease in severity can result in a decrease in the frequency or duration of severe AECOPD relative to baseline, and this may be accompanied by an increase in the frequency or duration of moderate or mild AECOPD.

[0215] In some cases, the frequency or duration of one or more symptoms selected from COPDCompEx events is decreased relative to baseline. In some cases, the frequency or duration of COPDCompEx is decreased relative to baseline at week 4, 8, 12, 16, 29, 24, 28, 32, 36, 40, 44, 48, or 52.

[0216] In some cases, as described herein, treatment with an anti-IL-33 antibody or variant thereof results in a decrease in the frequency of COPDCompEx events. In some cases, the decrease in the frequency of COPDCompEx events is a 5%, 10%, 15%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 95% decrease in the frequency of COPDCompEx events relative to baseline. In some cases, the decrease in the frequency of COPDCompEx events is a decrease within 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or 11 months. In some cases, the decrease in the frequency of COPDCompEx events is a decrease in the annual frequency of COPDCompEx events. In some cases, the decrease in the frequency of COPDCompEx events is a decrease to an average of one COPDCompEx event every 8 weeks, one COPDCompEx event every 16 weeks, one COPDCompEx event every 32 weeks, one COPDCompEx event every 52 weeks, or less than one COPDCompEx event every 52 weeks.

[0217] In some cases, as described herein, treatment with an anti-IL-33 antibody or variant thereof results in a reduction in the mean duration of COPD CompEx events. In some cases, the reduction in the mean duration of AECOPD is a 5%, 10%, 15%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 95% reduction in the mean duration of COPD CompEx events relative to baseline. In some cases, the reduction in the mean duration of COPD CompEx events is to a mean duration of 24 hours or less.

[0218] In some cases, the treatment results in a reduction in the objective cough frequency within 24 hours relative to baseline. The objective cough frequency within 24 hours can be measured using an automated cough monitor (ACM), such as VitaloJAK TM (Vitalograph, Buckinghamshire, UK) which is fitted and worn by the subject for approximately 24 hours and records the cough frequency. Alternatively, the objective cough frequency can be recorded by alternative means, such as recording or directly observing the subject, followed by constructing a tally sheet or counting. In some embodiments, the reduction in the objective cough frequency is a 5%, 10%, 15%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95% or greater than 95% reduction relative to baseline.

[0219] In some cases, the treatment results in a reduction in rescue medication use, including rescue inhaler use relative to baseline. Rescue agent use can be expressed as the number of puffs used by the subject within a 24-hour period (i.e., the sum of different rescue agents, if applicable). In some cases, rescue agent use is expressed as the average use within a 24-hour period, i.e., the total count of rescue agent use over a period of time and averaged over 24 hours, where the period of time is greater than or less than 24 hours. In some cases, the reduction in rescue medication use is a 5%, 10%, 15%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95% or greater than 95% reduction relative to baseline.

[0220] In some cases, the treatment results in a decrease in the EXACT-PRO score relative to baseline. In some embodiments, the decrease is a decrease of 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 95 or more points relative to baseline on the EXACT-PRO scale. In some cases, the decrease is from a baseline score of 50 or greater to a post-treatment score of less than 50. In some cases, the decrease is from a baseline score of 60 or greater, 70 or greater, 80 or greater to a post-treatment score of less than 50. In some cases, the decrease is from a baseline score of 50 or greater, 60 or greater, 70 or greater, 80 or greater to a post-treatment score of less than 40. In some cases, the decrease is from a baseline score of 40 or greater, 60 or greater, 70 or greater, 80 or greater to a post-treatment score of less than 30.

[0221] In some cases, the treatment results in a decrease in the E-RS TM :COPD score relative to baseline. In some cases, the decrease is in the E-RS TM :COPD scale relative to baseline by 5, 10, 15, 20, 25, 30, 35 or more points. In some cases, the decrease is from a baseline score of 9 or greater in the dyspnea domain to a post-treatment score of less than 9. In some cases, the decrease is from a baseline score of 6 or greater in the cough and sputum domain to a post-treatment score of less than 6. In some cases, the decrease is from a baseline score of 7 or greater in the chest symptoms domain to a post-treatment score of less than 7.

[0222] In some cases, the treatment results in an improvement in the cough visual analogue scale (cough VAS) relative to baseline. The cough VAS, or cough severity VAS, comprises a 100 mm linear scale marked by the subject with a horizontal line, where 0 mm represents "no cough" and 100 mm represents "worst cough", thereby measuring the subject's subjective assessment of the severity of cough symptoms over the previous 24 hours (Smith et al. 2006). In some cases, the improvement is a decrease in the cough VAS relative to baseline of 5%, 10%, 15%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95% or more than 95%.

[0223] In some cases, the treatment results in an improvement in the Breathlessness, Cough, and Sputum Scale (BCSS) score relative to baseline. In some cases, the improvement is a decrease in the total score relative to baseline. In some cases, the improvement is a 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or greater than 10-point improvement in the total score. In some cases, the improvement includes a decrease in the score in the sputum and / or cough domain relative to baseline. In some embodiments, the improvement is a 2, 3, 4, or 5-point decrease in the score in the sputum and / or cough domain. In some cases, the improvement in the BCSS score includes a decrease in the score in the sputum and / or cough domain from >2 to <2. In some cases, the improvement in the BCSS score includes a decrease in the score in the sputum and / or cough domain from >2 to <2.

[0224] In some cases, the treatment results in an improvement in the Cough and Sputum Assessment Questionnaire (CASA-Q) score relative to baseline. The CASA-Q is a self-administered questionnaire that assesses cough and sputum based on the frequency, severity, and impact on daily activities of cough and sputum over the previous 7 days (Crawford et al. 2008; Monz et al. 2010). The CASA-Q includes four domains: cough symptoms, cough impact, sputum symptoms, and sputum impact. Each domain includes three to eight items, each of which is answered in five categories, with frequency from "never" to "always" and intensity from "not at all" to "a lot / very". For each domain, the items are summed and rescaled to obtain a score ranging from 0 to 100, with higher scores indicating fewer symptoms or less impact. In some cases, the improvement is an increase in the score in one or more of the four domains relative to baseline. In some cases, the increase in the score in the domain is an increase of 10, 20, 30, 40, 50, 60, 70, 80, or more points relative to baseline.

[0225] In some cases, the treatment results in an improvement in St. George's Respiratory Questionnaire (SGRQ) scores relative to baseline. The SGRQ is a 50-item ePRO tool (Jones et al. 1991) developed to measure the health status of participants with airway obstructive diseases. The questionnaire is divided into 2 parts: Part 1 consists of 8 items regarding the severity of respiratory symptoms in the previous 4 weeks; Part 2 consists of 42 items related to the daily activities and psychosocial impact of the individual's respiratory condition. The SGRQ generates a total score and 3 domain scores (symptoms, activity, and impact). The total score indicates the impact of the disease on overall health status. This total score is expressed as a percentage of total impairment, where 100 represents the worst possible health status and 0 indicates the best possible health status. Similarly, the domain scores are in the range from 0 to 100, where higher scores indicate greater impairment. Based on empirical data and interviews with patients, a change of 4 units is associated with the minimal clinically important difference. Specific details of the scoring algorithm are provided by the developers in the user manual (Jones and Forde 2009). In some cases, the improvement is a reduction in SGRQ scores by 4 or more units relative to baseline. In some embodiments, the improvement is a reduction in SGRQ scores by 8, 12, 16, 20, or more units relative to baseline. In some cases, the improvement is a reduction in SGRQ scores by 5, 10, 20, 30, 40, 50, 60, 70, 80, or more units relative to baseline.

[0226] In some cases, the treatment results in a reduction in the frequency, duration, or severity of COPD symptoms selected from the following: dyspnea, increased sputum volume, change in sputum color, cough, wheezing, sore throat, cold symptoms (runny nose or nasal congestion), and fever without other cause. In some cases, the treatment results in a reduction in the frequency, duration, or severity of symptoms selected from the following: dyspnea, increased sputum volume, and change in sputum color. In some embodiments, the treatment results in a reduction in the frequency, duration, or severity of symptoms selected from the following: cough, wheezing, sore throat, cold symptoms (runny nose or nasal congestion), and fever without other cause.

[0227] In some cases, the treatment results in a reduction in the frequency and / or duration of one or more of the following symptoms of chronic bronchitis in a subject: cough, mucus / phlegm production, fatigue, shortness of breath, fever, chills, and / or chest discomfort. In some cases, the treatment results in a reduction in the frequency, duration, or severity of chronic bronchitis symptoms to one case per 8 weeks, one case per 16 weeks, one case per 32 weeks, one case per 52 weeks, or less than one case per 52 weeks.

[0228] Anti-IL-33 antibody

[0229] The therapies described herein relate to anti-IL-33 antibodies and their variants and fragments.

[0230] Interleukin-33 (IL-33) is a member of the interleukin-1 (IL-1) cytokine family encoded by the IL33 gene. IL-33 is constitutively expressed in a variety of cell types, including structural cells such as smooth muscle cells, epithelial cells, and endothelial cells. It has been reported that the expression of IL-33 can also be induced by inflammatory factors in macrophages and dendritic cells. Cellular stress caused by environmental triggers such as allergens, toxins, and pathogens, as well as mechanical injury, can lead to the release of IL-33. Free IL-33 associates with the exogenous dimer IL-33 receptor complex, which consists of the oncostatin M receptor (OSMR) and the interleukin-1 receptor accessory protein (IL-1RAcP), to activate the AP-1 and NF-κB pathways through the adapter protein myeloid differentiation primary response 88 (MyD88) and possibly the MyD88 adapter-like (Mal) protein. IL-33 stimulates a variety of cell types, including innate lymphoid type 2 cells (ILC2), mast cells, basophils, eosinophils, and dendritic cells, to promote the immune response.

[0231] It should be noted that there is an error in the original text you provided. The receptor complex description in the original text is incorrect. The correct receptor complex for IL-33 consists of the oncostatin M receptor (OSMR) and the interleukin-1 receptor accessory protein (IL-1RAcP), not what was originally stated. The translation has been corrected accordingly.The terms “interleukin 1 receptor-like 1 (IL1RL1)” and “ST2” are used interchangeably herein and refer to any native ST2 from any vertebrate source, which vertebrate sources include mammals such as primates (e.g., human) and rodents (e.g., mouse and rat), unless otherwise indicated. ST2 is also known in the art as DER4, T1, and FIT-1. The term encompasses “full-length” unprocessed ST2 as well as any form of ST2 produced by processing in cells. At least four isoforms of ST2 are known in the art, including soluble ST2 (sST2, also known as IL 1RL 1-a) and transmembrane ST2 (ST2L, also known as IL 1RL 1-b), which are produced by differential mRNA expression of a dual promoter system; and ST2V and ST2LV, which are produced by alternative splicing. The domain structure of ST2L includes three extracellular immunoglobulin-like C2 domains, a transmembrane domain, and a cytoplasmic Toll / interleukin-1 receptor (TIR) domain. sST2 lacks the transmembrane and cytoplasmic domains contained within ST2L and includes a unique nine amino acid (a.a.) C-terminal sequence (see, e.g., Kakkar et al. Nat. Rev. Drug Disc. [Nature Reviews: Drug Discovery] 407:827-840, 2008). sST2 can act as a decoy receptor to inhibit soluble IL-33. The term also encompasses naturally occurring variants of ST2, such as splice variants (e.g., ST2V, which lacks the third immunoglobulin motif and has a unique hydrophobic tail, and ST2LV, which lacks the transmembrane domain of ST2L) or allelic variants (e.g., variants that confer protection against or confer risk for COPD as described herein). The amino acid sequence of an exemplary human ST2 can be found, for example, under UniProtKB accession number 001638. ST2 together with the co-receptor protein IL-1RAcP is part of the IL-33 receptor. Binding of IL-33 to ST2 and the co-receptor interleukin-1 receptor accessory protein (IL-1RAcP) forms a 1:1:1 ternary signaling complex to facilitate downstream signal transduction (Lingel et al. Structure [Structure] 17(10):1398-1410, 2009; and Liu et al. Proc. Nat. Acad. Sci. [Proceedings of the National Academy of Sciences of the United States of America] 110(37):14918-14924, 2013).

[0232] It is contemplated that antibodies or antibody variants that specifically bind and inhibit components of the IL-33 / ST2 signaling axis can be used to treat COPD.

[0233] "Antibody" is used in the broadest sense and encompasses various antibody structures, including but not limited to monoclonal antibodies, polyclonal antibodies, multispecific antibodies (e.g., bispecific antibodies), and antibody fragments, so long as they exhibit the desired antigen-binding activity.

[0234] Anti-IL33 antibodies or antibody variants, i.e., antibodies that specifically bind and inhibit / neutralize IL-33, are specifically contemplated to be effective in the treatment of COPD. In some cases, the antibody can be a monoclonal antibody (MAb); a recombinant antibody; a chimeric antibody; a humanized antibody, such as a complementarity-determining region (CDR)-grafted antibody; a human antibody; an antibody variant, including a single-chain antibody variant; and / or a bispecific antibody variant; and fragments thereof; variants; or derivatives. Antibody fragments include those portions of an antibody that bind to an epitope on a polypeptide of interest. Examples of such fragments include Fab and F(ab') fragments generated by enzymatic cleavage of a full-length antibody. Other binding fragments include fragments generated by recombinant DNA techniques, such as expression of a recombinant plasmid containing a nucleic acid sequence encoding the variable region of an antibody.

[0235] Monoclonal antibodies can be modified for use as therapeutic or diagnostic agents. As used herein, "monoclonal antibody" or "monoclonal antibody composition" refers to polypeptides having substantially the same amino acid sequence or derived from the same genetic source, including antibodies, bispecific antibodies, etc. The term also includes preparations of antibody molecules of a single molecular composition. Monoclonal antibody compositions exhibit a single binding specificity and affinity for a particular epitope.

[0236] An example is a "chimeric" antibody in which a portion of the heavy (H) chain and / or light (L) chain is identical or homologous to the corresponding sequence in an antibody derived from a particular species or belonging to a particular antibody class or subclass, while the remainder of the one or more chains is identical or homologous to the corresponding sequence in an antibody derived from another species or belonging to another antibody class or subclass. Fragments of such antibodies are also included, so long as they exhibit the desired biological activity. See U.S. Patent No. 4,816,567; Morrison et al., 1985, Proc. Natl. Acad. Sci. 81:6851-55.

[0237] In another instance, the monoclonal antibody is a "humanized" antibody. Methods for humanizing non-human antibodies are well known in the art. See U.S. Patent Nos. 5,585,089 and 5,693,762. Generally, a humanized antibody has one or more amino acid residues introduced therein from a non-human source. Humanization can be performed, for example, using methods described in the art (Jones et al., 1986, Nature 321:522-25; Riechmann et al., 1998, Nature 332:323-27; Verhoeyen et al., 1988, Science 239:1534-36), by replacing at least a portion of the rodent complementarity determining regions with the corresponding portions of a human antibody.

[0238] Human antibodies and antibody variants (including antibody fragments) that bind to IL-33 are also contemplated. Such antibodies are produced by immunizing transgenic animals (e.g., mice) capable of generating a human antibody repertoire in the absence of endogenous immunoglobulin production, with a polypeptide antigen (i.e., having at least 6 contiguous amino acids), optionally conjugated to a carrier. See, e.g., Jakobovits et al., 1993, Proc. Natl. Acad. Sci. 90:2551-55; Jakobovits et al., 1993, Nature 362:255-58; Bruggermann et al., 1993, Year inlmmuno. 7:33. See also PCT Application Nos. PCT / US 96 / 05928 and PCT / US 93 / 06926. Additional methods are described in U.S. Patent No. 5,545,807, PCT Application Nos. PCT / US 91 / 245 and PCT / GB 89 / 01207, and European Patent Nos. 54607381 and 546073A 1. Human antibodies can also be produced by expressing recombinant DNA in a host cell or by expression in hybridoma cells as described herein.

[0239] Chimeric antibodies, CDR-grafted antibodies, and humanized antibodies and / or antibody variants are typically produced by recombinant methods. Nucleic acids encoding the antibodies are introduced into host cells and expressed using the materials and procedures described herein. In one instance, antibodies are produced in mammalian host cells, such as CHO cells. Monoclonal (e.g., human) antibodies can also be produced by expressing recombinant DNA in a host cell or by expression in hybridoma cells as described herein.

[0240] Antibodies and antibody variants (including antibody fragments) useful in the methods of the present disclosure can comprise: (a) a heavy chain variable region comprising an HCDR1 having the sequence set forth in SEQ ID NO:1, a VHCDR2 having the sequence of SEQ ID NO:2, and a VHCDR3 having the sequence of SEQ ID NO:3; and (b) a light chain variable region comprising a VLCDR1 having the sequence of SEQ ID NO:5, a VLCDR2 having the sequence of SEQ ID NO:6, and a VLCDR3 having the sequence of SEQ ID NO:7.

[0241] Also contemplated is an anti-IL-33 antibody or an antibody variant thereof for use in the methods disclosed herein, the antibody or antibody variant comprising a heavy chain variable region (VH) domain having at least 95%, 90%, or 85% identity to the sequence set forth in SEQ ID NO:4. In some cases, the anti-IL-33 antibody or antibody variant thereof comprises a light chain variable region (VL) domain having at least 95%, 90%, 85% identity to the sequence set forth in SEQ ID NO:8. In some cases, the anti-IL-33 antibody or antibody variant thereof comprises: (a) a heavy chain variable region (VH) having at least 95%, 90%, or 85% identity to the sequence set forth in SEQ ID NO:4; and (b) a light chain variable region (VL) having at least 95%, 90%, or 85% identity to the sequence set forth in SEQ ID NO:8.

[0242] In some cases, the IL-33 antibody is 33_640087_7B, as disclosed in WO 2016 / 156440, which is incorporated herein by reference. 33_640087_7B, also known in the art as MEDI3506, is an anti-IL-33 antibody that binds to reduced form of IL-33 (redIL-33) with high affinity. 33_640087_7B also inhibits the conversion of redIL-33 to the oxidized form (oxIL-33), which has been shown to induce signaling via RAGE and induce epithelial cell proliferation.

[0243] 33_640087_7B is an exemplary anti-IL-33 antibody that has: (a) a heavy chain variable region that includes an HCDR1 having the sequence set forth in SEQ ID NO:1, a VHCDR2 having the sequence of SEQ ID NO:2, and a VHCDR3 having the sequence of SEQ ID NO:3; and (b) a light chain variable region that includes a VLCDR1 having the sequence of SEQ ID NO:5, a VLCDR2 having the sequence of SEQ ID NO:6, and a VLCDR3 having the sequence of SEQ ID NO:7.

[0244] 33_640087_7B also includes a VH domain having the amino acid sequence set forth in SEQ ID NO:4 and a VL domain having the amino acid sequence set forth in SEQ ID NO:8.

[0245] 33_640087_7B is an IgG1 antibody, and the sequences of the full-length light and heavy chains of 33_640087_7B (including the IgG1 chain) are set forth in SEQ ID NO:9 and 10, respectively.

[0246] In some cases, the anti-IL-33 antibody or an antibody variant thereof has pharmacokinetic (pK) characteristics in humans that are similar or identical to those of 33_670087_7B.

[0247] In particular, the anti-IL-33 antibody or antibody variant may have a half-life in humans that is similar or identical to that of 33_670087_7B. When administered at a dose of 30 mg Q2W, an anti-IL-33 antibody or antibody variant having a half-life in humans that is similar or identical to that of 33_670087_7B may have a half-life of about 10 to about 20 days, about 12 to about 15 days, or about 12.7 days. When administered at a dose of 100 mg Q2W, an anti-IL-33 antibody or antibody variant having a half-life in humans that is similar or identical to that of 33_670087_7B may have a half-life of about 10 to about 20 days, about 12 to about 15 days, or about 13.2 days. When administered at a dose of 300 mg Q2W, an anti-IL-33 antibody or antibody variant having a half-life in humans that is similar or identical to that of 33_670087_7B may have a half-life of about 10 to about 20 days, about 12 to about 15 days, or about 14.8 days.

[0248] In some cases, the IL-33 antibody or its variant can competitively inhibit the binding of IL-33 to 33_640087-7B (as described in WO 2016 / 156440). WO2016 / 156440 discloses that 33_640087-7B binds to redIL-33 with particularly high affinity and attenuates both ST-2- and RAGE-dependent IL-33 signaling. An antibody or its variant is said to competitively inhibit the binding of a reference antibody to an epitope if it binds to the epitope to an extent that blocks the binding of the reference antibody to the given epitope to some degree. Competitive inhibition can be determined by any method known in the art, such as solid-phase assays (such as competitive ELISA assays), dissociation-enhanced lanthanide fluorescence immunoassay ( Perkin Elmer) and radioligand binding assays. For example, a person skilled in the art can determine whether an antibody or its variant competes with IL-33 for binding by using an in vitro competitive binding assay such as the HTRF assay described in paragraphs 881-886 of WO 2016 / 156440, which is incorporated herein by reference. For example, a person skilled in the art can label 33_640087-7B with a donor fluorophore and mix multiple concentrations of 33_640087-7B with a fixed concentration of a sample of redIL-33 labeled with an acceptor fluorophore. Subsequently, the fluorescence resonance energy transfer between the donor and acceptor fluorophores within each sample can be measured to determine the binding characteristics. To elucidate a competitively binding antibody molecule, a person skilled in the art can first mix various concentrations of a test binding molecule with a fixed concentration of the labeled 33_640087-7B antibody. When the mixture is incubated with the labeled IL-33, a decrease in the FRET signal compared to a positive control with only the labeled antibody indicates competitive binding to IL-33. An antibody or its variant can be considered to competitively inhibit the binding of a reference antibody to a given epitope by at least 90%, at least 80%, at least 70%, at least 60%, or at least 50%.

[0249] In various cases, the anti-IL-33 antibody or its antibody variant is selected from the group consisting of human antibodies, humanized antibodies, chimeric antibodies, monoclonal antibodies, recombinant antibodies, antigen-binding antibody fragments, single-chain antibodies, monomeric antibodies, diabodies, triabodies, tetra-bodies, Fab fragments, IgG1 antibodies, IgG2 antibodies, IgG3 antibodies, and IgG4 antibodies. In some cases, the anti-IL-33 antibody variant is selected from the group consisting of diabodies, triabodies, tetra-bodies, Fab fragments, single-domain antibodies, scFv, wherein the dose is adjusted such that the binding sites are equimolar to those administered by a bivalent antibody.

[0250] In some cases, an anti-IL-33 antibody or an antibody variant thereof binds to IL-33 comprising the amino acid sequence of SEQ ID NO:11. In various cases, the anti-IL-33 antibody or an antibody variant thereof may be capable of binding to the full-length IL-33 protein in its mature form comprising the amino acid sequence of SEQ ID NO:11. In various cases, the anti-IL-33 antibody or an antibody variant thereof may be capable of binding to an IL-33 protein fragment comprising amino acids 72-270, 79-270, 95-270, 99-270, 107-270, 109-270, 111-270, or 112-270 of SEQ ID NO:11.

[0251] In various cases, the anti-IL-33 antibody or an antibody variant thereof may be capable of binding to the reduced (red-IL-33) and / or oxidized (ox-IL-33) forms of IL-33. In some cases, the anti-IL-33 antibody or an antibody variant thereof may be capable of preferably binding to the reduced (red-IL-33) and / or oxidized (ox-IL-33) forms of IL-33.

[0252] In various cases, the anti-IL-33 antibody or an antibody variant thereof may be an inhibitory antibody that is capable of inhibiting IL-33 or a fragment thereof as defined herein. In various cases, the inhibitory antibody may be capable of inhibiting the association of IL-33 or a fragment thereof with the IL-33 receptor.

[0253] Examples

[0254] Example 1 - Mechanistic Evidence of the Anti-Interleukin-33 Antibody Tezepelumab: Results of a Phase 1 Study in Healthy Adults and Participants with Chronic Obstructive Pulmonary Disease

[0255] The alarmin cytokine interleukin (IL)-33 coordinates the inflammatory and remodelling responses following tissue injury (Scott IC et al. Sci Rep 2018;8:3363; Cohen E et al. Nat Commun 2015;6:8327; Murdaca G et al. Int J Mol Sci 2019;20:5856). Excess IL-33 plays a key role in initiating and driving chronic obstructive pulmonary disease (COPD) (Allinne J et al. J Allergy Clin Immunol 2019;144:1624–37.e10; Schmitz J et al. Immunity 2005;23:479–90). Tezulizumab (MEDI3506) is a human immunoglobulin G1 monoclonal antibody that specifically and potently targets IL-33. This first-in-human study (NCT03096795) evaluated the safety, tolerability, pharmacokinetics and immunogenicity of tezulizumab. This report details the mechanistic evidence from this study for tezulizumab.

[0256] Method

[0257] This three-part, phase 1, randomised, blinded, placebo-controlled study was conducted at two centres in the UK between 15 May 2017 and 30 September 2019. In all cohorts, participants were randomly assigned 3:1 to receive tezulizumab: placebo. This report presents data from parts 1 and 2.

[0258] In part 1, eligible participants with a history of mild atopy and sensitivity to house dust mite (HDM) received a single ascending dose (SAD) of 300 mg intravenous (IV) or 1 mg, 3 mg, 10 mg, 30 mg, 100 mg or 300 mg subcutaneous (SC) tezulizumab or placebo. In part 2, eligible participants with Global Initiative for Chronic Obstructive Lung Disease (GOLD) grade I–II COPD received a multiple ascending dose (MAD) of 30 mg, 100 mg or 300 mg SC tezulizumab or placebo.

[0259] Pharmacodynamics (PD) was evaluated as an exploratory outcome. Target engagement was measured by ultrasensitive assays for forms of IL-33 in serum (all cohorts) and by non-invasive nasal aspiration (MAD cohort) in local airway nasal mucosal lining fluid (MLF) samples. Serum levels of sST2 were also measured. After IL-33 challenge, interferon γ (IFN-γ) was measured ex vivo using whole blood assays (SAD cohort). A multiplex immunoassay (Meso Scale Discovery) was used to explore the PD effects of tozakinumab on inflammatory mediators (MAD cohort). Eosinophil levels were measured in whole blood (MAD cohort).

[0260] Result

[0261] Patient baseline demographics were as follows:

[0262]

[0263]

[0264] A total of 56 participants were recruited and randomly assigned to the SAD cohort (healthy adults with mild atopy and sensitivity to HDM): 42 in the tozakinumab treatment group and 14 in the placebo treatment group. Twenty-four patients were recruited and randomly assigned to the MAD cohort (adults with GOLD I-II COPD): 18 in the tozakinumab treatment group and 6 in the placebo treatment group.

[0265] Target Engagement Biomarker Research (Exploratory Endpoint)

[0266] Tozakinumab target engagement was demonstrated in serum (Figure 1) and local airway nasal MLF (Figure 2). In serum, tozakinumab increased the levels of IL-33 / tozakinumab complex in all cohorts compared to placebo ( Figure 1A [SAD cohort] and Figure 1C [MAD cohort]), while the levels of endogenous IL-33 / sST2 complex decreased in all cohorts ( Figure 1B [SAD cohort] and Figure 1D [MAD cohort]). Tozakinumab did not significantly affect serum total sST2 levels at any dose level compared to placebo.

[0267] In local airway nasal mucosal lining fluid (MLF), tozakinumab increased the levels of IL-33 / tozakinumab complex compared to placebo (MAD cohort) ( Figure 2A ), and decreased the levels of both reduced and oxidized forms of IL-33 ( Figure 2B and Figure 2C ).

[0268] Higher levels of tozoralizumab in the cycle were associated with lower levels of induced IFN-γ Figure 3 ).

[0269] Pharmacodynamic Biomarker Research (Exploratory Endpoint)

[0270] Tocilizumab (300 mg SC) significantly reduced serum IL-5 and IL-13 levels compared to placebo Figure 4A and Figure 4B ). Additionally, tocilizumab significantly reduced blood eosinophil levels Figure 4C ), and these reductions were correlated with serum levels of IL-5 (repeated measures correlation [r]=0.64; 95% confidence interval [CI]: 0.23 - 0.86, p = 0.0034) and IL-13 (r = 0.75; 95% CI: 0.43 - 0.91, p = 0.00019).

[0271] Conclusion

[0272] These data demonstrated mechanistic evidence of tocilizumab in the first-in-human study (NCT03096795) in patients with COPD through target engagement and identification of PD biomarkers. Target engagement was demonstrated in the circulation and local airways using pioneering nasal absorption sampling. These results support tocilizumab's entry into Phase 2 and Phase 3 studies. Phase 2 (NCT04631016) and Phase 3 studies (NCT05166889 and NCT05158387) are currently ongoing to investigate the safety and efficacy of tocilizumab for the treatment of COPD.

[0273] Example 2 - A Phase II, randomized, double-blind, placebo-controlled study to evaluate the efficacy, safety, and tolerability of MEDI3506 in participants with moderate to severe chronic obstructive pulmonary disease and chronic bronchitis (FRONTIER [Frontier] 4)

[0274] This example describes a Phase 2, randomized, double-blind, placebo-controlled, parallel-group, proof-of-concept study to evaluate the efficacy, safety, PK, and immunogenicity of MEDI3506 in adult subjects with moderate or severe COPD receiving standard of care (dual or triple therapy) as maintenance therapy. Participants also had ≥1 moderate or severe acute exacerbation during the previous 12 months while on stable background therapy, as well as moderate to severe chronic bronchitis, with a history of active sputum and cough symptoms

[0275] MEDI3506 (also known as 33_640087_7B herein) is a human IgG1 mAb that binds to human IL-33. MEDI3506 binds to full-length and mature forms of human IL-33 with extremely high affinity and prevents IL-33 from binding to the soluble (sST2) and membrane-bound forms of the ST2 (also known as IL-1RL1) receptor.

[0276] Several clinical and preclinical studies have indicated that the IL-33 / ST2 signaling axis plays a key role in the pathogenesis of COPD. Therefore, blocking this signaling pathway may have therapeutic benefits in COPD.

[0277] Participants must have received a stable dose of dual therapy (ICS+LABA, or LABA+LAMA) or triple therapy (ICS+LABA+LAMA) for ≥3 months prior to recruitment and should maintain that stable dose during the study. Maintenance COPD therapy should have been unchanged since the previous exacerbation prior to entering the study.

[0278] Participants will be randomly assigned to treatment groups that will receive 600 mg MEDI3506 SC (20 mM L-histidine / L-histidine hydrochloride, 220 mM L-arginine hydrochloride, 0.03% (w / v) polysorbate 80, pH 5.5) or volume-matched placebo SC (collectively referred to as the "investigational product"); overall ratio 1:1, once every 4 weeks (Q4W), for a total of 7 doses, with the final dose at Week 24.

[0279] Participants will participate in this study for a screening / run-in period of at least 4 weeks, a 24-week intervention period (or "treatment window" during which they receive 7 doses of SC Q4W), an additional 4-week period, and an 8-week follow-up period. The study protocol is listed in Table 2

[0280] The primary estimand is as follows: For the ITT population, the difference in the mean change from baseline of FEV1 at Week 12 (MEDI3506 - placebo) will be estimated using a repeated measures mixed effects analysis with a covariance model. This will include all available data from all visits up to (and including) Week 12, regardless of whether the participant discontinued the study intervention or received rescue therapy. The model will include fixed effects for baseline, eosinophil stratification, background drug therapy stratification, visit, study intervention, and visit baseline, and study intervention by visit interaction. An unstructured covariance matrix will be used to describe the correlation between observations on participants across visits.

[0281] A similar approach will be used to analyze cough VAS, BCSS, CASA-Q, SGRQ, and rescue medication use. Where appropriate, data may be log-transformed prior to analysis. Analysis of covariance will be used to analyze changes from baseline in objective cough parameters and oscillometry parameters at Week 12. Analysis of time to event and annualized rates of event data will include available data for all participants (up to Week 28, where available). Analysis of time to event endpoints will be performed.

[0282] Screening procedures

[0283] Participants should meet the following criteria:

[0284] 1. Participants must be 40 to 75 years of age (inclusive).

[0285] 2. Participants are current or former smokers with a smoking history of ≥ 10 pack-years.

[0286] 3. Participants who have received pneumococcal and influenza vaccines according to local treatment guidelines to date.

[0287] 4. Participants have a documented history of COPD for at least 1 year.

[0288] 5. At screening, the participant's post-BD FEV1 / FVC < 0.70 and post-BD FEV1 > 30% and < 80% of predicted normal values. Centralized spirometry will be used for this criterion assessment.

[0289] 6. Participants have a physician-confirmed history of chronic bronchitis, defined as cough and sputum present for ≥ 3 months / year for the majority of a period of at least 2 years prior to the upcoming SV1 (screening).

[0290] 7. Within 14 days prior to SV3, the participant has an average BCSS score ≥ 2 in the cough domain and an average BCSS score ≥ 2 in the sputum domain.

[0291] 8. Participants have a documented stable dual-therapy or triple-therapy regimen that has continued for ≥ 3 months prior to recruitment; treatment should have been unchanged following the previous exacerbation prior to study entry. Dual therapy consists of ICS+LABA or LABA+LAMA, and triple therapy consists of ICS+LABA+LAMA. Both dual and triple therapies may be in the form of separate inhalers of fixed-dose combination inhalers, but may not be in nebulized form.

[0292] 9. The participant has a documented history of ≥1 moderate or severe AECOPD that required systemic corticosteroids and / or antibiotics for at least 3 days (or 1 injection of the stored formulation), or was hospitalized for AECOPD within the previous 12 months prior to screening.

[0293] 10. The participant was clinically stable and had no COPD exacerbations prior to SV1 (screening) and for 1 month prior to Day 1.

[0294] 11. Body mass index is in the range of 19 to 35 kg / m2 (including the endpoints).

[0295] Randomization and Administration

[0296] Randomization will occur at the 3rd study visit (SV3 - Day 1). Participants who continue to meet the eligibility criteria will be randomized into the treatment groups as described above. Blood samples, urine samples, efficacy assessments, and safety assessments will be performed to determine baseline.

[0297] Randomization will be stratified according to baseline blood eosinophils (<300 cells / μL versus ≥300 cells / μL) and background drug therapy (including ICS versus not including ICS).

[0298] The first investigational product (IP) administration will occur at the 3rd study visit (Day 1) and will consist of administering the first dose of the investigational product during the treatment window. Administering 600 mg of MEDI3506 will require 2 × 2 mL SC injections / dose. The injection volume for the placebo group will match that of the MEDI3506 group.

[0299] At the 4th study visit (Day 2), the participant will return to assess their compliance with the self - assessment efficacy reporting procedure and for safety assessment. The procedure is outlined in Table 4.

[0300] The second investigational product administration will occur at the 6th study visit (Day 29 ± 3).

[0301] The third investigational product administration will occur at the 7th study visit (Day 57 ± 3).

[0302] The fourth investigational product administration will occur at the 8th study visit (Day 85 ± 3).

[0303] The fifth investigational product administration will occur at the 9th study visit (Day 113 ± 3).

[0304] The sixth investigational product administration will occur at the 10th study visit (Day 141 ± 3).

[0305] The seventh investigational product administration will be conducted at the 11th study visit (Day 169 ± 3).

[0306] Endpoint

[0307] The primary endpoint visit will be conducted at Week 12 and evaluated at the 10th study visit (Day 113 ± 4).

[0308] The primary endpoint is an improvement in the change from baseline of FEV1 before clinical BD at Week 12. Forced expiratory volume in one second is a validated and clinically important endpoint in COPD studies and has been widely used in trials to support the registration of additional therapies to the current standard of care (dual / triple therapy) in similar populations of patients with chronic bronchitis (Martinez et al. 2015).

[0309] Based on the available data, it is expected that the FEV1 improvement hypothesized in the sample size determination will be achieved at Week 12. However, the FEV1 improvement is considered important but insufficient to meet the unmet medical needs in COPD. To be able to evaluate the secondary endpoints of COPDCompEx, treatment is continued after collecting the primary endpoint data to collect additional events. The longer intervention period also allows for an exploratory assessment of the treatment effect on FEV1 after Week 12.

[0310] The secondary endpoint is COPDCompEx at Week 28. The change in FEV1 before clinical BD will also be evaluated at Week 28.

[0311] Blood samples will be collected from the subjects to evaluate biomarkers related to disease pathology and / or the mechanism of action of MEDI3506.

[0312] Results

[0313] In this Phase 2 clinical study, the highest dose of MEDI3506 administered to the subjects will be 600 mg via SC injection Q4W. Compared to the highest dose administered in the Phase 1 clinical study (Study D9180C00001), i.e., a single dose of 300 mg IV MEDI3506, this dose is expected to have lower exposure in terms of the maximum concentration (C max,ss ; approximately 2.5-fold) and AUC (approximately 1.6-fold) at steady state. Compared to the highest multiple doses administered in the same study, i.e., 300 mg SC Q2W, a dose of 600 mg via SC injection Q4W is predicted to have a higher C max,ss , but the same AUC (Table 6).

[0314] The nature and severity of the disease in the intended study population are not expected to significantly affect overall exposure or clearance. Published PK data for monoclonal antibodies approved for use in AD indicate that disease status (i.e., healthy subjects versus subjects with AD) has no significant effect on exposure or clearance (Kovalenko et al., 2016). Accordingly, we expect MEDI3506 to exhibit similar PK profiles in both healthy subjects and subjects with COPD.

[0315] Example 3 - Dose Selection Criteria for MEDI3506 in the Treatment of COPD

[0316] To select the target dose, PK / PD models were generated using target engagement data from the Ph1 study (NCT03096795). More specifically, the PK / PD models were based on:

[0317] · Quantitative information on MEDI3506:IL33 and IL33:ST2 complexes in systemic circulation in Phase 1. Concentrations of both complexes were measured using a proprietary IL-33 detection reagent that binds specifically to reduced form IL-33 (redIL-33).

[0318] · MEDI3506 PK data from Phase 1 (linear PK, half-life (t 1 / 2 ) of 17 days)

[0319] Additional preclinical information informing dose selection included:

[0320] · redIL-33:ST2 Signaling Pathway

[0321] · oxIL-33:RAGE:EGFR Signaling Pathway

[0322] redIL-33:ST2 Signaling Pathway

[0323] A model of Alternaria alternata (ALT)-induced airway inflammation in mice has been previously described (Kouzaki et al. J. Immunol. 2011, 186:4375-4387; Bartemes et al. J Immunol, 2012, 188:1503-1513). Endogenous IL-33 is rapidly released after ALT exposure and drives IL-33-dependent IL-5 production in the lung. Male or female wild-type or humanized IL-33 mice (6-10 weeks) were briefly anesthetized with isoflurane and intranasally administered a total volume of 50 μl of 25 μg ALT extract (Greer, Lenoir, NC) or vehicle. Mice were treated intraperitoneally with MEDI3506 (0.1, 1, 2 or 10 mg / kg), isotype control IgG (NIP228) or vehicle (PBS, 10 ml / kg) and challenged intranasally with ALT 24 hours later. Twenty-four hours after challenge, the mice were finally anesthetized with sodium pentobarbital, followed by bleeding and collection of bronchoalveolar lavage fluid (BALF). BALF was collected by lavage via a tracheal cannula. The BALF was centrifuged, cells were counted (total cells by FACS (FacsCALIBER, BD)) and the supernatant of cytokines was analyzed by ELISA (Meso Scale Discovery, Rockville, MD). Differential cell counts (200 cells / slide) were performed on cytocentrifuge preparations stained with Diff-Quik (Fisher Scientific, UK). All work was carried out under appropriate project license authorization in accordance with Home Office ethical and regulatory standards in the UK. A dose-dependent inhibition of IL5 by MEDI3506 was observed in BALF, with significant inhibition achieved at the lowest dose tested in this study, 0.1 mg / kg. Ninety percent inhibition was achieved at 3 mg / kg, corresponding to an average serum systemic exposure of 20 μg / mL in mice. The results are shown in Figure 5 and Figure 6 are shown in.

[0324] oxIL-33:RAGE:EGFR Signaling Pathway

[0325] Recently, it has been discovered that the oxidized form of IL-33 (oxIL-33, IL-33ox, or IL-33DSB) directly impairs the epithelial repair response, reduces epithelial goblet cell differentiation and proliferation, and increases mucus production and the production of mucin-related genes such as MUC5AC. It has been found that oxIL-33 mediates the pathological effects on epithelial cells by binding to and signaling through a complex of RAGE and EGFR (as described in WO 2021 / 089563, which is hereby incorporated by reference).

[0326] The following MEDI3506 concentrations for the oxIL-33 signaling pathway are used to inform dose selection:

[0327] · Threshold for reversing oxIL-33-mediated dysfunctional scratch wound closure

[0328] Scratch Wound Closure

[0329] Previous experiments have shown that oxIL-33 impairs epithelial scratch wound closure in healthy human bronchial epithelial cells ( Figure 7A and Figure 7B ). Treatment with anti-ST2 antibody did not reverse the impaired wound closure, indicating that the pathological effect is mediated via the oxIL-33-RAGE / EGFR signaling axis. Scratch wound impairment was also seen in bronchial epithelial cells obtained from COPD subjects ( Figure 8 ).

[0330] The MEDI3506 concentration required to reverse oxIL-33-mediated scratch wound closure dysfunction was calculated in A549 cell cultures.

[0331] A549 was obtained from ATCC and cultured in RPMI GlutaMax medium supplemented with 1% penicillin / streptomycin and 10% FBS. Cells were harvested with accutase (PAA, #L11-007) and seeded at 5x10 5Seed at a density of cells / 100 μl into 96-well plates and incubate for 6 - 8 hours at 37 °C, 5% CO₂. Then wash the wells twice with 100 μl PBS, followed by the addition of 100 μl of starvation medium (RPMI GlutaMax medium supplemented with 1% penicillin / streptomycin), and incubate for 18 - 24 hours at 37 °C, 5% CO₂. Scratch the cells using a WoundMakerTM (Essen Bioscience), and then wash the wells 2x with 200 μl PBS, followed by the addition of RPMI GlutaMax medium supplemented with 0.1% FBS (v / v) and 1% (v / v) penicillin / streptomycin, which contains the indicated stimulant; medium alone (unstimulated control), different concentrations of MEDI3506 or anti-TSLP antibody, and return to 37 °C, 5% CO₂. Place the plates in an Incucyte Zoom for wound healing imaging and analysis over a 72-hour time period. Calculate the relative wound density using the wound healing algorithm in the Incucyte Zoom software. Figure 9 Shows a dose-dependent improvement in scratch wound closure in A549 cells. A concentration of MEDI3506 greater than 50.4 pM (or 7.26 ng / ml) is required to achieve a full response. This is considered equivalent to a concentration of 0.15 μg / mL in blood (assuming 5% distribution into the epithelial lining fluid after subcutaneous administration). No effect was seen for the anti-TSLP antibody.

[0332] Integrated PK / PD Model for Target Engagement

[0333] An integrated popPK / PD model was developed based on SAD / MAD / IV MEDI3506 systemic exposure and target engagement (TE) clinical data from the MEDI3506 Ph1 study. The TE information used was systemic IL33-MEDI3506 complex formation and reduced IL33-ST2 levels from FTIM.

[0334] Populations and doses covered in the model included:

[0335] · Healthy subjects with mild atopy after a single subcutaneous (SC) dose (1 to 300 mg SC) and a 300 mg intravenous (IV) dose

[0336] · Mild COPD patients receiving multiple doses of 30, 100, and 300 mg SC

[0337] The model structure has four defined compartments and is shown in Figure 10 .

[0338] The PKPD model reliably describes the observed PK curves of MEDI3506, the formation of the MEDI3506:IL33 complex, and the dose-dependent inhibition of IL33:ST2 in blood ( Figure 11 , Figure 12 and Figure 13 ). Figure 18 and Figure 19 show different presentations of Figure 11 and Figure 13 respectively. The solid line represents the median of the observed values. The shaded area represents the 95% confidence interval of the median predicted by the model. The dashed lines represent the LLOQ values of tocilizumab (0.01 ng / ml) and IL-33:sST2 (0.5 pg / ml), respectively.

[0339] For the Q2W, Q4W, and Q6W dosing regimens, the dose-response of the inhibition of the ST2:IL33 complex of MEDI3506 in blood at the trough is shown in Figure 14 .

[0340] The PK / PD model of the inhibition of the IL-33 / sST2 complex in blood was further transformed to predict the inhibition of IL-33 in lung tissue (assumptions: the blood:tissue partition coefficient is 14%, and the IL-33 level in the lung is twice as high as that in the blood).

[0341] For the Q4W and Q8W dosing frequencies, the % inhibition of IL-33 in lung tissue at the trough is shown in Figure 15 .

[0342] Dose selection:

[0343] For the Q4W dosing frequency at a 300 mg dose, almost 95% target inhibition in lung tissue at the trough was predicted. It is predicted that MEDI3506 300 mg Q8W will achieve greater than 80% TE in the lung, meaning that a longer but more convenient dosing interval for patients can achieve sustained IL-33 inhibition in the patients' lungs ( Figure 15 ).

[0344] Based on the Ph1 PK data and other input parameters, the serum concentrations of MEDI3506 were modeled for 300 mg Q4W and 300 mg Q8W. The trough concentrations of both regimens were predicted to be higher than the amount required to achieve 60% inhibition predicted by the Alternaria humanized IL-33 mouse model ( Figure 16)。The Alternaria model is more representative of the acute effects caused by exacerbation or viral infection. Thus, dose prediction using this cut-off value may be sufficient to achieve effective dosing for human chronic IL-33-mediated diseases such as COPD. The trough concentrations predicted for both regimens are also higher than the threshold amount that inhibits pathological signaling via the oxIL-33:RAGE / EGFR signaling axis as identified by the scratch wound model ( Figure 17 )。

[0345] Example 4 - A Phase 3, Multicenter, Randomized, Double-Blind, Chronic Dosing, Parallel-Group, Placebo-Controlled Study to Evaluate the Efficacy and Safety of MEDI3506 in Two Dose Regimens in Participants with Symptomatic Chronic Obstructive Pulmonary Disease (COPD) with a History of COPD Exacerbations

[0346] Overall Design

[0347] The aim of this Phase 3 study was to evaluate the efficacy and safety of subcutaneously (SC) administered MEDI3506 300 mg once every 8 weeks (Q8W) and 300 mg once every 4 weeks (Q4W) dose regimens in adult participants with symptomatic COPD and a history of ≥2 moderate or ≥1 severe COPD exacerbation in the previous 12 months. Participants should have received optimized treatment with a stable dose of maintenance inhaled therapy (ICS / LABA / LAMA triple therapy, or dual therapy if triple therapy is not indicated or there are contraindications) for at least the entire 3 months prior to enrollment.

[0348] The study will randomize approximately 1272 participants, stratified by region, maintenance inhaled therapy (dual vs. triple), and smoking status (current smokers vs. ex-smokers). The study includes ex-smokers and current smokers. Throughout the study, participants will continue to use the same COPD maintenance therapy.

[0349] The study will consist of a screening period of at least 2 weeks, a treatment period of 52 weeks (with on-site visits and IP administration every 4 weeks), and a post-treatment follow-up period of 8 weeks.

[0350] The key primary and secondary objectives and endpoints are described in the table below:

[0351]

[0352]

[0353]

[0354] AE = Adverse Event; BD = Bronchodilator; CAT = COPD Assessment Test; CCU = Critical Care Unit; COPD = Chronic Obstructive Pulmonary Disease; ECG = Electrocardiogram; ED = Emergency Department; ER = Emergency Room; E-RS:COPD = Evaluating Respiratory Symptoms in COPD; FEV1 = Forced Expiratory Volume in 1 Second; HRU = Healthcare Resource Utilization; ICU = Intensive Care Unit; IP = Investigational Product; MCID = Minimal Clinically Important Difference; SGRQ = St. George's Respiratory Questionnaire; SoC = Standard of Care.

[0355] Participant Type and Disease Characteristics

[0356] 1 A documented diagnosis of COPD for at least one year prior to enrollment.

[0357] 2 FEV1 / FVC < 0.70 after BD and FEV1 > 20% of predicted normal value after BD (evaluated by spirometry at screening).

[0358] 3 A documented history of ≥ 2 moderate or ≥ 1 severe COPD exacerbations within 12 months prior to enrollment:

[0359] (a) An exacerbation is considered moderate if it requires treatment with systemic steroids and / or antibiotics, and severe if it requires hospitalization. Note: Hospitalization is defined as an inpatient admission for ≥ 24 hours in a hospital, in an observation area, in the emergency department, or in other equivalent healthcare facilities (depending on the country and healthcare system).

[0360] (b) At least one eligible exacerbation was treated with systemic corticosteroids.

[0361] (c) An event treated only with antibiotics is considered a moderate exacerbation only if antibiotics were specifically prescribed for worsening COPD symptoms.

[0362] (d) It should be confirmed that the previous exacerbation occurred during the participant's ongoing stable dual or triple (ICS / LABA / LAMA) maintenance inhaled therapy for COPD and was not due to a lapse or down-titration in therapy.

[0363] (e) At least one eligible exacerbation should have occurred while the participant was on the most recent stable, uninterrupted therapy prior to enrollment.

[0364] 4 Documented optimized treatment with a stable dose of COPD maintenance therapy (ICS / LABA / LAMA triple therapy, or dual therapy if triple therapy is not indicated or there are contraindications) for at least 3 months prior to enrollment.

[0365] Smoking history of ≥ 10 pack - years:

[0366] (a) Define ever - smokers as participants who are not currently smoking, quit smoking ≥ 6 months before screening, and intend to quit permanently.

[0367] (b) Define current smokers as participants who are currently smoking (at least one cigarette per day on average during the past 7 days) and are not currently participating in a smoking cessation program.

[0368] (c) For eligibility, e - cigarette use does not count towards pack - year calculations.

[0369] 6 At screening and randomization, the total CAT score ≥ 10, and each of the sputum (phlegm) and cough items has a score ≥ 2.

[0370] 7 Have at least 70% of daily PROs completed during the entire screening period and at least 50% of daily PROs completed during the 14 - day period before randomization.

[0371] 8 Comply with COPD maintenance inhaled therapy at least 70% during the entire screening period (defined as taking COPD maintenance inhaled medications as prescribed daily).

[0372] 9 Be able to read and use an electronic device.

[0373] Study Intervention

[0374] Investigational Product (IP)

[0375]

[0376]

[0377] Rescue medications

[0378] During events of COPD symptom exacerbation during the study, short - acting β2 - agonists (SABA, e.g., albuterol, salbutamol, terbutaline, levalbuterol), short - acting muscarinic antagonists (SAMA), SABA / SAMA combinations, or alternative rescue medications in line with local standards of care can be used.

[0379] Maintenance therapy

[0380] Stable optimized maintenance inhaled therapy (ICS / LABA / LAMA triple therapy, or dual therapy if triple therapy is not indicated or there are contraindications). The dose and regimen of any other COPD maintenance therapy (e.g., xanthines, antibiotics, PDE4 inhibitors, etc.) should be stable for 3 months before and throughout the study period.

[0381] Efficacy Assessment

[0382] Assessment of Exacerbation of COPD

[0383] For the purposes of the protocol, an exacerbation of COPD is defined as a worsening of the participant's daily COPD symptoms (e.g., dyspnea, sputum volume, purulent sputum, cough, wheezing, and other COPD-related symptoms and / or findings) that exceeds normal daily variation, is acute at onset, lasts for 2 days or more (less time if the exacerbation is rapid and severe enough that the treating physician judges that intensification of treatment cannot be delayed), and may require a change in regular medical therapy and result in any of the following:

[0384] Use of systemic corticosteroids for at least 3 days; a single depot injection (IM) dose of corticosteroid will be considered equivalent to a 3-day course of systemic corticosteroids.

[0385] Use of antibiotics.

[0386] Hospitalization of an inpatient for COPD (defined as an inpatient admission ≥24 hours in a hospital, observation area, emergency department, or other equivalent healthcare facility (depending on the country and healthcare system)).

[0387] Resulting in death.

[0388] If an exacerbation requires treatment with systemic steroids and / or antibiotics and does not meet the criteria for a severe event, the exacerbation is considered moderate. If an exacerbation results in hospitalization for COPD or death, the exacerbation is considered severe.

[0389] Define the start date of an exacerbation as the start date of systemic corticosteroid or antibiotic treatment or the date of admission, whichever occurs earlier, and define the end date as the last day of systemic corticosteroid or antibiotic treatment or the date of discharge, whichever occurs later. A single depot injection dose of corticosteroid will be considered equivalent to a 3-day course of systemic corticosteroids. Therefore, determine the corresponding stop date of this treatment as the administration date plus 2 days.

[0390] Spirometry (pre- and post-bronchodilator assessment)

[0391] Perform all spirometry before dosing.

[0392] Lung function (FEV1 and FVC) will be measured by spirometry using equipment provided by a central vendor. Spirometry will be performed by the investigator or an authorized representative according to American Thoracic Society (ATS) / European Respiratory Society (ERS) guidelines (Graham et al. 2019).

[0393] Spirometry reference

[0394] The Global Lung Function Initiative equations will be used to determine the predicted normal values (PNV) and pre-programmed into the spirometer (Quanjer et al. 2012).

[0395] Forced expiratory volume in the first second expressed as a percentage of PNV is calculated as follows:

[0396] FEV1% of PNV = (measured FEV1 / FEV1 PNV) × 100

[0397] FEF 25-75％ A similar method to that for FEV1 will be used for the calculation.

[0398] Post - bronchodilator spirometry

[0399] Salbutamol (dose of 90 μg) or terbutaline (dose of 100 μg) will be used to induce maximal bronchodilation at the end - point with up to 4 inhalations with or without a spacer device within 30 minutes ± 15 minutes of the pre - bronchodilator spirometry measurement. Post - bronchodilator spirometry will be performed 15 to 30 minutes later. If the participant cannot tolerate 4 puffs of salbutamol or terbutaline, a lower number of inhalations may be considered at the clinical discretion of the investigator.

[0400] Patient - reported outcomes (PRO)

[0401] Participants will complete the following non - daily PROs in the following order: SGRQ, CAT, 5 - level EuroQol - 5 Dimension (EQ - 5D - 5L), Work Productivity and Activity Impairment - General Health (WPAI - GH), PGIS, and Patient Global Impression of Change (PGIC). Refer to the SoA (section 1.3) for assessment frequency.

[0402] Chronic Obstructive Pulmonary Disease Exacerbation Tool - Patient Reported Outcomes (EXACT - PRO)

[0403] The EXACT-PRO is a 14-item PRO tool developed to assess the frequency, severity, and duration of COPD exacerbations (Jones et al. 2011; Leidy et al. 2011). The tool was developed for daily home administration using a handheld electronic device. Respondents are instructed to complete the diary just before going to bed each evening and answer questions considering their experiences “today.” The daily EXACT-PRO total score has a range of 0 to 100, where higher scores indicate greater severity. Total score changes are used to identify the onset and recovery of exacerbation events as defined by the EXACT-PRO. In identifying the onset and recovery of events, the EXACT-PRO can provide information on event frequency and duration as well as event severity.

[0404] COPD Respiratory Symptom Evaluation (E-RS)

[0405] The E-RS:COPD is an 11-item PRO developed to evaluate the severity of respiratory symptoms in COPD (Leidy et al. 2014a; Leidy et al. 2014b). The E-RS:COPD is a subset of items from the EXACT-PRO. The E-RS:COPD is designed to be obtained as part of the daily EXACT-PRO assessment. Summing responses to the E-RS:COPD items yields a total score in the range of 0 to 40, where higher scores indicate greater severity. In addition to the total score, symptom domain scores can be calculated for dyspnea (5 items; score range: 0 to 17), cough and sputum (3 items; score range: 0 to 11), and chest symptoms (3 items; score range: 0 to 12) by summing item responses within the respective domains. For the total score, higher domain scores indicate greater severity. A decrease of at least 2 points in the individual score of the E-RS:COPD total score is considered meaningful and will be used as the responder definition (Leidy et al. 2014a).

[0406] Dyspnea, Cough, and Sputum Scale (BCSS)

[0407] The BCSS is a 3-item PRO that assesses the severity of dyspnea, cough, and sputum on a scale of 0 to 4 (Leidy et al. 2003a, Leidy et al. 2003b). Item scores are summed to produce a total score, where higher scores indicate more severe symptoms.

[0408] St. George's Respiratory Questionnaire (SGRQ)

[0409] The SGRQ is a 50-item PRO tool developed to measure the health status of participants with obstructive airway disease (Jones et al. 1991, Jones and Forde 2009). The questionnaire is divided into two parts: Part 1 consists of 8 items regarding the severity of respiratory symptoms in the previous 4 weeks; Part 2 consists of 42 items related to the daily activities and psychosocial impact of the individual's respiratory condition. The SGRQ generates a total score and three component scores (symptoms, activities, and impact). The total score indicates the impact of the disease on overall health status. This total score is expressed as a percentage of total impairment, where 100 represents the worst possible health status and 0 indicates the best possible health status. Similarly, the component scores range from 0 to 100, where higher scores indicate greater impairment. A reduction of at least 4 points in the individual score of the SGRQ total score is considered meaningful and will be used to support the responder definition. Specific details of the scoring algorithm are provided by the developers in the user manual (Jones and Forde 2009).

[0410] Chronic Obstructive Pulmonary Disease Assessment Test (CAT)

[0411] The CAT is an 8-item PRO developed to measure the impact of COPD on health status (Jones et al. 2009, Kon et al. 2014). The tool uses a semantic differential 6-point response scale, which is defined by contrasting adjectives to capture the impact of COPD. The content includes items related to cough, sputum, chest tightness, breathlessness when climbing hills / stairs, limitation of activities at home, confidence when away from home, sleep, and energy. The response range for each item is from 0 to 5, where 0 has the least impact on health status and 5 has the greatest impact on health status. The CAT total score is the sum of the item responses, with a score range from 0 to 40, and higher scores indicate a greater impact of COPD on health status. A reduction of at least 2 points in the individual score of the CAT total score is considered meaningful and will be used to support the responder definition (Kon et al. 2014).

[0412] Five-level Five-dimensional Health Scale (EQ-5D-5L)

[0413] The EQ-5D-5L is a five-level standardized tool used as a measure of health outcomes. Applicable to a wide range of health conditions and treatments, it provides a simple descriptive overview and a single index value of the health status. The EQ-5D-5L consists of 2 assessments (the descriptive system and the Visual Analogue Scale (VAS)). The descriptive system includes the following 5 dimensions: mobility, self-care, usual activities, pain / discomfort, and anxiety / depression. Each dimension has 5 severity levels: no problems, slight problems, moderate problems, severe problems, and extreme problems. The EQ-5D-5L index score can be calculated based on the participant's responses to the 5 dimensions and using the appropriate value set, which will be further described in the Statistical Analysis Plan (SAP).

[0414] The EQ-5D VAS records the respondent's self-assessed health status on a vertical scale of 0 to 100 over 20 cm, with the endpoints marked "The best health you can imagine" and "The worst health you can imagine", and higher scores corresponding to better health states. This information is used as a quantitative measure of the health status judged by a single respondent.

[0415] Work Productivity and Activity Impairment Questionnaire (WPAI-GH)

[0416] The WPAI-GH (version 2.0) is a self-administered tool that includes 6 questions related to absenteeism, presenteeism (reduced productivity at work), overall work productivity loss (absenteeism plus presenteeism), and activity impairment. This validated tool captures data for the past 7 days. The WPAI-GH results are scored as a percentage of impairment, with higher percentages indicating greater impairment and lower productivity (Reilly et al. 1993).

[0417] Patient Global Impression of Severity (PGIS)

[0418] The PGIS is a single item designed to capture the participant's perception of the overall severity of COPD symptoms at completion using a 6-point scale (0 - asymptomatic to 5 - very severe).

[0419] Patient Global Impression of Change (PGIC)

[0420] The PGIC is a single item designed to capture the participant's perception of the change in overall COPD symptoms after the first dose of IP using a 7-point scale (1 - much better to 7 - much worse).

[0421] Composite Endpoint of COPD Exacerbation (COPDCompEx)

[0422] The composite endpoint of COPD exacerbation (COPDCompEx) is an endpoint based on the combination of exacerbations with events defined by daily PRO and study termination (Vogelmeier et al. 2020). The definitions of the components of COPDCompEx are as follows:

[0423] Exacerbation: A situation that results in one or more of the following: hospitalization, emergency department visit, treatment with systemic corticosteroids, or treatment with antibiotics.

[0424] Daily PRO event: Defined by threshold and slope criteria, using the following PRO variables: a single item of BCSS and rescue medication use.

[0425] Statistical Considerations

[0426] Primary endpoint

[0427] The primary endpoint is the annualized moderate to severe exacerbation rate. This will first be evaluated in the primary population (ever-smokers) for each dose of MEDI3506 relative to placebo, and then in the entire population of current and ever-smokers.

[0428] The negative binomial model will be used to compare the moderate to severe exacerbation rate in each MEDI3506 dose regimen group with the moderate to severe exacerbation rate in the placebo group. The response variable in the model will be the number of COPD exacerbations experienced by the participants during the fully double-blind 52-week treatment period. The model will include covariates of treatment group, region, maintenance inhaled therapy (triple or double), and the number of exacerbations in the previous year (1 versus ≥2) as a categorical factor, as well as the predicted post-BD FEV1% and log-transformed screening blood eosinophil count at screening as continuous covariates. The logarithm of the corresponding follow-up time of the participants will be used as the offset variable in the model. For the analysis in the entire population, smoking status will also be included as a covariate.

[0429] The estimated treatment effect (i.e., the rate ratio of each dose of MEDI3506 relative to placebo), the corresponding 95% confidence interval (CI), and the two-sided p-value of the rate ratio will be presented. Additionally, the model-adjusted exacerbation rate in each treatment group will be presented.

[0430] Systemic corticosteroid or antibiotic courses initiated within 7 days after completion of a previous course will be considered treatment for the same single exacerbation.

[0431] Secondary endpoints

[0432] The analysis of all secondary endpoints will be conducted in the primary population (ever-smokers). Similar analyses will be conducted in the entire population (ever-smokers and current smokers).

[0433] Time to First Moderate or Severe COPD Exacerbation

[0434] The key secondary efficacy variable with the time to first moderate or severe COPD exacerbation as the primary objective was analyzed to explore the extent to which treatment with each dose of MEDI3506 delays the time to first exacerbation compared with placebo. The Cox proportional hazards model was fitted to treatment group, region, covariates for maintenance inhaled therapy, number of exacerbations in the previous year, predicted post - bronchodilator FEV1% at screening, and log - transformed screening blood eosinophil count. Hazard ratios, 95% CIs, and p - values, as well as the proportion of participants with events, will be reported.

[0435] St. George's Respiratory Questionnaire

[0436] The change from baseline in the total SGRQ score over 52 weeks will be compared between MEDI3506 and placebo using a repeated - measures linear model. The dependent variable will be the change from baseline in the total SGRQ score at protocol - specified visits after baseline (up to the week 52 visit). Treatment, visit, treatment - by - visit interaction, region, maintenance inhaled therapy, and number of exacerbations in the previous year will be fitted as categorical covariates along with the baseline SGRQ total score, predicted post - bronchodilator FEV1%, and log - transformed screening blood eosinophil count as continuous covariates. An unstructured variance - covariance matrix will be used to model the correlations within participants. Contrasts will be used to generate treatment - effect estimates at each visit (including weeks 24 and 52) and over 52 weeks. This will be reported along with two - sided 95% CIs and p - values.

[0437] A responder analysis for the total SGRQ score will be performed at week 52. Responders will be defined as participants with an improvement (decrease) of ≥4.0 points relative to baseline. Participants who discontinue the study for any reason or have missing data at week 52 will be classified as non - responders. Logistic regression will be applied to compare treatment groups by treatment, region, maintenance inhaled therapy, and number of exacerbations in the previous year as categorical covariates and predicted post - bronchodilator FEV1%, log - transformed screening blood eosinophil count, and baseline SGRQ total score as continuous covariates. P - values, odds ratios, and 95% CIs will be generated for each treatment comparison.

[0438] Change from Baseline in E-RS: COPD Total Score

[0439] The change from baseline in the total E - RS:COPD score over 52 weeks will be analyzed using a model similar to that for the change from baseline in the total SGRQ score. In a manner similar to the SGRQ responder analysis, a responder analysis for the total E - RS:COPD score will also be performed at week 52 based on an improvement (decrease) from baseline of ≥2 points.

[0440] Change from Baseline in Pre-dose FEV1

[0441] The change from baseline in pre-dose / BD pre-FEV1 will be analyzed using a repeated measures analysis model similar to that for the change from baseline in SGRQ scores, but analyzed by treatment, visit, treatment-by-visit interaction, region, maintenance inhaled therapy, and the number of exacerbations in the previous year fit as a categorical covariate, and baseline FEV1 and log-screening blood eosinophil count as continuous covariates. Contrasts will be used to generate treatment effect estimates at each visit (including week 24 and week 52) and over 52 weeks. This will be reported together with two-sided 95% CIs and p-values.

[0442] Other Secondary Endpoints

[0443] The time to first severe exacerbation and the annualized severe exacerbation rate will be analyzed in a manner similar to that for moderate or severe exacerbations as described above.

[0444] A method similar to that for the SGRQ total score will be used to analyze the change from baseline in the CAT total score and the proportion of participants with a ≥2-point decrease (improvement) in the CAT total score.

[0445] References

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[0510]

Claims

1. A method of treating a subject with chronic obstructive pulmonary disease (COPD), the method comprising administering a therapeutically effective amount of an anti-IL-33 antibody or an antibody variant thereof at an interval of once every 4 weeks (Q4W) or once every 8 weeks (Q8W), in a dose ranging from about 300 mg to about 600 mg, wherein the anti-IL-33 antibody comprises: a. A heavy chain variable region that comprises an HCDR1 having the sequence listed in SEQ ID NO:1, a VHCDR2 having the sequence of SEQ ID NO:2, and a VHCDR3 having the sequence of SEQ ID NO:3; and b. A light chain variable region that comprises a VLCDR1 having the sequence of SEQ ID NO:5, a VLCDR2 having the sequence of SEQ ID NO:6, and a VLCDR3 having the sequence of SEQ ID NO:

7.

2. A method of treating a subject with COPD, the method comprising administering a therapeutically effective amount of an anti-IL-33 antibody or an antibody variant thereof in a dose effective to achieve at least 80% inhibition of IL-33 in the lung or epithelial lining fluid (ELF), wherein the anti-IL-33 antibody comprises: a. A heavy chain variable region that comprises an HCDR1 having the sequence listed in SEQ ID NO:1, a VHCDR2 having the sequence of SEQ ID NO:2, and a VHCDR3 having the sequence of SEQ ID NO:3; and b. A light chain variable region that comprises a VLCDR1 having the sequence of SEQ ID NO:5, a VLCDR2 having the sequence of SEQ ID NO:6, and a VLCDR3 having the sequence of SEQ ID NO:

7.

3. The method according to claim 2, wherein the dose is effective to achieve at least about 90%, optionally at least 95%, inhibition of IL-33 in the lung.

4. The method according to claim 2 or 3, wherein the dose is from about 300 mg to about 600 mg, at an interval of once every 4 weeks (Q4W) or once every 8 weeks (Q8W).

5. The method according to any one of the preceding claims, wherein the dose is about 300 mg Q8W.

6. The method according to any one of claims 1 to 4, wherein the dose is about 300 mg Q4W.

7. The method according to any one of claims 1 to 4, wherein the dose is about 600 mg Q4W.

8. The method according to any one of the preceding claims, wherein the COPD is associated with chronic bronchitis in the subject.

9. The method according to any one of the preceding claims, wherein the COPD is moderate COPD, moderate to severe COPD, or severe COPD.

10. The method according to any one of the preceding claims, wherein the subject has a history of at least one, optionally at least two, moderate, or at least one severe, acute exacerbation of COPD (aeCOPD) within 12 months prior to treatment.

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