Treatment of chronic obstructive pulmonary disease with an Anti-interleukin-33 antibody

Abstract

This disclosure relates to a method for treating COPD, specifically by administering an anti-IL-33 antibody or an antibody variant thereof in a specified dosing regimen.

Description

Technical Field

[0001] This disclosure relates to a method for treating COPD, specifically by administering anti-IL-33 antibodies or antibody variants thereof. Prior Technology

[0002] 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 one second (FEV1) / forced vital capacity (FVC) < 0.70 after bronchodilator [BD]), which is caused by airway and / or alveolar abnormalities, usually resulting from significant exposure to toxic particles or gases, and is influenced by host factors, including lung developmental abnormalities. Severe comorbidities can impact morbidity and mortality (GOLD [Global Initiative for Chronic Obstructive Pulmonary Disease] 2020). COPD is a life-threatening respiratory condition characterized by long-term capacity loss, leading to a significant loss of health-related quality of life (van Manen et al., 2003).

[0003] Chronic obstructive pulmonary disease (COPD) is not entirely reversible, is typically progressive, and is associated with an enhanced chronic inflammatory response in the lungs. A growing body of evidence demonstrates that the overall symptomatic burden has a significant 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).

[0004] COPD exacerbations are symptom worsenings with significant adverse consequences for patients (Wedzicha and Seemungal 2007). Higher exacerbation frequency is associated with accelerated lung function decline, impaired health-related quality of life, and increased mortality (Donaldson et al. 2002, Seemungal et al. 1998, Soler-Cataluna et al. 2005). Furthermore, with the increasing incidence of COPD, exacerbations place a greater burden on the healthcare system, resulting in over 10 million out-of-plan visits annually in the United States (Mannino and Braman 2007). In the United States, the direct cost of COPD treatment exceeds $32 billion annually, with exacerbations estimated to account for 50% to 75% of these costs (Celli et al. 2004, Guarascio et al. 2013, Toy et al. 2010). Exacerbations are also an important outcome measure for COPD; the goal of acute treatment is to accelerate recovery, while long-term maintenance inhalation therapy aims to prevent and reduce their frequency and severity (Ritchie and Wedzicha 2020).

[0005] Despite adequate treatment with optimized maintenance inhalation therapy, approximately 30% to 40% of patients continue to experience moderate to 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); therefore, a significant unmet medical need remains. Summary of the Invention

[0006] This disclosure provides methods for treating COPD. The methods disclosed herein include administering anti-IL-33 antibodies or antibody variants thereof.

[0007] Interleukin-33 is elevated 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 may disrupt the circulation of inflammatory structures damaged in the lungs of patients with COPD, thereby providing therapeutic benefits to patients with COPD.

[0008] In one aspect, this disclosure provides a method for 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 doses 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, 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.

[0009] On the other hand, this disclosure provides a method for 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 a 4-week (Q4W) interval, the dose being approximately 150 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.

[0010] On the other hand, this disclosure provides a method for treating a subject with COPD, the method comprising administering a therapeutically effective amount of an anti-IL-33 antibody or an antibody variant thereof at a dose that effectively achieves at least 80% IL-33 inhibition in the lung or epithelial cell lining fluid (ELF), 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.

[0011] In some cases, this dose is effective in achieving at least approximately 90% IL-33 inhibition in the lungs, and at least 95% as needed.

[0012] In some cases, the dose is approximately 300 mg to approximately 600 mg, administered every 4 weeks (Q4W) or every 8 weeks (Q8W). In some cases, the dose is approximately 300 mg Q8W. In some cases, the dose is approximately 300 mg Q4W. In some cases, the dose is approximately 150 mg Q4W.

[0013] In some cases, COPD was associated with chronic bronchitis in the subjects.

[0014] In some cases, the COPD is moderate COPD, moderate to severe COPD, or severe COPD.

[0015] In some cases, subjects awaiting treatment have a history of at least one, and if necessary, at least two, moderate or at least one severe acute exacerbation of COPD (aeCOPD) within the 12 months prior to treatment.

[0016] In some cases, prior to treatment, the subject's forced expiratory volume in one second (FEV1) to forced vital capacity (FVC) ratio (post-BD FEV1 / FVC) was less than (<) 0.70. In some cases, prior to treatment, the subject's post-BD FEV1 was > 20% of the predicted normal value.

[0017] 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.

[0018] In some cases, the patient awaiting treatment is receiving COPD inhaled maintenance therapy, including long-acting β2 agonists (LABA), long-acting muscarinic receptor antagonists (LAMA), and / or inhaled corticosteroids (ICS). In some cases, this inhaled maintenance therapy includes LABA and LAMA, ICS and LABA, or ICS, LABA, and LAMA.

[0019] In some cases, the anti-IL-33 antibody or its antibody variants are selected from: human antibodies, humanized antibodies, chimeric antibodies, monoclonal antibodies, recombinant antibodies, antigen-binding antibody fragments, single-chain antibodies, monomeric antibodies, biantibodies, triantibodies, tetraantibodies, Fab fragments, IgG1 antibodies, IgG2 antibodies, IgG3 antibodies, and IgG4 antibodies.

[0020] In some cases, the anti-IL-33 antibody or its antibody variant IgG1.

[0021] In some cases, the anti-IL-33 antibody or its antibody variants are human antibodies.

[0022] In some cases, the anti-IL-33 antibody or its antibody variants contain a VH domain having at least 95%, 90%, or 85% identity with the sequence listed in SEQ ID NO:4 and a VL domain having at least 95%, 90%, or 85% identity with the sequence listed in SEQ ID NO:8.

[0023] In some cases, the anti-IL-33 antibody contains a VH domain sequence as listed in SEQ ID NO:4 and a VL domain sequence as listed in SEQ ID NO:8.

[0024] In some cases, the anti-IL-33 antibody contains a light chain sequence as listed in SEQ ID NO:9 and a heavy chain sequence as listed in SEQ ID NO:10.

[0025] In some cases, this anti-IL-33 antibody variant has the same pharmacokinetic (pK) characteristics in humans as 33_670087_7B (MEDI3506 / tozolamizumab).

[0026] In some cases, this anti-IL-33 anti-system is tozolatumab.

[0027] In some cases, the throw is a subcutaneous throw.

[0028] On the other hand, this disclosure provides a method for improving biomarkers 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), in 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. The biomarkers were selected from: annualized moderate to severe COPD exacerbation rate, time to first moderate to severe COPD exacerbation, FEV1, forced expiratory volume in one second (FEV1), FEV1 / FVC ratio (FEV1 / FVC), or BCSS score, COPD assessment test (CAT) score, and St. George's Respiratory Questionnaire (SGRQ) score.

[0029] 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.

[0030] On the other hand, this disclosure provides a method for reducing the annualized rate of moderate to severe COPD exacerbations in subjects, 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 doses 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, 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.

[0031] On the other hand, this disclosure provides a method for improving pre-bronchodilator FEV1 in subjects 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), in doses 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, 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.

[0032] On the other hand, this disclosure provides a method for improving the E-RS:COPD score of 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), in 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.

[0033] On the other hand, this disclosure provides a method for improving the SGRQ score of subjects 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), in doses 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, 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] On the other hand, this disclosure provides a method for improving the CAT score of subjects 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), in doses 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, 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. Simple Explanation of the Diagram

[0035] [ [picture] [1A] shows the amount of IL-33 / tozorakimab complex measured in the serum of healthy participants from Part I of NCT03096795.

[0036] [ [picture] [1B] shows the amount of IL-33 / sST2 complex measured in the serum of healthy participants from Part I of NCT03096795.

[0037] [ [picture] [1C] shows the amount of IL-33 / tozolamib complex measured in the serum of participants with COPD from Part II of NCT03096795.

[0038] [ [picture] [1D] shows the amount of IL-33 / sST2 complex measured in the serum of participants with COPD from Part II of NCT03096795.

[0039] [ [picture] [2A] shows the nasal mucosal lining fluid levels of free IL-33red plus IL-33red / tozolamib measured on day 29 in a 300 mg MAD series.

[0040] [ [picture] [2B] shows the level of free IL-33 red in the nasal mucosal lining measured on day 29 in a 300 mg MAD series.

[0041] [ [picture] [2C] shows the level of free IL-33ox in nasal mucosal fluid measured on day 29 in a 300 mg MAD series.

[0042] [ [picture] [3] shows that tozolatumab inhibits isolated IL-33 attack from whole blood of healthy participants.

[0043] [ [picture] [4A] shows serum IL-5 levels in participants in the 300 mg MAD cohort at days 1, 14, and 28 (placebo, n = 6; tozolatumab (n = 6)). The figure shows mean ± SEM. A mixed-effects longitudinal model was used to generate p-values ​​to compare the biomarker trajectories between tozolatumab and placebo. (p = 0.0037)

[0044] [ [picture] [4B] shows serum IL-13 levels in participants in the 300 mg MAD cohort at days 1, 14, and 28 (placebo, n = 6; tozolatumab (n = 6)). The figure shows mean ± SEM. A mixed-effects longitudinal model was used to generate p-values ​​to compare the biomarker trajectories between tozolatumab and placebo. (p = 0.034)

[0045] [ [picture] [4C] shows serum eosinophil levels in participants in the 300 mg MAD series on days 1, 14, and 28 (placebo, n = 6; tozolatumab (n = 6)). The figure shows mean ± SEM. A mixed-effects longitudinal model was used to generate p-values ​​to compare the trajectories of biomarkers between tozolatumab and placebo. (p = 0.0023)

[0046] [ [picture] [5] demonstrated that Alternaria alternata induces rapid IL-33 release in bronchoalveolar lavage fluid (BALF) of humanized IL-33 mice.

[0047] [ [picture] [6] This demonstrates the inhibition of ALT-induced BALF IL-5 by tozolaziumab in humanized IL-33 mice. The test substance was administered intranasally 24 hours before ALT challenge. BALF was harvested 24 hours after ALT challenge, and the presence of IL-5 was analyzed. The significance of the test substance was determined using a one-way ANOVA with Bonfranné multiple comparisons test. ***p < 0.001, **p < 0.01 (n = 4)

[0048] [ [picture] [7A]] illustrates the repair of scratch wounds on normal human bronchial epithelial cells after treatment with wild-type IL-33 (IL-33), oxIL-33, and oxIL-33+ anti-ST2 antibodies. []

[0049] [ [picture] [7B] shows the quantification of wound closure percentage as described in Figure 3A for scratch wound determination.

[0050] [ [picture] [8] showed that scratch wound lesions were also observed in bronchial epithelial cells obtained from COPD subjects.

[0051] [ [picture] [9] shows scratch closure % in A549 cells with increased concentrations of tozolatumab and anti-TSLP antibody.

[0052] [ [picture]

[10] Description of the PK / PD target binding model

[0053] [ [picture]

[11] shows the predicted systemic concentrations of tozolatumab from the Ph1 dose series relative to the observed systemic concentrations of tozolatumab.

[0054] [ [picture]

[12] shows the predicted values ​​of tozolatumab:IL-33 complex formulations from the Ph1 dose series relative to the observed tozolatumab:IL-33 complex formulations.

[0055] [ [picture]

[13] shows the predicted reduction in IL-33:sST2 complex from the Ph1 dose series relative to the observed reduction in IL-33:sST2 complex.

[0056] [ [picture]

[14] shows the dose-response prediction of IL-33 inhibition by inhibition of the IL33 / sST2 complex in blood (Q2W - top row; Q4W - middle row; Q6W - bottom row)

[0057] [ [picture]

[15] shows the predicted IL-33 inhibition in the lungs at the troughs produced by tozolaziamib (Q4W - top row; Q8W - bottom row). []

[0058] [ [picture]

[16] shows the predicted serum concentrations of tozolatumab based on 300 mg Q4W (ascending) and 300 mg Q8W (descending). The serum concentrations required for 60%, 80%, and 90% as identified by the spp. mouse model are indicated by dashed lines. []

[0059] [ [picture]

[17] Serum concentrations of tozolatumab predicted based on 300 mg Q4W (ascending) and 150 mg Q4W (descending) are shown. The serum concentration thresholds for the response in the scratch wound closure assay are shown as dashed lines. []

[0060] [ [picture]

[18] The predicted and observed tozolatumab system concentrations in the Ph1 dose series are also shown.

[0061] [ [picture]

[19] also shows a comparison between the predicted and observed reductions in the IL-33:sST2 complex in the Ph1 dose series. Implementation

[0062] The terms "about" or "approximately" mean an acceptable error for a particular value as determined by one skilled in the art, depending in part on how the value is measured or determined. In some embodiments, the terms "about" or "approximately" mean within 1, 2, 3, or 4 standard deviations. In some embodiments, the terms "about" or "approximately" mean 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 value in a series of two or more values, it should be understood that the term "about" or "approximately" applies to each value in the series. [, COPD , ] [, treatment , ] [, , ]

[0063] Chronic obstructive pulmonary disease (COPD) is a chronic inflammatory lung disease that obstructs airflow in the lungs. Symptoms include shortness of breath, cough, mucus production (sputum), and wheezing.

[0064] COPD is characterized by persistent respiratory symptoms and airflow limitation, as reported by airway vital capacity measurements, preferably post-bronchodilator (BD) airway vital capacity measurements. As used herein, "post-bronchodilator (BD) airway vital capacity measurements" refers to airway vital capacity measurements performed after administration of a bronchodilator (typically via inhaler or nebulizer). In some embodiments, the bronchodilator is selected from salbutamol or salbutamol. BD airway vital capacity measurements can be expressed as forced expiratory volume in one second (FEV1) or forced vital capacity (FVC).

[0065] This disclosure provides information on the treatment of COPD. In some cases, the COPD is moderate to severe. Moderate to severe COPD is typically characterized by a subject's forced expiratory volume in one second (FEV1) after BD being < 80% of the predicted normal value (i.e., the predicted normal value for healthy individuals). In some cases, the subject's FEV1 after BD is < 80%, < 75%, < 70%, < 65%, < 60%, < 55%, < 50%, < 45%, < 40%, or < 35% of the predicted normal value. In some cases, the subject's FEV1 after BD is < 70% and > 30% of the predicted normal value. In some cases, the subjects' post-BD FEV1 was < 80% and > 30% of the predicted normal value, < 75% and > 30%, < 70% and > 30%, < 65% and > 30%, < 60% and > 30%, < 55% and > 30% of the predicted normal value, < 50% and > 30% of the predicted normal value, < 45% and > 30% of the predicted normal value, and < 40% and > 30% of the predicted normal value. In some cases, the subject's post-BD FEV1 was <80% and >35% of the predicted normal, <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%. In some cases, the subject's post-BD FEV1 was <60% and >40% of the predicted normal, <55% and >40%, <50% and >40%, or <45% and >40%.

[0066] In some cases, the subject's post-BD FEV1 was >20% of the predicted normal value. In some cases, the subject's post-BD FEV1 was >21%, >22%, >23%, >24%, >25%, >26%, >27%, >28%, >29%, or >30% of the predicted normal value. In some cases, the subject's post-BD FEV1 was >30% of the predicted normal value.

[0067] In some cases, COPD is characterized by a post-BD FEV1 / FVC ratio of < 0.70, < 0.65, < 0.60, < 0.55, < 0.50, < 0.45, < 0.40, < 0.35, or < 0.30. In other cases, COPD is characterized by a post-BD FEV1 / FVC ratio of < 0.70.

[0068] COPD is a chronic condition whose severity can fluctuate. Therefore, individuals with COPD may experience one or more acute exacerbations of COPD (AECOPD, also referred to as "COPD exacerbations" in this article), which may be separated by periods of relatively fewer symptoms.

[0069] As used herein, "AECOPD" or "aeCOPD" refers to a change in a subject's common COPD symptoms that lasts for two or more days, exceeds the normal daily variation, is acute at the time of an flare-up, and may require a change in routine medication. The change in symptoms may include at least one major or minor COPD symptom from the following list: • Main COPD symptoms: shortness of breath, increased sputum volume, and changes in sputum color Secondary COPD symptoms: cough, wheezing, sore throat, cold symptoms (nasal discharge or congestion), and fever without other cause.

[0070] In some cases, the symptom variation includes at least two COPD symptoms from the list above. In some cases, the symptom variation includes at least one major COPD symptom from the list above. In some cases, the symptom variation includes at least one major COPD symptom and at least one other major or minor symptom from the list above.

[0071] AECOPD can be classified as mild, moderate, or severe. As used herein, "severe AECOPD" refers to a condition that results in COPD-related hospitalization (e.g., hospitalization due to COPD exacerbation or admission to an observation ward, emergency department, or other equivalent healthcare facility for ≥ 24 hours, depending on the country and healthcare system). Severe AECOPD can lead to COPD-related death. "Moderate AECOPD" refers to a condition that does not meet the criteria for "severe" (i.e., hospitalization). Moderate and severe AECOPD result in the use of systemic corticosteroids and / or antibiotics, or a single-dose, stock-loaded dose of corticosteroids. In some cases, AECOPD is confirmed to occur while the subject is receiving 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 criteria for "severe" or "moderate".

[0072] The start date of AECOPD can be the date of hospitalization (for severe AECOPD) or the date of start of systemic corticosteroid or antibiotic treatment (for moderate AECOPD), whichever is earlier, and the end date can be the date of end of systemic corticosteroid or antibiotic treatment or the date of discharge, whichever is later.

[0073] In some cases, the subject to be treated may have a history of at least one episode of moderate or severe AECOPD within 12 months prior to treatment (i.e., before the first dose). In some cases, the subject may have a history of at least one, and as needed, at least two episodes of moderate or severe AECOPD within 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 month prior to treatment (i.e., before the first dose). In some cases, the subject may have a history of at least two episodes of moderate AECOPD within 12 months prior to treatment. In some cases, the subject may have a history of at least two episodes of moderate AECOPD within 52 weeks prior to treatment. In some cases, the subject may have a history of at least one episode of severe AECOPD within 12 months prior to treatment. In some cases, the subject may have a history of at least one episode of severe AECOPD within 52 weeks prior to treatment.

[0074] Another method for 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, Vol. 173, November 2020, 106-175). COPDCompEx is a composite endpoint for COPD exacerbations, combining acute exacerbations with events defined by participants' electronic diaries and PEF. The two types of exacerbations are defined as follows: COPDCompEx defines an exacerbation as one or more of the following: hospitalization, emergency room visit, treatment with OCS, or treatment with antibiotics. Diary events are defined by threshold and slope criteria using the following diary and home spirometry variables: overall symptom score, nocturnal awakenings due to symptoms, use of symptom-relieving medications, and PEF. Advantageously, COPDCompEx events tend to be more frequent and provide diagnostic capability for COPD severity over a shorter time frame compared to AECOPD events as described above.

[0075] In some cases, a subject awaiting treatment may have a history of at least one COPD CompEx event within 12 months prior to treatment (i.e., prior to the first dose). A subject awaiting treatment may have a history of at least one COPD CompEx event within 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 month prior to treatment (i.e., prior to the first dose).

[0076] COPD can also be classified by the shortness of breath, cough, and sputum scale (BCSS) score relative to baseline. As used herein, “baseline”, for any COPD markers disclosed herein (such as BCSS score), means the value of that parameter before or at the time of the patient’s first administration of IL-33 therapy.

[0077] The BCSS is a daily diary of three items assessing the severity of three symptoms (Leidy et al. 2003): shortness of breath, sputum, and cough, each with a 5-point scale. Item scores can be reported as domain scores and summed to produce a total score. In some cases, subjects 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 anti-IL33 antibodies or fragments thereof. In some cases, subjects had a score of 2 or greater, 3 or greater, 4 or greater, or 5 in the cough domain before treatment with anti-IL33 antibodies or fragments thereof. In some implementations, subjects had a score of 2 or greater, 3 or greater, 4 or greater, or 5 in the sputum domain before treatment with anti-IL33 antibodies or fragments thereof. In some cases, the "pre-treatment" BSCC score is the average of daily scores recorded over a 4-week period prior to treatment with anti-IL33 antibodies or fragments thereof as described herein.

[0078] In some cases, COPD is classified using the Chronic Lung Disease Exacerbation Tool - Patient-Reported Outcomes (EXACT-PRO) score. EXACT-PRO is a 14-item ePRO 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 were instructed to complete a diary each night before bedtime and answer questions while reflecting on their experiences "that day." The daily EXACT-PRO total score ranges from 0 to 100, with higher scores indicating greater severity. Changes in the total score were used to identify exacerbation events and recoveries as defined by EXACT-PRO. In identifying exacerbation and recovery events, EXACT-PRO can provide information about the frequency and duration of events, as well as their severity. In some cases, subjects awaiting treatment had an EXACT-PRO score of at least 50, at least 60, at least 70, or at least 80 prior to treatment with an anti-IL33 antibody or fragment thereof as described herein.

[0079] 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 obstructive airway disease. The overall score ranges from 0 to 100. Scores are calculated across three domains: Symptoms, Activities, and Impacts (psycho-social), as well as the total score. Lower scores indicate better quality of life (QoL). Part I ("Symptoms") assesses symptomatology, including the frequency of cough, sputum production, wheezing, and shortness of breath, as well as the duration and frequency of shortness of breath or wheezing episodes. Part II has two components: "Activities" and "Impacts." The "Activities" section addresses activities that cause or limit shortness of breath. The "Impacts" section covers a range of factors, including impact on employment, health management, panic, scarring, need for medication, side effects of prescription therapies, expectations of health, and disruption to daily life. The questionnaire recall period is within the past 4 weeks. The psychological test has demonstrated its reproducibility, reliability, and validity. Sensitivity has been demonstrated in clinical trials. After testing by patients and clinicians, the minimum change of 4 units (“minimum clinically important difference”) was determined to be clinically relevant (Jones COPD 2005 2(1):75-9).

[0080] In some cases, COPD can be categorized using the COPD Assessment Test (CAT) score. The CAT is a questionnaire designed for patients with COPD to measure the impact of the disease on their quality of life. The CAT is an eight-item questionnaire completed by the patient, which assesses the overall impact of COPD (cough, sputum, shortness of breath, chest tightness) on their health. The CAT score ranges from 0 to 40. A higher score indicates a more severe impact of COPD on the subject's life. In some cases, subjects awaiting treatment have a CAT score of at least 10 before starting treatment.

[0081] In some cases, COPD can be classified using E-RS™:COPD, an 11-item ePRO developed to assess the severity of respiratory symptoms in COPD (Leidy et al. 2014a; Leidy et al. 2014b). E-RS™:COPD is a subset of the items from EXACT-PRO. E-RS™:COPD was designed to be obtained as part of the daily EXACT-PRO assessment. The summation of responses to the E-RS™:COPD items yielded a total score ranging from 0 to 40, with higher scores indicating greater severity. In addition to this total score, symptom domain scores can be calculated by summing responses to items within corresponding domains for shortness of breath (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). In some cases, subjects awaiting treatment have an E-RS™:COPD score of at least 20, at least 25, at least 30, or at least 35. In some cases, the subject awaiting treatment has an E-RS™:COPD score of at least 6, at least 7, at least 8, at least 9, at least 10, or 11 in the cough and sputum domain. In some cases, the subject awaiting treatment has an E-RS™:COPD score of at least 7, at least 8, at least 9, at least 10, at least 11, or 12 in the chest symptoms domain. In some cases, the subject awaiting treatment has an E-RS™:COPD score 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 shortness of breath domain.

[0082] In some cases, COPD is associated with chronic bronchitis in subjects. 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 time that lasts longer than 8 weeks, 16 weeks, 32 weeks, or 52 weeks.

[0083] In some cases, the subjects awaiting treatment are current or former smokers. In other cases, the subjects awaiting treatment have a smoking history of 10 or more pack-years. A pack-year is calculated as the average number of cigarettes per day × number of years / 20. For example, 1 pack-year = 20 cigarettes per day for 1 year or 10 cigarettes per day for 2 years.

[0084] In some cases, the subject was a current smoker.

[0085] In some cases, the subject is a former smoker. A "former smoker" can be defined as a subject who is not smoking at the start of treatment and has quit smoking for at least 6 months prior to the start of treatment and intends to quit permanently.

[0086] In some embodiments, the subject has a history of inadequate response or intolerance to other pharmacological treatments for COPD, such as inhaled corticosteroids (ICS), long-acting beta-agonists (LABA), and / or long-acting muscarinic antagonists (LAMA), or such other pharmacological treatments for COPD may otherwise be medically undesirable. As used herein, "inadequate response" is defined as the administration of said treatment not resulting in short-term and / or long-term improvement of one or more symptoms of COPD as described herein. Alternatively, inadequate response may result in a relapse of the condition to a moderate to severe level after the cessation of said treatment. In some embodiments, COPD has been previously treated with ICS and LABA, ICS and LAMA, LABA and LAMA, or ICS, LABA and LAMA, and has shown no response to said treatment. COPD may be classified as inadequate response if, despite treatment, the COPD remains moderate to severe, or if the subject experiences a moderate or severe AECOPD event during or after treatment.

[0087] In some cases, the subject awaiting treatment 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 the anti-IL-33 antibody or its antibody variant as described herein. In some cases, this course of treatment begins at least 3 months before the first dose of the anti-IL-33 antibody or its antibody variant as described herein and may last at least 3 months. In some cases, this course of treatment begins at least 3 months before the first dose of the anti-IL-33 antibody or its antibody variant as described herein and is in progress at the start of treatment with the anti-IL-33 antibody or its antibody variant and continues during the treatment window.

[0088] As used herein, "inhaled corticosteroids (ICS)" refers to corticosteroid therapy for the treatment of COPD administered via a nebulizer, inhaler, or sprayer. ICS may be selected from fluticasone propionate, budesonide, and / or beclomethasone dipropionate.

[0089] As used herein, "long-acting β-adrenergic receptor agonists (LABAs)" refers to any β-adrenergic receptor agonist with a duration of action of approximately 12 hours or longer. This contrasts with short-acting β-agonists (SABAs) such as salbutamol, which have a duration of action of approximately 4-6 hours. Exemplary LABAs include amoterol, bambuterol, clenbuterol, formoterol, salmeterol, and proprolol. LABAs can also be "ultra-LABAs" with a duration of action of 24 hours or longer, such as indacaterol, olodaterol, or vilanterol. LABAs can be administered by any suitable route, such as by using a nebulizer, inhaler, or spray.

[0090] As used herein, long-acting muscarinic antagonists (LAMAs) are anticholinergic agents that block the activity of muscarinic acetylcholine receptors. Exemplary LAMAs include tiotropium bromide, glycopyrronium bromide, and adecyl bromide. LAMAs can be administered by any suitable route, such as by using a nebulizer, inhaler, or sprayer.

[0091] Subjects who are “intolerant” to treatment are those for whom the treatment causes one or more side effects that make continued treatment undesirable. For example, an allergic reaction to treatment can indicate intolerance.

[0092] In some cases, the COPD patient awaiting treatment is of moderate to severe severity. In some cases, moderate to severe COPD is characterized by: • Associated with chronic bronchitis in the subjects. • A history of at least one, and if necessary, at least two moderate or at least one severe acute exacerbation of COPD within the 12 months prior to treatment. • The ratio of forced expiratory volume in one second (FEV1) to forced vital capacity (FVC) after bronchodilator administration (FEV1 / FVC) < 0.70, and / or FEV1 after bronchodilator administration > 30% and < 80% of the predicted normal value. • Average BCSS score >2 in the cough domain and / or >2 in the sputum domain.

[0093] In some cases, COPD requiring treatment is characterized by: • A history of at least two moderate or at least one severe acute exacerbation of COPD within 52 weeks prior to treatment. • The ratio of forced expiratory volume in one second (FEV1) to forced vital capacity (FVC) after bronchodilator administration (FEV1 / FVC after BD) < 0.70 • After BD, FEV1 is > 20% of the predicted normal value. • Prior to treatment, the CAT score was greater than or equal to 10, and each of the sputum and cough items was greater than or equal to 2.

[0094] In some cases, subjects had a blood eosinophil count of approximately 300 cells / µl or less prior to treatment. [, investment plan , ] [, , ]

[0095] This disclosure relates to dosing regimens for anti-IL-33 antibodies or antibody variants that are particularly effective in the treatment of COPD. The dosing regimen consists of one or more doses of controlled size administered throughout the entire therapeutic window. In cases where more than one dose is available, the doses are separated by dosing intervals. The anti-IL-33 antibody or antibody variant is administered at a therapeutically effective amount. As used herein, an "effective amount" or "therapeutically effective amount" of an agent containing an IL-33 antibody (e.g., a pharmaceutical formulation) means the amount that effectively achieves the desired therapeutic or preventative outcome at the required dose and for the required duration.

[0096] The dosage of anti-IL-33 antibodies or antibody variants thereof can be expressed as the weight of the anti-IL-33 antibody or antibody variant. In some cases, anti-IL-33 antibodies or antibody variants thereof are administered at doses 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.

[0097] 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, so that the 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 mean doses administered simultaneously or sequentially, without intervals or separated only by a minimum time interval (e.g., less than 1 hour, less than 30 minutes, less than 15 minutes, less than 5 minutes).

[0098] In some cases, anti-IL-33 antibodies or antibody variants thereof are administered at doses 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.

[0099] In some cases, the dose is 300 mg. In some cases, the anti-IL-33 antibody or its antibody variant is formulated for subcutaneous injection at 150 mg / mL, so that the 300 mg dose is administered as a 2 mL treatment. In some cases, the 300 mg dose of the anti-IL-33 antibody or its antibody variant may be administered as two parallel 150 mg doses. As used herein, "parallel" doses mean doses administered simultaneously or sequentially, without intervals or separated only by a minimum time interval (e.g., less than 1 hour, less than 30 minutes, less than 15 minutes, less than 5 minutes).

[0100] In some cases, the dose is 150 mg. In some cases, anti-IL-33 antibody or its antibody variant is formulated for subcutaneous injection at 150 mg / mL, so that a dose of 150 mg is administered as 1 mL of treatment.

[0101] The dosage of anti-IL-33 antibodies or their variants can be expressed as the amount of active compound manipulated to provide a specific level of plasma drug concentration, based on the plasma drug concentration delivered by the dose. Those skilled in the art can control plasma concentrations in subjects by varying the amount of antibody or variant administered, bioavailability, or time / frequency. Because plasma concentrations vary over time according to drug uptake and clearance, they can be expressed in various standardized ways—such as maximum, minimum (trough), or over time.

[0102] In some cases, the dosage is selected to provide a Cmax,ss (the 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, Cmax,ss refers to the maximum concentration observed during the dosing period. In this context, "dosing period" refers to the time between two consecutive doses.

[0103] Examples show that a 300 mg Q4W or Q8W dosing regimen of MEDI3506 is predicted to achieve the serum concentrations required to inhibit both the redIL-33:ST2 signaling axis and the oxIL-33:RAGE / EGFR signaling axis, thus achieving sustained dual-pathway inhibition (Figures 16 and 17). Serum concentrations of MEDI3506 from anti-drug antibody reagents can be measured using suitable assays (and thus used to determine Cmax.ss) to capture and detect MEDI3506 from biological samples (e.g., blood). In some cases, the assay can use an anti-IgG1 capture mAb and a stabilized MEDI3506 antigen labeled with a detectable biomarker. The detectable biomarker can be quantified to determine the concentration of MEDI3506. In some cases, the MEDI3506 antigen (IL-33) can be stabilized in a reductive form, for example, by mutating one or more cysteine ​​residues to serine to prevent redIL-33 from converting to its oxidized form (oxIL-33) via disulfide bond formation. The assay and platform for detecting serum biomarkers are well-known to those familiar with this technology.

[0104] In some cases, a dose is selected to provide 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, between about 15 and about 20 µg / mL, or about 18.6 µg / mL.

[0105] In some cases, anti-IL-33 antibodies or antibody variants thereof are selected to provide a dose dosing with an area under the plasma concentration-time curve over the entire dosing period (AUC).

[0106] In some cases, the dosage is selected to provide an AUC between about 400 and about 800 µg / mL, between about 500 and about 750 µg / mL, between about 600 and about 700 µg / mL, between about 600 and about 650 µg / mL, between about 600 and about 620 µg / mL, between about 610 and about 620 µg / mL, or about 616 µg / mL during the dosing period.

[0107] In some cases, the dosage is selected to provide an AUC of about 200 to about 515 µg / mL, about 250 to about 500 µg / mL, about 300 to about 450 µg / mL, about 300 to about 350 µg / mL, or about 323 µg / mL over the period of administration.

[0108] In some cases, the dosage is selected to provide an AUC of about 100 to about 300 µg / mL, about 100 to about 250 µg / mL, about 100 to about 200 µg / mL, about 150 to about 200 µg / mL, or about 161.5 µg / mL over the period of administration.

[0109] The administration of anti-IL-33 antibody or its antibody variants is performed as multiple doses separated by dosing intervals. In some cases, the dosing intervals are 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).

[0110] In some cases, a dose may be administered, for example, as two or more sub-dose over multiple days. As used herein, a "sub-dose" is a portion of a dose of therapeutic agent such that the total amount of therapeutic agent administered in sub-dose is equal to the total dose. Any portion may be used, such that two, three, four, five, or more sub-dose constitute a single dose. In some cases, a dose may be administered as two or more sub-dose separated by time periods of 1, 2, 3, 4, 5, or 6 days. In some cases, a dose may be administered as two or more sub-dose separated by time periods of 1, 2, or 3 weeks. Sub-dose may be administered consecutively for two, three, four, or more days. Sub-dose constituting a dose may be equal in size or different in size, as long as their total amount equals the dose.

[0111] Therefore, as used herein, a 600 mg dose with a 4-week dosing window (Q4W) can be replaced by a 150 mg dose once weekly (Q1W), a 300 mg dose once every two weeks (Q2W), or a 450 mg dose once every three weeks (Q3W), all of which provide an equivalent dosing regimen of 600 mg once every four weeks. A 300 mg dose with a 4-week dosing window (Q4W) can be replaced by a 150 mg dose once every two weeks (Q2W) or a 75 mg dose once weekly (Q1W). A 300 mg dose with an 8-week dosing window (Q8W) can be replaced by a 150 mg dose once every four weeks (Q4W), a 75 mg dose once every two weeks (Q2W), or a 37.5 mg dose once weekly (Q1W).

[0112] When the dosing interval is expressed as weeks, a certain margin of error is allowed, such that a week can be expressed as 7 days ± 1 day. In some embodiments, a week can be expressed 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 for each 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.

[0113] In some cases, anti-IL-33 antibodies or antibody variants thereof are administered during a “treatment window,” as used herein, meaning the period from the administration of the first dose until the administration of the final dose of the anti-IL-33 antibody or antibody variant thereof. The date of administration of the first dose is referred to as “day 1” of “week 0,” week 1 begins 7 days later, week 2 begins 7 days later thereafter, and so on. In some embodiments, the treatment window length is 12 weeks (i.e., running from week 0 to week 12). In some embodiments, the treatment window length is 16 weeks (i.e., running from week 0 to week 15), and the dosing interval is 4 weeks, resulting in a total of 4 doses 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 the dose is administered on day 1 (week 0), day 29 ± 4 (week 4), day 57 ± 4 (week 8), and day 85 ± 4 (week 12).

[0114] 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.

[0115] In some cases, anti-IL-33 antibodies or their variants are administered at approximately 300 mg Q4W. Examples show that administration of MEDI3506 300 mg Q4W is predicted to achieve approximately 94% consumption (target binding) in the lungs. This level of target binding is potentially greater than that achieved by the anti-IL-33 antibody itepekimab, which recently led to a significant reduction in COPD exacerbations and a significant improvement in FEV1 in former smokers in a phase II study of COPD (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) is reported as 30 days in US 2021 / 0000949 - see

[0411] therein).

[0116] In some cases, anti-IL-33 antibodies or their variants are administered at approximately 300 mg Q8W. Examples show that administration of MEDI3506 300 mg Q8W (i.e., twice the dosing window) is predicted to provide approximately 83% IL 33 inhibition at the trough in lung tissue; therefore, it can provide sufficient efficacy in COPD and its dosing frequency is more convenient for patients compared to Q4W.

[0117] Therefore, in some cases, IL-33 antibody or its antibody variants are administered at a dose that achieves at least 80%, 85%, or 90% target binding in the lungs. In some cases, this dose achieves at least 90% target binding in the lungs. In some cases, this dose achieves at least 91%, 92%, 93%, or 94% target binding in the lungs. In some cases, the percentage of target binding is achieved at trough concentrations. [, COPD , ] [, logo , ] [, , ]

[0118] In some cases, the methods disclosed in this paper improve one or more biomarkers of COPD (also referred to as "COPD biomarkers").

[0119] COPD biomarkers include: annualized moderate to severe COPD exacerbation rate, time to first moderate to severe COPD exacerbation, time to first severe COPD exacerbation, FEV1, FVC, E-RS COPD total score, SGRQ score, and CAT score.

[0120] In some cases, an improvement in E-RS COPD score means that the subject's CAT score decreased by more than or equal to 2 compared to baseline ("minimum clinically important difference" or "MCID").

[0121] In some cases, an improvement in CAT score means that the subject's CAT score decreased by more than or equal to 2 compared to baseline ("minimum clinically important difference" or "MCID").

[0122] In some cases, an improvement in SGRQ score means that the subject’s total SGRQ score decreased by more than or equal to 4 compared to baseline (“minimum clinically important difference” or “MCID”).

[0123] In some cases, changes in biomarkers are observed after the treatment window. In some cases, observation is performed immediately after the treatment window. In some cases, observation is performed after an additional time period following the treatment window. This additional time period can be 1, 2, 3, 4, 5, 6, or more days. This additional time period can be 1, 2, 3, 4, or more weeks. This additional time period can be 1, 2, 3, 4, or more months. The additional time period can be the same length as the dosing interval, such that the additional time period follows the final dose and runs until the point where another dose expires. The treatment window plus any additional time period can be referred to as the "intervention window." Some treatment outcomes can be measured after the intervention window, such as changes in FEV1 or FEV1 i / FVC before or after BD.

[0124] In some cases, the additional time period is 4 weeks and the treatment window is 8 weeks, resulting in a total length of 12 weeks for the treatment window plus the additional time period. In some embodiments, the additional time period is 4 weeks and the treatment window is 12 weeks, resulting in a total length of 16 weeks for the treatment window plus the additional time period. In other embodiments, the additional time period is 4 weeks and the treatment window is 24 weeks, resulting in a total length of 28 weeks for the treatment window plus the additional time period.

[0125] Alternatively or additionally, changes in biomarkers can be observed during the treatment window. Biomarkers can be observed at the end of a dosing period, such as the first, second, third, fourth, fifth, sixth, seventh, or other dosing periods. Alternatively, biomarkers can be observed or measured one day after the end of a dosing period, such as the first, second, third, fourth, fifth, sixth, seventh, or other dosing periods. Biomarkers can be observed or measured one day before the end of a dosing period, such as the first, second, third, fourth, fifth, sixth, seventh, or other dosing periods. Biomarkers can be observed two days after the end of a dosing period, such as the first, second, third, fourth, fifth, sixth, seventh, or other dosing periods. Biomarkers can be observed two days before the end of a dosing period, such as the first, second, third, fourth, fifth, sixth, seventh, or other dosing periods. Biomarkers can be observed three days after the end of a dosing period, such as the first, second, third, fourth, fifth, sixth, seventh, or other dosing periods. Biomarkers can be observed three days before the end of a dosing period, such as the first, second, third, fourth, fifth, sixth, seventh, or other dosing periods. Biomarkers can be observed four days after the end of a dosing period, such as the first, second, third, fourth, fifth, sixth, seventh, or other dosing periods. Biomarkers can also be observed four days before the end of a dosing period, such as the first, second, third, fourth, fifth, sixth, seventh, or other dosing periods. In some embodiments, the treatment window is 24 weeks, and changes in symptoms are observed during the 12th week.

[0126] Certain treatment outcomes, such as changes in pre-BD FEV1 or FEV1 i / FVC scores, can be measured at time points of 4, 12, 24, 28, 36, or 52 weeks.

[0127] As described herein, treatment with anti-IL-33 antibodies or variants 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 time periods as defined herein). In some cases, an increase in FEV1 relative to baseline was 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 was observed at weeks 4, 12, 24, 36, or 52. In some cases, the increase in FEV1 was an increase of 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 was an increase to >70%, >75%, or >80% of the predicted normal value.

[0128] In some cases, as described herein, treatment with anti-IL-33 antibodies or their variants results in an increase in FEV1 / FVC relative to baseline. In some cases, the increase in FEV1 / FVC is defined as an increase of 5%, 10%, 15%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, or more than 100% of FEV1 / FVC relative to baseline after BD. In some cases, the increase in FEV1 / FVC is defined as 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 defined as an increase to >0.70. In some cases, the increase in FEV1 / FVC is defined as an increase to >0.75, >0.80, >0.85, >0.90, >0.95, or >0.99.

[0129] In some cases, one or more markers are selected from a decrease in the frequency, duration, or severity of AECOPD relative to baseline, and as needed, a decrease in the frequency, duration, or severity of moderate or severe AECOPD. In some cases, a decrease in the frequency, duration, or severity of AECOPD relative to baseline is observed at weeks 4, 8, 12, 16, 29, 24, 28, 32, 36, 40, 44, 48, or 52. In some cases, a decrease in the frequency, duration, or severity of AECOPD relative to baseline is observed at week 52.

[0130] In some cases, as described herein, treatment with anti-IL-33 antibodies or their variants results in a reduction in the frequency of AECOPD. In some cases, the reduction in AECOPD frequency is defined as 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 reduction in AECOPD frequency occurs within 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 months. In some cases, the reduction in AECOPD frequency occurs within 12 months. In some cases, the reduction in AECOPD frequency is an annual reduction in AECOPD frequency. In some cases, the reduction in AECOPD frequency is a reduction to an average of one AECOPD every 8 weeks, one AECOPD every 16 weeks, one AECOPD every 32 weeks, one AECOPD every 52 weeks, or less than one AECOPD every 52 weeks.

[0131] In some cases, as described herein, treatment with anti-IL-33 antibodies or their variants results in a reduction in the mean duration of AECOPD. In some cases, this reduction in mean duration of AECOPD is defined as a decrease in the mean duration of AECOPD relative to baseline of 5%, 10%, 15%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 95%. In some cases, the reduction in mean duration of AECOPD is defined as a reduction to a mean duration of 24 hours or less.

[0132] In some cases, as described in this article, treatment with anti-IL-33 antibodies or variants thereof results in a reduction in the severity of AECOPD. This reduction in severity can lead to a decrease in the frequency or duration of moderate and / or severe AECOPD relative to baseline, and may be accompanied by an increase in the frequency or duration of mild AECOPD. Conversely, a reduction in severity can lead to a decrease in the frequency or duration of severe AECOPD relative to baseline, and may be accompanied by an increase in the frequency or duration of moderate or mild AECOPD.

[0133] In some cases, one or more symptoms are selected from a decrease in the frequency or duration of COPD CompEx events relative to baseline. In some cases, a decrease in the frequency or duration of COPD CompEx events relative to baseline was observed at weeks 4, 8, 12, 16, 29, 24, 28, 32, 36, 40, 44, 48, or 52.

[0134] In some cases, as described herein, treatment with anti-IL-33 antibodies or variants thereof results in a reduction in the frequency of COPD CompEx events. In some cases, the reduction in the frequency of COPD CompEx events is a decrease in the frequency of COPD CompEx events relative to baseline of 5%, 10%, 15%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 95%. In some cases, the reduction in the frequency of COPD CompEx events occurs over 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or 11 months. In some cases, the reduction in the frequency of COPD CompEx events is an annual reduction in the frequency of COPD CompEx events. In some embodiments, the reduction in the frequency of COPD CompEx events is a reduction to an average of one COPD CompEx event every 8 weeks, one COPD CompEx event every 16 weeks, one COPD CompEx event every 32 weeks, one COPD CompEx event every 52 weeks, or less than one COPD CompEx event every 52 weeks.

[0135] In some cases, as described herein, treatment with anti-IL-33 antibodies or their variants results in a reduction in the mean duration of COPD CompEx events. In some cases, the reduction in the mean duration of AECOPD refers to a 5%, 10%, 15%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 95% decrease in the mean duration of COPD CompEx events relative to baseline. In some cases, the reduction in the mean duration of COPD CompEx events refers to a decrease to a mean duration of 24 hours or less.

[0136] In some cases, the treatment results in a decrease in objective cough frequency relative to baseline over 24 hours. Objective cough frequency over 24 hours can be measured using an automated cough detector (ACM), such as VitaloJAK™ (Vitalograph, Buckinghamshire, UK), which is fitted and worn by the subject for approximately 24 hours and records cough frequency. Alternatively, objective cough frequency can be recorded by alternative means, such as recording or directly observing the subject and then constructing an integrator or counting. In some implementations, the decrease in objective cough frequency is defined as a reduction of 5%, 10%, 15%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, or more than 95% relative to baseline.

[0137] In some cases, this treatment results in a decrease in the use of a reliever medication, including a decrease in the use of a reliever inhaler relative to baseline. Relief medication use can be expressed as the number of inhalations used by the subject over a 24-hour period (i.e., the sum of different relievers, if applicable). In some cases, reliever medication use is expressed as an average of use over a 24-hour period, i.e., the total count of reliever medication use over a period of time averaged over 24 hours, where the period is longer or shorter than 24 hours. In some cases, a decrease in reliever medication use is defined as a decrease of 5%, 10%, 15%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, or more than 95% relative to baseline.

[0138] In some cases, the treatment results in a decrease in the EXACT-PRO score relative to baseline. In some implementations, this decrease is defined as a reduction 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 defined as a reduction from a baseline score of 50 or greater to a post-treatment score of less than 50. In some cases, the decrease is defined as a reduction from a baseline score of 60 or greater, 70 or greater, or 80 or greater to a post-treatment score of less than 50. In some cases, the decrease is defined as a reduction from a baseline score of 50 or greater, 60 or greater, 70 or greater, or 80 or greater to a post-treatment score of less than 40. In some cases, the decrease is defined as a reduction from a baseline score of 40 or greater, 60 or greater, 70 or greater, or 80 or greater to a post-treatment score of less than 30.

[0139] In some cases, this treatment resulted in a decrease in the E-RS™:COPD score relative to baseline. In some cases, this decrease was measured as a reduction of 5, 10, 15, 20, 25, 30, 35, or more points relative to baseline on the E-RS™:COPD scale. In some cases, this decrease was measured as a reduction in the shortness of breath domain from a baseline score of 9 or greater to a post-treatment score of less than 9. In some cases, this decrease was measured as a reduction in the cough and sputum domain from a baseline score of 6 or greater to a post-treatment score of less than 6. In some cases, this decrease was measured as a reduction in the chest symptoms domain from a baseline score of 7 or greater to a post-treatment score of less than 7.

[0140] In some cases, this treatment resulted in improvement on 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 horizontal lines, where 0 mm represents "no cough" and 100 mm represents "most severe cough," measuring the subject's subjective assessment of the severity of cough symptoms over the previous 24 hours (Smith et al. 2006). In some cases, this improvement was defined as a 5%, 10%, 15%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, or more reduction in the Cough VAS relative to baseline.

[0141] In some cases, the treatment results in an improvement in the BCSS (Breakfast, Cough, and Sputum Scale) 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 an improvement of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or more than 10 points in the total score. In some cases, the improvement includes a decrease in the sputum and / or cough area score relative to baseline. In some embodiments, the improvement is a decrease of 2, 3, 4, or 5 points in the sputum and / or cough area score. In some cases, the improvement in the BCSS score includes a decrease in the sputum and / or cough area score from >2 to <2. In some cases, the improvement in the BCSS score includes a decrease in the sputum and / or cough area score from >2 to <2.

[0142] In some cases, the treatment resulted 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 comprises four domains: cough symptoms, cough impact, sputum symptoms, and sputum impact. Each domain includes three to eight items, each answered in five categories, with frequency ranging from "never" to "always" and intensity from "never at all" to "very / extremely". 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 was an increase in the score of one or more of the four domains relative to baseline. In some cases, the increase in the domain score was an increase of 10, 20, 30, 40, 50, 60, 70, 80, or more points relative to baseline.

[0143] In some cases, this treatment resulted in an improvement in the St. George's Respiratory Questionnaire (SGRQ) score relative to baseline. The SGRQ is a 50-item ePRO tool developed to measure the health status of participants with obstructive airway disease (Jones et al., 1991). The questionnaire is divided into two parts: Part 1 consists of eight items regarding the severity of respiratory symptoms over the first four weeks; Part 2 consists of 42 items related to the individual's daily activities and psychosocial impacts of respiratory illness. The SGRQ produces a total score and three domain scores (symptoms, activities, and impacts). 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 represents the best possible health status. Similarly, domain scores range from 0 to 100, with higher scores indicating greater impairment. Based on empirical data and interviews with patients, changes in these four units were associated with minimal clinically significant differences. Specific details of the scoring algorithm are provided by the developers in the user manual (Jones and Forde, 2009). In some cases, the improvement resulted in a reduction of four or more units in the SGRQ score relative to baseline. In some implementations, the improved SGRQ score is reduced by 8, 12, 16, 20 or more units relative to the baseline. In some cases, the improved SGRQ score is reduced by 5, 10, 20, 30, 40, 50, 60, 70, 80 or more units relative to the baseline.

[0144] In some cases, this treatment results in a reduction in the frequency, duration, or severity of COPD symptoms selected from: difficulty breathing, increased sputum volume, changed sputum color, cough, wheezing, sore throat, cold symptoms (nasal discharge or congestion), and fever without other cause. In some implementations, this treatment results in a reduction in the frequency, duration, or severity of symptoms selected from: cough, wheezing, sore throat, cold symptoms (nasal discharge or congestion), and fever without other cause.

[0145] In some cases, the treatment resulted in a reduction in the frequency or duration of one or more of the following symptoms of chronic bronchitis in the subject: cough, mucus / sputum production, fatigue, shortness of breath, fever, chills, and / or chest discomfort. In some cases, the treatment resulted in a reduction in the frequency, duration, or severity of chronic bronchitis symptoms to once every 8 weeks, once every 16 weeks, once every 32 weeks, once every 52 weeks, or less than once every 52 weeks. [, anti- , ] [, IL-33 , ] [, Antibody , ] [, , ]

[0146] The therapies described in this article involve anti-IL-33 antibodies and their variants and fragments.

[0147] 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 various cell types, including structural cells such as smooth muscle cells, epithelial cells, and endothelial cells. IL-33 expression has also been reported to be induced by inflammatory factors in macrophages and dendritic cells. Cellular stress induced by environmental triggers (such as allergens, toxins, and pathogens) and mechanical damage can lead to IL-33 release. Free IL-33 associates with the heterodimeric IL-33 receptor complex, which consists of the inhibition of the tumorigenic 2 (ST2) protein and the interleukin-1 receptor accessory protein (IL-1 RAcP), to activate the AP-1 and NF-κB pathways via the transfer protein myeloid differentiation primary response 88 (MyD88) and the possible MyD88 adapter-like (Mal) protein. IL-33 stimulates multiple cell types, including innate lymphoid type II cells (ILC2), obesity cells, basophils, eosinophils, and dendritic cells, to promote an immune response.

[0148] The terms “interleukin-1 receptor-like 1 (IL1RL1)” and “ST2” are used interchangeably herein and refer to any natural ST2 from any vertebrate source, including mammals such as primates (e.g., humans) and rodents (e.g., mice and rats), unless otherwise indicated. ST2 is also referred to in the art as DER4, T1, and FIT-1. The term encompasses “full-length” untreated ST2 as well as any form of ST2 produced by cellular treatment. At least four isoforms of ST2 are known in the art, including soluble ST2 (sST2, also known as IL1RL1-a) and transmembrane ST2 (ST2L, also known as IL1RL1-b), which are produced by differential mRNA expression from 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 9-amino acid (aa) C-terminal sequence (see, for example, Kakkar et al., Nat. Rev. Drug Disc. [Nature Review: Drug Discovery] 40 7: 827-840, 2008). sST2 can act as a decoy receptor to inhibit soluble IL-33. The term also covers naturally occurring variants of ST2, such as splice variants (e.g., ST2V lacking a third immunoglobulin motif and having a unique hydrophobic tail, and ST2LV lacking the transmembrane domain of ST2L) or paired gene variants (e.g., variants that provide protection against or confer COPD risk as described herein). An exemplary human ST2 amino acid sequence can be found, for example, under UniProtKB accession number 001638. ST2, along with the co-receptor protein IL-1 RAcP, is part of the IL-33 receptor. IL-33 binds to ST2 and the co-receptor interleukin-1 receptor accessory protein (IL-1 RAcP) to form a 1:1:1 ternary signaling complex to facilitate downstream signal transduction (Lingel et al., Structure 17(10): 1398-1410, 2009; and Liu et al., Proc. Nat. Acad. Sci. 110(37): 14918-14924, 2013).

[0149] It is envisioned that antibodies or antibody variants that specifically bind to and inhibit components of the IL-33 / ST2 signaling axis could be used to treat COPD.

[0150] "Antibody" is used in the broadest sense and encompasses a variety of antibody structures, including but not limited to monoclonal antibodies, polyclonal antibodies, multispecific antibodies (e.g., bispecific antibodies), and antibody fragments, as long as they exhibit the desired antigen-binding activity.

[0151] Anti-IL33 antibodies or antibody variants, specifically those that specifically bind to and inhibit / neutralize IL-33, are envisioned to be effective in treating COPD. In some cases, the antibody may be a monoclonal antibody (MAb); a recombinant antibody; a chimeric antibody; a humanized antibody, such as an antibody grafted with a complementarity-determining region (CDR); a human antibody; an antibody variant, including single-chain antibody variants; and / or bispecific antibody variants; and fragments thereof; variants; or derivatives thereof. Antibody fragments include those portions of the antibody that bind to epitopes on the 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 technology, such as recombinant plasmids expressing nucleic acid sequences encoding antibody variable regions.

[0152] 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 originating from the same genetic source, including antibodies, bispecific antibodies, etc. The term also includes formulations of antibody molecules that are single-molecule compositions. Monoclonal antibody compositions exhibit single binding specificity and affinity for a specific epitope.

[0153] One example is a "chimeric" antibody, in which a portion of the heavy (H) chain and / or light (L) chain is identical or homologous to a corresponding sequence in an antibody derived from a specific species or belonging to a specific antibody class or subclass, while the remainder of one or more chains is identical or homologous to a corresponding sequence in an antibody derived from another species or belonging to another antibody class or subclass. Fragments of such antibodies are also included, provided they exhibit the desired biological activity. See U.S. Patent No. 4,816,567; Morrison et al., 1985, Proc. Natl. Acad. Sci. [Proceedings of the National Academy of Sciences] 81:6851-55.

[0154] In another example, a monoclonal antibody system 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. Typically, humanized antibodies have one or more amino acid residues introduced 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 region with the corresponding portion of a human antibody.

[0155] Human antibodies and antibody variants (including antibody fragments) that bind to IL-33 are also envisioned. Such antibodies could be generated using transgenic animals (e.g., mice) capable of producing a library of human antibodies in the absence of endogenous immunoglobulin production, by immunization with a polypeptide antigen (i.e., having at least six consecutive amino acids), conjugated to a vector as needed. See, for example, Jakobovits et al., 1993, Proc. Natl. Acad. Sci. [Proceedings of the National Academy of Sciences] 90:2551-55; Jakobovits et al., 1993, Nature [Nature] 362:255-58; Bruggermann et al., 1993, Year in lmmuno. [Year of Immunology] 7:33. See also PCT applications PCT / US 96 / 05928 and PCT / US 93 / 06926. Other methods are described in U.S. Patent No. 5,545,807, PCT applications PCT / US 91 / 245 and PCT / GB 89 / 01207, and European Patent Nos. 54607381 and 546073A 1. Human antibodies can also be generated by expressing recombinant DNA in host cells or by expressing it in fusion tumor cells as described herein.

[0156] Chimeric antibodies, CDR-grafted antibodies, and humanized antibodies and / or antibody variants are typically produced via recombinant methods. The nucleic acid encoding the antibody is introduced into a host cell and expressed using the materials and procedures described herein. In one instance, the antibody is produced in mammalian host cells, such as CHO cells. Monoclonal (e.g., human) antibodies can also be produced by expressing recombinant DNA in host cells or by expressing it in fusion tumor cells as described herein.

[0157] Antibodies and antibody variants (including antibody fragments) that can be used in this disclosure method may comprise: (a) 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 (b) 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.

[0158] An anti-IL-33 antibody or an antibody variant thereof for use in the methods disclosed herein is also envisioned, comprising a heavy chain variable region (VH) domain having at least 95%, 90%, or 85% identity with the sequence listed in SEQ ID NO:4. In some cases, the anti-IL-33 antibody or an antibody variant thereof comprises a light chain variable region (VL) domain having at least 95%, 90%, or 85% identity with the sequence listed in SEQ ID NO:8. In some cases, the anti-IL-33 antibody or an antibody variant thereof comprises: (a) a heavy chain variable region (VH) having at least 95%, 90%, or 85% identity with the sequence listed in SEQ ID NO:4; and (b) a light chain variable region (VL) having at least 95%, 90%, or 85% identity with the sequence listed in SEQ ID NO:8.

[0159] In some cases, the IL-33 anti-system 33_640087_7B, as disclosed in WO2016 / 156440, is incorporated herein by reference. 33_640087_7B, also known in the art as MEDI3506, is an anti-IL-33 antibody that binds to the reduced form of IL-33 (redIL-33) with high affinity. 33_640087_7B also inhibits the conversion of redIL-33 to its oxidized form (oxIL-33), which has been shown to induce signaling via RAGE and to induce epithelial cell proliferation.

[0160] 33_640087_7B is an exemplary anti-IL-33 antibody having: (a) 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 (b) 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.

[0161] 33_640087_7B also includes a VH domain having an amino acid sequence as listed in SEQ ID NO:4 and a VL domain having an amino acid sequence as listed in SEQ ID NO:8.

[0162] 33_640087_7B is an IgG1 antibody. The full-length light chain and heavy chain (including the IgG1 chain) sequences of 33_640087_7B are listed in SEQ ID NO:9 and 10, respectively.

[0163] In some cases, the anti-IL-33 antibody or its antibody variants have similar or identical pharmacokinetic (pK) characteristics to 33_670087_7B in humans.

[0164] Specifically, the anti-IL-33 antibody or antibody variant may have a half-life similar to or the same as 33_670087_7B in humans. When administered at a dose of 30 mg Q2W, the anti-IL-33 antibody or antibody variant with a half-life similar to or the same as 33_670087_7B in humans 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, the anti-IL-33 antibody or antibody variant with a half-life similar to or the same as 33_670087_7B in humans 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, anti-IL-33 antibodies or antibody variants with a similar or identical half-life to 33_670087_7B in humans may have a half-life of about 10 to about 20 days, about 12 to about 15 days, or about 14.8 days.

[0165] In some cases, the IL-33 antibody or its variants can competitively inhibit the binding of IL-33 to 33_640087-7B (as described in WO 2016 / 156440). WO 2016 / 156440 discloses that 33_640087-7B binds to redIL-33 with a particularly high affinity and attenuates both ST-2-dependent and RAGE-dependent IL-33 communication. An antibody or its variant is said to competitively inhibit the binding of the reference antibody to a given epitope if it binds specifically to that epitope to the extent that it blocks the binding of the reference antibody to that epitope. Competitive inhibition can be determined by any method known in the art, such as solid-phase assays (e.g., competitive ELISA assays), dissociation-enhanced lanthanide fluorescence immunoassays (DELFIA®, PerkinElmer), and radioligand binding assays. For example, researchers can determine whether an antibody or its variant competitively binds to IL-33 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 instance, researchers can label 33_640087-7B with a donor fluorophore and mix multiple concentrations of 33_640087-7B with a fixed concentration of redIL-33 labeled with a receptor fluorophore. Subsequently, fluorescence resonance energy transfer (FRET) between the donor and receptor fluorophores within each sample can be measured to determine the binding signature. To elucidate the competitive binding of antibody molecules, researchers can first mix various concentrations of the test binding molecule with a fixed concentration of labeled 33_640087-7B antibody. When the mixture is incubated with labeled IL-33, a reduction in the FRET signal compared to a positive control containing only the labeled antibody indicates competitive binding to IL-33. An antibody or a variant thereof may 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%.

[0166] In various cases, anti-IL-33 antibodies or their antibody variants are selected from human antibodies, humanized antibodies, chimeric antibodies, monoclonal antibodies, recombinant antibodies, antigen-binding antibody fragments, single-chain antibodies, monomeric antibodies, biantibodies, triantibodies, tetraantibodies, Fab fragments, IgG1 antibodies, IgG2 antibodies, IgG3 antibodies, and IgG4 antibodies. In some cases, anti-IL-33 antibody variants are selected from the group consisting of biantibodies, triantibodies, tetraantibodies, Fab fragments, single-domain antibodies, and scFv, wherein the dosage is adjusted such that the binding site is identical to those binding sites administered via bivalent antibodies.

[0167] In some cases, anti-IL-33 antibodies or antibody variants thereof bind to IL-33 containing the amino acid sequence of SEQ ID NO:11. In various cases, anti-IL-33 antibodies or antibody variants thereof may be able to bind to the full-length IL-33 protein in its mature form containing the amino acid sequence of SEQ ID NO:11. In various cases, anti-IL-33 antibodies or antibody variants thereof may be able to bind to IL-33 protein fragments containing amino acids 72-270, 79-270, 95-270, 99-270, 107-270, 109-270, 111-270, or 112-270 of SEQ ID NO:11.

[0168] In various cases, anti-IL-33 antibodies or their variants may be able to bind to both reduced (red-IL-33) and / or oxidized (ox-IL-33) forms of IL-33. In some cases, anti-IL-33 antibodies or their variants may be able to bind more preferably to both reduced (red-IL-33) and / or oxidized (ox-IL-33) forms of IL-33.

[0169] In various cases, anti-IL-33 antibodies or their variants may be inhibitory antibodies that inhibit IL-33 or fragments thereof as defined herein. In various cases, inhibitory antibodies may be able to inhibit the association of IL-33 or fragments thereof with the IL-33 receptor. [] [Example] [] [, Example , ] [, 1 - , ] [, Anti-interleukin , ] [, -33 , ] [, Mechanistic evidence for the antibody tozolaziumab: in healthy adults and participants with chronic obstructive pulmonary disease. , ] [, 1 , ] [, Results of the study , ] [, , ]

[0170] Alarming cytokines, interleukin (IL)-33, coordinate inflammatory and remodeling responses following tissue injury (Scott IC et al., Sci Rep [Scientific Reports] 2018;8:3363; Cohen E et al., Nat Commun [Nature Communications] 2015;6:8327; Murdaca G et al., Int J Mol Sci [International Journal of Molecular Sciences] 2019;20:5856). Excess IL-33 plays a key role in activating and driving chronic obstructive pulmonary disease in COPD (Allinne J et al., J Allergy Clin Immunol [Journal of Allergy and Clinical Immunology] 2019;144:1624-37.e10; Schmitz J et al., Immunity [Immunity] 2005;23:479-90). Tozolatumab (MEDI3506) is a human immunoglobulin G1 monoclonal antibody that specifically and effectively targets IL-33. This first-in-human study (NCT03096795) evaluated the safety, tolerability, pharmacokinetics, and immunogenicity of tozolatumab. This report details the mechanistic evidence for tozolatumab based on this study. method

[0171] This phase 1 randomized, blinded, placebo-controlled, three-part study was conducted at two centers in the UK between 15 May 2017 and 30 September 2019. In all cohorts, participants were randomized 3:1 to receive tozolaziumab:placebo. This report presents data from Part 1 and Part 2.

[0172] Part 1: Eligible participants with a mild history of heterotopia and susceptibility to house house dust mites (HDM) received a single ascending dose (SAD) of 300 mg intravenously (IV) or 1 mg, 3 mg, 10 mg, 30 mg, 100 mg, or 300 mg subcutaneously (SC) of tropozopramizumab or placebo. Part 2: Eligible participants with Global Initiative for Chronic Obstructive Lung Disease (GOLD) stage I-II COPD received multiple ascending doses (MAD) of 30 mg, 100 mg, or 300 mg SC of tropozopramizumab or placebo.

[0173] Pharmacodynamics (PD) was evaluated as an exploratory outcome. Target binding was measured in serum (all assays) for IL-33 by superselective assay and in local airway nasal mucosal lining (MLF) samples by non-invasive nasal adsorption (MAD assay). Serum levels of sST2 were also measured. Interferon-γ (IFN-γ) was measured in vitro using a whole blood assay (SAD assay) following IL-33 challenge. The PD effect of tozolaziumab on inflammatory mediators was explored using a multiplex immunoassay (Meso Scale Discovery) (MAD assay). Eosinophil levels were measured in whole blood (MAD assay). result The patient's baseline demographic data is as follows: [SAD] [Standing in line] [(] [n = 56] [)] [MAD] [Standing in line () [n = 24] [)] [Japanese people queue (] [n = 8] [)] [Tozo] [n = 42] [Placebo] [n = 14] [Tozo] [n = 18] [Placebo] [n = 6] [Tozo] [n = 6] [Placebo] [n = 2] [male,] [n] [(] [%] [)] 41 (97.6) 14 (100.0) 10 (55.6) 5(83.3) 6 (100.0) 2 (100.0) [Age, years,] [average value(] [SD] [)] 37.2 (8.9) 37.6 (9.7) 64.2(5.6) 66.2(4.1) 32.2(9.6) 31.5 (9.2) [Ethnicity] [n] [(] [%] [)] Asian 6(14.3) 3(21.4) 0 (0.0) 0 (0.0) 6 (100.0) 2 (100.0) Black or African American 1(2.4) 1(7.1) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) white people 30(71.4) 8(57.1) 18 (100.0) 6 (100.0) 0 (0.0) 0 (0.0) other 5(11.9) 1(7.1) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) Body Mass Index (BMI) [kg / m, 2 , ] [,average value(] [SD] [)] 24.7(2.7) 26.9(2.4) 28.0 (4.8) 25.6 (4.0) 23.8(2.4) 21.0(1.2)

[0174] A total of 56 participants were recruited and randomized to the SAD cohort (healthy adults with mild ectopicness and sensitivity to HDM): 42 in the tozolactumab treatment group and 14 in the placebo treatment group. 24 patients were recruited and randomized to the MAD cohort (adults with Gold I-II COPD): 18 in the tozolactumab treatment group and 6 in the placebo treatment group. Target-binding biomarker research (exploratory endpoint)

[0175] Tozolatumab target binding was demonstrated in serum (Fig. 1) and local airway nasal MLF (Fig. 2). In serum, compared with placebo, tozolatumab increased IL-33 / tozolatumab complex levels in all columns (Fig. 1A [SAD column] and Fig. 1C [MAD column]), while endogenous IL-33 / sST2 complex levels decreased in all columns (Fig. 1B [SAD column] and Fig. 1D [MAD column]). Compared with placebo, tozolatumab did not significantly affect serum total sST2 levels at any dose level.

[0176] In local airway nasal mucosal liner (MLF), compared with placebo, tozolatumab increased the level of the IL-33 / tozolatumab complex (MAD series) (Figure 2A) and decreased the levels of both reduced and oxidized forms of IL-33 (Figures 2B and 2C).

[0177] Higher levels of tozolamizumab in circulation were associated with lower levels of induced IFN-γ (Figure 3). Pharmacodynamic biomarker research (exploratory endpoint)

[0178] Compared with placebo, tozolatumab (300 mg SC) significantly reduced serum IL-5 and IL-13 levels (Figures 4A and 4B). Furthermore, tozolatumab significantly reduced serum eosinophil levels (Figure 4C), and these reductions were correlated with serum 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) levels. in conclusion

[0179] These data demonstrate mechanistic evidence for tozolatumab in a first-in-human study (NCT03096795) in patients with COPD through target binding and identification of PD biomarkers. Target binding was demonstrated in both circulating and local airways using pioneering nasal adsorption sampling. These results support the advancement of tozolatumab to Phase 2 and Phase 3 studies. Phase 2 (NCT04631016) and Phase 3 studies (NCT05166889 and NCT05158387) are currently underway to investigate the safety and efficacy of tozolatumab for the treatment of COPD. [, Example , ] [,2 - , ] [, Used for evaluation , ] [, MEDI3506 , ] [, Efficacy, safety, and tolerability in participants with moderate to severe chronic obstructive pulmonary disease and chronic bronchitis , ] [, II , ] [, Randomized, double-blind, placebo-controlled study ( , ] [, FRONTIER , ] [, cutting edge , ] [, ] 4 , ] [, ) , ] [, , ]

[0180] This example describes a phase 2 randomized, double-blind, placebo-controlled, parallel-group, proof-of-concept study to evaluate the efficacy, safety, pharmacokinetics, and immunogenicity of MEDI3506 in adult subjects with moderate to severe COPD receiving standard of care (dual or triple therapy) as maintenance therapy. Participants had a history of ≥1 moderate or severe acute exacerbation and moderate to severe chronic bronchitis with active sputum and cough symptoms during stable background treatment within the previous 12 months.

[0181] MEDI3506 (also referred to herein as 33_640087_7B) is a human IgG1 mAb that binds to human IL-33. MEDI3506 binds to both 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 ST2 (also referred to as IL-1RL1) receptors.

[0182] Several clinical and non-clinical studies have indicated that the IL-33 / ST2 signaling axis plays a crucial role in the pathogenesis of COPD. Therefore, blocking this signaling pathway may have therapeutic benefits in COPD.

[0183] 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 enrollment and should maintain this stable dose during the study. Maintenance COPD treatment should remain unchanged following the previous exacerbation prior to enrollment in the study.

[0184] Participants will be randomly assigned to either a treatment group or a volume-matched placebo group (collectively referred to as the “survey product”) and will receive either 600 mg MEDI3506 SC (20 mM L-histidine / L-histidine salt, 220 mM L-arginine salt, 0.03% (w / v) polysorbate 80, pH 5.5) or a volume-matched placebo SC; the overall ratio will be 1:1, administered every 4 weeks (Q4W) for a total of 7 doses, with the final dose administered at week 24.

[0185] Participants will enroll in this study, including a screening / adjustment period of at least 4 weeks, an intervention period of 24 weeks (or "treatment window," during which they will 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.

[0186] The main estimators are as follows: For the ITT population, repeated measures mixed-effects analysis using a covariance model will be used to estimate the difference in the mean change from baseline in FEV1 at week 12 (MEDI3506 - placebo). This will include all available data from all visits up to (and including) week 12, regardless of whether participants discontinued the study intervention or received remission therapy. The model will include baseline, eosinophil stratification, background drug treatment stratification, visits, study intervention, and visit baseline, as well as the fixed effect of the study intervention via visit interactions. An unstructured covariance matrix will be used to describe the correlations between observations of participants across visits.

[0187] A similar approach will be used to analyze cough VAS, BCSS, CASA-Q, SGRQ, and relieving medication treatment. Where appropriate, logarithmic transformation of the data may be performed prior to analysis. Covariance analysis will be used to analyze the changes from baseline in objective cough parameters and oscillometric parameters at week 12. Analysis of the timing of events and the annualization rate of event data will include available data from all participants (up to week 28, where available). The timing of the event endpoint will be analyzed. [Filtering Procedure] Participants should meet the following criteria:

[0188] 1. Participants must be between 40 and 75 years old (inclusive).

[0189] 2. Participants are current smokers or former smokers with a smoking history of ≥ 10 pack-years.

[0190] 3. Participants who have received pneumococcal and influenza vaccines to date, in accordance with local treatment guidelines.

[0191] 4. Participants must have a documented history of COPD for at least one year.

[0192] 5. At screening, participants had a post-BD FEV1 / FVC < 0.70 and a post-BD FEV1 > 30% and < 80% of the predicted normal value. Centralized spirometry will be used to assess this criterion.

[0193] 6. Participants must have a physician-confirmed history of chronic bronchitis, defined as having cough and sputum for at least 3 months / year for most of the 2 years preceding the SV1 (screening) period.

[0194] 7. Within 14 days prior to SV3, participants had a mean BCSS score ≥ 2 in the cough domain and a mean BCSS score ≥ 2 in the sputum domain.

[0195] 8. Participants must have a stable dual or triple therapy regimen with a history of ≥ 3 months prior to recruitment; treatment should remain unchanged after the previous exacerbation prior to enrollment in the study. Dual therapy consists of ICS + LABA or LABA + LAMA, and triple therapy consists of ICS + LABA + LAMA. Both dual and triple therapies can be administered as a single inhaler with a fixed-dose combination inhaler, but not necessarily as a nebulizer.

[0196] 9. Participants must have a documented history of at least one episode of moderate or severe AECOPD requiring systemic corticosteroids and / or antibiotics for at least 3 days (or one injection of a stock preparation), or have been hospitalized for AECOPD within the previous 12 months prior to screening.

[0197] 10. Participants were clinically stable and had no COPD exacerbation one month prior to SV1 (screening) and day 1.

[0198] 11. Body mass index is in the range of 19 to 35 kg / m2 (inclusive). [Random allocation and distribution] []

[0199] Randomization will take place at the third study visit (SV3 - Day 1). Participants who continue to meet the eligibility criteria will be randomly assigned to the treatment group as described above. Blood and urine samples will be collected, and efficacy and safety assessments will be performed to establish baselines.

[0200] Randomization will be stratified based on baseline blood eosinophil count (< 300 cells / μL vs. ≥ 300 cells / μL) and background drug therapy (including ICS vs. excluding ICS).

[0201] The first investigational product (IP) administration will be performed at the third study visit (day 1) and will include the administration of the first dose of the investigational product during the treatment window. Administration of 600 mg MEDI3506 will require 2 × 2 mL SC injections / dose. The injection volume for the placebo group will be matched to that for the MEDI3506 group.

[0202] At the fourth study visit (day 2), participants will return to assess their adherence to the self-assessment efficacy reporting procedure and to conduct a safety assessment. The procedure is outlined in Table 4.

[0203] The second survey product input will be conducted at the 6th study visit (day 29 ± 3).

[0204] The third survey product input will be conducted at the 7th research visit (day 57 ± 3).

[0205] The fourth survey product input will be conducted at the 8th research visit (day 85 ± 3).

[0206] The fifth survey product input will be conducted at the 9th study visit (day 113 ± 3).

[0207] The sixth survey product input will be conducted at the 10th study visit (day 141 ± 3).

[0208] The seventh survey product input will be conducted at the 11th study visit (day 169 ± 3). [end] []

[0209] The primary endpoint visit was conducted at week 12 and assessed at the 10th study visit (day 113 ± 4).

[0210] The primary endpoint was an improvement in baseline FEV1 before clinical BD at week 12. Forced expiratory volume in one second (FEV1) is a validated and clinically important endpoint in COPD studies and has been widely used in trials to support the registration of supplemental therapies to the current standard of care (dual / triple therapy) in similar populations of patients with chronic bronchitis (Martinez et al. 2015).

[0211] Based on available data, the FEV1 improvement hypothesized in the expected sample size determination was to be achieved at week 12. However, FEV1 improvement was considered significant but insufficient to meet unmet medical needs in COPD. To evaluate secondary endpoints of COPDCompEx, treatment was continued after primary endpoint data collection to collect additional events. The longer intervention duration also allowed for exploratory assessment of FEV1 efficacy beyond week 12.

[0212] The secondary endpoint is COPDCompEx at week 28. Changes in pre-clinical BD FEV1 will also be assessed at week 28.

[0213] Blood samples will be collected from subjects to assess biomarkers related to disease pathology and / or the mechanism of action of MEDI3506. [result] []

[0214] In this Phase 2 clinical trial, the highest dose of MEDI3506 administered to subjects will be 600 mg via SC injection Q4W. Compared to the highest dose administered in the Phase 1 clinical trial (Study D9180C00001), i.e., a single dose of 300 mg IV MEDI3506, this dose is expected to have lower exposures in terms of steady-state maximum concentration (Cmax, ss; approximately 2.5 times) and AUC (approximately 1.6 times). Compared to the highest multiple doses administered in the same study (i.e., 300 mg SC Q2W), the 600 mg dose via SC injection Q4W is predicted to have a higher Cmax, ss, but the same AUC (Table 6).

[0215] The nature and severity of the disease in the 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 relative to subjects with AD) has no significant effect on exposure or clearance (Kovalenko et al., 2016). Therefore, we expect MEDI3506 to exhibit similar PK curves in both healthy and COPD subjects. [, Example , ] [, 3 - COPD , ] [, During treatment , ] [, MEDI3506 , ] [, Dosage selection criteria , ] [, , ]

[0216] To select the target dose, a PK / PD model was generated using target binding data from the Ph1 study (NCT03096795). More specifically, the PK / PD model is based on: • MEDI3506:Quantitative information on the IL33 and IL33:ST2 complexes in phase 1 systemic circulation. The concentrations of the two complexes were measured using a proprietary IL-33 assay that specifically binds to the reduced form of IL-33 (redIL-33). • MEDI3506 PK data from Phase 1 (linear PK, half-life (t 1 / 2) is 17 days)

[0217] Additional preclinical information that informs dosage selection includes: • redIL-33:ST2 communication channel • oxIL-33:RAGE:EGFR communication path redIL-33:ST2 communication channel

[0218] A mouse model of airway inflammation induced by Alternaria alternifolia (ALT) has been previously described (Kouzaki et al. J. Immunol. [Journal of Immunology] 2011, 186: 4375-4387; Bartemes et al. J Immunol [Journal of Immunology], 2012, 188: 1503-1513). Endogenous IL-33 is rapidly released upon ALT exposure and drives IL-33-dependent IL-5 production in the lungs. Male or female wild-type or humanized IL-33 mice (6-10 weeks old) were simply anesthetized with isoflurane and administered IL-33 via intranasal injection at a total volume of 50 mg / L. [, 25 µg of ALT extract (Greer, Lenoir, NC) or the medium was administered intraperitoneally to mice. Mice were treated with MEDI 3506 (0.1, 1, 2, or 10 mg / kg), isotype control IgG (NIP228), or the medium (PBS, 10 ml / kg) 24 hours later and challenged intranasally with ALT. 24 hours post-challenge, mice were finally anesthetized with sodium pentobarbital, followed by exsanguination and collection of bronchoalveolar lavage fluid (BALF). BALF was collected via tracheostomy. The BALF was centrifuged, and the cells (total cells by FACS (FacsCALIBER, BD)) and the supernatant was analyzed by ELISA (Meso Scale Discovery, Rockville, MD). According to Diff-Quik (Fisher Technology, UK) [, Cells were classified and counted using centrifuged smears stained with [Scientific, UK] . All work was performed in accordance with UK Home Office Ethics and Governance Standards under appropriate project licenses. 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. 90% inhibition was achieved at 3 mg / kg, corresponding to a mean serum systemic exposure of 20 µg / mL in mice. Results are shown in Figures 5 and 6. oxIL-33:RAGE:EGFR communication pathway

[0219] It has recently been found that oxidized forms of IL-33 (oxIL-33, IL-33ox, or IL-33DSB) directly impair the epithelial cell repair response, reduce epithelial goblet cell differentiation and proliferation, and increase mucus production and the generation of mucin-related genes (such as MUC5AC). oxIL-33 has been found to mediate its pathological effects on epithelial cells by binding to and signaling with a complex of RAGE and EGFR (as described in WO 2021 / 089563, which is hereby incorporated).

[0220] The following MEDI 3506 concentrations for the oxIL-33 signaling pathway are used to provide information for dosage selection: • Reversing the threshold of oxIL-33-mediated dysfunctional scratch wound closure Scratch wound closure

[0221] Previous experiments have shown that oxIL-33 impairs epithelial scratch wound closure in bronchial epithelial cells of healthy individuals (Figs. 7A and 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 communication axis. Scratch wound damage was also observed in bronchial epithelial cells obtained from COPD subjects (Fig. 8).

[0222] The required concentration of MEDI3506 to reverse oxIL-33-mediated scratch wound closure dysfunction was calculated in A549 cell cultures.

[0223] A549 cells were obtained from ATCC and cultured in RPMI GlutaMax medium supplemented with 1% penicillin / streptomycin and 10% FBS. Cells were harvested with acutase (PAA, #L1 1-007) and seeded at 5 x 10⁵ cells / 100 µl into 96-well plates and incubated at 37°C, 5% CO₂ for 6–8 h. The wells were then washed twice with 100 µl of PBS, followed by the addition of 100 µl of starvation medium (RPMI GlutaMax medium supplemented with 1% penicillin / streptomycin) and incubated at 37°C, 5% CO₂ for 18–24 h. Cells were scratched using WoundMaker™ (Essen Bioscience), and wells were washed 2x with 200 µl PBS, followed by addition of RPMI GlutaMax medium supplemented with 0.1% FBS (v / v) and 1% (v / v) penicillin / streptomycin, containing the indicated stimulant; separate media (non-stimulated control), different concentrations of MEDI3506, or anti-TSLP antibody, and returned to 37°C, 5% CO2. Plates were placed in IncucyteZoom for wound healing imaging and analysis over a 72-hour period. Relative wound density was calculated using a wound healing algorithm in the Incucyte Zoom software. Figure 9 shows the dose-dependent improvement in MEDI3506 closure of scratch wounds in A549 cells. A concentration greater than 50.4 pM (or 7.26 ng / ml) of MEDI3506 was required for a complete response. This is considered equivalent to a concentration of 0.15 µg / mL in blood (assuming 5% distribution to the epithelial liner after subcutaneous administration). No effect was observed with anti-TSLP antibodies. Integrative PK / PD model of target binding

[0224] Based on clinical data from the MEDI3506 Ph1 study on systemic exposure and target binding (TE) of SAD / MAD / IV MEDI3506, an integrated popPK / PD model was established. The TE information used was systemic IL33-MEDI3506 complex formation and IL33-ST2 levels reduced by FTIM.

[0225] The populations and doses covered in the model include: • Healthy subjects with mild atopy following a single subcutaneous (SC) dose (1 to 300 mg SC) and a 300 mg intravenous (IV) dose. • Mild COPD patients receiving multiple doses of 30, 100, and 300 mg SC

[0226] The model structure has four defined compartments, as shown in Figure 10.

[0227] The PKPD model reliably described the observed PK curves of MEDI3506, the formation of the MEDI3506:IL33 complex, and the dose-dependent inhibition of IL33:ST2 in the blood (Figures 11, 12, and 13). Figures 18 and 19 show different representations of Figures 11 and 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 tozolaziumab (0.01 ng / ml) and IL-33:sST2 (0.5 pg / ml), respectively.

[0228] For the Q2W, Q4W, and Q6W dosing regimens, the dose response of inhibition of the ST2:IL33 complex of MEDI3506 in the blood at the trough is shown in Figure 14.

[0229] Further transform the PK / PD model of IL-33 / sST2 complex inhibition in blood to predict IL-33 inhibition in lung tissue (hypothesis: blood:tissue distribution coefficient is 14%, and IL-33 level in lung is twice as high as in blood).

[0230] The %IL-33 inhibition in the lung tissue at the trough for Q4W and Q8W dosing frequencies is shown in Figure 15. Dosage selection:

[0231] The 300 mg Q4W dosing frequency predicted nearly 95% target inhibition in the valvular lung tissue. The MEDI3506 300 mg Q8W was predicted to achieve greater than 80% TE in the lungs, meaning that longer but more convenient dosing intervals could achieve sustained IL-33 inhibition in the lungs (Figure 15).

[0232] Based on Ph1 PK data and other input parameters, serum concentrations of MEDI3506 were modeled for 300 mg Q4W and 300 mg Q8W. The predicted trough concentrations for both regimens were higher than the amounts predicted by the *Plasmodium* humanized IL-33 mouse model to achieve 60% inhibition (Figure 16). The *Plasmodium* model is more representative of acute effects caused by exacerbations or viral infections. Therefore, dose prediction using this cutoff value may be sufficient to achieve effective doses for human chronic IL-33-mediated diseases such as COPD. The predicted trough concentrations for both regimens were also higher than the threshold amounts identified by the scratch wound model for inhibiting pathological communication via the oxIL-33:RAGE / EGFR communication axis (Figure 17). [, Example , ] [, 4 - , ] [, Used to evaluate two dosage regimens , ] [, MEDI3506 , ] [, In having , ] [, COPD , ] [, Patients with a history of exacerbation of symptomatic chronic obstructive pulmonary disease (COPD) , ] [, COPD , ] [, Efficacy and safety in participants , ] [, III , ] [, Phase-one, multicenter, randomized, double-blind, chronically administered, parallel-group, placebo-controlled study , ] Overall Design

[0233] The objective of this Phase III study was to evaluate the efficacy and safety of subcutaneous (SC) MEDI3506 300 mg every 8 weeks (Q8W) and 300 mg every 4 weeks (Q4W) in adult participants with symptomatic COPD and a history of ≥ 2 moderate or ≥ 1 severe COPD exacerbation within 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 no triple therapy is indicated or there are contraindications) for at least 3 months prior to enrollment.

[0234] This study will randomize approximately 1272 participants, stratifying them by region, maintenance inhalation therapy (double vs. triple), and smoking status (current smokers vs. former smokers). The study includes both former and current smokers. Participants will continue using the same COPD maintenance therapy throughout the study.

[0235] 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 delivery every 4 weeks), and an 8-week post-treatment follow-up period. Key primary and secondary objectives and endpoints are described in the table below: [Target] [end] [ / ] [Estimated Quantity] [main] To evaluate the effect of SoC plus two doses of MEDI3506 (as an adjunct therapy) on the rate of moderate to severe COPD exacerbations in former smokers compared to SoC plus placebo. Endpoint: Annualized rate of moderate to severe COPD exacerbation. General measure: rate ratio. Population: Full analysis set, former smokers. Participants who were former smokers had symptomatic COPD with a history of exacerbations and were receiving optimized treatment with maintenance inhalation therapy. Intermittent events: Treatment guidelines. All data up to week 52 will be included, regardless of changes in IP discontinuation or maintenance of inhalation therapy. Supportive analysis: during treatment (c). [Key Secondary] To evaluate the effect of SoC plus two doses of MEDI3506 (as an adjunct therapy) on the rate of moderate to severe COPD exacerbations in former and current smokers compared to SoC plus placebo. Endpoint: Annualized rate of moderate to severe COPD exacerbation. General measure: rate ratio. Population: The entire analysis set, including former and current smokers. Participants who were former or current smokers had symptomatic COPD with a history of exacerbations and were receiving optimized treatment with maintenance inhalation therapy. Intermittent events: treatment strategy. To evaluate the effect of SoC plus two doses of MEDI3506 (as an adjunct therapy) on the time to moderate to severe COPD exacerbations compared to SoC plus placebo. Endpoint: Time to first moderate to severe COPD exacerbation. General measure: risk ratio. Group: The entire analysis set, former smokers. Intermittent events: treatment strategy. To evaluate the effect of SoC plus two doses of MEDI3506 (as an adjunct therapy) on changes in lung function after BD compared to SoC plus placebo. US key secondary Endpoint: Change from baseline in pre-BD and pre-dose trough FEV1 (mL) at week 52. General measure: the difference in average change from the baseline. Group: The entire analysis set, former smokers. Intermittent events: treatment strategy. Former key U.S. deputy Endpoint: Change from baseline in pre-BD and pre-dose trough FEV1 (mL) over 52 weeks. General measure: the difference in average change from the baseline. Group: The entire analysis set, former smokers. Intermittent events: treatment strategy. To evaluate the effect of SoC plus two doses of MEDI3506 (as an adjunct therapy) on respiratory symptoms compared to SoC plus placebo. US key secondary Endpoint: The percentage of participants who achieved the MCID of E-RS:COPD total score (the percentage of participants whose E-RS:COPD total score decreased by ≥ 2 points from baseline at week 52). General measure: advantage ratio. Group: The entire analysis set, former smokers. Intermittent events: components. Former key U.S. deputy Endpoint: Change from baseline in E-RS: COPD total score over 52 weeks. General measure: the difference in average change from the baseline. Group: The entire analysis set, former smokers. Intermittent events: treatment strategy. To evaluate the impact of SoC plus two doses of MEDI3506 (as an adjunct therapy) on respiratory health status / health-related quality of life compared to SoC plus placebo. US key secondary Endpoint: The percentage of MCID participants who achieved the SGRQ score (the percentage of participants whose total SGRQ score decreased by ≥ 4 points from baseline at week 52). General measure: advantage ratio. Group: The entire analysis set, former smokers. Intermittent events: components. Former key U.S. deputy Endpoint: Change in total SGRQ score from baseline over 52 weeks. General measure: the difference in average change from the baseline. Group: The entire analysis set, former smokers. Intermittent events: treatment strategy. [secondary] To evaluate the effect of SoC plus two doses of MEDI3506 (as an adjunct therapy) on severe COPD exacerbations compared to SoC plus placebo. b. The time of the first severe COPD exacerbation. Annualized rate of severe COPD exacerbation. Further evaluate the impact of SoC plus two doses of MEDI3506 (as an adjunct therapy) on COPD health status / health-related quality of life compared to SoC plus placebo. Changes in CAT total score from baseline in week 52. The percentage of participants who achieved the MCID score in the CAT (the percentage of participants whose total CAT score decreased by ≥ 2 points from baseline in week 52). To evaluate the effects of SoC plus two dose regimens of MEDI3506 (as an adjunct therapy) on overall and COPD-related HRU compared to SoC plus placebo. The proportion of participants with ≥ 1 HRU type. Annualized hospitalization rate. Annualized ER / ED visit rate. Combined annualized hospitalization and ER / ED visit rates. Length of stay, measured by the total number of days spent in the hospital, general ward, ICU, CCU, and any other HRU, if sufficient data is available. Annualized off-plan access / testing / procedure rate, including off-plan access to research sites due to COPD. Readmission rate. To evaluate the impact of SoC plus two dose regimens of MEDI3506 (as an adjunct therapy) on routine emergency medication use compared to SoC plus placebo. Changes in emergency medication use from baseline over 52 weeks (difference in average number of sprays per day).

[0236] AE = Adverse Events; 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 One Second; HRU = Healthcare Resource Utilization; ICU = Intensive Care Unit; IP = Survey Product; MCID = Minimum Clinically Significant Difference; SGRQ = St. George's Respiratory Questionnaire; SoC = Standard of Care. Participant types and disease characteristics

[0237] 1. A history of COPD diagnosis for at least one year prior to recruitment.

[0238] 2. FEV1 / FVC < 0.70 after BD and FEV1 > 20% of the predicted normal value (assessed by central spirometry at screening).

[0239] 3. Medical history of at least two moderate or at least one severe COPD exacerbation within the 12 months prior to recruitment: (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 stay in a hospital, observation ward, emergency department, or other equivalent healthcare facility (depending on the country and healthcare system) for ≥ 24 hours. (b) At least one eligible exacerbation treated with systemic corticosteroids. (c) Events treated with antibiotics alone are considered moderate exacerbations only when antibiotics are prescribed specifically for worsening COPD symptoms. (d) It should be confirmed that the previous exacerbation occurred while the participant was receiving stable dual or triple (ICS / LABA / LAMA) maintenance inhalation therapy for COPD and was not due to an interval or decrease in treatment. (e) At least one eligible exacerbation should have occurred while receiving the latest stable non-interrupted therapy prior to recruitment.

[0240] 4. Recorded optimized treatment with a stable dose of COPD maintenance therapy (ICS / LABA / LAMA triple therapy, or dual therapy if no triple therapy is indicated or there are contraindications) for at least 3 months prior to recruitment.

[0241] 5 ≥ 10 pack-years of smoking history: (a) Former smokers are defined as participants who are currently non-smokers and have quit smoking for ≥ 6 months prior to screening and intend to quit permanently. (b) Current smokers are defined as participants who currently smoke (at least one cigarette per day on average over the past 7 days) and are not currently participating in smoking cessation. (c) For eligible conditions, the use of electronic cigarettes (e-cigarettes) does not constitute an annual subscription.

[0242] 6. During screening and randomization, the total CAT score is ≥ 10, and each of the sputum (mucus) and cough items has a score of ≥ 2.

[0243] 7. At least 70% of daily PRO completions must be achieved throughout the screening period, and at least 50% of daily PRO completions must be achieved in the 14-day period prior to random assignment.

[0244] 8. At least 70% adherence to COPD maintenance inhalation therapy (defined as scheduled daily administration of COPD maintenance inhalation medication) throughout the screening period.

[0245] 9. Able to read and use electronic devices. Research Intervention [Survey Product()] [IP] [)] [] [Group Name] MEDI3506 300 mg Q8W MEDI3506 300 mg Q4W placebo [Intervention Name] MEDI3506 MEDI3506 placebo [type] biological agents biological agents placebo [Dosage Form] small bottle small bottle small bottle [Unit dose intensity] 150 mg / mL 150 mg / mL not applicable [Dose Level] Administer 300 mg MEDI 3506 alternately with placebo every 4 weeks. 300 mg Q4W Same volume as MEDI3506 Q4W [Investment method] SC injection SC injection SC injection [IMP] [and] [NIMP] IMP IMP NIMP [source] The test commissioner provides centralized services The test commissioner provides centralized services The test commissioner provides centralized services [Packaging and Labeling] Each vial kit contains a uniquely numbered bottle, which is printed on all labels within the kit (i.e., the outer carton label and the inner bottle label). Labels will be prepared in accordance with GMP and local regulations. Each vial is a set with a unique serial number, which is printed on all labels within the set (i.e., the outer carton label and the label on the vial inside the carton). Labels will be prepared in accordance with GMP and local regulations. Each vial is a set with a unique serial number, which is printed on all labels within the set (i.e., the outer carton label and the label on the vial inside the carton). Labels will be prepared in accordance with GMP and local regulations. [Emergency medication] []

[0246] In cases of COPD symptom exacerbation during the study period, short-acting β2-agonists (SABAs, such as salbutamol, terbutaline, levosalbutamol), short-acting muscarinic antagonists (SAMAs), SABA / SAMA combinations, or alternative emergency medications that meet local standards of care may be used. [Maintenance therapy] []

[0247] Stable and optimized maintenance inhaled therapy (ICS / LABA / LAMA triple therapy, or dual therapy if no triple therapy is indicated or there are contraindications). The dosage and regimen of any other COPD maintenance therapy (e.g., xanthine, antibiotics, PDE4 inhibitors, etc.) should be stabilized for 3 months prior to the study and throughout the study period. Efficacy evaluation [COPD] [Intensified assessment] []

[0248] For the purposes of this protocol, COPD exacerbation is defined as a worsening of a 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 the time of exacerbation, lasts for 2 days or more (or less if the exacerbation is rapid and significant enough that the treating physician determines that intensified treatment cannot be delayed), and may require a change in routine medication and result in any of the following:

[0249] Use systemic corticosteroids for at least 3 days; a single infusion (IM) dose of corticosteroids will be considered equivalent to a 3-day course of systemic corticosteroids.

[0250] Use antibiotics.

[0251] Hospitalized patients due to COPD (defined as hospitalized patients who have been in a hospital, observation ward, emergency department, or other equivalent healthcare facility for ≥ 24 hours).

[0252] It can lead to death.

[0253] If an exacerbation requires systemic steroid and / or antibiotic treatment and does not meet the criteria for a severe event, then the exacerbation is considered a serious event. [Moderate]. An exacerbation is considered severe if it leads to hospitalization or death due to COPD. [Severe]

[0254] The onset of exacerbation is defined as the date of commencement of systemic corticosteroid or antibiotic treatment or hospital admission, whichever occurs earlier, and the end date is defined as the last day of systemic corticosteroid or antibiotic treatment or discharge, whichever occurs later. A single stock-load injection of corticosteroids will be considered equivalent to a 3-day course of systemic corticosteroids. Therefore, the corresponding discontinuation date of this treatment is determined as the date of administration plus 2 days. [Lung capacity measurement method (assessment before and after bronchodilator use)] []

[0255] All vital capacity measurements were performed before the dose was administered.

[0256] Lung function (FEV1 and FVC) will be measured using equipment provided by a central supplier via spirometry. Speech measurement will be performed by the investigator or authorized representative according to the American Thoracic Society (ATS) / European Respiratory Society (ERS) guidelines (Graham et al. 2019). [Reference for Lung Capacity Measurement Methods] []

[0257] The Global Lung Function Initiative formula will be used to determine the predicted normal value (PNV) and pre-programmed into spirometers (Quanjer et al. 2012).

[0258] Forced expiratory volume in the first second (FNV) is expressed as a percentage of PNV and is calculated as follows: FEV 1% of PNV = (Measured FEV 1 / FEV 1PNV) × 100 FEF 25-75% will be calculated using a method similar to FEV 1. [BD] [Post-spiral capacity measurement method] []

[0259] Within 30 minutes ± 15 minutes of the final pre-BD spirometry measurement, salbutamol (90 μg dose) or salbutamol (100 μg dose) will be administered to induce the endpoint of maximum BD, with or without a spacer device, to achieve a maximum of 4 inhalations. Post-BD spirometry will be performed 15 to 30 minutes later. If participants cannot tolerate 4 inhalations of salbutamol or salbutamol, a lower number of inhalations may be considered based on the investigator's clinical judgment. [Patient Report Results()] [PRO] [)] []

[0260] 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 SoA (part 1.3) to assess frequency. [, Tools for exacerbating chronic lung disease , ] [, - , ] [, Patient-reported results ( , ] [, EXACT-PRO , ] [, ) , ] [, , ]

[0261] 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 use using a handheld electronic device. Respondents were instructed to complete a diary entry each night before bedtime and answer questions while reflecting on their experiences "that day." The daily EXACT-PRO total score ranged from 0 to 100, with higher scores indicating greater severity. Variations in the total score were used to identify exacerbation events and remissions as defined by EXACT-PRO. In identifying event attacks and remissions, EXACT-PRO can provide information about event frequency and duration, as well as event severity. [, COPD , ] [, Respiratory Symptom Assessment Form ( , ] [, E-RS , ] [, ) , ] []

[0262] The E-RS:COPD was developed using an 11-item PRO to assess the severity of respiratory symptoms in COPD (Leidy et al. 2014a; Leidy et al. 2014b). The E-RS:COPD is derived from a subset of the EXACT-PRO items. The E-RS:COPD was designed to be obtained as part of a daily EXACT-PRO assessment. The summation of responses to the E-RS:COPD items produced a total score ranging from 0 to 40, with higher scores indicating greater severity. In addition to this total score, symptom domain scores were calculated by summing responses within corresponding domains for shortness of breath (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). For this total score, higher domain scores indicated greater severity. A decrease of at least 2 points in the total E-RS:COPD score was considered significant and used as a responder definition (Leidy et al. 2014a). [, Shortness of breath, cough and sputum volume scale ( , ] [, BCSS , ] [, ) , ] [, , ]

[0263] The BCSS assesses the severity of shortness of breath, cough, and sputum on a scale of 0 to 4 using three PRO items (Leidy et al. 2003a, Leidy et al. 2003b). Item scores are summed to produce a total score, with higher scores indicating more severe symptoms. [, St. George Respiratory Questionnaire ( , ] [, SGRQ , ] [, ) , ] [, , ]

[0264] 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 over the first 4 weeks; Part 2 consists of 42 items related to the individual's daily activities and psychosocial impacts of respiratory illness. The SGRQ produces a total score and three component scores (symptoms, activities, and impacts). 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 represents the best possible health status. Similarly, component scores range from 0 to 100, with higher scores indicating greater impairment. A reduction of at least 4 points in a single SGRQ total score is considered significant 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). [, COPD , ] [, Evaluation test ( , ] [, CAT , ] [, ) , ] [, , ]

[0265] The CAT (Chronic Differential Response) system was developed to measure the impact of COPD on health status using an 8-item PRO (Jones et al. 2009, Kon et al. 2014). The tool uses a 6-point Semantic Differential Response Scale, defined by contrasting adjectives to capture the impact of COPD. Items include those related to cough, phlegm, chest tightness, shortness of breath when climbing hills / stairs, limited mobility at home, confidence to leave home, sleep, and energy. Responses to each item range from 0 to 5, with 0 indicating the least impact on health status and 5 indicating the greatest impact. The total CAT score is the sum of the item responses, ranging from 0 to 40, with higher scores indicating a greater impact of COPD on health status. A decrease of at least 2 points in a single item in the total CAT score is considered significant and will be used to support the respondent definition (Kon et al. 2014). [, Five-level five-dimensional health scale ( , ] [, EQ-5D-5L , ] [, ) , ] [, , ]

[0266] 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 for the health condition. EQ-5D-5L consists of two assessments: a descriptive system and a visual analogy scale (VAS). The descriptive system includes five dimensions: mobility, self-care, daily activities, pain / discomfort, and anxiety / depression. Each dimension has five severity levels: no problem, minor problem, moderate problem, severe problem, and extreme problem. The EQ-5D-5L index score can be calculated based on participants' responses to the five dimensions using an appropriate set of values, which will be further described in the Statistical Analysis Plan (SAP).

[0267] The EQ-5D VAS records respondents' self-assessment of their health status on a 20 cm vertical scale from 0 to 100. The endpoints are marked as "the best health status you can imagine" and "the worst health status you can imagine," with higher scores corresponding to better health. This information is used as a quantitative measure of health status as judged by an individual respondent. [, Questionnaire on Decreased Work Efficiency and Activity Level , ] [, WPAI-GH , ] [, ) , ] [, , ]

[0268] WPAI-GH (version 2.0) is a self-administered tool that includes six questions covering absenteeism, attendance-based behavior (reduced work efficiency), overall work efficiency loss (absence plus attendance-based behavior), and decreased activity level. This validated tool captures data from the past seven days. WPAI-GH results are scored as a percentage of impairment, with higher percentages indicating greater impairment and lower efficiency (Reilly et al., 1993). [, Patient Severity Overall Impression Scale (SES) , ] [, Patient Global Impression of Severity , ] [, , , ] [, PGIS , ] [, ) , ] [, , ]

[0269] The PGIS system was designed to use a 6-point scale (0 - asymptomatic to 5 - very severe) to capture participants' perceptions of the overall severity of their COPD symptoms at completion. [, Patient Global Impression Change Scale ( , ] [, PGIC , ] [, ) , ] [, , ]

[0270] The PGIC system was designed to use a 7-point scale (1 - much better to 7 - much worse) to capture a single item of participants’ perceptions of changes in overall COPD symptoms after the first dose of IP. [, COPD , ] [, Aggravated composite endpoint ( , ] [, COPDCompEx , ] [, ) , ] [, , ]

[0271] The composite endpoint for COPD exacerbation (COPDCompEx) is based on an endpoint that combines exacerbation with daily PRO-defined events and study termination (Vogelmeier et al. 2020). The components of COPDCompEx are defined as follows: Worsening: Leading to one or more of the following: hospitalization, emergency room visit, treatment with systemic corticosteroids, or treatment with antibiotics. Daily PRO events: Defined by threshold and slope criteria, using the following PRO variables: individual BCSS items and first aid medication use. Statistical considerations [Main Destination] []

[0272] The primary endpoint is the annualized rate of moderate to severe worsening. This will be evaluated first in the primary cohort (former smokers) for each dose of MEDI3506 relative to placebo, and then in the entire cohort of current smokers and former smokers.

[0273] A negative binomial model will be used to compare the rate of moderate to moderate exacerbations in each MEDI3506 dosage regimen group with the rate of moderate to moderate exacerbations in the placebo group. The response variable in the model will be the number of COPD exacerbations experienced by participants during the fully double-blind 52-week treatment period. The model will include covariates for treatment group, region, maintenance inhalation therapy (triple or dual), and the number of exacerbations in the previous year as a categorical factor (1 vs. ≥2), as continuous covariates for predicted post-BD FEV1% and log-selected blood eosinophil count. The logarithm of the corresponding follow-up time for participants will be used as the shift variable in the model. For analyses of the entire population, smoking status will also be included as a covariate.

[0274] The estimated treatment effects (i.e., the rate ratio of MEDI3506 to placebo for each dose) will be presented, along with the corresponding 95% confidence interval (CI) and two-sided p-values ​​for the rate ratios. Additionally, the model-adjusted aggravation rate in each treatment group will be presented.

[0275] A course of systemic corticosteroids or antibiotics initiated within 7 days of completing a previous course of treatment will be considered as treatment for the same single exacerbation. [Secondary destination] []

[0276] All secondary endpoint analyses will be conducted in the primary group (former smokers). Similar analyses will be conducted across the entire group (former smokers and current smokers). Time of first moderate or severe COPD exacerbation

[0277] The time to first moderate or severe COPD exacerbation was analyzed as a key secondary efficacy variable with the primary objective of determining the extent to which treatment with each dose of MEDI3506 delayed the time to first exacerbation compared to placebo. Cox proportional hazards models were fitted with covariates including treatment group, region, maintenance inhalation therapy, number of exacerbations in the previous year, predicted post-BD FEV1% at screening, and logarithmic screening blood eosinophil count. Hazard ratios, 95% CI, and p-values, as well as the proportion of participants with the event, will be reported. St. George Respiratory Questionnaire

[0278] Repeated measures linear models will be used to compare the change in total SGRQ score from baseline over 52 weeks between MEDI3506 and placebo. The dependent variable will be the change in total SGRQ score from baseline at the protocol-specified visit (up to week 52). Treatment, visits, treatment-while-visit interaction, region, maintenance inhalation therapy, and the number of exacerbations in the previous year will be fitted as categorical covariates to the baseline total SGRQ score, predicted post-BD FEV1%, and log-screened blood eosinophil count as continuous covariates. An unstructured variable 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 bilateral 95% CI and p-values.

[0279] Responder analysis of the SGRQ total score will be performed at week 52. Responders are defined as participants who showed an improvement (decrease) of ≥ 4.0 points relative to baseline. Participants who discontinued the study for any reason or lost data at week 52 will be classified as non-responders. Logistic regression will be applied to compare the treatment groups by treatment, region, maintenance inhalation therapy, and the number of exacerbations in the previous year as a categorical covariate, and predicted post-BD FEV1%, log-screened blood eosinophil count as continuous covariates, and baseline SGRQ total score. P-values, odds ratios, and 95% CIs will be generated for each treatment comparison. E-RS: Change from baseline in COPD total score

[0280] The change in E-RS:COPD total score from baseline over 52 weeks will be analyzed using a model similar to that used for the change in SGRQ total score from baseline. Similar to the SGRQ responder analysis, a responder analysis of E-RS:COPD total score at week 52 will also be conducted based on an improvement (reduction) of ≥ 2 points from baseline. Change in FEV1 from baseline before dose

[0281] Changes in pre-dose / pre-BD FEV1 from baseline will be analyzed using a repeated measures analysis model similar to that used for changes in SGRQ scores from baseline, but with analysis by treatment, visits, treatment-while-visit interactions, region, maintenance inhalation therapy, and the number of exacerbations fitted as a categorical covariate in the previous year, as well as baseline FEV1 and log-screened blood eosinophil counts as continuous covariates. Comparisons will be used to generate treatment effect estimates at each visit (including weeks 24 and 52) and within 52 weeks. This will be reported along with bilateral 95% CI and p-values. Other secondary endpoints

[0282] The time of first severe exacerbation and the annualized severe exacerbation rate will be analyzed in a manner similar to that described above for moderate or severe exacerbation.

[0283] We will use a method similar to that used for the SGRQ total score to analyze the change in the CAT total score from baseline and the proportion of participants with a decrease (improvement) of ≥ 2 points in the CAT total score. [] [References] []

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Wedzicha JA, Seemungal TA. COPD exacerbations: defining their cause and prevention. Lancet.2007;370(9589):786-96. Corhay JL, Vincken W, Schlesser M, Bossuyt P and Imschoot J. Chronic bronchitis in COPD patients is associated with increased risk of exacerbations: a cross-sectional multicentre study. Int J Clin Pract 2013;67(12):1294-301. Crawford B, Monz B, Hohlfeld J, Roche N, Rubin B, Magnussen H, et al. Development and validation of a cough and sputum assessment questionnaire. Respir Med2008;102(11):1545-55. de Oca MM, Halbert RJ, Lopez MV, Perez-Padilla R, Tálamo C, Moreno D, et al. The chronic bronchitis phenotype in subjects with and without COPD: the PLATINO study. Eur Respir J 2012;40(1):28-36. Jones PW and Forde Y. St George’s respiratory questionnaire manual. 2009. Version 2.3. Kim V, Han MK, Vance GB, Make BJ, Newell JD, Hokanson JE, et al. The chronic bronchitic phenotype of COPD: an analysis of the COPDGene Study. Chest 2011;140(3):626-33. Kim V and Criner GJ. Chronic bronchitis and chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2013;187(3):228-37. Martinez FJ, Calverley PM, Goehring U-M, Brose M, Fabbri LM, Rabe KF. Effect of roflumilast on exacerbations in patients with severe chronic obstructive pulmonary disease uncontrolled by combination therapy (REACT): a multicentre randomised controlled trial. Lancet 2015;358(9971):857-66. <<MASK_ >Monz BU, Sachs P, McDonald J, Crawford B, Nivens MC and Tetzlaff K. Responsiveness of the cough and sputum assessment questionnaire in exacerbations of COPD and chronic bronchitis. Respir Med 2010;104(4):534-41. NIH. Guidelines for the prevention and treatment of opportunistic infections in adults and adolescents with HIV. Available from URL: https: / / aidsinfo.nih.gov / contentfiles / lvguidelines / adult_oi.pdf. Published in 2019. Accessed on March 17, 2020. Smith J, Owen E, Earis J and Woodcock A. Cough in COPD: correlation of objective monitoring with cough challenge and subjective assessments. Chest 2006;130(2):379-85. Woodruff PG, Barr RG, Bleecker E, Christenson SA, Couper D, Curtis JL, et al. Clinical Significance of Symptoms in Smokers with Preserved Pulmonary Function. N Engl J Med 2016;374(19):1811-21. For standard molecular biology techniques, see Sambrook, J., Russel, D.W. Molecular Cloning, A Laboratory Manual.3 ed. 2001, Cold Spring Harbor, New York: Cold Spring Harbor Laboratory Press [Sequence] [ ] [SEQ ID NO:] [Description] [Sequence] 1. ​​​​​​​​​​​​​​​ 4. MEDI3506 VH domain (amino acid) EVQLLESGGGLVQPGGSLRLSCAASGFTFSSYAMSWVRQAPGKGLEWVSGISAIDQSTYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARQKFMQLWGGGLRYPFGYWGQGTMVTVSS 5. MEDI3506 VLCDR1 (Amino Acid) SGEGMGDKYAA 6. MEDI3506 VLCDR2 (Amino Acid) RDTKRPS 7. MEDI3506 VLCDR3 (Amino Acid) GVIQDNTGV 8. MEDI3506 VL domain (amino acid) SYVLTQPPSVSVSPGQTASITCSGEGMGDKYAAWYQQKPGQSPVLVIYRDTKRPSGIPERFSGSNSGNTATLTISGTQAMDEADYYCGVIQDNTGVFGGGTKLTVL 9. MEDI3506 Light Chain (Amino Acids) SYVLTQPPSVSVSPGQTASITCSGEGMGDKYAAWYQQKPGQSPVLVIYRDTKRPSGIPERFSGSNSGNTATLTISGTQAMDEADYYCGVIQDNTGVFGGGTKLTVL GQPKAAPSVTLFPPSSEELQANKATLVCLISDFYPGAVTVAWKADSSPVKAGVETTTPSKQSNNKYAASSYLSLTPEQWKSHRSYSCQVTHEGSTVEKTVAPTECS 10. MEDI3506 Heavy Chain (Amino Acids) EVQLLESGGGLVQPGGSLRLSCAASGFTFSSYAMSWVRQAPGKGLEWVSGISAIDQSTYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARQKFMQLWGGGLRYPFGYWGQGTMVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK 11 Full-length IL-33 protein MKPKMKYSTNKISTAKWKNTASKALCFKLGKSQQKAKEVCPMYFMKLRSGLMIKKEACYFRRETTKRPSLKTGRKHKRHLVLAACQQQSTVECFAFGISGVQKYTRALHDSSITGISPITEYLASLSTYNDQSITFALEDESYEIYVEDLKKDEKKDKVLLSYYESQHPSNESGDGVDGKMLMVTLSPTKDFWLHANNKEHSVELHKCEKPLPDQAFFVLHNMHSNCVSFECKTDPGVFIGVKDNHLALIKVDSSENLCT ENILFKLSET

[0285] None

[0286] None

[0287] TW202327648A_111132194_SEQL.xml

Claims

1. Use of a pharmaceutical composition for preparing a pharmaceutical product for chronic obstructive pulmonary disease (COPD) in an individual, wherein the pharmaceutical composition comprises an anti-IL-33 antibody or an antibody variant thereof, and the pharmaceutical composition is administered to the individual at an interval of about 300 mg of the anti-IL-33 antibody or an antibody variant thereof every 2 weeks (Q2W), every 4 weeks (Q4W), or every 8 weeks (Q8W), or at an interval of about 600 mg of the anti-IL-33 antibody or an antibody variant thereof every 4 weeks (Q4W), wherein the anti-IL-33 antibody or an antibody variant thereof comprises a VH domain having the sequence shown in SEQ ID NO:4 and a VL domain having the sequence shown in SEQ ID NO:

8.

2. As requested in item 1, wherein the COPD is associated with chronic bronchitis in the individual.

3. As requested in item 1, wherein the COPD is moderate COPD, moderate to severe COPD, or severe COPD.

4. As requested in item 1, wherein the individual has a history of at least one or two moderate or at least one severe acute exacerbation of COPD (aeCOPD) within the 12 months prior to treatment.

5. For the purposes of request item 1, wherein prior to treatment, the individual’s forced expiratory volume in one second (FEV1) to forced vital capacity (FVC) ratio (FEV1 / FVC after bronchodilator (BD)) is less than (<) 0.70 and / or FEV1 after BD is greater than 20% of the predicted normal value.

6. As requested in item 1, wherein the system is for current or former smokers, or wherein the individual has a smoking history of at least 10 pack-years.

7. For the purposes of claim 1, wherein the individual is receiving COPD inhaled maintenance therapy, including long-acting β2 agonists (LABA), long-acting muscarinic receptor antagonists (LAMA), and / or inhaled corticosteroids (ICS).

8. As claimed in claim 7, wherein the inhaled maintenance therapy comprises LABA and LAMA, ICS and LABA, or ICS, LABA and LAMA.

9. As claimed in claim 1, wherein the annualized rate of moderate to severe COPD exacerbation is reduced in the individual by administration of the pharmaceutical composition and / or the time of first moderate to severe COPD exacerbation is increased in the individual by administration of the pharmaceutical composition.

10. As claimed in claim 1, wherein the post-bronchodilator FEV1 and / or the FEV1 to forced vital capacity (FVC) ratio (FEV1 / FVC) is improved in the individual by administration of the pharmaceutical composition.

11. As requested in item 1, wherein scores from one or more of the following questionnaires are improved in the individual upon administration of the pharmaceutical composition: the COPD Respiratory Symptom Assessment Scale (E-RS), the St. George Respiratory Questionnaire (SGRQ), the COPD Assessment Test (CAT), the Chronic Lung Disease Exacerbation Tool - Patient Reported Outcomes (EXACT-PRO), the Shortness of Breath, Cough and Sputum Scale (BCSS), the Five Levels Five Dimensions Health Scale (EQ-5D-5L), the Work Efficiency and Activity Levels Questionnaire (WPAI-GH), the Patient Severity Global Impression Scale (PGIS), or the Patient Global Impression Change Scale (PGIC).

12. As requested in item 11, wherein the minimum clinically significant difference in the E-RS:COPD score, SGRQ score, and / or CAT score is achieved.

13. As requested in claim 1, wherein the dose effectively achieves a Cmax.ss from about 10 to 35 µg / ml during the administration period.

14. As claimed in claim 1, wherein the anti-IL-33 antibody or an antibody variant thereof is selected from: human antibodies, humanized antibodies, chimeric antibodies, monoclonal antibodies, recombinant antibodies, antigen-binding antibody fragments, single-chain antibodies, monomeric antibodies, biantibodies, triantibodies, tetraantibodies, Fab fragments, IgG1 antibodies, IgG2 antibodies, IgG3 antibodies, and IgG4 antibodies.

15. As claimed in claim 1, wherein the anti-IL-33 antibody or its antibody variant IgG1.

16. As claimed in claim 1, wherein the anti-IL-33 antibody comprises a light chain sequence as shown in SEQ ID NO:9 and a heavy chain sequence as shown in SEQ ID NO:

10.

17. As used in claim 1, wherein the anti-IL-33 system is 33_670087_7B (MEDI3506).

18. As requested in item 1, wherein the investment is a subcutaneous investment.

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