CN117858898A

CN117858898A - Treatment of chronic obstructive pulmonary disease with anti-interleukin-33 antibodies

Info

Publication number: CN117858898A
Application number: CN202280051952.9A
Authority: CN
Inventors: M·W·萨迪克; E·J·洛萨诺
Original assignee: MedImmune Ltd
Current assignee: MedImmune Ltd
Priority date: 2021-08-27
Filing date: 2022-08-26
Publication date: 2024-04-09

Abstract

The present disclosure relates to methods of treating COPD, in particular by administering anti-IL-33 antibodies or antibody variants thereof in a prescribed dosing regimen.

Description

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

Technical Field

The present disclosure relates to methods of treating COPD, in particular by administering anti-IL-33 antibodies or antibody variants thereof.

Background

Chronic obstructive pulmonary disease is the fourth leading cause of death in the world and is expected to be the third leading cause of death worldwide by 2030 (Adeloye et al 2015). Chronic obstructive pulmonary disease is characterized by sustained respiratory symptoms and restricted airflow (first second forced expiratory volume [ FEV1 ]/forced vital capacity [ FVC ] < 0.70) following bronchodilators [ BD ], due to airway and/or alveoli abnormalities, typically caused by exposure to toxic particles or gases in large amounts, and affected by host factors including pulmonary dysplasia. Serious co-diseases may have an impact on morbidity and mortality (GOLD global initiative for chronic obstructive pulmonary disease 2020). Chronic obstructive pulmonary disease is a life-threatening respiratory disorder, and the course of the disease is characterized by long-term disability, which results in significant loss of health-related quality of life (van Manen et al 2003).

Chronic obstructive pulmonary disease is not fully reversible, is often progressive, and is associated with an increase in chronic inflammatory response in the lung. There is increasing evidence that the overall symptomatic burden has a significant adverse impact on health-related quality of life and also leads to increased risk of exacerbation and worsening of disease prognosis (miravitles and Ribera 2017).

Acute exacerbations of COPD are symptomatic exacerbations with significant adverse consequences for the patient (Wedzicha and seemngal 2007). Higher exacerbation frequencies are associated with accelerated lung function decline, impaired health-related quality of life, and increased mortality (Donaldson et al 2002, seemngal et al 1998, solar-Cataluna et al 2005). Furthermore, as COPD incidence increases, exacerbations place a greater burden on healthcare systems, resulting in over 1000 tens of thousands of unscheduled visits per year in the united states (Mannino and Braman 2007). In the united states, the direct cost of COPD treatment exceeds $ 320 million per year, estimated to be 50% to 75% of these medical 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 is aimed at preventing and reducing its frequency and severity (ritche and Wedzicha 2020).

Despite adequate treatment by optimized maintenance inhalation therapy, about 30% to 40% of patients continue to develop moderate or severe exacerbations (Mullerova et al 2017, vestbo et al 2017). Even the maximum triple therapy (laba+lama+ics) may remain inadequate (Rabe et al 2020); thus, there is still a great unmet medical need.

Disclosure of Invention

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

Interleukin-33 expression increases 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 potentially disrupts circulation of inflammatory structural damage in the lungs of patients with COPD and thereby provides therapeutic benefit to patients with COPD.

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

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

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

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

In some cases, the dose is about 300mg to about 600mg, at intervals of once every 4 weeks (Q4W) or once every 8 weeks (Q8W). In some cases, the dose is about 300mg of 8w. In some cases, the dose is about 300mg q4w. In some cases, the dose is about 150mg q4w.

In some cases, the COPD is associated with chronic bronchitis in the subject.

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

In some cases, the subject to be treated has a history of at least one, optionally at least two, moderate, or at least one acute exacerbation of severe COPD (aecpd) within 12 months prior to treatment.

In some cases, the subject's first second Forced Expiratory Volume (FEV) after bronchodilator prior to treatment ₁ ) Ratio to Forced Vital Capacity (FVC) (post BD FEV ₁ FVC) is less than%<) 0.70. In some cases, the subject has post BD FEV1 prior to treatment>20% of normal values were predicted.

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

In some cases, the subject to be treated is receiving COPD inhalation maintenance therapy, including a long-acting β2 agonist (LABA), a long-acting muscarinic receptor antagonist (LAMA), and/or an Inhaled Corticosteroid (ICS). In some cases, the inhalation maintenance therapy comprises LABA and LAMA, ICS and LABA, or ICS, LABA and LAMA.

In some cases, the anti-IL-33 antibody or antibody variant thereof is selected from the group consisting of: human antibodies, humanized antibodies, chimeric antibodies, monoclonal antibodies, recombinant antibodies, antigen-binding antibody fragments, single chain antibodies, monomeric antibodies, diabodies, triabodies, tetrabodies, fab fragments, lgG1 antibodies, lgG2 antibodies, lgG3 antibodies, and lgG4 antibodies.

In some cases, the anti-IL-33 antibody or antibody variant thereof is IgG1.

In some cases, the anti-IL-33 antibody or antibody variant thereof is a human antibody.

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

In some cases, the anti-IL-33 antibody comprises a VH domain sequence as set forth in SEQ ID NO. 4 and a VL domain sequence as set forth in SEQ ID NO. 8.

In some cases, the anti-IL-33 antibody comprises a light chain sequence as set forth in SEQ ID NO. 9 and a heavy chain sequence as set forth in SEQ ID NO. 10.

In some cases, the anti-IL-33 antibody variant has the same pharmacokinetic (pK) profile in humans as 33_670087_7b (MEDI 3506/tolazolyl mab (tolazolakimab)).

In some cases, the anti-IL-33 antibody is tolazolidone.

In some cases, the administration is subcutaneous.

In another aspect, the present disclosure provides a method of improving a marker of Chronic Obstructive Pulmonary Disease (COPD) in a subject, the method comprising: a therapeutically effective amount of an anti-IL-33 antibody or antibody variant thereof, at a dose of from about 300mg to about 600mg, administered at once every 4 weeks (Q4W) or once every 8 weeks (Q8W) intervals, wherein the anti-IL-33 antibody comprises: a heavy chain variable region comprising HCDR1 having a sequence as set forth in SEQ ID No. 1, VHCDR2 having a sequence of SEQ ID No. 2, VHCDR3 having a sequence of SEQ ID No. 3; and a light chain variable region comprising a VLCDR1 having the sequence of SEQ ID NO. 5, a VLCDR2 having the sequence of SEQ ID NO. 6, and a VLCDR3 having the sequence of SEQ ID NO. 7. The marker is selected from: the rate of annual moderate to severe COPD exacerbations, time to first moderate to severe COPD exacerbations, FEV1, first second forced expiratory volume (FEV 1), ratio of FEV1 to Forced Vital Capacity (FVC) (FEV 1/FVC), or breathlessness, cough and sputum scale (BCSS) score, COPD Assessment Test (CAT) score and san jose respiratory questionnaire (SGRQ) score.

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

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

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

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

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

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

Drawings

FIG. 1A shows the amount of IL-33/tolazolidone complexes measured in serum from healthy participants from part I of NCT03096795

FIG. 1B shows the amount of IL-33/sST2 complex measured in serum from healthy participants from part I of NCT03096795

FIG. 1C shows the amount of IL-33/tolazolyl mab complex measured in serum from participants with COPD from part II of NCT03096795

FIG. 1D shows the amount of IL-33/sST2 complex measured in serum from participants with COPD from part II of NCT03096795

FIG. 2A shows free IL-33 measured on day 29 in a 300mg MAD queue ^red IL-33 addition ^red Nasal mucosal lining fluid level of tolazolyl mab

FIG. 2B shows free IL-33 measured on day 29 in a 300mg MAD queue ^red Is a nasal mucosa lining liquid level

FIG. 2C shows free IL-33 measured on day 29 in a 300mg MAD queue ^ox Is a nasal mucosa lining liquid level

FIG. 3 shows that tolazolidone inhibits ex vivo IL-33 attack in whole blood from healthy participants

Fig. 4A shows serum levels of IL-5 for participants in the 300mg MAD cohort on days 1, 14 and 28 (placebo, n=6; tolazolidone (n=6)). The graph shows mean ± SEM. The p-value was generated using a mixed effect longitudinal model to compare the trajectories of biomarkers between tolazolidone and placebo. (p=0.0037)

Fig. 4B shows serum levels of IL-13 for participants in the 300mg MAD cohort on days 1, 14 and 28 (placebo, n=6; tolazolidone (n=6)). The graph shows mean ± SEM. The p-value was generated using a mixed effect longitudinal model to compare the trajectories of biomarkers between tolazolidone and placebo. (p=0.034)

Fig. 4C shows serum levels of eosinophils of participants in the 300mg MAD cohort on days 1, 14 and 28 (placebo, n=6; tolazolidone (n=6)). The graph shows mean ± SEM. The p-value was generated using a mixed effect longitudinal model to compare the trajectories of biomarkers between tolazolidone and placebo. (p=0.0023)

FIG. 5 shows that Alternaria alternata (Alternaria alternata) induces rapid IL-33 release in bronchoalveolar lavage (BALF) of humanized IL-33 mice

FIG. 6 shows that tolazolidone inhibits ALT-induced BALF IL-5 in humanized IL-33 mice. The test substance was given intranasally-24 hours prior to challenge with ALT. BALF was harvested 24 hours after ALT challenge and analyzed for the presence of IL-5. Significant effects of test substances were determined by the Ponfronitude multiple comparison test using one-way ANOVA. * P <0.001, < p <0.01 (n=4)

FIG. 7A shows scarification wound repair of normal human bronchial epithelial cells after treatment with wild type IL-33 (IL-33), oxIL-33 and oxIL-33+ anti-ST 2 antibodies

FIG. 7B shows quantification of% wound closure for the scratch wound assay depicted in FIG. 3A

FIG. 8 shows that scarified wound lesions are also seen in bronchial epithelial cells obtained from COPD subjects

FIG. 9 shows% scratch closure in A549 cells with increased concentrations of tolazolidone and anti-TSLP antibody

FIG. 10 is a PK/PD target engagement model depiction

FIG. 11 shows the predicted value of systemic concentration of tolazolidone from Ph1 dose cohort versus observed systemic concentration of tolazolidone

FIG. 12 shows predicted values of tolazolidone IL-33 complex formulation versus observed tolazolidone IL-33 complex formulation from Ph1 dose cohort

FIG. 13 shows predicted IL-33:sST2 complex reduction from Ph1 dose cohort versus observed IL-33:sST2 complex reduction

FIG. 14 shows predicted IL-33 inhibition by dose response inhibition by the IL33/sST2 complex in blood (Q2W-top row; Q4W-middle row; Q6W-bottom row)

FIG. 15 shows predicted IL-33 inhibition at valleys produced by tolazolidone in the lung (Q4W-top row; Q8W-bottom row)

Fig. 16 shows the predicted serum concentrations of tolazolyl mab from 300mg q4w (up) and 300mg qos 8w (down). The required serum concentrations of 60%, 80% and 90% identified by the Alternaria mouse model are indicated by dashed lines

Fig. 17 shows the predicted serum concentrations of tolazolyl mab from 300mg q4w (up) and 150mg q4w (down). The serum concentration threshold of the reaction in the scratch wound closure assay is shown as a dashed line

Fig. 18 also shows the predicted value of systemic concentration of tolazolidone from Ph1 dose cohort versus observed systemic concentration of tolazolidone

FIG. 19 also shows the predicted decrease in IL-33:sST2 complex from the Ph1 dose cohort relative to the observed decrease in IL-33:sST2 complex

Detailed Description

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

Treatment of COPD

Chronic Obstructive Pulmonary Disease (COPD) is a chronic inflammatory lung disease that causes obstruction of pulmonary airflow. Symptoms include dyspnea, cough, mucous (sputum) production, and wheezing.

COPD is characterized by persistent respiratory symptoms and airflow limitation as reported by airway spirometry, preferably post-bronchodilator (post BD) airway spirometry. As used herein, "post bronchodilator (post BD) airway spirometry" refers to airway spirometry performed after administration of a bronchodilator (typically via an inhaler or nebulizer). In some embodiments, the bronchodilator is selected from albuterol or salbutamol. Post BD spirometry results can be expressed as first second forced expiratory volume (FEV 1) or Forced Vital Capacity (FVC).

The present disclosure provides for the treatment of COPD. In some cases, the COPD is moderate to severe COPD. Moderate to severe COPD is generally characterized by a first second forced expiratory volume (FEV 1) following BD in a subject<80% of the normal value (i.e., the normal value predicted for a healthy patient) is predicted. In some cases, the subject's post BD FEV ₁ <80% of the predicted normal value,<75％、<70％、<65％、<60％、<55％、<50％、<45％、<40% or<35%. In some cases, the subject is post BD FEV1<Predicting 70% of normal value and>30%. In some cases, the subject's post BD FEV ₁ <Predict 80% of normal value and>30％、<75% and>30％、<70% and>30％、<65% and>30％、<60% and>30％，<predict 55% of normal value and>30％，<predict 50% of normal value and>30％，<45% of normal values are predicted and>30％，<predict 40% of normal value and>30%. In some cases, the subject is post BD FEV1<Predict 80% of normal value and>35％、<75% and>35％、<70% and>35％、<65% and>35％、<60% and>35％，<predict 55% of normal value and>35％，<predict 50% of normal value and>35％，<45% of normal values are predicted and>35, or<Predict 40% of normal value and>35%. In some cases, the subject is post BD FEV1<Predicting 60% of normal value and>40％，<predict 55% of normal value and>40％，<predict 50% of normal value and>40, or<45% of normal values are predicted and >40％。

In some cases, the subject is post BD FEV1>20% of normal values were predicted. In some cases, the subject's post-DB FEV ₁ >21% of the predicted normal value,>22％、>23％、>24％、>25％、>26％、>27％、>28％、>29% or>30%. In some cases, the subject is post BD FEV1>30% of normal values were predicted.

In some cases, COPD is characterized by the presence of BD post FEV 1/Forced Vital Capacity (FVC) of <0.70, <0.65, <0.60, <0.55, <0.50, <0.45, <0.40, <0.35 or < 0.30. In some cases, COPD is characterized by the presence of a BD post FEV1/FVC of < 0.70.

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

As used herein, "AECOPD" or "aecpdd" is a change in a subject's common COPD symptoms that persists for 2 days or more, beyond the normal daily change, is acute at the time of onset and may require modification of conventional medication. The change in symptoms may include at least one primary or secondary COPD symptom from the list of:

major COPD symptoms: dyspnea, increased sputum volume, and altered sputum color

Secondary COPD symptoms: cough, wheezing, sore throat, cold symptoms (rhinorrhea or nasal obstruction), and fever without other causes.

In some cases, the change in symptoms includes at least two COPD symptoms from the list above. In some cases, the change in symptoms includes at least one symptom of primary COPD from the list above. In some cases, the change in symptoms includes at least one symptom of primary COPD and at least one other primary or secondary symptom from the list above.

AECOPD may be classified as mild, moderate, or severe. As used herein, "severe AECOPD" is a disease that results in COPD-related hospitalization of an inpatient (e.g., a subject is hospitalized or admitted to a viewing area, emergency department, or other equivalent healthcare facility for ∈24 hours due to exacerbation of COPD, depending on the country and medical regime). Severe AECOPD may lead to COPD-related deaths. "moderate AECOPD" refers to diseases that do not meet the "severe" criteria (i.e., hospitalization). Moderate and severe AECOPD results in the use of systemic corticosteroids and/or antibiotics, or single depot injections of corticosteroid. In some cases, AECOPD is confirmed to occur during the subject being subjected to stable dual or triple maintenance therapies for COPD, and not due to intervals or drops in treatment. Finally, "mild AECOPD" refers to exacerbations that do not meet the "severe" or "moderate" criteria.

The date of onset of AECOPD may be the date of hospitalization (for severe AECOPD) or the date of onset of systemic corticosteroid or antibiotic treatment (for moderate AECOPD), whichever is earlier, and the date of end may be the date of end of systemic corticosteroid or antibiotic treatment or the date of discharge, whichever is later.

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

Another approach to classifying AECOPD is the COPD complex exacerbation (COPDCompEx) algorithm, as described in "copdcompex: A novel composite endpoint for COPD exacerbations to enable faster clinical development [ COPDCompEx: a novel integrated endpoint that enables the realization of a more rapidly clinically developed exacerbation of COPD is outlined in "(Vogelmeier et al Respiratory Medicine [ respiratory medicine ], volume 173, 11/month 2020, 106175). COPDCompEx is a comprehensive endpoint of COPD exacerbation that combines acute exacerbations with events defined by the participants' electronic diaries and PEFs. The definition of two types of exacerbations is as follows: COPDCompEx defines emphasis: resulting in one or more of the following: hospitalization, emergency room visits, treatment with OCS, or treatment with antibiotics. Diary event: by threshold and slope criteria definition, the following diary and home spirometry variables were used: total symptom score, nocturnal arousal due to symptoms, treatment with palliative medication, PEF. Advantageously, COPDCompEx events tend to be more frequent and provide diagnostic capability for the severity of COPD in a shorter time frame than AECOPD events as described above.

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

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

BCSS is a 3-item daily diary (Leidy et al 2003) that evaluates the severity of 3 symptoms: breathlessness, sputum, and cough, each with a 5-component scale. The item scores may be reported as domain scores and summed to produce a total score. In some cases, the subject has a BCSS 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 prior to treatment with the anti-IL 33 antibody or fragment thereof. In some cases, the subject has a score of 2 or greater, 3 or greater, 4 or greater, or 5 in the cough area prior to treatment with the anti-IL 33 antibody or fragment thereof. In some embodiments, the subject has a score of 2 or greater, 3 or greater, 4 or greater, or 5 in the sputum field prior to treatment with the anti-IL 33 antibody or fragment thereof. In some cases, the BSCC score "prior to treatment" is the average of the daily scores recorded within 4 weeks prior to treatment with an anti-IL 33 antibody or fragment thereof as described herein.

In some cases, COPD is classified using chronic lung exacerbation tool-patient report outcome (EXACT-PRO) scores. The EXACT-PRO is a 14 project ePRO tool developed to evaluate the frequency, severity and duration of COPD exacerbations (Jones et al 2011; leidy et al 2011). The tool was developed for daily home applications using a handheld electronic device. Respondents were instructed to complete a diary every night just before bedtime and answer questions while considering their "today's" experience. The daily EXACT-PRO total score has a range of 0 to 100, with higher scores indicating greater severity. The total score change was used to identify onset and recovery of exacerbation events as defined by EXACT-PRO. In identifying event episodes and resumptions, the EXACT-PRO can provide information about the frequency and duration of events and the severity of the events. In some cases, the subject to be treated has an EXACT-PRO score of at least 50, at least 60, at least 70, or at least 80 prior to treatment with an anti-IL 33 antibody or fragment thereof as described herein.

In some cases, COPD may be classified using the Sheng Georgette Respiratory Questionnaire (SGRQ). SGRQ is a 50-item questionnaire developed to measure the health status (quality of life) of patients with airway obstructive disease. The overall score ranges from 0 to 100. The scores of three fields are calculated according to dimensions: symptoms, activities and effects (psycho-social) and total score. A lower score indicates better quality of life (QoL). The first part ("symptom") evaluates symptomatology, including cough, sputum production, wheezing, the frequency of breathlessness, and the duration and frequency of breathlessness or wheezing episodes. The second part has two components: "Activity" and "impact". The "activity" part relates to activities that result in or are restricted by shortness of breath. The term "effect" encompasses, in part, a range of factors including the impact on employment, control of health, panic, plaque formation, the need for medication, side effects of prescribed therapy, the desire for health, and disturbances in daily life. The recall period of the questionnaire was within the past 4 weeks. Psychological tests have demonstrated its repeatability, reliability and effectiveness. Sensitivity has been demonstrated in clinical trials. After patient and clinician testing, the minimum change of 4 units ("the smallest clinically significant difference") was determined to be clinically relevant (Jones COPD 2005 2 (1): 75-9).

In some cases, COPD may be classified by a COPD evaluation test (CAT) score. CAT is a questionnaire designed for patients with COPD that is used to measure the impact of disease on their quality of life. CAT is an 8-item questionnaire completed by patients that overall evaluates the impact of COPD (cough, sputum, dyspnea, chest tightness) on health. CAT ranges from 0 to 40. Higher scores represent more severe effects of COPD on the life of the subject. In some cases, the subject to be treated has a CAT score of at least 10 prior to therapy.

In some cases, COPD may be through E-RS ^TM COPD is classified as 11 items ePRO (Leidy et al 2014a; leidy et al 2014 b) developed to evaluate the severity of respiratory symptoms of COPD. E-RS ^TM COPD is a subset of items from EXACT-PRO. E-RS ^TM COPD is designed to be obtained as part of a daily EXACT-PRO assessment. For E-RS ^TM COPD project response summation yields 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 for breathlessness (5 items; score range: 0 to 17), cough and sputum (3 items; score range: 0 to 11), and chest symptoms (3 items; score range: 0 to 12) by summing the item responses in the corresponding fields. In some cases, the subject to be treated has at least 20. At least 25, at least 30, or at least 35E-RS ^TM COPD score. In some cases, the subject to be treated has an E-RS of at least 6, at least 7, at least 8, at least 9, at least 10, or 11 in the cough and sputum fields ^TM COPD score. In some cases, the subject to be treated has an E-RS of at least 7, at least 8, at least 9, at least 10, at least 11, or 12 in the field of chest symptoms ^TM COPD score. In some cases, the subject to be treated has an E-RS of at least 9, at least 10, at least 11, at least 12, at least 13, at least 14, at least 15, at least 16, or 17 in the field of breathlessness ^TM COPD score.

In some cases, COPD is associated with chronic bronchitis in the subject. Subjects with chronic bronchitis may have symptoms of bronchitis (cough, mucous/sputum production, fatigue, shortness of breath, fever, chill, and/or chest discomfort) for a period of time exceeding 8 weeks, exceeding 16 weeks, exceeding 32 weeks, or exceeding 52 weeks.

In some cases, the subject to be treated is a current smoker or a smoker. In some cases, the subject to be treated has a smoking history of 10 or more years. Years of packing was calculated as the average number of cigarettes per day x years/20. For example, 1 pack year = 20 cigarettes per day for 1 year or 10 cigarettes per day for 2 years.

In some cases, the subject is a current smoker.

In some cases, the subject is a smoker. "smokers" can be defined as subjects who do not smoke at the beginning of the therapy and who quit smoking for a minimum of 6 months before the beginning of the therapy and who intend to quit smoking permanently.

In some embodiments, the subject has a history of inadequate or intolerance to other drug treatments of COPD, such as Inhaled Corticosteroids (ICS), long-acting beta agonists (LABA), and/or long-acting muscarinic antagonists (LAMA), or other drug treatments of these COPD may be otherwise medically undesirable. As used herein, an "insufficient response" to a treatment if administration of the treatment does not result in short-term and/or long-term improvement of one or more symptoms of COPD as described herein. Alternatively, an insufficient response may lead to a recovery of the condition to moderate to severe levels after cessation of the 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 been shown to be unresponsive to such treatment. COPD may be classified as hyporesponsive to therapy if, despite treatment, COPD is moderate to severe, or if the subject develops a moderate or severe AECOPD event after the course of therapy is discontinued or completed.

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

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

As used herein, "long acting beta-2 adrenergic receptor agonist (LABA)" refers to any beta-adrenergic receptor agonist that has a duration of action of about 12 hours or more. This is in contrast to Short Acting Beta Agonists (SABA) such as salbutamol, which have a duration of action of about 4-6 hours. Exemplary LABAs include amorolfine, bambuterol, clenbuterol, formoterol, salmeterol, and praline Luo Tuochun. The LABA may be a "super LABA" with an action duration of 24 hours or more, such as indacaterol, odaterol, or vilanaterol. LABA can be administered by any suitable route, for example by using a nebulizer, inhaler, or nebulizer.

As used herein, a Long Acting Muscarinic Antagonist (LAMA) is an anticholinergic agent that blocks the activity of a muscarinic acetylcholine receptor. Exemplary LAMAs include tiotropium bromide, glycopyrrolate, and aclidinium bromide. LAMA may be administered by any suitable route, for example by using a nebulizer, inhaler, or nebulizer.

A subject that is "intolerant" to treatment is one for whom treatment causes one or more side effects that make continued treatment undesirable. For example, an allergic response to treatment may be indicative of intolerance.

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

in association with chronic bronchitis in a subject,

a medical history of acute exacerbations of at least one, optionally at least two, moderate or at least one severe COPD within 12 months prior to treatment,

the ratio of first second forced expiratory volume (FEV 1) to Forced Vital Capacity (FVC) after bronchodilator (FEV 1/FVC after BD) <0.70, and/or FEV1> after BD predicts 30% and <80% of normal value.

Average breathlessness, cough and sputum scale (BCSS) score >2 in the cough area and/or >2 in the sputum area.

In some cases, COPD to be treated is characterized by:

a medical history of at least two acute exacerbations of moderate or at least one severe COPD within 52 weeks prior to treatment,

ratio of forced expiratory volume (FEV 1) to Forced Vital Capacity (FVC) first second after bronchodilator (BD post FEV 1/FVC) <0.70

FEV1> after BD predicts 20% of normal value.

Prior to treatment, CAT score is greater than or equal to 10, and each of the sticky sputum and cough projects is greater than or equal to 2.

In certain instances, the subject has a blood eosinophil count of greater than or equal to about 300 cells/μl or less than 300 cells/μl prior to treatment. In some cases, the subject has a blood eosinophil count of greater than or equal to 300 cells/μl prior to treatment.

Administration protocol

The present disclosure relates to dosage regimens for anti-IL-33 antibodies or antibody variants that are particularly effective in the treatment of COPD. The dosage regimen consists of one or more controlled-size doses administered throughout the treatment window. Where there is more than one dose, the doses are separated by a dosing interval. The anti-IL-33 antibody or antibody variant is administered in a therapeutically effective amount. As used herein, an "effective amount" or "therapeutically effective amount" of an agent (e.g., a pharmaceutical formulation) comprising an IL-33 antibody refers to an amount effective to achieve a desired therapeutic or prophylactic result at the requisite dosage and for the requisite period of time.

The dose size of an anti-IL-33 antibody or antibody variant thereof may be expressed in terms of the weight of the anti-IL-33 antibody or antibody variant. In certain instances, the anti-IL-33 antibody or antibody variant thereof is administered at a dose of about 400 to about 800mg, about 450 to about 750mg, about 500 to about 700mg, about 510 to about 690mg, about 520 to about 680mg, about 530 to about 670mg, about 540 to about 660mg, about 550 to about 650mg, about 560 to about 640mg, about 570 to about 630mg, about 580 to about 620mg, about 590 to about 630mg, or about 600mg.

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

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

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

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

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

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

The examples show that a 300mg Q4W or Q8W dosing regimen of MEDI3506 would be predicted to achieve the serum concentrations required to inhibit both the redIL-33:st2 signaling axis and the oxIL-33:rage/EGFR signaling axis, thereby achieving sustained dual pathway inhibition (fig. 16 and 17). Can be suitably measuredMEDI3506 serum concentration of anti-drug antibody reagent (and thus used to determine C) _max.ss ) To capture and detect MEDI3506 from a biological sample (e.g., blood). In some cases, the assay may use an anti-IgG 1 capture mAb and a stabilized MEDI3506 antigen labeled with a detectable marker. The detectable marker may be quantified to determine the concentration of MEDI3506. In some cases, the MEDI3506 antigen (IL-33) may be stabilized in a reduced form, for example, by mutating one or more cysteine residues to serine, to prevent conversion of redIL-33 to an oxidized form (oxIL-33) by disulfide bond formation. Assays and platforms suitable for detecting serum biomarkers are well known to those skilled in the art.

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

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

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

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

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

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

In some cases, one dose may be administered over multiple days, e.g., as two or more sub-doses. As used herein, a "sub-dose" is a component of a dose of therapeutic agent such that the total amount of therapeutic agent administered in the sub-dose is equal to the total amount of the dose. Any component may be used, for example such that two, three, four, five or more sub-doses constitute a single dose. In some cases, one dose may be administered as two or more sub-doses separated by a period of 1, 2, 3, 4, 5, or 6 days. In some cases, one dose may be administered as two or more sub-doses separated by a period of 1, 2, or 3 weeks. Sub-doses may be administered for two, three, four or more consecutive days. The sub-doses constituting a dose may be equal in size or may be different in size, so long as the total amount is equal to the dose.

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

When the dosing interval is expressed as a number of weeks, a certain margin of error is allowed so that one week can be expressed as 7 days ± 1 day. In some embodiments, a week may be expressed as 7 days ± 0.5 days, 7 days ± 0.25 days, or just 7 days. When the dosing interval is several weeks, the weekly error magnitudes may 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 period 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.

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

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 more.

In some cases, the anti-IL-33 antibody or antibody variant thereof is administered at about 300mg q4 w. The examples show that administration of MEDI3506 300mg q4w is predicted to achieve approximately 94% depletion (target engagement) in the lung. This level of target engagement is potentially greater than that achieved by the predicted anti-IL-33 antibody, et Ji Shan anti (itepekimab), of which recentlyPhase II studies of COPD resulted in significant reductions in COPD exacerbations and significant improvements in FEV1 in the smokers (Rabe et al 2021). Compared to MEDI3506, etide Ji Shan anti has a significantly longer reported half-life (etide Ji Shan anti t _1/2 (which is also referred to as SAR440340 and REGN 3500) is reported in US2021/0000949 as 30 days-see [411 ] therein])。

In some cases, the anti-IL-33 antibody or antibody variant thereof is administered at about 300mg qos. The examples show that administration of MEDI3506 300mg qmw (i.e., twice the dosing window) would be predicted to provide IL 33 inhibition in lung tissue of approximately 83% at the trough; thus, it may provide sufficient efficacy in COPD, with a frequency of doses that is more convenient for the patient than Q4W.

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

Marker for COPD

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

COPD markers include: annual 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, CAT score.

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

In some cases, an improvement in CAT score means that the CAT score of the subject is reduced by more than or equal to 2 ("minimal clinically significant difference" or "MCID") as compared to baseline.

In some cases, an improvement in SGRQ score means that the subject's total SGRQ score is reduced by more than or equal to 4 ("minimal clinically significant difference" or "MCID") as compared to baseline.

In some cases, a change in the marker is observed after the treatment window. In some cases, observations are made immediately after the treatment window. In some cases, observations are made after an additional period of time running immediately from the treatment window. The additional period of time may be 1, 2, 3, 4, 5, 6, or more days. The additional period of time may be 1, 2, 3, 4, or more weeks. The additional period of time may be 1, 2, 3, 4, or more months. The additional period of time may be the same length as the dosing interval such that the additional period of time follows the final dose and runs until the point at which another dose expires. The treatment window plus any additional time period may be referred to as an "intervention window". Some therapeutic results may be measured after an intervention window, such as changes in pre-or post-BD FEV1 or FEV1 i/FVC.

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

Alternatively or additionally, changes in the markers may be observed during the treatment window. The marker may be observed at the end of a dosing period, e.g., a first, second, third, fourth, fifth, sixth, seventh, or additional dosing period. Alternatively, the marker may be observed or measured one day after the end of a dosing period, e.g., a first, second, third, fourth, fifth, sixth, seventh, or additional dosing period. The marker may be observed or measured one day before the end of the administration period, e.g., the first, second, third, fourth, fifth, sixth, seventh, or additional administration period. The marker may be observed two days after the end of a dosing period, e.g., a first, second, third, fourth, fifth, sixth, seventh, or additional dosing period. The marker may be observed two days before the end of the dosing period, e.g., the first, second, third, fourth, fifth, sixth, seventh, or additional dosing period. The marker may be observed three days after the end of a dosing period, e.g., a first, second, third, fourth, fifth, sixth, seventh, or additional dosing period. The marker may be observed three days before the end of the dosing period, e.g., the first, second, third, fourth, fifth, sixth, seventh, or additional dosing period. The marker may be observed four days after the end of a dosing period, e.g., a first, second, third, fourth, fifth, sixth, seventh, or additional dosing period. The marker may be observed four days before the end of the dosing period, e.g., the first, second, third, fourth, fifth, sixth, seventh, or additional dosing period. In some embodiments, the treatment window is 24 weeks, and changes in symptoms are observed during cycle 12.

Certain treatment results, such as changes in pre-BD FEV1 or FEV1 i/FVC scores, can be measured at week 4, 12, 24, or 28, 36, or 52 time points.

As described herein, treatment with an anti-IL-33 antibody or variant thereof may result in an increase in first second forced expiratory volume (FEV 1) as defined herein, particularly an increase relative to baseline observed after the treatment window (and any additional period of time as defined herein). In some cases, an increase in FEV1 relative to baseline is observed at weeks 2, 4, 8, 12, 16, 20, 24, 28, 32, 36, or 52. In some cases, FEV was observed at weeks 4, 12, 24, 36 or 52 ₁ Increased relative to baseline. In some cases, FEV ₁ An increase is an increase of 5%, 10%, 15%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, or more than 100% of FEV1 observed prior to treatment. In some cases, FEV ₁ The increase is to the predicted normal value>70％、>75% or>80％。

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

In some cases, the one or more markers are selected from a decrease in frequency, duration, or severity of AECOPD relative to baseline, optionally a decrease in 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.

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

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

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

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

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

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

In some cases, the treatment results in a decrease in objective cough frequency over 24 hours relative to baseline. Objective cough frequency within 24 hours can be measured using an automated cough detector (ACM), such as VitaloJAK ^TM (Vitalograph, white gold Hanshire, UK) and the detector was mounted and worn by the subject for approximately 24 hours and the cough frequency recorded. Alternatively, the objective cough frequency may be recorded by alternative means, such as recording or directly observing the subject, followed by building an integral table or count. In some embodiments, the objective cough frequency reduction is a 5%, 10%, 15%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95% or more than 95% reduction from baseline.

In some cases, the treatment results in a reduced usage of the drug treatment, including a reduced usage of the relief inhaler relative to baseline. The use of the mitigator may be expressed as the number of injections (i.e., the sum of the different mitigators, if applicable) used by the subject over a 24 hour period. In some cases, the usage of the mitigator is expressed as an average usage over a 24 hour period, i.e., the total count of the usage of the mitigator over a period of time and averaged over 24 hours, wherein the period of time is greater than or less than 24 hours. In some cases, the reduction in remission drug therapy use is a 5%, 10%, 15%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95% or more than 95% reduction relative to baseline.

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

In some cases, the treatment results in E-RS ^TM COPD score decreased relative to baseline. In some cases, the decrease is in E-RS ^TM 5, 10, 15, 20, 25, 30, 35 or more points on the COPD scale relative to baseline. In some cases, the decrease is from a baseline score of 9 or greater to a post-treatment score of less than 9 in the breathlessness domain. In some cases, the decrease is from a baseline score of 6 or greater to a post-treatment score of less than 6 in the area of cough and sputum. In some cases, the decrease is from a baseline score of 7 or greater to a post-treatment score of less than 7 in the field of chest symptoms.

In some cases, the treatment results in an improvement of the cough visual analog scale (cough VAS) relative to baseline. Cough VAS, or cough severity VAS, comprising a 100mm linear scale marked by a horizontal line by the subject, wherein 0mm indicates "no cough" and 100mm indicates "most severe cough", thereby measuring subjective assessment of cough symptom severity by the subject for the first 24 hours (Smith et al 2006). In some cases, the improvement is a 5%, 10%, 15%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95% or more than 95% decrease in cough VAS from baseline.

In some cases, the treatment results in an improvement in breathlessness, cough, and sputum scale (BCSS) scores relative to baseline. In some cases, the improvement is a decrease in total score relative to baseline. In some cases, the improvement is a 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or more than 10 point improvement in total. In some cases, the improvement comprises a decrease in sputum and/or cough area score relative to baseline. In some embodiments, the improvement is a 2, 3, 4, or 5 point decrease in sputum and/or cough area score. In some cases, the improvement in BCSS score includes a reduction in sputum and/or cough domain score from >2 to <2. In some cases, the improvement in BCSS score includes a reduction in sputum and/or cough domain score from >2 to <2.

In some cases, the treatment results in an improvement in cough and sputum assessment questionnaire (CASA-Q) scores over baseline. CASA-Q is a self-filling questionnaire that evaluates cough and sputum based on the frequency, severity, and impact on daily activity of cough and sputum over the previous 7 days (Crawford et al 2008; monz et al 2010). CASA-Q includes four fields: cough symptoms, cough effects, sputum symptoms, and sputum effects. Each field includes three to eight items, each item being answered in five categories, with frequencies from "never" to "always" and intensities from "completely never" to "many/very". For each domain, items are rescaled to obtain scores ranging from 0 to 100, with higher scores, fewer symptoms or less impact. In some cases, the improvement is an increase in the score of one or more of the four areas relative to the baseline. In some cases, the fractional increase in the field is a 10, 20, 30, 40, 50, 60, 70, 80, or more fractional increase relative to baseline.

In some cases, the treatment results in an improvement in the sheng-georgette respiratory questionnaire (SGRQ) score relative to baseline. SGRQ is a 50 project ePRO tool developed to measure the health status of participants with airway obstructive disease (Jones et al 1991). The questionnaire is divided into 2 parts: part 1 consists of 8 items concerning the severity of respiratory symptoms in the first 4 weeks; part 2 consists of 42 items related to the daily activities and psychosocial effects of an individual's respiratory illness. SGRQ produces a total score and 3 domain scores (symptoms, activities, and effects). The total score indicates the effect of the disease on the overall health condition. This total score is expressed as a percentage of total damage, where 100 represents the worst possible health condition and 0 indicates the best possible health condition. Likewise, the domain score ranges from 0 to 100, with higher scores indicating greater impairment. Based on empirical data and interviews with patients, a change of 4 units is associated with a minimum clinically significant difference. Specific details of the scoring algorithm are provided by the developer in the user manual (Jones and Forde 2009). In some cases, the improvement is a 4 or more unit decrease in SGRQ score from baseline. In some embodiments, the improvement is an SGRQ score decrease of 8, 12, 16, 20 or more units from baseline. In some cases, the improvement is a 5, 10, 20, 30, 40, 50, 60, 70, 80 or more units decrease in SGRQ score from baseline.

In some cases, the treatment results in a reduction in the frequency, duration, or severity of COPD symptoms selected from the group consisting of: dyspnea, increased sputum volume, altered sputum color, cough, wheezing, sore throat, cold symptoms (rhinorrhea or nasal obstruction), and fever without other causes. In some cases, the treatment results in a decrease in the frequency, duration, or severity of a symptom selected from the group consisting of: dyspnea, increased sputum volume, and altered sputum color. In some embodiments, the treatment results in a reduction in the frequency, duration, or severity of a symptom selected from the group consisting of: cough, wheezing, sore throat, cold symptoms (rhinorrhea or nasal obstruction), and fever without other causes.

In some cases, the treatment results in a decrease in the frequency, duration, of one or more of the following symptoms of chronic bronchitis in the subject: cough, mucous/sputum production, fatigue, shortness of breath, fever, chill, and/or chest discomfort. In some cases, the treatment results in a decrease in the frequency, duration, or severity of symptoms of chronic bronchitis 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 antibodies

The therapies described herein relate to anti-IL-33 antibodies and variants and fragments thereof.

Interleukin-33 (IL-33) is a member of the interleukin-1 (IL-1) cytokine family encoded by the IL33 gene. IL-33 is constitutively expressed in a variety of cell types, including structural cells, such as smooth muscle cells, epithelial cells, and endothelial cells. Expression of IL-33 is also reported to be induced by inflammatory factors in macrophages and dendritic cells. Cellular stress and mechanical damage caused by environmental triggers (such as allergens, toxins, and pathogens) can lead to IL-33 release. Free IL-33 associates with an exogenous dimeric IL-33 receptor complex consisting of inhibition of tumorigenic 2 (ST 2) protein and interleukin-1 receptor accessory protein (IL-1 RAcP) to activate AP-1 and NF- κb pathways through adaptor protein myeloid differentiation primary response 88 (MyD 88) and possibly MyD88 adaptor-like (Mal) proteins. IL-33 stimulates a variety of cell types, including congenital lymphoid type II cells (ILC 2), mast cells, basophils, eosinophils, and dendritic cells, to promote an immune response.

The terms "interleukin 1 receptor like 1 (IL 1RL 1)" and "ST2" are used interchangeably herein to refer to any native 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 known in the art as DER4, T1, and FIT-1. The term encompasses "full-length" untreated ST2 as well as any form of ST2 resulting from treatment in a cell. At least four isoforms of ST2 are known in the art, including soluble ST2 (sST 2, also known as IL1rl 1-a) and transmembrane ST2 (ST 2L, also known as IL1rl 1-b), which result from differential mRNA expression by the dual promoter system; and ST2V and ST2LV, which result from alternative splicing. The domain structure of ST2L includes three extracellular immunoglobulin-like C2 domains, one transmembrane domain and one cytoplasmic Toll/interleukin-1 receptor (TIR) domain. sST2 lacks the transmembrane and cytoplasmic domains contained within ST2L and includes a unique 9 amino acid (a.a.) C-terminal sequence (see, e.g., kakkar et al Nat. Rev. Drug Disc. [ Nature reviewed: drug discovery ] 40:827-840,2008). sST2 may act as a decoy receptor to inhibit soluble IL-33. The term also encompasses naturally occurring variants of ST2, such as splice variants (e.g., ST2V lacking the third immunoglobulin motif and having a unique hydrophobic tail and ST2LV lacking the transmembrane domain of ST 2L) or allelic variants (e.g., variants having a protective effect on or conferring risk of COPD as described herein). The amino acid sequence of exemplary human ST2 can be found, for example, under UniProtKB accession number 001638. ST2 together with the co-receptor protein IL-1RAcP is part of the IL-33 receptor. 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 signaling (Lingel et al Structure 17 (10): 1398-1410,2009; and Liu et al Proc. Nat. Acad. Sci. [ Proc. Natl. Sci. USA 11 0 (37): 14918-14924,2013).

It is envisaged that antibodies or antibody variants that specifically bind to and inhibit components of the IL-33/ST2 signaling axis may be used to treat COPD.

"antibody" is used in its 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 so long as they exhibit the desired antigen-binding activity.

It is specifically contemplated that anti-IL 33 antibodies or antibody variants, i.e., antibodies that specifically bind and inhibit/neutralize IL-33, are effective in treating COPD. In some cases, the antibody may be a monoclonal antibody (MAb); a recombinant antibody; a chimeric antibody; humanized antibodies, such as Complementarity Determining Region (CDR) grafted antibodies; a human antibody; antibody variants, including single chain antibody variants; and/or bispecific antibody variants; and fragments thereof; variants; or a derivative. Antibody fragments include those portions of an antibody that bind to an epitope on a polypeptide of interest. Examples of such fragments include Fab and F (ab') fragments produced by enzymatic cleavage of full length antibodies. Other binding fragments include fragments produced by recombinant DNA techniques, such as expression of recombinant plasmids containing nucleic acid sequences encoding antibody variable regions.

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

One example is a "chimeric" antibody in which a portion of the heavy (H) and/or light (L) chains are identical or homologous to corresponding sequences in antibodies derived from a particular species or belonging to a particular antibody class or subclass, while the remainder of the one or more chains are identical or homologous to corresponding sequences in antibodies derived from another species or belonging to another antibody class or subclass. Fragments of such antibodies are also included as long as they exhibit the desired biological activity. See U.S. Pat. nos. 4,816,567; morrison et al, 1985, proc.Natl.Acad.Sci. [ Proc.Natl.Acad.Sci.Natl.Acad.Sci.USA ]81:6851-55.

In another example, the monoclonal antibody is a "humanized" antibody. Methods for humanizing non-human antibodies are well known in the art. See U.S. Pat. nos. 5,585,089 and 5,693,762. Typically, humanized antibodies have one or more amino acid residues introduced into them 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 substituting at least a portion of the rodent complementarity determining regions with corresponding portions of human antibodies.

Human antibodies and antibody variants (including antibody fragments) that bind to IL-33 are also contemplated. Such antibodies are produced by immunization with a polypeptide antigen (i.e., having at least 6 contiguous amino acids), optionally conjugated to a carrier, using a transgenic animal (e.g., a mouse) capable of producing a repertoire of human antibodies in the absence of endogenous immunoglobulin production. See, e.g., jakobovits et al, 1993, proc. Natl. Acad. Sci. [ Proc. Natl. Acad. Sci. USA ]90:2551-55; jakobovits et al, 1993, nature 362:255-58; bruggermann et al 1993,Year in lmmuno [ immunology year ]7:33. See also PCT application Nos. PCT/US 96/05928 and PCT/US 93/06926. Additional methods are described in U.S. Pat. No. 5,545,807, PCT application Nos. PCT/US 91/245 and PCT/GB 89/01107, and European patent Nos. 54607381 and 546073A 1. Human antibodies can also be produced by expressing recombinant DNA in host cells or by expression in hybridoma cells as described herein.

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

Antibodies and antibody variants (including antibody fragments) useful in the methods of the disclosure may comprise: (a) A heavy chain variable region comprising HCDR1 having a sequence as set forth in SEQ ID No. 1, VHCDR2 having a sequence of SEQ ID No. 2, VHCDR3 having a 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.

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

In some cases, the IL-33 antibody is 33_640087_7B, as disclosed in WO 2016/156440, which is incorporated herein by reference. 33_640087_7b, also known in the art as MEDI3506, is an anti-IL-33 antibody that binds with high affinity to reduced form of IL-33 (redIL-33). 33_640087_7b also inhibits the conversion of redIL-33 to an oxidized form (oxIL-33) that has been shown to induce signaling by RAGE and to induce epithelial cell proliferation.

33_640087_7b is an exemplary anti-IL-33 antibody having: (a) A heavy chain variable region comprising HCDR1 having a sequence as set forth in SEQ ID No. 1, VHCDR2 having a sequence of SEQ ID No. 2, VHCDR3 having a 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.

33_640087_7b further comprises a VH domain having the amino acid sequence set out in SEQ ID No. 4 and a VL domain having the amino acid sequence set out in SEQ ID No. 8.

33_640087_7b is an IgG1 antibody, and the sequences of the full length light and heavy chains (including IgG1 chains) of 33_640087_7b are set forth in SEQ ID NOs 9 and 10, respectively.

In some cases, the anti-IL-33 antibody or antibody variant thereof has similar or identical pharmacokinetic (pK) characteristics in humans as 33_670087_7b.

In particular, the anti-IL-33 antibody or antibody variant may have a half-life in humans similar to or the same as 33_670087_7b. An anti-IL-33 antibody or antibody variant having a half-life similar to or the same as 33_670087_7b in humans can 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 30mg q2 w. An anti-IL-33 antibody or antibody variant having a half-life similar to or the same as 33_670087_7b in humans can 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 100mg q2 w. An anti-IL-33 antibody or antibody variant having a half-life similar to or the same as 33_670087_7b in humans can have a half-life of about 10 to about 20 days, about 12 to about 15 days, or about 14.8 days when administered at a dose of 300mg q2 w.

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

In various cases, the anti-IL-33 antibody or antibody variant thereof is selected from the group consisting of a human antibody, a humanized antibody, a chimeric antibody, a monoclonal antibody, a recombinant antibody, an antigen-binding antibody fragment, a single chain antibody, a monomeric antibody, a diabody, a triabody, a tetrabody, a Fab fragment, a lgG1 antibody, a lgG2 antibody, a lgG3 antibody, and a lgG4 antibody. In some cases, the anti-IL-33 antibody variant is selected from the group consisting of a diabody, a triabody, a tetrabody, a Fab fragment, a single domain antibody, a scFv, wherein the dose is adjusted such that the binding sites are equimolar to those administered by the diabody.

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

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

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

Examples

Example 1-evidence of the mechanism of the anti-interleukin-33 antibody tolazolidone: results of phase 1 studies in healthy adults and participants with chronic obstructive pulmonary disease

The siren cytokine Interleukin (IL) -33 coordinates inflammatory and remodelling reactions following tissue injury (Scott IC et al Sci Rep [ science report ]2018;8:3363;Cohen E et al Nat Commun [ Nat-communication ]2015;6:8327;Murdaca G et al Int J Mol Sci [ J.International molecular sciences ]2019; 20:5856). Excess IL-33 plays a key role in COPD in the initiation and driving of chronic obstructive pulmonary disease (Alrine J et al J Allergy Clin Immunol [ J.allergy & clinical immunology ]2019;144:1624-37.e10; schmitz J et al Immunity 2005; 23:479-90). Toxazomib (MEDI 3506) is a human immunoglobulin G1 monoclonal antibody that specifically and effectively targets IL-33. This first human study (NCT 03096795) evaluated the safety, tolerability, pharmacokinetics and immunogenicity of tolazolidinab. This report details the mechanistic evidence of tolazolidone through this study.

Method

This three-part phase 1 randomized, blind placebo controlled study was conducted in two centers in the united kingdom during the period from 15 in 5.2017 to 30 in 9.2019. In all cohorts, participants were randomly assigned 3:1 to receive tolazolyl mab to placebo. This report presents data from part 1 and part 2.

Part 1 qualified participants with a history of mild atopy and sensitivity to House Dust Mites (HDM) received a Single Ascending Dose (SAD) of 300mg Intravenous (IV) or 1mg, 3mg, 10mg, 30mg, 100mg or 300mg Subcutaneous (SC) tolazolyl mab or placebo. Part 2 qualified participants with chronic obstructive pulmonary global initiative (GOLD) grade I-II COPD received Multiple Ascending Doses (MAD) of 30mg, 100mg or 300mg SC tolazolradiab or placebo.

Pharmacodynamics (PD) was evaluated as a exploratory result. Target engagement was measured by a super-selective assay for IL-33 form in serum (all cohorts) and by non-invasive nasal adsorption (MAD cohorts) in local airway nasal Mucosal Lining Fluid (MLF) samples. Serum levels of sST2 were also measured. After IL-33 challenge, interferon gamma (IFN- γ) was measured ex vivo using whole blood assay (SAD cohort). The PD effect of tolazoliding on inflammatory mediators (MAD cohort) was explored using multiplex immunoassays (mesoscale discovery company (Meso Scale Discovery)). Eosinophil levels were measured in whole blood (MAD cohort).

Results

Patient baseline demographics were as follows:

a total of 56 participants were enrolled and randomly assigned to the SAD cohort (healthy adults with mild atopy and sensitivity to HDM): the tolazolidone-treated group was 42 and the placebo-treated group was 14. 24 patients were enrolled and randomly assigned to the MAD cohort (adults with GOLD class I-II COPD): the tolazolidone-treated group was 18 and the placebo-treated group was 6.

Target engagement biomarker study (exploratory endpoint)

Tozoprasidmab target engagement was demonstrated in serum (FIG. 1) and local airway nasal MLF (FIG. 2). In serum, tolazolidone increased IL-33/tolazolidone complex levels in all the queues compared to placebo (FIG. 1A [ SAD queue ] and FIG. 1C [ MAD queue ]), while endogenous IL-33/sST2 complex levels were decreased in all the queues (FIG. 1B [ SAD queue ] and FIG. 1D [ MAD queue ]). Trazomib did not significantly affect serum total sST2 levels at any dose level compared to placebo.

In local airway nasal Mucosa Lining Fluid (MLF), tolazolidone increased the level of IL-33/tolazolidone complex (MAD cohort) compared to placebo (fig. 2A) and decreased the level of both reduced and oxidized forms of IL-33 (fig. 2B and 2C).

Higher levels of tolazolidone in the circulation correlated with lower levels of induced IFN- γ (fig. 3).

Pharmacodynamic biomarker study (exploratory endpoint)

Toxazomib (300 mg SC) significantly reduced serum IL-5 and IL-13 levels compared to placebo (FIGS. 4A and 4B). In addition, tolazolidone significantly reduced blood eosinophil levels (fig. 4C), and these reductions were correlated with serum levels of IL-5 (repeated measure 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).

Conclusion(s)

These data show evidence of the mechanism of tolazoliding through target engagement and identification of PD biomarkers in the first human study (NCT 03096795) in patients with COPD. Target engagement was demonstrated in the circulatory and local airways using open nasal adsorption sampling. These results support entry of tolazolyl mab into phase 2 and phase 3 studies. Phase 2 (NCT 04631016) and phase 3 studies (NCT 05166889 and NCT 05158387) are currently underway to investigate the safety and efficacy of tolazolidone for the treatment of COPD.

Example 2-phase II randomized, double-blind, placebo-controlled study (front 4) for assessing efficacy, safety and tolerability of MEDI3506 in participants with moderate to severe chronic obstructive pulmonary disease and chronic bronchitis

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

MEDI3506 (also referred to herein as 33_640087_7b) is a human IgG1 mAb that binds to human IL-33. MEDI3506 binds full-length and mature forms of human IL-33 with extremely high affinity and prevents IL-33 from binding to soluble (sST 2) and membrane-bound forms of ST2 (also known as IL-1RL 1) receptors.

Several clinical and non-clinical studies indicate that the IL-33/ST2 signaling axis plays a key role in the pathogenesis of COPD. Thus, blocking this signaling pathway may have therapeutic benefit in COPD.

Participants had to receive a stabilizing dose of either dual therapy (ics+laba, or laba+lama) or triple therapy (ics+laba+lama) for ≡3 months prior to recruitment and this stabilizing dose should be maintained during the study. The maintenance COPD treatment should not change after the previous exacerbation before entering the study.

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

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

The main estimation targets are as follows: for ITT populations, a duplicate measurement mix effect analysis of covariance model will be used to estimate the differences in mean change from baseline for week 12 FEV1 (MEDI 3506-placebo). This would include all available data from all visits by (and including) week 12, whether the participants discontinued study intervention or received palliative therapy. The model will include baseline, eosinophil stratification, background drug therapy stratification, interview, study intervention, and the fixed effects of interview baseline, and study intervention by interview interactions. Unstructured covariance matrices will be used to describe the correlation between observations of participants between accesses.

Similar methods will be used to analyze cough VAS, BCSS, CASA-Q, SGRQ and to alleviate drug treatment. Where appropriate, the data may be logarithmically converted prior to analysis. Analysis of covariance will be used to analyze the change from baseline in objective cough parameters and oscillometric parameters at week 12. Analysis of the time of the event and the annual rate of event data will include the available data for all participants (up to week 28, if available). The time of the event endpoint will be analyzed

Screening program

The participants should meet the following criteria:

1. participants must be 40 to 75 years old (inclusive).

2. The participants were current smokers or pre-smokers (ex-smoker) with a smoking history of ≡10 years.

3. Participants who received pneumococcal and influenza vaccines according to local treatment guidelines to date.

4. The participants had a recorded medical history of COPD for at least 1 year.

5. Participants at screening had a post BD FEV1/FVC <0.70 and post BD FEV1> predicted 30% and <80% of normal. Centralized spirometry will be used for this standard evaluation.

6. The participants had a history of chronic bronchitis confirmed by the physician, defined as cough and sputum present for most of the time at 3 months/year for a period of at least 2 years immediately prior to SV1 (screening).

7. Within 14 days prior to SV3, the average BCSS score of the participants in the cough field was ≡2, and the average BCSS score in the sputum field was ≡2.

8. Participants had a recorded stable dual or triple therapy regimen lasting ≡3 months prior to recruitment; before entering the study, there should be no change in treatment after the previous exacerbation. Wherein the dual therapy consists of ics+laba or laba+lama and the triple therapy consists of ics+laba+lama. Both the dual and triple therapies may be in the form of separate inhalers of a fixed dose combined inhaler, but may not be in the aerosolized form.

9. The participants had a recorded history of ≡1 moderate or severe AECOPD that required systemic corticosteroid and/or antibiotics for at least 3 days (or 1 storage formulation injection), or hospitalization for AECOPD in the previous 12 months prior to screening.

10. Participants were clinically stable and had no exacerbations of COPD 1 month before SV1 (screening) and 1 day.

11. Body mass index is in the range of 19 to 35kg/m2 (inclusive).

Random distribution and application

Random assignment will be performed at study visit 3 (SV 3-day 1). Participants who continued to meet the eligibility criteria will be randomly assigned to treatment groups as described above. Blood samples, urine samples, efficacy assessments and safety assessments will be performed to determine a baseline.

Random assignment will be stratified according to baseline blood eosinophils (< 300 cells/. Mu.L versus ≡300 cells/. Mu.L) and background drug treatments (including ICS versus not including ICS).

The first survey product (IP) administration will be at study visit 3 (day 1) and will include administration of a first dose of the survey product during the treatment window. Administration of 600mg MEDI3506 would require a 2X 2mL SC injection/dose. The injection volume of the placebo group will match that of the MEDI3506 group.

At study visit 4 (day 2), participants will return to evaluate their compliance with the self-assessment efficacy reporting program and make a safety assessment. The procedure is summarized in table 4.

The second survey product administration will be at study visit 6 (day 29±3).

The third survey product administration will be at study visit 7 (day 57±3).

The fourth survey product administration will be at study visit 8 (day 85±3).

The fifth survey product administration will be at study visit 9 (day 113±3).

The sixth survey product administration will be at study visit 10 (day 141±3).

Seventh survey product administration will be at study visit 11 (day 169±3).

Endpoint (endpoint)

The primary endpoint visit was performed at week 12 and the assessment was made at study visit 10 (day 113±4).

The primary endpoint was pre-BD FEV by week 12 clinical ₁ Is improved from baseline. The first second effort expiratory volume is a validated and clinically important endpoint in COPD studies and has been widely used in experiments to support registration of additional therapies for current standard of care (dual/triple therapies) in similar chronic bronchitis patient populations (Martinez et al 2015).

Based on available data, FEVs assumed in the expected sample size determination ₁ Improvement will be achieved at week 12. However, FEV1 improvement is considered important but insufficient to meet the unmet medical needs in COPD. To be able to evaluate COPD ompSecondary endpoint of Ex, treatment was continued after collecting primary endpoint data to collect additional events. Longer duration of intervention period also allows for FEV after week 12 ₁ Is subjected to exploratory evaluation.

The secondary endpoint was COPDCompEx at week 28. Preclinical BD FEV will also be evaluated at week 28 ₁ Is a variation of (c).

Blood samples will be collected from subjects to assess biomarkers related to disease pathology and/or the mechanism of action of MEDI 3506.

Results

In this phase 2 clinical study, the highest dose of MEDI3506 administered to the subjects would be 600mg of Q4W by SC injection. Compared to the highest dose administered in phase 1 clinical study (study D9180C 00001) (i.e., a single dose of 300mg IV MEDI3506), this dose is expected to be the maximum concentration at steady state (C _max,ss The method comprises the steps of carrying out a first treatment on the surface of the About 2.5 times) and AUC (about 1.6 times) with lower exposure. It is predicted that the 600mg dose of Q4W by SC injection will have a higher C than the highest multiple dose administered in the same study (i.e., 300mg SC Q2W) _max,ss But with the same AUC (table 6).

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

Example 3-dose selection criteria for in-treatment MEDI3506 of COPD

To select target doses, PK/PD models were generated using target engagement data from the Ph1 study (NCT 03096795). More specifically, the PK/PD model is based on:

Quantitative information of the MEDI3506: IL33 and IL33: ST2 complexes in the systemic circulation at stage 1. The concentration of both complexes was measured using proprietary IL-33 detection reagents that specifically bind to reduced forms of IL-33 (redIL-33).

MEDI3506 PK data from phase 1 (linear PK, half-life (t _1/2 ) For 17 days

Additional preclinical information that provides information for dose selection includes:

·RedIL-33 ST2 signaling pathway

·oxIL-33:rage:egfr signaling pathway

RedIL-33 ST2 signaling pathway

Models of Alternaria Alternata (ALT) -induced mouse airway inflammation have been previously described (Kouzaki et al J.Immunol. [ J.Immunol. ]2011,186:4375-4387; bartemes et al J Immunol [ J.Immunol. ],2012, 188:1503-1513). Endogenous IL-33 is rapidly released after ALT exposure and drives IL-33 dependent IL-5 production in the lung. Male or female wild-type or humanized IL-33 mice (6-10 weeks) were simply anesthetized with isoflurane and 25 μg ALT extract (Grier, raynaud, north Carolina (Greer, lenoir, NC)) or vehicle was administered intranasally in a total volume of 50 μl. Mice were treated intraperitoneally with MEDI3506 (0.1, 1, 2, or 10 mg/kg), isotype control IgG (NIP 228), or vehicle (PBS, 10 ml/kg) and challenged intranasally with ALT after 24 hours. 24 hours after challenge, mice were finally anesthetized with sodium pentobarbital, then exsanguinated and bronchoalveolar lavage (BALF) collected. BALF was collected by lavage via tracheal tube. BALF was centrifuged, cells were counted (total cells by FACS (FacsCALIBER, BD)) and cytokine supernatants were analyzed by ELISA (mesoscale discovery company, rocyvern, maryland (Meso Scale Discovery, rockville, MD)). Cell centrifugation smear preparations stained with Diff-Quik (feishier technologies, UK (Fisher Scientific, UK)) were subjected to differential cell counts (200 cells/slide). All work was done under the authority of the appropriate project license in accordance with the uk's internal ethical and regulatory standards. 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 3mg/kg, corresponding to an average serum systemic exposure of 20 μg/mL in mice. The results are shown in fig. 5 and 6.

oxIL-33:rage:egfr signaling pathway

Recently, it has been discovered that oxidized forms of IL-33 (oxIL-33, IL-33ox, or IL-33 DSB) directly impair the epithelial cell repair response, reduce epithelial goblet cell differentiation and proliferation, and increase mucus production and production of mucin-related genes (such as MUC5 AC). oxIL-33 was found to mediate pathological effects on epithelial cells by binding to and signaling through a complex of RAGE and EGFR (as described in WO 2021/089563, hereby incorporated by reference).

The following MEDI3506 concentrations for the oxIL-33 signaling pathway were used to provide information for dose selection:

threshold for reversing oxIL-33 mediated dysfunctional scratch wound closure

Scarified wound closure

Previous experiments showed that oxIL-33 could impair epithelial scarification wound closure in bronchial epithelial cells of healthy humans (fig. 7A and 7B). anti-ST 2 antibody treatment did not reverse damaged wound closure, indicating that pathological effects were mediated via the oxIL-33-RAGE/EGFR signaling axis. Scarified wound lesions were also seen in bronchial epithelial cells obtained from COPD subjects (fig. 8).

The concentration of MEDI3506 required to reverse oxIL-33 mediated wound closure dysfunction of scratches was calculated in a549 cell culture.

A549 was obtained from ATCC and cultured in RPMI GlutaMax medium supplemented with 1% penicillin/streptomycin and 10% FBS. Cells were harvested with accutase (PAA, #L1 1-007) and expressed as 5X 10 ⁵ Mu.l/100. Mu.l were inoculated into 96-well plates and incubated at 37℃with 5% CO ₂ Incubate for 6-8 hours. The wells were then washed twice with 100 μl PBS, followed by the addition of 100 μl starvation medium (RPMI GlutaMax medium supplemented with 1% penicillin/streptomycin) and 5% CO at 37deg.C ₂ Incubate for 18-24 hours. Cells were scratched using WoundMaker TM (Essen Bioscience), and wells were then washed 2x with 200 μl PBS, followed by the addition of penicillin/streptavidin supplemented with 0.1% FBS (v/v) and 1% (v/v)RPMI GlutaMax medium of plain, the medium containing the indicated stimulus; media alone (non-stimulated control), MEDI3506 or anti-TSLP antibodies at different concentrations, returned to 37 ℃, 5% CO ₂ . Plates were placed in an incumbezone for wound healing imaging and analysis over a 72 hour period. The relative wound density was calculated by the wound healing algorithm in the Incucyte Zoom software. Figure 9 shows MEDI3506 dose-dependent improvement of scratch wound closure in a549 cells. A concentration of MEDI3506 greater than 50.4pM (or 7.26 ng/ml) is required to achieve complete reaction. This is believed to correspond to a concentration of 0.15 μg/mL in the blood (assuming 5% distribution into epithelial lining fluid after subcutaneous administration). No effect was seen with anti-TSLP antibodies.

Integrated PK/PD model for target engagement

An integrated popPK/PD model was established based on SAD/MAD/IV MEDI3506 systemic exposure and Target Engagement (TE) clinical data from MEDI3506 Ph1 study. The TE information used was systemic IL33-MEDI3506 complex formation and reduced IL33-ST2 levels from FTIM.

The population and dose covered in the model included:

healthy subjects with mild atopy following a single Subcutaneous (SC) dose (1 to 300mg SC) and 300mg Intravenous (IV) dose

Mild COPD patients receiving multiple doses of 30, 100 and 300mg SC

The model structure has four defined compartments and is shown in fig. 10.

The PKPD model reliably described the observed PK profile of MEDI3506, MEDI3506: IL33 complex formation and IL33: ST2 dose-dependent inhibition in blood (fig. 11, 12 and 13). Fig. 18 and 19 show different presentation forms of fig. 11 and 13, respectively. The solid line represents the median of the observations. The shaded area represents the 95% confidence interval for the median of the model predictions. The dashed lines represent LLOQ values for tolazolyl mab (0.01 ng/ml) and IL-33:sST2 (0.5 pg/ml), respectively.

The dose response of ST2: IL33 complex inhibition of MEDI3506 in blood at the trough for Q2W, Q W and Q6W dosing regimens is shown in fig. 14.

The PK/PD model of IL-33/sST2 complex inhibition in blood was further transformed to predict IL-33 inhibition in lung tissue (assuming that the blood: tissue partition coefficient was 14% and IL-33 levels in the lung were twice as high as in blood).

For the Q4W and Q8W dosing frequency, the% IL-33 inhibition in lung tissue at the trough is shown in figure 15.

Dose selection:

target inhibition of almost 95% in lung tissue at the trough was predicted for a dosing frequency of 300mg dose Q4W. It was predicted that MEDI3506 300mg qos w would achieve greater than 80% TE in the lungs, which means that using a longer but more convenient dosing interval for the patient could achieve sustained IL-33 inhibition in the patient's lungs (fig. 15).

MEDI3506 serum concentrations were modeled for 300mg q4w and 300mg qos 8w based on Ph1 PK data and other input parameters. The trough concentrations of both regimens were predicted to be higher than the amount predicted by the alternaria humanized IL-33 mouse model to achieve 60% inhibition (figure 16). The Alternaria model is more representative of exacerbations or acute effects caused by viral infection. Thus, a dose prediction using this cut-off value may be sufficient to achieve an effective dose for a human chronic IL-33 mediated disease such as COPD. The trough concentrations of both protocols were also predicted to be above the threshold amount of inhibition of pathological signaling via the oxIL-33:rage/EGFR signaling axis identified by the scratch wound model (fig. 17).

Example 4-efficacy and safety of MEDI3506 for evaluation of two dosage regimens in phase III, multicentric, randomized, double-blind, chronic dosing, parallel group, placebo-controlled study in participants with symptomatic Chronic Obstructive Pulmonary Disease (COPD) with history of COPD exacerbation

Overall design

The purpose of this phase III study was to evaluate efficacy and safety of Subcutaneous (SC) administered MEDI3506 300mg once every 8 weeks (Q8W) and 300mg once every 4 weeks (Q4W) dosing regimen in adult participants with symptomatic COPD and a history of ≡2 moderate or ≡1 severe COPD exacerbations in the previous 12 months. The participants should receive optimized treatment with a steady dose of maintenance inhalation therapy (ICS/LABA/LAMA triple therapy, or double therapy if triple therapy is not indicated or contraindicated) throughout at least 3 months prior to recruitment.

The study will randomize about 1272 participants, stratified by region, maintenance inhalation therapy (dual versus triple), and smoking status (current smoker versus ever). The study included both the smoker and the current smoker. The participants will continue to use the same COPD maintenance therapy throughout the study.

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

The key primary and secondary targets and endpoints are described in the following table:

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AE = adverse event; BD = bronchodilator; cat=copd assessment test; CCU = critical ward; COPD = chronic obstructive pulmonary disease; ECG = electrocardiogram; ED = emergency department; er=emergency room; E-RS: COPD = COPD respiratory symptom evaluation table (Evaluating Respiratory Symptoms in COPD); FEV (FEV) ₁ =first second forced expiratory volume; HRU = medical resource utilization; ICU = intensive care unit; IP = investigation product; MCID = minimal clinically significant difference; SGRQ = saint georgette respiratory questionnaireThe method comprises the steps of carrying out a first treatment on the surface of the SoC = standard of care.

Participant type and disease characteristics

1 record diagnosis of COPD for at least one year prior to recruitment.

2BD post FEV ₁ /FVC<0.70 and BD post FEV ₁ >20% of the predicted normal values (assessed by centro-pulmonary mass spectrometry at screening).

Recorded history of ≡2 moderate or ≡1 severe COPD exacerbations in 12 months prior to 3 recruitment:

(a) An exacerbation is considered moderate if it requires treatment with systemic steroids and/or antibiotics, and severe if it requires hospitalization. Note that: hospitalization is defined as hospitalization of greater than or equal to 24 hours in a hospital, in an observation area, emergency department, or other equivalent healthcare facility (depending on the country and medical system).

(b) At least one eligible exacerbation is treated with a systemic corticosteroid.

(c) Events treated with antibiotics only were counted as moderate exacerbations only when antibiotics were specifically prescribed for COPD symptom exacerbations.

(d) It should be confirmed that the previous emphasis occurs during the time that the participants are receiving stable dual or triple (ICS/LABA/LAMA) maintenance inhalation therapy for COPD and not due to intervals or drops in treatment.

(e) At least one eligible exacerbation should occur when receiving the latest stable uninterrupted therapy prior to recruitment.

4 record-optimized treatment with a stable dose of COPD maintenance therapy (ICS/LABA/LAMA triple therapy, or double therapy if triple therapy is not indicated or contraindicated) for at least 3 months prior to recruitment.

5. Smoking history of > 10 years:

(a) A smoker is defined as a participant who is not currently smoking and who is quitting smoking for more than or equal to 6 months prior to screening and who intends to quit smoking permanently.

(b) Current smokers are defined as participants who are currently smoking (average at least one cigarette per day over the past 7 days) and are not currently participating in quitting smoking.

(c) For acceptable conditions, electronic cigarette (e-cigarette) usage does not constitute a year count.

6 at screening and random distribution, CAT total score > 10, and each of sticky sputum and cough program had a score > 2.

7 has at least 70% daily PRO completion during the entire screening period and at least 50% daily PRO completion during the 14 day period prior to random distribution.

8 at least 70% compliance with COPD maintenance inhalation therapy (defined as daily scheduled administration of COPD maintenance inhalation medication) throughout the screening period.

9 are capable of reading and using the electronic device.

Research intervention

Investigation Product (IP)

First-aid medicine

In the event of exacerbation of COPD symptoms during the study, short acting β2-agonists (SABA, e.g. salbutamol, terbutaline, levalbuterol), short Acting Muscarinic Antagonists (SAMA), SABA/SAMA combinations or alternative rescue medications meeting local standards of care may be used.

Maintenance therapy

Stable optimization maintains inhalation therapy (ICS/LABA/LAMA triple therapy, or dual therapy if triple therapy is not indicated or contraindicated). Any other COPD maintenance therapy (e.g., xanthine, antibiotics, PDE4 inhibitors, etc.) doses and regimens should be stable for 3 months prior to and throughout the study period.

Efficacy assessment

Assessment of COPD exacerbations

COPD exacerbations are defined for purposes of this regimen as exacerbations of the participants' daily COPD symptoms (e.g., dyspnea, sputum volume, purulent sputum, cough, wheezing, and other COPD-related symptoms and/or findings) that are more than normal daily changes, acute at onset, for 2 days or more (less time if exacerbations are rapid and significant such that the treating physician decides cannot delay the intensification of treatment), and may require changes to conventional medication and lead to any of the following:

Systemic corticosteroids are used for at least 3 days; a single depot Injection (IM) dose of corticosteroid would be considered equivalent to a 3 day course of systemic corticosteroid.

Antibiotics are used.

Hospitalization is due to COPD hospitalization (defined as hospitalization being admitted to a hospital, viewing area, emergency department, or other equivalent healthcare facility (depending on the country and medical system) for > 24 hours.

Resulting in death.

An exacerbation is considered moderate if it requires treatment with systemic steroids and/or antibiotics and does not meet the criteria for severe events. Exacerbations will be considered severe if they result from hospitalization or death due to COPD.

The onset of exacerbations is defined as the onset date or admission of systemic corticosteroid or antibiotic treatment, whichever occurs earlier, and the end date is defined as the last day or discharge of systemic corticosteroid or antibiotic treatment, which occurs later. A single depot injected dose of corticosteroid would be considered equivalent to a 3 day course of systemic corticosteroid. Thus, the corresponding cessation date for this treatment was determined as the date of administration plus 2 days.

Spirometry (bronchodilators front and back evaluation)

All spirometry was performed prior to dosing.

Pulmonary Function (FEV) ₁ And FVC) will be provided using a central providerIs measured by a spirometry method. The spirometry will be performed by a researcher or authorized representative according to the American society of thoracic (ATS)/European Respiratory Society (ERS) guidelines (Graham et al 2019).

Pulmonary mass spectrometry reference

The global lung function initiative formula will be used to determine the Predicted Normal Value (PNV) and is preprogrammed into the spirometer (Quanjer et al 2012).

The first second forced expiratory volume, expressed as a percentage of PNV, is calculated as follows:

FEV of PNV ₁ % = (FEV measured ₁ /FEV ₁ PNV)×100

FEF _25-75％ Will use and FEV ₁ A similar method was calculated.

post-BD spirometry

The endpoint maximum BD was induced using albuterol (90 μg metered dose) or salbutamol (100 μg metered dose) with or without a spacer device to a maximum of 4 inhalations within 30 min ± 15 min of the final pre-BD spirometry measurement. BD postpneumometry will be performed after 15 to 30 minutes. If the participants were unable to tolerate 4 puffs of albuterol or salbutamol, a lower number of inhalations could be considered at the discretion of the investigator.

Patient Reporting Outcome (PRO)

The participants will complete the following non-daily PRO in the following order: SGRQ, CAT, five-level five-dimensional Health scale (5-level EuroQol-5 dimension, eq-5D-5L), work efficiency and activity decline questionnaire-General Health (Work Productivity and Activity Impairment-General Health, WPAI-GH), PGIS, and patient global impression change scale (Patient Global Impression of Change, PGIC). Reference is made to SoA (part 1.3) to evaluate frequency.

Chronic pulmonary exacerbation tool-patient reporting outcome (EXACT-PRO)

The EXACT-PRO is a 14 project PRO tool developed to evaluate the frequency, severity and duration of COPD exacerbations (Jones et al 2011; leidy et al 2011). The tool was developed for daily home applications using a handheld electronic device. Respondents were instructed to complete a diary every night just before bedtime and answer questions while considering their "today's" experience. The daily EXACT-PRO total score has a range of 0 to 100, with higher scores indicating greater severity. The total score change was used to identify onset and recovery of exacerbation events as defined by EXACT-PRO. In identifying event episodes and resumptions, the EXACT-PRO can provide information about the frequency and duration of events and the severity of the events.

COPD respiratory symptoms evaluation chart (E-RS)

The E-RS COPD was developed to evaluate 11 projects PRO (Leidy et al 2014a; leidy et al 2014 b) for severity of respiratory symptoms of COPD. E-RS COPD is a subset of items from EXACT-PRO. E-RS COPD is designed to be obtained as part of a daily EXACT-PRO assessment. Summing the E-RS COPD project responses produces 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 for breathlessness (5 items; score range: 0 to 17), cough and sputum (3 items; score range: 0 to 11), and chest symptoms (3 items; score range: 0 to 12) by summing the item responses in the corresponding fields. For this total score, a higher domain score indicates a greater severity. E-RS a single score decrease of at least 2 points in the total score of COPD is considered significant and will be used as a reactant definition (Leidy et al 2014 a).

Breathlessness, cough and sputum scale (BCSS)

The BCSS is 3 items PRO (Leidy et al 2003a, leidy et al 2003 b) evaluating the severity of breathlessness, cough, and sputum on a scale of 0 to 4. The item scores are summed to produce a total score, with higher scores indicating more severe symptoms.

Shengqiao respiratory questionnaire (SGRQ)

The SGRQ is a 50 project PRO tool developed to measure the health status of participants with airway obstruction disease (Jones et al 1991, jones and Forde 2009). The questionnaire is divided into 2 parts: part 1 consists of 8 items concerning the severity of respiratory symptoms in the first 4 weeks; part 2 consists of 42 items related to the daily activities and psychosocial effects of an individual's respiratory illness. SGRQ produces a total score and 3 component scores (symptoms, activities, and effects). The total score indicates the effect of the disease on the overall health condition. This total score is expressed as a percentage of total damage, where 100 represents the worst possible health condition and 0 indicates the best possible health condition. Also, the component scores range from 0 to 100, with higher scores indicating greater damage. A single score decrease of at least 4 points in the 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 developer in the user manual (Jones and Forde 2009).

COPD Assessment Test (CAT)

The CAT is 8 projects PRO developed to measure the effect of COPD on health (Jones et al 2009, kon et al 2014). The tool uses a semantic discrimination 6-point response scale, which is defined by contrasting adjectives to capture the effects of COPD. Content includes items related to coughing, sticky sputum, chest tightness, climbing mountains/stairs, shortness of breath, limited home activity, away from home confidence, sleep, and energy. Each project response ranges from 0 to 5, with 0 having the least impact on health and 5 having the greatest impact on health. The CAT total score is the sum of the project responses, with scores ranging from 0 to 40, higher scores indicating greater impact of COPD on health. A single score decrease of at least 2 points in the CAT total score is considered significant and will be used to support the reactant definition (Kon et al 2014).

Five-level five-dimensional health scale (EQ-5D-5L)

EQ-5D-5L is a five-level normalization tool used as a measure of health outcome. Is suitable for a wide range of health conditions and treatments, and provides a simple descriptive overview and a single index value for the health condition. EQ-5D-5L consists of 2 evaluations (describing System and Visual Analog Scale (VAS)). The description system includes the following 5 dimensions: mobility, self-care, daily activities, pain/discomfort, and anxiety/depression. Each dimension has 5 severity levels: no problems, mild problems, moderate problems, severe problems, and extreme problems. The EQ-5D-5L index score may be calculated based on the participant's response to 5 dimensions and using an appropriate set of values, as will be further described in the Statistical Analysis Plan (SAP).

The EQ-5D VAS records the respondents' self-assessed health status on a 20cm vertical scale of 0 to 100, with endpoints labeled "best health status you can imagine" and "worst health status you can imagine", with higher scores corresponding to better health status. This information is used as a quantitative measure of the health condition judged by the individual respondents.

Work efficiency and mobility decline questionnaire (WPAI-GH)

WPAI-GH (version 2.0) is a self-filling tool that includes 6 problems related to absences, attendance (reduced efficiency in work), overall work efficiency loss (absences from attendance), and reduced mobility. This validated tool captured data for the past 7 days. WPAI-GH results were scored as percent lesions, with higher percentages indicating greater lesions and lower efficiency (reily et al 1993).

Patient severity global impression scale (Patient Global Impression of Severity, PGIS)

PGIS is a single item designed to capture participants' opinion on the severity of overall COPD symptoms at completion using a 6-component scale (0-asymptomatic to 5-very severe).

Patient global impression change meter (PGIC)

PGIC is a single item designed to capture participants' opinion of overall COPD symptom change after a first dose of IP using a 7-component scale (1-much better to 7-much worse).

Comprehensive endpoint of COPD exacerbation (COPDCompEx)

The integrated endpoint of COPD exacerbation (COPDCompEx) is an endpoint based on combining exacerbations with daily PRO-defined events and study termination (Vogelmeier et al 2020). The COPDCompEx component is defined as follows:

weighting: resulting in one or more of the following: hospitalization, emergency room visits, treatment with systemic corticosteroids, or treatment with antibiotics.

Daily PRO event: by threshold and slope criteria definition, the following PRO variables are used: single item and emergency drug use of BCSS.

Statistical considerations

Primary endpoint

The primary endpoint was an annual moderate to severe exacerbation rate. This will be evaluated against placebo for each dose of MEDI3506 first in the main population (smokers) and then in the entire population of current and smokers.

The medium to medium exacerbation rate in each MEDI3506 dose regimen group will be compared to the medium to medium exacerbation rate in the placebo group using a negative two-term model. The response variable in the model will be the number of COPD exacerbations experienced by the participants during the full double blind 52 week treatment period. The model will include the covariates of treatment groups, regions, maintenance inhalation therapies (triple or double), and number of exacerbations of the previous year (1 vs.gtoreq.2) as a classification factor, as well as post-BD FEV1% and log-screen blood eosinophil counts predicted at screening as continuous covariates. The logarithm of the participant's corresponding follow-up time will be used as a displacement variable in the model. For analysis throughout the population, smoking status will also be included as covariates.

The estimated therapeutic effect (i.e., the rate ratio of MEDI3506 to placebo for each dose), the corresponding 95% Confidence Interval (CI), and the bilateral p-value of the rate ratio will be presented. In addition, the rate of exacerbations of model adjustment will be presented for each treatment group.

Systemic corticosteroid or antibiotic courses beginning within 7 days after completion of the previous course will be considered treatment of the same single exacerbation.

Secondary endpoint

Analysis of all secondary endpoints will be performed in the primary population (smokers). Similar analysis will be performed throughout the population (both the once smoker and the current smoker).

Time to first exacerbation of moderate or severe COPD

The time to onset of moderate or severe COPD exacerbations was analyzed as a key secondary efficacy variable of the primary objective to explore the extent to which treatment with each dose of MEDI3506 delayed the onset of exacerbation time compared to placebo. The Cox proportional hazards model will fit to the treatment group, region, covariates of maintenance inhalation therapy, number of exacerbations in the previous year, predicted post BD FEV1% at screening, and log-screened blood eosinophil count. The hazard ratio, 95% CI and p values, and the proportion of participants with events will be reported.

Shengqiao respiratory questionnaire

The change from baseline in SGRQ total scores over 52 weeks will be compared between MEDI3506 and placebo using a repeated measure linear model. The dependent variable will be the change from baseline in SGRQ total score at post-baseline regimen specified visit (week 52 visit cut). Treatment, visit interactions with treatment, area, maintenance inhalation therapy and number of exacerbations in the previous year will be fitted as a classification covariate to baseline SGRQ total score as a continuous covariate, predicted post BD FEV1%, and log-screened blood eosinophil count. The unstructured variance-covariance matrix will be used to model the correlation within the participants. The comparison will be used to produce an estimate of the therapeutic effect at each visit (including weeks 24 and 52) and within week 52. This will be reported with double sided 95% CI and p values.

The SGRQ total score will be analyzed for responders at week 52. The responders were defined as participants with an improvement (decrease) of ≡4.0 points over 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 treatment groups by treatment, area, maintenance inhalation therapy, and number of exacerbations in the previous year as a classification covariate and predicted post BD FEV1% as a continuous covariate, log-screened blood eosinophil count, and baseline SGRQ total score. P-values and odds ratios will be generated for each treatment comparison, as well as 95% CI.

E-RS change from baseline in COPD total score

The change from baseline in the total score of COPD will be analyzed for E-RS over 52 weeks using a model similar to the change from baseline in the total score of SGRQ. In a similar manner to the SGRQ responders analysis, the responders analysis of E RS: COPD total score at week 52 based on baseline improvement (decrease) gtoreq 2 score was also performed.

Changes from baseline in pre-dose FEV1

The change from baseline in pre-dose/pre-BD FEV1 will be analyzed using a repeated measure analysis model similar to the change from baseline in SGRQ score, but analyzed by treatment, visit-while-treatment interaction, area, maintenance inhalation therapy and number of exacerbations for the previous year as a categorical covariate fit, as well as baseline FEV1 as a continuous covariate and log-screened blood eosinophil count. The comparison will be used to produce an estimate of the therapeutic effect at each visit (including weeks 24 and 52) and within week 52. This will be reported with double sided 95% CI and p values.

Other secondary endpoints

The time of the first severe exacerbation and the annual severe exacerbation rate will be analyzed in a similar manner to the moderate or severe exacerbation described above.

A similar method to SGRQ score will be used to analyze the change from baseline in CAT score and the proportion of participants in CAT score with a decrease (improvement) of > 2.

Reference to the literature

Numerous publications are cited above to more fully describe and disclose the invention and the level of skill in the art to which the invention pertains. The complete citations for these references are provided below. Each of these references is incorporated herein in its entirety.

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Claims

1. A method of treating Chronic Obstructive Pulmonary Disease (COPD) in a subject, comprising administering a therapeutically effective amount of an anti-IL-33 antibody or antibody variant thereof at intervals of once every 4 weeks (Q4W) or once every 8 weeks (Q8W) at a dose of from about 300mg to about 600mg, wherein the anti-IL-33 antibody comprises:

a. a heavy chain variable region comprising HCDR1 having a sequence as set forth in SEQ ID No. 1, VHCDR2 having a sequence of SEQ ID No. 2, VHCDR3 having a sequence of SEQ ID No. 3; and

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

2. A method of treating COPD in a subject, the method comprising administering a therapeutically effective amount of an anti-IL-33 antibody or antibody variant thereof at a dose effective to achieve at least 80% IL-33 inhibition in the lung or Epithelial Lining Fluid (ELF), wherein the anti-IL-33 antibody comprises:

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

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

5. The method according to any preceding claim, wherein the dose is about 300mg qos w.

6. The method according to any one of claims 1 to 4, wherein the dose is about 300mg q4w.

7. The method according to any one of claims 1 to 4, wherein the dose is about 600mg q4w.

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

9. A method according to any preceding claim, wherein the COPD is moderate COPD, moderate to severe COPD or severe COPD.

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

11. The method according to any preceding claim, wherein the subject's bronchodilator first second after Forced Expiratory Volume (FEV) prior to treatment ₁ ) Ratio to Forced Vital Capacity (FVC) (post-bronchodilator (post-BD) -FEV ₁ FVC) is less than%<)0.70。

12. The method according to any preceding claim, wherein the subject's post BD FEV1> predicts 20% of normal prior to treatment.

13. The method according to any preceding claim, wherein the subject is a current smoker or a smoker.

14. The method according to claim 13, wherein the subject has a history of smoking of at least 10 years.

15. The method according to any preceding claim, wherein the subject is undergoing COPD inhalation maintenance therapy, comprising a long-acting β2 agonist (LABA), a long-acting muscarinic receptor antagonist (LAMA), and/or an Inhaled Corticosteroid (ICS).

16. The method of claim 15, wherein the inhalation maintenance therapy comprises LABA and LAMA, ICS and LABA, or ICS, LABA and LAMA.

17. The method according to any preceding claim, wherein the rate of annual moderate to severe COPD exacerbations is reduced in the subject.

18. The method of any preceding claim, wherein the time to first exacerbation of moderate to severe COPD is increased.

19. The method of any preceding claim, wherein the time to exacerbation of first severe COPD is increased.

20. A method according to any preceding claim, wherein the rate of exacerbation of annual severe COPD is reduced in the subject.

21. The method according to any preceding claim, wherein the post bronchodilator FEV ₁ Improved in the subject.

22. The method according to any preceding claim, wherein the score of one or more questionnaires selected from the group consisting of: COPD respiratory symptom assessment table (E-RS), sheng Georget Respiratory Questionnaire (SGRQ), COPD Assessment Test (CAT), chronic lung exacerbation tool-patient report results (EXACT-PRO), breathlessness, cough and sputum scale (BCSS), five-level five-dimensional health scale (EQ-5D-5L), work efficiency and mobility decline questionnaire (WPAI-GH), patient severity global impression scale (PGIS) and patient global impression change scale (PGIC).

23. The method according to any preceding claim, wherein the dose is effective to achieve a C of from about 10 to 35 μg/ml during the administration period _max.ss 。

24. The method according to any preceding claim, wherein the anti-IL-33 antibody or antibody variant thereof is selected from the group consisting of: human antibodies, humanized antibodies, chimeric antibodies, monoclonal antibodies, recombinant antibodies, antigen-binding antibody fragments, single chain antibodies, monomeric antibodies, diabodies, triabodies, tetrabodies, fab fragments, lgG1 antibodies, lgG2 antibodies, lgG3 antibodies, and lgG4 antibodies.

25. The method according to any preceding claim, wherein the anti-IL-33 antibody or antibody variant thereof is IgG1.

26. The method according to any preceding claim, wherein the anti-IL-33 antibody or antibody variant thereof is a human antibody.

27. The method according to any preceding claim, wherein the anti-IL-33 antibody or antibody variant thereof comprises a VH domain having at least 95%, 90% or 85% identity to the sequence set forth in SEQ ID No. 4 and a VL domain having at least 95%, 90% or 85% identity to the sequence set forth in SEQ ID No. 8.

28. The method according to any preceding claim, wherein the anti-IL-33 antibody comprises a VH domain sequence as set forth in SEQ ID No. 4 and a VL domain sequence as set forth in SEQ ID No. 8.

29. The method according to any preceding claim, wherein the anti-IL-33 antibody comprises a light chain sequence as set forth in SEQ ID No. 9 and a heavy chain sequence as set forth in SEQ ID No. 10.

30. The method according to any preceding claim, wherein the anti-IL-33 antibody variant has the same pharmacokinetic (pK) profile in humans as 33_670087_7b.

31. The method according to any preceding claim, wherein the anti-IL-33 antibody is 33-670087_7b (MEDI 3506).

32. The method according to any preceding claim, wherein the administration is subcutaneous.

33. A method of improving a marker of Chronic Obstructive Pulmonary Disease (COPD) in a subject, the method comprising: a therapeutically effective amount of an anti-IL-33 antibody or antibody variant thereof, at a dose of from about 300mg to about 600mg, administered at once every 4 weeks (Q4W) or once every 8 weeks (Q8W) intervals, wherein the anti-IL-33 antibody comprises:

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

Wherein the marker is selected from the group consisting of: annual moderate to severe or severe COPD exacerbation rate, time to first moderate to severe or severe COPD exacerbation, FEV ₁ First second forced expiratory volume (FEV ₁ ) Ratio of FEV1 to Forced Vital Capacity (FVC) (FEV ₁ FVC), or breathlessness, cough and sputum scale (BCSS) scores, COPD Assessment Test (CAT) scores and sajor-control respiratory questionnaire (SGRQ) scores.

34. The method according to claim 33, wherein the improvement of the marker is related to baseline.

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

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

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

38. The anti-IL-33 antibody or antibody variant thereof according to any preceding claim for use in a method of treating COPD, wherein the method is according to the method of any preceding claim.

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

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

41. Pre-bronchodilator FEV for improving subjects suffering from COPD ₁ Comprising administering a therapeutically effective amount of an anti-IL-33 antibody or antibody variant thereof at intervals of once every 4 weeks (Q4W) or once every 8 weeks (Q8W) at a dose of from about 300mg to about 600mg, wherein the anti-IL-33 antibody comprises:

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

43. The method of claim 42, wherein the method achieves a minimum clinically significant difference in E-RS:COPD scores.

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

45. The method according to claim 44, wherein the method achieves a minimum clinically significant difference in SGRQ scores.

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

47. The method of claim 46, wherein the method achieves a minimal clinically significant difference in CAT scores.

48. The method of any one of claims 40-47, wherein the dose is about 300mg qos w.

49. The method of any one of claims 40-47, wherein the dose is about 300mg q4w.

50. The method of any one of claims 40-47, wherein the dose is about 600mg q4w comprising a VLCDR1 having the sequence of SEQ ID No. 5, a VLCDR2 having the sequence of SEQ ID No. 6, and a VLCDR3 having the sequence of SEQ ID No. 7.