Methods of treating and selecting subjects

Abstract

The present disclosure relates to methods of treating a subject having chronic obstructive pulmonary disease, methods of improving lung function in a subject having chronic obstructive pulmonary disease, and methods of selecting a subject having chronic obstructive pulmonary disease for treatment.

Description

[0001] Cross-referencing of related patent applications

[0002] This specification claims priority to U.S. Provisional Patent Application No. 63 / 574,724 (filed April 4, 2024). The entire text of the aforementioned patent application is incorporated herein by reference. Technical Field

[0003] This disclosure relates to methods for treating subjects with chronic obstructive pulmonary disease (COPD), methods for improving lung function in subjects with COPD, and methods for selecting subjects with COPD for treatment. Background Technology

[0004] The following discussion is provided to help readers understand this disclosure and does not constitute any endorsement of the content or relevance of the prior art.

[0005] Chronic obstructive pulmonary disease (COPD) is the fourth leading cause of death worldwide and is projected to become the third leading cause of death by 2030 (Adeloye et al., 2015). COPD is characterized by persistent respiratory symptoms and airflow limitation (FEV1 / FVC < 0.70 after BD), due to airway and / or alveolar abnormalities, usually caused by significant exposure to harmful particles or gases, and influenced by host factors including abnormal lung development. Significant comorbidities can impact morbidity and mortality (GOLD 2020). COPD is not entirely reversible, is typically progressive, and is associated with an enhanced chronic inflammatory response in the lungs. Patients with active chronic bronchitis symptoms bear a greater disease burden than those without, and are characterized by faster loss of lung function, increased mortality, and increased risk of exacerbation (Kim et al., 2011; de Oca et al., 2012; Corhay et al., 2013; Kim and Criner, 2013; Woodruff et al., 2016; Lahousse et al., 2017). Interleukin-33 expression is upregulated in the lungs of patients with COPD, negatively correlated with lung function, and plays a role in the inflammatory and epithelial processes of COPD.

[0006] A growing body of evidence demonstrates that overall symptom burden has a substantial detrimental effect on health-related quality of life, and also leads to an increased risk of exacerbation and worse disease prognosis (Miravitlles and Ribera, 2017).

[0007] Acute exacerbations of COPD are episodes of symptom deterioration that have significant adverse consequences for patients (Wedzicha and Seeungal, 2007). Higher frequency of exacerbations is associated with accelerated decline in lung function, impaired health-related quality of life, and increased mortality (Donaldson et al., 2002; Seeungal et al., 1998; Soler-Cataluna et al., 2005). Furthermore, with the increasing incidence of COPD, exacerbations place a greater burden on the healthcare system, resulting in more than 10 million unplanned visits annually in the United States (Mannino and Braman, 2007). In the United States, the direct cost of COPD treatment exceeds $32 billion annually, with exacerbations estimated to account for 50% to 75% of these healthcare costs (Celli et al., 2004; Guarascio et al., 2013; Toy et al., 2010). Exacerbations are also an important outcome measure for COPD, with acute treatments aimed at accelerating recovery from such exacerbations, while chronic treatments typically refer to long-term maintenance inhalation therapy, which is designed to prevent and reduce their frequency and severity (Ritchie and Wedzicha, 2020).

[0008] Despite adequate treatment with optimized maintenance inhalation therapy, approximately 30% to 40% of patients continue to experience moderate to severe exacerbations (Müllerová et al., 2017; Vestbo et al., 2017). Even with the most maximal triple therapy (LABA+LAMA+ICS), it may still be insufficient (Rabe et al., 2020).

[0009] Like many other diseases, COPD patients exhibit significant variability in disease severity, onset, and progression rate. Due to this substantial variability, different patient subgroups can receive optimal care through different and more targeted treatments. Consequently, a significant amount of unmet medical needs remain. This disclosure aims to address one or more of the aforementioned problems in the art. Therefore, one or more aspects of this disclosure and further examples thereof are defined below.

[0010] Rabe et al., Lancet Respir Med. 2021 Nov; 9(11):1288-1298 published results from a randomized, double-blind, phase 2a trial investigating the safety and efficacy of itepekimab. Yousuf et al., Lancet Respir Med. 2022 May; 10(5):469-477 published results from COPD-ST2OP: a phase 2a, placebo-controlled trial investigating the efficacy of astegolimab in chronic obstructive pulmonary disease. WO2023 / 02593 published a phase III, multicenter, randomized, double-blind, chronically administered, parallel-group, placebo-controlled study to evaluate the efficacy and safety of two dosing regimens of tozorakimab in participants with symptomatic chronic obstructive pulmonary disease (COPD) and a history of COPD exacerbations (NCT05166889). Summary of the Invention

[0011] In a first aspect, a method for treating a subject suffering from COPD is provided, the method comprising: administering an effective amount of an IL-33 signaling axis antagonist to the subject, wherein, prior to the administration, the subject has a blood eosinophil count of <250 cells / μl to ≥150 cells / μl.

[0012] In a second aspect, a method for improving lung function in a subject with COPD is provided, the method comprising: administering an effective amount of an IL-33 signaling axis antagonist to the subject, wherein, prior to the administration, the subject has a blood eosinophil count of <250 cells / μl to ≥150 cells / μl.

[0013] In a third aspect, a method for treating a subject with COPD is provided, the method comprising: administering an effective amount of an IL-33 signaling axis antagonist to the subject, wherein, prior to the administration, the subject has a blood eosinophil count of <250 cells / μl to ≥150 cells / μl, and wherein the subject is a current smoker.

[0014] In a fourth aspect, a method for improving lung function in a subject with COPD is provided, the method comprising: administering an effective amount of an IL-33 signaling axis antagonist to the subject, wherein, prior to the administration, the subject has a blood eosinophil count of <250 cells / μl to ≥150 cells / μl, and wherein the subject is a current smoker.

[0015] In a fifth aspect, a method is provided to increase the time to the first CompEx event in a subject with COPD, the method comprising: administering an effective amount of an IL-33 signaling axis antagonist to the subject, wherein the subject is a current smoker.

[0016] In a sixth aspect, a method is provided for reducing the rate of CompEx events in a subject with COPD, the method comprising: administering an effective amount of an IL-33 signaling axis antagonist to the subject, wherein the subject is a current smoker.

[0017] On the other hand, a method is provided to increase the time to the first CompEx event in a subject with COPD, the method comprising: administering an effective amount of an IL-33 signaling axis antagonist to the subject, wherein the subject is a current smoker, and wherein prior to the administration, the subject has a blood eosinophil count of <250 cells / μl to ≥150 cells / μl.

[0018] On the other hand, a method for reducing the rate of CompEx events in subjects with COPD is provided, the method comprising: administering an effective amount of an IL-33 signaling axis antagonist to the subject, wherein the subject is a current smoker.

[0019] On the other hand, a method is provided to increase the pre-BD FEV1 of a subject with COPD by at least 50 ml (such as at least 60 ml), the method comprising: administering an effective amount of an IL-33 signaling axis antagonist to the subject, wherein prior to the administration, the subject has a blood eosinophil count of <250 cells / μl to ≥150 cells / μl.

[0020] On the other hand, a method is provided to increase the pre-BD FEV1 of a subject with COPD by at least 50 ml (such as at least 60 ml), the method comprising: administering an effective amount of an IL-33 signaling axis antagonist to the subject, wherein, prior to the administration, the subject has a blood eosinophil count of <250 cells / μl to ≥150 cells / μl, and wherein the subject is a current smoker.

[0021] On the other hand, an IL-33 signaling axis antagonist is provided for treating COPD in subjects, wherein, prior to administration of the IL-33 signaling axis antagonist, the subject has a blood eosinophil count of <250 cells / μl to ≥150 cells / μl.

[0022] On the other hand, an IL-33 signaling axis antagonist is provided for improving lung function in subjects with COPD, wherein, prior to administration of the IL-33 signaling axis antagonist, the subject has a blood eosinophil count of <250 cells / μl to ≥150 cells / μl. Optionally, this aspect can be used to treat COPD by improving lung function.

[0023] On the other hand, an IL-33 signaling axis antagonist for treating COPD in subjects is provided, wherein, prior to administration of the IL-33 signaling axis antagonist, the subject has a blood eosinophil count of <250 cells / μl to ≥150 cells / μl, and wherein the subject is a current smoker.

[0024] On the other hand, an IL-33 signaling axis antagonist is provided for improving lung function in subjects with COPD, wherein, prior to administration of the IL-33 signaling axis antagonist, the subject has a blood eosinophil count of <250 cells / μl to ≥150 cells / μl, and wherein the subject is a current smoker. Optionally, this aspect can be used to treat COPD by improving lung function.

[0025] On the other hand, an IL-33 signaling axis antagonist is provided, which is used to increase the time to first CompEx event in subjects with COPD, wherein the subject is a current smoker. Optionally, this aspect can be used to treat COPD by increasing the time to first CompEx event.

[0026] On the other hand, an IL-33 signaling axis antagonist is provided for reducing the CompEx event rate in subjects with COPD, wherein the subject is a current smoker. Optionally, this aspect can be used to treat COPD by reducing the CompEx event rate.

[0027] On the other hand, an IL-33 signaling axis antagonist is provided for increasing the time to first CompEx event in a subject with COPD, wherein the subject is a current smoker and wherein, prior to administration of the IL-33 signaling axis antagonist, the subject has a blood eosinophil count of <250 cells / μl to ≥150 cells / μl. Optionally, this aspect can be used to treat COPD by increasing the time to first CompEx event.

[0028] On the other hand, an IL-33 signaling axis antagonist is provided for reducing the rate of CompEx events in subjects with COPD, wherein the subject is a current smoker and wherein, prior to administration of the IL-33 signaling axis antagonist, the subject has a blood eosinophil count of <250 cells / μl to ≥150 cells / μl. Optionally, this aspect can be used to treat COPD by reducing the rate of CompEx events.

[0029] On the other hand, an IL-33 signaling axis antagonist is provided for increasing pre-BD FEV1 in a subject with COPD by at least 50 ml (e.g., at least 60 ml), wherein, prior to administration of the IL-33 signaling axis antagonist, the subject has a blood eosinophil count of <250 cells / μl to ≥150 cells / μl. Optionally, this aspect can be used to treat COPD by increasing pre-BD FEV1.

[0030] On the other hand, an IL-33 signaling axis antagonist is provided for increasing pre-BD FEV1 in a subject with COPD by at least 50 ml (e.g., at least 60 ml), wherein, prior to administration of the IL-33 signaling axis antagonist, the subject has a blood eosinophil count of <250 cells / μl to ≥150 cells / μl, and wherein the subject is a current smoker. Optionally, this aspect can be used to treat COPD by increasing pre-BD FEV1.

[0031] In a seventh aspect, a method is provided for selecting a subject suffering from COPD to be treated with an effective amount of an IL-33 signaling axis antagonist, the method comprising: measuring the subject's blood eosinophil count; selecting the subject for treatment if the subject's blood eosinophil count is <250 cells / μl to ≥150 cells / μl; and optionally administering an effective amount of the IL-33 signaling axis antagonist to the subject.

[0032] In an eighth aspect, a method is provided for selecting a subject suffering from COPD to be treated with an effective amount of an IL-33 signaling axis antagonist, the method comprising: measuring the subject's blood eosinophil count; selecting the subject for treatment if the subject's blood eosinophil count is <250 cells / μl to ≥150 cells / μl and the subject is a current smoker; optionally administering an effective amount of the IL-33 signaling axis antagonist to the subject.

[0033] In the ninth aspect, the use of an IL-33 signaling axis antagonist in the manufacture of a medicament for treating a subject with COPD is provided, wherein, prior to administration of the IL-33 signaling axis antagonist, the subject has a blood eosinophil count of <250 cells / μl to ≥150 cells / μl.

[0034] In a tenth aspect, the use of an IL-33 signaling axis antagonist in the manufacture of a medicament for improving lung function in a subject suffering from COPD is provided, wherein, prior to administration of the IL-33 signaling axis antagonist, the subject has a blood eosinophil count of <250 cells / μl to ≥150 cells / μl. Optionally, this aspect can be used to treat COPD by improving lung function.

[0035] In the eleventh aspect, the use of an IL-33 signaling axis antagonist in the manufacture of a medicament for treating a subject with COPD is provided, wherein the subject has a blood eosinophil count of <250 cells / μl to ≥150 cells / μl prior to administration of the IL-33 signaling axis antagonist, and wherein the subject is a current smoker.

[0036] In a twelfth aspect, the use of an IL-33 signaling axis antagonist in the manufacture of a medicament for improving lung function in a subject suffering from COPD is provided, wherein, prior to administration of the IL-33 signaling axis antagonist, the subject has a blood eosinophil count of <250 cells / μl to ≥150 cells / μl, and wherein the subject is a current smoker. Optionally, this aspect can be used to treat COPD by improving lung function.

[0037] In the thirteenth aspect, the use of an IL-33 signaling axis antagonist in the manufacture of a medicament for increasing the time to first CompEx event in a subject suffering from COPD, wherein the subject is a current smoker. Optionally, this aspect can be used to treat COPD by increasing the time to first CompEx event.

[0038] In the fourteenth aspect, the use of an IL-33 signaling axis antagonist in the manufacture of a medicament for reducing the CompEx event rate in a subject suffering from COPD, wherein the subject is a current smoker. Optionally, this aspect can treat COPD by reducing the CompEx event rate.

[0039] In the fifteenth aspect, the use of an IL-33 signaling axis antagonist in the manufacture of a medicament for increasing the time to first CompEx event in a subject suffering from COPD, wherein the subject is a current smoker, and wherein, prior to administration of the IL-33 signaling axis antagonist, the subject has a blood eosinophil count of <250 cells / μl to ≥150 cells / μl. Optionally, this aspect can be used to treat COPD by increasing the time to first CompEx event.

[0040] In a sixteenth aspect, the use of an IL-33 signaling axis antagonist in the manufacture of a medicament for reducing the rate of CompEx events in a subject suffering from COPD, wherein the subject is a current smoker, and wherein, prior to administration of the IL-33 signaling axis antagonist, the subject has a blood eosinophil count of <250 cells / μl to ≥150 cells / μl. Optionally, this aspect can be used to treat COPD by reducing the rate of CompEx events.

[0041] In a seventeenth aspect, the use of an IL-33 signaling axis antagonist in the manufacture of a medicament for increasing pre-BD FEV1 in a subject with COPD by at least 50 ml (such as at least 60 ml), wherein, prior to administration of the IL-33 signaling axis antagonist, the subject has a blood eosinophil count of <250 cells / μl to ≥150 cells / μl. Optionally, this aspect can be used to treat COPD by increasing pre-BD FEV1.

[0042] In the eighteenth aspect, the use of an IL-33 signaling axis antagonist in the manufacture of a medicament for increasing pre-BD FEV1 in a subject with COPD by at least 50 ml (such as at least 60 ml), wherein, prior to administration of the IL-33 signaling axis antagonist, the subject has a blood eosinophil count of <250 cells / μl to ≥150 cells / μl, and wherein the subject is a current smoker. Optionally, this aspect can be used to treat COPD by increasing pre-BD FEV1.

[0043] In another alternative aspect of this disclosure, a method for treating a subject with COPD is provided, the method comprising: administering an effective amount of an IL-33 signaling axis antagonist to the subject, wherein the subject is a current smoker.

[0044] In a further alternative aspect of this disclosure, a method for improving lung function in a subject with COPD is provided, the method comprising: administering an effective amount of an IL-33 signaling axis antagonist to the subject, wherein the subject is a current smoker.

[0045] In a further alternative aspect of this disclosure, a method is provided to increase the pre-BD FEV1 of a subject with COPD by at least 50 mL (such as at least 60 mL), the method comprising: administering an effective amount of an IL-33 signaling axis antagonist to the subject, wherein the subject is a current smoker.

[0046] In a further alternative aspect of this disclosure, an IL-33 signaling axis antagonist is provided for treating a subject with COPD, wherein the subject is a current smoker.

[0047] In a further alternative aspect of this disclosure, an IL-33 signaling axis antagonist is provided for improving lung function in a subject with COPD, wherein the subject is a current smoker. Optionally, this aspect can be used to treat COPD by improving lung function.

[0048] In a further alternative aspect of this disclosure, an IL-33 signaling axis antagonist is provided for increasing pre-BD FEV1 by at least 50 mL (e.g., at least 60 mL) in a subject with COPD, wherein the subject is a current smoker. Optionally, this aspect can be used to treat COPD by increasing pre-BD FEV1.

[0049] In a further alternative aspect of this disclosure, the use of an IL-33 signaling axis antagonist in the manufacture of a medicament for treating a subject with COPD, wherein the subject is a current smoker is provided.

[0050] In a further alternative aspect of this disclosure, the use of an IL-33 signaling axis antagonist in the manufacture of a medicament for improving lung function in a subject suffering from COPD, wherein the subject is a current smoker. Optionally, this aspect can be used to treat COPD by improving lung function.

[0051] In a further alternative aspect of this disclosure, the use of an IL-33 signaling axis antagonist in the manufacture of a medicament for increasing pre-BD FEV1 by at least 50 ml (e.g., at least 60 ml) in a subject with COPD, wherein the subject is a current smoker. Optionally, this aspect can be used to treat COPD by increasing pre-BD FEV1.

[0052] FRONTIER-4 (NCT04631016) was a phase II, randomized, double-blind, placebo-controlled study evaluating toledizumab (MEDI3506) in participants with COPD and chronic bronchitis. This trial demonstrated that a specific subset of patients with COPD exhibited enhanced treatment responses when administered an anti-IL-33 antibody, such as toledizumab. This disclosure aims to capture the treatment potential of this subset of patients who may benefit more from treatment with such IL-33 signaling axis antagonists, such as toledizumab.

[0053] Further features and instances of the aspects defined above are described in the heading sections below. Each section can be combined with any of the aspects mentioned above in any compatible combination. Attached Figure Description

[0054] Figure 1 The changes in pre-BD FEV1 (L) (clinical) and (ITT population) from baseline to week 36 are shown (MEDI 350 6600 mg vs. placebo).

[0055] Figure 2 The changes in pre-BD FEV1 (L) at week 12 are shown in the subgroup with higher BCSS or SGRQ scores among former smokers and current smokers (lower emphysema or COPD worsening >2) in the 12 months prior to enrollment.

[0056] Figure 3 The clinically measured changes in FEV1 after BD are shown (MEDI3506 600mg vs. placebo).

[0057] Figure 4 The changes in pre-BD FVC (L) (clinical) and (ITT population) from baseline to week 36 are shown (MEDI 350 6600 mg vs. placebo).

[0058] Figure 5 The Kaplan-Meier curve (ITT population) shows the time (in days) to the first COPD CompEx event (MEDI3506 600mg vs. placebo).

[0059] Figure 6A The time to the first CompEx event is shown for former smokers compared to those treated with a placebo.

[0060] Figure 6B The time to the first CompEx event is shown for current smokers compared to those treated with a placebo. Detailed Implementation

[0061] definition

[0062] The term "about" or "approximately" refers to an acceptable error in 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 some instances, the term "about" or "approximately" means within 1, 2, 3, or 4 standard deviations. In some instances, 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, it should be understood that the term "about" or "approximately" applies to every value in that series.

[0063] In some instances, the symbol “<” means the specified number following the “less than” sign, and ">” means the specified number following the “greater than” sign, wherein the specified number following the symbol is not included in the range. In contrast, the symbol “≤” means the specified number following the “less than or equal to” sign, and the symbol “≥” means the specified number following the “greater than or equal to” sign, wherein the specified number following the symbol is included in the range.

[0064] It should be noted that the terms “an” or “a” entity refer to one or more of that entity; for example, “anti-IL-33 antibody” should be understood to mean one or more anti-IL-33 antibodies. Therefore, the terms “an” (or “a”), “one or more”, and “at least one” are used interchangeably herein.

[0065] As used herein, "IL-33" protein refers to interleukin 33, particularly mammalian interleukin 33 protein, such as the human protein deposited under UniProt number 095760. However, it is clear that this entity is not a single substance but exists in both reduced and oxidized forms. Given the rapid oxidation of the reduced form in vivo (e.g., over a period of 5 to 40 minutes) and in vitro, references to IL-33 in the prior art may actually refer to the oxidized form. Furthermore, commercial assays may not effectively distinguish between the reduced and oxidized forms. The terms "IL-33" and "IL-33 polypeptide" are used interchangeably. In some instances, IL-33 is the full-length form. In another instance, IL-33 is the mature, truncated IL-33 (amino acids 112-270). Recent studies have shown that full-length IL-33 is active (Cayrol and Girard, Proc Natl Acad Sci USA 106(22):9021-6 (2009); Hayakawa et al., Biochem Biophys Res Commun.387(1):218-22 (2009); Talabot-Ayer et al., J Biol Chem.284(29): 19420-6 (2009)). However, N-terminated or truncated IL-33, including but not limited to aa 72-270, 79-270, 95-270, 99-270, 107-270, 109-270, 111-270, and 112-270, can have enhanced activity (Lefrancais 2012, 2014). In another instance, IL-33 may include full-length IL-33, fragments thereof, or IL-33 mutant or variant peptides, wherein fragments of IL-33 or IL-33 variant peptides retain some or all of the functional properties of active IL-33.

[0066] It should be understood that references to “WT IL-33” or “IL-33” may refer to the reduced or oxidized form, or both, unless it is clear from the context in which they are used that they refer to one of the forms.

[0067] As used herein, the term “treatment” refers to therapeutic treatment and preventative or preventive measures aimed at preventing or mitigating (alleviating) undesirable physiological changes or symptoms. Beneficial or desired clinical outcomes include, but are not limited to, relief of symptoms, reduction of disease severity, stabilization of the disease state (i.e., non-deterioration), delay or slowing of disease progression, improvement or mitigation of the disease state, and detectable or undetectable remission (whether partial or complete). “Treatment” can also refer to extended survival compared to expected survival without treatment. Those who require treatment include those who already have symptoms or conditions, those who are susceptible to symptoms or conditions, and those who need to prevent symptoms or conditions.

[0068] The terms "subject," "individual," "animal," "patient," or "mammal" refer to any subject requiring diagnosis, prognosis, or treatment, particularly mammalian subjects, unless the subject is defined as a 'healthy subject.' Mammal subjects include humans; domesticated animals; farm animals; such as dogs, cats, guinea pigs, rabbits, rats, mice, horses, cattle, dairy cows, etc.

[0069] As used herein, "IL-33 signaling axis antagonist" refers to any agent that weakens IL-33 activity, such as reduced IL-33 activity, oxidized IL-33 activity, or both. Suitably, the IL-33 signaling axis antagonist may be selected from: antibodies, their antigen-binding fragments, aptamers, at least one heavy or light chain CDR of a reference antibody molecule, and at least six CDRs from one or more reference antibody molecules. Suitably, the IL-33 signaling axis antagonist is an antibody or its binding fragment. Suitably, the IL-33 signaling axis antagonist is an anti-IL-33 antibody or its binding fragment. Suitably, the anti-IL-33 antibody or its binding fragment specifically binds to IL-33.

[0070] The term “antibody” is used in the broadest sense and encompasses a wide range of immunoglobulin molecules and antibody structures, including but not limited to monoclonal antibodies, polyclonal antibodies, multispecific antibodies (e.g., bispecific antibodies), and antibody fragments, as long as they exhibit the desired antigen-binding activity, particularly full-length antibodies or molecules containing full-length antibodies, such as DVD-Ig molecules.

[0071] "Its binding fragment" and "its antigen-binding fragment" are interchangeable and refer to the epitope / antigen-binding fragment of the antibody fragment, such as containing a binding region, especially containing 6 CDRs, such as 3 CDRs in the heavy variable region and 3 CDRs in the light variable region.

[0072] The term "effective amount" or "therapeutic effective amount" for a pharmaceutical preparation (e.g., an IL-33 signaling axis antagonist or a pharmaceutical preparation containing an IL-33 signaling axis antagonist) refers to an amount sufficient to achieve a beneficial or therapeutic effect, such as improving the symptoms of a disease or condition, for example, an amount that effectively achieves the desired therapeutic or preventive outcome within the necessary dosage and time period.

[0073] As used in this article, the terms “complementarity-determining region” and “CDR” refer to the amino acid residues of the antibody or antigen-binding fragment responsible for antigen binding.

[0074] The terms “peptide,” “polypeptide,” and “protein” are used interchangeably and refer to compounds composed of amino acid residues covalently linked by peptide bonds. A protein or peptide must contain at least two amino acids, and there is no limit to the maximum number of amino acids that can constitute a protein or peptide sequence. A polypeptide includes any peptide or protein containing two or more amino acids linked together by peptide bonds. As used herein, the term refers to both short chains (which are also commonly referred to in the art, for example, peptides, oligopeptides, and oligomers) and longer chains (which are commonly referred to in the art, for example, proteins, of which there are many types). “Polypeptide” includes, for example, biologically active fragments, substantially homologous polypeptides, oligopeptides, homodimers, heterodimers, variants of polypeptides, modified polypeptides, derivatives, analogs, fusion proteins, etc. Polypeptides include native peptides, recombinant peptides, or combinations thereof.

[0075] The term "nucleic acid" or "polynucleotide" refers to deoxyribonucleic acid (DNA) or ribonucleic acid (RNA) in single-stranded or double-stranded form and their polymers. Unless otherwise specified, the term covers nucleic acids containing known analogs of natural nucleotides, which have similar binding properties to reference nucleic acids and are metabolized in a manner similar to naturally occurring nucleotides. Unless otherwise specified, a specific nucleic acid sequence also implicitly covers variants of its conserved modifications (e.g., degenerate codon substitutions), alleles, orthologs, SNPs, and complementary sequences, as well as explicitly specified sequences. Specifically, degenerate codon substitution can be achieved by producing a sequence in which the third position of one or more selected (or all) codons is substituted with a mixed base and / or deoxyinosine residue (Batzer et al., Nucleic Acid Res. 19:5081 (1991); Ohtsuka et al., J. Biol. Chem. 260:2605-2608 (1985); and Rossolini et al., Mol. Cell. Probes 8:91-98 (1994)).

[0076] The term "pack-year" refers to the average number of cigarettes smoked per day × number of years / 20.

[0077] The term "COPD" refers to chronic obstructive pulmonary disease.

[0078] The term "COPDCompEx" refers to a composite endpoint of COPD exacerbation. COPDCompEx combines the exacerbation of an event as defined by the participant's electronic diary with peak expiratory flow (PEF). Note that the definition of COPDCompEx typically includes withdrawal due to lack of efficacy as a CompEx event. However, in studies where "lack of efficacy" is not listed as a reason for discontinuation, the exit criteria for COPD CompEx may not be included.

[0079] A participant will be considered to have a CompEx event during the planned intervention period if they possess one or more of the following:

[0080] • Deterioration as defined by COPDCompEx, those collected in eCRF that meet at least one of the following criteria:

[0081] Related hospitalization = Yes;

[0082] o Systemic corticosteroids (injection and / or oral) = Yes;

[0083] o Antibiotics = Yes;

[0084] Any emergency room visits due to worsening COPD? = Yes.

[0085] • Diary events – objective deterioration, defined as a threshold criterion or slope criterion (or both), satisfying ≥ 2 consecutive days.

[0086] Therefore, "two consecutive days" means two consecutive days that are strictly identical when evaluating multiple requirements within those days. For electronic diary data (which is captured twice a day), a day will be defined by evening / morning pairings as other electronic diary endpoints in this experiment. Diary data recorded on the evening of day n and the morning of day n+1 will belong to day n of the study.

[0087] The objective deterioration criterion will be satisfied for each (individual) diary variable for the threshold and slope:

[0088] Threshold Standards - Threshold Assessment in Each 2-Day Rolling Cycle:

[0089] a. Morning PEF decreases by ≥12% from baseline.

[0090] b. The total daily rescue medication dose is increased by ≥1.75 doses from baseline (a day is defined as evening / morning paired. The number of rescue medication doses is defined as the number of inhalers recorded in the evening and morning, respectively). If the evening or morning result is lost, a single non-lost result will be used.

[0091] c. An increase of ≥0.75 from baseline or a maximum symptom score of 4 in at least one of the following symptom scores: dyspnea, cough, sputum production. Specifically:

[0092] i. An increase of ≥0.75 from baseline or a maximum symptom score of 4 in the daily dyspnea assessment;

[0093] ii. An increase of ≥0.75 from baseline or a maximum symptom score of 4 in the daily cough score; or

[0094] iii. An increase of ≥0.75 from baseline or a maximum symptom score of 4 in the daily sputum score.

[0095] The threshold criterion is met if [(a) or (b)] and at least one (c) are satisfied for two consecutive days.

[0096] Slope Criteria - Assessment of the regression slope in each previous 5-day rolling period:

[0097] d. Morning PEF slope ≤ -3% / .

[0098] e. Daily total rescue medication slope ≥ 0.4 doses / day

[0099] f. The slope of all symptom scores (dyspnea, cough, sputum) is ≥0.2 / day.

[0100] If all of [(d), (e), and (f)] are satisfied, and at least one of [(a), (b), or (c)] is satisfied, then the slope criterion is satisfied.

[0101] In all the above cases, the regression slope is a point estimate of the slope obtained from a linear regression of the absolute value of each variable relative to the number of days, and other variables are not included in the regression model.

[0102] The phrase “before application” refers to a period within one month of the start of treatment. Optionally, “before application” can refer to any time within one month of the start of treatment, such as 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 1 week, 2 weeks, 3 weeks, or 4 weeks before the start of treatment.

[0103] The term "emphysema" refers to damage to the alveoli in the lungs.

[0104] The term “chronic bronchitis” refers to long-term inflammation of the airways and can be defined as having cough and sputum production on most days for at least 2 years prior to the onset of the disease and lasting for ≥3 months / year.

[0105] The term "BCSS score" refers to a score derived from the Dyspnea, Cough, and Sputum Scale (BCSS). The BCSS is a 3-item PRO (Leidy et al., Chest. 2003; 124(6):2182-91; Leidy et al., Respir Med. 2003; 97 Supplement AS59-70) that assesses the severity of dyspnea, cough, and sputum on a scale of 0 (asymptomatic) to 4 (severe symptoms). Item scores are summed to obtain a total score; a higher score indicates more severe symptoms.

[0106] The term "SGRQ score" comes from the St. George's Respiratory Questionnaire (SGRQ). The SGRQ is a 50-item PRO tool developed to measure the health status of patients with airway obstruction disorders (Jones PW, Quirk FH, and Baveystock CM, The St. George's Respiratory Questionnaire. Respir Med 1991; 85 Supplement B: 25-31). The questionnaire is divided into two parts: Part 1 consists of 8 items relating to the severity of respiratory symptoms over the previous 4 weeks; Part 2 consists of 42 items relating to the daily activities and psychosocial impacts of an individual's respiratory condition. The SGRQ yields a total score and three domain scores (symptoms, activities, and impacts). The total score indicates the impact of the disease on overall health. This total score is expressed as a percentage of overall impairment, with 100 representing the worst possible health status and 0 representing the best possible health status. Similarly, domain scores range from 0 to 100, with higher scores indicating greater impairment. Specific details regarding the scoring algorithm are provided by the developers in the user manual (Jones and Forde Y., St. George's Respiratory Questionnaire Manual). Questionnaire manual (2009, version 2.3). The SGRQ is an eligible biomarker, and generally, a respondent is defined as a 4-point improvement from baseline. Therefore, in some cases, the minimum clinically significant difference in the SGRQ is 4.

[0107] The terms “FEV1 before BD” or “FEV1 before bronchodilator (BD)” refer to the forced expiratory volume one second before administration of a bronchodilator. This is a measurement of the subject’s forced expiratory volume within one second before administration of a bronchodilator. FEV1 before BD is an important measure of lung function.

[0108] The term “forced expiratory volume one second after bronchodilator (BD) administration” or “forced expiratory volume one second after bronchodilator administration” refers to the forced expiratory volume one second following bronchodilator administration. This is a measurement of the subject’s forced expiratory volume within one second after bronchodilator administration. FEV1 after BD is an important measure of lung function.

[0109] The term "pre-BD FVC" or "pre-BD forced vital capacity (FVC)" refers to forced vital capacity with bronchodilator administration. This is the total amount of air a subject exhales during a forced expiratory volume test or FVC test before administration of a bronchodilator. Pre-BD FVC is an important measure of lung function.

[0110] The term "forced vital capacity (FVC) after BD" or "forced expiratory volume (FVC) after bronchodilator (BD) administration" refers to the forced vital capacity following bronchodilator administration. This is the total amount of air a subject exhales during a forced expiratory volume (FVC) test after bronchodilator administration. FVC after BD is an important measure of lung function.

[0111] The term "bronchodilator" refers to a substance that dilates the bronchi and bronchioles, reduces airway resistance, and increases airflow to the lungs. Suitable bronchodilators include short-acting β2-adrenergic receptor agonists, such as salbutamol.

[0112] The term "minute ventilation" refers to the total amount of air a subject exhales per minute.

[0113] The term "vital capacity" refers to the total amount of air a subject can exhale after inhaling.

[0114] The term "functional residual capacity" refers to the amount of air remaining in a subject's lungs after a normal exhalation.

[0115] The term "residual volume" refers to the amount of air remaining in a subject's lungs after exhaling as much air as possible.

[0116] The term "total lung capacity" refers to the total amount of air a subject has when their lungs are filled with as much air as possible.

[0117] The term "forced expiratory flow rate" refers to the average flow rate of air exhaled by the subject during the middle half of the FVC test.

[0118] The term "peak expiratory flow rate" indicates the fastest rate at which a subject can force air out of the lungs.

[0119] The term "forced expiratory volume (FEV)" refers to the amount of air a subject exhales during the first, second, and third seconds of an FVC test. As explained above, the term FEV1 refers to the amount of air a subject exhales during the first second of an FVC test.

[0120] The term "forced vital capacity" (FVC) or the forced vital capacity test is a measurement of the total amount of air a subject can forcefully and rapidly exhale after inhaling as much air as possible.

[0121] The term "placebo group" refers to a group of control subjects who have the same characteristics as the subjects to be treated, but who do not receive an IL-33 signaling axis antagonist, but receive a placebo. Suitably, a placebo is a pharmacologically inert preparation or composition. Suitably, a placebo may contain the same ingredients as a pharmaceutical composition containing an IL-33 signaling axis antagonist, except that it does not contain an active IL-33 signaling axis antagonist.

[0122] Subjects

[0123] These methods and medical uses are performed on a subject. Where appropriate, a subject may be a person. Where appropriate, a subject may be receiving medical care. Where appropriate, a subject may be an individual requesting medical care. Where appropriate, a subject may be male or female. Where appropriate, a subject may be an adult or a child. Where appropriate, the term 'subject' is used interchangeably with the term 'patient' in this document.

[0124] Appropriately, the subject has COPD, is suspected of having COPD, or has symptoms consistent with COPD. Appropriately, "subject with COPD" may mean that the subject has a diagnosis of COPD. The subject may have a documented history of COPD, which, appropriately, must have been present for at least one year prior to undergoing the treatments disclosed herein.

[0125] In some instances, the subjects were current smokers. In other instances, the subjects were former smokers.

[0126] In some instances, the subject was a current smoker or former smoker with a tobacco history of 10 pack-years or more (=> or ≥). A pack-year is calculated as the average number of cigarettes smoked per day × number of years / 20. For example, 1 pack-year = 20 cigarettes smoked per day for 1 year or 10 cigarettes smoked per day for 2 years. In some instances, the subject may have a tobacco history of ≥5 pack-years, ≥6 pack-years, ≥7 pack-years, ≥8 pack-years, ≥9 pack-years, or ≥10 pack-years. Appropriately, the subject may have a tobacco history of ≥15 pack-years, ≥20 pack-years, ≥25 pack-years, ≥30 pack-years, ≥15 pack-years, or ≥15 pack-years. In some instances, the subject was a former smoker with a tobacco history of ≥10 pack-years. In some instances, the subject was a current smoker. In some instances, the subject was a current smoker with a tobacco history of ≥10 pack-years.

[0127] The results showed that torazumab (MEDI3506) had similar numerical improvements in pre-clinical BD FEV1 in both former smokers and current smokers (see [link to study]). Figure 1 and Figure 2 ), and improvements were observed in the time to the first CompEX event for both former and current smokers. Figure 6A and Figure 6BConversely, in a phase 2a trial evaluating the safety and efficacy of ecterazimab in patients with moderate to severe chronic obstructive pulmonary disease, in stable regimens with three inhalations or two inhalations as background maintenance therapy, current smokers treated with ecterazimab showed no beneficial effect on worsening or FEV1 compared to placebo (Rabe et al. (2021) Lancet Respi Med| 9:11; 1288-1298). Etergizumab is an anti-IL-33 monoclonal antibody.

[0128] In some instances, the subjects were non-smokers.

[0129] Suitably, prior to administration of an effective amount of the IL-33 signaling axis antagonist, the subject has a blood eosinophil count of ≥150 cells / µl. Suitably, prior to administration of an effective amount of the IL-33 signaling axis antagonist, the subject has a blood eosinophil count of <300 cells / µl. Suitably, prior to administration of an effective amount of the IL-33 signaling axis antagonist, the subject has a blood eosinophil count of <300 cells / µl to ≥150 cells / µl.

[0130] Suitably, prior to administration of an effective amount of the IL-33 signaling axis antagonist, the subject had a blood eosinophil count of <290 cells / µl to ≥150 cells / µl. Suitably, prior to administration of an effective amount of the IL-33 signaling axis antagonist, the subject had a blood eosinophil count of <280 cells / µl to ≥150 cells / µl. Suitably, prior to administration of an effective amount of the IL-33 signaling axis antagonist, the subject had a blood eosinophil count of <270 cells / µl to ≥150 cells / µl. Suitably, prior to administration of an effective amount of the IL-33 signaling axis antagonist, the subject had a blood eosinophil count of <260 cells / µl to ≥150 cells / µl.

[0131] Suitably, prior to administration of an effective amount of the IL-33 signaling axis antagonist, the subject had a blood eosinophil count of <230 cells / µl to ≥150 cells / µl. Suitably, prior to administration of an effective amount of the IL-33 signaling axis antagonist, the subject had a blood eosinophil count of <220 cells / µl to ≥150 cells / µl. Suitably, prior to administration of an effective amount of the IL-33 signaling axis antagonist, the subject had a blood eosinophil count of <210 cells / µl to ≥150 cells / µl. Suitably, prior to administration of an effective amount of the IL-33 signaling axis antagonist, the subject had a blood eosinophil count of <200 cells / µl to ≥150 cells / µl.

[0132] In some instances, prior to the administration, the subject had a blood eosinophil count of <300 cells / µl, <290 cells / µl, <280 cells / µl, <270 cells / µl, <260 cells / µl, <250 cells / µl, <240 cells / µl, <230 cells / µl, <220 cells / µl, <210 cells / µl, or <200 cells / µl.

[0133] In some instances, prior to administration, the subject had a blood eosinophil count of <250 cells / µl (suitably, excluding 250 cells / µl). In some specific instances, prior to administration, the subject had a blood eosinophil count of <250 cells / µl to ≥150 cells / µl (suitably, excluding 250 cells / µl).

[0134] In some instances, prior to administration, the subject had a blood eosinophil count of <240 cells / µl (suitably excluding 250 cells / µl). In some instances, prior to administration, the subject had a blood eosinophil count of <240 cells / µl to ≥150 cells / µl (suitably excluding 240 cells / µl).

[0135] The results showed that torazumab (MEDI3506) provided a sustained numerical improvement in pre-BD FEV1 in both clinical and home settings throughout the entire treatment period of up to 12 weeks in subjects with blood eosinophil counts ≥300 cells / µl, and the same was true for subjects with low blood eosinophil counts, ranging from less than 300 cells / µl to ≥150 cells / µl (see [link to treatment]). Figures 1-2 (See Figure 7). Throughout the entire treatment period of up to 28 weeks, improvements in pre-BD FEV1 were particularly evident in the subgroup of subjects with blood eosinophil counts between <250 cells / µl and ≥150 cells / µl, excluding 250 cells / µl (see Table 10 Results). No other IL-33 signaling axis antagonists have been shown to have such effects on lung function as demonstrated by pre-BD FEV1 in the subgroup with low eosinophil counts, specifically between <250 cells / µl and ≥150 cells / µl. Furthermore, the results showed that toledizumab (MEDI3506) reduced the rate of CompEx events in all subjects, but particularly in the subgroup of subjects with blood eosinophil counts ≥150 cells / µl (see Table 9).

[0136] In some instances, the subject was a current smoker or a former smoker. Appropriately, the subject was a former smoker. In some instances, the subject was a current smoker. Appropriately, the subject was a non-smoker.

[0137] Subjects can be current or former smokers and have a blood eosinophil count of <300 cells / µl to ≥150 cells / µl prior to administration of an effective dose of the IL-33 signaling axis antagonist. Subjects can be current or former smokers and have a blood eosinophil count of <290 cells / µl to ≥150 cells / µl prior to administration of an effective dose of the IL-33 signaling axis antagonist. Subjects can be current or former smokers and have a blood eosinophil count of <280 cells / µl to ≥150 cells / µl prior to administration of an effective dose of the IL-33 signaling axis antagonist. Subjects can be current or former smokers and have a blood eosinophil count of <270 cells / µl to ≥150 cells / µl prior to administration of an effective dose of the IL-33 signaling axis antagonist. Subjects can be current or former smokers and have a blood eosinophil count of <260 cells / µl to ≥150 cells / µl prior to administration of an effective amount of the IL-33 signaling axis antagonist.

[0138] In some instances, subjects had blood eosinophil counts ranging from <250 cells / µl to ≥150 cells / µl and were current or former smokers. In other instances, subjects had blood eosinophil counts ranging from <240 cells / µl to ≥150 cells / µl and were current or former smokers.

[0139] Subjects can be current or former smokers and have a blood eosinophil count of <230 cells / µl to ≥150 cells / µl prior to administration of an effective dose of the IL-33 signaling axis antagonist. Subjects can be current or former smokers and have a blood eosinophil count of <220 cells / µl to ≥150 cells / µl prior to administration of an effective dose of the IL-33 signaling axis antagonist. Subjects can be current or former smokers and have a blood eosinophil count of <210 cells / µl to ≥150 cells / µl prior to administration of an effective dose of the IL-33 signaling axis antagonist. Subjects can be current or former smokers and have a blood eosinophil count of <200 cells / µl to ≥150 cells / µl prior to administration of an effective dose of the IL-33 signaling axis antagonist.

[0140] In some instances, prior to the administration, the subject had a blood eosinophil count of <300 cells / µl, <290 cells / µl, <280 cells / µl, <270 cells / µl, <260 cells / µl, <250 cells / µl, <240 cells / µl, <230 cells / µl, <220 cells / µl, <210 cells / µl, or <200 cells / µl and was a current or former smoker.

[0141] In some instances, prior to administration, the subject had a blood eosinophil count of <250 cells / µl (suitably excluding 250 cells / µl) and was a current or former smoker. In some instances, prior to administration, the subject had a blood eosinophil count of <250 cells / µl to ≥150 cells / µl (suitably excluding 250 cells / µl) and was a current or former smoker.

[0142] In some instances, prior to administration, the subject had a blood eosinophil count of <240 cells / µl (suitably excluding 250 cells / µl) and was a current or former smoker. In other instances, prior to administration, the subject had a blood eosinophil count of <240 cells / µl to ≥150 cells / µl (suitably excluding 240 cells / µl) and was a current or former smoker.

[0143] In some instances, subjects had blood eosinophil counts ranging from <300 cells / µl to ≥150 cells / µl and were current smokers.

[0144] Subjects can be current smokers and have a blood eosinophil count of <290 cells / µl to ≥150 cells / µl prior to administration of an effective dose of the IL-33 signaling axis antagonist. Subjects can be current smokers and have a blood eosinophil count of <280 cells / µl to ≥150 cells / µl prior to administration of an effective dose of the IL-33 signaling axis antagonist. Subjects can be current smokers and have a blood eosinophil count of <270 cells / µl to ≥150 cells / µl prior to administration of an effective dose of the IL-33 signaling axis antagonist. Subjects can be current smokers and have a blood eosinophil count of <260 cells / µl to ≥150 cells / µl prior to administration of an effective dose of the IL-33 signaling axis antagonist.

[0145] In some instances, the subjects had blood eosinophil counts ranging from <250 cells / µl to ≥150 cells / µl and were current smokers. In some instances, the subjects had blood eosinophil counts ranging from <240 cells / µl to ≥150 cells / µl and were current smokers.

[0146] Subjects can be current smokers and have a blood eosinophil count of <230 cells / µl to ≥150 cells / µl prior to administration of an effective dose of the IL-33 signaling axis antagonist. Subjects can be current smokers and have a blood eosinophil count of <220 cells / µl to ≥150 cells / µl prior to administration of an effective dose of the IL-33 signaling axis antagonist. Subjects can be current smokers and have a blood eosinophil count of <210 cells / µl to ≥150 cells / µl prior to administration of an effective dose of the IL-33 signaling axis antagonist. Subjects can be current smokers and have a blood eosinophil count of <200 cells / µl to ≥150 cells / µl prior to administration of an effective dose of the IL-33 signaling axis antagonist.

[0147] In some instances, prior to the administration, the subject had a blood eosinophil count of <300 cells / µl, <290 cells / µl, <280 cells / µl, <270 cells / µl, <260 cells / µl, <250 cells / µl, <240 cells / µl, <230 cells / µl, <220 cells / µl, <210 cells / µl, <200 cells / µl, and was a current smoker.

[0148] In some instances, prior to administration, the subject had a blood eosinophil count of <250 cells / µl (suitably excluding 250 cells / µl) and was a current smoker. In some instances, prior to administration, the subject had a blood eosinophil count of <250 cells / µl to ≥150 cells / µl (suitably excluding 250 cells / µl) and was a current smoker.

[0149] In some instances, prior to administration, the subject had a blood eosinophil count of <240 cells / µl (suitably excluding 240 cells / µl) and was a current smoker. In some instances, prior to administration, the subject had a blood eosinophil count of <240 cells / µl to ≥150 cells / µl (suitably excluding 240 cells / µl) and was a current smoker.

[0150] In some instances, the treatment methods described herein may include an additional step of selecting subjects with a specific blood eosinophil count. Subjects may be selected from a group of subjects with a blood eosinophil count of <300 cells / µl to ≥150 cells / µl prior to administration of an IL-33 signaling axis antagonist.

[0151] Subjects may be selected from a group of subjects whose blood eosinophil count prior to administration was <290 cells / µl to ≥150 cells / µl. Subjects may be selected from a group of subjects whose blood eosinophil count prior to administration was <280 cells / µl to ≥150 cells / µl. Subjects may be selected from a group of subjects whose blood eosinophil count prior to administration was <280 cells / µl to ≥150 cells / µl. Subjects may be selected from a group of subjects whose blood eosinophil count prior to administration was <260 cells / µl to ≥150 cells / µl.

[0152] In some instances, subjects were selected from a group of subjects whose blood eosinophil counts prior to administration ranged from <250 cells / µl to ≥150 cells / µl. In some instances, subjects were selected from a group of subjects whose blood eosinophil counts prior to administration ranged from <240 cells / µl to ≥150 cells / µl.

[0153] Subjects may be selected from a group of subjects whose blood eosinophil count prior to administration was <230 cells / µl to ≥150 cells / µl. Subjects may be selected from a group of subjects whose blood eosinophil count prior to administration was <220 cells / µl to ≥150 cells / µl. Subjects may be selected from a group of subjects whose blood eosinophil count prior to administration was <210 cells / µl to ≥150 cells / µl. Subjects may be selected from a group of subjects whose blood eosinophil count prior to administration was <200 cells / µl to ≥150 cells / µl.

[0154] In some instances, the subjects were selected from a group of subjects whose blood eosinophil counts prior to the administration included <300 cells / µl, <290 cells / µl, <280 cells / µl, <270 cells / µl, <260 cells / µl, <250 cells / µl, <240 cells / µl, <230 cells / µl, <220 cells / µl, <210 cells / µl, and <200 cells / µl.

[0155] In some instances, subjects were selected from a group of subjects whose blood eosinophil count prior to administration was <250 cells / µl (suitably excluding 250 cells / µl). In some instances, subjects were selected from a group of subjects whose blood eosinophil count prior to administration was between <250 cells / µl and ≥150 cells / µl (suitably excluding 250 cells / µl).

[0156] In some instances, subjects were selected from a group of subjects whose blood eosinophil counts prior to the administration included <240 cells / µl (suitably excluding 250 cells / µl). In some instances, subjects were selected from a group of subjects whose blood eosinophil counts prior to the administration included <240 cells / µl to ≥150 cells / µl (suitably excluding 240 cells / µl).

[0157] Subjects can be selected from a group of current or former smokers who had a blood eosinophil count of <300 cells / µl to ≥150 cells / µl before administration of the IL-33 signaling axis antagonist. Subjects can also be selected from a group of current or former smokers who had a blood eosinophil count of <290 cells / µl to ≥150 cells / µl before administration of the IL-33 signaling axis antagonist. Other groups of current or former smokers can also be selected from a group of current or former smokers who had a blood eosinophil count of <280 cells / µl to ≥150 cells / µl before administration of the IL-33 signaling axis antagonist. Finally, subjects can be selected from a group of current or former smokers who had a blood eosinophil count of <270 cells / µl to ≥150 cells / µl before administration of the IL-33 signaling axis antagonist. Subjects can be selected from a group of subjects who were current or former smokers and whose blood eosinophil counts ranged from <260 cells / µl to ≥150 cells / µl before administration of the IL-33 signaling axis antagonist.

[0158] In some instances, subjects were selected from a group of current or former smokers who had a blood eosinophil count of <250 cells / µl to ≥150 cells / µl prior to administration.

[0159] Subjects can be selected from a group of current or former smokers who had a blood eosinophil count of <230 cells / µl to ≥150 cells / µl before administration of the IL-33 signaling axis antagonist. Subjects can also be selected from a group of current or former smokers who had a blood eosinophil count of <220 cells / µl to ≥150 cells / µl before administration of the IL-33 signaling axis antagonist. Other groups of current or former smokers can also be selected from a group of current or former smokers who had a blood eosinophil count of <210 cells / µl to ≥150 cells / µl before administration of the IL-33 signaling axis antagonist. Finally, subjects can be selected from a group of current or former smokers who had a blood eosinophil count of <200 cells / µl to ≥150 cells / µl before administration of the IL-33 signaling axis antagonist.

[0160] In some instances, subjects were selected from a group of subjects whose blood eosinophil counts included <300 cells / µl, <290 cells / µl, <280 cells / µl, <270 cells / µl, <260 cells / µl, <250 cells / µl, <240 cells / µl, <230 cells / µl, <220 cells / µl, <210 cells / µl, and <200 cells / µl of IL-33 signaling axis antagonists, and who were current or former smokers.

[0161] In some instances, subjects were selected from a group of current or former smokers whose blood eosinophil counts included <250 cells / µl (suitably excluding 250 cells / µl) of an IL-33 signaling axis antagonist. In other instances, subjects were selected from a group of current or former smokers whose blood eosinophil counts included <250 cells / µl to ≥150 cells / µl (suitably excluding 250 cells / µl) of an IL-33 signaling axis antagonist.

[0162] In some instances, subjects were selected from a group of current or former smokers who had blood eosinophil counts of <240 cells / µl (suitably excluding 250 cells / µl) of an IL-33 signaling axis antagonist. In other instances, subjects were selected from a group of current or former smokers who had blood eosinophil counts of <240 cells / µl to ≥150 cells / µl (suitably excluding 240 cells / µl) of an IL-33 signaling axis antagonist.

[0163] Subjects can be selected from a group of current smokers whose blood eosinophil counts were <300 cells / µl to ≥150 cells / µl before administration of the IL-33 signaling axis antagonist. Subjects can also be selected from a group of current smokers whose blood eosinophil counts were <290 cells / µl to ≥150 cells / µl before administration of the IL-33 signaling axis antagonist. Furthermore, subjects can be selected from a group of current smokers whose blood eosinophil counts were <280 cells / µl to ≥150 cells / µl before administration of the IL-33 signaling axis antagonist. Finally, subjects can be selected from a group of current smokers whose blood eosinophil counts were <270 cells / µl to ≥150 cells / µl before administration of the IL-33 signaling axis antagonist. Subjects can be selected from a group of current smokers who had a blood eosinophil count of <260 cells / µl to ≥150 cells / µl before administration of the IL-33 signaling axis antagonist.

[0164] In some instances, subjects were selected from a group of current smokers whose blood eosinophil counts were between <250 cells / µl and ≥150 cells / µl prior to administration. In some instances, subjects were selected from a group of current smokers whose blood eosinophil counts were between <240 cells / µl and ≥150 cells / µl prior to administration.

[0165] Subjects can be selected from a group of current smokers whose blood eosinophil counts were <230 cells / µl to ≥150 cells / µl before administration of the IL-33 signaling axis antagonist. Subjects can also be selected from a group of current smokers whose blood eosinophil counts were <220 cells / µl to ≥150 cells / µl before administration of the IL-33 signaling axis antagonist. Furthermore, subjects can be selected from a group of current smokers whose blood eosinophil counts were <210 cells / µl to ≥150 cells / µl before administration of the IL-33 signaling axis antagonist. Finally, subjects can be selected from a group of current smokers whose blood eosinophil counts were <200 cells / µl to ≥150 cells / µl before administration of the IL-33 signaling axis antagonist.

[0166] In some instances, subjects were selected from a group of current smokers whose blood eosinophil counts included IL-33 signaling axis antagonists of <300 cells / µl, <290 cells / µl, <280 cells / µl, <270 cells / µl, <260 cells / µl, <250 cells / µl, <240 cells / µl, <230 cells / µl, <220 cells / µl, <210 cells / µl, and <200 cells / µl.

[0167] In some instances, subjects were selected from a group of current smokers whose blood eosinophil counts included <250 cells / µl (suitably excluding 250 cells / µl) of an IL-33 signaling axis antagonist. In other instances, subjects were selected from a group of current smokers whose blood eosinophil counts included <250 cells / µl to ≥150 cells / µl (suitably excluding 250 cells / µl) of an IL-33 signaling axis antagonist.

[0168] In some instances, subjects were selected from a group of current smokers whose blood eosinophil counts included <240 cells / µl (suitably excluding 250 cells / µl) of an IL-33 signaling axis antagonist. In other instances, subjects were selected from a group of current smokers whose blood eosinophil counts included <240 cells / µl to ≥150 cells / µl (suitably excluding 240 cells / µl) of an IL-33 signaling axis antagonist.

[0169] In some instances, subjects also had chronic bronchitis. Subjects with active chronic bronchitis symptoms had a greater disease burden than those without active chronic bronchitis symptoms, and were characterized by more rapid loss of lung function, increased mortality, and an increased risk of exacerbation. Suitablely, subjects may have had cough and sputum production for most days for at least 2 years prior to receiving the treatment disclosed herein, lasting ≥3 months / year.

[0170] In some instances, subjects had BCSS scores of approximately 7 or higher, 7.1 or higher, 7.2 or higher, 7.3 or higher, 7.4 or higher, or 7.429 or higher. A BCSS scale exceeding 12 indicates a more severe disease. Appropriately, subjects had a BCSS score ≥6. Appropriately, subjects had a BCSS score ≥7. Appropriately, subjects had a BCSS score ≥7.1. Appropriately, subjects had a BCSS score ≥7.2. Appropriately, subjects had a BCSS score ≥7.3. Appropriately, subjects had a BCSS score of approximately 7.4. Appropriately, the BCSS score was measured immediately prior to the administration of an effective amount of the IL-33 signaling axis antagonist. Appropriately, the BCSS score may be given in terms of sputum production and / or cough. Suitablely, this can be assessed as a mean score over a period of several days, suitablely within a period of 2, 5, 7, 10, or 14 days, suitablely prior to the administration of an effective amount of the IL-33 signaling axis antagonist. Suitablely, subjects may have a mean BCSS score of ≥2 in the cough domain and a mean BCSS score of ≥2 in the sputum domain assessed within 14 days.

[0171] Appropriately, the term “BCSS score” refers to the score derived from the Dyspnea, Cough, and Sputum Scale (BCSS). The BCSS is a 3-item PRO (Leidy et al., Chest. 2003; 124(6):2182-91; Leidy et al., Respir Med. 2003; 97 Supplement AS59-70) that assesses the severity of dyspnea, cough, and sputum on a scale of 0 (asymptomatic) to 4 (severe symptoms). The item scores are summed to obtain a total score, with a higher score indicating more severe symptoms.

[0172] In some instances, subjects had SGRQ scores of approximately 58 or higher, 58.1 or higher, 58.2 or higher, or 58.239 or higher. The SGRQ scale exceeds 100, with higher scores indicating more severe disease. Appropriately, subjects had an SGRQ score ≥50. Appropriately, subjects had an SGRQ score ≥52. Appropriately, subjects had an SGRQ score ≥54. Appropriately, subjects had an SGRQ score ≥56. Appropriately, subjects had an SGRQ score ≥58. Appropriately, the SGRQ score should be measured immediately prior to the administration of an effective amount of the IL-33 signaling axis antagonist.

[0173] Appropriately, the term "SGRQ score" comes from the score of the St. George Respiratory Questionnaire (SGRQ). The SGRQ is a 50-item PRO tool developed to measure the health status of patients with airway obstruction disease (Jones PW, Quirk FH, and Baveystock CM, The St George's Respiratory Questionnaire. Respir Med 1991; 85 Supplement B:25-31). The questionnaire is divided into two parts: Part 1 consists of 8 items related to the severity of respiratory symptoms over the previous 4 weeks; Part 2 consists of 42 items related to the daily activities and psychosocial impacts of an individual's respiratory condition. The SGRQ yields a total score and three domain scores (symptoms, activities, and impacts). The total score indicates the impact of the disease on overall health. This total score is expressed as a percentage of overall impairment, where 100 represents the worst possible health status and 0 represents the best possible health status. Similarly, domain scores range from 0 to 100, with higher scores indicating greater impairment. Specific details regarding the scoring algorithm are provided by the developers in the user manual (Jones and Forde Y., St George's respiratory questionnaire manual. 2009. Version 2.3).

[0174] In some instances, the subject had <10% emphysema. Suitablely, alveolar damage was less than 10%. Suitablely, emphysema in the subject was <9%. Suitablely, emphysema in the subject was <8%. Suitablely, emphysema in the subject was <7%. Suitablely, emphysema in the subject was <6%. Suitablely, emphysema in the subject was <5%. Suitablely, the degree of emphysema should be measured immediately prior to the administration of an effective amount of the IL-33 signaling axis antagonist.

[0175] In some instances, the BCSS score, SGRQ score, and degree of emphysema are measured at baseline. The baseline can be a relevant value, level, or score of a subject with COPD prior to administration of an effective dose of an IL-33 signaling axis antagonist. In some instances, the baseline is a relevant value, level, or score of a subject immediately preceding the administration.

[0176] In some instances, subjects had ≥2 exacerbations in the preceding 12 months prior to treatment. As defined herein, an “exacerbation” of COPD may also be termed an acute exacerbation of COPD or “AECOPD,” requiring systemic corticosteroids and / or antibiotics for at least 3 days (or one injection of a long-acting formulation), or hospitalization for AECOPD. Results showed that subjects with 2 or more exacerbations in the preceding 12 months demonstrated an improvement in response to treatment with torrezizumab. Figure 2 ).

[0177] Appropriately, participants may be 40 years of age or older. Appropriately, participants may be under 80 years of age. Appropriately, participants may be under 75 years of age. Appropriately, participants may be between 40 and 75 years of age. Appropriately, participants may be between 40 and 45 years of age, 45 and 50 years of age, 50 and 55 years of age, 55 and 60 years of age, 60 and 65 years of age, 65 and 70 years of age, or 70 and 75 years of age. In one instance, the participant was 40 years of age or older.

[0178] Appropriately, the subjects may receive the latest vaccines, and appropriately, vaccines for respiratory diseases. Appropriately, the subjects have already received pneumococcal and influenza vaccines.

[0179] Suitablely, the subject may have already received COPD treatment or is currently receiving COPD treatment. Suitablely, the subject may have received or is receiving a documented, stable COPD treatment regimen. Suitablely, the treatment may include one or more currently available COPD medications. Suitablely, the subject may have received or is currently receiving dual or triple therapy for COPD. Suitablely, the dual therapy may include ICS+LABA or LABA+LAMA. Suitablely, the triple therapy may include ICS+LABA+LAMA. Suitablely, the subject may have received the treatment for ≥3 months.

[0180] In some instances, subjects may have post-bronchodilator FEV1 / FVC <0.70L and post-bronchodilator FEV1 >30%, as well as <80% of the predicted baseline nominal value mat. “Baseline” refers to the subject’s measurements prior to administration of the therapy disclosed herein.

[0181] Appropriately, the subject may have a documented history of ≥1 or >2 acute exacerbations of moderate or severe COPD (AECOPD) that require (i) continuous systemic corticosteroids and / or antibiotics for at least 3 days (or a single injection of a long-acting formulation) or (ii) hospitalization for AECOPD within the 12 months prior to administration of the therapy disclosed herein.

[0182] Appropriately, subjects may have a normal body mass index (BMI). Therefore, appropriately, subjects may have a body mass index ≥19 kg / m². 2 And ≤35kg / m 2 BMI. Appropriately, subjects may have a BMI ≥19 kg / m². 2 And ≤30kg / m 2 ≥19kg / m 2 And ≤25kg / m 2 BMI.

[0183] Treatment methods and ways to improve lung function

[0184] Appropriately, treatment of a subject with COPD results in improvement of the subject's lung function. Therefore, appropriately, in any of the treatment methods or medical uses described herein, COPD is treated by improving the subject's lung function.

[0185] In some instances, the lung function of a subject can be compared to that of a control subject. Suitablely, the control subject is a subject with COPD who has not received an IL-33 signaling axis antagonist (this could be a subject from the placebo group).

[0186] Appropriately, improvements in lung function can be measured by lung function tests such as spirometry and plethysmography. Therefore, appropriately, improvements in lung function can be an improvement in any of the following lung function parameters in a subject compared to a control: forced vital capacity (FVC), forced expiratory volume (FEV), forced expiratory flow, and peak expiratory flow (PEF). In some instances, “improvement” in any of the subsequent lung function parameters means “higher.” In some instances, “control” refers to the value of the lung function parameter at baseline. “Baseline” refers to the measurement results of the subject prior to the administration of the therapy disclosed herein.

[0187] Therefore, improvement in lung function can be defined as an improvement in lung function in a subject after administration of an IL-33 signaling axis antagonist, compared to baseline, i.e., compared to before administration of the IL-33 signaling axis antagonist. Thus, suitably, improvement in lung function can be any of the following: higher forced vital capacity (FVC), higher forced expiratory volume (FEV), higher forced expiratory flow, and higher peak expiratory flow (PEF) in the subject compared to the same baseline measurements in the same subject, i.e., before administration of the IL-33 signaling axis antagonist.

[0188] In some instances, treatment of subjects with COPD or improvement of lung function in subjects with COPD can lead to reversal of airway obstruction. Airway obstruction in a subject can be compared to that in the same subject prior to administration of an IL-33 signaling axis antagonist. Reversal of airway obstruction can be assessed by comparing FEV1 or FVC values ​​before (before) and / or after (after) administration of a bronchodilator (BD). Suitably, reversal of airway obstruction includes improvement in FEV1 following bronchodilator administration. Suitably, reversal of airway obstruction includes improvement in FVC following bronchodilator administration (i.e., improvement in FVC after BD).

[0189] In some instances, treating subjects with COPD or improving lung function in subjects with COPD can lead to an increase in pre-BD FEV1. A subject's pre-BD FEV1 can be compared to the pre-BD FEV1 of a control subject with COPD who did not receive an IL-33 signaling axis antagonist (such as a subject from the placebo group). Alternatively, a subject's pre-BD FEV1 can be compared to the baseline pre-BD FEV1 of the same subject (i.e., before administration of the IL-33 signaling axis antagonist).

[0190] In some instances, treatment of a subject with COPD or improvement of lung function in a subject with COPD resulted in an increase of at least 50 ml in the subject's pre-BD FEV1. Suitably, treatment of a subject with COPD or improvement of lung function in a subject with COPD resulted in an increase of at least 50 ml in the subject's pre-BD FEV1 compared to a control or baseline. Suitably, treatment of a subject with COPD or improvement of lung function in a subject with COPD resulted in an increase of at least 50 ml in the subject's pre-BD FEV1 at 12 weeks after administration of an IL-33 signaling axis antagonist compared to a control or baseline. Suitably, treatment of a subject with COPD or improvement of lung function in a subject with COPD resulted in an increase of at least 50 ml in the subject's pre-BD FEV1 at 28 weeks after administration of an IL-33 signaling axis antagonist compared to a control or baseline.

[0191] In some instances, treatment of a subject with COPD or improvement of lung function in a subject with COPD resulted in an increase of at least 60 ml in the subject's pre-BD FEV1. Suitably, treatment of a subject with COPD or improvement of lung function in a subject with COPD resulted in an increase of at least 60 ml in the subject's pre-BD FEV1 compared to a control or baseline. Suitably, treatment of a subject with COPD or improvement of lung function in a subject with COPD resulted in an increase of at least 60 ml in the subject's pre-BD FEV1 at 12 weeks after administration of an IL-33 signaling axis antagonist compared to a control or baseline. Suitably, treatment of a subject with COPD or improvement of lung function in a subject with COPD resulted in an increase of at least 60 ml in the subject's pre-BD FEV1 at 28 weeks after administration of an IL-33 signaling axis antagonist compared to a control or baseline.

[0192] In some instances, treatment of a subject with COPD or improvement of lung function in a subject with COPD resulted in an increase in the subject's pre-BD FEV1 of at least 50 ml, at least 51 ml, at least 52 ml, at least 53 ml, at least 54 ml, at least 55 ml, at least 56 ml, at least 57 ml, at least 58 ml, or at least 59 ml. Suitablely, treatment of a subject with COPD or improvement of lung function in a subject with COPD resulted in an increase in the subject's pre-BD FEV1 of at least 50 ml, at least 51 ml, at least 52 ml, at least 53 ml, at least 54 ml, at least 55 ml, at least 56 ml, at least 57 ml, at least 58 ml, or at least 59 ml compared to a control or baseline. Suitablely, treatment of a subject with COPD or improvement of lung function in a subject with COPD results in an increase of at least 50 ml, at least 51 ml, at least 52 ml, at least 53 ml, at least 54 ml, at least 55 ml, at least 56 ml, at least 57 ml, at least 58 ml, or at least 59 ml of pre-BD FEV1 in that subject at 12 weeks after administration of an IL-33 signaling axis antagonist, compared to a control or baseline. Suitablely, treatment of a subject with COPD or improvement of lung function in a subject with COPD results in an increase of at least 50 ml, at least 51 ml, at least 52 ml, at least 53 ml, at least 54 ml, at least 55 ml, at least 56 ml, at least 57 ml, at least 58 ml, or at least 59 ml of pre-BD FEV1 in that subject at 28 weeks after administration of an IL-33 signaling axis antagonist, compared to a control or baseline.

[0193] In some instances, treatment of a subject with COPD or improvement of lung function in a subject with COPD resulted in an increase in the subject's pre-BD FEV1 of at least 61 ml, at least 62 ml, at least 63 ml, at least 64 ml, at least 65 ml, at least 66 ml, at least 70 ml, at least 71 ml, at least 72 ml, at least 73 ml, at least 74 ml, at least 75 ml, at least 76 ml, at least 77 ml, at least 78 ml, at least 79 ml, or at least 80 ml. Suitablely, treatment of a subject with COPD or improvement of lung function in a subject with COPD resulted in an increase in the subject's pre-BD FEV1 of at least 60 ml, at least 61 ml, at least 62 ml, at least 63 ml, at least 64 ml, at least 65 ml, at least 66 ml, at least 70 ml, at least 71 ml, at least 72 ml, at least 73 ml, at least 74 ml, at least 75 ml, at least 76 ml, at least 77 ml, at least 78 ml, at least 79 ml, or at least 80 ml compared to a control or baseline. Appropriately, treatment of a subject with COPD or improvement of lung function in a subject with COPD results in an increase in pre-BD FEV1 of at least 60 ml, at least 61 ml, at least 62 ml, at least 63 ml, at least 64 ml, at least 65 ml, at least 66 ml, at least 70 ml, at least 71 ml, at least 72 ml, at least 73 ml, at least 74 ml, at least 75 ml, at least 76 ml, at least 77 ml, at least 78 ml, at least 79 ml, or at least 80 ml at 12 weeks after administration of an IL-33 signaling axis antagonist compared to a control or baseline. Appropriately, treatment of a subject with COPD or improvement of lung function in a subject with COPD resulted in an increase in pre-BD FEV1 of at least 60 ml, at least 61 ml, at least 62 ml, at least 63 ml, at least 64 ml, at least 65 ml, at least 66 ml, at least 70 ml, at least 71 ml, at least 72 ml, at least 73 ml, at least 74 ml, at least 75 ml, at least 76 ml, at least 77 ml, at least 78 ml, at least 79 ml, or at least 80 ml at 28 weeks after administration of an IL-33 signaling axis antagonist compared to a control or baseline.

[0194] In some instances, treatment of a subject with COPD or improvement of lung function in a subject with COPD resulted in an increase of at least 80 ml in the subject's pre-BD FEV1. Suitably, treatment of a subject with COPD or improvement of lung function in a subject with COPD resulted in an increase of at least 80 ml in the subject's pre-BD FEV1 compared to a control or baseline. Suitably, treatment of a subject with COPD or improvement of lung function in a subject with COPD resulted in an increase of at least 80 ml in the subject's pre-BD FEV1 at 12 weeks after administration of an IL-33 signaling axis antagonist compared to a control or baseline. Suitably, treatment of a subject with COPD or improvement of lung function in a subject with COPD resulted in an increase of at least 80 ml in the subject's pre-BD FEV1 at 28 weeks after administration of an IL-33 signaling axis antagonist compared to a control or baseline.

[0195] In some instances, treatment of a subject with COPD or improvement of lung function in a subject with COPD resulted in an increase of approximately 80 ml in the subject's pre-BD FEV1 compared to a control or baseline. Suitablely, treatment of a subject with COPD or improvement of lung function in a subject with COPD resulted in an increase of approximately 80 ml in the subject's pre-BD FEV1 compared to a control or baseline. Suitablely, treatment of a subject with COPD or improvement of lung function in a subject with COPD resulted in an increase of approximately 80 ml in the subject's pre-BD FEV1 at 12 weeks after administration of an IL-33 signaling axis antagonist compared to a control or baseline. Suitablely, treatment of a subject with COPD or improvement of lung function in a subject with COPD resulted in an increase of approximately 80 ml in the subject's pre-BD FEV1 at 28 weeks after administration of an IL-33 signaling axis antagonist compared to a control or baseline.

[0196] In some instances, treating subjects with COPD or improving lung function in subjects with COPD can lead to an increase in post-BD FEV1. A subject's post-BD FEV1 can be compared to that of a control subject with COPD who did not receive an IL-33 signaling axis antagonist (such as a subject from the placebo group). Alternatively, a subject's post-BD FEV1 can be compared to the same subject's baseline post-BD FEV1 (i.e., before administration of the IL-33 signaling axis antagonist).

[0197] In some instances, treatment of a subject with COPD or improvement of lung function in a subject with COPD resulted in an increase of at least 60 ml in post-BD FEV1. Suitably, treatment of a subject with COPD or improvement of lung function in a subject with COPD resulted in an increase of at least 60 ml in post-BD FEV1 compared to a control or baseline. Suitably, treatment of a subject with COPD or improvement of lung function in a subject with COPD resulted in an increase of at least 60 ml in post-BD FEV1 at 12 weeks after administration of an IL-33 signaling axis antagonist compared to a control or baseline. Suitably, treatment of a subject with COPD or improvement of lung function in a subject with COPD resulted in an increase of at least 80 ml in post-BD FEV1 at 28 weeks after administration of an IL-33 signaling axis antagonist compared to a control or baseline. Appropriately, treatment of subjects with COPD or improvement of lung function in subjects with COPD resulted in an increase of at least 90 ml in post-BD FEV1 at 28 weeks after administration of an IL-33 signaling axis antagonist compared to control or baseline.

[0198] In some instances, treatment of subjects with COPD or improvement of lung function in subjects with COPD resulted in an increase in FEV1 after BD of at least 60 ml, at least 61 ml, at least 62 ml, at least 63 ml, at least 64 ml, at least 65 ml, at least 66 ml, at least 70 ml, at least 71 ml, at least 72 ml, at least 73 ml, at least 74 ml, at least 75 ml, at least 76 ml, at least 77 ml, at least 78 ml, at least 79 ml, at least 80 ml, at least 81 ml, at least 82 ml, at least 83 ml, at least 84 ml, at least 85 ml, at least 86 ml, at least 87 ml, at least 88 ml, at least 89 ml, or at least 90 ml. Appropriately, treatment of a subject with COPD or improvement of lung function in a subject with COPD results in an increase in post-BD FEV1 of at least 60 ml, at least 61 ml, at least 62 ml, at least 63 ml, at least 64 ml, at least 65 ml, at least 66 ml, at least 70 ml, at least 71 ml, at least 72 ml, at least 73 ml, at least 74 ml, at least 75 ml, at least 76 ml, at least 77 ml, at least 78 ml, at least 79 ml, at least 80 ml, at least 81 ml, at least 82 ml, at least 83 ml, at least 84 ml, at least 85 ml, at least 86 ml, at least 87 ml, at least 88 ml, at least 89 ml, or at least 90 ml. Appropriately, treatment of a subject with COPD or improvement of lung function in a subject with COPD results in an increase in post-BD FEV1 of at least 60 ml, at least 61 ml, at least 62 ml, at least 63 ml, at least 64 ml, at least 65 ml, at least 66 ml, at least 70 ml, at least 71 ml, at least 72 ml, at least 73 ml, at least 74 ml, at least 75 ml, at least 76 ml, at least 77 ml, at least 78 ml, at least 79 ml, at least 80 ml, at least 81 ml, at least 82 ml, at least 83 ml, at least 84 ml, at least 85 ml, at least 86 ml, at least 87 ml, at least 88 ml, at least 89 ml, or at least 90 ml at 12 weeks after administration of an IL-33 signaling axis antagonist compared to a control or baseline.

[0199] In some instances, treatment of subjects with COPD or improvement of lung function in subjects with COPD resulted in an increase of approximately 80 or 90 ml in post-BD FEV1. Suitablely, treatment of subjects with COPD or improvement of lung function in subjects with COPD resulted in an increase of approximately 80 or 90 ml in post-BD FEV1 compared to a control or baseline. Suitablely, treatment of subjects with COPD or improvement of lung function in subjects with COPD resulted in an increase of approximately 80 ml in post-BD FEV1 at 12 weeks after administration of an IL-33 signaling axis antagonist compared to a control or baseline. Suitablely, treatment of subjects with COPD or improvement of lung function in subjects with COPD resulted in an increase of approximately 90 ml in post-BD FEV1 at 28 weeks after administration of an IL-33 signaling axis antagonist compared to a control or baseline.

[0200] In some instances, the increase in pre-BD or post-BD FEV1 in subjects was achieved at week 12 following administration of an effective dose of an IL-33 signaling axis antagonist. In other instances, the increase in pre-BD or post-BD FEV1 in subjects was achieved at week 28 following administration of an effective dose of an IL-33 signaling axis antagonist.

[0201] In some instances, treating subjects with COPD or improving lung function in subjects with COPD can lead to an increase in pre-BD FVC. A subject's pre-BD FVC can be compared to the pre-BD FVC of a control subject with COPD who has not received an IL-33 signaling axis antagonist (such as a subject from the placebo group). Alternatively, a subject's pre-BD FVC can be compared to the pre-BD FVC of the same subject at baseline (i.e., before administration of the IL-33 signaling axis antagonist).

[0202] In some instances, treatment of a subject with COPD or improvement of lung function in a subject with COPD resulted in an increase of at least 60 ml in the subject's pre-BD FVC. Suitably, treatment of a subject with COPD or improvement of lung function in a subject with COPD resulted in an increase of at least 60 ml in the subject's pre-BD FVC compared to a control or baseline. Suitably, treatment of a subject with COPD or improvement of lung function in a subject with COPD resulted in an increase of at least 60 ml in the subject's pre-BD FVC at 12 weeks after administration of an effective dose of an IL-33 signaling axis antagonist, compared to a control or baseline. Suitably, treatment of a subject with COPD or improvement of lung function in a subject with COPD resulted in an increase of at least 60 ml in the subject's pre-BD FVC at 28 weeks after administration of an effective dose of an IL-33 signaling axis antagonist, compared to a control or baseline.

[0203] In some instances, treatment of a subject with COPD or improvement of lung function in a subject with COPD resulted in an increase in the subject's pre-BD FVC of at least 60 ml, at least 61 ml, at least 62 ml, at least 63 ml, at least 64 ml, at least 65 ml, at least 66 ml, at least 70 ml, at least 71 ml, at least 72 ml, at least 73 ml, at least 74 ml, at least 75 ml, at least 76 ml, at least 77 ml, at least 78 ml, at least 79 ml, or at least 80 ml. Suitablely, treatment of a subject with COPD or improvement of lung function in a subject with COPD resulted in an increase in the subject's pre-BD FVC of at least 60 ml, at least 61 ml, at least 62 ml, at least 63 ml, at least 64 ml, at least 65 ml, at least 66 ml, at least 70 ml, at least 71 ml, at least 72 ml, at least 73 ml, at least 74 ml, at least 75 ml, at least 76 ml, at least 77 ml, at least 78 ml, at least 79 ml, or at least 80 ml compared to a control or baseline. Appropriately, treatment of a subject with COPD or improvement of lung function in a subject with COPD results in an increase in pre-BD FEV1 of at least 60 ml, at least 61 ml, at least 62 ml, at least 63 ml, at least 64 ml, at least 65 ml, at least 66 ml, at least 70 ml, at least 71 ml, at least 72 ml, at least 73 ml, at least 74 ml, at least 75 ml, at least 76 ml, at least 77 ml, at least 78 ml, at least 79 ml, or at least 80 ml compared to control or baseline at 12 weeks after administration of an effective amount of an IL-33 signaling axis antagonist. Appropriately, treatment of a subject with COPD or improvement of lung function in a subject with COPD results in an increase in pre-BD FEV of at least 60 ml, at least 61 ml, at least 62 ml, at least 63 ml, at least 64 ml, at least 65 ml, at least 66 ml, at least 70 ml, at least 71 ml, at least 72 ml, at least 73 ml, at least 74 ml, at least 75 ml, at least 76 ml, at least 77 ml, at least 78 ml, at least 79 ml, or at least 80 ml compared to control or baseline at 28 weeks after administration of an effective amount of an IL-33 signaling axis antagonist.

[0204] In some instances, treatment of a subject with COPD or improvement of lung function in a subject with COPD resulted in an increase of at least 70 ml in the subject's pre-BD FVC. Suitably, treatment of a subject with COPD or improvement of lung function in a subject with COPD resulted in an increase of at least 70 ml in the subject's pre-BD FVC compared to a control or baseline. Suitably, treatment of a subject with COPD or improvement of lung function in a subject with COPD resulted in an increase of at least 70 ml in the subject's pre-BD FVC at 12 weeks after administration of an effective dose of an IL-33 signaling axis antagonist, compared to a control or baseline. Suitably, treatment of a subject with COPD or improvement of lung function in a subject with COPD resulted in an increase of at least 70 ml in the subject's pre-BD FVC at 28 weeks after administration of an effective dose of an IL-33 signaling axis antagonist, compared to a control or baseline.

[0205] In some instances, treatment of a subject with COPD or improvement of lung function in a subject with COPD resulted in an increase of approximately 70 mL in the subject's pre-BD FVC. Suitablely, treatment of a subject with COPD or improvement of lung function in a subject with COPD resulted in an increase of approximately 70 mL in the subject's pre-BD FVC compared to a control or baseline. Suitablely, treatment of a subject with COPD or improvement of lung function in a subject with COPD resulted in an increase of approximately 70 mL in the subject's pre-BD FVC at 12 weeks after administration of an effective dose of an IL-33 signaling axis antagonist compared to a control or baseline. Suitablely, treatment of a subject with COPD or improvement of lung function in a subject with COPD resulted in an increase of approximately 70 mL in the subject's pre-BD FVC at 28 weeks after administration of an effective dose of an IL-33 signaling axis antagonist compared to a control or baseline.

[0206] Suitablely, treatment of a subject with COPD or improvement of lung function in a subject with COPD results in an increase of approximately 80 ml in the subject's pre-BD FVC. Suitablely, treatment of a subject with COPD or improvement of lung function in a subject with COPD results in an increase of approximately 80 ml in the subject's pre-BD FVC compared to a control or baseline. Suitablely, treatment of a subject with COPD or improvement of lung function in a subject with COPD results in an increase of approximately 80 ml in the subject's pre-BD FVC at 12 weeks after administration of an effective dose of an IL-33 signaling axis antagonist compared to a control or baseline. Suitablely, treatment of a subject with COPD or improvement of lung function in a subject with COPD results in an increase of approximately 80 ml in the subject's pre-BD FVC at 28 weeks after administration of an effective dose of an IL-33 signaling axis antagonist compared to a control or baseline.

[0207] In one instance, treatment of a subject with COPD or improvement of lung function in a subject with COPD resulted in an increase in post-BD FVC. The subject's post-BD FVC can be compared to the post-BD FVC of a control subject with COPD who did not receive an IL-33 signaling axis antagonist (such as a subject from the placebo group). Alternatively, the subject's post-BD FVC can be compared to the same subject's post-BD FVC at baseline (i.e., before administration of the IL-33 signaling axis antagonist).

[0208] In some instances, treatment of a subject with COPD or improvement of lung function in a subject with COPD resulted in an increase in post-BD FVC of at least 40 mL. Suitably, treatment of a subject with COPD or improvement of lung function in a subject with COPD resulted in an increase in post-BD FVC of at least 40 mL compared to a control or baseline. Suitably, treatment of a subject with COPD or improvement of lung function in a subject with COPD resulted in an increase in post-BD FVC of at least 40 mL compared to a control or baseline at 12 weeks after administration of an effective dose of an IL-33 signaling axis antagonist. Suitably, treatment of a subject with COPD or improvement of lung function in a subject with COPD resulted in an increase in post-BD FVC of at least 40 mL compared to a control or baseline at 28 weeks after administration of an effective dose of an IL-33 signaling axis antagonist.

[0209] In some instances, treatment of subjects with COPD or improvement of lung function in subjects with COPD resulted in an increase in post-BD FVC of at least 40 mL, at least 41 mL, at least 42 mL, at least 43 mL, at least 44 mL, at least 45 mL, at least 46 mL, at least 47 mL, at least 48 mL, at least 49 mL, at least 50 mL, at least 51 mL, at least 52 mL, at least 53 mL, at least 54 mL, at least 55 mL, at least 56 mL, at least 57 mL, at least 58 mL, at least 59 mL, or at least 60 mL. Appropriately, treatment of a subject with COPD or improvement of lung function in a subject with COPD results in an increase in post-BD FVC of 40 mL, at least 41 mL, at least 42 mL, at least 43 mL, at least 44 mL, at least 45 mL, at least 46 mL, at least 47 mL, at least 48 mL, at least 49 mL, at least 50 mL, at least 51 mL, at least 52 mL, at least 53 mL, at least 54 mL, at least 55 mL, at least 56 mL, at least 57 mL, at least 58 mL, at least 59 mL, or at least 60 mL compared to a control or baseline. Appropriately, treatment of a subject with COPD or improvement of lung function in a subject with COPD results in an increase in post-BD FVC of 40 mL, at least 41 mL, at least 42 mL, at least 43 mL, at least 44 mL, at least 45 mL, at least 46 mL, at least 47 mL, at least 48 mL, at least 49 mL, at least 50 mL, at least 51 mL, at least 52 mL, at least 53 mL, at least 54 mL, at least 55 mL, at least 56 mL, at least 57 mL, at least 58 mL, at least 59 mL, or at least 60 mL at 12 weeks after administration of an effective amount of an IL-33 signaling axis antagonist, compared to a control or baseline. Appropriately, treatment of a subject with COPD or improvement of lung function in a subject with COPD results in an increase in post-BD FVC of 40 mL, at least 41 mL, at least 42 mL, at least 43 mL, at least 44 mL, at least 45 mL, at least 46 mL, at least 47 mL, at least 48 mL, at least 49 mL, at least 50 mL, at least 51 mL, at least 52 mL, at least 53 mL, at least 54 mL, at least 55 mL, at least 56 mL, at least 57 mL, at least 58 mL, at least 59 mL, or at least 60 mL at 28 weeks after administration of an effective amount of an IL-33 signaling axis antagonist, compared to a control or baseline.

[0210] In some instances, treatment of a subject with COPD or improvement of lung function in a subject with COPD resulted in an increase in post-BD FVC of approximately 60 mL. Suitablely, treatment of a subject with COPD or improvement of lung function in a subject with COPD resulted in an increase in post-BD FVC of approximately 60 mL compared to a control or baseline. Suitablely, treatment of a subject with COPD or improvement of lung function in a subject with COPD resulted in an increase in post-BD FVC of approximately 60 mL at 12 weeks after administration of an effective dose of an IL-33 signaling axis antagonist, compared to a control or baseline. Suitablely, treatment of a subject with COPD or improvement of lung function in a subject with COPD resulted in an increase in post-BD FVC of approximately 60 mL at 28 weeks after administration of an effective dose of an IL-33 signaling axis antagonist, compared to a control or baseline.

[0211] In some instances, the increase in pre-BD or post-BD FVC in subjects occurred at week 12 following administration of an effective dose of an IL-33 signaling axis antagonist. In other instances, the increase in pre-BD or post-BD FVC in subjects occurred at week 28 following administration of an effective dose of an IL-33 signaling axis antagonist.

[0212] In some instances, increasing a subject's pre-BD FEV1, post-BD FEV1, pre-BD FVC, or post-BD FVC is relative to baseline levels. The baseline can be the level of a subject with COPD prior to administration of an effective dose of the IL-33 signaling axis antagonist. In some instances, the baseline is the level of the same subject prior to administration of the effective dose of the IL-33 signaling axis antagonist.

[0213] In some instances, treatment of subjects with COPD or improvement of lung function in subjects with COPD resulted in an increase in the time to first CompEx event. Therefore, suitably, in any of the treatments or medical uses described herein, treatment of COPD can be achieved by increasing the time to first CompEx event in a subject. Suitably, the time to first CompEx event is measured as follows after administration of an IL-33 signaling axis antagonist.

[0214] In some instances, compared to control subjects with COPD who did not receive an IL-33 signaling axis antagonist, the time to first CompEx event was increased by approximately 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, or approximately 6 weeks after administration of an IL-33 signaling axis antagonist. The time to first CompEx event may be increased by approximately 4 weeks, 5 weeks, or 6 weeks compared to control subjects with COPD who did not receive an IL-33 signaling axis antagonist. Suitablely, the time to first CompEx event was increased by at least 4 weeks compared to subjects in the placebo group. Suitablely, the time to first CompEx event was increased by at least 5 weeks compared to subjects in the placebo group. Suitablely, the time to first CompEx event was increased by at least 6 weeks compared to subjects in the placebo group.

[0215] In some instances, treatment of subjects with COPD or improvement of lung function in subjects with COPD following administration of an IL-33 signaling axis antagonist resulted in a reduction in the CompEx event rate in subjects with COPD. In some instances, the CompEx event rate was reduced by at least 10%, 15%, 20%, 25%, or at least 27%. Suitablely, the CompEx event rate was reduced by at least 20%, or at least 25%, or at least 27%. Suitablely, the CompEx event rate was reduced by at least 10%, 15%, 20%, 25%, or at least 27% compared to the CompEx event rate in control subjects with COPD who did not receive an IL-33 signaling axis antagonist. Suitablely, the CompEx event rate was reduced by at least 20%, at least 25%, or at least 27% compared to the CompEx event rate in control subjects with COPD who did not receive an IL-33 signaling axis antagonist. Suitablely, the CompEx event rate was reduced by at least 10%, 15%, 20%, 25%, or at least 27% compared to subjects in the placebo group, suitablely at least 20%, at least 25%, or at least 27%. Alternatively, the CompEx event rate was reduced by at least 10%, 15%, 20%, 25%, or at least 27% compared to the same subjects during the 12 months prior to administration of the IL-33 signaling axis antagonist, suitablely at least 20%, at least 25%, or at least 27%.

[0216] Suitable, the time to first CompEx event and / or CompEx event rate following administration of an effective dose of an IL-33 signaling axis antagonist should be compared with that of control subjects with COPD who did not receive an IL-33 signaling axis antagonist or a control subject group (suitably, which may be a placebo group). Suitable, the CompEx event rate following administration of an effective dose of an IL-33 signaling axis antagonist should be compared with the CompEx event rate of the same subjects during the 12 months prior to administration of the IL-33 signaling axis antagonist.

[0217] In some instances, the CompEx event rate decreased over a 28-week period following administration of an effective amount of the IL-33 signaling axis antagonist. Suitably, the time to the first CompEx event increased over a 28-week period following administration of an effective amount of the IL-33 signaling axis antagonist. Suitably, the decrease in the CompEx event rate occurred at week 28 following administration of an effective amount of the IL-33 signaling axis antagonist. Suitably, the increase in the time to the first CompEx event occurred at week 28 following administration of an effective amount of the IL-33 signaling axis antagonist.

[0218] Selecting subjects

[0219] This disclosure also relates to methods for selecting subjects with COPD for treatment. Suitably, any other method according to this disclosure may also include a subject selection step. Methods according to this disclosure may involve selecting a subgroup of subjects who would benefit more from administration of an IL-33 signaling axis antagonist compared to any subject alone.

[0220] Suitably, the method for selecting a subject with COPD for treatment includes the step of suitably measuring the subject's blood eosinophil count in a sample obtained from the subject. Suitably, the sample is a blood sample. Suitably, the blood eosinophil count can be measured using techniques known in the art. Suitably, the blood eosinophil count may be referred to herein as EOC or EOS. Suitably, the method for selecting a subject with COPD for treatment may also include the initial step of obtaining or acquiring a sample from the subject. Suitably, a blood sample is obtained or acquired from the subject. Suitably, the sample is obtained or acquired from the subject immediately before the administration of the IL-33 signaling axis antagonist.

[0221] Suitable methods for selecting subjects with COPD for treatment include selecting the subject if the subject has a blood eosinophil count of <300 cells / µl to ≥150 cells / µl. Suitable methods for selecting subjects with COPD for treatment include selecting the subject if the subject has a blood eosinophil count of <300 cells / µl to ≥150 cells / µl, and if they are current smokers or former smokers.

[0222] Suitable methods for selecting subjects with COPD for treatment include selecting the subject if the subject has a blood eosinophil count of <290 cells / µl to 150 cells / µl. Suitable methods for selecting subjects with COPD for treatment include selecting the subject if the subject has a blood eosinophil count of <280 cells / µl to 150 cells / µl. Suitable methods for selecting subjects with COPD for treatment include selecting the subject if the subject has a blood eosinophil count of <270 cells / µl to 150 cells / µl. Suitable methods for selecting subjects with COPD for treatment include selecting the subject if the subject has a blood eosinophil count of <260 cells / µl to 150 cells / µl.

[0223] Suitable methods for selecting subjects with COPD for treatment include selecting the subject if the subject has a blood eosinophil count of <290 cells / µl to 150 cells / µl. Suitable methods for selecting subjects with COPD for treatment include selecting the subject if the subject has a blood eosinophil count of <280 cells / µl to 150 cells / µl. Suitable methods for selecting subjects with COPD for treatment include selecting the subject if the subject has a blood eosinophil count of <270 cells / µl to ≥150 cells / µl and is a current smoker or a former smoker. Suitable methods for selecting subjects with COPD for treatment include selecting the subject if the subject has a blood eosinophil count of <260 cells / µl to ≥150 cells / µl and is a current smoker or a former smoker.

[0224] Suitable methods for selecting subjects with COPD for treatment include selecting the subject if the subject has a blood eosinophil count of <250 cells / µl to 150 cells / µl. In some instances, methods for selecting subjects with COPD for treatment include selecting the subject if the subject has a blood eosinophil count of <250 cells / µl to ≥150 cells / µl and is a current smoker or a former smoker.

[0225] Suitable methods for selecting subjects with COPD for treatment include selecting the subject if the subject has a blood eosinophil count of <240 cells / µl to 150 cells / µl. In some instances, methods for selecting subjects with COPD for treatment include selecting the subject if the subject has a blood eosinophil count of <240 cells / µl to ≥150 cells / µl and is a current smoker or a former smoker.

[0226] Suitable methods for selecting subjects with COPD for treatment include selecting the subject if the subject has a blood eosinophil count of <230 cells / µl to 150 cells / µl. Suitable methods for selecting subjects with COPD for treatment include selecting the subject if the subject has a blood eosinophil count of <220 cells / µl to 150 cells / µl. Suitable methods for selecting subjects with COPD for treatment include selecting the subject if the subject has a blood eosinophil count of <210 cells / µl to 150 cells / µl. Suitable methods for selecting subjects with COPD for treatment include selecting the subject if the subject has a blood eosinophil count of <200 cells / µl to 150 cells / µl.

[0227] Suitable methods for selecting subjects with COPD for treatment include selecting the subject if the subject has a blood eosinophil count of <230 cells / µl to ≥150 cells / µl and is a current or former smoker. Suitable methods for selecting subjects with COPD for treatment include selecting the subject if the subject has a blood eosinophil count of <220 cells / µl to ≥150 cells / µl and is a current or former smoker. Suitable methods for selecting subjects with COPD for treatment include selecting the subject if the subject has a blood eosinophil count of <210 cells / µl to ≥150 cells / µl and is a current or former smoker. Suitable methods for selecting subjects with COPD for treatment include selecting the subject if the subject has a blood eosinophil count of <200 cells / µl to ≥150 cells / µl and is a current or former smoker.

[0228] In some instances, the method for selecting subjects with COPD for treatment includes selecting the subject if the subject has a blood eosinophil count of <300 cells / µl, <290 cells / µl, <280 cells / µl, <270 cells / µl, <260 cells / µl, <250 cells / µl, <240 cells / µl, <230 cells / µl, <220 cells / µl, <210 cells / µl, or <200 cells / µl for an IL-33 signaling axis antagonist. In some instances, the method for selecting subjects with COPD for treatment includes selecting the subject if the subject has a blood eosinophil count of <300 cells / µl, <290 cells / µl, <280 cells / µl, <270 cells / µl, <260 cells / µl, <250 cells / µl, <240 cells / µl, <230 cells / µl, <220 cells / µl, <210 cells / µl, or <200 cells / µl of an IL-33 signaling axis antagonist and is a current smoker or a former smoker.

[0229] In some instances, the method of selecting a subject with COPD for treatment includes selecting the subject if the subject has a blood eosinophil count of <250 cells / µl (suitably, excluding 250 cells / µl) of an IL-33 signaling axis antagonist. In some instances, the method of selecting a subject with COPD for treatment includes selecting the subject if the subject has a blood eosinophil count of <250 cells / µl (suitably, excluding 250 cells / µl) of an IL-33 signaling axis antagonist and is a current smoker or a former smoker. In some instances, the method of selecting a subject with COPD for treatment includes selecting the subject if the subject has a blood eosinophil count of <250 cells / µl to ≥150 cells / µl (suitably, excluding 250 cells / µl) of an IL-33 signaling axis antagonist. In some instances, the method of selecting subjects with COPD for treatment includes the step of selecting the subject if the subject has a blood eosinophil count of IL-33 signaling axis antagonists of <250 cells / µl to ≥150 cells / µl (suitably, excluding 250 cells / µl) and is a current smoker or a former smoker.

[0230] In some instances, the method of selecting a subject with COPD for treatment includes selecting the subject if the subject has a blood eosinophil count of <240 cells / µl (suitably, excluding 250 cells / µl) of an IL-33 signaling axis antagonist. In some instances, the method of selecting a subject with COPD for treatment includes selecting the subject if the subject has a blood eosinophil count of <240 cells / µl (suitably, excluding 250 cells / µl) of an IL-33 signaling axis antagonist and is a current smoker or a former smoker. In some instances, the method of selecting a subject with COPD for treatment includes selecting the subject if the subject has a blood eosinophil count of <240 cells / µl to ≥150 cells / µl (suitably, excluding 240 cells / µl) of an IL-33 signaling axis antagonist. In some instances, the method of selecting subjects with COPD for treatment includes the step of selecting the subject if the subject has a blood eosinophil count of IL-33 signaling axis antagonists of <240 cells / µl to ≥150 cells / µl (suitably excluding 240 cells / µl), is a current smoker or a former smoker.

[0231] Suitable methods for selecting subjects with COPD for treatment include selecting the subject if the subject has a blood eosinophil count of <290 cells / µl to ≥150 cells / µl and is a current smoker. Suitable methods for selecting subjects with COPD for treatment include selecting the subject if the subject has a blood eosinophil count of <280 cells / µl to ≥150 cells / µl and is a current smoker. Suitable methods for selecting subjects with COPD for treatment include selecting the subject if the subject has a blood eosinophil count of <270 cells / µl to ≥150 cells / µl and is a current smoker. Suitable methods for selecting subjects with COPD for treatment include selecting the subject if the subject has a blood eosinophil count of <260 cells / µl to ≥150 cells / µl and is a current smoker.

[0232] Suitable methods for selecting subjects with COPD for treatment include selecting the subject if the subject has a blood eosinophil count of <250 cells / µl to ≥150 cells / µl and is a current smoker. In some instances, methods for selecting subjects with COPD for treatment include selecting the subject if the subject has a blood eosinophil count of <240 cells / µl to ≥150 cells / µl and is a current smoker.

[0233] Suitable methods for selecting subjects with COPD for treatment include selecting the subject if the subject has a blood eosinophil count of <230 cells / µl to ≥150 cells / µl and is a current smoker. Suitable methods for selecting subjects with COPD for treatment include selecting the subject if the subject has a blood eosinophil count of <220 cells / µl to ≥150 cells / µl and is a current smoker. Suitable methods for selecting subjects with COPD for treatment include selecting the subject if the subject has a blood eosinophil count of <210 cells / µl to ≥150 cells / µl and is a current smoker. Suitable methods for selecting subjects with COPD for treatment include selecting the subject if the subject has a blood eosinophil count of <200 cells / µl to ≥150 cells / µl and is a current smoker.

[0234] In some instances, the method for selecting subjects with COPD for treatment includes selecting the subject if the subject has a blood eosinophil count of <300 cells / µl, <290 cells / µl, <280 cells / µl, <270 cells / µl, <260 cells / µl, <250 cells / µl, <240 cells / µl, <230 cells / µl, <220 cells / µl, <210 cells / µl, <200 cells / µl of an IL-33 signaling axis antagonist and is a current smoker.

[0235] In some instances, the method of selecting a subject with COPD for treatment includes selecting the subject if the subject has a blood eosinophil count of <250 cells / µl (suitably, excluding 250 cells / µl) of an IL-33 signaling axis antagonist and is a current smoker.

[0236] In some instances, the method of selecting subjects with COPD for treatment includes selecting the subject if the subject has a blood eosinophil count of <240 cells / µl (suitably, excluding 250 cells / µl) of IL-33 signaling axis antagonists and is a current smoker.

[0237] Suitably, subjects with COPD may be selected for treatment with an effective amount of an IL-33 signaling axis antagonist if they meet one or more additional selection criteria defined above, in addition to the blood eosinophil count required herein. Therefore, suitably, subjects with COPD may be selected for treatment with an effective amount of an IL-33 signaling axis antagonist if they possess one or more characteristics as defined under the section “Subjects” herein. Therefore, suitably, methods for selecting subjects with COPD for treatment with an effective amount of an IL-33 signaling axis antagonist may include selecting the subject for treatment if the subject meets the following criteria:

[0238] (i) One or more other respiratory diseases or conditions, such as chronic bronchitis, which can be defined as bronchitis, which is defined as having cough and sputum production on most days for at least 2 years prior to receiving the treatment disclosed herein and lasting for ≥3 months / year.

[0239] (ii) If the subject has had one or more episodes of AECOPD within the 12 months prior to receiving the treatment disclosed herein;

[0240] (iii) If the subject is over 40 years old

[0241] (iv) If the subject is a current smoker or a former smoker and has a tobacco history of ≥5 pack-years, ≥6 pack-years, ≥7 pack-years, ≥8 pack-years, ≥9 pack-years or ≥10 pack-years;

[0242] (v) If the subject has received COPD treatment, or is currently receiving stable COPD treatment, such as a dual or triple therapy regimen documented elsewhere in this document; and / or

[0243] (vi) If the subject has a normal body mass index (BMI), such as BMI ≥ 19 kg / m² 2 And ≤ 35kg / m 2 .

[0244] In some instances, subjects may be selected to be treated with an effective amount of an IL-33 signaling axis antagonist if they also have a BCSS score of approximately 7 or higher, 7.1 or higher, 7.2 or higher, 7.3 or higher, 7.4 or higher, or 7.429 or higher. The BCSS score is as defined above.

[0245] In some instances, subjects may be selected to be treated with an effective amount of an IL-33 signaling axis antagonist if they also have an SGRQ score of approximately 58 or higher, 58.1 or higher, 58.2 or higher, or 58.239 or higher. The SGRQ score is as defined above.

[0246] In some instances, subjects may be selected to be treated with an effective dose of an IL-33 signaling axis antagonist if they also have <10% emphysema.

[0247] In some instances, subjects may be selected to be treated with an effective dose of an IL-33 signaling axis antagonist if they have had two or more episodes of AECOPD within the 12 months prior to treatment.

[0248] In some instances, subjects may be selected to be treated with an effective amount of an IL-33 signaling axis antagonist if they have two or more episodes of moderate AECOPD and / or one or more episodes of severe AECOPD within the 12 months prior to treatment.

[0249] The FRONTIER-4 results presented in these examples show that subjects with COPD and one or more of these additional criteria demonstrated numerical improvements in preclinical BD FEV1 compared to those who received treatment but did not meet one or more of these additional criteria (see [link to FRONTIER-4 results]). Figure 2 ).

[0250] Suitablely, any or more of the above selection criteria may be additionally applied in the method of selecting subjects with COPD for treatment with an effective amount of an IL-33 signaling axis antagonist. Suitablely, any or more of the above selection criteria may include the characteristics described in more detail above in the “Subjects” section and may be applied herein in the method of selecting subjects with COPD for treatment with an effective amount of an IL-33 signaling axis antagonist.

[0251] Suitablely, once a subject is selected for treatment, the subject is treated by administering an effective amount of an IL-33 signaling axis antagonist. Suitablely, the selection method may include the step of administering an effective amount of an IL-33 signaling axis antagonist to the subject, appropriately for treating the subject. Suitable IL-33 signaling axis antagonists, effective amounts, and routes of administration are defined elsewhere herein.

[0252] Suitably, a method according to any aspect of this disclosure may include the step of selecting a subject with a blood eosinophil count of <300 cells / µl to ≥150 cells / µl prior to administration of an IL-33 signaling axis antagonist. In some instances, a method according to any aspect of this disclosure includes the step of selecting a subject with a blood eosinophil count of <300 cells / µl to ≥150 cells / µl prior to said administration.

[0253] Methods according to any aspect of this disclosure may include the step of selecting subjects with a blood eosinophil count of <300 cells / µl to ≥150 cells / µl prior to administration of an IL-33 signaling axis antagonist. Methods according to any aspect of this disclosure may include the step of selecting subjects with a blood eosinophil count of <290 cells / µl to ≥150 cells / µl prior to administration of an IL-33 signaling axis antagonist. Methods according to any aspect of this disclosure may include the step of selecting subjects with a blood eosinophil count of <280 cells / µl to ≥150 cells / µl prior to administration of an IL-33 signaling axis antagonist. Methods according to any aspect of this disclosure may include the step of selecting subjects with a blood eosinophil count of <270 cells / µl to ≥150 cells / µl prior to administration of an IL-33 signaling axis antagonist. Methods according to any aspect of this disclosure may include the step of selecting subjects with a blood eosinophil count of <260 cells / µl to ≥150 cells / µl prior to administration of an IL-33 signaling axis antagonist.

[0254] Methods according to any aspect of this disclosure may include the step of selecting a subject with a blood eosinophil count of <300 cells / µl, <290 cells / µl, <280 cells / µl, <270 cells / µl, <260 cells / µl, <250 cells / µl, <240 cells / µl, <230 cells / µl, <220 cells / µl, <210 cells / µl, or <200 cells / µl of an IL-33 signaling axis antagonist.

[0255] Methods according to any aspect of this disclosure may include the step of selecting subjects with a blood eosinophil count of <250 cells / µl (suitably, excluding 250 cells / µl) of an IL-33 signaling axis antagonist. Methods according to any aspect of this disclosure may include the step of selecting subjects with a blood eosinophil count of <250 cells / µl to ≥150 cells / µl (suitably, excluding 250 cells / µl) of an IL-33 signaling axis antagonist.

[0256] Methods according to any aspect of this disclosure may include the step of selecting subjects with a blood eosinophil count of <240 cells / µl (suitably, excluding 250 cells / µl) of an IL-33 signaling axis antagonist. Methods according to any aspect of this disclosure may include the step of selecting subjects with a blood eosinophil count of <240 cells / µl to ≥150 cells / µl (suitably, excluding 240 cells / µl) of an IL-33 signaling axis antagonist.

[0257] Methods according to any aspect of this disclosure may include the step of selecting a subject who is a current smoker or a former smoker, having a blood eosinophil count of <300 cells / µl to ≥150 cells / µl prior to administration of an IL-33 signaling axis antagonist. Methods according to any aspect of this disclosure may include the step of selecting a subject who is a current smoker or a former smoker, having a blood eosinophil count of <290 cells / µl to ≥150 cells / µl prior to administration of an IL-33 signaling axis antagonist. Methods according to any aspect of this disclosure may include the step of selecting a subject who is a current smoker or a former smoker, having a blood eosinophil count of <280 cells / µl to ≥150 cells / µl prior to administration of an IL-33 signaling axis antagonist. Methods according to any aspect of this disclosure may include the step of selecting a subject who is a current smoker or a former smoker, having a blood eosinophil count of <270 cells / µl to ≥150 cells / µl prior to administration of an IL-33 signaling axis antagonist. Methods according to any aspect of this disclosure may include the step of selecting a subject who is a current smoker or a former smoker, having a blood eosinophil count of <260 cells / µl to ≥150 cells / µl prior to administration of an IL-33 signaling axis antagonist.

[0258] In some instances, the method according to any aspect of the invention includes the step of selecting subjects who are current smokers or former smokers and have a blood eosinophil count of <250 cells / µl to ≥150 cells / µl prior to administration of an IL-33 signaling axis antagonist. In some instances, the method according to any aspect of the invention includes the step of selecting subjects who are current smokers or former smokers and have a blood eosinophil count of <240 cells / µl to ≥150 cells / µl prior to administration of an IL-33 signaling axis antagonist.

[0259] Methods according to any aspect of this disclosure may include the step of selecting a subject who is a current smoker or a former smoker, having a blood eosinophil count of <230 cells / µl to ≥150 cells / µl prior to administration of an IL-33 signaling axis antagonist. Methods according to any aspect of this disclosure may include the step of selecting a subject who is a current smoker or a former smoker, having a blood eosinophil count of <220 cells / µl to ≥150 cells / µl prior to administration of an IL-33 signaling axis antagonist. Methods according to any aspect of this disclosure may include the step of selecting a subject who is a current smoker or a former smoker, having a blood eosinophil count of <220 cells / µl to ≥150 cells / µl prior to administration of an IL-33 signaling axis antagonist. Methods according to any aspect of this disclosure may include the step of selecting a subject who is a current smoker or a former smoker, having a blood eosinophil count of <210 cells / µl to ≥150 cells / µl prior to administration of an IL-33 signaling axis antagonist. Methods according to any aspect of this disclosure may include the step of selecting a subject who is a current smoker or a former smoker, having a blood eosinophil count of <200 cells / µl to ≥150 cells / µl prior to administration of an IL-33 signaling axis antagonist.

[0260] Methods according to any aspect of this disclosure may include the step of selecting a blood eosinophil count of an IL-33 signaling axis antagonist having <300 cells / µl, <290 cells / µl, <280 cells / µl, <270 cells / µl, <260 cells / µl, <250 cells / µl, <240 cells / µl, <230 cells / µl, <220 cells / µl, <210 cells / µl, or <200 cells / µl, for a subject who is a current smoker or a former smoker.

[0261] Methods according to any aspect of this disclosure may include the step of selecting a blood eosinophil count of an IL-33 signaling axis antagonist having a count of <250 cells / µl (suitably excluding 250 cells / µl) for a subject who is a current smoker or a former smoker. Methods according to any aspect of this disclosure may include the step of selecting a blood eosinophil count of an IL-33 signaling axis antagonist having a count of <250 cells / µl to ≥150 cells / µl (suitably excluding 250 cells / µl) for a subject who is a current smoker or a former smoker.

[0262] Methods according to any aspect of this disclosure may include the step of selecting a blood eosinophil count of an IL-33 signaling axis antagonist having a count of <240 cells / µl (suitably excluding 250 cells / µl) for a subject who is a current smoker or a former smoker. Methods according to any aspect of this disclosure may include the step of selecting a blood eosinophil count of an IL-33 signaling axis antagonist having a count of <240 cells / µl to ≥150 cells / µl (suitably excluding 240 cells / µl) for a subject who is a current smoker or a former smoker.

[0263] Methods according to any aspect of this disclosure may include the step of selecting a blood eosinophil count of <300 cells / µl to ≥150 cells / µl in a subject who is a current smoker prior to administration of an IL-33 signaling axis antagonist. Methods according to any aspect of this disclosure may include the step of selecting a blood eosinophil count of <290 cells / µl to ≥150 cells / µl in a subject who is a current smoker prior to administration of an IL-33 signaling axis antagonist. Methods according to any aspect of this disclosure may include the step of selecting a blood eosinophil count of <280 cells / µl to ≥150 cells / µl in a subject who is a current smoker prior to administration of an IL-33 signaling axis antagonist. Methods according to any aspect of this disclosure may include the step of selecting a blood eosinophil count of <270 cells / µl to ≥150 cells / µl in a subject who is a current smoker prior to administration of an IL-33 signaling axis antagonist. Methods according to any aspect of this disclosure may include the step of selecting a blood eosinophil count of <260 cells / µl to ≥150 cells / µl in a subject who is a current smoker prior to administration of an IL-33 signaling axis antagonist.

[0264] In some instances, the method according to any aspect of the invention includes the step of selecting a subject who is a current smoker and has a blood eosinophil count of <250 cells / µl to ≥150 cells / µl prior to administration of an IL-33 signaling axis antagonist. In some instances, the method according to any aspect of the invention includes the step of selecting a subject who is a current smoker and has a blood eosinophil count of <240 cells / µl to ≥150 cells / µl prior to administration of an IL-33 signaling axis antagonist.

[0265] Methods according to any aspect of this disclosure may include the step of selecting a blood eosinophil count of <230 cells / µl to ≥150 cells / µl in a subject who is a current smoker prior to administration of an IL-33 signaling axis antagonist. Methods according to any aspect of this disclosure may include the step of selecting a blood eosinophil count of <220 cells / µl to ≥150 cells / µl in a subject who is a current smoker prior to administration of an IL-33 signaling axis antagonist. Methods according to any aspect of this disclosure may include the step of selecting a blood eosinophil count of <220 cells / µl to ≥150 cells / µl in a subject who is a current smoker prior to administration of an IL-33 signaling axis antagonist. Methods according to any aspect of this disclosure may include the step of selecting a blood eosinophil count of <210 cells / µl to ≥150 cells / µl in a subject who is a current smoker prior to administration of an IL-33 signaling axis antagonist. Methods according to any aspect of this disclosure may include the step of selecting a blood eosinophil count of <200 cells / µl to ≥150 cells / µl in a subject who is a current smoker prior to administration of an IL-33 signaling axis antagonist.

[0266] Methods according to any aspect of this disclosure may include the step of selecting a blood eosinophil count of an IL-33 signaling axis antagonist having <300 cells / µl, <290 cells / µl, <280 cells / µl, <270 cells / µl, <260 cells / µl, <250 cells / µl, <240 cells / µl, <230 cells / µl, <220 cells / µl, <210 cells / µl, <200 cells / µl, in a subject who is a current smoker.

[0267] Methods according to any aspect of this disclosure may include the step of selecting a blood eosinophil count having <250 cells / µl (suitably excluding 250 cells / µl) of an IL-33 signaling axis antagonist for a subject who is a current smoker. Methods according to any aspect of this disclosure may include the step of selecting a blood eosinophil count having <250 cells / µl to ≥150 cells / µl (suitably excluding 250 cells / µl) of an IL-33 signaling axis antagonist for a subject who is a current smoker.

[0268] Methods according to any aspect of this disclosure may include the step of selecting a blood eosinophil count having <240 cells / µl (suitably excluding 250 cells / µl) of an IL-33 signaling axis antagonist for a subject who is a current smoker. Methods according to any aspect of this disclosure may include the step of selecting a blood eosinophil count having <240 cells / µl to ≥150 cells / µl (suitably excluding 240 cells / µl) of an IL-33 signaling axis antagonist for a subject who is a current smoker.

[0269] CompEx event

[0270] This disclosure also relates to a method for increasing the time to the first CompEx event and reducing the CompEx event rate in subjects with COPD. Suitably, any “CompEx event” may also be referred to as a “COPD CompEx event” in relation to COPD herein. Therefore, this disclosure relates to a method for increasing the time to the first COPD CompEx event and reducing the COPD CompEx event rate in subjects with COPD.

[0271] Appropriately, the term CompEx event refers to the composite endpoint of deterioration, and is suitably used herein for deterioration of COPD. A CompEx event typically combines deterioration with an event defined from a participant's diary, as appropriately defined below. Note that the definition of a CompEx event usually includes withdrawal due to lack of efficacy as a CompEx event. However, in studies where "lack of efficacy" is not listed as a reason for termination, the CompEx withdrawal criterion may not be included.

[0272] Appropriately, a participant is considered to have a CompEx event if it possesses one or more of the following:

[0273] • Deterioration, wherein at least one of the following criteria is met:

[0274] Related hospitalization = Yes;

[0275] o Systemic corticosteroids (injection and / or oral) = Yes;

[0276] o Antibiotics = Yes; and / or

[0277] o Any emergency room visits due to worsening COPD? = Yes; and / or

[0278] • A diary event that has objectively deteriorated, and is appropriately defined as a threshold criterion or slope criterion (or both), that satisfies ≥ 2 consecutive days.

[0279] Therefore, "two consecutive days" means two consecutive days that are strictly identical when assessing multiple requirements within those days. For diary data (which is captured twice in a day), a day will be defined by evening / morning pairings as other diary endpoints in this experiment. Diary data recorded on the evening of day n and the morning of day n+1 will belong to day n of the study.

[0280] The objective deterioration criterion will be satisfied for each diary variable for the threshold criterion and slope criterion, which are appropriately defined as follows.

[0281] Appropriately, the threshold criteria include:

[0282] a. Morning PEF decreases by ≥12% from baseline.

[0283] b. The total daily rescue medication dose increases by ≥1.75 doses from baseline. Suitablely, a day is defined as evening / morning paired. The number of rescue medication doses is defined as the number of inhalers drawn during the evening and morning sessions, respectively. Suitablely, if an evening or morning result is lost, a single non-lost result will be used.

[0284] c. An increase of ≥0.75 from baseline or a maximum symptom score of 4 in at least one of the following symptom scores: dyspnea, cough, and sputum production. Appropriately possessing:

[0285] i. An increase of ≥0.75 from baseline or a maximum symptom score of 4 in the daily dyspnea assessment;

[0286] ii. An increase of ≥0.75 from baseline or a maximum symptom score of 4 in the daily cough score; or

[0287] iii. An increase of ≥0.75 from baseline or a maximum symptom score of 4 in the daily sputum score.

[0288] Suitablely, the threshold criterion is met if at least one of [(a) or (b)] and (c) is satisfied. Suitablely, at least 2 consecutive days. Suitablely, 2, 3, 4, 5, 6, or 7 or more consecutive days.

[0289] Appropriately, slope criteria include:

[0290] d. Morning PEF slope ≤ -3% / .

[0291] e. Daily total rescue medication slope ≥ 0.4 doses / day

[0292] f. A slope ≥ 0.2 / day in all of the following symptom scores: dyspnea, cough, and sputum production.

[0293] Suitablely, the slope criterion is satisfied if all of [(d), (e), and (f)] are satisfied, and at least one of [(a), (b), or (c)] is also satisfied. Suitablely, the slope criterion is determined by a regression slope, which is generated by measuring the value of the above criteria over a previous 5-day rolling period.

[0294] In all the above cases, the regression slope is a point estimate of the slope obtained from a linear regression of the absolute value of each variable relative to the number of days, and other variables are not included in the regression model.

[0295] In some instances, the time to first CompEx event was increased by approximately 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, or 6 weeks compared to control subjects who did not receive an IL-33 signaling axis antagonist. The time to first CompEx event was increased by approximately 4 weeks, 5 weeks, or 6 weeks compared to control subjects with COPD who did not receive an IL-33 signaling axis antagonist. Suitablely, the time to first CompEx event was increased by at least 4 weeks compared to subjects in the placebo group. Suitablely, the time to first CompEx event was increased by at least 5 weeks compared to subjects in the placebo group. Suitablely, the time to first CompEx event was increased by at least 6 weeks compared to subjects in the placebo group.

[0296] In some instances, the CompEx event rate was reduced by at least 10%, 15%, 20%, 25%, or at least 27% in subjects or subject groups. In some instances, compared to control subjects or subject groups that did not receive an IL-33 signaling axis antagonist, the CompEx event rate was reduced by at least 10%, 15%, 20%, 25%, or at least 27% after administration of an effective amount of an IL-33 signaling axis antagonist, suitably at least 20%, at least 25%, or at least 27%. Compared to control subjects or subject groups with COPD who did not receive an IL-33 signaling axis antagonist, the CompEx event rate was reduced by at least 10%, 15%, 20%, 25%, or at least 27% after administration of an effective amount of an IL-33 signaling axis antagonist, suitably at least 20%, at least 25%, or at least 27%.

[0297] Suitablely, the CompEx event rate is reduced by at least 10%, 15%, 20%, 25%, or at least 27%. Suitablely, the CompEx event rate is reduced by at least 20%, at least 25%, or at least 27% compared to the CompEx event rate of control subjects with COPD who have not received an IL-33 signaling axis antagonist. Suitablely, the CompEx event rate is reduced by at least 20%, at least 25%, or at least 27% compared to the CompEx event rate of control subjects with COPD who have not received an IL-33 signaling axis antagonist. Suitablely, the CompEx event rate is reduced by at least 20%, at least 25%, or at least 27% compared to subjects from the placebo group.

[0298] Suitable, the time to first CompEx event and / or CompEx event ratio following administration of an effective amount of IL-33 signaling axis antagonist may be compared with the time to first CompEx event and / or CompEx event ratio in control subjects with COPD who did not receive IL-33 signaling axis antagonist or in a control subject group (suitably, which may be a placebo group).

[0299] In some instances, the CompEx event rate decreased over a 28-week period following administration of an effective amount of the IL-33 signaling axis antagonist. Suitably, the time to the first CompEx event increased over a 28-week period following administration of an effective amount of the IL-33 signaling axis antagonist. Suitably, the decrease in the CompEx event rate occurred at week 28 following administration of an effective amount of the IL-33 signaling axis antagonist. Suitably, the increase in the time to the first CompEx event occurred at week 28 following administration of an effective amount of the IL-33 signaling axis antagonist.

[0300] IL-33 signal axis antagonist

[0301] Appropriately, IL-33 signaling axis antagonists reduce, inhibit, or neutralize IL-33 activity. Interleukin-33 (IL-33) (also known as IL-1F11) is a member of the interleukin-1 (IL-1) cytokine family encoded by the IL33 gene. IL-33 is a 270-amino acid protein composed of two domains: a homologous domain and a cytokine (IL-1-like) domain. The homologous domain contains the nuclear localization signal (NLS). IL-33 is known to exist in different forms: a reduced form (redIL-33) and an oxidized form (oxIL-33). Previous studies have shown that the reduced form is rapidly oxidized under physiological conditions to form at least one disulfide bond in the oxidized form, and that the two forms may have different binding modes and functions.

[0302] IL-33 is constitutively expressed in a variety of cell types, including structural cells such as smooth muscle cells, epithelial cells, and endothelial cells. Inflammatory factors in macrophages and dendritic cells have also been reported to induce IL-33 expression. Cellular stress induced by environmental triggers such as allergens, toxins, and pathogens, as well as mechanical damage, can lead to IL-33 release. Free IL-33 binds to a heterodimeric IL-33 receptor complex composed of the inhibitory oncogenic 2 (ST2) protein and the interleukin-1 receptor accessory protein (IL-1 RacP), activating the AP-1 and NF-κB pathways via the adaptor protein Myeloid Differentiation Primary Response 88 (MyD88) and the possible MyD88 adaptor-like (Mal) protein. IL-33 stimulates various cell types, including innate lymphoid type II cells (ILC2), mast cells, basophils, eosinophils, and dendritic cells, to promote immune responses. Previously, the reduced form of IL-33 was found to bind to ST2, and it is in fact the only known ligand for the ST2 receptor expressed by Th2 cells and mast cells. Soluble ST2 (sST2) is considered a decoy receptor that blocks reduced IL-33 signaling.

[0303] Unless otherwise stated, the terms “interleukin-1 receptor-like 1 (IL1RL)” and “ST2” are used interchangeably herein and refer to any natural ST2 from any vertebrate source, including mammals such as primates (e.g., humans) and rodents (e.g., mice and rats). ST2 is also referred to in the art as DER4, T1, and FIT-1. The term encompasses “full-length”, unprocessed ST2, as well as any form of ST2 produced through cellular processing. At least four isoforms of ST2 are known in the art, including soluble (sST2, also known as IL1RL1-a) and transmembrane (ST2L, also known as IL1RL1-b) forms of differentially expressed mRNA from dual-promoter systems, and ST2V and ST2LV from alternative splicing. The domain structure of ST2L includes three extracellular immunoglobulin-like C2 domains, a transmembrane domain, and a cytoplasmic Toll / interleukin-1 receptor (TIR) ​​domain. sST2 lacks the transmembrane and cytoplasmic domains present in ST2L and includes a unique 9-amino acid (aa) C-terminal sequence (see, for example, Kakkar et al., Nat. Rev. Drug Disc. 40 7: 827-840, 2008). sST2 can act as a decoy receptor to inhibit soluble IL-33. The term also covers naturally occurring variants of ST2, such as splice variants (e.g., ST2V lacking the third immunoglobulin motif and having a unique hydrophobic tail, and ST2LV lacking the transmembrane domain of ST2L) or allelic variants (e.g., variants that prevent or induce COPD risk, as described herein). An exemplary amino acid sequence of human ST2 can be found, for example, in UniProtKB accession number 001638. ST2, along with the co-receptor protein IL-1 RacP, is part of the IL-33 receptor. IL-33 binds to ST2 and the co-receptor interleukin-1 receptor co-protein (IL-1 RacP) to form a 1:1:1 ternary signaling complex to promote downstream signal transduction (Lingel et al., Structure 17(10): 1398-1410, 2009, and Liu et al., Proc. Nat. Acad. Sci. 11 0(37): 14918-14924, 2013).

[0304] As used in this paper, the 'ST2 pathway' refers to the IL-33 / ST2 system, in which ST2 reduces IL-33 recognition, promotes IL-1RAcP dimerization on the cell surface, and recruits receptor complex components MyD88, TRAF6, and IRAK1-4 to the intracellular TIR domain. Therefore, ST2-dependent signaling / action can be interrupted or attenuated by interfering with the interaction between IL-33 and ST2 or by disrupting the interaction with IL-1RAcP.

[0305] This article considers that antibodies, binding fragments, or antibody variants that specifically bind to and inhibit the IL-33 signaling axis may be used to treat COPD.

[0306] Suitably, an IL-33 signaling axis antagonist is an antibody, its variant, or an antigen-binding fragment that specifically binds to and inhibits one or more components of the IL-33 / ST2 signaling axis. Suitably, an IL-33 signaling axis antagonist is an antibody, its variant, or an antigen-binding fragment that specifically binds to and inhibits the IL-33 receptor complex. Suitably, an IL-33 signaling axis antagonist is an antibody, its variant, or an antigen-binding fragment that specifically binds to and inhibits ST2. Suitably, an IL-33 signaling axis antagonist is an antibody, its variant, or an antigen-binding fragment that specifically binds to and inhibits IL-1 RacP.

[0307] In some instances, IL-33 signaling axis antagonists bind to and inhibit reduced IL-33. In some instances, IL-33 signaling axis antagonists are antibodies, variants, or antigen-binding fragments that specifically bind to and inhibit reduced IL-33. In some instances, IL-33 signaling axis antagonists bind to and inhibit oxidized IL-33. In some instances, IL-33 signaling axis antagonists are antibodies, variants, or antigen-binding fragments that specifically bind to and inhibit oxidized IL-33. In some instances, IL-33 signaling axis antagonists specifically bind to and inhibit both reduced and oxidized IL-33. In some instances, IL-33 signaling axis antagonists are antibodies, variants, or antigen-binding fragments that specifically bind to and inhibit both reduced and oxidized IL-33. In some instances, IL-33 signaling axis antagonists bind to and inhibit reduced IL-33 and inhibit the conversion of reduced IL-33 to oxidized IL-33. In some instances, IL-33 signaling axis antagonists are antibodies, variants of antibodies, or antigen-binding fragments that specifically bind to and inhibit reduced IL-33 and prevent the conversion of reduced IL-33 into oxidized IL-33.

[0308] Therefore, appropriately, the IL-33 signaling axis antagonists used in this article are binding molecules, which may be selected from: antibodies, their antigen-binding fragments, aptamers, at least one heavy or light chain CDR of a reference antibody molecule, and at least six CDRs from one or more reference antibody molecules.

[0309] In some instances, IL-33 signaling axis antagonists are antibodies or variants thereof, i.e., any antibody that specifically binds to and inhibits IL-33, which are effective in treating COPD.

[0310] "Its binding fragment" and "its antigen-binding fragment" are interchangeable and refer to the epitope / antigen-binding fragment of the antibody fragment, such as containing a binding region, especially containing 6 CDRs, such as 3 CDRs in the heavy variable region and 3 CDRs in the light variable region.

[0311] Suitablely, the antibody or its antigen-binding fragment is selected from: naturally occurring, polyclonal, monoclonal (Mab), recombinant, multispecific, mouse, human, humanized (such as complementarity-determining region (CDR) transplanted), primate, chimeric, and antibody variants, including single-chain, monomeric, and / or bispecific antibodies, as well as fragments or derivatives thereof.

[0312] Suitably, the IL-33 signaling axis antagonist is an antibody or an antigen-binding fragment thereof. Suitably, the antigen-binding fragment may be an epitope-binding fragment, such as Fab' and F(ab')2, Fd, Fv, single-chain Fv (scFv), disulfide-linked Fv (sdFv), a fragment containing a VL or VH domain, or a fragment generated from a Fab expression library. Suitably, Fab and F'ab') fragments can be generated by enzymatic cleavage of a full-length antibody. Other antigen-binding fragments include those generated by recombinant DNA technologies, such as expressing recombinant plasmids containing nucleic acid sequences encoding variable regions of antibodies. Suitably, the antibody or antigen-binding fragment may be a microantibody, a biantibody, a triantibody, a tetraantibody, or a single-chain antibody. Suitably, the antibody or its antigen-binding fragment is a monoclonal antibody. scFv molecules are known in the art and described, for example, in U.S. Patent No. 5,892,019. In some instances, the anti-IL-33 antibody variant or its antigen-binding fragment is selected from the group consisting of bivalent antibodies, trivalent antibodies, tetravalent antibodies, Fab fragments, single-domain antibodies, and scFv, wherein the dosage is adjusted so that the binding site is equimolar with the binding site of the bivalent antibody.

[0313] Monoclonal antibodies can be modified for use as therapeutic or diagnostic agents. As used herein, "monoclonal antibody" or "monoclonal antibody composition" refers to polypeptides, including antibodies, bispecific antibodies, etc., that have substantially the same amino acid sequence or originate from the same genetic source. The term also includes antibody molecular formulations composed of single molecules. Monoclonal antibody compositions exhibit single binding specificity and affinity for specific epitopes.

[0314] One example is a “chimeric” antibody, in which a portion of the heavy chain (H) and / or light chain (L) is identical or homologous to the corresponding sequence in an antibody derived from a specific species or belonging to a specific antibody class or subclass, while the remaining chain is identical or homologous to the corresponding sequence in an antibody derived from another species or belonging to another antibody class or subclass. Fragments of such antibodies are also included, provided they exhibit the desired biological activity. See U.S. Patent No. 4,816,567; Morrison et al., 1985, Proc. Natl. Acad. Sci. 81:6851-55.

[0315] In another instance, the monoclonal antibody is a “humanized” antibody. Methods for humanizing nonhuman antibodies are well known in the art. See U.S. Patent Nos. 5,585,089 and 5,693,762. Typically, humanized antibodies have one or more amino acid residues introduced therein from a nonhuman source. Humanization can be performed, for example, using methods described in the art (Jones et al., 1986, Nature 321:522-25; Riechmann et al., 1998, Nature 332:323-27; Verhoeyen et al., 1988, Science 239:1534-36), by replacing the corresponding region of a human antibody with at least a portion of a rodent complementarity-determining region.

[0316] Human antibodies and antibody variants (including antibody fragments) that bind to IL-33 are also considered. Such antibodies are generated using transgenic animals (e.g., mice) capable of producing a human antibody library in the absence of endogenous immunoglobulin production, by immunization with a polypeptide antigen optionally conjugated to a vector (i.e., having at least six consecutive amino acids). See, for example, Jakobovits et al., 1993, Proc. Natl. Acad. Sci. 90:2551-55; Jakobovits et al., 1993, Nature 362:255-58; Bruggermann et al., 1993, Year in lmmuno. 7:33. See also PCT applications PCT / US96 / 05928 and PCT / US93 / 06926. Other methods are described in U.S. Patent No. 5,545,807, PCT applications PCT / US91 / 245 and PCT / GB89 / 01207, and European Patent Nos. 54607381 and 546073A1. As described herein, human antibodies can also be generated by expression of recombinant DNA in host cells or by expression in hybridoma cells.

[0317] Chimeric, CDR-transplanted, and humanized antibodies and / or antibody variants are typically generated via recombinant methods. Nucleic acid encoding the antibody is introduced into a host cell and expressed using the materials and procedures described herein. In one example, the antibody is generated in mammalian host cells such as CHO cells. As described herein, monoclonal (e.g., human) antibodies can be generated via expression of recombinant DNA in host cells or via expression in hybridoma cells.

[0318] The immunoglobulin or antibody molecules disclosed herein can be of any type (e.g., IgG, IgE, IgM, IgD, IgA, and IgY), class (e.g., IgG1, IgG2, IgG3, IgG4, IgA1, and IgA2, etc.), or subclass of immunoglobulin molecules. In one example, the IL-33 signaling axis antagonist is an IgG1 antibody, an IgG2 antibody, an IgG3 antibody, or an IgG4 antibody. In some examples, the IL-33 signaling axis antagonist that can be used in the methods of the present invention is a monoclonal IgG1 antibody.

[0319] In some instances, IL-33 signaling axis antagonists are anti-IL-33 antibodies, anti-ST2 antibodies, anti-IL1-RacP antibodies, their binding fragments, or variants. Suitably, anti-IL-33 antibodies, their variants, or binding fragments specifically bind to IL-33, either reduced IL-33 or oxidized IL-33.

[0320] In some instances, the IL-33 signaling axis antagonist is an anti-IL-33 antibody, its binding fragment, or a variant thereof. Suitably, any anti-IL-33 antibody, its binding fragment, or a variant thereof may be used in the methods of this disclosure.

[0321] In some instances, anti-IL-33 antibodies, their binding fragments, or antibody variants comprise IL-33 bound to the amino acid sequence comprising SEQ ID NO: 45. In various instances, anti-IL-33 antibodies, their binding fragments, or antibody variants may be able to bind to the mature form of the full-length IL-33 protein comprising the amino acid sequence comprising SEQ ID NO: 45. In various instances, anti-IL-33 antibodies, their binding fragments, or antibody variants may be able to bind to fragments of the IL-33 protein comprising amino acids 72-270, 79-270, 95-270, 99-270, 107-270, 109-270, 111-270, or 112-270 of SEQ ID NO: 45.

[0322] In various instances, anti-IL-33 antibodies, their binding fragments, or antibody variants may be able to bind to both reduced (red-IL-33) and / or oxidized (ox-IL-33) forms of IL-33. In some instances, anti-IL-33 antibodies, their binding fragments, or antibody variants may be able to preferentially bind to both reduced (red-IL-33) and / or oxidized (ox-IL-33) forms of IL-33.

[0323] Suitable, anti-IL-33 antibodies, their binding fragments, or antibody variants are in quantities of less than 5 × 10⁻⁶. -2 M, 10 -2 M, 5×10 -3 M, 10 -3 M, 5×10 -4 M, 10 -4 M, 5×10 -5 M, 10 -5 M, 5×10 -6 M, 10 -6 M, 5×10 -7 M, 10 -7 M, 5×10 -8 M, 10 -8 M, 5×10 -9 M, 10 -9 M, 5×10 -10 M, 10 -10 M, 5×10 -11 M, 10 -11 M, 5×10 -12 M, 10 -12 M, 5×10 -13 M, 10 -13 M, 5×10-14 M, 10 -14 M, 5×10 -15 M or 10 -15 The binding affinity (Kd) of M specifically binds to redIL-33. Suitablely, the binding affinity to redIL-33 is less than 5 × 10⁻⁶. -14 M (i.e., 0.05 pM). Suitablely, binding affinity is determined using kinetic exclusion assays (KinExA) or BIACORE. TM KinExA is suitably used, measured using protocols such as those described in WO2016 / 156440 (see, for example, Example 11), which is hereby incorporated in its entirety by reference. Anti-IL-33 antibodies, their binding fragments, or antibody variants bound to redIL-33 with this binding affinity appear to bind tightly enough to prevent dissociation of the binding molecule / redIL-33 complex within a biologically relevant timescale. Not wishing to be bound by theory, this binding strength is considered to prevent the release of the antigen before the antibody / antigen complex degrades in vivo, thus preventing the release of redIL-33 and its conversion to oxIL-33. Therefore, when bound to redIL-33 with this binding affinity, anti-IL-33 antibodies, their binding fragments, or antibody variants can inhibit or attenuate their activity by preventing the formation of oxIL-33.

[0324] Suitable, the anti-IL-33 antibody, its binding fragment, or antibody variant may be greater than or equal to 10. 3 M -1 s -1 5×10 3 M -1 s -1 10 4 M -1 s -1 Or 5×10 4 M -1 s -1 The association rate (k(on)) specifically binds to redIL-33. For example, the anti-IL-33 antibody, its binding fragment, or antibody variant disclosed herein may have a binding rate greater than or equal to 10. 5 M -1 s -1 5×10 5 M -1 s -1 10 6 M -1 s -1 Or 5×10 6 M -1 s -1Or 10 7 M -1 s -1 The association rate (k(on)) binds to redIL-33 or its fragments or variants. Suitably, the k(on) rate is greater than or equal to 10. 7 M -1 s -1 .

[0325] Suitable, the anti-IL-33 antibody, its binding fragment, or antibody variant may be less than or equal to 5 × 10⁻⁶. -1 s -1 10 -1 s -1 5×10 -2 s -1 10 -2 s -1 5×l0 -3 s -1 Or 10 -3 s -1 The dissociation rate (k(off)) specifically binds to redIL-33. For example, it can be said that the anti-IL-33 antibody, its binding fragment, or antibody variant of this disclosure binds to redIL-33 at a dissociation rate of less than or equal to 5 × 10⁻⁶. -4 s -1 10 -4 s -1 5 × 10 -5 s -1 10 -5 s -1 5 × 10 -6 s -1 10 -6 s -1 5×10 -7 s -1 Or 10 -7 s -1 The dissociation rate (k(off)) binds to redIL-33 or its fragments or variants. Suitably, the k(off) rate is less than or equal to 10. -3 s -1IL-33 is an alarm cytokine that is rapidly and intensely released in response to inflammatory stimuli. RedIL-33 is converted to its oxidized form approximately 5 to 45 minutes after release into the extracellular environment. Therefore, to prevent the conversion of redIL-33 to oxIL-33, the anti-IL-33 antibodies, their binding fragments, or antibody variants described herein can bind to redIL-33 at these k(on) and / or k(off) rates. Without being bound by theory, it is assumed that these k(on) / k(off) rates ensure that anti-IL-33 antibodies, their binding fragments, or antibody variants can rapidly bind to redIL-33 before its conversion to oxIL-33, thereby reducing the formation of oxIL-33.

[0326] In various instances, anti-IL-33 antibodies, their binding fragments, or antibody variants may be inhibitory antibodies capable of inhibiting IL-33 or fragments thereof as defined herein. In various instances, inhibitory antibodies may be capable of inhibiting the association of IL-33 or fragments thereof with the IL-33 receptor complex, ST2, and / or IL-1 RacP.

[0327] Suitable anti-IL-33 antibodies used in the methods of this disclosure are known in the art and may comprise any of the following anti-IL-33 antibodies: 33_640087-7B (as described in WO2016 / 156440), ANB020 known as etozymeab (as described in WO2015 / 106080), 9675P (as described in US2014 / 0271658), A25-3H04 (as described in US2017 / 0283494), Ab43 (as described in WO2018 / 081075), IL33-158 (as described in US2018 / 0037644), 10C12.38.H6.87Y.581 lgG4 (as described in WO2016 / 077381), or combinations thereof, each of which is incorporated herein by reference. All of these antibodies are referenced in Table 1. Suitable anti-IL-33 antibodies for use in the methods of this disclosure are known in the art and may also comprise any of: TCQ-2938 (as described in WO2021 / 228091) or a binding fragment thereof, 9MW1911 (as described in WO2021 / 147937) or a binding fragment thereof, 621 (as described in WO2022 / 063281) or a binding fragment thereof, wherein the VH and VL domains are fully described and are incorporated herein by reference.

[0328] Suitablely, anti-IL-33 antibodies, their binding fragments, or antibody variants contain complementarity-determining regions (CDRs) selected from the variable heavy domain (VH) and variable light domain (VL) pairs listed in Table 1. Pair 1 corresponds to the VH and VL domain sequences of 33_640087-7B described in WO2016 / 156440. 33_640087-7B is also referred to herein as toretzimab. Pairs 2-7 correspond to the VH and VL domain sequences of the antibody described in US2014 / 0271658. Pairs 8-12 correspond to the VH and VL domain sequences of the antibody described in US2017 / 0283494. Pair 13 corresponds to the VH and VL domain sequences of ANB020 described in WO2015 / 106080. Pairs 14-16 correspond to the VH and VL domain sequences of the antibody described in WO2018 / 081075. Pair 17 corresponds to the VH and VL domain sequence of IL33-158 described in US2018 / 0037644. Pair 18 corresponds to the VH and VL domain sequence of 10C12.38.H6.87Y.581 lgG4 described in WO2016 / 077381.

[0329] Table 1: Exemplary anti-IL-33 antibodies VH and VL against [various antibodies]

[0330]

[0331]

[0332]

[0333] Suitablely, anti-IL-33 antibodies, their binding fragments, or antibody variants comprise a complementarity-determining region (CDR) of the heavy chain variable region (VH) containing the sequence of SEQ ID NO: 1 and a complementarity-determining region (CDR) of the light chain variable region (VL) containing the sequence of SEQ ID NO: 19. These CDRs correspond to those derived from toltazolizumab 33_640087-7B (as described in WO2016 / 156440), which binds reduced IL-33 and inhibits its conversion to oxidized IL-33. Toltazolizumab or 33_640087-7B is fully described in WO2016 / 156440, which is incorporated herein by reference.

[0334] Suitablely, anti-IL-33 antibodies, their binding fragments, or antibody variants comprise a complementarity-determining region (CDR) of the heavy chain variable region (VH) containing the sequence of SEQ ID NO: 7 and a complementarity-determining region (CDR) of the light chain variable region (VL) containing the sequence of SEQ ID NO: 25. These CDRs correspond to those derived from antibody 9675P. 9675P is fully described in US2014 / 0271658, which is incorporated herein by reference.

[0335] Suitablely, anti-IL-33 antibodies, their binding fragments, or antibody variants comprise a complementarity-determining region (CDR) of the heavy chain variable region (VH) containing the sequence of SEQ ID NO: 11 and a complementarity-determining region (CDR) of the light chain variable region (VL) containing the sequence of SEQ ID NO: 29. These CDRs correspond to those derived from antibody A25-3H04. A25-3H04 is fully described in US2017 / 0283494, which is incorporated herein by reference.

[0336] Suitablely, anti-IL-33 antibodies, their binding fragments, or antibody variants comprise a complementarity-determining region (CDR) of the heavy chain variable region (VH) containing the sequence of SEQ ID NO: 13 and a complementarity-determining region (CDR) of the light chain variable region (VL) containing the sequence of SEQ ID NO: 31. These CDRs correspond to those derived from antibody ANB020. ANB020 is fully described in WO2015 / 106080, which is incorporated herein by reference.

[0337] Suitablely, anti-IL-33 antibodies, their binding fragments, or antibody variants comprise a complementarity-determining region (CDR) of the heavy chain variable region (VH) containing the sequence of SEQ ID NO: 16 and a complementarity-determining region (CDR) of the light chain variable region (VL) containing the sequence of SEQ ID NO: 34. These CDRs correspond to those derived from antibody Ab43, which is fully described in WO2018 / 081075, and is incorporated herein by reference.

[0338] Suitablely, anti-IL-33 antibodies, their binding fragments, or antibody variants comprise a complementarity-determining region (CDR) of the heavy chain variable region (VH) containing the sequence of SEQ ID NO: 17 and a complementarity-determining region (CDR) of the light chain variable region (VL) containing the sequence of SEQ ID NO: 35. These CDRs correspond to those derived from antibody IL33-158. IL33-158 is fully described in US2018 / 0037644, which is incorporated herein by reference.

[0339] Suitablely, anti-IL-33 antibodies, their binding fragments, or antibody variants comprise a complementarity-determining region (CDR) of the heavy chain variable region (VH) containing the sequence of SEQ ID NO: 18 and a complementarity-determining region (CDR) of the light chain variable region (VL) containing the sequence of SEQ ID NO: 36. These CDRs correspond to those derived from antibody 10C12.38.H6.87Y.581 lgG4. 10C12.38.H6.87Y.581 lgG4 is fully described in WO2016 / 077381, which is incorporated herein by reference.

[0340] Suitablely, anti-IL-33 antibodies, their binding fragments, or antibody variants comprise a complementarity-determining region (CDR) of the heavy chain variable region (VH) containing the sequence of SEQ ID NO: 46 and a complementarity-determining region (CDR) of the light chain variable region (VL) containing the sequence of SEQ ID NO: 47. These CDRs correspond to those derived from antibody QX007N. QX007N is fully described in WO2023 / 029280, which is incorporated herein by reference.

[0341] Suitablely, those skilled in the art are familiar with available methods in the art for identifying CDRs within the heavy and light variable regions of an antibody or its antigen-binding fragment. Suitablely, for example, those skilled in the art can perform sequence-based annotation. Regions between CDRs are often highly conserved, and therefore, CDR locations can be determined using logical rules. Those skilled in the art can use a set of sequence-based rules used for routine antibodies (Pantazes and Maranas, Protein Engineering, Design and Selection, 2010), or alternatively, rules that can be refined based on multiple sequence alignment. Alternatively, those skilled in the art can use the BLASTP command of BLAST+ to compare the antibody sequence with publicly available databases operated on the Kabat, Chothia, or IMGT methods to identify the most similar annotated sequence. Each of these methods has a unique residue numbering scheme according to which residues in the hypervariable region are numbered, and then the start and end of each of the six CDRs are determined based on certain key positions. After alignment with the most similar annotated sequence, for example, CDRs can be extrapolated from the annotated sequence to the non-annotated sequence to identify the CDR. Suitable tools / databases include, for example, Kabat database, Kabatman, Scalinger, IMGT, and Abnum.

[0342] Suitable, anti-IL-33 antibodies, their binding fragments, or antibody variants contain a variable heavy domain (VH) and variable light domain (VL) pair selected from Table 1.

[0343] Suitablely, the anti-IL-33 antibody, its binding fragment, or antibody variant comprises the VH domain of the sequence of SEQ ID NO: 1 and the VL domain of the sequence of SEQ ID NO: 19.

[0344] Suitablely, the anti-IL-33 antibody, its binding fragment, or antibody variant comprises the VH domain of the sequence of SEQ ID NO: 7 and the VL domain of the sequence of SEQ ID NO: 25.

[0345] Suitablely, the anti-IL-33 antibody, its binding fragment or antibody variant comprises the VH domain of the sequence of SEQ ID NO: 11 and the VL domain of the sequence of SEQ ID NO: 29.

[0346] Suitablely, the anti-IL-33 antibody, its binding fragment or antibody variant comprises the VH domain of the sequence of SEQ ID NO: 13 and the VL domain of the sequence of SEQ ID NO: 31.

[0347] Suitablely, the anti-IL-33 antibody, its binding fragment, or antibody variant comprises the VH domain of the sequence of SEQ ID NO: 16 and the VL domain of the sequence of SEQ ID NO: 34.

[0348] Suitablely, the anti-IL-33 antibody, its binding fragment or antibody variant comprises the VH domain of the sequence of SEQ ID NO: 17 and the VL domain of the sequence of SEQ ID NO: 35.

[0349] Suitablely, the anti-IL-33 antibody, its binding fragment, or antibody variant comprises the VH domain of the sequence of SEQ ID NO: 46 and the VL domain of the sequence of SEQ ID NO: 47.

[0350] Therefore, suitablely, anti-IL-33 antibodies, their binding fragments, or antibody variants may contain three CDRs, for example, in the heavy chain variable region independently selected from SEQ ID NO: 1, 7, 11, 13, 16, 17, and 18.

[0351] Suitablely, the anti-IL-33 antibody, its binding fragment, or antibody variant contains three CDRs in the heavy chain variable region according to SEQ ID NO: 1.

[0352] Suitablely, the anti-IL-33 antibody, its binding fragment, or antibody variant contains three CDRs in the light chain variable region independently selected from SEQ ID NO: 19, 25, 29, 31, 34, 35, and 36.

[0353] Suitablely, the anti-IL-33 antibody, its binding fragment, or antibody variant contains three CDRs in the light chain variable region according to SEQ ID NO: 19.

[0354] Therefore, suitablely, anti-IL-33 antibodies, their binding fragments, or antibody variants may contain three CDRs, for example, in the heavy chain variable region independently selected from SEQ ID NO: 1, 7, 11, 13, 16, 17, and 18, and for example, in the light chain variable region independently selected from SEQ ID NO: 19, 25, 29, 31, 34, 35, and 36.

[0355] Therefore, suitably, the anti-IL-33 antibody, its binding fragment, or antibody variant contains three CDRs in the heavy chain variable region according to SEQ ID NO: 1 and three CDRs in the light chain variable region according to SEQ ID NO: 19.

[0356] Therefore, suitablely, anti-IL-33 antibodies, their binding fragments, or antibody variants comprise a variable heavy domain (VH) and a variable light domain (VL), the variable heavy domain having VH CDRs 1-3 having sequences SEQ ID NO: 37, 38, and 39, respectively, wherein one or more VHCDRs have three or fewer single amino acid substitutions, insertions, and / or deletions.

[0357] Therefore, suitablely, the anti-IL-33 antibody, its binding fragment or antibody variant includes a VH domain containing VHCDR 1-3 of SEQ ID NO: 37, SEQ ID NO: 38 and SEQ ID NO: 39, respectively.

[0358] Therefore, appropriately, anti-IL-33 antibodies, their binding fragments, or antibody variants contain a VH domain comprising VHCDR 1-3, which are composed of SEQ ID NO: 37, SEQ ID NO: 38, and SEQ ID NO: 39, respectively.

[0359] Therefore, suitablely, anti-IL-33 antibodies, their binding fragments, or antibody variants comprise a variable heavy domain (VH) and a variable light domain (VL), the variable light domain having VL CDRs 1-3 having sequences SEQ ID NO: 40, 41, and 42, respectively, wherein one or more VLCDRs have three or fewer single amino acid substitutions, insertions, and / or deletions.

[0360] Therefore, suitablely, the anti-IL-33 antibody, its binding fragment or antibody variant includes a VL domain containing VLCDR 1-3 of SEQ ID NO: 40, SEQ ID NO: 41 and SEQ ID NO: 42, respectively.

[0361] Therefore, suitably, the anti-IL-33 antibody, its binding fragment or antibody variant includes a VL domain comprising VLCDR 1-3 consisting of SEQ ID NO: 40, SEQ ID NO: 41 and SEQ ID NO: 42, respectively.

[0362] Therefore, suitably, the anti-IL-33 antibody, its binding fragment, or antibody variant comprises VHCDR1 having the sequence of SEQ ID NO: 37, VHCDR2 having the sequence of SEQ ID NO: 38, VHCDR3 having the sequence of SEQ ID NO: 39, VLCDR1 having the sequence of SEQ ID NO: 40, VLCDR2 having the sequence of SEQ ID NO: 41, and VLCDR3 having the sequence of SEQ ID NO: 42.

[0363] Therefore, suitably, anti-IL-33 antibodies, their binding fragments, or antibody variants comprise VH and VL, wherein VH has an amino acid sequence that is at least 90%, such as 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to VH according to SEQ ID NO: 1, 7, 11, 13, 16, 17, 18, and 46.

[0364] Therefore, suitably, the anti-IL-33 antibody, its binding fragment, or antibody variant comprises VH and VL, wherein the VH has an amino acid sequence that is at least 90%, such as 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the VH according to SEQ ID NO: 1.

[0365] Therefore, appropriately, anti-IL-33 antibodies, their binding fragments, or antibody variants comprise VH and VL, wherein the VH disclosed above has a sequence in which one, two, three, or four amino acids are deleted, inserted, and / or independently substituted by different amino acids within the frame.

[0366] Therefore, suitably, anti-IL-33 antibodies, their binding fragments, or antibody variants comprise VH and VL, wherein VL has an amino acid sequence that is at least 90%, such as 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the VL according to SEQ ID NO: 19, 25, 29, 31, 34, 35, 36, and 47.

[0367] Therefore, suitably, the anti-IL-33 antibody, its binding fragment, or antibody variant comprises VH and VL, wherein the VL has an amino acid sequence that is at least 90%, such as 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the VL according to SEQ ID NO: 19.

[0368] Therefore, appropriately, anti-IL-33 antibodies, their binding fragments, or antibody variants comprise VH and VL, wherein the VL disclosed above has a sequence in which one, two, three, or four amino acids in the frame are independently deleted, inserted, and / or substituted with different amino acids.

[0369] Therefore, suitably, the anti-IL-33 antibody, its binding fragment, or antibody variant comprises VH and VL, wherein VH has an amino acid sequence that is at least 90%, such as 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the VH according to SEQ ID NO: 1, 7, 11, 13, 16, 17, 18, and 46, and VL has an amino acid sequence that is at least 90%, such as 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the VL according to SEQ ID NO: 19, 25, 29, 31, 34, 35, 36, and 47.

[0370] Therefore, suitably, the anti-IL-33 antibody, its binding fragment, or antibody variant comprises VH and VL, wherein VH has an amino acid sequence consisting of SEQ ID NO: 1, 7, 11, 13, 16, 17, 18, and 46, and VL has an amino acid sequence consisting of SEQ ID NO: 19, 25, 29, 31, 34, 35, 36, and 47.

[0371] Therefore, suitably, the anti-IL-33 antibody, its binding fragment, or antibody variant comprises VH and VL, wherein VH has an amino acid sequence consisting of SEQ ID NO: 1, and VL has an amino acid sequence consisting of SEQ ID NO: 19.

[0372] In some instances, the anti-IL-33 antibody, its binding fragment, or variant thereof, which can be used in the methods of the present invention, comprises the heavy chain shown in SEQ ID NO: 43 or a sequence having 80%, 85%, 90%, or 95% identity therewith, and / or the light chain shown in SEQ ID NO: 44 or a sequence having 80%, 85%, 90%, or 95% identity therewith. In some instances, the heavy chain has the sequence shown in SEQ ID NO: 43, and the light chain has the sequence shown in SEQ ID NO: 44. In some instances, the anti-IL-33 antibody, its binding fragment, or variant thereof, which can be used in the methods of the present invention, comprises a heavy chain consisting of the sequence shown in SEQ ID NO: 43 and a light chain consisting of the sequence shown in SEQ ID NO: 44.

[0373] In some instances, the IL-33 signaling axis antagonist is antibody 33_640087_7B, as disclosed in WO2016 / 156440, which is incorporated herein by reference. 33_640087_7B is also known in the art as MEDI3506 or tozolizumab. Torazumab is a monoclonal antibody that binds to IL-33 and effectively and specifically blocks all forms of IL-33 to prevent its signaling. Torazumab is an example of an IL-33 signaling axis antagonist. Torazumab also inhibits the conversion of redIL-33 to its oxidized form (oxIL-33).

[0374] Tozolimab is an exemplary anti-IL-33 antibody having: (a) a heavy chain variable region comprising VHCDR1 having the sequence shown in SEQ ID NO: 37, VHCDR2 having the sequence shown in SEQ ID NO: 38, and VHCDR3 having the sequence shown in SEQ ID NO: 39; and (b) a light chain variable region comprising VLCDR1 having the sequence shown in SEQ ID NO: 40, VLCDR2 having the sequence shown in SEQ ID NO: 41, and VLCDR3 having the sequence shown in SEQ ID NO: 42.

[0375] Tozolizumab also comprises a VH domain having the amino acid sequence shown in SEQ ID NO: 1 and a VL domain having the amino acid sequence shown in SEQ ID NO: 19.

[0376] Tozolimab is an IgG1 antibody. The full-length heavy chain and light chain (including the IgG1 chain) sequences of tozolimab are shown in SEQ ID NO: 43 and 44, respectively.

[0377] Therefore, in some instances, the antibody is tozolizumab or its binding fragment or variant. Suitably, in some instances, the IL-33 signaling axis antagonist is torazumab or its binding fragment or variant. Therefore, suitably, in some instances, the IL-33 signaling axis antagonist is torazumab.

[0378] In some instances, IL-33 signaling axis antagonists are anti-IL-33 antibodies, their binding fragments, or antibody variants that have similar or identical pharmacokinetic (pK) characteristics to torezizumab in humans.

[0379] Specifically, the anti-IL-33 antibody, binding fragment, or antibody variant used in the methods of the present invention may have a half-life similar to or the same as tozolizumab in humans. When administered at a dose of 30 mg Q2W, the anti-IL-33 antibody, binding fragment, or antibody variant having a half-life similar to or the same as tozolizumab in humans may have a half-life of about 10 to about 20 days, about 12 to about 15 days, or about 12.7 days. When administered at a dose of 100 mg Q2W, the anti-IL-33 antibody, binding fragment, or antibody variant having a half-life similar to or the same as tozolizumab in humans may have a half-life of about 10 to about 20 days, about 12 to about 15 days, or about 13.2 days. When administered at a dose of 300 mg Q2W, anti-IL-33 antibodies, binding fragments, or antibody variants with a half-life similar to or the same as tozolizumab in humans may have a half-life of about 10 to about 20 days, about 12 to about 15 days, or about 14.8 days.

[0380] In some instances, IL-33 antibodies, their binding fragments, or variants can competitively inhibit the binding of IL-33 to tozolizumab (as described in WO2016 / 156440). WO2016 / 156440 discloses that tozolizumab binds to redIL-33 with a particularly high affinity. An antibody, its binding fragment, or variant is considered to competitively inhibit the binding of a reference antibody to a given epitope if it specifically binds to that epitope to a degree that blocks the binding of a reference antibody to that epitope. Competitive inhibition can be determined by any method known in the art, such as solid-phase assays, competitive ELISA assays, dissociation-enhanced lanthanide fluorescence immunoassay (DELFIA). ®(Perkin Elmer) and radioligand binding assays. For example, a technician can determine whether an antibody, its binding fragment, or variant competitively binds 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 technician can label tozolizumab with a donor fluorophore and mix samples of redIL-33 labeled with a fixed concentration of the receptor fluorophore. The fluorescence resonance energy transfer between the donor and receptor fluorophores within each sample can then be measured to determine the binding characteristics. To elucidate the competitive binding antibody molecule, a technician can first mix different concentrations of the test binding molecule with a fixed concentration of labeled tozolizumab antibody. When the mixture is incubated with labeled IL-33, a reduction in the FRET signal compared to a positive control containing only the labeled antibody will indicate competitive binding to IL-33. An antibody, its binding fragment, or variant may be considered to competitively inhibit the binding of a reference antibody to a given epitope by at least 90%, at least 80%, at least 70%, at least 60%, or at least 50%.

[0381] Pharmaceutical Composition

[0382] In some instances, an effective amount of tozolizumab or an IL-33 signaling axis antagonist is included in a pharmaceutical composition comprising one or more excipients. Suitably, tozolizumab or the IL-33 signaling axis antagonist is administered to the subject in the form of a pharmaceutical composition.

[0383] Suitablely, any reference herein to 'a tozolizumab or an IL-33 signaling axis antagonist' may also refer to a pharmaceutical composition comprising a tozolizumab or an IL-33 axis antagonist. Suitablely, a pharmaceutical composition may comprise one or more IL-33 signaling axis antagonists.

[0384] Pharmaceutical compositions can be formulated with suitable carriers, excipients, and other agents that provide suitable transfer, delivery, tolerability, etc. Many formulations can be found in formulations known to all medicinal chemists: Remington's Pharmaceutical Sciences, Mack Publishing Company, Easton, PA. Therefore, in addition to the active ingredient (i.e., the anti-IL-33 antibody), a pharmaceutical composition may also contain pharmaceutically acceptable excipients, carriers, buffers, stabilizers, or other substances well known to those skilled in the art. Such substances should be non-toxic and should not interfere with the efficacy of the active ingredient. The precise properties of the carrier or other substances will depend on the route of administration, which may be by injection, such as intravenous or subcutaneous injection.

[0385] For subcutaneous injection, the drug composition can be an aqueous solution that is pyrogen-free and has suitable pH, isotonicity, and stability.

[0386] The pharmaceutical composition may be a liquid formulation provided in the form of a container with a defined volume, including sealed and sterile plastic or glass vials, ampoules, and syringes, as well as in the form of a large-volume container such as a bottle. Suitably, in the methods described herein, the pharmaceutical composition is a liquid formulation.

[0387] Suitablely, the anti-IL-33 antibody may be present in the pharmaceutical composition at a concentration of 100 mg / ml to 200 mg / ml, more preferably 150 mg / ml. In particular, when using an antibody dose of 300 mg, the antibody (especially torazumab) may be provided in 2 ml of a 150 mg / ml liquid composition.

[0388] Suitablely, anti-IL-33 antibodies can be buffered to pH 5.2 to 5.7, most preferably 5.5 (e.g., ±0.1). This choice of pH imparts significant stability to the pharmaceutical composition.

[0389] It should be understood that references to "pharmaceuticalally acceptable excipients" include any excipients conventionally used in pharmaceutical compositions. Such excipients typically include one or more surfactants, inorganic or organic salts, stabilizers, diluents, solubilizers, reducing agents, antioxidants, chelating agents, preservatives, etc.

[0390] Suitably, the surfactant is present in the pharmaceutical composition in an amount of 0.001% to 0.1% (w / w). Suitably, the surfactant is polysorbate-80 (PS-80).

[0391] Anti-IL-33 (especially torazumab) can be provided in a pharmaceutical composition comprising L-histidine and / or L-histidine hydrochloride, L-arginine hydrochloride, and polysorbate 80. This composition may particularly contain 20 mM ± 10% L-histidine / L-histidine hydrochloride, for example, 20 mM ± 2.5%, 5%, or 7.5% L-histidine / L-histidine hydrochloride. That is, L-histidine / L-histidine hydrochloride may be present in the composition at concentrations of 18 mM-22 mM, 18.5 mM-21.5 mM, 19 mM-21 mM, or 19.5 mM-20.5 mM, suitably at a concentration of 20 mM.

[0392] The composition may specifically contain 220 mM ± 10% L-arginine hydrochloride, such as 220 mM ± 2.5%, 5%, or 7.5% L-arginine hydrochloride. For example, L-arginine hydrochloride may be present in the composition at a concentration of 220 mM, suitablely at a concentration of 200 mM-240 mM, 205 mM-235 mM, 210 mM-230 mM, or 215 mM-225 mM.

[0393] The composition may particularly contain 0.03% w / v ± 10% polysorbate 80, such as 0.03% w / v ± 2.5%, 5% or 7.5% polysorbate 80. For example, polysorbate 80 may be present in the composition at a concentration of 0.027%-0.033%, 0.028%-0.032% or 0.029%-0.031% w / v, suitably at a concentration of 0.03% w / v.

[0394] The pH of the composition can be 5.2-5.7, 5.3-5.6 or 5.4-5.5, preferably 5.5.

[0395] In a specific example, the pharmaceutical composition comprises 20 mM L-histidine / L-histidine hydrochloride, 220 mM L-arginine hydrochloride, and 0.03% polysorbate 80, and has a pH of 5.5. Suitably, the pharmaceutical composition also comprises 150 mg / ml toledizumab. When the composition contains 150 mg / ml toledizumab, a dose of 300 mg of antibody can be administered in 2 ml of the composition.

[0396] Application plan

[0397] This disclosure also relates to dosage regimens of IL-33 signaling axis antagonists, which are particularly effective in treating COPD.

[0398] A dosing regimen consists of one or more controlled-size doses administered over the entire therapeutic window. In the presence of more than one dose, the doses are separated by dosing intervals. Il-33 signaling axis antagonists are administered at a therapeutically effective amount. As defined above, an "effective amount" or "therapeutically effective amount" of a drug (e.g., a pharmaceutical formulation containing an anti-IL-33 antibody) refers to an effective amount that achieves the desired therapeutic or preventative outcome within the necessary dose and time period.

[0399] Therefore, in some instances, an IL-33 signaling axis antagonist or a pharmaceutical composition thereof is administered at a dose that achieves at least 80%, 85%, or 90% target binding in the lungs. In some instances, this dose achieves at least 90% target binding in the lungs. In some instances, this dose achieves at least 91%, 92%, 93%, or 94% target binding in the lungs. In some instances, target binding is achieved at the trough concentration.

[0400] Methods of administering an IL-33 signaling axis antagonist or a pharmaceutical composition thereof to a subject in need are well known or readily determined by those skilled in the art and are described below. The dosage of the IL-33 signaling axis antagonist may be expressed in weight. In some instances, the IL-33 signaling axis antagonist is administered at doses of about 400 mg to about 800 mg, about 450 mg to about 750 mg, about 500 mg to about 700 mg, about 510 mg to about 690 mg, about 520 mg to about 680 mg, about 530 mg to about 670 mg, about 540 mg to about 660 mg, about 550 mg to about 650 mg, about 560 mg to about 640 mg, about 570 mg to about 630 mg, about 580 mg to about 620 mg, about 590 mg to about 630 mg, or about 600 mg. In some instances, the dose is 600 mg. In some instances, IL-33 signaling axis antagonists are formulated for subcutaneous injection at 150 mg / mL, such that a 600 mg dose of the IL-33 signaling axis antagonist is administered in 4 mL of therapeutic volume. The 600 mg dose of the IL-33 signaling axis antagonist can be administered as two simultaneous 300 mg doses. As used herein, a “simultaneous” dose means a dose administered simultaneously or sequentially with no or only the shortest possible time interval between them (e.g., less than 1 hour, less than 30 minutes, less than 15 minutes, less than 5 minutes).

[0401] In some instances, IL-33 signaling axis antagonists are administered at doses of about 200 mg to about 400 mg, about 250 mg to about 350 mg, about 260 mg to about 340 mg, about 270 mg to about 330 mg, about 280 mg to about 320 mg, about 290 mg to about 310 mg, about 295 mg to about 305 mg, or about 300 mg.

[0402] In some instances, the dose is 300 mg. In some instances, the IL-33 signaling axis antagonist is formulated for subcutaneous injection at 150 mg / mL, such that a 300 mg dose is administered in 2 mL of therapeutic agent. In some instances, a 300 mg dose of the IL-33 signaling axis antagonist may be administered in two simultaneous 150 mg doses. As used herein, a “simultaneous” dose means doses administered simultaneously or sequentially with no or only the shortest possible time interval between them (e.g., less than 1 hour, less than 30 minutes, less than 15 minutes, less than 5 minutes).

[0403] In some instances, the dose is 150 mg. In some instances, the IL-33 signaling axis antagonist is formulated for subcutaneous injection at a dose of 150 mg / mL, such that the 150 mg dose is administered in 1 mL of therapeutic agent.

[0404] The dosage of IL-33 signaling axis antagonists can be expressed as the plasma drug concentration provided by the dose, i.e., manipulating the amount of the active compound to provide a specific level of plasma drug concentration. Technicians can control the subject's plasma concentration by varying the amount of antibody or variant administered, bioavailability, or time / frequency. Since plasma concentrations vary over time as the drug is absorbed and cleared, they can be expressed in various standardized ways—e.g., as maximum, minimum (trough), or changes over time.

[0405] In some instances, dosages are selected to provide C from approximately 20 µg / mL to approximately 50 µg / mL, approximately 25 µg / mL to approximately 45 µg / mL, approximately 30 µg / mL to approximately 40 µg / mL, approximately 35 µg / mL to approximately 40 µg / mL, or approximately 37 µg / mL. max,ss (The maximum concentration observed at steady state). In some instances, C was observed during the dosing period. maz.ss In this article, "dosing period" refers to the time between two consecutive doses.

[0406] Serum concentrations of IL-33 signaling axis antagonists can be measured using appropriate assays to capture and detect them from biological samples (e.g., blood) against antidote antibody reagents (and thus used to determine C). max.ss In some instances, the assay may use an anti-IgG1 capture mAb and a stabilized torazolimumab labeled with a detectable biomarker (e.g.). The detectable biomarker can be quantified to determine the concentration of torazolimumab. In some instances, the torazolimumab antigen (IL-33) can be stabilized in a reducing form, for example, by mutating one or more cysteine ​​residues to serine. Assays and platforms suitable for detecting serum biomarkers are well known to those skilled in the art.

[0407] In some instances, dosages are selected to provide approximately 10 µg / mL to approximately 35 µg / mL, approximately 15 µg / mL to approximately 30 µg / mL, approximately 15 µg / mL to approximately 30 µg / mL, approximately 15 µg / mL to approximately 25 µg / mL, approximately 15 µg / mL to approximately 20 µg / mL, or approximately 18.6 µg / mL of C. max,ss .

[0408] In some instances, IL-33 signaling axis antagonists are administered at a selected dose to provide the area under the plasma concentration-time curve (AUC) throughout the dosing period.

[0409] In some instances, the dosage was chosen to deliver approximately 400 µg over the dosing period. Daily / mL to approximately 800µg Daily / mL, approximately 500µg Daily / mL to approximately 750µg Daily / mL, approximately 600µg Daily / mL to approximately 700µg Daily / mL, approximately 600µg Daily / mL to approximately 650µg Daily / mL, approximately 600µg Daily / mL to approximately 620µg Daily / mL, approximately 610µg Daily / mL to approximately 620µg Daily / mL or approximately 616µg AUC per day / mL.

[0410] In some cases, a dosage is selected to provide approximately 200 µg over the dosing period. Daily / mL to approximately 515µg Daily / mL, approximately 250µg Daily / mL to approximately 500µg Daily / mL, approximately 300µg Daily / mL to approximately 450µg Daily / mL, approximately 300µg Daily / mL to approximately 350µg Daily / mL or approximately 323µg AUC per day / mL.

[0411] In some cases, a dosage is selected to provide approximately 100 µg over the dosing period. Daily / mL to approximately 300µg Daily / mL, approximately 100µg Daily / mL to approximately 250µg Daily / mL, approximately 100µg Daily / mL to approximately 200µg Daily / mL, approximately 150µg Daily / mL to approximately 200µg Daily / mL or approximately 161.5µg AUC per day / mL.

[0412] IL-33 signaling axis antagonists are administered in multiple doses separated by dosing intervals. In some instances, the dosing intervals are 2 weeks (14 days), 3 weeks (21 days), 4 weeks (28 days), or 5 weeks (35 days). In some instances, the dosing interval is 4 weeks (28 days). In some instances, the dosing interval is approximately 2 weeks (i.e., 14 ± 4 days). In some instances, the dosing interval is approximately 4 weeks (i.e., 28 ± 4 days). In some instances, the dosing interval is approximately 8 weeks (i.e., 56 ± 4 days).

[0413] In some cases, a dose may be administered over multiple days, for example, as two or more sub-dose. As used herein, a “sub-dose” is a fraction of a therapeutic dose such that the total amount of therapeutic agent administered at a sub-dose is equal to the amount of therapeutic agent administered at the full dose. Any fraction may be used, such that two, three, four, five, or more sub-dose constitute a single dose. In some cases, a dose may be administered as two or more sub-dose separated by time periods of 1, 2, 3, 4, 5, or 6 days. In some cases, a dose may be administered as two or more sub-dose separated by time periods of 1, 2, or 3 weeks. Sub-dose may be administered over two, three, four, or more consecutive days. Sub-dose comprising a dose may be of equal or different sizes, as long as their sum equals the dose.

[0414] Therefore, as used herein, a 600 mg dose with a 4-week dosing window (Q4W) can replace weekly administration of 150 mg (Q1W), 2-week administration of 300 mg (Q2W), or 3-week administration of 450 mg (Q3W), all of which provide a dosing regimen equivalent to 600 mg every 4 weeks. Thus, in some instances, the dose is approximately 300 mg Q2W. A 300 mg dose with a 4-week dosing window (Q4W) can replace 2-week administration of 150 mg (Q2W) or weekly administration of 75 mg (Q1W). A 300 mg dose with an 8-week dosing window (Q8W) can replace 4-week administration of 150 mg (Q4W), 2-week administration of 75 mg (Q2W), or weekly administration of 37.5 mg (Q1W).

[0415] In some instances, subjects were administered an IL-33 signaling axis antagonist or a pharmaceutical composition thereof every 2 weeks (Q2W), 4 weeks (Q4W), 5 weeks (Q5W), 6 weeks (Q6W), 7 weeks (Q7W), or 8 weeks (Q8W).

[0416] In some instances, an IL-33 signaling axis antagonist or a pharmaceutical composition thereof is administered at approximately 300 mg every 2 weeks. In some instances, an IL-33 signaling axis antagonist or a pharmaceutical composition thereof is administered at approximately 600 mg every 4 weeks. In some instances, an IL-33 signaling axis antagonist or a pharmaceutical composition thereof is administered at approximately 300 mg every 4 weeks. In some instances, an IL-33 signaling axis antagonist or a pharmaceutical composition thereof is administered at approximately 300 mg every 8 weeks.

[0417] In some instances, the effective dose of an IL-33 signaling axis antagonist is a dose between 300 mg and 600 mg. The effective dose of an IL-33 signaling axis antagonist can be a dose of torazumab between 300 mg and 600 mg.

[0418] In some instances, an IL-33 signaling axis antagonist or a pharmaceutical composition thereof was administered to subjects at a dose of 600 mg every 4 weeks (Q4W). In some instances, tozolizumab or a pharmaceutical composition thereof was administered to subjects at a dose of 600 mg every 4 weeks (Q4W). In some instances, an IL-33 signaling axis antagonist or a pharmaceutical composition thereof was administered to subjects at a dose of 300 mg every 2 weeks (Q2W). In some instances, tozolizumab or a pharmaceutical composition thereof was administered to subjects at a dose of 300 mg every 2 weeks (Q2W).

[0419] In some instances, an IL-33 signaling axis antagonist or a pharmaceutical composition thereof was administered to subjects at a dose of 300 mg every 4 weeks (Q4W). In some instances, toledizumab or a pharmaceutical composition thereof was administered to subjects at a dose of 300 mg every 4 weeks (Q4W). In some instances, an IL-33 signaling axis antagonist or a pharmaceutical composition thereof was administered to subjects at a dose of 300 mg every 8 weeks (Q8W). In some instances, toledizumab or a pharmaceutical composition thereof was administered to subjects at a dose of 300 mg every 8 weeks (Q8W).

[0420] When dosing intervals are expressed in weeks, a margin of error is permissible, allowing a week to be expressed as 7 days ± 1 day. In some instances, a week may be expressed as 7 days ± 0.5 days, 7 days ± 0.25 days, or exactly 7 days. When the dosing interval spans multiple weeks, the margin of error for each week can be combined. For example, in some instances, the dosing interval is 4 weeks ± 4 days. In some instances, the dosing interval is 4 weeks ± 3 days. In some instances, the dosing interval is 4 weeks ± 2 days. In some instances, the dosing interval is 4 weeks ± 1 day. In some instances, the dosing interval is exactly 4 weeks. In some instances, the dosing interval is 8 weeks ± 4 days. In some instances, the dosing interval is 8 weeks ± 3 days. In some instances, the dosing interval is 8 weeks ± 2 days. In some instances, the dosing interval is 8 weeks ± 1 day. In some instances, the dosing interval is exactly 8 weeks.

[0421] In some instances, IL-33 signaling axis antagonists or pharmaceutical compositions thereof are administered during a “treatment window,” which, as used herein, refers to the period from the administration of the first dose until the administration of the final dose of the anti-IL-33 antibody or an antibody variant thereof. The date of administration of the first dose is referred to as “day 1” of “week 0,” week 1 begins 7 days later, week 2 begins 7 days later, and so on. In some instances, the treatment window is 12 weeks long (i.e., from week 0 to week 12). In some instances, the treatment window is 16 weeks long (i.e., from week 0 to week 15), and the dosing interval is 4 weeks, resulting in a total of 4 doses administered (at weeks 0, 4, 8, and 12, respectively). In some instances, the treatment window is 12 weeks long and the dosing interval is 4 weeks, so that the dose is administered on day 1 (week 0), day 29±4 (week 4), day 57±4 (week 8), and day 85±4 (week 12).

[0422] In some instances, the treatment window is 12, 14, 16, 18, 20, 22, 24, 26, 28, 30, 32, 34, 36, 38, 40, 42, 44, 46, 48, 50, 52 weeks or longer. In some instances, the treatment window is 52 weeks or longer. In some instances, the treatment window is 48 weeks or longer. In one instance, the treatment window is 24 weeks. In one instance, the treatment window is 24 weeks long, and the dosing interval is 4 weeks.

[0423] In some instances, the IL-33 signaling axis antagonist or a pharmaceutical composition thereof was administered subcutaneously to the subject. In some instances, the IL-33 signaling axis antagonist or a pharmaceutical composition thereof was administered to the subject by injection. In some instances, the IL-33 signaling axis antagonist or a pharmaceutical composition thereof was administered to the subject by subcutaneous injection.

[0424] In some instances, particularly in those where the IL-33 signaling axis antagonist is an anti-IL-33 antibody (such as toretinoin), the antibody may be provided as a pharmaceutical composition comprising L-histidine and / or L-histidine hydrochloride, L-arginine hydrochloride, and polysorbate 80. This composition may particularly comprise 20 mM ± 10% L-histidine / L-histidine hydrochloride, for example, 20 mM ± 2.5%, 5%, or 7.5% L-histidine / L-histidine hydrochloride. That is, L-histidine / L-histidine hydrochloride may be present in the composition at concentrations of 18 mM-22 mM, 18.5 mM-21.5 mM, 19 mM-21 mM, or 19.5 mM-20.5 mM, suitably at a concentration of 20 mM.

[0425] In some instances, the composition comprises 220 mM ± 10% L-arginine hydrochloride, such as 220 mM ± 2.5%, 5%, or 7.5% L-arginine hydrochloride. For example, L-arginine hydrochloride may be present in the composition at a concentration of 220 mM, such as 200 mM-240 mM, 205 mM-235 mM, 210 mM-230 mM, or 215 mM-225 mM.

[0426] In some instances, the composition comprises 0.03% w / v ± 10% polysorbate 80, such as 0.03% w / v ± 2.5%, 5%, or 7.5% polysorbate 80. For example, polysorbate 80 may be present in the composition at a concentration of 0.027%-0.033%, 0.028%-0.032%, or 0.029%-0.031% w / v, suitably at a concentration of 0.03% w / v.

[0427] In some instances, the pH of the composition may be 5.2-5.7, 5.3-5.6, or 5.4-5.5, suitably 5.5.

[0428] In one example, the pharmaceutical composition comprises 20 mM L-histidine / L-histidine hydrochloride, 220 mM L-arginine hydrochloride, and 0.03% polysorbate 80, and has a pH of 5.5. Suitably, the pharmaceutical composition also comprises 150 mg / ml toretzimab.

[0429] The following aspects are not claims, but rather numbered examples applicable to this disclosure:

[0430] Example

[0431] Example 1 — A phase II, randomized, double-blind, placebo-controlled study to evaluate MEDI3506 in patients with moderate to severe illness. Efficacy, safety, and tolerability in participants with severe chronic obstructive pulmonary disease and chronic bronchitis (FRONTIER 4)

[0432] This embodiment describes a phase 2, randomized, double-blind, placebo-controlled, parallel-group, proof-of-concept study to evaluate the efficacy, safety, pharmacokinetics, and immunogenicity of MEDI3506 (torezizumab) in adult subjects with moderate to severe COPD receiving standard of care (dual or triple therapy) as maintenance therapy. Participants had a history of ≥1 moderate or severe acute exacerbation and moderate to severe chronic bronchitis with active sputum and cough symptoms within the previous 12 months while receiving stable background therapy. The intervention lasted for 28 weeks (7 doses).

[0433] Tozzolizumab (also referred to herein as 33_640087_7B) is a human IgG1 mAb that binds to human IL-33. Tozzolizumab binds to both full-length and mature forms of human IL-33 with exceptionally high affinity and blocks IL-33 from binding to both the soluble form of ST2 (sST2) and the membrane-bound form of ST2 (also referred to as IL-1RL1) receptor.

[0434] Several clinical and non-clinical studies have indicated that the IL-33 / ST2 signaling axis plays a crucial role in the pathogenesis of COPD. Therefore, blocking this signaling pathway may have therapeutic benefits in COPD.

[0435] Participants must receive a stable dose of dual therapy (ICS+LABA or LABA+LAMA) or triple therapy (ICS+LABA+LAMA) for ≥ 3 months prior to enrollment and should maintain this regimen during the study. Maintenance COPD treatment should remain unchanged following previous exacerbations prior to enrollment.

[0436] Approximately 140 participants will be randomly assigned to either the treatment group or a volume-matched placebo group (collectively, the “Investigation Product” or “IP”) to 600 mg torrezimab SC (20 mM L-histidine / L-histidine hydrochloride, 220 mM L-arginine hydrochloride, 0.03% (w / v) polysorbate 80, pH 5.5); the overall ratio will be 1:1, administered 7 times every 4 weeks (Q4W), with the last dose at week 24.

[0437] Participants will be enrolled in this study after a screening / preparation period of at least 4 weeks, an intervention period (or “treatment window”) of 24 weeks (during which they will receive 7 doses of SC Q4W), an additional period of 4 weeks, and a follow-up period of 8 weeks.

[0438] The main estimates are as follows: For the ITT (Intended Treatment) population, repeated measures mixed-effects analysis using a covariance model will be used to estimate the mean change from baseline in pre-BD FEV1 at week 12 (torezizumab-placebo). This will include all available data up to and including all visits up to week 12, regardless of whether participants interrupted the study intervention or received remission therapy. The model will include fixed effects of baseline, eosinophil layer, background drug layer, visits, study intervention, and baseline / visit interaction and study intervention / visit interaction. An unstructured covariance matrix will be used to describe the correlations between participants' observations across visits.

[0439] The primary endpoints, along with key secondary or exploratory endpoints, are described in Table 2 below:

[0440] Table 2: Study Endpoints

[0441]

[0442]

[0443] AE = Adverse Event; AECOPD = Acute Exacerbation of Chronic Obstructive Pulmonary Disease; AO = Air Wave Oscillation Method; BCSS = Dyspnea, Cough, and Sputum Scale; BD = Bronchodilator; CASA-Q = Cough and Sputum Assessment Questionnaire; COPD = Chronic Obstructive Pulmonary Disease; COPDCompEx = COPD Complex Exacerbation; E-RS: COPD = Assessment of Respiratory Symptoms of COPD; FEV1 = Forced Expiratory Volume in One Second; FVC = Forced Vital Capacity; IL = Interleukin; SGRQ = St. George's Respiratory Questionnaire; sST2 = Soluble Inhibition of Tumorigenicity 2; ST2 = Inhibition of Tumorigenicity 2.

[0444] research group

[0445] Each participant should meet all inclusion criteria in order to be assigned / randomized to the study intervention:

[0446] Inclusion criteria

[0447] 1. Participants must be between 40 and 75 years old (inclusive).

[0448] 2. Participants must be current smokers or former smokers with a smoking history of ≥10 pack-years. Pack-year is calculated as the average number of cigarettes smoked per day × number of years / 20.

[0449] 3. Participants who received pneumococcal and influenza vaccines in a timely manner according to local treatment guidelines.

[0450] 4. Participants with a history of COPD of at least 1 year, as recorded.

[0451] 5. Participants selected for screening who have a post-BD FEV1 / FVC <0.70, a post-BD FEV1 >30%, and a predicted normal value <80%. Centralized vital capacity measurement will be used for this criterion assessment.

[0452] 6. Participants with a confirmed history of chronic bronchitis, defined as having cough and sputum on most days for at least 2 years prior to screening, lasting ≥3 months / year.

[0453] 7. Participants who were assessed within 14 days prior to Subject Visit (SV) 3 and had a mean BCSS score ≥2 for cough and a mean BCSS score ≥2 for sputum.

[0454] 8. Participants with a stable regimen of dual or triple therapy recorded for ≥3 months prior to enrollment; treatment should not have changed after a previous exacerbation prior to enrollment. Dual therapy consists of ICS+LABA or LABA+LAMA, and triple therapy consists of ICS+LABA+LAMA. Both dual and triple therapies can be administered via a single inhaler of a fixed-dose combination inhaler, but not via nebulizer.

[0455] 9. Participants who have a record of having ≥1 episode of moderate or severe AECOPD within the 12 months prior to screening and requiring systemic corticosteroids and / or antibiotics for at least 3 days (or 1 injection of a long-acting formulation) or hospitalization for AECOPD.

[0456] 10. Participants whose clinical condition was stable and who had no COPD exacerbation within one month prior to screening and day 1.

[0457] 11. Body mass index (BMI) of 19 kg / m² 2 Up to 35kg / m 2 Within the range (including endpoints).

[0458] Randomization and Dosing

[0459] A sample size of 140 participants (70 participants in each group) will provide 80% capability to detect the difference in mean change from baseline in 90 mL of FEV1 at week 12 at a statistically significant one-sided 10% level (assumed SD of 250 mL) between the two randomization groups. To allow for 2% of participants who would not qualify for the initial analysis, approximately 144 participants were randomized in the study (72 participants in each group).

[0460] Randomization will be performed at study visit 3 (SV3 - Day 1). Participants who continue to meet eligibility criteria will be randomly assigned to the treatment groups as described above. Blood and urine samples will be collected, and efficacy and safety assessments will be conducted to establish a baseline. Generally, the last measurement prior to the first IP injection will be used as the baseline measurement for efficacy and safety endpoints. The absolute and percentage changes from baseline will be derived as follows: Absolute change from baseline outcome variable = (randomized value - baseline value). Percentage change from baseline = ((randomized value - baseline value) / baseline value) × 100. For any variable that has undergone logarithmic transformation, the change from baseline calculated and summarized on a logarithmic scale will be inversely transformed and presented as the “baseline scaling ratio” (BSR). The percentage change will then be calculated as (BSR-1) x 100.

[0461] Randomization will be stratified based on baseline blood eosinophil count (<300 cells / μL vs. ≥300 cells / μL) and background medications (including ICS vs. excluding ICS).

[0462] The first investigational product (IP) administration will be performed at study visit 3 (day 1) and will include administering the first dose of the investigational product during the treatment window. Administration of 600 mg MEDI3506 will require 2 × 2 mL SC injections per dose. The injection volume in the placebo group will be matched to that in the MEDI3506 group.

[0463] During study visit 4 (day 2), participants will return for an assessment to understand their compliance with and safety assessment of the self-assessment efficacy reporting procedure.

[0464] The second administration of the investigational product will be performed during the 6th study visit (day 29±3).

[0465] The third administration of the investigational product will be performed on study visit 7 (day 57±3).

[0466] The fourth administration of the study product will be performed during study visit 8 (day 85±3).

[0467] The fifth administration of the study product will be performed on study visit 9 (day 113±3).

[0468] The sixth administration of the investigational product will be performed on study visit 10 (day 141±3).

[0469] The seventh and final administration of the study product will be performed on study visit 11 (day 169±3).

[0470] Whenever data is summarized over time, the study day will be calculated based on the actual evaluation date. All data will be summarized relative to the date of the first IP application.

[0471] end

[0472] If assessed at study visit 10 (day 113±4), the primary endpoint visit was conducted at week 12.

[0473] The primary endpoint was the improvement in FEV1 from baseline to week 12 before clinical BD. Forced expiratory volume in one second (FEV1) is a validated and clinically important endpoint in COPD studies and has been widely used in trials supporting addition therapy registration as current standard of care (dual / triple therapy) in similar chronic bronchitis populations (Martinez et al., 2015).

[0474] Based on available data, the expected improvement in FEV1 in the sample size assay was anticipated to be achieved at week 12. However, while FEV1 improvement was considered significant, it was insufficient to address unmet medical needs in COPD. To assess secondary endpoints of COPDCompEx, treatment was continued after primary endpoint data collection to gather further event data. The extended intervention duration also allowed for exploratory assessment of FEV1 treatment efficacy beyond week 12.

[0475] The secondary endpoint is COPDCompEx at week 28. Changes in pre-clinical BD FEV1 will also be assessed at week 28.

[0476] Secondary endpoints (changes from baseline to week 28 in terms of FEV1 and FVC before and after BD) will be analyzed by the degree of emphysema (<10% vs. ≥10%).

[0477] The exploratory endpoint (based on the time from baseline to week 28 to the first COPDCompEx event and the change in BCSS cough and sputum scores from baseline to week 28) will be analyzed by the degree of emphysema (<10% vs. ≥10%).

[0478] Subgroup analyses will also be performed on the following: baseline blood eosinophil count (<150 cells / μL vs ≥150 cells / μL), smoking status at baseline (current smokers vs former smokers), baseline BCSS based on 14-day mean (<median vs ≥median), baseline total SGRQ score (<median vs ≥median), and degree of emphysema (<10% vs ≥10%).

[0479] The change from baseline in pre-BD FEV1 measured clinically at week 12 was the primary endpoint of this study. The change from baseline in pre-BD FVC measured clinically and the FEV1 / FVC ratio were exploratory endpoints. Lung function (FEV1 and FVC) will be measured using standard equipment via spirometry. The FEV1 / FVC ratio will be determined using a spirometry device.

[0480] The change from baseline in 4-week mean pre-BD FEV1 measured using a home spirometry device was the exploratory endpoint of the study. Additionally, the change from baseline in 4-week mean PEF measured at home was analyzed. During the intervention period, participants were required to monitor their lung function at home using a home spirometry device to record FEV1 and PEF daily. The four-week mean pre-BD FEV1 and PEF were calculated as the average of the values ​​collected during the assessment period.

[0481] COPDCompEx is a composite endpoint for COPD deterioration. COPDCompEx combines deterioration with events defined from participants' electronic diaries and PEFs, as defined in the relevant sections above. Satisfaction of objective deterioration criteria will be calculated for each (individual) diary variable for thresholds and slopes, as explained in the relevant sections above.

[0482] The time to the first COPD CompEx event is a secondary endpoint of the study. The time to the first COPD exacerbation in the study will be calculated as the start date of the first COPD exacerbation minus the date of the first IP administration plus one: [start date of the first event or review date of the first dose of the study intervention + 1]. The date of the first event will be the first start date of the COPD CompEx event as defined above. For participants who did not experience a COPD CompEx event during treatment, the review date will be the date of the last dose plus the minimum of 28 days, or, if earlier, the last day of the electronic diary entry.

[0483] When defining the risk time for COPDCompEx event ratios, the time during the event and the 7 days following each event will not be considered.

[0484] At weeks 12 and 28, the time to first moderate or severe AECOPD, the annualized rate of moderate or severe COPD exacerbations, and the proportion of participants with ≥1 COPD exacerbation were exploratory endpoints of this study. AECOPD will be defined as a change in a participant's usual COPD symptoms that lasts for 2 days or more, exceeds normal daily variation, is acute, and may require regular medication. Symptom changes must include at least one major COPD symptom and at least one other major or minor symptom from the following list: • Major COPD symptoms: abnormal breathing, sputum volume and color; minor COPD symptoms: cough, wheezing, sore throat, cold symptoms (runny nose or nasal congestion), chest tightness, and fever, without other cause. AECOPD will be considered severe if it results in: • COPD-related hospitalization; or • COPD-related death.

[0485] The time to first moderate or severe AECOPD will be calculated based on the time from baseline to 4 weeks after the last dose (week 28) and to the end of the follow-up period (week 36) during the intervention period. For participants who did not experience moderate or severe AECOPD during the study period, the time to first moderate or severe AECOPD will be reviewed at the last visit date of the intervention (for the week 28 analysis), the last follow-up visit date (for the week 36 analysis), or an early termination date of the study (for participants who terminated before week 28 or 36).

[0486] The change in mean BCSS© score from baseline to week 12 over the first 4 weeks was a secondary endpoint of this study. BCSS© is a 3-item daily diary that assesses the severity of three symptoms: dyspnea, sputum production, and cough, each assessed using a 5-point scale known in the art. Item scores are reported as domain scores and summed to produce a total score. Higher scores in each domain, and therefore a higher total score, indicate more severe symptoms. BCSS is captured nightly via an electronic diary. The 4-week mean BCSS score is calculated as the sum of all non-missing daily scores over the 28-day assessment period divided by the number of non-missing daily scores. If there are at least 14 completed days during the 28-day assessment period, the 4-week mean is calculated, where one day = evening + the following morning.

[0487] The SGRQ is a 50-item PRO tool developed to measure the health status of patients with airway obstructive disease (Jones et al., 1991). The SGRQ yields one total score and three domain scores (symptoms, activities, and impact). The total score indicates the impact of the disease on overall health status. This total score is expressed as a percentage of overall impairment, with 100 representing the worst possible health status and 0 representing the best possible health status. Similarly, domain scores range from 0 to 100, with higher scores indicating greater impairment. Specific details regarding the scoring algorithm are provided by the developers in the user manual (Jones and Forde, 2009). The SGRQ will be performed using an electronic diary and will use a 4-week recall version. The key outcome variable for the SGRQ will be the change in the total SGRQ score from baseline to week 12, but changes in the total score from baseline to weeks 4 and 28 will also be derived. Changes in domain scores from baseline to weeks 4, 12, and 28 will also be derived.

[0488] The degree of emphysema will be assessed and classified based on baseline and week 28 chest CT scans, as follows:

[0489] <5% emphysema (visual score = 1)

[0490] Emphysema ≥5% to <10% (Visual score = 2)

[0491] Emphysema ≥10% to <20% (Visual score = 3)

[0492] ≥20% emphysema (visual score = 4)

[0493] Blood samples were collected from subjects to assess biomarkers related to disease pathology and / or the mechanism of action of MEDI3506. Blood eosinophil counts were collected as part of laboratory assessments, and whole blood samples were also collected for hematological and eosinophilic evaluation. Eosinophil counts were determined microscopically per 100 cells.

[0494] result

[0495] Although there was no statistically significant improvement in pre-BD FEV1 at week 12 in the toricizumab 600 mg group compared to the placebo group, a numerical improvement of 24 mL was observed (Table 3 and Figure 1 The summaries of pre-BD FEV1 (L) from baseline to week 12 are presented in Table 4.

[0496] Table 3: Changes in FEV1 (L) (as clinically measured) before BD from baseline to week 12 (ITT population)

[0497]

[0498] Results were based on repeated measures mixed-effects model (MMRM) analysis. Fixed factors in the model included log-transformed eosinophil count, background drug layer, geographic region, number of exacerbations during the first 12 months, visits, study intervention, and the interaction between baseline and study intervention visits. Baseline values ​​were considered covariates. In-subject visits were considered repeated measures. Abbreviation: BD bronchodilator. CI confidence interval. FEV1 (forced expiratory volume in one second). LS (least squared mean). Repeated measures mixed-effects analysis of the MMRM covariance model. N (number of subjects in the treatment group). n (number of subjects in the analysis). SE (standard error).

[0499] An unstructured covariance matrix was used to describe the correlation between observations of subjects between visits, and Kenward-Roger correction was used to generate an approximation of the degrees of freedom in the model. The significance of treatment effect was tested at a 10% one-sided significance level.

[0500] Table 4: Summary of pre-clinical BD FEV1(L) from baseline to week 12 (ITT population)

[0501]

[0502] Additional MMRM analyses of the primary endpoint using data from visits up to and including week 36 were largely consistent with the primary analysis. Nominally significant differences between the toretzimab 600 mg group and placebo were observed only at week 24 (mean difference in LS 0.044 L [80% CI: 0.003, 0.086] p = 0.086) and week 32 (mean difference in LS 0.055 L [80% CI: 0.012, 0.098] p = 0.051).

[0503] from Figure 1 In the second week, clear separation of the lines can be seen, which remains throughout the treatment period and also during follow-up.

[0504] Figure 2 The changes in pre-BD FEV1 from baseline to week 12, measured clinically using the mean LS, are shown by subgroup. Participants receiving toricumab 600 mg had a greater numerical improvement in clinical pre-BD FEV1 at week 12 compared to placebo, due to higher BCSS (85 mL) or SGRQ (77 mL) scores, higher ICS use (56 mL), baseline eosinophils ≥150 cells / μL (82 mL), or ≥2 previous COPD exacerbations within the previous 12 months (69 mL). Toricumab 600 mg showed a similar numerical improvement in clinical pre-BD FEV1 in both former and current smokers. Figure 2 ).

[0505] The changes in FEV1 from baseline after BD at weeks 12 and 28 are summarized in Table 5 and Figure 3 In the mean LS difference of 0.067 L [80% CI: 0.017, 0.116] and at week 28 (mean LS difference of 0.070 L [80% CI: 0.020, 0.120]), a trend toward improvement was observed, favoring torazumab 600 mg compared to placebo. This difference can be observed in... Figure 3 This can be seen in the separation of lines.

[0506] Table 5: Changes in FEV1 (L) (as clinically measured) from baseline to week 28 after BD treatment, MMRM (ITT) group)

[0507]

[0508] Results were based on MMRM analysis. The fixed factors for the model were log-transformed eosinophil count, background drug layer, geographic region, number of exacerbations during the first 12 months, visits, study intervention, and baseline. Visits and research interventions Visit interaction. Baseline values ​​were considered covariates. Visits within subjects were considered repeated measures. Unstructured covariance matrices were used to describe the correlations between subject observations across visits, and Kenward-Roger correction was used to generate approximations of degrees of freedom in the model. The significance of treatment effects was tested at a 10% one-sided significance level. Abbreviation: BD bronchodilator. CI confidence interval. FEV1 (forced expiratory volume in one second). LS (least squared mean). Repeated measures mixed-effects analysis of the MMRM covariance model. N (number of subjects in the treatment group). N (number of subjects in the analysis). SE standard error.

[0509] For the secondary endpoint of change in pre-BD FVC from baseline to week 28 based on emphysema severity (<10% and ≥10%), a clinically significant improvement was observed at week 28 with torrezizumab 600 mg compared to placebo in participants with baseline emphysema severity ≥10% (mean difference LS 0.191 L [80% CI: 0.047, 0.335]). No statistically or clinically significant difference was observed in participants with emphysema severity <10%.

[0510] Regarding the change in FVC from baseline to week 28 after BD according to the degree of emphysema (<10% and ≥10%), for participants with emphysema ≥10%, clinically and statistically significant differences favorable to torezizumab were observed at both week 12 (mean difference in LS 0.131 L [80% CI: 0.018, 0.244]) and week 28 (mean difference in LS 0.164 L [80% CI: 0.029, 0.300]). For participants with emphysema <10%, no statistically or clinically significant improvement was observed.

[0511] Table 6 shows the results of the exploratory endpoint of the change in FVC from baseline to week 36 before BD.

[0512] Table 6: Changes in FVC (L) (if clinically measured) from baseline to week 36 in pre-BD treatment comparisons, MMRM (ITT group) body)

[0513]

[0514] Results were based on MMRM analysis. The fixed factors for the model were log-transformed eosinophil count, background drug layer, geographic region, number of exacerbations during the first 12 months, visits, study intervention, and baseline. Visits and research interventions Visit interaction. Baseline values ​​were considered covariates. Visits within subjects were considered repeated measures. Unstructured covariance matrices were used to describe the correlations between subject observations across visits, and Kenward-Roger correction was used to generate approximations of degrees of freedom in the model. The significance of treatment effects was tested at a 10% one-sided significance level. Abbreviation: BD bronchodilator. CI confidence interval. FVC forced vital capacity. LS mean (least squared mean). Repeated measures mixed effects analysis of the MMRM covariance model. n: number of subjects in the analysis. SE standard error.

[0515] Compared to the placebo group, there was a consistent numerical trend favoring the toretinoin 600 mg group. The lines clearly separated from week 2. Figure 4 ).

[0516] Compared to placebo (52.9%), fewer participants experienced COPD CompEx events in the toricumab group (41.8%). Compared to the placebo group, there was no statistically significant difference in time to first CompEx event between the toricumab and placebo groups based on the time from baseline to week 28 (Table 7); however, the hazard ratio (HR) indicated a 21% reduction in the risk value of CompEx events at any time point. The Kaplan-Meier curves for time to first COPD CompEx event are shown in [Table 7]. Figure 5 The study showed that there were some line separations that favored the torazumab 600mg group throughout the study, which is clinically significant.

[0517] Table 7: Time to first COPD CompEx event based on the time period from baseline to 4 weeks (week 28) after the last dose. Time (Number of Days) (ITT Group)

[0518]

[0519] Subgroups - based on smoking status and eosinophil count

[0520] For subgroup analyses of time to first CompEx event based on smoking status, from baseline to week 28, compared with placebo, torrezimab 600 mg had a significantly lower risk of CompEx for former smokers (hazard ratio 0.72, 80% CI (0.48, 1.07) than for current smokers (hazard ratio 0.86, 80% CI (0.47, 1.56)) (see [link to relevant documentation]). Figure 6A and Figure 6B (and Table 8).

[0521] Table 8: Time to first COPD CompEx event (days) - Cox regression analysis by subgroup (ITT population)

[0522]

[0523] [a] The number (%) of subjects who had the event in the analysis (n). Cox regression models were used to investigate intervention, log-transformed eosinophil count, background drug layer, geographic region, number of exacerbations during the first 12 months, subgroups, and subgroups. Intervention interactions were studied as covariates, and hazard ratios and their 80% confidence intervals (CIs) were assessed. If eos were subgroups, log-transformed eos values ​​were not included as covariates. Time to the first COPD CompEx event (in days) was calculated as (minimum (review date, start date of the first event) - randomization date) + 1. Abbreviation: CI confidence interval. n: Number of participants in the analysis. This table is based on events occurring during the treatment period (i.e., from baseline to the last dose date + 28 days).

[0524] For subgroup analyses of time to the first CompEx event based on blood eosinophil count (150 cells / μL or ≥150 cells / μL), based on the time period from baseline to week 28, the reduction in the risk of CompEx with toledizumab 600 mg compared to placebo was similar in both subgroups for either class of eosinophil count (25% reduction for <150 cells / μL and 24% reduction for ≥150 cells / μL) (see Table 9).

[0525] Table 9: Time to First COPD CompEx Event (Days) - Cox Regression Analysis by Subgroup (ITT Population) - EOS Subgroup

[0526]

[0527] [a] The number (%) of subjects who had the event in the analysis (n). Cox regression models were used to investigate intervention, log-transformed eosinophil count, background drug layer, geographic region, number of exacerbations during the first 12 months, subgroups, and subgroups. Intervention interactions were studied as covariates, and hazard ratios and their 80% confidence intervals (CIs) were assessed. If eos were subgroups, log-transformed eos values ​​were not included as covariates. Time to the first COPD CompEx event (in days) was calculated as (minimum (review date, start date of the first event) - randomization date) + 1. CI confidence interval. n: Number of participants in the analysis. This table is based on events occurring during the treatment period (i.e., from baseline to the last dose date + 28 days).

[0528] Efficacy evaluation conclusion

[0529] Primary endpoint

[0530] • Although, as clinically measured, the change in pre-BD FEV1 from baseline in the toretzimab 600 mg group at week 12 did not show a statistically significant difference compared to placebo, a numerical improvement of 24 mL was observed. This effect was enhanced in the subgroups with baseline eosinophils ≥150 cells / μL (82 mL) and ≥2 previous COPD exacerbations within the previous 12 months (69 mL).

[0531] Secondary endpoint

[0532] • Numerical improvements were observed in pre-BD FEV1 and time to first COPD Compex event in both current and former smokers.

[0533] • An improving trend in FEV1 after BD was observed at both week 12 (mean difference in LS 0.067 L [80% CI: 0.017, 0.116]) and week 28 (mean difference in LS 0.070 L [80% CI: 0.020, 0.120]), which was beneficial to torazumab 600 mg compared to placebo.

[0534] • The degree of emphysema (<10% and ≥10% at baseline) did not appear to affect the change in pre-BD FEV1 from baseline to week 28; however, for participants with ≥10% emphysema, clinically significant differences in post-BD FEV1 were observed at both week 12 and week 28.

[0535] • For participants with baseline emphysema ≥10%, a clinically significant trend of improvement in pre-BD FVC was observed from week 4 to week 28, which was not replicated for participants with emphysema <10%. However, for participants with emphysema ≥10%, clinically significant differences in post-BD FVC were observed at both week 12 and week 28.

[0536] • Fewer participants experienced COPD CompEx events in the toricumab group compared to placebo (52.9%) (41.8%). Although there was no statistically significant difference in the time to first CompEx event between the toricumab 600 mg group and the placebo group based on the time from baseline to week 28, toricumab reduced the risk of COPD CompEx events by 21% in the ITT population. The reduction in the risk of CompEx events was more significant in the subgroup of subjects with two or more exacerbations in the first 12 months (39% reduction) and in former smokers (28% reduction).

[0537] • Additional analyses were performed to determine treatment response within different EOS subgroups, demonstrating that from week 2 onwards, subjects with EOS >= 150 to < 250 showed improvement in pre-clinical BD FEV1 compared to placebo (Table 10). Improvement in pre-clinical BD FEV1 was also observed in the EOS >= 250 group (Table 10). No numerical improvement in pre-clinical BD FEV1 was observed in subjects with EOS <= 150 (Table 10).

[0538] Table 10: Comparison of pre-BD FEV1 (L) (as clinically measured) treatment in different EOS subgroups from baseline to 28 Weekly variation, MMRM (ITT group) eos <150, >=150 to <250 (excluding 250), >=250

[0539]

[0540]

[0541] sequence

[0542] In addition to the sequences listed in Table 1, we also provide the following additional sequences:

[0543] MEDI3506 VHCDR1 SEQ ID NO 37: SYAMS

[0544] MEDI3506 VHCDR2 SEQ ID NO 38: GISAIDQSTYYADSVKG

[0545] MEDI3506 VHCDR3 SEQ ID NO 39: QKFMQLWGGGLRYPFGY

[0546] MEDI3506 VLCDR1 SEQ ID NO 40: SGEGMGDKYAA

[0547] MEDI3506 VLCDR2 SEQ ID NO 41: RDTKRPS

[0548] MEDI3506 VLCDR3 SEQ ID NO 42: GVIQDNTGV

[0549] SEQ ID NO:43 MEDI3506 heavy chain

[0550] EVQLLESGGGLVQPGGSLRLSCAASGFTFSSYAMSWVRQAPGKGLEWVSGISAIDQSTYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARQKFMQLWGGGLRYPFGYWGQGTMVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK

[0551] SEQ ID NO:44 MEDI3506 light chain

[0552] SYVLTQPPSVSVSPGQTASITCSGEGMGDKYAAWYQQKPGQSPVLVIYRDTKRPSGIPERFSGSNSGNTATLTISGTQAMDEADYYCGVIQDNTGVFGGGTKLTVLGQPKAAPSVTLFPPSSEELQANKATLVCLISDFYPGAVTVAWKADSSPVKAGVETTTPSKQSNNKYAASSYLSLTPEQWKSHRSYSCQVTHEGSTVEKTVAPTECS

[0553] SEQ ID NO:45 IL-33 protein

[0554] MKPKMKYSTNKISTAKWKNTASKALCFKLGKSQQKAKEVCPMYFMKLRSGLMIKKEACYFRRETTKRPSLKTGRKHKRHLVLAACQQQSTVECFAFGISGVQKYTRALHDSSITGISPITEYLASLSTYNDQSITFALEDESYEIYVEDLKKDEKKDKVLLSYYESQHPSNESGDGVDGKMLMVTLSPTKDFWLHANNKEHSVELHKCEKPLPDQAFFVLHNMHSNCVSFECKTDPGVFIGVKDNHLALIKVDSSENLCT ENILFKLSET.

Claims

1. A method for treating a subject with COPD, the method comprising: The subject was administered an effective amount of an IL-33 signaling axis antagonist, wherein, prior to administration, the subject had a blood eosinophil count of <250 cells / μl to ≥150 cells / μl.

2. A method for improving lung function in a subject with COPD, the method comprising: The subject was administered an effective amount of an IL-33 signaling axis antagonist, wherein, prior to administration, the subject had a blood eosinophil count of <250 cells / μl to ≥150 cells / μl.

3. The method according to claim 1 or 2, wherein the subject is a current smoker or a former smoker.

4. The method according to any one of claims 1 to 3, wherein the subject is a current smoker.

5. A method for treating a subject with COPD, the method comprising: The subject is given an effective amount of an IL-33 signaling axis antagonist, wherein, prior to the administration, the subject has a blood eosinophil count of <250 cells / μl to ≥150 cells / μl, and wherein the subject is a current smoker.

6. A method for improving lung function in a subject with COPD, the method comprising: The subject is given an effective amount of an IL-33 signaling axis antagonist, wherein, prior to the administration, the subject has a blood eosinophil count of <250 cells / μl to ≥150 cells / μl, and wherein the subject is a current smoker.

7. The method according to any one of claims 1 to 6, wherein prior to the administration, the subject has a blood eosinophil count of <240 cells / µl to ≥150 cells / µl.

8. The method according to any one of claims 1 to 7, wherein prior to the administration, the subject has a blood eosinophil count of <200 cells / µl to ≥150 cells / µl.

9. The method according to any one of claims 1 or 5, wherein treatment of a subject with COPD results in improvement of the subject's lung function.

10. The method according to any one of claims 1 to 9, wherein treating a subject with COPD or improving lung function in a subject with COPD results in reversal of airway obstruction.

11. The method according to any one of claims 1 to 10, wherein the blood eosinophil count is a count immediately preceding the administration of an effective amount of the IL-33 signaling axis antagonist.

12. The method according to any one of claims 1 to 6, 9 to 11, wherein the subject is selected from a group of subjects whose blood eosinophil count prior to the administration comprises < 250 cells / µl to ≥ 150 cells / µl.

13. The method of claim 12, wherein the subject is selected from a group of subjects whose blood eosinophil count prior to the administration comprises < 240 cells / µl to ≥ 150 cells / µl.

14. The method of claim 12 or 13, wherein the subject is selected from a group of subjects whose blood eosinophil count prior to the administration comprises < 200 cells / µl to ≥ 150 cells / µl.

15. The method according to any one of claims 1 to 6, 9 to 11, wherein the method further comprises the step of selecting a subject having a blood eosinophil count of < 250 cells / µl to ≥ 150 cells / µl prior to the administration.

16. The method of claim 15, wherein the method further comprises the step of selecting a subject having a blood eosinophil count of < 240 cells / µl to ≥ 150 cells / µl prior to the administration.

17. The method of claim 15 or 16, wherein the method further comprises the step of selecting a subject having a blood eosinophil count of <200 cells / µl to ≥150 cells / µl prior to the administration.

18. The method according to any one of claims 1 to 17, wherein treating a subject with COPD or improving lung function in a subject with COPD results in an increase of at least 50 ml in the subject's pre-bronchodilator (BD) FEV1.

19. The method according to any one of claims 1 to 18, wherein treating a subject with COPD or improving lung function in a subject with COPD results in an increase of at least 60 ml in the subject's pre-bronchodilator (BD) FEV1.

20. The method according to any one of claims 1 to 19, wherein the treatment of a subject with COPD or the improvement of lung function in a subject with COPD results in an increase of at least 80 ml in the subject's pre-BD FEV1.

21. The method according to any one of claims 1 to 19, wherein the treatment of a subject with COPD or the improvement of lung function in a subject with COPD results in an increase of approximately 80 ml in the subject's pre-BD FEV1.

22. The method according to any one of claims 1 to 21, wherein the treatment of a subject with COPD or the improvement of lung function in a subject with COPD results in an increase in FEV1 of at least 60 ml after bronchodilator (BD) administration to the subject.

23. The method according to any one of claims 18 to 22, wherein the increase in the subject's pre-BD FEV1 or post-BD FEV1 is achieved at week 12 following administration of the effective amount of the IL-33 signal axis antagonist.

24. The method according to any one of claims 18 to 22, wherein the increase in the subject's pre-BD FEV1 or post-BD FEV1 is achieved at week 28 following the administration of the effective amount of the IL-33 signal axis antagonist.

25. The method according to any one of claims 1 to 24, wherein the treatment of a subject with COPD or the improvement of lung function in a subject with COPD results in an increase of at least 60 ml in the subject's forced vital capacity (FVC) before bronchodilator (BD).

26. The method according to any one of claims 1 to 24, wherein the treatment of a subject with COPD or the improvement of lung function in a subject with COPD results in an increase of at least 70 ml in the subject's pre-BD FVC.

27. The method according to any one of claims 1 to 24, wherein the treatment of a subject with COPD or the improvement of lung function in a subject with COPD results in an increase of approximately 70 ml in the subject's pre-BD FVC.

28. The method according to any one of claims 1 to 27, wherein the treatment of a subject with COPD or the improvement of lung function in a subject with COPD results in an increase in FVC of at least 60 ml after bronchodilator (BD) administration to the subject.

29. The method according to any one of claims 1 to 27, wherein the treatment of a subject with COPD or the improvement of lung function in a subject with COPD results in an increase in FVC of approximately 60 ml after bronchodilator (BD) administration to the subject.

30. The method according to any one of claims 25 to 29, wherein the increase in the subject's pre-BD FVC or post-BD FVC is achieved at week 12 following the administration of the effective amount of the IL-33 signal axis antagonist.

31. The method according to any one of claims 25 to 29, wherein the increase in the subject's pre-BD FVC or post-BD FVC is achieved at week 28 following the administration of the effective amount of the IL-33 signal axis antagonist.

32. The method of any one of claims 1 to 31, wherein the treatment of a subject with COPD or the improvement of lung function in a subject with COPD results in an increase in the time to the first CompEx event in the subject.

33. The method of claim 32, wherein, relative to a control subject with COPD who did not receive the IL-33 signaling axis antagonist, the time to the first CompEx event in the subject is increased by about 4 weeks, or about 5 weeks, or about 6 weeks.

34. The method of any one of claims 1 to 33, wherein the treatment of the subject with COPD or the improvement of lung function in the subject with COPD results in a reduction in the rate of CompEx events in the subject with COPD.

35. The method of claim 34, wherein, compared with control subjects with COPD who did not receive the IL-33 signaling axis antagonist, the rate of CompEx events was reduced by at least 20%, at least 25%, and at least 27% after administration of an effective amount of the IL-33 signaling axis antagonist.

36. The method of claim 34 or 35, wherein the rate of the CompEx event decreases over a period of 28 weeks.

37. The method according to any one of claims 1 to 36, wherein the subject suffers from chronic bronchitis.

38. A method for increasing the time to first CompEx event in a subject with COPD, the method comprising: An effective amount of an IL-33 signaling axis antagonist was administered to the subject, wherein the subject was a current smoker.

39. A method for reducing the rate of CompEx events in subjects with COPD, the method comprising: An effective amount of an IL-33 signaling axis antagonist was administered to the subject, wherein the subject was a current smoker.

40. The method of claim 39, wherein, relative to a control subject with COPD who did not receive the IL-33 signaling axis antagonist, the time to the first CompEx event in the subject is increased by about 4 weeks, or about 5 weeks, or about 6 weeks.

41. The method of claim 39 or 40, wherein the rate of CompEx events is reduced by at least 20%, or at least 25%, or at least 27% after administration of an effective amount of the IL-33 signaling axis antagonist compared to a control subject who did not receive the IL-33 signaling axis antagonist.

42. The method according to any one of claims 39 to 41, wherein the ratio of the CompEx events decreases over a period of 28 weeks.

43. The method according to any one of claims 38 to 42, wherein, Prior to the administration, the subject had a blood eosinophil count of ≥150 cells / µl.

44. The method according to any one of claims 38 to 42, wherein, Prior to the administration, the subject had a blood eosinophil count of <250 cells / µl to ≥150 cells / µl.

45. The method according to any one of claims 38 to 44, wherein, Prior to the administration, the subject had a blood eosinophil count of <240 cells / µl to ≥150 cells / µl.

46. ​​The method according to any one of claims 38 to 45, wherein, Prior to administration, the subject had a blood EoS count of <200 cells / µl to ≥150 cells / µl.

47. The method according to any one of claims 38 to 46, wherein the blood eosinophil count is a count immediately preceding the administration.

48. The method according to any one of claims 38 to 47, wherein the subject is selected from a group of subjects who included the blood eosinophil count prior to the administration.

49. The method of any one of claims 38 to 48, wherein the method further comprises the step of selecting a subject having the blood eosinophil count prior to the administration.

50. A method for selecting a subject with COPD to treat with an effective amount of an IL-33 signaling axis antagonist, the method comprising: Measure the eosinophil count in the subject's blood; If the subject's blood eosinophil count is <250 cells / μl to ≥150 cells / μl, then the subject is selected for the treatment.

51. The method of selecting a subject according to claim 50, wherein the method further comprises administering an effective amount of an IL-33 signaling axis antagonist to the subject.

52. The method for selecting a subject according to claim 50 or 51, wherein the subject is a current smoker.

53. The method according to any one of claims 1 to 52, wherein the subject has a BCSS score of approximately 7 or higher, 7.1 or higher, 7.2 or higher, 7.3 or higher, 7.4 or higher, or 7.429 or higher.

54. The method according to any one of claims 1 to 53, wherein the subject has an SGRQ score of approximately 58 or higher, 58.1 or higher, 58.2 or higher, or 58.239 or higher.

55. The method according to any one of claims 1 to 54, wherein the subject has a degree of emphysema of <10%.

56. The method according to any one of claims 1 to 55, wherein the subject has had two or more episodes of AECOPD within the 12 months prior to treatment.

57. The method according to any one of claims 1 to 55, wherein the subject has two or more episodes of moderate AECOPD and / or one or more episodes of severe AECOPD within 12 months prior to treatment.

58. The method according to any one of claims 18 to 31, wherein the increase in the subject's pre-BD FEV1, post-BD FEV1, pre-BD forced vital capacity (FVC), and post-BD FVC are relative to baseline levels.

59. The method according to any one of claims 53, 54 or 55, wherein the BCSS score, the SGRQ score and the degree of emphysema are measured at baseline.

60. The method of claim 58 or 59, wherein the baseline is the level of the subject prior to the administration.

61. The method according to any one of the preceding claims, wherein the IL-33 signaling axis antagonist is an antibody, its antigen-binding fragment, or a variant thereof.

62. The method of claim 61, wherein the antibody is an anti-IL-33 antibody, an anti-ST2 antibody, an anti-IL1-RacP antibody, an antigen-binding fragment thereof, or a variant thereof.

63. The method according to claim 61 or 62, wherein the antibody is an anti-IL-33 antibody, its antigen-binding fragment, or a variant thereof.

64. The method of claim 63, wherein the anti-IL-33 antibody, its antigen-binding fragment or variant comprises a VH domain and a VL domain, the VH domain comprising VHCDR1 having the sequence shown in SEQ ID NO:37, VHCDR2 having the sequence shown in SEQ ID NO:38, and VHCDR3 having the sequence shown in SEQ ID NO:39, and the VL domain comprising VLCDR1 having the sequence shown in SEQ ID NO:40, VLCDR2 having the sequence shown in SEQ ID NO:41, and VLCDR3 having the sequence shown in SEQ ID NO:

42.

65. The method according to claim 63 or 64, wherein the anti-IL-33 antibody, its antigen-binding fragment or variant comprises a VH domain and a VL domain, the VH domain having the sequence shown in SEQ ID NO:1 or a sequence having 80%, 85%, 90% or 95% identity therewith, and the VL domain having the sequence shown in SEQ ID NO:19 or a sequence having 80%, 85%, 90% or 95% identity therewith.

66. The method according to claim 63, 64 or 65, wherein the anti-IL-33 antibody, its antigen-binding fragment or variant comprises a VH domain and a VL domain, the VH domain having the sequence shown in SEQ ID NO:1 and the VL domain having the sequence shown in SEQ ID NO:

19.

67. The method according to any one of claims 61 to 66, wherein the antibody is present.

68. The method of claim 67, wherein the antibody is a monoclonal antibody.

69. The method of claim 68, wherein the monoclonal antibody is IgG1.

70. The method according to any one of claims 67 to 69, wherein the anti-IL-33 antibody comprises a heavy chain and a light chain, the heavy chain having the sequence shown in SEQ ID NO:43 or a sequence having 80%, 85%, 90%, or 95% identity therewith, and the light chain having the sequence shown in SEQ ID NO:44 or a sequence having 80%, 85%, 90%, or 95% identity therewith.

71. The method of claim 70, wherein the anti-IL-33 antibody comprises a heavy chain and a light chain, the heavy chain having the sequence shown in SEQ ID NO:43 and the light chain having the sequence shown in SEQ ID NO:

44.

72. The method according to any one of claims 61 to 71, wherein the antibody is toretinoin.

73. The method according to claims 1 to 72, wherein the effective amount of the IL-33 signal axis antagonist is included in the pharmaceutical composition, the pharmaceutical composition comprising one or more excipients.

74. The method according to claims 1 to 73, wherein the effective amount of the IL-33 signal axis antagonist is a dose between 300 mg and 600 mg.

75. The method according to claims 1 to 74, wherein the IL-33 signaling axis antagonist or a pharmaceutical composition thereof is administered to the subject every 2 weeks (Q2W), every 4 weeks (Q4W), every 5 weeks (Q5W), every 6 weeks (Q6W), every 7 weeks (Q7W), or every 8 weeks (Q8W).

76. The method according to any one of the preceding claims, wherein the IL-33 signaling axis antagonist or a pharmaceutical composition thereof is administered to the subject at a dose of 600 mg every 4 weeks (Q4W).

77. The method according to any one of the preceding claims, wherein the IL-33 signaling axis antagonist or a pharmaceutical composition thereof is administered to the subject at a dose of 300 mg every 2 weeks (Q2W).

78. The method according to any one of the preceding claims, wherein the IL-33 signaling axis antagonist or a pharmaceutical composition thereof is administered to the subject at a dose of 300 mg every 4 weeks (Q4W).

79. The method according to any one of the preceding claims, wherein the IL-33 signaling axis antagonist or a pharmaceutical composition thereof is administered to the subject at a dose of 300 mg every 8 weeks (Q8W).

80. The method according to any one of the preceding claims, wherein the IL-33 signaling axis antagonist or a pharmaceutical composition thereof is administered subcutaneously to the subject.

81. The method according to any one of the preceding claims, wherein the IL-33 signaling axis antagonist or a pharmaceutical composition thereof is administered to the subject by injection.

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