Bronchiectasis treatment

Abstract

Provided herein are methods of treating bronchiectasis with an antibody which binds IL-33 and inhibits its activation of EGFR / RAGE. The antibody may be tozorakimab.

Description

[0001] BRONCHIECTASIS TREATMENT

[0002] CROSS-REFERENCE TO RELATED PATENT APPLICATION

[0003] This specification claims the benefit of priority to European Patent Application 24176882.9 (filed 20 May 2024) and European Patent Application EP24216958.9 (filed 2 December 2024). The entire text of the above-referenced patent applications are incorporated by reference into this specification.

[0004] FIELD

[0005] Provided herein are methods of treating bronchiectasis with an antibody against IL-33.

[0006] BACKGROUND

[0007] Bronchiectasis is a chronic disease characterized by abnormal and permanent dilation of the bronchi resulting in chronic cough, sputum production, shortness of breath, haemoptysis and recurrent bacterial infections of the airway. Patients with bronchiectasis suffer from considerable morbidity due to exacerbations (i.e. deteriorations in symptoms) that potentially lead to hospitalisation in addition to impairing quality of life, and lead to progressively reduced lung function. Most commonly exacerbations are caused by bacterial or viral infections, though environmental factors and inflammation in the lungs can also have an impact (Choi & Chalmers, Annals of Translational Medicine 11 (1): 25, 2023).

[0008] There is a significant unmet medical need for treatment of bronchiectasis as there is currently no approved pharmacological treatment for the underlying disease. At present treatment extends only to supportive care, including physiotherapy, and antibiotics in the case of bacterial colonisation of the bronchi (e.g. by Pseudomonas aeruginosa) or to treat acute exacerbations (European Respiratory Society (ERS) guidelines for the management of adult bronchiectasis, European Respiratory Journal 50: 1700629, 2017).

[0009] IL-33 is a pleiotropic nuclear alarmin cytokine from the IL-1 superfamily, which has recently been identified as a putative factor in certain chronic airway diseases, including COPD. A full-length, reduced form of IL-33 (I L-33red) is released from damaged epithelial and endothelial barrier cells and alerts the immune system to tissue damage. IL-33 drives pulmonary inflammation through its receptor complex ST2 / IL1 RAcP via the NF-KB pathway, which is expressed by several inflammatory cell types including mast cells, type 1 and 2 innate lymphoid cells, macrophages and endothelial cells. The IL-33 / ST2 signalling pathway leads to production of inflammatory cytokines such as IL-6 and granulocytemacrophage colony-stimulating factor by these cell types (Chakerian et al., Journal of Immunology 179(4): 2552-2555, 2007). Following cellular release, IL-33 is rapidly oxidised to form I L-33OX, in which two disulphide bridges are formed causing an extensive conformational change in the cytokine (Cohen et al., Nature Communications 6: 8327, 2015). I L-33OXcannot bind the ST2 receptor, but recently an ST2-independent IL-33 signalling pathway has been identified. I L-33OXbinds a complex of RAGE / EGFR to signal via the JNK pathway, driving epithelial remodelling and dysfunction, including mucus hypersecretion and defective damage repair (Strickson et al., European Respiratory Journal 62: 2202210, 2023).

[0010] The anti-IL-33 antibody tozorakimab has been found to be capable of blocking both IL-33 signalling pathways. Tozorakimab binds IL-33redwith high affinity, blocking its binding to the ST2 receptor. Tozorakimab has also been found to inhibit oxidation of I L-33red, indirectly inhibiting EGFR / RAGE activation (England et al., Scientific Reports 13: 9825, 2023).

[0011] SUMMARY

[0012] Provided herein are methods of treating bronchiectasis using an antibody (or antigen-binding fragment thereof) which binds IL-33 and inhibits its activation of EGFR / RAGE. The antibody may be tozorakimab.

[0013] Thus in a first aspect, provided herein is a method of treating bronchiectasis in a patient, the method comprising administering to the patient an antibody or antigen-binding fragment thereof which binds IL-33 and inhibits IL-33-mediated activation of EGFR / RAGE.

[0014] In a second aspect, provided herein is a method of improving forced expiratory volume in 1 second (FEV1) in a patient with bronchiectasis, the method comprising administering to the patient an antibody or antigen-binding fragment thereof which binds IL-33 and inhibits IL-33-mediated activation of EGFR / RAGE.

[0015] In a third aspect, provided herein is a method of reducing bronchiectasis exacerbations in a patient with bronchiectasis, the method comprising administering to the patient an antibody or antigen-binding fragment thereof which binds IL-33 and inhibits IL-33- mediated activation of EGFR / RAGE.

[0016] In a fourth aspect, provided herein is a method of reducing the need for intravenous or nebulised antibiotics in a patient with bronchiectasis, the method comprising administering to the patient an antibody or antigen-binding fragment thereof which binds IL-33 and inhibits IL-33-mediated activation of EGFR / RAGE.

[0017] In a fifth aspect, provided herein is a method of stabilizing lung function in a patient with bronchiectasis, the method comprising administering to the patient an antibody or antigen-binding fragment thereof which binds IL-33 and inhibits IL-33-mediated activation of EGFR / RAGE.

[0018] In a sixth aspect, provided herein is a method of reducing bronchiectasis symptoms in a patient with bronchiectasis, the method comprising administering to the patient an antibody or antigen-binding fragment thereof which binds IL-33 and inhibits IL-33-mediated activation of EGFR / RAGE.

[0019] In a seventh aspect, provided herein is a method of reducing cough severity in a patient with bronchiectasis, the method comprising administering to the patient an anti-IL-33 antibody or antigen-binding fragment thereof which binds IL-33 and inhibits IL-33-mediated activation of EGFR / RAGE.

[0020] In an eighth aspect, provided herein is a method of reducing the severity of bronchiectasis in a patient with bronchiectasis, the method comprising administering to the patient an antibody or antigen-binding fragment thereof which binds IL-33 and inhibits IL-33- mediated activation of EGFR / RAGE.

[0021] In a ninth aspect, provided herein is a method of improving the quality of life of a patient with bronchiectasis, the method comprising administering to the patient an antibody or antigen-binding fragment thereof which binds IL-33 and inhibits IL-33-mediated activation of EGFR / RAGE.

[0022] In a related aspect, provided herein is an anti-IL-33 antibody or antigen-binding fragment thereof for use in a method of treating bronchiectasis, the method comprising administering to the patient the anti-IL-33 antibody or antigen-binding fragment thereof, wherein the antibody or fragment inhibits IL-33-mediated activation of EGFR / RAGE.

[0023] In a related aspect, provided herein is an anti-IL-33 antibody or antigen-binding fragment thereof for use in a method of treating cough in a patient with bronchiectasis, the method comprising administering to the patient the anti-IL-33 antibody or antigen-binding fragment thereof, wherein the antibody or fragment inhibits IL-33-mediated activation of EGFR / RAGE.

[0024] In a further related aspect, provided herein is the use of an anti-IL-33 antibody or antigen-binding fragment thereof in the manufacture of a medicament for treating bronchiectasis, wherein the antibody or fragment thereof inhibits IL-33-mediated activation of EGFR / RAGE.

[0025] In a further related aspect, provided herein is the use of an anti-IL-33 antibody or antigen-binding fragment thereof in the manufacture of a medicament for treating cough in a patient with bronchiectasis, wherein the antibody or fragment thereof inhibits IL-33-mediated activation of EGFR / RAGE.

[0026] In a further related aspect, provided herein is the use of an anti-IL-33 antibody or antigen-binding fragment thereof to treat bronchiectasis, wherein the antibody or fragment thereof inhibits IL-33-mediated activation of EGFR / RAGE.

[0027] In a further related aspect, provided herein is the use of an anti-IL-33 antibody or antigen-binding fragment thereof to treat cough in a patient with bronchiectasis, wherein the antibody or fragment thereof inhibits IL-33-mediated activation of EGFR / RAGE. In a further related aspect, provided herein is a pharmaceutical composition comprising an anti-IL-33 antibody or antigen-binding fragment thereof for use in a method of treating bronchiectasis, wherein the antibody or fragment thereof inhibits IL-33-mediated activation of EGFR / RAGE.

[0028] In a further related aspect, provided herein is a pharmaceutical composition comprising an anti-IL-33 antibody or antigen-binding fragment thereof for use in a method of treating cough in a patient with bronchiectasis, wherein the antibody or fragment thereof inhibits IL-33-mediated activation of EGFR / RAGE.

[0029] In general, the antibody or fragment thereof also inhibits IL-33 mediated activation of ST2 / IL1 RAcP. That is to say, generally the anti-IL-33 antibody binds IL-33 and inhibits IL-33 mediated activation of EGFR / RAGE and IL-33 mediated activation of ST2 / IL1 RAcP.

[0030] In some embodiments of the methods and related aspects, the patient is a human, in particular a human adult.

[0031] In some embodiments of the methods and related aspects, the patient has airway neutrophilia.

[0032] In some embodiments of the methods and related aspects, the patient has sputum neutrophilia.

[0033] In some embodiments of the methods and related aspects, the patient has a history of at least 2 moderate to severe bronchiectasis exacerbations per year requiring antibiotics, and / or at least 1 exacerbation requiring hospital care.

[0034] In some embodiments of the methods and related aspects, the patient is on longterm antibiotics.

[0035] In some embodiments of the methods and related aspects, the patient also has chronic obstructive pulmonary disease (COPD).

[0036] In other embodiments of the methods and related aspects, the patient does not have COPD.

[0037] In some embodiments of the methods and related aspects, the patient also has asthma.

[0038] In other embodiments of the methods and related aspects, the patient does not have asthma.

[0039] In some embodiments of the methods and related aspects, the patient does not have acute respiratory distress syndrome (ARDS) or acute respiratory failure (ARF), and is not at risk of developing ARDS or ARF.

[0040] In some embodiments of the methods and related aspects, the administration of the antibody or fragment thereof reduces bacterial load in sputum cultures obtained from the patient. In some embodiments of the methods and related aspects, the administration of the antibody or fragment thereof reduces sputum production by the patient.

[0041] In some embodiments of the methods and related aspects, the administration of the antibody or fragment thereof reduces the viscosity of sputum produced by the patient.

[0042] In some embodiments of the methods and related aspects, the administration of the antibody or fragment thereof reduces the patient’s need for antibiotics.

[0043] In some embodiments of the methods and related aspects, the antibody or fragment thereof comprises:

[0044] (a) a heavy chain variable region comprising a VHCDR1 comprising the sequence of SEQ ID NO: 1, a VHCDR2 comprising the sequence of SEQ ID NO: 2, and a VHCDR3 comprising the sequence of SEQ ID NO: 3; and

[0045] (b) a light chain variable region comprising a VLCDR1 comprising the sequence of SEQ ID NO: 4, a VLCDR2 comprising the sequence of SEQ ID NO: 5, and a VLCDR3 comprising the sequence of SEQ ID NO: 6.

[0046] In some embodiments of the methods and related aspects, the antibody or fragment thereof comprises a heavy chain variable region comprising the sequence of SEQ ID NO: 7, or an amino acid sequence with at least 80 % sequence identity thereto; and a light chain variable region comprising the sequence of SEQ ID NO: 8, or an amino acid sequence with at least 80 % sequence identity thereto.

[0047] In some embodiments of the methods and related aspects, the antibody or fragment thereof is tozorakimab.

[0048] In some embodiments of the methods and related aspects, the anti-IL-33 antibody or antigen-binding fragment thereof is administered to the subject subcutaneously.

[0049] In some embodiments of the methods and related aspects, the anti-IL-33 antibody or antigen-binding fragment thereof (particularly tozorakimab) is administered to the patient at a dose of 250 to 350 mg every 1 to 4 weeks.

[0050] In some embodiments of the methods and related aspects, the anti-IL-33 antibody or antigen-binding fragment thereof is administered to the patient over a course of therapy lasting at least 3 months or at least 6 months.

[0051] FIGURE LEGENDS

[0052] Figure 1 shows the concentration-dependent inhibition of IL-33 mediated, ST2-dependent IFNy release from PBMCs treated with the specified anti-IL-33 antibodies. Antibody activity is expressed as a percentage of IFNy release, where 100 % reflects uninhibited IFNy release, corrected for background signal. The graphed curves show the mean of 4-6 PBMC donors. Figure 2 shows the promotion of scratch wound repair by tozorakimab (A), which was not demonstrated by any of the other tested antibodies (B). Figure 3 shows a comparison of soluble ST2 (sST2) levels in sputum samples from healthy individuals and non-cystic fibrosis bronchiectasis (NCFB) patients. A: BRONC UK cohort of NCFB (n=64) and healthy individuals (n=31). B: INFLAMMAGING cohort of NCFB (n=48) and healthy individuals (n=11).

[0053] Figure 4 shows the production of the mucin MUC5AC by healthy nasal epithelial cells and nasal epithelial cells from non-cystic fibrosis bronchiectasis (NCFBE) patients which were either untreated or treated with tozorakimab, itepekimab or an lgG1 isotype control. MUC5AC levels were measured in apical washes from 3D nasal airway epithelium cultures by immunoassay. Individual datapoints are shown (n=4 individual healthy control donors and n=7 individual NCFBE donors), error bars indicate standard error of the mean (SEM).

[0054] * = p < 0.05; ** = p < 0.005; *** = p < 0.001 (non-parametric Kruskal-Wallis test with multiple comparisons). NS = not significant.

[0055] DETAILED DESCRIPTION

[0056] The term "about" or "approximately" means an acceptable error for a particular value as determined by one of ordinary skill in the art, which depends in part on how the value is measured or determined. In certain embodiments, the term "about" or "approximately" means within 1, 2, 3, or 4 standard deviations. In certain embodiments, the term "about" or "approximately" means within 30%, 25%, 20%, 15%, 1 0%, 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 numerical value in a series of two or more numerical values, it is understood that the term "about" or "approximately" applies to each one of the numerical values in that series. It is to be understood that whenever the term "about" or "approximately" precedes a numerical value, the exact numerical value is explicitly disclosed.

[0057] It is to be noted that the term "a" or "an" entity refers to one or more of that entity; for example, "an antibody," is understood to represent one or more antibodies. As such, the terms “a” (or “an”), “one or more”, and “at least one” can be used interchangeably herein.

[0058] Furthermore, “and / or” where used herein is to be taken as specific disclosure of each of the two specified features or components with or without the other. Thus, the term “and / or” as used in a phrase such as “A and / or B” herein is intended to include “A and B”, “A or B”, “A” (alone) and “B” (alone). Likewise, the term “and / or” as used in a phrase such as “A, B and / or C” is intended to encompass each of the following aspects: A, B and C; A, B or C; A or C; A or B; B or C; A and C; A and B; B and C; A (alone); B (alone); and C (alone).

[0059] It is understood that wherever aspects are described herein with the language “comprising”, otherwise analogous aspects described in terms of “consisting of” and / or “consisting essentially of” are also provided. Herein, the terms “comprises”, “comprising”, “containing” and “having” and the like can mean “includes”, “including” and the like; “consisting essentially of” or “consists essentially of” are open-ended, allowing for the presence of more than that which is recited so long as basic or novel characteristics of that which is recited is not changed by the presence of more than that which is recited, but excludes prior art aspects.

[0060] Units, prefixes, and symbols are denoted in their Systeme International de Unites (SI) accepted form. Numeric ranges are inclusive of the numbers defining the range.

[0061] Unless otherwise indicated, amino acid sequences are written left to right in amino to carboxy orientation.

[0062] Unless defined otherwise, technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which the present methods and related aspects pertain. For example, the Concise Dictionary of Biomedicine and Molecular Biology, Juo, Pei-Show, 2nd ed., 2002, CRC Press; The Dictionary of Cell and Molecular Biology, 3rd ed., 1999, Academic Press; and the Oxford Dictionary of Biochemistry and Molecular Biology, Revised, 2000, Oxford University Press, provide one of skill with a general dictionary of many of the terms used herein.

[0063] Throughout, references to “an anti-IL-33 antibody” encompass antigen-binding fragments of such antibodies, except where the context makes clear that a full-length antibody is meant.

[0064] Bronchiectasis

[0065] The present methods and associated aspects relate to treatment of bronchiectasis in patients in need of such treatment, i.e. patients with bronchiectasis.

[0066] Bronchiectasis is a chronic, and frequently progressive, lung condition characterized by symptoms including chronic (i.e. persistent) cough, sputum production, shortness of breath, haemoptysis (i.e. coughing up blood), wheezing and chest pain. Bronchiectasis is caused by abnormal and permanent dilation of the bronchi, which can be visualised on a computed tomography (CT) scan. Commonly, this structural damage to the bronchi is caused by an infection, an allergic reaction or an immunodeficiency.

[0067] Bronchiectasis can also be caused by cystic fibrosis. Bronchiectasis caused by cystic fibrosis may be referred to as cystic fibrosis (CF) bronchiectasis, whereas bronchiectasis having another cause may be referred to as non-CF bronchiectasis. Herein, all references to “bronchiectasis” refer to non-CF bronchiectasis, unless the context clearly dictates otherwise. Thus the methods of treatment provided herein are for the treatment of non-CF bronchiectasis.

[0068] Human lungs comprise 5 lobes: the right lung consists of three lobes (upper, middle and lower) and the left lung of two lobes (upper and lower). In an individual with bronchiectasis any number of lobes may be affected (with a minimum of one). Generally, the more lobes that are affected, the more severe is the bronchiectasis.

[0069] Bronchiectasis is associated with defective immune activity in the airway. Bronchiectasis patients are at heightened risk of lower respiratory tract infections (both viral and bacterial), and bacterial colonisation of the lower airways is often seen. Common colonising bacteria include Haemophilus influenzae and Pseudomonas spp., particularly Pseudomonas aeruginosa. Bacterial colonisation is associated with worsened disease symptoms and increased disease progression, as bacterial colonisation of the airways drives inflammation resulting in progressive lung injury and a gradual worsening of symptoms.

[0070] Many bronchiectasis patients experience periodic “exacerbations” (sometimes alternatively known as “flare-ups”). A bronchiectasis exacerbation is an acute worsening of symptoms, generally sustained for at least several days. Specifically, a bronchiectasis “exacerbation” is defined herein as a deterioration in three or more of the following symptoms for at least 48 hours: cough; sputum volume and / or consistency; sputum purulence; breathlessness and / or exercise tolerance; fatigue and / or malaise; haemoptysis, which is determined by a clinician to require a change in bronchiectasis treatment. This is in accordance with the universal definition of an exacerbation agreed at the World Bronchiectasis Conference in Hannover, Germany, in 2016 (Hill et al., European Respiratory Journal 49: 1700051 , 2017).

[0071] Most commonly bronchiectasis exacerbations are caused by infections (either bacterial or viral), and the standard treatment for exacerbations is antibiotic therapy. In severe cases exacerbations can cause respiratory difficulty requiring hospitalisation. On average, patients experience about 2 exacerbations per year. A higher frequency and / or severity of exacerbations is associated with worsened symptoms and quality of life, reduced lung function and mortality. Patients experiencing more frequent exacerbations (e.g. at least 3 exacerbations per year) may be prescribed long-term oral or inhaled antibiotic therapy (generally using an antibiotic of the macrolide class) to reduce exacerbation frequency. Though seemingly effective, this does risk driving macrolide resistance in bronchiectasis patients.

[0072] The severity of bronchiectasis in a patient can be assessed in various ways. Most commonly, the Bronchiectasis Severity Index (BSI) is used. The BSI scores a patient’s condition based on factors including age, body mass index (BMI), recent hospital admissions and exacerbation frequency. A score of 0-4 is defined as low severity bronchiectasis, 5-8 is defined as medium severity bronchiectasis and 9+ is defined as high severity bronchiectasis. Patients with high severity bronchiectasis are at increased risk of severe exacerbations, hospitalisation and death from the condition. The BSI is described in Chalmers et al., American Journal of Respiratory and Critical Care Medicine 189(5): 576-585, 2014, which is incorporated herein by reference.

[0073] Patients

[0074] The patient treated according to the present methods is a subject who has been diagnosed with, or is suspected of suffering from, bronchiectasis. Generally the patient is a human. Most commonly, the patient is an adult human, though children may also be treated according to the methods provided herein.

[0075] The bronchiectasis may have any cause. For example, the bronchiectasis may have been caused by an immunodeficiency. Such an immunodeficiency may be a primary immunodeficiency or a secondary immunodeficiency. As referred to herein, a primary immunodeficiency is an immunodeficiency with a genetic cause, whereas a secondary immunodeficiency is an immunodeficiency with an acquired or environmental cause (e.g. a disease such as HIV, or medical treatment such as chemotherapy). The bronchiectasis may have been caused by an antibody deficiency (i.e. a deficiency resulting in impaired antibody production by B cells, also referred to as hypogammaglobulinaemia), which may be a primary antibody deficiency or a secondary antibody deficiency. Primary antibody deficiencies which may be associated with bronchiectasis include common variable immunodeficiency (CVID), X-linked agammaglobulinemia, hyper-IgM syndrome and IgG deficiency. Secondary immunodeficiencies which may be associated with bronchiectasis include therapy with immunosuppressants, e.g. post-organ transplant, chemotherapy and infections, e.g. HIV.

[0076] Other genetic factors may also cause bronchiectasis. For example, the bronchiectasis may have been caused by alpha-1 antitrypsin (AAT) deficiency. AAT is an inhibitor of neutrophil serine proteases, and without being bound by theory it is believed that it acts to dampen neutrophil-driven inflammation. AAT deficiency may therefore result in increased neutrophil-driven inflammation, which in the lungs results in tissue damage promoting bronchiectasis development, and a correlation between AAT deficiency and bronchiectasis has been observed (see e.g. Stockley etal., Orphanet Journal of Rare Diseases 18: 243, 2023).

[0077] The patient may have bronchiectasis caused by defective cilia, resulting in improper mucus clearance from the airways. For example, the bronchiectasis may have been caused by Young’s syndrome or primary cilia dyskinesia. The bronchiectasis may have been caused by a severe lung infection, e.g. pneumonia or tuberculosis. The bronchiectasis may have been caused by an allergic reaction or condition within the lungs, which drives inflammation of the airways causing progressive damage to their structure. For example, the bronchiectasis may have been caused by allergic bronchopulmonary aspergillosis (ABPA). The bronchiectasis may have been caused by an inflammatory disease, e.g. rheumatoid arthritis, Sjogren's syndrome, Crohn's disease or ulcerative colitis. In many bronchiectasis patients the condition is idiopathic, i.e. its cause is unknown.

[0078] The patient has bronchiectasis affecting at least one lobe of their lungs (i.e. one or more lobes of their lungs). In some embodiments the patient has bronchiectasis affecting at least 2, at least 3 or at least 4 lobes of their lungs. In some embodiments the patient has bronchiectasis affecting no more than 1 , no more than 2, no more than 3 or no more than 4 lobes of their lungs. In some embodiments the patient has bronchiectasis affecting 1, 2, 3, 4 or 5 lobes of their lungs.

[0079] As noted above, the patient may have been diagnosed with bronchiectasis. Any suitable technique may be used for diagnosis of bronchiectasis. Generally, the patient was diagnosed with bronchiectasis by a CT scan of the chest (“chest CT”).

[0080] Thus the patient may have bronchiectasis which was diagnosed (or confirmed) by chest CT demonstrating (or showing) bronchiectasis affecting one or more lobes of their lungs. In some embodiments the patient has bronchiectasis which was diagnosed (or confirmed) by chest CT demonstrating (or showing) bronchiectasis affecting at least 2, 3 or 4 lobes of their lungs.

[0081] In other embodiments, the patient has bronchiectasis which was diagnosed (or confirmed) by chest CT demonstrating (or showing) bronchiectasis affecting no more than 1, no more than 2, no more than 3 or no more than 4 lobes of their lungs.

[0082] In other embodiments, the patient has bronchiectasis which was diagnosed (or confirmed) by chest CT demonstrating (or showing) bronchiectasis affecting 1, 2, 3, 4 or all 5 lobes of their lungs.

[0083] Diagnosis by chest CT may be of particular importance for non-CF bronchiectasis, as CF can be diagnosed by sweat test (measuring the amount of salt in a person’s sweat) and / or a genetic test to identify mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) associated with CF.

[0084] The patient may have bronchiectasis of any subtype, i.e. cylindrical (or tubular), varicose or cystic. Cylindrical bronchiectasis is characterised by uniform bronchi, which do not taper and have parallel walls. Varicose bronchiectasis has a beaded appearance with interspersed sites of narrowing. Cystic bronchiectasis is the most severe form, characterised by saccular dilatation of bronchi that extends to the pleural surfaces. Specific bronchiectasis subtypes can be identified by CT scan. In some embodiments, the patient has multiple subtypes of bronchiectasis, i.e. different sub-types of bronchiectasis at different locations within their lungs.

[0085] In some embodiments, the patient has bronchiectasis which is predominantly cylindrical (i.e. more of the affected bronchi display a cylindrical form than any other form of bronchiectasis). In some embodiments, the patient has bronchiectasis which is predominantly varicose. In some embodiments the patient has bronchiectasis which is predominantly cystic. In some embodiments, the predominant bronchiectasis subtype is the majority subtype in the patient (i.e. more than 50 % of affected bronchi display that particular subtype).

[0086] In some embodiments, the patient has airway neutrophilia or sputum neutrophilia. The term “airway neutrophilia” refers to an accumulation of neutrophils in the airspace of the lungs. In particular, a patient with airway neutrophilia has a greater accumulation of neutrophils in the airspace of the lungs compared to healthy controls. Airway neutrophilia may be identified by an increased neutrophil count in bronchoalveolar lavage fluid or by increased neutrophil biomarkers (e.g. neutrophil elastase or myeloperoxidase) in bronchial fluid compared to healthy controls.

[0087] The term “sputum neutrophilia” refers to the accumulation of neutrophils in the sputum of a patient. In particular, a patient with sputum neutrophilia has a greater accumulation of neutrophils in the sputum compared to healthy controls. “Sputum”, also known as phlegm, is thick mucus made in the lungs. In cases of sputum neutrophilia, the sputum becomes purulent. Whereas in a healthy individual, sputum is essentially clear or translucent, purulent sputum is off-white, yellow or green and opaque. This change in colour is indicative of a high concentration of neutrophils. Sputum neutrophilia may be identified by an increased sputum neutrophil count or by increased neutrophil biomarkers (e.g. neutrophil elastase or myeloperoxidase) in sputum compared to healthy controls. Sputum may be obtained from expectoration, or by e.g. hypertonic saline induction.

[0088] Commonly, airway neutrophilia and sputum neutrophilia are associated, so in some embodiments the patient has airway neutrophilia and sputum neutrophilia.

[0089] Airway and sputum neutrophilia are common in bronchiectasis and have been found to correlate with overall disease severity, in a vicious cycle. Airway damage results in impaired mucus clearance, promoting acute bacterial infection and chronic bacterial colonisation of the airways, driving airway inflammation. Neutrophils are recruited to the site of inflammation, causing airway and sputum neutrophilia. Chronic inflammation and neutrophil presence and activity causes further damage to the airways.

[0090] The patient may have a history of at least two moderate to severe bronchiectasis exacerbations per year. As defined herein, a bronchiectasis exacerbation of at least moderate severity is defined as an exacerbation requiring antibiotics. Thus the patient may have a history of at least two bronchiectasis exacerbations requiring antibiotic treatment per year. By “a history” of such exacerbations may be meant that the patient has had at least two bronchiectasis exacerbations requiring antibiotic treatment in the previous year (e.g. in the previous 12 months, or the previous calendar year), or that on average, over a number of years, the patient has had at least two bronchiectasis exacerbations requiring antibiotic treatment per year. For example, the patient may have had an average of at least two bronchiectasis exacerbations requiring antibiotic treatment per year over the previous 2, 3, 4 or 5 years, or more, or since being diagnosed with bronchiectasis. Where the patient has had an average of at least two bronchiectasis exacerbations requiring antibiotic treatment per year over a number of past years, the patient may not have had as many as two exacerbations requiring antibiotic treatment in the previous year. By an exacerbation requiring antibiotics (or requiring antibiotic treatment) is meant an exacerbation for which the patient was prescribed antibiotic treatment by a physician.

[0091] In other embodiments, the patient has a history of at least one exacerbation requiring hospital care. That is to say, the patient may have been hospitalised due to an exacerbation at least once since their bronchiectasis diagnosis. By hospitalisation “due to an exacerbation” is meant that the patient was admitted to hospital (i.e. as an inpatient) due to the severity of the symptoms of a bronchiectasis exacerbation. The hospitalisation may be recent or unrecent, e.g. less than a year previous or less than 2 years previous, or at least 2, 3, 4 or 5 years previous. The patient may have been hospitalised due to an exacerbation only once or more than once, e.g. at least 2, 3, 4 or 5 times. The hospitalisation may have been for any length of time, e.g. less than a day or for at least 1 , 2, 3, 4, 5, 6, 7, 8, 9 or 10 days. The hospitalisation may have been of any severity and any nature and degree of treatment may have been required.

[0092] In some embodiments, the patient is on (i.e. is being prescribed) long-term antibiotics. The patient may be being prescribed any kind or class of antibiotic, though commonly the antibiotics prescribed for long-term treatment are macrolides, e.g. azithromycin or erythromycin. By “long-term” antibiotic treatment is meant treatment with an antibiotic which lasts longer than for an acute infection. Generally, by “long-term” antibiotic treatment is meant a course of antibiotic treatment which lasts for at least a month, in particular for at least 3 months, for at least 6 months or for at least 1 year. During long-term antibiotic treatment, the course of antibiotic treatment may require at least daily dosing of an antibiotic, e.g. the patient may be prescribed at least one dose of antibiotic per day. Alternatively the dosing during long-term antibiotic treatment may be less than daily, e.g. every other day, or weekly, or two or three times per week.

[0093] During long-term antibiotic treatment of a bronchiectasis patient, the patient may be prescribed an antibiotic for administration in any suitable way. For example, in some cases the patient may be prescribed long-term treatment with an oral antibiotic (i.e. an antibiotic taken orally, e.g. an antibiotic tablet or capsule, or an antibiotic liquid). In other cases, the patient may be prescribed long-term treatment with a nebulised antibiotic, i.e. an inhalable antibiotic. A liquid antibiotic, dissolved in e.g. saline solution, can be nebulised using a nebuliser.

[0094] In some embodiments, the bronchiectasis patient has at least one other respiratory condition. For example, the patient may have chronic obstructive pulmonary disease (COPD). That is to say, the patient may have both COPD and bronchiectasis. For example, the patient may have been diagnosed with, or be suspected of suffering from, both COPD and bronchiectasis. COPD is a chronic inflammatory lung disease that causes obstructed airflow from the lungs, generally as a result of abnormalities of the airways (e.g. the bronchi and bronchioles) or the alveoli. Like bronchiectasis, COPD may be diagnosed by CT scan, or by other suitable methods known in the art. The patient may be being treated for COPD, e.g. with a bronchodilator and / or a steroid.

[0095] The patient may have asthma. That is to say, the patient may have both asthma and bronchiectasis. For example, the patient may have been diagnosed with, or be suspected of suffering from, both asthma and bronchiectasis. Asthma is an inflammatory disease of the airways of the lungs, which may be diagnosed using any suitable method in the art, e.g. spirometry. The patient may be being treated for asthma, e.g. with a bronchodilator and / or a steroid.

[0096] In other embodiments, the patient does not have COPD. That is to say, the patient may have bronchiectasis but not COPD.

[0097] In some embodiments, the patient does not have acute respiratory distress syndrome (ARDS) or acute respiratory failure (ARF), and is not at risk of developing ARDS or ARF.

[0098] Acute respiratory distress syndrome (ARDS) is a life-threatening condition where the lungs are unable to work properly. It is caused by injury to the capillary wall either from illness or a physical injury such as major trauma. This results in the wall becoming leaky, leading to a build-up of fluid and the eventual collapse of the air sacs, leaving the lungs unable to exchange oxygen and carbon dioxide. Acute respiratory failure (ARF) is a term often used alongside ARDS, but it is a broader term that refers to the failure of the lungs from any cause. A subject suffering from ARDS and / or ARF may be defined as a subject who is unable to ventilate adequately to provide sufficient oxygen to the blood and systemic organs. In severe cases, or in cases in which patients have other underlying risk factors, bronchiectasis patients can be at risk of ARDS or ARF.

[0099] In some embodiments, the patient does not have ARDS or ARF, i.e. the patient is able to adequately ventilate themselves by breathing.

[0100] In some embodiments, the patient does not have ARDS or ARF, and is not at risk of ARDS or ARF. As referred to herein, a patient “at risk of developing ARDS or ARF” is a patient considered by a physician to be at sufficient risk of ARDS or ARF that specific, preventative treatment is required. That is to say, by “at risk of ARDS or ARF” is not meant simply that the patient could conceivably develop ARDS or ARF at an undefined point in the future (which may be universally applicable). Nor does “at risk of ARDS or ARF” simply mean a heightened risk of developing ARDS or ARF in the future compared to the general population (which may apply widely to bronchiectasis patients). Rather, the patient has specific symptoms or a particular condition which is considered to put them at particular risk of ARDS or ARF, compared to the average bronchiectasis patient.

[0101] In some embodiments, a patient who is not at risk of developing ARDS or ARF is not hospitalised (by which is meant not hospitalised due to a respiratory condition, e.g. bronchiectasis symptoms). In some embodiments, a patient who is not at risk of developing ARDS or ARF does not require supplemental oxygen.

[0102] The patient may have bronchiectasis defined as mild, moderate or severe according to the bronchiectasis severity index (BSI). The BSI is described in Chalmers et al., American Journal of Respiratory and Critical Care Medicine 189(5): 576-585, incorporated herein by reference in its entirety. As set out in Chalmers et al., the severity of bronchiectasis can be scored using the following system:

[0103] 1FEV1 = forced expiratory volume in 1 second, see further definition below.

[0104] 2Hospital admission due to bronchiectasis or respiratory tract infection, not including unrelated illnesses or injuries.

[0105] 3MRC (Medical Research Council) dyspnoea scoring system is described in e.g. Bestall et al., Thorax 54: 581-586, 1999, incorporated herein by reference in its entirety. According to the system, dyspnoea is scored as follows: no dyspnoea (only breathless on strenuous exercise) = 1 ; mild dyspnoea (breathless when hurrying or walking up a slight hill) = 2; moderate dyspnoea (has to walk slower than others of same age and / or stop for breath when walking at own pace on level ground) = 3; severe dyspnoea (has to stop for breath after walking 100 metres or after a few minutes on level ground) = 4; very severe dyspnoea (too breathless to leave house) = 5.

[0106] Based on the BSI score calculated according to the table above, a patient is defined as having mild bronchiectasis if their score is 0-4, moderate bronchiectasis if their score is 5- 8 or severe bronchiectasis if their score is 9 or above. The patient treated according to the methods provided herein may have mild, moderate or severe bronchiectasis. In some embodiments, the patient has mild or moderate bronchiectasis according to the BSI, i.e. a BSI score of 0-8 (alternatively described as a BSI score of less than 9). Patients with mild or moderate bronchiectasis can be seen as not being at risk of developing ARDS or ARF.

[0107] In some embodiments the patient does not have an immunodeficiency. That is to say, the patient does not have a primary immunodeficiency or a secondary immunodeficiency, such as are described above. In such embodiments the patient does not have HIV.

[0108] Immunodeficient patients are at increased risk of viral infections, particularly severe viral infections, which are the primary cause of ARDS and ARF. Thus patients who do not have an immunodeficiency can be seen as not being at risk of developing ARDS or ARF. In some embodiments, the patient has mild or moderate bronchiectasis according to the BSI (i.e. a

[0109] BSI score of 0-8) and does not have an immunodeficiency.

[0110] Treating Bronchiectasis

[0111] The methods provided herein comprise treating bronchiectasis in a patient using an anti- IL-33 antibody. Such treatment of bronchiectasis causes an improvement in the patient’s condition. Such an improvement may be an absolute improvement, i.e. a reduction or decreased severity of disease symptoms. Alternatively, the improvement may be a relative improvement, i.e. improvement of the patient’s condition may mean a reduction in severity compared to how severe the condition would be without the treatment. Thus an improvement may mean stabilisation of the disease (i.e. prevention of disease progression, where otherwise the disease would progress), or a reduced rate of disease progression. By “disease progression” is meant herein a gradual worsening of symptoms over time.

[0112] In some embodiments provided herein, administration of the anti-IL-33 antibody to the patient results in reduced exacerbations. That is to say, in one aspect the method of treating bronchiectasis provided herein can be seen as a method of reducing exacerbations in a patient with bronchiectasis. By “reducing exacerbations” is meant that the frequency and / or severity of exacerbations is reduced, compared to their frequency / severity prior to the commencement of treatment with the anti-IL-33 antibody. The reduction in frequency of exacerbations may last for at least 1 , 2, 3, 4 or 5 years, or for the duration of the course of treatment with the anti-IL-33 antibody.

[0113] For example, the frequency of exacerbations may be reduced by at least 20 %, 40 %, 60 % or 80 %. In some embodiments, where the frequency of exacerbations is reduced following commencement of treatment with the antibody, the patient may experience an average of no more than 2 exacerbations per year, or an average of no more than 1 exacerbation per year, or an average of no more than 0.5 exacerbations per year (i.e. no more than 1 exacerbation every 2 years). In some embodiments, the treatment may prevent bronchiectasis exacerbations.

[0114] Where the treatment reduces the severity of exacerbations, the treatment may reduce exacerbations requiring hospitalization. An exacerbation “requiring hospitalisation” (or requiring hospital care) is defined above. By reducing such exacerbations is meant that the overall number or frequency of exacerbations requiring hospitalisation is reduced. For example, the frequency of exacerbations requiring hospitalisation may be reduced by at least 20 %, 40 %, 60 % or 80 %. In some embodiments, where the frequency of exacerbations requiring hospitalisation is reduced following commencement of treatment with the antibody, the patient may experience an average of no more than 2 exacerbations requiring hospitalisation per year, or an average of no more than 1 exacerbation requiring hospitalisation per year, or an average of no more than 0.5 exacerbations requiring hospitalisation per year (i.e. no more than 1 exacerbation requiring hospitalisation every 2 years). In some embodiments, the treatment may prevent bronchiectasis exacerbations requiring hospitalisation. In such embodiments, the treatment may reduce the overall number of exacerbations as well as the number requiring hospitalisation. Alternatively, the overall number may remain essentially unchanged, but their severity reduced so that fewer exacerbations result in hospitalization. Thus it will be understood that even as the number of exacerbations requiring hospitalization is reduced, the proportion of exacerbations requiring hospitalization may be unchanged, or may decrease or even increase.

[0115] Additionally, or alternatively, to reducing exacerbations requiring hospitalization, where the treatment reduces the severity of exacerbations it may reduce exacerbations requiring antibiotics. By this is meant that the treatment reduces the overall number or frequency of exacerbations of sufficient severity to require antibiotic treatment. As set out above, an exacerbation requiring antibiotic treatment is defined herein as being of at least moderate severity. Thus the bronchiectasis treatment may reduce the overall number or frequency of exacerbations of at least moderate severity.

[0116] In some embodiments, the frequency of exacerbations requiring antibiotic treatment may be reduced by at least 20 %, 40 %, 60 % or 80 %. In some embodiments, where the frequency of exacerbations requiring antibiotic treatment is reduced following commencement of treatment with the antibody, the patient may experience an average of no more than 2 exacerbations requiring antibiotic treatment per year, or an average of no more than 1 exacerbation requiring antibiotic treatment per year, or an average of no more than 0.5 exacerbations requiring antibiotic treatment per year (i.e. no more than 1 exacerbation requiring antibiotic treatment every 2 years). In some embodiments, the treatment may prevent bronchiectasis exacerbations requiring antibiotic treatment. In such embodiments, the treatment may reduce the overall number of exacerbations as well as the number requiring antibiotic treatment. Alternatively, the overall number may remain essentially unchanged, but their severity reduced so that fewer exacerbations require antibiotic treatment. Thus it will be understood that even as the number of exacerbations requiring antibiotic treatment is reduced, the proportion of exacerbations requiring antibiotic treatment may be unchanged, or may decrease or even increase.

[0117] In some embodiments of the methods provided herein, treatment with the anti-IL-33 antibody reduces the patient’s need for antibiotics (i.e., compared to the patient’s need for antibiotics prior to the commencement of treatment with the anti-IL-33 antibody). A reduction of a patient’s need for antibiotics may be as a result of reducing the number of exacerbations requiring antibiotic treatment, as described above. A reduction in a patient’s need for antibiotics may be as a result of a reduction in severity of exacerbations meaning that shorter courses of antibiotics are required to treat them. In some embodiments, the patient is on long-term antibiotics, and the treatment provided herein reduces the patient’s need for the antibiotics, such that the dose is reduced (by reducing the frequency of dosing and / or the dose size). For example, the overall dose of antibiotic administered to the patient across a given time period (e.g. a week or a month) may be reduced by at least 10 %, 20 %, 30 %, 40 %, 50 %, 60 % or 70 %. In some cases, treatment of the patient with the anti-IL-33 antibody means that the patient no longer requires long-term antibiotic therapy. Effective substitution of antibiotic therapy with anti-IL-33 therapy may be advantageous due to e.g. reduced side-effects, increased convenience as the anti-IL-33 antibody would likely be administered less frequently than the antibiotic, and reduced risk of driving development of antibiotic resistance in bacterial populations resulting from their long-term exposure to them. In some embodiments, the reduction in the patient’s need for antibiotics is a reduction in the patient’s need for intravenous antibiotics. This is particularly the case when the treatment reduces exacerbations requiring hospitalisation and antibiotic therapy. By a reduction in a patient’s need for intravenous antibiotics means that either (1) the frequency with which the patient requires intravenous antibiotic therapy is reduced; and / or (2) the total average time spent annually on intravenous antibiotic therapy is reduced. A reduction in the need for intravenous antibiotics may mean that the patient’s need for antibiotic treatment is reduced overall. Alternatively, or additionally, the average condition of the patient may be improved following the commencement of anti-IL-33 treatment, such that when the patient needs antibiotic therapy, oral or nebulised antibiotics more frequently suffice and intravenous antibiotics are required less frequently.

[0118] In some embodiments, the reduction in a patient's need for antibiotics is a reduction in the patient's need for nebulised antibiotics. This is particularly the case when the treatment reduces the patient’s need for long-term antibiotic therapy.

[0119] In some aspects, the treatments provided herein stabilise or improve lung function in the patient.

[0120] In some aspects, the treatments provided herein improve airflow through the lungs of the patient. Airflow through the lungs can be measured as forced expiratory volume in 1 second (FEV1). FEV1 is the maximum volume of air that an individual can forcibly expel during the first second following maximum inhalation. FEV1 is one measure of lung function. Conveniently, FEV1 can be measured by spirometry, as is well known in the art. The higher the FEV1 value, the greater the level of airflow through the patient’s lungs; conversely, the lower the FEV1 value, the worse the airflow through the patient’s lungs. Accordingly, in some aspects, the treatments provided herein improve (i.e. increase) FEV1 in the patient.

[0121] In some cases, the increase in FEV1 is by at least 5 %, 10 %, 15 %, 20 %, 30 %, 40 %, 50 %, 60 %, 70 %, 80 %, 90 % or 100 %, relative to the FEV1 observed prior to the commencement of treatment.

[0122] In some cases, prior to treatment, the patient has an FEV1 less than 80 % of the predicted normal value (i.e. the value expected for a healthy patient of that age, sex and size). Predicted normal FEV1 values can be obtained from the Global Lung Function Initiative. An FEV1 less than 80 % of the predicted normal value is considered subnormal. In some cases, prior to treatment, the patient has an FEV1 less than 70, 60, 50, 40 or 30 % of the predicted normal value. Following commencement of treatment with the anti-IL-33 antibody, the patient may have an improved FEV1 of at least 30, 40, 50, 60, 70 or 80 % of the predicted normal value. Thus in some instances, the patient may have a subnormal FEV1 prior to commencing treatment with the anti-IL-33 antibody, which improves to fall within the normal range following commencement of treatment with the anti-IL-33 antibody. The improvement in FEV1 may be observed at any timepoint following commencement of treatment with the anti-IL-33 antibody. In some cases the improvement is observed at week 4, 8, 12, 24, 36 or 52 following commencement of the anti-IL-33 treatment. That is to say, the improvement in FEV1 may occur within 4, 8, 12, 24, 36 or 52 weeks of the first administration of the anti-IL-33 antibody.

[0123] FEV1 can be improved by administration of an inhaled bronchodilator (e.g. salbutamol). The values described above relate to the patient’s baseline FEV1 , i.e. without administration of an inhaled bronchodilator.

[0124] Thus in some embodiments, improvement of lung function is achieved by improvement of FEV1. In some embodiments, lung function is stabilised by stabilising the patient’s FEV1. I.e., in some embodiments treatment with the anti-IL-33 antibody stabilises the patient’s FEV1, i.e. it prevents the patient’s FEV1 from reducing.

[0125] Another measurement of lung function is forced vital capacity (FVC), which is the total volume of air which can be forcibly exhaled after maximum inhalation. Conveniently, FVC may be measured by spirometry. A reduction in lung function can cause a reduction in FVC. Thus in some embodiments, stabilisation of lung function causes stabilisation of the patient’s FVC, i.e. it prevents the patient’s FVC from reducing. In some embodiments, treatment with the anti-IL-33 antibody causes an improvement in lung function, resulting in an increase in FVC. In some cases, the increase in FVC is by at least 5 %, 10 %, 15 %, 20 %, 30 %, 40 %, 50 %, 60 %, 70 %, 80 %, 90 % or 100 %, relative to the FVC observed prior to the commencement of treatment. In some cases the improvement in FVC is observed at week 4, 8, 12, 24, 36 or 52 following commencement of the anti-IL-33 treatment.

[0126] Another measurement of lung function is the modified Tiffeneau-Pinelli index, also referred to as the FEV1 / FVC ratio. An FEV1 / FVC ratio of less than 0.7 may be deemed to indicate an obstructive lung disease, with values of less than 0.6 indicating at least a moderate degree of obstruction and values of less than 0.5 indicating severe obstruction. Values of 0.7 and above may be deemed healthy. A reduction in lung function can cause a reduction in FEV1 / FVC ratio. Generally, the FEV1 / FVC ratio is calculated used readings taken post administration of an inhaled bronchodilator.

[0127] In some embodiments, the patient has a post-bronchodilator FEV1 / FVC ratio of less than 0.7, 0.6, 0.5, 0.4 or 0.3 prior to commencing anti-IL-33 treatment. In some embodiments, stabilisation of lung function causes stabilisation of the patient’s FEV1 / FVC ratio, i.e. it prevents the patient’s FEV1 / FVC ratio from reducing. In some embodiments, treatment with the anti-IL-33 antibody causes an improvement in lung function, resulting in an increase in FEV1 / FVC ratio. In some embodiments, the increase in FEV1 / FVC ratio is of at least 5 %, 10 %, 15 %, 20 %, 30 %, 40 %, 50 %, 60 %, 70 %, 80 %, 90 % or 100 %, relative to the ratio prior to commencing anti-IL-33 treatment. In some embodiments, the increase in FEV1 / FVC is an absolute increase of at least 0.1 , 0.2, 0.3, 0.4, 0.5, 0.6 or 0.7. In some embodiments, the increase in FEV1 / FVC ratio is to > 0.5, 0.6 or 0.7. In some embodiments, the increase in FEV1 / FVC ratio is to > 0.75, > 0.80, > 0.85, > 0.90 or > 0.95. In some cases the improvement in FVC is observed at week 4, 8, 12, 24, 36 or 52 following commencement of the anti-IL-33 treatment.

[0128] In some aspects, the treatment provided herein reduce bronchiectasis symptoms in the patient. For example, the treatment may reduce the severity of the patient’s cough, sputum production, dyspnoea, haemoptysis, sputum production, wheezing and / or chest pain. In some embodiments, the treatment provided herein may prevent, or put an end to, the patient’s cough, sputum production, dyspnoea, haemoptysis, sputum production, wheezing and / or chest pain. I.e. the anti-IL-33 treatment may cause one or more of the bronchiectasis patient’s symptoms to reduce in severity or disappear.

[0129] In particular aspects, the treatment herein provides a method of treating cough in a patient with bronchiectasis. Also provided is a method of reducing cough in a patient with bronchiectasis. In particular, provided herein is a method of reducing cough severity in a patient with bronchiectasis. Cough severity may be measured in any suitable way.

[0130] In some embodiments, the treatment results in a decrease in objective cough frequency over 24 hours, relative to baseline. Objective cough frequency over 24 hours may be measured using an automated cough monitor (ACM), for example the VitaloJAK™ (Vitalograph, Buckinghamshire, UK), which is fitted and worn by the subject for approximately 24 hours and records cough frequency. Alternatively, objective cough frequency may be recorded through alternative means, for example recording or direct observation of the subject, followed by construction of a tally or count. In some embodiments, the decrease in objective cough frequency is at least 5 %, 10 %, 15 %, 20 %, 30 %, 40 %, 50 %, 60 %, 70 %, 80 %, 90 % or 95 % relative to the frequency before commencing anti-IL-33 treatment.

[0131] In some embodiments, the treatment results in a reduction in severity as measured by the cough visual analogue scale (cough VAS). Cough VAS, or cough severity VAS, comprises a 100 mm linear scale marked with a horizontal line by the subject, with 0 mm representing “no cough” and 100 mm representing “worst cough”, measuring subjective assessment by the subject of the prior 24 hrs for severity of cough symptoms (Nguyen et al., Therapeutic Advances in Respiratory Disease 15: 17534666211049743, 2021). In some instances, the reduction in cough severity according to the cough VAS is of at least 5 %, 10 %, 15 %, 20 %, 30 %, 40 %, 50 %, 60 %, 70 %, 80 %, 90 % or 95 % relative to the severity before commencing anti-IL-33 treatment.

[0132] In some embodiments, the treatment results in a reduction in severity as measured by the cough severity index (CSI), which is scored from 0-40 based on a 10-question questionnaire (Shembel et al., The Laryngoscope 123(8): 1931-1936, 2013). In some instances, the reduction in cough severity according to the CSI is of at least 5 %, 10 %, 15 %, 20 %, 30 %, 40 %, 50 %, 60 %, 70 %, 80 %, 90 % or 95 % relative to the severity before commencing anti-IL-33 treatment.

[0133] In some embodiments, the reduction in cough is observed at week 4, 8, 12, 24, 36 or 52 following commencement of the anti-IL-33 treatment.

[0134] In some embodiments, the methods of treatment provided herein reduce sputum production by the patient. Sputum production may be measured based on the total volume of sputum coughed up by the patient during a given length of time, e.g. over the course of a day. The patient may be provided with a collection vessel and instructed to collect the sputum they produce over the specified period of time. The treatment may cause a reduction in sputum production in a given period of time of at least 5 %, 10 %, 15 %, 20 %, 30 %, 40 %, 50 %, 60 %, 70 %, 80 %, 90 % or 95 % relative to the amount of sputum produced in the same period of time prior to the commencement of the anti-IL-33 treatment. In some embodiments, the reduction in sputum production is observed at week 4, 8, 12, 24, 36 or 52 following commencement of the anti-IL-33 treatment.

[0135] In some embodiments, the methods of treatment provided herein reduce the viscosity of sputum produced by the patient. Bronchiectasis is commonly characterised by the production of highly viscous sputum, which is believed to be caused by high concentrations of mucins and DNA in the sputum. Sputum hyperviscosity results in impaired sputum transport / clearance from the lungs, contributing to bacterial infection and colonisation. The viscosity of sputum produced by bronchiectasis patients can be analysed by any suitable method. For instance, sputum can either be collected following spontaneous expectoration, or by hypertonic saline induction. Sputum viscosity can be measured by e.g. cone and plate rheology. Mucin concentration in sputum can be measured by e.g. mass spectrometry, and DNA concentration in sputum can be measured using a commercial DNA quantification assay, e.g. the Quant-iT™ PicoGreen™ dsDNA assay (Thermo Fisher, USA).

[0136] The treatment may cause a reduction in sputum viscosity of at least 5 %, 10 %, 15 %, 20 %, 30 %, 40 % or 50 %, relative to the sputum viscosity before commencing anti- IL-33 treatment. The treatment may cause a reduction in mucin concentration in the sputum of at least 5 %, 10 %, 15 %, 20 %, 30 %, 40 % or 50 %, relative to the sputum mucin concentration before commencing anti-IL-33 treatment. The treatment may cause a reduction in DNA concentration in the sputum of at least 5 %, 10 %, 15 %, 20 %, 30 %, 40 %, 50 %, 60 %, 70 %, 80 %, 90 % or 95 % relative to the sputum DNA concentration before commencing anti-IL-33 treatment. In some embodiments, the reduction in sputum viscosity, sputum mucin concentration and / or sputum DNA concentration is observed at week 4, 8, 12, 24, 36 or 52 following commencement of the anti-IL-33 treatment. The Examples below demonstrate that an anti-IL-33 antibody as described herein reduces production of the mucin MLIC5AC by airway epithelial cells derived from bronchiectasis patients. Reduction of MLIC5AC production may reduce the mucin concentration in sputum in bronchiectasis patients and thus reduce sputum viscosity, as described above. In some embodiments, the treatment provided herein causes a reduction in MLIC5AC concentration in sputum of at least 10, 20, 30, 40, 50, 60, 70, 80 or 90 %, relative to the sputum MLIC5AC concentration before commencing anti-IL-33 treatment. As noted above, the reduction in MUC5AC concentration may be observed at week 4, 8, 12, 24, 36 or 52 following commencement of the anti-IL-33 treatment.

[0137] Thus, in a further aspect, provided herein is a method for reducing mucin production in a subject with bronchiectasis, the method comprising administering the subject an anti -IL- 33 antibody or antigen-binding fragment thereof, as described herein. Specifically, the method may be seen as a method for reducing MUC5AC production in a subject with bronchiectasis, the method comprising administering the subject an anti-IL-33 antibody or antigen-binding fragment thereof, as described herein. In these methods, the reduction in mucin or MUC5AC production may be a reduction in mucin or MUC5AC production by airway epithelial cells in the subject. A reduction in mucin or MUC5AC production may be measured by determining the mucin or MUC5AC concentration in sputum from the subject: a reduction in mucin or MUC5AC concentration in the sputum indicates a reduction in mucin or MUC5AC production by the subject (particularly the airway epithelial cells of the subject).

[0138] Human MUC5AC has the UniProt accession number P98088. MUC5AC may be detected and quantified in sputum by any suitable method in the art, e.g. immunoassay (such as ELISA) as demonstrated in the Examples below. MUC5AC ELISA kits are commercially available, e.g. from Novus Biologicals, USA.

[0139] In some embodiments the treatment causes a reduction in the bacterial load in sputum cultures obtained from the patient. Bacterial infection or colonisation of the patient’s lungs results in the presence of bacteria in the patient’s sputum. The amount of bacteria in the patient’s sputum is referred to herein as the bacterial load. An increased bacterial load is associated with more severe bronchiectasis disease and worse outcomes, primarily due to increased lung inflammation in patients with increased bacterial colonisation. Sputum bacterial load can be routinely measure by sputum culture, methods for which are well known in the art. Sputum is collected as described above, optionally diluted and then plated onto growth medium and incubated, and the resulting number of colonies counted. Bacterial load is measured in colony forming units (cfu) per gram of sputum (cfu / g). A bacterial load of at least 107cfu / g has previously been identified as a bronchiectasis “inflammatory threshold”, at which the bacterial load drives worsening inflammation, worse symptoms and more exacerbations (Sibila et al., American Journal of Respiratory and Critical Care Medicine 200(1): 33-41 , 2019).

[0140] The treatment may cause a reduction in bacterial load of at least 5 %, 10 %, 15 %, 20 %, 30 %, 40 %, 50 %, 60 %, 70 %, 80 %, 90 %, 95 % or 99 %, relative to the bacterial load before commencing anti-IL-33 treatment. In some embodiments, the reduction in bacterial load is observed at week 4, 8, 12, 24, 36 or 52 following commencement of the anti-IL-33 treatment.

[0141] In some aspects, the methods of treatment provided herein reduce the severity of bronchiectasis in the patient. That is to say, the methods of treatment provided herein may cause a reduction in severity of bronchiectasis, as measured by the BSI (discussed above). In some embodiments, the methods of treatment provided herein cause a reduction in BSI score of at least 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 points, relative to the BSI score prior to the commencement of treatment. In some embodiments, the methods of treatment provided herein cause a reduction in the grading of the severity of the patient’s bronchiectasis, as measured by the BSI. By “a reduction in the grading of the severity of the patient’s bronchiectasis” is meant that the BSI score is reduced from a “severe” grade (i.e. a score of at least 9) to a moderate or mild grade (score of 0-8), or from a moderate grade (score of 5- 8) to a mild grade (score of 0-4). The reduction in bronchiectasis severity may be observed at week 4, 8, 12, 24, 52 or 104 following commencement of the anti-IL-33 treatment.

[0142] In some embodiments, the methods of treatment provided herein reduce mucus plugging in the patient. Mucus plugging (also referred to as mucoid impaction) refers to the filling and blocking of an airway with mucus, due to failure to clear the mucus from the airway. Mucus plugging may occur in bronchiectasis, particularly plugging of the bronchi. Mucus plugging may be visualised by CT scanning. The treatments provided herein may reduce mucus plugging. In some embodiments, the treatment may reduce or entirely remove existing mucus plugging from one or more bronchi. In some embodiments, the treatment may prevent the development of mucus plugging, or may prevent existing mucus plugging from worsening (e.g. the treatment may cause stabilisation of mucus plugging). Reduction, stabilisation or prevention of mucus plugging may be visualised by CT scanning.

[0143] In some aspects, the methods of treatment provided herein improve the quality of life of the bronchiectasis patient. The quality of life of a bronchiectasis patient may be quantified by any suitable assessment tool. For example, the Quality of Life-Bronchiectasis (QOL-B) questionnaire (Quittner et al., Thorax 70: 12-20, 2015). This analyses 8 aspects of the impact of bronchiectasis on the patient (respiratory symptoms, physical, role, emotional and social functioning, vitality, health perceptions and treatment burden). Alternatively, the St George’s Respiratory Questionnaire (SGRQ) may be used (Wilson et al., American Journal of Respiratory and Critical Care Medicine 156(2): 536-541, 1997). In a further alternative, the Bronchiectasis Impact Measure (BIM) may be used (Crichton etal., European Respiratory Journal 57: 2003156, 2021). In some embodiments, the improvement in quality of life is observed at week 4, 8, 12, 24, 36 or 52 following commencement of the anti-IL-33 treatment.

[0144] Anti-IL-33 Antibodies

[0145] As set out above, the methods of treatment provided herein comprise administering an anti- IL-33 antibody or fragment thereof to the bronchiectasis patient.

[0146] As defined herein, in line with standard terminology in the art, an antibody is an antigen-binding protein comprising two heavy chains and two light chains. The light chains are shorter (and thus lighter) than the heavy chains. The heavy chains comprise an N-terminal heavy chain variable domain, alternatively referred to as a variable region (VH), and the light chains comprise an N-terminal light chain variable domain (VL). The heavy and light chains each comprise constant domains (alternatively referred to as constant regions) C terminal to the respective variable domain.

[0147] Both the light and heavy chains of an antibody comprise three hypervariable complementarity-determining regions (CDRs) located within the variable domain. In a pair of a light chain and a heavy chain, the CDRs of the two chains form the antigen-binding site. The three CDRs of a heavy chain are known as VHCDR1 , VHCDR2 and VHCDR3, from N- terminus to C-terminus, and the three CDRs of a light chain are known as VLCDR1 , VLCDR2 and VLCDR3, from N terminus to C terminus. Framework regions are located in between the CDRs and between the CDRs and ends of the variable domains. The framework regions largely adopt a p-sheet conformation and the CDRs form loops that connect, and in some cases form part of, the p-sheet structure. Thus, framework regions act to form a scaffold that provides for positioning the CDRs in correct orientation by inter-chain, non-covalent interactions. The antigen binding domain formed by the positioned CDRs defines a surface complementary to the epitope on the immunoreactive antigen. This complementary surface promotes the non-covalent binding of the antibody to its cognate epitope.

[0148] The constant domains of the light chain (CL) and the heavy chain (CH1 , CH2 or CH3) confer important biological properties such as secretion, transplacental mobility, Fc receptor binding, complement binding, and the like. By convention the numbering of the constant region domains increases as they become more distal from the antigen binding site or N-terminus of the antibody.

[0149] As used herein, the terms "antibody" and "immunoglobulin" are used interchangeably. The term "antibody" encompasses monoclonal antibodies, chimeric antibodies, humanized antibodies, human antibodies, bispecific antibodies, and any other immunoglobulin molecule so long as the antibodies exhibit the desired biological activity. An antibody can be of any of the five major classes of immunoglobulins: IgA, I g D, IgE, IgG, and IgM, or subclasses (isotypes) thereof (e.g. lgG1 , lgG2, lgG3, lgG-4, lgA1 , and lgA2), based on the identity of their heavy-chain constant domains referred to as alpha (a), delta (5), epsilon (5), gamma (y), and mu (p), respectively. The different classes of antibodies have different and well-known subunit structures and three-dimensional configurations.

[0150] Light chains are classified as either kappa or lambda (K or A). Each heavy chain class can be bound with either a kappa or lambda light chain. In general, the light and heavy chains are covalently bonded to each other, and the "tail" portions of the two heavy chains are bonded to each other by covalent disulfide linkages or non-covalent linkages when the immunoglobulins are generated either by hybridomas, B cells or genetically engineered host cells. In the heavy chain, the amino acid sequences run from an N-terminus at the forked ends of the Y configuration to the C-terminus at the bottom of each chain.

[0151] Antigen-binding fragments of antibodies are fragments or synthetic constructs comprising one or more antigen-binding sites of an antibody, but not the entire antibody. Generally an antigen-binding fragment of an antibody comprises the entire VL and VH domain sequences, but lacks at least part of the heavy and / or light chain constant domains. An antigen-binding fragment of an antibody can be monovalent or multi-valent (e.g. bivalent). An antigen-binding fragment of an antibody can be monospecific or multi-specific (e.g. bispecific).

[0152] The term "epitope" as used herein refers to an antigenic determinant that interacts with a specific antigen-binding site in the variable regions of an antibody molecule known as a paratope. Epitopes may be either conformational or linear. A conformational epitope is produced by spatially juxtaposed amino acids from different segments of the linear polypeptide chain. A linear epitope is one produced by adjacent amino acid residues in a polypeptide chain. In certain circumstances, an epitope may include post-translational modifications, such as moieties of saccharides, phosphoryl groups or sulfonyl groups on the antigen.

[0153] Generally, the anti-IL-33 antibody or fragment thereof used herein is a monoclonal antibody or fragment thereof. A “monoclonal antibody” (or antigen-binding fragment thereof) refers to a homogeneous antibody or antigen-binding fragment population. This is in contrast to polyclonal antibodies, which are heterogenous antibody populations that typically include antibodies directed against different antigenic determinants.

[0154] The anti-IL-33 antibody (or fragment thereof) binds IL-33 and inhibits IL-33 mediated activation of EGFR / RAGE. Generally, the anti-IL-33 antibody also inhibits IL-33 mediated activation of ST2 / IL1 RAcP. That is to say, the anti-IL-33 antibody binds IL-33 and generally inhibits IL-33 mediated activation of both EGFR / RAGE and ST2 / IL1 RAcP. Without being bound by theory, it is postulated that blockade of both IL-33 receptors may improve bronchiectasis treatment compared to blockade of just one or the other receptor.

[0155] Anti-IL-33 antibodies may be generated and identified using any suitable method known in the art. Inhibition of IL-33 mediated activation of EGFR / RAGE may be assessed using e.g. the scratch wound healing assay using A549 epithelial cells described in England et al., supra. Inhibition of IL-33 mediated activation of ST2 / IL1 RAcP may be determined using the human umbilical vein endothelial cell (HUVEC) NF-KB / cytokine release assay also described in England et al., supra.

[0156] As set out above, the oxidised form of IL-33 (I L-33OX) binds and activates the RAGE / EGFR complex, whereas the reduced form of IL-33 (IL-33red) binds and activates the ST2 / ILI RAcP complex. The anti-IL-33 antibody for use herein may bind I L-33OXand block its interaction with RAGE / EGFR. In some embodiments, the anti-IL-33 antibody binds I L-33OXand IL-33red, blocking the interaction of I L-33OXwith RAGE / EGFR and the interaction of I L-33redwith ST2 / ILI RAcP. Alternatively, the antibody may inhibit IL-33 interactions with RAGE / EGFR and ST2 / ILI RAcP by binding IL-33redand blocking both the binding of IL-33redto ST2 / ILI RAcP, and the oxidation of I L-33red(thereby inhibiting activation of RAGE / EGFR by IL-33).

[0157] Thus in some embodiments, the anti-IL-33 antibody binds IL-33red; in some embodiments the anti-IL-33 antibody binds IL-33OX; and in some embodiments the anti-IL-33 antibody binds both IL-33redand I L-33OX. Where the antibody binds I L-33redand IL-33OX, the antibody may bind both the reduced and oxidised forms of IL-33 with approximately the same affinity, or it may bind one form of IL-33 with higher affinity than the other. I.e. the antibody may bind I L-33redwith higher affinity than I L-33OX, or it may bind I L-33OXwith higher affinity than IL-33red.

[0158] In some embodiments, the antibody binds I L-33OXwith an affinity (i.e. KD) of at least IO’7M, 5 x 10’8M, 10’8M, 5 x 10’9M, 10’9M, 5 x 1O’10M or 1O’10M. By “a KDof at least 10'7M” is meant a KD of 10'7M or less. In some embodiments, the antibody binds IL-33redwith an affinity (i.e. KD) of at least 1 IO’10M, 5 x 10’11M, 10’11M, 5 x 10 some embodiments, the antibody binds I L-33redwith an affinity at least equivalent to the affinity of IL-33redfor ST2 (i.e. 90 fM, see England et al., supra). Thus in some embodiments, the antibody binds I L-33redwith an affinity of at least 90 fM, 80 fM, 70 fM, 60 fM, 50 fM, 40 fM or 30 fM.

[0159] In some embodiments, the antibody binds I L-33redwith an affinity at least equivalent to the affinity of I L-33redfor ST2, and binds IL-33OXwith an affinity of at least 100 nM, 90 nM, 80 nM, 70 nM, 60 nM or 50 nM. The anti-IL-33 antibody generally binds IL-33 specifically, in particular human IL-33. As defined herein, an antibody which binds specifically to human IL-33 is an antibody which binds to human IL-33 with a greater affinity than that with which it binds to other molecules, or at least most other molecules. An antibody which binds specifically to human IL-33 may display cross-reactivity with IL-33 from other species, but generally does not bind other human proteins, particularly other human proteins related to IL-33, or binds them with a much lower affinity than with which it binds IL-33. For example, the antibody generally does not bind other members of the IL-1 family, such as I L-1a and IL-1 p, or binds them only much more weakly than it binds IL-33. For instance, the antibody may bind other proteins, such as other IL-1 family members, at least 3, 4, 5, 6, 7 or 8 orders of magnitude more weakly than it binds to IL-33. The anti-IL-33 antibody may specifically bind human I L-33red, human IL-33OXor both human I L-33redand I L-33OX.

[0160] The antibody used herein may comprise:

[0161] (a) a heavy chain variable region comprising a VHCDR1 comprising the sequence of SEQ ID NO: 1 , a VHCDR2 comprising the sequence of SEQ ID NO: 2, and a VHCDR3 comprising the sequence of SEQ ID NO: 3; and

[0162] (b) a light chain variable region comprising a VLCDR1 comprising the sequence of SEQ ID NO: 4, a VLCDR2 comprising the sequence of SEQ ID NO: 5, and a VLCDR3 comprising the sequence of SEQ ID NO: 6.

[0163] The antibody or antigen-binding fragment thereof used herein may be a human antibody or antigen-binding fragment thereof. In particular, the human antibody or fragment thereof may comprise the CDRs of SEQ ID NOs: 1 -6, as detailed above. As used herein, the term “human antibody” includes antibodies having the amino acid sequence of a human immunoglobulin and includes antibodies isolated from human immunoglobulin libraries or from animals transgenic for one or more human immunoglobulins and that do not express endogenous immunoglobulins.

[0164] The antibody or fragment thereof used herein may comprise a heavy chain variable region comprising the sequence set forth in SEQ ID NO: 7, or an amino acid sequence with at least 80, 85, 90 or 95 % sequence identity thereto. When a heavy chain variable region is used which is a variant of SEQ ID NO: 7 (i.e. it comprises an amino acid sequence with at least 80 %, but less than 100 %, identity to SEQ ID NO: 7), the heavy chain CDR sequences are as set out in SEQ ID NOs: 1-3, i.e. any sequence variation is located in the framework sequences.

[0165] The antibody or fragment thereof used herein may comprise a light chain variable region comprising the sequence set forth in SEQ ID NO: 8, or an amino acid sequence with at least 80, 85, 90 or 95 % sequence identity thereto. When a light chain variable region is used which is a variant of SEQ ID NO: 8 (i.e. it comprises an amino acid sequence with at least 80 %, but less than 100 %, identity to SEQ ID NO: 8), the light chain CDR sequences are as set out in SEQ ID NOs: 4-6, i.e. any sequence variation is located in the framework sequences.

[0166] The antibody or fragment thereof used herein may comprise a heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 7, or an amino acid sequence with at least 80, 85, 90 or 95 % sequence identity thereto; and a light chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 8, or an amino acid sequence with at least 80, 85, 90 or 95 % sequence identity thereto.

[0167] In some embodiments, the antibody or fragment thereof used herein comprises a heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 7, and a light chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 8.

[0168] As used herein, the term “sequence identity” or “identity” denotes a property of sequences that measures their similarity or relationship. The term “sequence identity” or “identity” as used herein means the percentage of pair-wise identical residues - following (homologous) alignment of a sequence of a protein or polypeptide of interest with a reference sequence - with respect to the number of residues in the longer of these two sequences. Sequence identity is measured by dividing the number of identical amino acid residues by the total number of residues and multiplying the product by 100.

[0169] A skilled artisan will recognize available computer programs, for example BLAST (Altschul et al., Nucleic Acids Res, 1997), BLAST2 (Altschul et al., J Mol Biol, 1990), FASTA (which uses the method of Pearson and Lipman (1988)), the TBLASTN program, of Altschul et al. (1990) supra, GAP (Wisconsin GCG package, Accelerys Inc, San Diego USA) and Smith-Waterman (Smith and Waterman, J Mol Biol, 1981), for determining sequence identity using standard parameters. The percentage of sequence identity can, for example, be determined herein using the program BLASTP, version 2.2.5, November 16, 2002 (Altschul et al., Nucleic Acids Res, 1997). In this instance, the percentage of homology is based on the alignment of the entire protein or polypeptide sequences (matrix: BLOSUM 62; gap costs: 11.1 ; cut off value set to 10'3). It is calculated as the percentage of numbers of “positives” (homologous amino acids) indicated as result in the BLASTP program output divided by the total number of amino acids selected by the program for the alignment. Sequence identity is commonly defined with reference to the algorithm GAP (Wisconsin GCG package, Accelerys Inc, San Diego USA). GAP uses the Needleman and Wunsch algorithm to align two complete sequences, maximising the number of matches and minimising the number of gaps, which are spaces in an alignment that are the result of additions or deletions of amino acids. Generally, default parameters are used, with a gap creation penalty equalling 12 and a gap extension penalty equalling 4. In some embodiments, the patient is administered an anti-IL-33 antibody (that is to say, a full-length anti-IL-33 antibody). The full-length antibody may be of any isotype or subclass thereof. In particular, the antibody may be an IgG, e.g. lgG1 , lgG2, lgG3 or lgG4 antibody. Most particularly, the antibody may be an IgG 1 antibody. In particular, the antibody may comprise a human lgG1 constant region.

[0170] In particular embodiments, the antibody used herein is tozorakimab, as disclosed in WO 2016 / 156440, which is incorporated herein by reference. Tozorakimab is also referred to in the art as MEDI3506 and 33_640087_7B. The heavy chain of tozorakimab has the amino acid sequence set forth in SEQ ID NO: 9, and the light chain of tozorakimab has the amino acid sequence set forth in SEQ ID NO: 10.

[0171] Tozorakimab is a fully human I gG 1 monoclonal antibody that is being developed for the treatment of inter alia chronic obstructive pulmonary disease (COPD). As set out above, tozorakimab binds human I L-33redand prevents binding of IL 33redto the ST2 receptor, and prevents oxidation of I L-33red. Tozorakimab binds human IL-33redwith an exceptionally high affinity of approximately 30 fM, and fully neutralises full-length and all mature forms of endogenous IL-33red(Scott et a / ., ERS International Congress 2022, Barcelona (ES), Abstract OA2254).

[0172] In other embodiments, an anti-IL-33 antibody is used which is not tozorakimab, but which has similar, or the same, pharmacokinetic (pK) characteristics as tozorakimab in humans.

[0173] For example, the anti-IL-33 antibody may have a similar, or the same, half-life in humans as tozorakimab. The anti-IL-33 antibody having a similar, or the same, half-life in humans as tozorakimab, when administered at a dose of 30 mg Q2W, may have a half-life of about 10 to about 20 days, about 12 to about 15 days, or of about 12.7 days. The anti-IL-33 antibody having a similar, or the same, half-life in humans as tozorakimab, when administered at a dose of 100 mg Q2W, may have a half-life of about 10 to about 20 days, about 12 to about 15 days, or of about 13.2 days. The anti-IL-33 antibody having a similar, or the same, half-life in humans as tozorakimab, when administered at a dose of 300 mg Q2W, may have a half-life of about 10 to about 20 days, about 12 to about 15 days, or of about 14.8 days.

[0174] In some embodiments, the IL-33 antibody may competitively inhibit binding of IL-33 to tozorakimab. An antibody is said to competitively inhibit binding of a reference antibody to a given epitope if it specifically binds to (or close to) that epitope to the extent that it blocks, to some degree, binding of the reference antibody to its epitope. Competitive inhibition may be determined by any method known in the art, for example, solid phase assays such as competition ELISA assays, Dissociation-Enhanced Lanthanide Fluorescent Immunoassays (DELFIA®, Perkin Elmer), and radioligand binding assays. For example, the skilled person could determine whether an antibody competes for binding to IL-33 by using an in vitro competitive binding assay, such as the HTRF assay described in WO 2016 / 156440, paragraphs 881-886, which is incorporated herein by reference. For example, the skilled person could label tozorakimab with a donor fluorophore and mix multiple concentrations with fixed concentration samples of acceptor fluorophore labelled-l L-33red. Subsequently, the fluorescence resonance energy transfer between the donor and acceptor fluorophore within each sample can be measured to ascertain binding characteristics. To elucidate competitive binding antibody molecules, the skilled person could first mix various concentrations of a test binding molecule with a fixed concentration of the labelled tozorakimab antibody. A reduction in the FRET signal when the mixture is incubated with labelled IL-33 in comparison with a labelled antibody-only positive control would indicate competitive binding to IL-33. An antibody may be said to competitively inhibit binding of tozorakimab to IL-33 if it reduces tozorakimab binding to IL-33 by at least 90 %, at least 80 %, at least 70 %, at least 60 %, or at least 50 %, when both it and tozorakimab are used at the same concentration.

[0175] Alternatively, the patient may be administered an antigen-binding fragment of an anti- IL-33 antibody. In some embodiments, the patient is administered an antigen-binding fragment of tozorakimab. Antigen-binding fragments of antibodies are discussed in Rodrigo et al., Antibodies, Vol. 4(3), p. 259-277, 2015. Antibody fragments which may be used herein include, for example, Fab, F(ab')2, Fab' and Fv fragments. Fab fragments are discussed in Nelson, mAbs 2(1): 77-83, 2010. A Fab fragment consists of the antigen-binding domain of an antibody, i.e. an individual antibody may be seen to contain two Fab fragments, each consisting of a light chain and its conjoined N-terminal section of the heavy chain. Thus a Fab fragment contains an entire light chain and the VH and CH1 domains of the heavy chain to which it is bound. Fab fragments may be obtained by digesting an antibody with papain.

[0176] F(ab')2 fragments consist of the two Fab fragments of an antibody, plus the hinge regions of the heavy domains, including the disulphide bonds linking the two heavy chains together. In other words, a F(ab')2 fragment can be seen as two covalently joined Fab fragments. F(ab')2 fragments may be obtained by digesting an antibody with pepsin.

[0177] Reduction of F(ab')2 fragments yields two Fab' fragments, which can be seen as Fab fragments containing an additional sulfhydryl group which can be useful for conjugation of the fragment to other molecules.

[0178] Fv fragments consist of just the variable domains of the light and heavy chains. These are not covalently linked and are held together only weakly by non-covalent interactions. Fv fragments can be modified to produce a synthetic construct known as a single chain Fv (scFv) molecule. Such a modification is typically performed recombinantly, by engineering the antibody gene to produce a fusion protein in which a single polypeptide comprises both the VH and VL domains. scFv fragments generally include a peptide linker covalently joining the VH and VL regions, which contributes to the stability of the molecule. The linker may comprise from 1 to 20 amino acids, such as for example 1 , 2, 3 or 4 amino acids, 5, 10 or 15 amino acids, or other intermediate numbers in the range 1 to 20 as convenient. The peptide linker may be formed from any generally convenient amino acid residues, such as glycine and / or serine. One example of a suitable linker is Gly4Ser. Multimers of such linkers may be used, such as for example a dimer, a trimer, a tetramer or a pentamer, e.g. (Gly4Ser)2, (Gly4Ser)3, (Gly4Ser)4 or (Gly4Ser)s. However, it is not essential that a linker be present, and the VL domain may be linked to the VH domain by a peptide bond. An scFv is herein defined as an antibody fragment, or antigen-binding fragment of an antibody. Thus the antibody fragment used herein may be a Fab, F(ab')2, Fab', Fv or scFv.

[0179] In some embodiments, the antibody fragment used herein is multivalent, e.g. a diabody, triabody or tetrabody. Diabodies, triabodies and tetrabodies are described in Cuesta et al., Trends in Biotechnology 28(7): 355-362, 2010.

[0180] Antibody Administration

[0181] The antibody may be administered within a pharmaceutical composition. The pharmaceutical compositions may be formulated with suitable carriers, excipients, and other agents that provide suitable transfer, delivery, tolerance, and the like. A multitude of formulations can be found in the formulary known to all pharmaceutical chemists: Remington's Pharmaceutical Sciences, Mack Publishing Company, Easton, PA. Thus, the pharmaceutical compositions may comprise, in addition to the active ingredient (i.e. the anti-IL-33 antibody), a pharmaceutically acceptable excipient, carrier, buffer, stabiliser or other material well known to those skilled in the art. Such materials should be non-toxic and should not interfere with the efficacy of the active ingredient. The precise nature of the carrier or other material will depend on the route of administration, which may be by injection.

[0182] The pharmaceutical composition may be an aqueous solution which is pyrogen-free and has suitable pH, isotonicity and stability. The pharmaceutical composition may be a liquid formulation or a lyophilized formulation which is reconstituted before use. As excipients for a lyophilized formulation, for example, sugar alcohols, or saccharides (e.g. mannitol or glucose) may be used. In the case of a liquid formulation, the pharmaceutical composition is usually provided in the form of containers with defined volume, including sealed and sterilized plastic or glass vials, ampoules and syringes, as well as in the form of large volume containers like bottles. Generally, in the methods described herein, the pharmaceutical composition is a liquid formulation. Commonly, such a liquid pharmaceutical composition is provided in a vial. When the anti-IL-33 antibody is provided in a liquid composition, the composition may be buffered to a pH of 5.2 to 5.7, most suitably about 5.5 (± 0.1). It will be appreciated that references to a "pharmaceutically acceptable excipient" includes references to any excipient conventionally used in pharmaceutical compositions. Such excipients may typically include one or more surfactant, inorganic or organic salt, stabilizer, diluent, solubilizer, reducing agent, antioxidant, chelating agent, preservative and the like.

[0183] In some embodiments, a surfactant is present within the pharmaceutical composition in an amount of from 0.001 % to 0.1 % (w / w). For example, the surfactant may be polysorbate-80 (PS-80).

[0184] The anti-IL-33 antibody (particularly tozorakimab) may be provided in a pharmaceutical composition comprising L-histidine and / or L-histidine hydrochloride, L-arginine hydrochloride and polysorbate 80. The composition may in particular comprise 20 mM ± 10 % L-histidine / L-histidine hydrochloride, e.g. 20 mM ± 2.5 %, 5 % or 7.5 % L-histidine / L-histidine hydrochloride. That is to say L-histidine / L-histidine hydrochloride may be present in the composition at a concentration from 18-22, 18.5-21.5, 19-21 or 19.5- 20.5 mM, in particular at a concentration of 20 mM.

[0185] The composition may in particular comprise 220 mM ± 10 % L-arginine hydrochloride, e.g. 220 mM ± 2.5 %, 5 % or 7.5 % L-arginine hydrochloride. For instance, L-arginine hydrochloride may be present in the composition at a concentration from 200-240, 205-235, 210-230 or 215-225 mM, in particular at a concentration of 220 mM.

[0186] The composition may in particular comprise 0.03 % w / v ± 10 % polysorbate 80, e.g. 0.03 % w / v ± 2.5 %, 5 % or 7.5 % polysorbate 80. For instance, polysorbate 80 may be present in the composition at a concentration from 0.027-0.033, 0.028-0.032 or 0.029-0.031 % w / v, in particular at a concentration of 0.03 % w / v.

[0187] The composition may have a pH from 5.2-5.7, 5.3-5.6 or 5.4-5.5, in particular 5.5.

[0188] In some embodiments, the pharmaceutical composition comprises 20 mM L-histidine / L-histidine hydrochloride, 220 mM L-arginine hydrochloride and 0.03 % w / v polysorbate 80, and has a pH of 5.5.

[0189] The anti-IL-33 antibody may be administered to the subject by any suitable route known in the art. In particular, the anti-IL-33 antibody may be administered to the patient subcutaneously.

[0190] The anti-IL-33 antibody is administered in a therapeutically effective amount. As used herein, an “effective amount” or “therapeutically effective amount” of the anti-IL-33 antibody refers to an amount effective, at dosages and for periods of time necessary, to achieve the desired therapeutic result.

[0191] Any suitable antibody dosage may be used. Generally, the antibody is administered as a flat dose (i.e. a body weight-independent dose). In some embodiments, the anti-IL-33 antibody is administered in a dose of about 200 to about 400 mg, about 250 to about 350 mg, about 260 to about 340 mg, about 270 to about 330 mg, about 280 to about 320 mg, about 290 to about 310 mg, about 295 to about 305 mg or about 300 mg.

[0192] In some embodiments, the dose is 300 mg. In some embodiments, the anti-IL-33 antibody is formulated for subcutaneous injection at 150 mg / ml, such that a 300 mg dose is administered as a 2 ml treatment. In some embodiments, a 300 mg dose of the anti-IL-33 antibody is administered as two concurrent 150 mg doses. As used herein, the term “concurrent doses” refers to doses which are administered simultaneously, or sequentially with no or only a minimal time period (e.g. less than 1 hour, less than 30 minutes, less than 15 minutes, less than 5 minutes) separating them.

[0193] The size of the dose of the anti-IL-33 antibody may be expressed in terms of the plasma drug concentration provided by the dose, as the amount of active compound administered so as to provide a plasma drug concentration of a certain level. By varying the amount, bioavailability, or timing / frequency of the antibody administered, the skilled person can control the plasma concentration in the subject. As plasma concentrations vary across time with drug uptake and clearance, they may be expressed in various standardised ways - for example as a maximum, minimum (trough) or across time.

[0194] In some embodiments, the dose is selected so as to provide a Cmax.ss (the observed maximum concentration at steady state) of between about 20 and about 50 pg / ml, between about 25 and about 45 pg / ml, between about 30 and about 40 pg / ml, between about 35 and about 40 pg / ml, or about 37 pg / ml. In some embodiments, the dose is selected so as to provide a Cmax.ss of between about 10 and about 35 pg / ml, between about 15 and about 30 pg / ml, between about 15 and about 30 pg / ml, between about 15 and about 25 pg / ml, about 15 to about 20 pg / ml, or about 18.6 pg / ml. In some instances, the Cmax.ss is that observed during the dosing period. In this context, the “dosing period” refers to the time between two consecutive doses.

[0195] In some embodiments, the anti-IL-33 antibody is administered at a dose selected so as to provide an area under the plasma concentration-time curve throughout a dosing period (AUC).

[0196] In some embodiments, the dose is selected so as to provide an AUC of between about 400 and about 800 pg ■ day / ml, between about 500 and about 750 pg ■ day / ml, between about 600 and about 700 pg ■ day / ml, between about 600 and about 650 pg ■ day / ml, between about 600 and about 620 pg ■ day / ml, between about 610 and about 620 pg ■ day / ml, or about 616 pg ■ day / ml over the dosing period. In some embodiments, the dose is selected so as to provide an AUC of between about 200 and about 515 pg ■ day / ml, between about 250 and about 500 pg ■ day / ml, between about 300 and about 450 pg ■ day / ml, between about 300 and about 350 pg ■ day / ml, or about 323 pg ■ day / ml over the dosing period. In some embodiments, the dose is selected so as to provide an AUC of between about 100 and about 300 pg ■ day / ml, between about 100 and about 250 pg ■ day / ml, between about 100 and about 200 pg ■ day / ml, between about 150 and about 200 pg ■ day / ml, or about 161.5 pg ■ day / ml over the dosing period.

[0197] Administration of the anti-IL-33 antibody is performed as multiple doses separated by a dosing interval. In some embodiments, the dosing interval is 1 to 4 weeks, e.g. 1 week (7 days), 2 weeks (14 days), 3 weeks (21 days) or 4 weeks (28 days).

[0198] In particular embodiments, the anti-IL-33 antibody is administered to the patient at a dose of 250 to 350 mg every 1 to 4 weeks. In particular embodiments, tozorakimab is administered to the patient at a dose of 250 to 350 mg every 1 to 4 weeks.

[0199] In particular embodiments, the anti-IL-33 antibody (in particular tozorakimab) is administered to the patient at a dose of 250 to 350 mg every 2 weeks or every 4 weeks.

[0200] In particular embodiments, the anti-IL-33 antibody (in particular tozorakimab) is administered to the patient at a dose of 300 mg every 2 weeks or every 4 weeks.

[0201] In particular embodiments, the anti-IL-33 antibody (in particular tozorakimab) is administered to the patient at a dose of 300 mg every 2 weeks.

[0202] When the dosing interval is expressed as a number of weeks, a margin of error is permissible such that a week may be expressed as 7 days ± 1 day. Where the dosing interval is multiple weeks, the margins of error in each week may be combined. For example, the dosing interval may be 2 weeks ± 2 days, or 4 weeks ± 4 days.

[0203] According to the methods provided herein, the anti-IL-33 antibody is administered over a course of therapy. The course of therapy is a period of time commencing at the administration of the first dose and running until the administration of the final dose of the anti-IL-33 antibody.

[0204] In some embodiments, the course of therapy lasts at least 12 weeks, 16 weeks, 20 weeks, 24 weeks, 28 weeks, 32 weeks, 36 weeks, 40 weeks, 44 weeks, 48 weeks or 52 weeks. In some embodiments, the course of therapy lasts at least 3, 4, 5, 6, 7, 8, 9, 10, 11 , 12, 15, 18, 21 or 24 months. In some embodiments, the course of therapy lasts at least 1, 2, 3, 4 or 5 years. In some embodiments, the course of therapy is lifelong, i.e. it is not stopped until the patient dies.

[0205] In particular embodiments, the patient is administered tozorakimab for a course of therapy lasting at least 12 weeks, 16 weeks, 20 weeks, 24 weeks, 28 weeks, 32 weeks, 36 weeks, 40 weeks, 44 weeks, 48 weeks or 52 weeks; 3, 4, 5, 6, 7, 8, 9, 10, 11 , 12, 15, 18, 21 or 24 months; or 1 , 2, 3, 4 or 5 years.

[0206] In particular embodiments, the patient is administered tozorakimab every 1 -4 weeks over a course of therapy lasting at least 12 weeks, 16 weeks, 20 weeks, 24 weeks, 28 weeks, 32 weeks, 36 weeks, 40 weeks, 44 weeks, 48 weeks or 52 weeks; 3, 4, 5, 6, 7, 8, 9, 10, 11 , 12, 15, 18, 21 or 24 months; or 1 , 2, 3, 4 or 5 years. In particular embodiments, the patient is administered 250-350 mg tozorakimab every 1-4 weeks over a course of therapy lasting at least 12 weeks, 16 weeks, 20 weeks, 24 weeks, 28 weeks, 32 weeks, 36 weeks, 40 weeks, 44 weeks, 48 weeks or 52 weeks; 3, 4, 5, 6, 7, 8, 9, 10, 11 , 12, 15, 18, 21 or 24 months; or 1, 2, 3, 4 or 5 years.

[0207] In particular embodiments, the patient is administered 250-350 mg tozorakimab every 2 or 4 weeks over a course of therapy lasting at least 12 weeks, 16 weeks, 20 weeks, 24 weeks, 28 weeks, 32 weeks, 36 weeks, 40 weeks, 44 weeks, 48 weeks or 52 weeks; 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 15, 18, 21 or 24 months; or 1 , 2, 3, 4 or 5 years.

[0208] In particular embodiments, the patient is administered 300 mg tozorakimab every 2 or 4 weeks over a course of therapy lasting at least 12 weeks, 16 weeks, 20 weeks, 24 weeks, 28 weeks, 32 weeks, 36 weeks, 40 weeks, 44 weeks, 48 weeks or 52 weeks; 3, 4, 5, 6, 7, 8, 9, 10, 11 , 12, 15, 18, 21 or 24 months; or 1, 2, 3, 4 or 5 years.

[0209] In particular embodiments, the patient is administered 300 mg tozorakimab every 2 weeks over a course of therapy lasting at least 12 weeks, 16 weeks, 20 weeks, 24 weeks, 28 weeks, 32 weeks, 36 weeks, 40 weeks, 44 weeks, 48 weeks or 52 weeks; 3, 4, 5, 6, 7, 8, 9, 10, 11 , 12, 15, 18, 21 or 24 months; or 1 , 2, 3, 4 or 5 years.

[0210] It will be understood that the features set out in the detailed description above, though commonly described in the context of the methods provided herein, are applicable to all aspects provided here. I.e. the features described above are applicable to the various methods provided herein, the anti-IL-33 antibody or antigen-binding fragment thereof for use in methods of treatment provided herein, the uses of an anti-IL-33 antibody or antigenbinding fragment thereof in the manufacture of a medicament provided herein, the uses of an anti-IL-33 antibody or antigen-binding fragment thereof provided herein, and the pharmaceutical composition comprising an anti-IL-33 antibody or antigen-binding fragment thereof for use in methods of treatment provided herein, along with any and all other related aspects which may be considered to be provided herein.

[0211] EXAMPLES

[0212] Example 1 - Distinct Pharmacological Profiles of IL-33 Antibodies

[0213] The biological activities of 5 anti-IL-33 antibodies were tested: tozorakimab, APE4909 (AnaptysBio, WO 2015 / 106080), 9675P (WO 2014 / 164959), Ab43 (Eli Lilly,

[0214] WO 2018 / 081075) and IL-33158LS (Pfizer, WO 2017 / 187307). 9675P has the variable domains of itepekimab. Antibodies were expressed in CHO cells and evaluated for their capability to block ST2- and EGFR / RAGe-dependent IL-33 activity.

[0215] ST2-dependent activity was determined by co-stimulating PBMCs with IL-12 and I L-33red, and measuring IFNy release. Human PBMCs were sourced and isolated from healthy donors who had provided informed consent, with ethical approval from the RTB (ethics number 16 / EE / 0334); all methods were carried out in accordance with RTB guidelines and regulations. PBMCs were isolated from leukocyte cones using a polysucrose gradient and maintained in RPMI-1640 (supplemented with 10 % v / v heat-inactivated fetal bovine serum and 1 % v / v penicillin / streptomycin). PBMCs were stimulated with human IL-12 (5 ng / ml) and oxidation-resistant mutant IL-33 (IL-33C>S, 0.1 ng / ml). Cells were incubated at 37°C with 5 % CO2 for 48 hours with varying concentrations of an anti-IL-33 antibody or the control antibody NIP228 (a mouse lgG1 kappa antibody against 4-hydroxy-3- iodo-5-nitrophenylacetic acid).

[0216] Media supernatants were collected and soluble IFNy was measured by enzyme- linked immunosorbent assay (ELISA) using anti-human IFNy capture antibody (BD Pharmingen, Franklin Lakes, New Jersey, USA, catalogue number 551221), biotinylated anti-human IFN-y detection antibody (BD Pharmingen, Franklin Lakes, New Jersey, USA, catalogue number 554550) and DELFIA Europium-labelled streptavidin (PerkinElmer, Waltham, Massachusetts, USA) for fluorescent detection and quantification. Data ware analyzed using Prism 8 or Prism 9 software (GraphPad, La Jolla, California, USA), with curve fitting using a four-parameter logistic equation.

[0217] Inhibition of IFNy release indicated blockade of IL-33-mediated ST2 signalling. All tested anti-IL-33 antibodies potently inhibited ST2-mediated IL-33 signalling (Fig. 1).

[0218] EGFR / RAGE-dependent activity was determined by an A549 epithelial cell scratch wound repair assay (England et al., supra). A549 cells (ATCC, CCL-185) were cultured in RPMI medium with GlutaMAX (Thermo Fisher Scientific Inc., 61870036) containing 10 % foetal bovine serum (FBS) and 1 % penicillin / streptomycin. Cells were harvested using accutase (PAA Laboratories, L11-007), seeded at 5 x 105cells / 100 pl into Incucyte Imagelock 96-well plates (Sartorius, BA-04857) and incubated for 6 h at 37°C, 5 % CO2. Cells were washed with PBS, serum starved (RPMI medium with GlutaMax without FBS) and incubated for 16-20 h. Cells were scratched using a WoundMaker™ (Essen Bioscience), washed and treated with RPMI medium with GlutaMAX supplemented with 0.1 % (v / v) FBS and 1 % (v / v) penicillin / streptomycin. Cells were incubated with indicated concentrations of antibodies or were left untreated. Incucyte S3 systems (Essen Bioscience) were used for wound closure imaging and analysis over a 72 h period. Relative wound density was calculated using the wound closure algorithm (Essen Bioscience) and Incucyte S3 software (Essen Bioscience). Data was analysed by normalising the readings to the control wells containing untreated cells.

[0219] Tozorakimab promoted scratch wound repair, indicating blockade of IL-33 mediated RAGE / EGFR signalling (Fig. 2A), unlike the other anti-IL-33 antibodies tested (Fig. 2B). Again, NIP228 was used as negative control. Example 2 - sST2 Dysfunction in Bronchiectasis Patients

[0220] Serum stimulation-2 (also known as ST2, ST2L and IL-1 receptor-like 1 [IL1 RL1]) is the receptor for reduced IL-33. Soluble ST2 (sST2), a secreted variant of ST2, is a soluble decoy receptor for IL-33 that potently inhibits IL-33 activities. Circulating sST2 levels are typically elevated during inflammatory and infectious diseases (Dieplinger et al., Clinica Chimica Acta 409(1-2): 33-40, 2009).

[0221] Levels of sST2 levels in bronchiectasis patients were investigated. NCFB sputum samples were provided by Prof. Antony DeSoyza (Newcastle upon Tyne Hospitals NHS Foundation Trust). Sputum from healthy individuals were purchased from BiolVT, LLC). sST2 was measured using the Quantikine immunoassay (Biotechnie R&D Systems, DST200) according to manufacturer’s instructions. In the two independent cohorts tested, sST2 levels in sputum from bronchiectasis patients were significantly lower than in sputum from healthy individuals (Fig. 3).

[0222] The lowered levels of the IL-33 inhibitor sST2 in bronchiectasis patient sputum indicates that IL-33 activity is increased in bronchiectasis patients. Treatment with an IL-33 inhibitor such as tozorakimab can inhibit excess IL-33 activities in the airways of bronchiectasis patients to reduce IL-33 driven inflammation and tissue remodelling.

[0223] Example 3 - Tozorakimab Reduces Mucin Secretion in 3D Epithelial Cultures from NCFBE The ability of two different anti-IL-33 antibodies to reduce mucin production was tested.

[0224] Human nasal epithelial cells (HNEC) cells from healthy controls or patients with non- cystic fibrosis bronchiectasis (NCFBE) were received from the University of Dundee. Cells were expanded in human airway cell (hAC) Culture Medium (Epithelix, EP09AM) containing 10 pM of Y27632 (Selleckchem, S1573) in a T-75 cm2flask and then frozen in cryovials.

[0225] Transwell membranes (Corning® 0.4 pM pore polyester 24-well, 3470) were coated with collagen I (StemCell, 07001 prepared in dH2O) and incubated at 37°C for between 1 and 16 hours. The collagen I solution was removed and the transwells were washed with PBS. 0.5 ml of hAC Culture Medium containing 10 pM Y27632 was included in the basolateral compartment and 0.25 ml was added to the apical region which contained cells from the cryovial at 5x105 / ml. Cells were kept submerged until a confluent layer formed (typically 7 days) and the media was refreshed every Monday, Wednesday and Friday. Once a confluent layer could be observed the media was removed from the basolateral and apical side and 0.5 ml of complete PneumaCult™-ALI Medium (Stemcell, 05001) containing Hydrocortisone Stock Solution (Stemcell, 07925) and Heparin Solution (Stemcell, 07980) was added to only the basolateral compartment. Cells were left to differentiate for at least four weeks with media changes in the basolateral compartment with complete PneumaCult™-ALI Medium every Monday, Wednesday and Friday.

[0226] Fully differentiated normal (healthy) cultures were not treated. Fully differentiated NCFBE cultures were left untreated or treated with 1 pg / ml tozorakimab (33_640087-7B), 1 pg / ml itepekimab (WV9KZ9PS1A; heavy chain of SEQ ID NO: 11 and light chain of SEQ ID NO: 12) or 1 pg / ml NIP228 (lgG1 isotype control) for 7 days by inclusion of treatments in the media supplied to the basal side of the culture. A media change was performed every Monday, Wednesday and Friday (containing relevant treatments).

[0227] Following 7-day treatments (Table 1) of ALI cultures, 200 pl 37°C DPBS (ThermoFisher Scientific, 14190086) was added to the apical region (Transwell surface) of each Transwell and placed in an incubator for 30 min. The apical wash was stored at -80°C for mucin analysis. Apical washes were thawed and Triton™ X-100 (Sigma Aldrich, X100- 100ML) was added to a final concentration of 0.3 % (v / v) and placed on an orbital shaker at 400 rpm for 15 mins at room temperature. The apical washes were then diluted 1:800 in DPBS (v / v) and levels of MLIC5AC were analysed using a MLIC5AC immunoassay (Novus NBP2-76703) according to manufacturer’s protocol. Concentrations were extrapolated from recombinant MLIC5AC protein standard curves.

[0228] The results are shown in Fig. 4. Untreated nasal epithelial cells from bronchiectasis patients produced much higher levels of MUC5AC than healthy nasal epithelial cells. However, treatment of nasal epithelial cells from bronchiectasis patients with tozorakimab significantly reduced MUC5AC expression, almost to the level of healthy nasal epithelial cells. Itepekimab treatment had no effect on MUC5AC expression (there was no significant difference between the levels of MUC5AC produced by bronchiectasis cells treated with itepekimab and those treated with the isotype control). It is postulated that the effect of tozorakimab on MUC5AC expression results from its inhibition of EGFR / RAGE signalling, which itepekimab is not capable of. This suggests the increased mucin expression displayed by nasal epithelial cells from bronchiectasis patients is driven by IL-33OX.

[0229] SEQUENCE LISTING

[0230] SEQ ID NO: 1 - Tozorakimab VHCDR1

[0231] SYAMS

[0232] SEQ ID NO: 2 - Tozorakimab VHCDR2

[0233] GISAIDQSTYYADSVKG

[0234] SEQ ID NO: 3 - Tozorakimab VHCDR3

[0235] QKFMQLWGGGLRYPFGY

[0236] SEQ ID NO: 4 - Tozorakimab VLCDR1

[0237] SGEGMGDKYAA

[0238] SEQ ID NO: 5 - Tozorakimab VLCDR2

[0239] RDTKRPS

[0240] SEQ ID NO: 6 - Tozorakimab VLCDR3

[0241] GVIQDNTGV

[0242] SEQ ID NO: 7 - Tozorakimab VH

[0243] EVQLLESGGGLVQPGGSLRLSCAASGFTFSSYAMSWVRQAPGKGLEWVSGISAIDQSTYY

[0244] ADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARQKFMQLWGGGLRYPFGYWGQG TMVTVSS

[0245] SEQ ID NO: 8 - Tozorakimab VL

[0246] SYVLTQPPSVSVSPGQTASITCSGEGMGDKYAAWYQQKPGQSPVLVIYRDTKRPSGIPERF

[0247] SGSNSGNTATLTISGTQAMDEADYYCGVIQDNTGVFGGGTKLTVL

[0248] SEQ ID NO: 9 - Tozorakimab Heavy Chain

[0249] EVQLLESGGGLVQPGGSLRLSCAASGFTFSSYAMSWVRQAPGKGLEWVSGISAIDQSTYY

[0250] ADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARQKFMQLWGGGLRYPFGYWGQG TMVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFP AVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAP

[0251] ELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPRE

[0252] EQYNSTYRWSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPS

[0253] REEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKS

[0254] RWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK

[0255] SEQ ID NO: 10 - Tozorakimab Light Chain

[0256] SYVLTQPPSVSVSPGQTASITCSGEGMGDKYAAWYQQKPGQSPVLVIYRDTKRPSGIPERF

[0257] SGSNSGNTATLTISGTQAMDEADYYCGVIQDNTGVFGGGTKLTVLGQPKAAPSVTLFPPSS EELQANKATLVCLISDFYPGAVTVAWKADSSPVKAGVETTTPSKQSNNKYAASSYLSLTPEQ WKSHRSYSCQVTHEGSTVEKTVAPTECS SEQ ID NO: 11 - Itepekimab Heavy Chain

[0258] EVQLVESGGNLEQPGGSLRLSCTASGFTFSRSAMNWVRRAPGKGLEWVSGISGSGGRTY

[0259] YADSVKGRFTISRDNSKNTLYLQMNSLSAEDTAAYYCAKDSYTTSWYGGMDVWGHGTTVT

[0260] VSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQ SSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPEFLGGPS

[0261] VFLFPPKPKDTLMISRTPEVTCWVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNST

[0262] YRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTK NQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGN VFSCSVM H EALH N H YTQKSLSLSLG K

[0263] SEQ ID NO: 12 - Itepekimab Light Chain

[0264] DIQMTQSPSSVSASVGDRVTITCRASQGIFSWLAWYQQKPGKAPKLLIYAASSLQSGVPSR

[0265] FSGSGSGTDFTLTISSLQPEDFAIYYCQQANSVPITFGQGTRLEIKRTVAAPSVFIFPPSDEQL

[0266] KSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKAD YEKHKVYACEVTHQGLSSPVTKSFNRGEC

Claims

CLAIMS1. A method of treating bronchiectasis in a patient in need thereof, the method comprising administering to the patient an anti-IL-33 antibody or antigen-binding fragment thereof, wherein the antibody or fragment comprises:(a) a heavy chain variable region comprising a VHCDR1 comprising the sequence of SEQ ID NO: 1, a VHCDR2 comprising the sequence of SEQ ID NO: 2, and a VHCDR3 comprising the sequence of SEQ ID NO: 3; and(b) a light chain variable region comprising a VLCDR1 comprising the sequence of SEQ ID NO: 4, a VLCDR2 comprising the sequence of SEQ ID NO: 5, and a VLCDR3 comprising the sequence of SEQ ID NO: 6.

2. A method of improving forced expiratory volume in 1 second (FEV1) in a patient with bronchiectasis, the method comprising administering to the patient an anti-IL-33 antibody or antigen-binding fragment thereof, wherein the antibody or fragment thereof comprises:(a) a heavy chain variable region comprising a VHCDR1 comprising the sequence of SEQ ID NO: 1, a VHCDR2 comprising the sequence of SEQ ID NO: 2, and a VHCDR3 comprising the sequence of SEQ ID NO: 3; and(b) a light chain variable region comprising a VLCDR1 comprising the sequence of SEQ ID NO: 4, a VLCDR2 comprising the sequence of SEQ ID NO: 5, and a VLCDR3 comprising the sequence of SEQ ID NO: 6.

3. A method of reducing bronchiectasis exacerbations in a patient with bronchiectasis, the method comprising administering to the patient an anti-IL-33 antibody or antigen-binding fragment thereof, wherein the antibody or fragment thereof comprises:(a) a heavy chain variable region comprising a VHCDR1 comprising the sequence of SEQ ID NO: 1, a VHCDR2 comprising the sequence of SEQ ID NO: 2, and a VHCDR3 comprising the sequence of SEQ ID NO: 3; and(b) a light chain variable region comprising a VLCDR1 comprising the sequence of SEQ ID NO: 4, a VLCDR2 comprising the sequence of SEQ ID NO: 5, and a VLCDR3 comprising the sequence of SEQ ID NO: 6.

4. The method of claim 3, wherein the administration reduces bronchiectasis exacerbations requiring hospitalization.

5. The method of claim 3 or 4, wherein the administration reduces bronchiectasis exacerbations requiring antibiotics.

6. A method of reducing the need for intravenous antibiotics in a patient with bronchiectasis, the method comprising administering to the patient an anti-IL-33 antibody or antigen-binding fragment thereof, wherein the antibody or fragment thereof comprises:(a) a heavy chain variable region comprising a VHCDR1 comprising the sequence of SEQ ID NO: 1, a VHCDR2 comprising the sequence of SEQ ID NO: 2, and a VHCDR3 comprising the sequence of SEQ ID NO: 3; and(b) a light chain variable region comprising a VLCDR1 comprising the sequence of SEQ ID NO: 4, a VLCDR2 comprising the sequence of SEQ ID NO: 5, and a VLCDR3 comprising the sequence of SEQ ID NO: 6.

7. A method of stabilizing lung function in a patient with bronchiectasis, the method comprising administering to the patient an anti-IL-33 antibody or antigen-binding fragment thereof, wherein the antibody or fragment thereof comprises:(a) a heavy chain variable region comprising a VHCDR1 comprising the sequence of SEQ ID NO: 1, a VHCDR2 comprising the sequence of SEQ ID NO: 2, and a VHCDR3 comprising the sequence of SEQ ID NO: 3; and(b) a light chain variable region comprising a VLCDR1 comprising the sequence of SEQ ID NO: 4, a VLCDR2 comprising the sequence of SEQ ID NO: 5, and a VLCDR3 comprising the sequence of SEQ ID NO: 6.

8. A method of reducing cough severity in a patient with bronchiectasis, the method comprising administering to the patient an anti-IL-33 antibody or antigen-binding fragment thereof, wherein the antibody or fragment thereof comprises:(a) a heavy chain variable region comprising a VHCDR1 comprising the sequence of SEQ ID NO: 1, a VHCDR2 comprising the sequence of SEQ ID NO: 2, and a VHCDR3 comprising the sequence of SEQ ID NO: 3; and(b) a light chain variable region comprising a VLCDR1 comprising the sequence of SEQ ID NO: 4, a VLCDR2 comprising the sequence of SEQ ID NO: 5, and a VLCDR3 comprising the sequence of SEQ ID NO: 6.

9. The method of any one of claims 1 to 8, wherein the non-cystic fibrosis bronchiectasis was confirmed by chest computed tomography (CT) demonstrating bronchiectasis affecting one or more lobes.

10. The method of any one of claims 1 to 9, wherein the patient has airway neutrophilia.

11. The method of any one of claims 1 to 10, wherein the patient has sputum neutrophilia.

12. The method of any one of claims 1 to 11 , wherein the patient has a history of at least 2 moderate to severe bronchiectasis exacerbations per year requiring antibiotics.

13. The method of any one of claims 1 to 12, wherein the patient has a history of at least 1 exacerbation requiring hospital care.

14. The method of any one of claims 1 to 13, wherein the patient is on long-term antibiotics.

15. The method of any one of claims 1 to 14, wherein the patient has chronic obstructive pulmonary disease (COPD).

16. The method of any one of claims 1 to 14, wherein the patient does not have COPD.

17. The method of any one of claims 1 to 16, wherein the patient has asthma.

18. The method of any one of claims 1 to 17, wherein the administration reduces bacterial load in sputum cultures obtained from the patient, optionally wherein the reduction occurs within 12 weeks of the first administration, within 8 weeks of the first administration, or within 4 weeks of the first administration.

19. The method of any one of claims 1 to 18, wherein the administration reduces sputum production by the patient.

20. The method of any one of claims 1 to 19, wherein the administration reduces the viscosity of sputum produced by the patient.

21. The method of any one of claims 1 to 20, wherein the administration reduces the patient’s need for antibiotics.

22. The method of any one of claims 1 to 21 , wherein the patient is an adult.

23. The method of any one of claims 1 to 22, wherein the patient does not have acute respiratory distress syndrome (ARDS) or acute respiratory failure (ARF), and is not at risk of developing ARDS or ARF.

24. The method of claim 23, wherein the patient is not hospitalized and / or does not require supplemental oxygen.

25. The method of claim 23 or 24, wherein the patient has a bronchiectasis severity index score of less than 9.

26. The method of any one of claims 23 to 25, wherein the patient does not have an immunodeficiency.

27. The method of any one of claims 1 to 26, wherein the antibody or antigen-binding fragment thereof is human.

28. The method of any one of claims 1 to 27, wherein the anti-IL-33 antibody comprises a heavy chain variable region comprising the sequence of SEQ ID NO: 7, or an amino acid sequence with at least 80 % sequence identity thereto; and a light chain variable region comprising the sequence of SEQ ID NO: 8, or an amino acid sequence with at least 80 % sequence identity thereto.

29. The method of claim 28, wherein the anti-IL-33 antibody comprises a heavy chain variable region comprising the sequence of SEQ ID NO: 7; and a light chain variable region comprising the sequence of SEQ ID NO: 8.

30. The method of any one of claims 1 to 29, wherein the patient is administered an anti- IL-33 antibody.

31. The method of claim 30, wherein the antibody is an IgG 1 antibody.

32. The method of claim 31 , wherein the anti-IL-33 antibody is tozorakimab.

33. The method of any one of claims 1 to 29, wherein the patient is administered an antigen-binding fragment of an anti-IL-33 antibody.

34. The method of claim 33, wherein the antigen-binding fragment is a Fab, F(ab')2, Fab', Fv, scFv, diabody, triabody or tetrabody.

35. The method of any one of claims 1 to 34, wherein the anti-IL-33 antibody or antigenbinding fragment thereof is administered to the subject subcutaneously.

36. The method of any one of claims 1 to 35, wherein the anti-IL-33 antibody or antigenbinding fragment thereof is administered to the patient at a dose of 250 to 350 mg every 1 to 4 weeks.

37. The method of claim 36, wherein the anti-IL-33 antibody or antigen-binding fragment thereof is administered to the patient at a dose of 300 mg every 2 weeks or every 4 weeks.

38. The method of any one of claims 1 to 37, wherein the anti-IL-33 antibody or antigenbinding fragment thereof is administered to the patient over a course of therapy lasting at least 3 months or at least 6 months.

39. An anti-IL-33 antibody or antigen-binding fragment thereof for use in a method of treating bronchiectasis, the method comprising administering to the patient the anti-IL-33 antibody or antigen-binding fragment thereof, wherein the antibody or fragment comprises:(a) a heavy chain variable region comprising a VHCDR1 comprising the sequence of SEQ ID NO: 1, a VHCDR2 comprising the sequence of SEQ ID NO: 2, and a VHCDR3 comprising the sequence of SEQ ID NO: 3; and(b) a light chain variable region comprising a VLCDR1 comprising the sequence of SEQ ID NO: 4, a VLCDR2 comprising the sequence of SEQ ID NO: 5, and a VLCDR3 comprising the sequence of SEQ ID NO: 6.

40. The anti-IL-33 antibody or antigen-binding fragment thereof for use according to claim 39, wherein the method, patient, bronchiectasis and / or antibody or antigen-binding fragment thereof are as defined in any one of claims 2 to 38.

41. Use of an anti-IL-33 antibody or antigen-binding fragment thereof in the manufacture of a medicament for treating bronchiectasis, the treatment comprising administering to the patient the anti-IL-33 antibody or antigen-binding fragment thereof, wherein the antibody or fragment comprises:(a) a heavy chain variable region comprising a VHCDR1 comprising the sequence of SEQ ID NO: 1, a VHCDR2 comprising the sequence of SEQ ID NO: 2, and a VHCDR3 comprising the sequence of SEQ ID NO: 3; and(b) a light chain variable region comprising a VLCDR1 comprising the sequence of SEQ ID NO: 4, a VLCDR2 comprising the sequence of SEQ ID NO: 5, and a VLCDR3 comprising the sequence of SEQ ID NO: 6.

42. Use of an anti-IL-33 antibody or antigen-binding fragment thereof for treating bronchiectasis, the method comprising administering to the patient the anti-IL-33 antibody or antigen-binding fragment thereof, wherein the antibody or fragment comprises:(a) a heavy chain variable region comprising a VHCDR1 comprising the sequence of SEQ ID NO: 1, a VHCDR2 comprising the sequence of SEQ ID NO: 2, and a VHCDR3 comprising the sequence of SEQ ID NO: 3; and(b) a light chain variable region comprising a VLCDR1 comprising the sequence of SEQ ID NO: 4, a VLCDR2 comprising the sequence of SEQ ID NO: 5, and a VLCDR3 comprising the sequence of SEQ ID NO: 6.

43. The use of claim 41 or 42, wherein the treatment, patient, bronchiectasis and / or antibody or antigen-binding fragment thereof are as defined in any one of claims 2 to 38.

44. A pharmaceutical composition comprising an anti-IL-33 antibody or antigen-binding fragment thereof for use in a method of treating bronchiectasis, the method comprising administering to the patient the anti-IL-33 antibody or antigen-binding fragment thereof, wherein the antibody or fragment comprises:(a) a heavy chain variable region comprising a VHCDR1 comprising the sequence of SEQ ID NO: 1, a VHCDR2 comprising the sequence of SEQ ID NO: 2, and a VHCDR3 comprising the sequence of SEQ ID NO: 3; and(b) a light chain variable region comprising a VLCDR1 comprising the sequence of SEQ ID NO: 4, a VLCDR2 comprising the sequence of SEQ ID NO: 5, and a VLCDR3 comprising the sequence of SEQ ID NO: 6.

45. The pharmaceutical composition of claim 44, wherein the method, patient, bronchiectasis and / or antibody or antigen-binding fragment thereof are as defined in any one of claims 2 to 38.

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