Method of selecting patient for treatment with IL-33 axis antagonist

Abstract

The present disclosure relates to a method of treating respiratory distress in a subject suffering from respiratory distress or preventing respiratory distress in a subject at risk of respiratory distress with an IL-33 axis antagonist, to a method of determining whether such a subject will respond to treatment with an IL-33 axis antagonist, and to a method of selecting a subject for treatment with an IL-33 axis antagonist by determining whether the IL-33 / sST2 level in a sample obtained from the subject is greater than or equal to a given reference level. The invention also provides a use corresponding to the method.

Description

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This application claims the benefit under 35 U.S.C. §119(e) of U.S. Provisional Patent Application No. 63 / 371,936, filed on August 19, 2022, which is incorporated herein by reference in its entirety for all purposes.

[0003] Reference to a sequence listing submitted electronically

[0004] This application incorporates by reference the sequence listing submitted in computer readable form (CRF) with this application, which is a text file named "IL33-601-WO-PCT Sequence Listing" created on August 17, 2023 and has a size of 51,179 bytes. Technical Field

[0005] The present disclosure relates to a method for treating a subject with respiratory distress or preventing respiratory distress in a subject at risk of respiratory distress with an IL-33 axis antagonist, a method for determining whether such a subject will respond to treatment with an IL-33 axis antagonist, and a method for selecting a subject for treatment with an IL-33 axis antagonist by determining whether the IL-33 / sST2 level in a sample obtained from the subject is greater than or equal to a given reference level. Uses corresponding to the methods are also provided. Background Art

[0006] Interleukin-33 (IL-33), also known as IL-1F11, is a member of the IL-1 family of cytokines. IL-33 is a 270 amino acid protein composed of two domains: a homeodomain and a cytokine (IL-1-like) domain. The homeodomain contains a nuclear localization signal (NLS). IL-33 is known to exist in different forms; a reduced form (redIL-33) and an oxidized form (oxIL-33). Previous studies have shown that the reduced form is rapidly oxidized under physiological conditions to form at least one disulfide bond in the oxidized form, and that the two forms may have different biochemical properties and biological functions.

[0007] The reduced form of IL-33 has previously been found to bind to ST2 and is in fact the only known ligand for the ST2 receptor expressed by immune cells including Th2 cells and mast cells. Reduced IL-33 stimulates target cells by binding to ST2 and subsequently activating the NFkB and MAP kinase pathways, leading to the production of cytokines and chemokines such as IL-4, IL-5, and IL-13 to promote inflammation. Soluble ST2 (sST2) is considered a decoy receptor that blocks IL-33 signaling by binding to reduced IL-33 and forming an IL-33 / sST2 complex.

[0008] Recently, it was discovered that the oxidized form of IL-33 is also biologically active. Oxidized IL-33 was found not to bind ST2, but to bind to the receptor for advanced glycation end products (RAGE) and signal through this alternative pathway to regulate airway epithelial remodeling.

[0009] As a result, there has been intense interest in IL-33 as a therapeutic target, primarily because its reduced form is now known to stimulate ST2 and lead to a potent inflammatory effect, and now also because its oxidized form can stimulate RAGE-EGFR signaling, which is associated with a wide range of diseases.

[0010] IL-33 antagonists have been developed as therapeutic agents that target and bind to various IL-33 forms present in the IL-33 axis. Several antibody therapeutics that target and inhibit reduced IL-33 are now known. Such antibodies include tozorakimab (binding molecule 33_640087-7B, as described in WO2016 / 156440), etokimab (as described in WO2015 / 106080), itepekimab, and torudokimab.

[0011] While some of these antibody therapies have shown good results in the treatment of subjects with IL-33-mediated diseases (such as inflammatory diseases or respiratory diseases), not all subjects respond to the treatment in the same way, and for some patients, treatment with such therapies is more beneficial than other therapies.

[0012] Tracking and monitoring a subject's response to such therapies targeting the IL-33 axis has been difficult because historically there has been no sensitive and reliable IL-33 assay that can distinguish between the different forms of IL-33. Now an assay has been developed that can detect such forms of IL-33 and can provide the user with information about biological pathways that may be inhibited or activated in a given biological sample and how this relates to the patient's status. The highly sensitive assay can detect not only one IL-33 form in a biological sample, but each of the different forms of IL-33; i.e., reduced IL33, oxidized IL33, and combined IL33 / sST2.

[0013] Using this assay, the inventors also discovered for the first time that patients with respiratory distress can be stratified into patients who are more likely to experience a beneficial therapeutic effect from treatment with such IL-33 axis antagonist therapies and patients who are less likely to experience a therapeutic effect. The inventors surprisingly found that the level of the IL-33 / sST2 complex in a biological sample indicates the therapeutic effect of an IL-33 axis antagonist therapy. The inventors believe that measuring IL-33 / sST2 in a biological sample can provide information about medical treatment options and determine the likelihood of responding to IL-33 axis antagonist therapies (such as those mentioned above).

[0014] Accordingly, one or more aspects of the present disclosure and further features thereof are defined hereinafter. Summary of the invention

[0015] According to a first aspect of the present disclosure, there is provided a method for treating a subject suffering from respiratory distress or preventing respiratory distress in a subject at risk of respiratory distress, the method comprising administering to the subject an effective amount of an IL-33 axis antagonist, wherein the IL-33 / sST2 level in a sample obtained from the subject is greater than or equal to a reference level of about 25 pg / ml.

[0016] According to an alternative first aspect of the present disclosure, there is provided an IL-33 axis antagonist for treating a subject with respiratory distress or for preventing respiratory distress in a subject at risk of respiratory distress, wherein the IL-33 / sST2 level in a sample obtained from the subject is greater than or equal to a reference level of about 25 pg / ml. In one example, the subject has an IL-33 / sST2 level greater than or equal to a reference level of about 25 pg / ml. In one example, the subject has a baseline IL-33 / sST2 level greater than or equal to a reference level of about 25 pg / ml. In one example, the subject has a baseline serum IL-33 / sST2 level greater than or equal to a reference level of about 25 pg / ml.

[0017] According to a second aspect of the present disclosure, a method for treating a subject suffering from respiratory distress or preventing respiratory distress in a subject at risk of respiratory distress is provided, wherein the method comprises: measuring the IL-33 / sST2 level in a sample obtained from the subject; and if the IL-33 / sST2 level in the sample is greater than or equal to a reference level of about 25 pg / ml, administering an effective amount of an IL-33 axis antagonist to the subject.

[0018] According to an alternative second aspect of the present disclosure, there is provided an IL-33 axis antagonist for use in a method for treating a subject suffering from respiratory distress or for preventing respiratory distress in a subject at risk of respiratory distress, wherein the method comprises: measuring the IL-33 / sST2 level in a sample obtained from the subject; and if the IL-33 / sST2 level in the sample is greater than or equal to a reference level of about 25 pg / ml, administering an effective amount of the IL-33 axis antagonist to the subject.

[0019] According to a third aspect of the present disclosure, there is provided a method for preventing acute respiratory failure in a subject at risk of acute respiratory failure, the method comprising administering an effective amount of an IL-33 axis antagonist to the subject, wherein the IL-33 / sST2 level in a sample obtained from the subject is greater than or equal to a reference level of about 25 pg / ml.

[0020] According to an alternative third aspect of the invention, there is provided an IL-33 axis antagonist for use in preventing acute respiratory failure in a subject at risk of acute respiratory failure, wherein the IL-33 / sST2 level in a sample obtained from the subject is greater than or equal to a reference level of about 25 pg / ml.

[0021] In one example, the method of the third aspect may include measuring the level of IL-33 / sST2 in a sample obtained from a subject; and administering an effective amount of an IL-33 axis antagonist to the subject if the level of IL-33 / sST2 in the sample is greater than or equal to a reference level of about 25 pg / ml.

[0022] In one example, the subject at risk in the method of the third aspect is a subject suffering from respiratory distress.

[0023] According to a fourth aspect of the present disclosure, there is provided a method for reducing the likelihood of death and / or acute respiratory failure in a subject having or at risk of respiratory distress, the method comprising administering to the subject an effective amount of an IL-33 axis antagonist, wherein the IL-33 / sST2 level in a sample obtained from the subject is greater than or equal to a reference level of about 25 pg / ml.

[0024] According to an alternative fourth aspect of the invention, there is provided an IL-33 axis antagonist for reducing the likelihood of death and / or acute respiratory failure in a subject having or at risk of respiratory distress, wherein the IL-33 / sST2 level in a sample obtained from the subject is greater than or equal to a reference level of about 25 pg / ml.

[0025] In one example, the method of the fourth aspect may include measuring the level of IL-33 / sST2 in a sample obtained from a subject; and administering an effective amount of an IL-33 axis antagonist to the subject if the level of IL-33 / sST2 in the sample is greater than or equal to a reference level of about 25 pg / ml.

[0026] In one example, the method of the fourth aspect comprises significantly reducing the likelihood of death and / or respiratory failure, suitably significantly reducing the likelihood of acute respiratory failure. Suitably, the likelihood of death and / or respiratory failure is reduced compared to a subject who has not received an effective amount of an IL-33 axis antagonist.

[0027] In one example of the method of the fourth aspect, reducing the likelihood may include reducing the rate of death and / or respiratory failure in a subject suffering from or at risk of suffering from respiratory distress.

[0028] In one example, the method of the fourth aspect may comprise treating a subject with respiratory distress by reducing the likelihood of death and / or acute respiratory failure.

[0029] In one example, the methods may include a method of selectively treating a subject with respiratory distress or selectively preventing respiratory distress in a subject. Suitably, wherein the methods may include the step of selectively administering an effective amount of an IL-33 axis antagonist if the level of IL-33 / sST2 in a sample obtained from the subject is greater than or equal to a reference level of about 25 pg / ml.

[0030] According to a fifth aspect of the present disclosure, there is provided a method for selecting a subject having or at risk of having respiratory distress for treatment with an IL-33 axis antagonist, the method comprising: measuring the level of IL-33 / sST2 in a sample obtained from the subject; and selecting the subject for said treatment if the level of IL-33 / sST2 in the sample is greater than or equal to a reference level of about 25 pg / ml.

[0031] In one example, the method can include selecting a subject having or at risk of having respiratory distress who will respond to or benefit from treatment with an IL-33 axis antagonist.

[0032] In another example, the method may include identifying a subject having or at risk of respiratory distress for treatment with an IL-33 axis antagonist. In another example, the method may include identifying a subject having or at risk of respiratory distress who will respond to or benefit from treatment with an IL-33 axis antagonist.

[0033] In one example, the method further comprises the step of administering to the subject an effective amount of an IL-33 axis antagonist.

[0034] In an alternative fifth aspect of the present disclosure, a method of selecting a subject for treatment with an IL-33 axis antagonist is provided, the method comprising: measuring the level of IL-33 / sST2 in a sample obtained from the subject; and selecting the subject for said treatment if the level of IL-33 / sST2 in the sample is greater than or equal to a reference level of about 25 pg / ml.

[0035] In one example, the method can include selecting a subject who will respond to or benefit from treatment with an IL-33 axis antagonist.

[0036] In another example, the method may include identifying a subject for treatment with an IL-33 axis antagonist. In another example, the method may include identifying a subject who will respond to or benefit from treatment with an IL-33 axis antagonist.

[0037] In one example, the subject suffers from a disease, disorder, condition or infection. In one example, the subject suffers from, or is at risk of suffering from, respiratory distress, which may suitably be caused by a disease, disorder, condition or infection.

[0038] In one example, the method further comprises the step of administering to the subject an effective amount of an IL-33 axis antagonist.

[0039] According to a sixth aspect of the present disclosure, there is provided a method for determining whether a subject having respiratory distress or at risk of having respiratory distress is likely to respond to treatment with an IL-33 axis antagonist, the method comprising: measuring the level of IL-33 / sST2 in a sample obtained from the subject; and determining that the subject is likely to respond to the treatment if the measured level of IL-33 / sST2 in the sample is greater than or equal to a reference level.

[0040] In one example, the method may include determining whether a subject having respiratory distress or at risk of respiratory distress will respond to treatment with an IL-33 axis antagonist. In one example, the method may include determining whether a subject having respiratory distress or at risk of respiratory distress may benefit from treatment with an IL-33 axis antagonist. In one example, the method may include determining whether a subject having respiratory distress or at risk of respiratory distress will benefit from treatment with an IL-33 axis antagonist.

[0041] In one example, the method further comprises the step of administering to the subject an effective amount of an IL-33 axis antagonist.

[0042] In an alternative sixth aspect of the present disclosure, there is provided a method for determining whether a subject is likely to respond to treatment with an IL-33 axis antagonist, the method comprising: measuring the level of IL-33 / sST2 in a sample obtained from the subject; and determining that the subject is likely to respond to the treatment if the measured level of IL-33 / sST2 in the sample is greater than or equal to a reference level.

[0043] In one example, the method may include determining whether the subject will respond to treatment with an IL-33 axis antagonist. In one example, the method may include determining whether the subject is likely to benefit from treatment with an IL-33 axis antagonist. In one example, the method may include determining whether the subject will benefit from treatment with an IL-33 axis antagonist.

[0044] In one example, the subject suffers from a disease, disorder, condition or infection. In one example, the subject suffers from, or is at risk of suffering from, respiratory distress, which may suitably be caused by a disease, disorder, condition or infection.

[0045] In one example, the method further comprises the step of administering to the subject an effective amount of an IL-33 axis antagonist.

[0046] In one example, the method of the sixth aspect may comprise determining or predicting the likelihood that a subject suffering from or at risk of suffering from respiratory distress will respond to or benefit from treatment with an IL-33 axis antagonist. Suitably, wherein the methods comprise determining or predicting that the subject has an increased likelihood of responding to or benefiting from said treatment if the measured level of IL-33 / sST2 in the sample is greater than or equal to a reference level. Suitably, the increased likelihood relative to a reference subject as defined herein.

[0047] In an example of any of the methods, the IL-33 axis antagonist comprises a heavy chain variable region having VHCDRs 1-3 of SEQ ID NO: 37, SEQ ID NO: 38, and SEQ ID NO: 39, respectively, and a light chain variable region having VLCDRs 1-3 of SEQ ID NO: 40, SEQ ID NO: 41, and SEQ ID NO: 42, respectively. In an example of any of the methods, the IL-33 axis antagonist is torelizumab.

[0048] In one example of any of the methods, the subject suffers from, or is at risk of suffering from, acute respiratory failure (ARF).

[0049] In one example, any of the methods can include a step of comparing the measured level of IL-33 / sST2 in the sample to a reference level of about 25 pg / ml.

[0050] In one example, the measuring step of any method may include assaying a sample obtained from a subject, suitably to measure the level of IL-33 / sST2. In one example, any method may include the steps of: (a) contacting the sample with one or more binding molecules capable of binding to IL-33 / sST2 under conditions sufficient to form a complex; and (b) detecting the level of IL-33 / sST2 complex in the sample.

[0051] For the avoidance of doubt, each aspect or example of a "method" of treatment includes compositions for use in said method of treatment and use of said composition in the manufacture of a medicament for use in said method of treatment.

[0052] definition

[0053] As used herein, "IL-33" protein refers to interleukin 33, in particular mammalian interleukin 33 protein, such as the human protein deposited under UniProt No. 095760. However, in light of the inventors' discoveries, it is apparent that the entity is not a single substance, but exists in reduced and oxidized forms. The terms "IL-33" and "IL-33 polypeptide" are used interchangeably. In some instances, IL-33 is full-length. In another instance, IL-33 is mature, truncated IL-33 (amino acids 112-270). Recent studies have shown that full-length IL-33 is active (Cayrol and Girard, Proc Natl Acad Sci USA 106(22):9021-6 (2009); Hayakawa et al., Biochem Biophys Res Commun. 387(1):218-22 (2009); Talabot-Ayer et al., J Biol Chem. 284(29):19420-6 (2009)). However, N-terminally processed or truncated IL-33, including but not limited to aa 72-270, 79-270, 95-270, 99-270, 107-270, 109-270, 111-270, 112-270 may have enhanced activity (Lefrancais 2012, 2014). In another example, IL-33 may include full-length IL-33, fragments thereof, or IL-33 mutant or variant polypeptides, wherein the fragment of IL-33 or IL-33 variant polypeptide retains some or all of the functional properties of active IL-33.

[0054] "Oxidized IL-33" or "oxIL-33" is a protein that is visible as a distinct band, for example, by Western blot analysis under non-reducing conditions, particularly having a mass 4 Da less than the corresponding reduced form. Specifically, it refers to a protein having one or two disulfide bonds between cysteines independently selected from cysteine ​​208, 227, 232 and 259. In one example, oxidized IL-33 appears to not bind to ST2.

[0055] As used herein, "reduced IL-33" or "redIL-33" refers to a form of IL-33 that binds to ST2 and triggers ST2-mediated signaling. Specifically, cysteine ​​208, 227, 232, and 259 in the reduced form are not disulfide bonded.

[0056] As used herein, "IL-33 / sST2" refers to the reduced IL-33 form that binds to the soluble ST2 receptor. As used herein, "IL-33 / sST2" may also be referred to as an "IL-33 / sST2 complex".

[0057] As used herein, "antigenic different forms of IL-33" refers to any form of IL-33 that can act as an antigen and be recognized by an antibody or its binding fragment, which in the context of the present disclosure generally refers to oxidized IL-33, reduced IL-33, and reduced IL-33 / sST2 complex.

[0058] It should be noted that the term "a" or "an" entity refers to one or more (one or more) of the entity; for example, "anti-IL-33 antibody" should be understood to mean one or more anti-IL-33 antibodies. Therefore, the terms "a" (or "a"), "one or more (one or more)" and "at least one (kind)" are used interchangeably herein.

[0059] As used herein, the term "treatment" refers to therapeutic treatment and prophylactic or preventive measures, i.e., prevention, wherein the goal is to prevent or slow down (mitigate) undesirable physiological changes or illnesses. Beneficial or desired clinical results include, but are not limited to, relieving symptoms, reducing the extent of the disease, stabilizing the disease state (i.e., not worsening), delaying or slowing disease progression, improving or alleviating the disease state, and detectable or undetectable relief (whether partial or complete). "Treatment" can also refer to extending the survival period compared to the expected survival period if not treated. Those that need treatment include those that have already suffered from a condition or illness, and those that are susceptible to a condition or illness or those that are to prevent a condition or illness. The term "prevention" is used herein to refer to preventing, delaying or treating the development or continuation or aggravation of a condition or illness, or preventing, delaying and treating the development or continuation or aggravation of a condition or illness when appropriate.

[0060] "Subject" or "individual" or "animal" or "patient" or "mammal" means any subject, particularly a mammalian subject, for whom diagnosis, prognosis or therapy is desired, unless the subject is defined as a "healthy subject". Mammalian subjects include humans; domestic animals; farm animals; such as dogs, cats, guinea pigs, rabbits, rats, mice, horses, cattle, cows, etc.

[0061] The term "determining" is used to refer to the act of identifying, screening, detecting, testing, measuring or determining, which can be performed by any conventional means. The term "detection" (etc.) refers to the act of extracting specific information from a given source, which can be direct or indirect. In some examples of the methods disclosed herein, the presence of IL-33 / sST2 in a biological sample (e.g., its level, etc.) is detected. The terms "determining" and "determining" take into account the transformation of a substance, for example, by physically testing a biological sample (e.g., a serum sample) to convert the sample from one state to another.

[0062] The term "obtain" means to acquire, for example, to come into possession in any manner, such as through physical intervention (eg, biopsy) or non-physical intervention (eg, transmission of information through a server), and the like.

[0063] The term "pharmaceutical composition" is defined herein to mean a mixture or solution containing at least one therapeutic agent to be administered to a subject (eg, a mammal or a human) in order to prevent or treat a particular disease or condition.

[0064] The term "pharmaceutically acceptable" is defined herein to refer to those compounds, materials, compositions, and / or dosage forms which are, within the scope of sound medical judgment, suitable for contact with the tissues of a subject (e.g., a mammal or a human) without excessive toxicity, irritation, allergic response, and other problematic complications, and are commensurate with a reasonable benefit / risk ratio.

[0065] As used herein, "selection" or "identification" of a subject is used to refer to the specific selection of a particular subject from a larger group of subjects based on (because) the particular subject has a predetermined criterion (e.g., equal to or greater than a reference level of IL-33 / sST2). Similarly, "selectively treating" refers to providing treatment to a subject, wherein the subject is specifically selected from a larger group of subjects based on the particular subject having a predetermined criterion (e.g., equal to or greater than a reference level of IL-33 / sST2). Similarly, "selectively administering" refers to administering a drug to a subject specifically selected from a larger group of subjects based on (because) the particular subject has a predetermined criterion (e.g., a specific biomarker, such as equal to or greater than a reference level of IL-33 / sST2). Selecting, identifying, selectively treating, and selectively administering refer to delivering personalized therapy to a subject based on the patient's specific biology, rather than delivering a standard treatment regimen to the subject based solely on the subject having a specific disease or condition or being at risk for a specific disease or condition. With respect to treatment methods as used herein, selection does not refer to accidental treatment of subjects who may happen to have a reference level of IL-33 / sST2 equal to or greater than the reference level, but rather refers to the deliberate selection of administering an IL-33 axis antagonist to a subject based on the subject having a reference level of IL-33 / sST2 equal to or greater than the reference level. Thus, selective treatment is different from standard treatment, which delivers a specific drug to all subjects without regard to the biomarker.

[0066] As used herein, "predict" or "determine" indicates that the methods described herein provide information to enable a health care provider to determine the likelihood that an individual with a reference level of IL-33 / sST2 equal to or greater than a reference level will respond to treatment with an IL-33 axis antagonist or will respond more favorably to it. This does not refer to the ability to predict a response with 100% accuracy. Instead, the skilled artisan will understand that this refers to an increased probability.

[0067] As used herein, "likelihood" and "likely" are a measure of how likely an event is to occur. It can be used interchangeably with "probability". Likelihood refers to a probability that is greater than a guess but less than certainty. Therefore, if a reasonable person, using common sense, training, or experience, concludes that an event is likely to occur under given circumstances, then the event is possible. The phrase "increased likelihood" means that the probability that an event will occur increases. For example, some methods herein allow prediction of whether a subject will show an increased likelihood of responding to treatment with an IL-33 axis antagonist compared to a reference subject that does not have a certain reference level of IL-33 / sST2 that is equal to or greater than IL-33 / sST2.

[0068] Further features of the aspects defined above are described in the following subsections with headings. Each subsection can be combined with any of the above mentioned aspects in any compatible combination. DETAILED DESCRIPTION

[0069] Subjects

[0070] The methods of the present disclosure relate to treating a subject, determining whether a subject will benefit from a treatment, and selecting a treatment for a subject. Each of these methods comprises using a sample obtained from a subject, suitably measuring IL-33 / sST2 levels in the sample.

[0071] Suitably, the subject may be a human. The subject may be receiving medical care, or may be requesting medical care. Suitably, the subject is male or female. Suitably, the subject is an adult or a child.

[0072] Suitably, the subject is suffering from, or is believed to be suffering from, respiratory distress. Suitably, the subject may have, or may be believed to have, a condition, disease, disorder or infection. Suitably, the condition, disease, disorder or infection causes respiratory distress, as further explained below.

[0073] Suitably, the subject may have one or more symptoms consistent with respiratory distress, such as higher than normal respiratory rate, low blood oxygen concentration, difficulty breathing, shortness of breath, low blood pressure, higher than normal heart rate, chest pain, changes in skin color, sweating, wheezing, confusion, fatigue, etc.

[0074] Thus, suitably the subject may be a patient.

[0075] Alternatively, the subject may be a subject considered to be at risk of respiratory distress, suitably, at risk of developing such a condition, disease, disorder or infection that causes respiratory distress. For example, a subject at risk may already have a condition, disease, disorder or infection that causes respiratory distress, or may have been in contact with an individual having such a condition, disease, disorder or infection that causes respiratory distress, may have a related condition, disease, disorder or infection that causes respiratory distress, or may meet risk factors associated with such a condition, disease, disorder or infection, such as smoking, old age, allergies, etc. Additional definitions of subjects at risk of respiratory distress are provided below.

[0076] Respiratory distress

[0077] The methods of the present disclosure are directed to a subject having, or at risk of, respiratory distress.

[0078] Suitably, a subject suffering from respiratory distress may be defined as a subject who is unable to ventilate adequately to supply sufficient oxygen to the blood and organs throughout the body.

[0079] Suitably, a subject with respiratory distress has one or more of the following symptoms: a higher than normal respiratory rate, a low blood oxygen concentration, difficulty breathing, shortness of breath, low blood pressure, a higher than normal heart rate, chest pain, changes in skin color, sweating, wheezing, confusion, and fatigue. Suitably, respiratory distress may be defined as a subject having at least one of the following symptoms: a higher than normal respiratory rate, a low blood oxygen concentration, difficulty breathing, shortness of breath, and may additionally include one or more of the following symptoms: low blood pressure, a higher than normal heart rate, chest pain, changes in skin color, sweating, wheezing, confusion, and fatigue.

[0080] Suitably, a subject at risk of respiratory distress may develop one or more of the following symptoms: higher than normal respiratory rate, low blood oxygen concentration, difficulty breathing, shortness of breath, low blood pressure, higher than normal heart rate, chest pain, changes in skin color, sweating, wheezing, confusion and fatigue. Suitably, a subject at risk of respiratory distress may have few or no such symptoms, but may be at risk of developing further symptoms. Suitably, a subject at risk of respiratory distress may have a disease, disorder, condition or infection associated with or that may cause respiratory distress as identified elsewhere herein.

[0081] Suitably, the subject with respiratory distress may be a subject requiring oxygen or a subject requiring ventilation. In one example, the subject with respiratory distress requires supplemental oxygen. In one example, the subject requiring supplemental oxygen may have an oxygen saturation (SpO2) of ≤90%. In one example, the subject requiring supplemental oxygen may have an SpO2 of ≤92% and a viral lower respiratory tract infection (or disease - "vLRTD"). In some examples, vRLTD is determined by the presence of radiographic infiltrates compatible with viral lung infection observed by chest X-ray / CT scan. In another example, the subject requiring supplemental oxygen may have an SpO2 of ≤92% and is using accessory respiratory muscles or has a respiratory rate of >22 / minute.

[0082] In one example, a subject with respiratory distress is hospitalized. Suitably, prior to carrying out the methods of the invention. Suitably, the subject may be suffering from respiratory failure, or may be at risk of respiratory failure, suitably, acute respiratory failure (ARF) or chronic respiratory failure (CRS). Suitably, respiratory failure may be type 1 (hypoxic), type 2 (hypercapnic), type 3 (perioperative) or type 4 (shock-induced).

[0083] In one example, the subject suffers from, or is at risk of, acute respiratory failure (ARF). In one example, the subject suffers from, or is at risk of, hypoxic (Type 1) acute respiratory failure. In one example, the subject suffers from, or is at risk of, hypercapnic (Type 2) acute respiratory failure.

[0084] Suitably, a subject at risk of acute or other respiratory failure may be a subject having any one or more of the above symptoms of respiratory distress, such as higher than normal respiratory rate, low blood oxygen concentration, difficulty breathing, shortness of breath, low blood pressure, higher than normal heart rate, chest pain, changes in skin color, sweating, wheezing, confusion and fatigue.

[0085] Suitably, a subject at risk of acute or other respiratory failure is a subject suffering from respiratory distress. Suitably, respiratory distress may typically lead to respiratory failure if left untreated. Thus, in one example, a subject may suffer from respiratory distress and be at risk of developing respiratory failure, suitably acute respiratory failure.

[0086] Suitably, respiratory distress such as acute respiratory failure (ARF) may be caused by a condition, disease, disorder or infection. Suitably, the condition, disease, disorder or infection is a respiratory disease. Suitably, a respiratory disease is a disease affecting the trachea, bronchi, bronchioles, alveolar ducts and / or alveoli.

[0087] Suitably, respiratory distress, such as acute respiratory failure (ARF), may be caused by any of the following conditions, diseases or disorders: acute respiratory distress syndrome (ARDS), chronic obstructive pulmonary disease (COPD), asthma, bronchitis, bronchiectasis, emphysema, heart failure, myocardial ischemia, mitral stenosis, pulmonary edema, pulmonary embolism, thromboembolism, cystic fibrosis, amyotrophic lateral sclerosis, muscular dystrophy, Guillain-Barre syndrome, myasthenia gravis, poliomyelitis, polymyositis, botulism, hypokalemia, hypophosphatemia, myxedema, hypothyroidism, sepsis, stroke, acute pancreatitis, transfusion, reperfusion, drug or alcohol overdose, chest trauma, viral or bacterial infection, inhalation injury (caused by inhalation of smoke, fumes or chemicals), aspiration, drowning. Thus, suitably, the subject may have any of these conditions, diseases or disorders. Suitably, the subject may have any of these conditions, diseases or disorders and be at risk of respiratory distress such as acute respiratory failure (ARF).

[0088] In one example, the subject suffers from asthma. In one example, the subject suffers from COPD.

[0089] Suitably, the respiratory distress such as acute respiratory failure (ARF) is caused by a bacterial or viral infection, suitably a bacterial or viral respiratory tract infection, suitably a bacterial or viral lower respiratory tract infection. Thus, suitably, the subject may have a bacterial or viral infection, suitably a bacterial or viral lower respiratory tract infection. Suitably, the subject may have a bacterial or viral infection, suitably a bacterial or viral lower respiratory tract infection, and is at risk of respiratory distress such as acute respiratory failure (ARF).

[0090] In one example, the subject with respiratory distress has or is suspected of having a viral lower respiratory tract infection or disease.

[0091] Suitable bacterial or viral respiratory infections may be selected from: tonsillitis, scarlet fever, pharyngitis, laryngitis, diphtheria, pharyngitis, Lemmiere's syndrome, tularemia, plague, enterocolitis, colds, influenza, mononucleosis, HIV infection, pneumonia (suitably viral pneumonia), bronchitis, psittacosis, SARS, MERS and COVID-19.

[0092] Suitably, such infection may be caused by the following bacteria or viruses: Streptococcus sp., Arcanobacterium haemolyticum, Neisseria gonorrhoeae, Corynebacterium diphtheriae, Fusobacterium necrophorum, Francisella tulareniss, Yersinia pestis, Yersinia enterocolitica, Adenovirus sp., Herpes simplex virus (HSV), HIV, Coxsackievirus sp., Coronavirus sp., Rhinovirus sp., Influenza A or B virus, Parainfluenza virus, Bocaparvovirus sp., Metapneumovirus sp. sp.), respiratory syncytial virus (RSV), Epstein Barr virus, Cytomegalovirus sp., Mycoplasma pneumoniae, Chlamydophla pneumoniae, and Chhlmaydophla psittaci.

[0093] In one example, respiratory distress, such as acute respiratory failure (ARF), is caused by coronavirus infection. Therefore, suitably, the subject may suffer from coronavirus infection. Suitably, the subject may suffer from coronavirus infection and be at risk of respiratory distress such as acute respiratory failure (ARF). Suitably, coronavirus infection can be an alpha coronavirus infection or a beta coronavirus infection. Suitably, alpha coronavirus infection can be an infection of the following viruses: alpha coronavirus 1 (TGEV, feline coronavirus, canine coronavirus), human coronavirus 229E, human coronavirus NL63, long-winged bat (Miniopterus bat) coronavirus 1, long-winged bat coronavirus HKU8, porcine epidemic diarrhea virus (Porcine epidemic diarrhea virus), horseshoe bat (Rhinolophus bat) coronavirus HKU2 and high-headed bat (Scotophilus bat) coronavirus 512. Suitably, the betacoronavirus infection may be an infection with any of the following viruses: betacoronavirus 1 (bovine coronavirus, human coronavirus OC43), hedgehog coronavirus 1, human coronavirus HKU1, Middle East respiratory syndrome-related coronavirus, mouse coronavirus, Pipistrellus bat coronavirus HKU5, Rousettus bat coronavirus HKU9, severe acute respiratory syndrome-related coronavirus (SARS-CoV, SARS-CoV-2) and Tylonycteris bat coronavirus HKU4.

[0094] In one example, the coronavirus infection is a SARS infection, suitably a SARS-CoV-2 infection. In one example, respiratory distress, such as acute respiratory failure (ARF), is caused by COVID-19 derived from a SARS-CoV-2 infection. In one example, the subject suffers from respiratory distress or acute respiratory failure caused by COVID-19 or SARS-CoV-2 infection. In one example, the subject suffers from COVID-19 and is at risk of respiratory distress, or is at risk of acute respiratory failure.

[0095] In one example, the subject has or has COVID-19 or SARS-CoV-2 infection. In one example, the subject is at risk of COVID-19 or at risk of SARS-CoV-2 infection.

[0096] In one example, respiratory distress such as acute respiratory failure (ARF) is caused by influenza A or B virus, parainfluenza virus, coronavirus or respiratory syncytial virus infection. In one example, respiratory distress, such as acute respiratory failure (ARF), is caused by viral pneumonia derived from any one of influenza A or B virus, parainfluenza virus, coronavirus or respiratory syncytial virus infection. Therefore, suitably, the subject may have influenza A or B virus, parainfluenza virus, coronavirus or respiratory syncytial virus infection, and is at risk of respiratory distress such as acute respiratory failure (ARF). Therefore, suitably, the subject may have influenza A or B virus, parainfluenza virus, coronavirus or respiratory syncytial virus infection and is at risk of viral pneumonia.

[0097] In one example, the subject suffers from respiratory distress or acute respiratory failure caused by pneumonia, suitably viral pneumonia. In one example, the subject suffers from or has pneumonia, suitably viral pneumonia. In one example, the subject is at risk of pneumonia or viral pneumonia.

[0098] In one example, viral pneumonia is caused by COVID-19, suitably derived from a coronavirus infection that can be selected from any one of the above-listed ones, suitably derived from SARS-CoV-2 infection. In some examples, pneumonia is caused by influenza A virus, influenza B virus, respiratory syncytial virus, human parainfluenza virus, adenovirus, metapneumovirus, SARS-COV, Middle East respiratory syndrome virus (MERS-CoV), hantavirus, herpes simplex virus, varicella-zoster virus, measles virus, rubella virus, cytomegalovirus, smallpox virus or dengue virus. In some examples, pneumonia is caused by influenza A virus, influenza B virus, respiratory syncytial virus or human parainfluenza virus.

[0099] Thus, suitably, in some instances, the subject suffers from or has COVID-19 and viral pneumonia. In some instances, wherein the viral pneumonia is caused by infection with COVID-19 or SARS-CoV-2. In some instances, the subject suffers from COVID-19 and is at risk of viral pneumonia.

[0100] Suitably, in any of the above examples, the subject has tested positive for SARS-CoV-2 infection. Suitably, any available test in the art may be used to determine whether the subject has SARS-CoV-2 infection, such as an antigen test, an antibody test, or a nucleic acid-based test. Suitably, nucleic acid-based tests include PCR tests. Suitably, any method of the present disclosure may further include the step of testing the subject for the presence of SARS-CoV-2 infection or the presence of COVID-19.

[0101] Suitably, any reference herein to a subject having any condition, disease, disorder or infection may also be a reference to a subject at risk of suffering from the condition, disease, disorder or infection. Suitably, the IL-33 axis antagonist may also be used to prevent a condition, disease, disorder or infection in a subject at risk of a condition, disease, disorder or infection, wherein the level of IL-33 / sST2 in a sample obtained from the subject is greater than or equal to a reference level of about 25 pg / ml.

[0102] Thus, suitably, the present disclosure further provides a method of preventing a condition, disease, disorder or infection in a subject at risk of the condition, disease, disorder or infection. Suitably, the method of prevention comprises administering to the subject an effective amount of an IL-33 axis antagonist as described elsewhere herein.

[0103] Suitably, as identified above, the subject may be at risk of respiratory distress, or at risk of acute respiratory failure. Accordingly, suitably, the present disclosure provides a method of preventing respiratory distress in a subject at risk of respiratory distress or preventing death and / or acute respiratory failure in a subject at risk of death and / or acute respiratory failure, wherein the level of IL-33 / sST2 in a sample obtained from the subject is greater than or equal to a reference level of about 25 pg / ml.

[0104] In one example, a method of preventing acute respiratory failure in a subject at risk of acute respiratory failure is provided, the method comprising administering to the subject an effective amount of an anti-IL-33 antibody or an antigen-binding fragment thereof, the anti-IL-33 antibody or antigen-binding fragment thereof comprising a heavy chain variable region and a light chain variable region, the heavy chain variable region having VHCDRs 1-3 of SEQ ID NO: 37, SEQ ID NO: 38, and SEQ ID NO: 39, respectively, and the light chain variable region having VLCDRs 1-3 of SEQ ID NO: 40, SEQ ID NO: 41, and SEQ ID NO: 42, respectively, wherein the IL-33 / sST2 level in a sample obtained from the subject is greater than or equal to a reference level of about 25 pg / ml.

[0105] In one example, a method of preventing acute respiratory failure in a subject with acute respiratory distress is provided, the method comprising administering to the subject an effective amount of an anti-IL-33 antibody or an antigen-binding fragment thereof, the anti-IL-33 antibody or antigen-binding fragment thereof comprising a heavy chain variable region and a light chain variable region, the heavy chain variable region having VHCDRs 1-3 of SEQ ID NO: 37, SEQ ID NO: 38, and SEQ ID NO: 39, respectively, and the light chain variable region having VLCDRs 1-3 of SEQ ID NO: 40, SEQ ID NO: 41, and SEQ ID NO: 42, respectively, wherein the IL-33 / sST2 level in a sample obtained from the subject is greater than or equal to a reference level of about 25 pg / ml.

[0106] In one example, a method of preventing acute respiratory failure in a subject with COVID-19, pneumonia, or viral pneumonia is provided, the method comprising administering to the subject an effective amount of an anti-IL-33 antibody or an antigen-binding fragment thereof, the anti-IL-33 antibody or antigen-binding fragment thereof comprising a heavy chain variable region and a light chain variable region, the heavy chain variable region having VHCDRs 1-3 of SEQ ID NO: 37, SEQ ID NO: 38, and SEQ ID NO: 39, respectively, and the light chain variable region having VLCDRs 1-3 of SEQ ID NO: 40, SEQ ID NO: 41, and SEQ ID NO: 42, respectively, wherein the IL-33 / sST2 level in a sample obtained from the subject is greater than or equal to a reference level of about 25 pg / ml.

[0107] Suitably, the present disclosure also provides methods for reducing the likelihood of death and / or acute respiratory failure in a subject at risk of death and / or acute respiratory failure, suitably a subject with respiratory distress. Suitably, the present disclosure also provides methods for reducing the rate of death and / or acute respiratory failure in a subject at risk of death and / or acute respiratory failure, suitably a subject with respiratory distress.

[0108] In an example of any method described herein, the subject has or is suspected of having a viral lower respiratory tract infection, and optionally may be hospitalized, and / or optionally may require supplemental oxygen or ventilation. In an example of any method described herein, the subject has a viral lower respiratory tract infection, is hospitalized and requires supplemental oxygen or ventilation.

[0109] sample

[0110] The present disclosure relies on measuring IL-33 / sST2 levels in a sample obtained from a subject. Suitably, the sample may be a test sample.

[0111] Suitably, the sample is a biological sample. As used herein, the term "biological sample" refers to a sample from a subject that can be used for identification, diagnosis, prediction or monitoring purposes. Suitably, the sample is a body fluid sample. Alternatively, a suitable sample may include a tissue sample, such as a biopsy.

[0112] Suitable body fluid samples may include: a blood sample (e.g., a whole blood sample, a plasma sample, or a serum sample, or a combination thereof); a mucosal lining fluid sample (e.g., mucosal lining fluid from an epithelium); a lavage sample (e.g., a lung or bronchoalveolar lavage sample); or a supernatant sample (e.g., from a culture of epithelial cells).

[0113] Suitably, the supernatant sample may be an epithelial cell supernatant sample. Suitably, from a bronchial epithelial culture. Suitably, the supernatant may be from the cells or from the air-liquid interface of the culture.

[0114] Suitably, the mucosal lining fluid samples or lavage samples contain biological cells, suitably these samples contain epithelial cells.

[0115] Suitably, IL-33 / sST2 is ubiquitously present in serum. Thus, in one example, the sample is a serum sample.

[0116] Suitably, the method of the present disclosure may further comprise the step of obtaining a sample. Suitably, the sample is obtained from a subject. Suitably, this step occurs before measuring the IL-33 / ST2 level in the sample. Alternatively, the sample may have been previously obtained before carrying out the method of the present disclosure.

[0117] Suitably, a sample is obtained prior to any treatment of the subject and the level of IL-33 / ST2 in the sample is measured. Thus, suitably, the baseline level of IL-33 / sST2 in the sample is measured.

[0118] Suitably, the blood sample may be obtained by drawing blood from the subject. Suitably, the serum sample may be obtained from the blood sample by coagulating the blood and centrifuging the blood to obtain a serum supernatant.

[0119] Suitably, the mucosal lining fluid sample may be obtained by nasal swab from the subject.

[0120] Suitably, the lavage sample may be obtained by lavage of the subject's lungs.

[0121] Suitably, the supernatant sample may be obtained by culturing cells from a subject. Suitably, by culturing epithelial cells isolated from an epithelium of a subject. Suitably, isolated from respiratory epithelium of a subject.

[0122] Suitably, the sample represents the cytokine levels in the subject to which the method of the present disclosure is being practiced. Suitably, the sample represents the interleukin levels in the subject to which the method is being practiced. Suitably, the sample represents the IL-33 levels in the subject to which the method is being practiced. Suitably, the sample represents the IL-33 / sST2 levels in the subject to which the method is being practiced. Suitably, the sample represents the baseline IL-33 / sST2 levels in the subject to which the method is being practiced.

[0123] The sample may be processed to enrich for IL-33 / sST2. Techniques suitable for such enrichment may be determined with reference to the properties of the sample. In general, examples of suitable techniques (such as techniques for separating biomolecules from a sample) will be well known to those skilled in the art. Suitably, the sample may be filtered, purified, concentrated, etc.

[0124] Measurement of IL-33 / sST2

[0125] The methods of the present disclosure may include the step of measuring the level of IL-33 / sST2 in a sample obtained from a subject, or refers to a subject having a certain level of IL-33 / sST2 that has been measured in a sample from the subject.

[0126] Suitably, "level" refers to any suitable quantification of the amount of IL-33 / sST2 in a sample. Suitably, "level" may refer to the mass, volume or concentration of IL-33 / sST2 in a sample. Suitably, level refers to the concentration of IL-33 / sST2 in a sample. Suitably, concentration can be measured in suitable units, such as: international units per milliliter (IU / ml), grams per milliliter (g / ml), % weight / volume, molar (M). In one example, the concentration is measured in grams per milliliter (g / ml), suitably in micrograms per milliliter (ug / ml), nanograms per milliliter (ng / ml), picograms per milliliter (pg / ml), femtograms per milliliter (fg / ml). In one example, the concentration of IL-33 / sST2 is measured in picograms per milliliter (pg / ml).

[0127] Suitably, as explained above, the level of IL-33 / sST2 is the baseline level of IL-33 / sST2. Suitably, the baseline serum level of IL-33 / sST2. In one example, the subject has a reference level of IL-33 / sST2 greater than or equal to about 25pg / ml. In one example, the subject has a reference level of baseline IL-33 / sST2 greater than or equal to about 25pg / ml. In one example, the subject has a reference level of baseline serum IL-33 / sST2 greater than or equal to about 25pg / ml.

[0128] Suitably, the level of IL-33 / sST2 is measured in a sample obtained from a subject of interest. Suitably, any method for measuring IL-33 / sST2 in a sample may be used. Suitably, any method capable of determining the level of IL-33 / sST2 in a sample.

[0129] Examples of suitable samples are described elsewhere herein.It will be appreciated that the nature of the sample may then determine the nature of the assay techniques that may be used to practice the methods of the present disclosure.

[0130] IL-33 / sST2 is formed by two proteins bound together in a complex. Thus, suitably, the assay technique is a protein assay technique. Thus, suitably, the methods of the present disclosure may comprise the step of measuring IL-33 / sST2 in a sample obtained from a subject using an assay, suitably assaying the sample obtained from the subject to determine the level of IL-33 / sST2 in the sample.

[0131] Protein levels can be determined by various assay techniques such as S-plex, ELISA, radioimmunoassay, immunoprecipitation, Western blot and mass spectrometry. Such assay techniques will be known to those skilled in the art.

[0132] Suitably, the level of IL-33 / sST2 in a sample obtained from a subject is determined by an immunoassay. Thus, suitably, the methods of the present disclosure may comprise the step of measuring the level of IL-33 / sST2 in a sample obtained from a subject using an immunoassay, suitably performing an immunoassay on a sample obtained from a subject to determine the level of IL-33 / sST2 in the sample.

[0133] Immunoassays generally require a capture reagent (such as an antibody) to capture the analyte of interest, and optionally a probe reagent to detect the analyte of interest. Suitable immunoassay techniques are: ELISA (enzyme-linked immunosorbent assay), S-plex, Western blot, immunocytochemistry, immunoprecipitation, affinity chromatography, Bio-Layer Interferometry (Octet, ForteBio) and biochemical assays such as Dissociation Enhanced Lanthanide Fluorescence Immunoassay ( Perkin Elmer), Förster resonance energy transfer (FRET) assays (e.g., homogeneous time-resolved fluorescence ( Cis Biointernational) and radioimmunoassay / radioligand binding assays.

[0134] Western blot analysis generally includes preparation of protein samples, electrophoresis of protein samples in polyacrylamide gels (e.g., 8-20 SDS-PAGE, depending on the molecular weight of the antigen), transfer of protein samples from polyacrylamide gels to membranes such as nitrocellulose, PVDF or nylon, blocking of the membrane in a blocking solution (e.g., PBS with 3% BSA or skim milk), washing of the membrane in a wash buffer (e.g., PBS-Tween 20), blocking of the membrane with a primary antibody (antibody of interest) diluted in a blocking buffer, washing of the membrane in a wash buffer, blocking of the membrane with a secondary antibody (which recognizes the primary antibody, e.g., anti-human antibody) conjugated to an enzyme substrate (e.g., horseradish peroxidase or alkaline phosphatase) or a radioactive molecule (e.g., 32P or 125I) diluted in a blocking buffer, washing of the membrane in a wash buffer, and detection of the presence of the antigen. Those skilled in the art will know the parameters that can be modified to increase the detected signal and reduce background noise. For further discussion of Western blotting protocols, see, e.g., Ausubel et al., eds. (1994) Current Protocols in Molecular Biology (John Wiley & Sons, Inc., NY) Vol. 1 10.8.1.

[0135] ELISA includes preparing an antigen, coating the wells of a 96-well microtiter plate with the antigen, adding an antibody of interest conjugated to a detectable compound such as an enzyme substrate (e.g., horseradish peroxidase or alkaline phosphatase) to the wells and incubating for a period of time, and detecting the presence of the antigen. In ELISA, the antibody of interest does not have to be conjugated to the detectable compound; instead, a second antibody (which recognizes the antibody of interest) conjugated to the detectable compound can be added to the well. In addition, instead of coating the wells with the antigen, the antibody can be coated on the wells. In this case, the second antibody conjugated to the detectable compound can be added after the antigen of interest is added to the coated wells. Those skilled in the art will know that the parameters that can be modified to increase the detected signal and other variations of ELISA known in the art. For further discussion of ELISA, see, for example, Ausubel et al., ed. (1994) Current Protocols in Molecular Biology (John Wiley & Sons, Inc., NY) Vol. 1 13.2.1.

[0136] Suitably, the IL-33 / sST2 level in the sample is determined by immunoassay. Suitably, by using a modified ELISA known as the S-plex assay. The S-plex assay can be obtained from Meso Scale Diagnostics LLC together with suitable instructions for use.

[0137] Immunoassays will generally include the steps of incubating the sample in the presence of one or more binding molecules capable of specifically binding to the protein of interest, and detecting the bound molecules by any of a variety of techniques well known in the art. The assays described herein follow this general format.

[0138] Suitably, the level of IL-33 / sST2 is measured in a sample by an assay (suitably an immunoassay), which assay may comprise the following steps:

[0139] (a) contacting the sample with one or more binding molecules capable of binding to IL-33 / sST2 under conditions sufficient to form a complex;

[0140] (b) Detection of IL-33 / sST2 complex levels in samples.

[0141] Optionally, the method may comprise the step (c) of contacting the complexes with one or more reporter molecules capable of binding to the one or more complexes. In such examples, the detecting step (b) comprises detecting the level of bound reporter molecules in the sample.

[0142] Therefore, suitably, any method of the present disclosure may further comprise steps (a) and (b) above, and optionally step (c).

[0143] Thus, suitably, in one example, a method of treating a subject having respiratory distress or preventing respiratory distress in a subject at risk of respiratory distress may comprise: (a) measuring the level of IL-33 / sST2 in a sample obtained from the subject by (i) contacting the sample with one or more binding molecules capable of binding to IL-33 / sST2 under conditions sufficient to form a complex and (ii) detecting the level of IL-33 / sST2 complex in the sample; and (b) administering to the subject an effective amount of an IL-33 axis binding antagonist if the level of IL-33 / sST2 in the sample is greater than or equal to a reference level of about 25 pg / ml.

[0144] Thus, suitably, in one example, a method of selecting a subject having or at risk of having respiratory distress for treatment with an IL-33 axis antagonist may comprise: (a) measuring the level of IL-33 / sST2 in a sample obtained from the subject by (i) contacting the sample with one or more binding molecules capable of binding to IL-33 / sST2 under conditions sufficient to form a complex and (ii) detecting the level of IL-33 / sST2 complex in the sample; and (b) selecting the subject for said treatment if the level of IL-33 / sST2 in the sample is greater than or equal to a reference level of about 25 pg / ml.

[0145] Thus, suitably, in one example, a method of determining whether a subject having respiratory distress or at risk of having respiratory distress is likely to respond to treatment with an IL-33 axis binding antagonist may comprise: (a) measuring the level of IL-33 / sST2 in a sample obtained from the subject by (i) contacting the sample with one or more binding molecules capable of binding to IL-33 / sST2 under conditions sufficient to form a complex and (ii) detecting the level of IL-33 / sST2 complex in the sample; and (b) determining that the subject is likely to respond to the treatment if the measured level of IL-33 / sST2 in the sample is greater than or equal to a reference level.

[0146] Suitably, any binding molecule that specifically binds to IL-33 / sST2 may be used. Suitably, any reporter molecule that specifically binds to the IL-33 / sST2-binding molecule complex may be used.

[0147] Alternatively, the reporter molecule and the binding molecule are the same entity. In such examples, the binding molecule directly binds to IL-33 / sST2 and is able to indicate so. Therefore, suitably, the binding molecule can be labeled. Suitably, the binding molecule can be detectably labeled.

[0148] Suitably, the one or more reporter molecules, if present, are capable of indicating their presence and / or binding. Suitably, the one or more reporter molecules are labelled. Suitably, the one or more reporter molecules are detectably labelled.

[0149] Suitably, the binding molecule is contacted with the biological sample for a sufficient time to form a complex. Suitably, the reporter molecule (if present) is contacted with the biological sample for a sufficient time to bind to the one or more complexes.

[0150] Suitably, this time may be referred to as the incubation time. Suitably, the incubation time will vary depending on the binding molecule used and optionally the reporter molecule used and the biological sample.

[0151] Suitably, sufficient incubation time may be between 5 minutes and 180 minutes, suitably between 10 minutes and 150 minutes, suitably between 20 minutes and 120 minutes, suitably between 30 minutes and 100 minutes, suitably between 45 minutes and 90 minutes, suitably about 60 minutes.

[0152] Suitably, the one or more binding molecules are contacted with the biological sample for approximately 120 minutes.

[0153] Suitably, the reporter molecule(s), if present, is / are contacted with the complex / biological sample for approximately 120 minutes.

[0154] Suitably, contacting the biological sample with the binding molecule or reporter molecule (if present) comprises bringing the binding molecule or reporter molecule and the biological sample together such that binding can occur.

[0155] Suitably, the biological sample may be contacted with the binding molecule or reporter molecule (if present) in any suitable manner using known assay techniques.

[0156] The sample can be contacted with one or more binding molecules by using a solid support or carrier. Suitably, the sample or binding molecule can be fixed to a support or carrier.

[0157] Suitably, the support may then be washed. Suitably, the support is washed with a suitable buffer. Suitably, the method of the present disclosure may include one or more washing steps. Suitably, washing occurs after adding one or more binding molecules and before adding one or more reporter molecules (if present). Suitably, after adding one or more reporter molecules (if present) and before the detection step.

[0158] Suitably, at least one washing step occurs after step (a), and suitably before step (b).

[0159] Suitably, the support may be contacted with one or more reporter molecules after step (a). Thus, suitably, the step of contacting the complex with one or more reporter molecules capable of binding to one or more complexes may comprise contacting the complex immobilized on the support with one or more reporter molecules capable of binding to one or more complexes. Suitably, the support may then be washed a second time to remove unbound reporter molecules. Thus, suitably, a second washing step may occur after contacting the complex with one or more reporter molecules.

[0160] Optionally, the binding molecule or reporter molecule (if present) may comprise a detectable label, or they may be subsequently labeled. Suitable labels are discussed elsewhere herein. The amount of the binding label that can be bound to the solid support may then be detected by conventional means, suitably as described in step (b).

[0161] "Solid support or carrier" is intended to mean any support capable of binding an antigen or antibody. Well-known supports or carriers include glass, polystyrene, polypropylene, polyethylene, dextran, nylon, nitrocellulose, amylase, natural and modified cellulose, polyacrylamide and magnetite. For the purposes of this disclosure, the nature of the carrier may be soluble or insoluble to a certain extent. The support material may have almost any possible structural configuration, as long as the coupled molecule is capable of binding to the antigen or antibody. Thus, the support configuration may be spherical (as in beads) or cylindrical (as in the inner surface of a test tube or the outer surface of a rod). Alternatively, the surface may be flat, such as a sheet, a test strip, etc. Preferred supports include polystyrene beads. Those skilled in the art will know many other suitable supports for binding antibodies or antigens, or will be able to determine them by using routine experiments.

[0162] Suitably, the reporter molecules (if present) are detected by detecting a detectable label associated with each reporter molecule. Suitably, the detectable label may be part of the reporter molecule or may be added separately, suitably after the reporter molecule has bound to one or more IL-33 / sST2 complexes in the sample.

[0163] Alternatively, detecting one or more IL-33 / sST2 complexes in a sample may include detecting the level of one or more bound binding molecules in the sample. In such examples, suitably, the binding molecules are detected directly by detecting a detectable label associated with each binding molecule. Suitably, in such examples, a reporter molecule is not required. Suitably, the detectable label may be part of the binding molecule or may be added separately, suitably, after the binding molecule has been bound to the IL-33 / sST2 in the sample.

[0164] Suitable detectable labels may be radioactive labels, fluorescent labels, enzymes, chromophores. Suitably, the label may be detectable only upon stimulation. Suitable stimuli will vary depending on the label used, for example when an enzyme label is used, the stimuli may be a substrate, when a chromophore label is used, the stimuli may be radiation of a specific wavelength. Such stimuli may be considered irritants.

[0165] Suitable fluorescent labels may include: rhodamine, fluorescein, Cy5, ruthenium, diimine complexes, and phosphorescent porphyrin dyes.

[0166] Suitable enzyme labels may include: peroxidase, glucose oxidase, alkaline phosphatase (AP), β-galactosidase, catalase or luciferase. The substrate to be used with a particular enzyme is generally selected to produce a detectable color change when hydrolyzed by the corresponding enzyme. For example, p-nitrophenyl phosphate is suitable for use with alkaline phosphatase conjugates; for peroxidase conjugates, 1,2-phenylenediamine or toluidine are generally used. Suitable fluorescent substrates that produce fluorescent products can be used.

[0167] Alternatively, binding molecule or reporter molecule (if present) may not be labeled. In such examples, binding molecule or reporter molecule may be able to be labeled and combined, suitably combined with a detectable label. Suitably, a detectable label can be combined with these binding molecules or reporter molecules and so indicated. Suitably, a detectable label has specificity for a corresponding binding molecule or reporter molecule.

[0168] Thus, suitably, the assay method may further comprise the step of adding a detectable label to the sample.Suitably, step (b) may comprise detecting the detectable label associated with the one or more binding molecules.

[0169] Alternatively, step (b) may comprise detecting a detectable label associated with one or more reporter molecules (if present).

[0170] In one example, the reporter molecule comprises a detectable label conjugated thereto. In such examples, the reporter molecule is detected by detecting the conjugated detectable label.

[0171] In one example, the one or more reporter molecules are detectably labeled. In one example, the one or more reporter molecules comprise a detectable label conjugated thereto. In one example, the one or more reporter molecules are sulfo-tagged.

[0172] In one example, the binding molecule comprises a detectable label conjugated thereto. In such examples, the binding molecule is detected by detecting the conjugated detectable label.

[0173] Suitably, the assay used is highly sensitive. Suitably, the assay is capable of detecting IL-33 / sST2 in a sample at a concentration of micrograms / ml or less, nanograms / ml or less, picograms / ml or less, femtograms / ml or less. In an example, the assay is capable of detecting IL-33 / sST2 in a sample at a concentration of picograms / ml.

[0174] Suitably, the lower limit of detection is a concentration of micrograms / ml or less, nanograms / ml or less, picograms / ml or less, femtograms / ml or less. Suitably, the lower limit of detection is a concentration of femtograms / ml.

[0175] Binding molecules and reporter molecules

[0176] Suitably, the level of IL-33 / sST2 may be measured in a sample obtained from a subject by performing an assay (suitably an immunoassay comprising the steps described above).

[0177] Suitably, the binding molecules and reporter molecules used in the assay are selected from the group consisting of: an antibody, an antigen binding fragment thereof, an aptamer, at least one heavy or light chain CDR of a reference antibody molecule, and at least six CDRs from one or more reference antibody molecules.

[0178] In one example, the binding molecule and the reporter molecule are antibodies or antigen-binding fragments thereof.

[0179] Suitably, the binding molecule is an anti-IL-33 / sST2 antibody or a binding fragment thereof Suitably, the reporter molecule is an anti-IL-33 / sST2-binding molecule complex antibody or a binding fragment thereof.

[0180] As used herein, "antibody" refers to an immunoglobulin molecule, particularly a full-length antibody or a molecule comprising a full-length antibody, such as a DVD-Ig molecule, etc., as discussed in more detail below.

[0181] "Binding fragment thereof" is interchangeable with "antigen binding fragment thereof" and refers to an epitope / antigen binding fragment of an antibody fragment, e.g., comprising the binding region, particularly comprising 6 CDRs, such as 3 CDRs in the heavy variable region and 3 CDRs in the light variable region.

[0182] Suitably, the antibody or its binding fragment is selected from: naturally occurring, polyclonal, monoclonal, multispecific, mouse, human, humanized, primatized or chimeric. Suitably, the antibody or its binding fragment can be an epitope binding fragment, for example, Fab' and F(ab')2, Fd, Fv, single-chain Fv (scFv), disulfide-linked Fv (sdFv), a fragment comprising a VL or VH domain, or a fragment produced by a Fab expression library. Suitably, the antibody or its binding fragment can be a mini-antibody, a double antibody, a three-antibody, a four-antibody or a single-chain antibody. Suitably, the antibody or its binding fragment is a monoclonal antibody. ScFv molecules are known in the art and are described in, for example, U.S. Patent No. 5,892,019.

[0183] The immunoglobulin or antibody molecules of the present disclosure can be of any type (e.g., IgG, IgE, IgM, IgD, IgA, and IgY), class (e.g., IgG1, IgG2, IgG3, IgG4, IgA1, and IgA2, etc.), or subclass of immunoglobulin molecules.

[0184] Suitably, the antibody or binding fragment thereof used as binding molecule is a capture antibody.

[0185] Suitably, the antibody or binding fragment thereof used as a reporter molecule is a probe antibody.

[0186] Suitably, the binding molecule and the reporter molecule are paired so that each capture antibody has a corresponding probe antibody. Suitably, the capture antibody is paired with the probe antibody.

[0187] Suitable binding and reporter molecules, such as antibodies, having such capabilities are available in the art and can be ordered from reagent companies such as, for example, R&D systems.

[0188] However, suitably the binding molecule and / or reporter molecule used in the assay comprises the following sequence.

[0189] IL33 / sST2 Binding Molecule - AB1070008

[0190] Suitably, a binding molecule that binds to IL-33 / sST2 may comprise 3 CDRs, for example in the heavy chain variable region (VH) according to SEQ ID NO:43, and / or may comprise 3 CDRs in the light chain variable region (VL) according to SEQ ID NO:44.

[0191] Suitably, the binding molecule that binds to IL-33 / sST2 comprises 3 CDRs in the heavy chain variable region, wherein the VH has an amino acid sequence that is at least 90%, such as 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the VH according to SEQ ID NO:43, and / or comprises 3 CDRs in the light chain variable region, wherein the VL has an amino acid sequence that is at least 90%, such as 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the VL according to SEQ ID NO:44.

[0192] Suitably, the binding molecule that binds to IL-33 / sST2 may comprise a variable heavy domain (VH) and a variable light domain (VL), the variable heavy domain having VHCDRs 1-3 of SEQ ID NOs: 45, 46 and 47, wherein one or more VHCDRs have 3 or fewer single amino acid substitutions, deletions or insertions.

[0193] Suitably, 3, 2, 1 or no single amino acid substitutions, deletions or insertions.

[0194] Suitably, the binding molecule that binds to IL-33 / sST2 may comprise a variable heavy domain (VH) and a variable light domain (VL), the variable light domain having VLCDR1-3 of SEQ ID NO: 48, 49 and 50, wherein one or more VLCDRs have 3 or fewer single amino acid substitutions, deletions or insertions.

[0195] Suitably, 3, 2, 1 or no single amino acid substitutions, deletions or insertions.

[0196] Suitably, the binding molecule that binds to IL-33 / sST2 may comprise a VH having VHCDR1-3 of SEQ ID NOs: 45, 46 and 47 and a VL having VLCDR of SEQ ID NOs: 48, 49 and 50.

[0197] Suitably, the binding molecule that binds to IL-33 / sST2 may comprise a VHCDR1 having a sequence of SEQ ID NO:45, a VHCDR2 having a sequence of SEQ ID NO:46, a VHCDR3 having a sequence of SEQ ID NO:47, a VLCDR1 having a sequence of SEQ ID NO:48, a VLCDR2 having a sequence of SEQ ID NO:49, and a VLCDR3 having a sequence of SEQ ID NO:50.

[0198] Thus, suitably, the binding molecule that binds to IL-33 / sST2 is an antibody or a binding fragment thereof comprising VH and VL, wherein VH has an amino acid sequence that is at least 90%, such as 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to VH according to SEQ ID NO: 43.

[0199] Thus, suitably, the binding molecule that binds to IL-33 / sST2 is an antibody or a binding fragment thereof comprising VH and VL, wherein VL has an amino acid sequence that is at least 90%, such as 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the VL according to SEQ ID NO: 44.

[0200] Thus, suitably, the binding molecule that binds to IL-33 / sST2 is an antibody or a binding fragment thereof comprising VH and VL, wherein VH has an amino acid sequence consisting of SEQ ID NO:43 and VL has an amino acid sequence consisting of SEQ ID NO:44.

[0201] sST2 reporter

[0202] Suitably, the reporter molecule that binds to sST2 can be obtained from any suitable supplier. For example, suitably, the reporter molecule that binds to sST2 is MAB5232 from R&D Systems. Other examples of sST2 binding molecules that can be used in the assay disclosed herein are MAB523, AF523, MAB5231 from R&D Systems.

[0203] Reference Level

[0204] The methods of the present disclosure are based on comparing the measured level of IL-33 / sST2 in a sample from a subject with a reference level of IL-33 / sST2. Suitably, the reference level is a determinative level. Suitably, the reference level determines whether a subject is likely to respond to or benefit from treatment with an IL-33 axis antagonist.

[0205] The inventors have recognized that a certain level of baseline IL-33 / sST2 in a sample from a subject can indicate the likelihood of successful treatment of the subject with an IL-33 axis antagonist (such as those described herein). The inventors have found that those subjects having IL-33 / sST2 levels greater than or equal to a reference level of IL-33 / sST2 in a sample obtained therefrom are more likely to benefit from treatment and respond to treatment with an IL-33 axis antagonist. Therefore, suitably, the reference level can be considered a threshold level. More specifically, the present disclosure illustrates that in hospitalized subjects diagnosed with COVID-19 with respiratory distress who have higher levels of the IL-33 / sST2 complex, there is a greater numerical reduction in death and / or respiratory failure when treated with torelizumab compared to the standard of care.

[0206] Thus, suitably, the methods of the present disclosure may comprise a step of comparing the measured level of IL-33 / sST2 with a reference level. Suitably, such a step may be automated.

[0207] Thus, suitably, the methods of the present disclosure may include a step of determining whether the measured level of IL-33 / sST2 is greater than or equal to a reference level. Suitably, such a step may be automated.

[0208] Suitably, the measured level of IL-33 / sST2 is a baseline level of IL-33 / sST2. Suitably, a baseline serum level of IL-33 / sST2.

[0209] Suitably, the comparing step and / or determining step occurs after any measuring step in the methods of the present disclosure.

[0210] Suitably, if the sample contains a level of IL-33 / sST2 greater than or equal to the reference level, this indicates that the subject may respond to, or may benefit from, treatment with an IL-33 axis antagonist. Suitably, if the sample contains a level of IL-33 / sST2 greater than or equal to the reference level, this indicates that the subject should be selected for treatment with an IL-33 axis antagonist. Therefore, suitably, the method of the present disclosure may further include the step of selecting a subject for treatment with an IL-33 axis antagonist, suitably if the sample contains a level of IL-33 / sST2 greater than or equal to the reference level. Suitably, if the sample contains a level of IL-33 / sST2 greater than or equal to the reference level, this indicates that the subject should be treated with an IL-33 axis antagonist.

[0211] Thus, suitably, the methods of the invention may further comprise the step of treating the subject with an IL-33 axis antagonist, suitably if the sample contains a level of IL-33 / sST2 greater than or equal to the reference level. Suitably, treating the subject may comprise administering to the subject an effective amount of an IL-33 axis antagonist as described elsewhere herein.

[0212] Suitably, if the sample contains a level of IL-33 / sST2 less than the reference level, this indicates that the subject may not respond to treatment with an IL-33 axis antagonist, or may not benefit from it. Suitably, if the sample contains a level of IL-33 / sST2 less than the reference level, this indicates that the subject should not be selected for treatment with an IL-33 axis antagonist. Suitably, if the sample contains a level of IL-33 / sST2 less than the reference level, this indicates that the subject should not be treated with an IL-33 axis antagonist. Suitably, if the sample contains a level of IL-33 / sST2 less than the reference level, this indicates that the subject is less likely to respond to or benefit from the treatment. Suitably, the likelihood is reduced compared to a subject with an IL-33 / sST2 level greater than or equal to the reference level.

[0213] Suitably, a subject having greater than or equal to a reference level of IL-33 / sST2 in a sample obtained therefrom may be more likely to respond to or benefit from treatment with an IL-33 axis antagonist than a subject having less than a reference level of IL-33 / sST2 in a sample obtained therefrom. Suitably, a subject having greater than or equal to a reference level of IL-33 / sST2 in a sample obtained therefrom may have an increased likelihood of responding to or benefiting from treatment with an IL-33 axis antagonist compared to a subject having less than a reference level of IL-33 / sST2 in a sample obtained therefrom. Suitably, a subject having less than a reference level of IL-33 / sST2 in a sample obtained therefrom may be referred to as a "reference subject". Therefore, suitably, a subject having greater than or equal to a reference level of IL-33 / sST2 in a sample obtained therefrom may be more likely to respond to or benefit from treatment with an IL-33 axis antagonist than a reference subject.

[0214] Suitably, the measured level must be greater than or equal to the reference level to indicate treatment, selection of a subject for treatment, or determination of the likelihood of responding to or benefiting from treatment. Suitably, the measured level must be greater than the reference level to indicate treatment, selection of a subject for treatment, or determination of the likelihood of responding to or benefiting from treatment.

[0215] Suitably, "likely to respond to treatment" may mean that the subject will respond to treatment. Suitably, "likely to benefit from treatment" may mean that the subject will benefit from treatment. Thus, suitably, if the sample contains an IL-33 / sST2 level greater than or equal to the reference level, this indicates that the subject will respond to, or will benefit from, treatment with an IL-33 axis antagonist.

[0216] Suitably, the reference level is about 25 picograms per milliliter (pg / ml). Suitably, the reference level is about 26pg / ml, about 27pg / ml, about 28pg / ml, about 29pg / ml, about 30pg / ml. In an example, the reference level is about 30pg / ml. More specifically, in an example, the reference level is 30.15pg / ml, and suitably, if the IL-33 / sST2 level in the sample obtained therefrom is greater than or equal to 30.15pg / ml, the subject is treated, the subject is selected for treatment, or the subject is more likely to respond to treatment. In an example, if the IL-33 / sST2 level in the sample obtained therefrom is greater than 30.15pg / ml, the subject is treated, the subject is selected for treatment, or the subject is more likely to respond to treatment.

[0217] Suitably, "about" means that the measured value may vary from the stated value by + / - 10%. Suitably, "about" means that the measured value may vary from the stated value by + / - 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9% or 10%.

[0218] Suitably, treatment with or responsive to an IL-33 axis antagonist may include any improvement in the subject's physiology. Suitably, any improvement in the subject's condition, disease, disorder or infection, suitably, any improvement in the subject's respiratory distress. Suitably, treatment with or responsive to an IL-33 axis antagonist may include a reduction in the subject's respiratory distress. Suitably, a reduction in respiratory distress may include any of: a reduction in respiratory rate, an increase in blood oxygen concentration, a reduction in shortness of breath, an increase in blood pressure, a reduction in heart rate, a reduction in chest pain, a normal skin color, a reduction in sweating, a reduction in wheezing, a reduction in confusion, and a reduction in fatigue.

[0219] Suitably, treatment with or response to treatment with an IL-33 axis antagonist may include removal of the subject's oxygen or ventilator support, or a reduction in the number of days that the subject requires oxygen or ventilation.

[0220] Suitably, treatment with or response to an IL-33 axis antagonist may comprise a clinical improvement of at least 2 points on a 9 point category ordinal scale. Suitably, a response to treatment with an IL-33 axis antagonist may comprise achieving a score of 0, 1 or 2 on the ordinal scale.

[0221] Suitably, treatment with an IL-33 axis antagonist or response to such treatment may include reducing the likelihood of death and / or acute respiratory failure, or may include preventing respiratory failure and / or death. Suitably, the reduction in the likelihood of death and / or acute respiratory failure may be compared to a subject who has not received treatment with an IL-33 axis antagonist. Suitably, the subject is less likely to experience death and / or acute respiratory failure than a subject who has not received treatment with an IL-33 axis antagonist. Suitably, the reduction in the likelihood of death and / or acute respiratory failure may be compared to a subject having IL-33 / sST2 below a reference level in a sample obtained therefrom, which subjects may be referred to as "reference subjects". Suitably, the subject is less likely to experience death and / or acute respiratory failure than a subject having IL-33 / sST2 below a reference level in a sample obtained therefrom.

[0222] Suitably, treatment with an IL-33 axis antagonist or response to such treatment may include reducing the rate of death and / or acute respiratory failure. Suitably, the rate of death and / or acute respiratory failure in subjects at risk of death and / or acute respiratory failure is reduced. Suitably, the rate of death and / or acute respiratory failure in a population of subjects may be reduced. Suitably, the rate of death and / or acute respiratory failure may be defined as the number of subjects experiencing death and / or acute respiratory failure in a population, suitably, a population at risk of death and / or acute respiratory failure, suitably, a population with respiratory distress. Suitably, the reduction in the rate of death and / or acute respiratory failure may be compared to subjects who have not received treatment with an IL-33 axis antagonist. Suitably, the rate of death and / or acute respiratory failure in subjects treated with an IL-33 axis antagonist is lower than in subjects who have not received treatment with an IL-33 axis antagonist. Suitably, the reduction in the rate of death and / or acute respiratory failure may be compared to subjects having IL-33 / sST2 below a reference level in a sample obtained therefrom, which subjects may be referred to as "reference subjects". Suitably, the rate of death and / or acute respiratory failure in a subject is reduced compared to a subject having IL-33 / sST2 below a reference level in a sample obtained therefrom.

[0223] Suitably, in the context of a method of preventing respiratory distress in a subject, responding to or benefiting from treatment with an IL-33 axis antagonist may be considered to prevent the occurrence of respiratory distress in the subject, suitably, such that the subject does not experience respiratory distress. Suitably, in such instances, responding to or benefiting from treatment with an IL-33 axis antagonist may be considered to prevent any symptom associated with the occurrence of respiratory distress, as defined above. Suitably, in such instances, responding to or benefiting from treatment with an IL-33 axis antagonist may be considered to prevent all symptoms associated with the occurrence of respiratory distress, as defined above. In some instances of methods of preventing respiratory distress in a subject, responding to or benefiting from treatment with an IL-33 axis antagonist may be considered to prevent the occurrence of acute respiratory failure in the subject, suitably, such that the subject does not experience acute respiratory failure. Suitably, in the context of a method of preventing acute respiratory failure in a subject, responding to or benefiting from treatment with an IL-33 axis antagonist may be considered to prevent the need to ventilate or provide oxygen to the subject, suitably, prevent the subject from requiring ventilation or oxygen. Suitably, in such examples, responding to or benefiting from the treatment may be considered to prevent the need to assist the subject with breathing, suitably, prevent the subject from requiring any respiratory assistance.

[0224] Suitably, the response to treatment with the IL-33 axis antagonist occurs within 2 months of first treatment, suitably within about 6 weeks of first treatment, suitably within about 1 month of first treatment, suitably within 29 days of first treatment.

[0225] In one example, response to treatment with an IL-33 axis antagonist can include prevention of respiratory failure or death within 29 days of first treatment.

[0226] Suitably, the phrases "responsive to" or "benefiting from" are used interchangeably herein and may refer to the same response in a subject as identified above.

[0227] IL-33 axis antagonists

[0228] The methods of the present disclosure include treating a subject with an IL-33 axis antagonist, or preventing the development of a condition, disease, or disorder in a subject with an IL-33 axis antagonist.

[0229] As used herein, "IL-33 axis antagonist" refers to any agent that directly or indirectly attenuates IL-33 activity. The antagonist may attenuate the activity of reduced IL-33, oxidized IL-33, or both. Alternatively, the antagonist may attenuate the activity of other molecules in the IL-33 signaling pathway or "axis", such as ST2, IL1-RaP, MyD88, IRAK1, IRAK4, TRAF6, MAPK, AP-1, NFkB, p38, Foxp3, GATA3, and IRF1. Suitably, the IL-33 axis antagonist may attenuate the activity of reduced IL-33, oxidized IL-33, ST2, and / or IL1-RaP.

[0230] Suitably, the IL-33 axis antagonist is specific for reduced and / or oxidized IL-33, and suitably, attenuates the activity of reduced and / or oxidized IL-33. Suitably, in such cases, the IL-33 axis antagonist may be referred to simply as an "IL-33 antagonist".

[0231] Suitably, the IL-33 axis antagonist is specific for ST2 and, suitably, attenuates the activity of ST2. Suitably, in such cases, the IL-33 axis antagonist may be referred to as a "ST2 antagonist". An example of a suitable ST2 antagonist is the anti-ST2 antibody astegolimab, also known as MSTT1041A, AMG282 and RG6149.

[0232] Suitably, the IL-33 axis antagonist is specific for IL1-RaP, and suitably, attenuates the activity of IL1-RaP. Suitably, in such circumstances, the IL-33 axis antagonist may be referred to as an "IL1-RaP antagonist".

[0233] Suitably, the attenuation is achieved by binding to the reduced or oxidized form of IL-33, or to ST2, or to IL1-RaP. Suitably, where the antagonist attenuates reduced IL-33 activity and oxidized IL-33 activity, the attenuation is achieved by binding to the reduced form of IL-33 (i.e. by binding to reduced IL-33).

[0234] Suitably, the IL-33 axis antagonist is a binding molecule or fragment thereof. Thus, suitably, the IL-33 axis antagonist may be referred to as an IL-33 axis binding antagonist.

[0235] "Binding molecules" or "antigen binding molecules" of the present disclosure refer to molecules that specifically bind to antigenic determinants in their broadest sense. Suitably, the binding molecule specifically binds to IL-33 (particularly reduced IL-33 or oxidized IL-33), ST2 or IL1 RaP. In one example, the binding molecule specifically binds to reduced IL-33.

[0236] Suitably, the binding molecule may be selected from: an antibody, an antigen-binding fragment thereof, an aptamer, at least one heavy chain or light chain CDR of a reference antibody molecule, and at least six CDRs from one or more reference antibody molecules.

[0237] Suitably, the IL-33 axis antagonist is an antibody or a binding fragment thereof. Suitably, the IL-33 axis antagonist is an anti-IL-33 antibody or a binding fragment thereof, an anti-ST2 antibody or a binding fragment thereof, or an anti-IL1 RaP antibody or a binding fragment thereof. Suitably, the anti-IL-33 antibody or a binding fragment thereof specifically binds to IL-33, in particular reduced IL-33 or oxidized IL-33.

[0238] In one example, the IL-33 axis antagonist is an anti-IL-33 antibody or a binding fragment thereof.

[0239] As used herein, "antibody" refers to an immunoglobulin molecule, particularly a full-length antibody or a molecule comprising a full-length antibody, such as a DVD-Ig molecule, etc., as discussed in more detail below.

[0240] "Binding fragment thereof" is interchangeable with "antigen binding fragment thereof" and refers to an epitope / antigen binding fragment of an antibody fragment, e.g., comprising the binding region, particularly comprising 6 CDRs, such as 3 CDRs in the heavy variable region and 3 CDRs in the light variable region.

[0241] Suitably, the antibody or its binding fragment is selected from: naturally occurring, polyclonal, monoclonal, multispecific, mouse, human, humanized, primatized or chimeric. Suitably, the antibody or its binding fragment can be an epitope binding fragment, for example, Fab' and F(ab')2, Fd, Fv, single-chain Fv (scFv), disulfide-linked Fv (sdFv), a fragment comprising a VL or VH domain, or a fragment produced by a Fab expression library. Suitably, the antibody or its binding fragment can be a mini-antibody, a double antibody, a three-antibody, a four-antibody or a single-chain antibody. Suitably, the antibody or its binding fragment is a monoclonal antibody. ScFv molecules are known in the art and are described in, for example, U.S. Patent No. 5,892,019.

[0242] The immunoglobulin or antibody molecules of the present disclosure can be of any type (e.g., IgG, IgE, IgM, IgD, IgA, and IgY), class (e.g., IgG1, IgG2, IgG3, IgG4, IgA1, and IgA2, etc.), or subclass of immunoglobulin molecules.

[0243] Suitably, the IL-33 axis antagonist is a reduced IL-33 antagonist. In other words, the IL-33 axis antagonist attenuates the activity of reduced IL-33. Suitably, the attenuation is achieved by binding to reduced IL-33.

[0244] Suitably, the binding molecule or fragment thereof is present in an amount less than 5×10 -2 M, 10 -2 M, 5×10 -3 M, 10 -3 M, 5×10 -4 M, 10 - 4 M, 5×10 -5 M, 10 -5 M, 5×10 -6 M, 10 -6 M, 5×10 -7 M, 10 -7 M, 5×10 -8 M, 10 -8 M, 5×10 -9 M, 10 -9 M, 5×10 -10 M, 10 -10 M, 5×10 -11 M, 10 -11 M, 5×10 -12 M, 10 -12 M, 5×10 -13 M, 10 -13 M, 5×10 -14 M, 10-14 M, 5×10 - 15 M or 10 -15 The binding affinity (Kd) of M specifically binds to reduced IL-33. Suitably, the binding affinity for reduced IL-33 is less than 5×10 -14 M (i.e. 0.05pM). Suitably, the binding affinity is measured using a kinetic exclusion assay (KineticExclusion Assays, KinExA) or BIACORETM, suitably using KinExA, using a scheme such as those described in WO2016 / 156440 (see, e.g., Example 11), which is hereby incorporated by reference in its entirety. The binding molecules that bind to reduced IL-33 with this binding affinity appear to be tightly bound to reduced IL-33 to prevent the binding molecule / reduced IL-33 complex from dissociating within a biologically relevant time scale. Without wishing to be bound by theory, this binding strength is believed to prevent the release of antigens before the antibody / antigen complex is degraded in vivo, so that reduced IL-33 is not released.

[0245] Suitably, the binding molecule or fragment thereof may be greater than or equal to 10 3 M -1 s -1 , 5×10 3 M -1 s-1, 104M -1 s-1 or 5×10 4 M -1 s -1 The binding rate (k(on)) of the present disclosure can be greater than or equal to 10 5 M -1 s -1 , 5×10 5 M -1 s 1 , 10 6 M -1 s -1 or 5×10 6 M -1 s -1 or 10 7 M -1 s -1 The association rate (k(on)) of the reduced IL-33 or its fragment or variant is greater than or equal to 10 7 M -1 s -1 .

[0246] Suitably, the binding molecule or fragment thereof may be less than or equal to 5×10 -1s-1, 10 -1 s -1 , 5×10 -2 s-1, 10 -2 s -1 ,5×l0 -3 s -1 or 10 -3 s -1 For example, it can be said that the binding molecules of the present disclosure specifically bind to reduced IL-33 at a dissociation rate (k(off)) of less than or equal to 5×10 -4 s -1 , 10 -4 s -1 , 5×10 -5 s -1 , 10 -5 s -1 , 5×10 -6 s -1 , 10 -6 s -1 , 5×10 -7 s -1 or 10 -7 s -1 The dissociation rate (k(off)) of the reduced IL-33 or its fragment or variant is less than or equal to 10 -3 s -1 IL-33 is an alarmin cytokine that is released rapidly and in high concentrations in response to inflammatory stimuli.

[0247] Suitably, the IL-33 binding molecule can competitively inhibit the binding of IL-33 to the binding molecule 33_640087-7B, also known as torelqimab and MEDI3506 (as described in WO2016 / 156440). Suitably, WO2016 / 156440 describes that 33_640087-7B binds to reduced IL-33 with particularly high affinity. The light chain of torelqimab has the amino acid sequence shown in SEQ ID NO: 52, and the heavy chain of torelqimab has the amino acid sequence shown in SEQ ID NO: 51.

[0248] Torreqi monoclonal antibody is a fully human IgG1 monoclonal antibody, which is being developed for the treatment of chronic obstructive pulmonary disease (COPD) in particular. Torreqi monoclonal antibody binds to the human reduced form (IL-33red) of IL-33 and prevents IL 33red from binding to its receptor ST2. Torreqi monoclonal antibody binds to human IL-33 with an abnormally high affinity of about 30fM, and completely neutralizes the full-length form and all mature forms of endogenous IL-33red (Scott et al., ERS International Congress 2022, Barcelona (ES), Abstract OA2254). By combining with IL33red, Torreqi monoclonal antibody effectively inhibits ST2-dependent inflammatory response in several primary human cells and in an in vivo lung epithelial injury model driven by allergens. The IL-33 oxidized form (IL 33ox) that cannot be combined with ST2 is signaled via the RAGE / EGFR pathway. Torreqimab cannot bind to IL-33ox, but can prevent IL-33 oxidation and IL-33ox-dependent signaling via the RAGE / EGFR complex, and mimic the mechanism of action of ST2 (Scott et al., supra). Torreqimab's inhibition of IL-33ox signaling can improve airway epithelial repair function and reverse airway epithelial dysfunction in respiratory diseases, including excessive mucus secretion (Scott et al., supra). Therefore, a binding molecule that competitively inhibits the binding of IL-33 to the binding molecule 33_640087-7B is very likely to inhibit reduced IL-33 and oxidized IL-33 signaling.

[0249] A binding molecule or fragment thereof is considered to competitively inhibit binding of a reference antibody to a given epitope if the binding molecule or fragment thereof specifically binds to the epitope to such an extent that it blocks, to some extent, the binding of the reference antibody to the epitope. Competitive inhibition can be determined by any method known in the art, for example, solid phase assays such as competition ELISA assays, dissociation enhanced lanthanide fluorescence immunoassays (DELAFIs), and the like. Perkin Elmer) and radioligand binding assays. For example, a skilled person can determine whether a binding molecule or fragment thereof competes for binding to redIL-33 by using an in vitro competitive binding assay, such as a derivative of the HTRF assay described in Example 1 of WO2016 / 156440, which is hereby incorporated by reference. For example, a skilled person can label a recombinant antibody of Table 1 with a donor fluorophore and mix multiple concentrations with a fixed concentration of a redIL-33 sample labeled with an acceptor fluorophore. Subsequently, fluorescence resonance energy transfer between the donor and acceptor fluorophores within each sample can be measured to determine the binding characteristics. To elucidate a competitive binding molecule, a skilled person can first mix different concentrations of a test binding molecule with a fixed concentration of a labeled antibody of Table 1. When the mixture is incubated with labeled IL-33, a reduction in the FRET signal compared to a positive control of labeled antibody alone will indicate competitive binding to IL-33. A binding molecule or fragment thereof can be said to competitively inhibit the binding of a reference antibody to a given epitope by at least 90%, at least 80%, at least 70%, at least 60%, or at least 50%.

[0250] In some examples, the IL-33 axis binding antagonist is selected from any of the following anti-IL-33 antibodies: 33_640087-7B, known as toretuzumab (as described in WO2016 / 156440), ANB020, known as etretuzumab (as described in WO2015 / 106080), 9675P or etretuzumab (as described in US2014 / 0271658), A25-3H04 (as described in US2017 / 0283494), Ab43 (as described in WO2018 / 081075), IL33-158 (as described in US2018 / 0037644), 10C12.38.H6.87Y.581lgG4 (as described in WO2016 / 077381), or binding fragments thereof, each of which is incorporated herein by reference. All of these antibodies are referenced in Table 1.

[0251] Suitably, the IL-33 axis binding antagonist is an antibody or antigen binding fragment comprising a complementarity determining region (CDR) of a heavy chain variable region (HCVR or VH) and a light chain variable region (LCVR or VL) pair selected from Table 1. Pair 1 corresponds to the HCVR and LCVR sequences of torelizumab (33_640087-7B) described in WO2016 / 156440. Pairs 2-7 correspond to the HCVR and LCVR sequences of the antibody described in US2014 / 0271658. Pairs 8-12 correspond to the HCVR and LCVR sequences of the antibody described in US2017 / 0283494. Pair 13 corresponds to the HCVR and LCVR sequences of ANB020 described in WO2015 / 106080. Pairs 14-16 correspond to the HCVR and LCVR sequences of the antibody described in WO2018 / 081075. Pair 17 corresponds to the HCVR and LCVR sequences of IL33-158 described in US2018 / 0037644. Pair 18 corresponds to the HCVR and LCVR sequences of 10C12.38.H6.87Y.581 IgG4 described in WO2016 / 077381.

[0252] Table 1: Exemplary anti-IL-33 antibody HCVR and LCVR pairs

[0253]

[0254]

[0255]

[0256] Suitably, the technician knows the available methods for identifying the CDR in the heavy and light variable regions of antibodies or their antigen-binding fragments in the art. Suitably, for example, the technician can perform sequence-based annotations. The region between CDRs is usually highly conserved, so the CDR position can be determined using logical rules. The technician can use a set of sequence-based rules (Pantazes and Maranas, Protein Engineering, Design and Selection, 2010) for conventional antibodies, or or in addition, it can refine the rules based on multiple sequence alignments. Alternatively, the technician can use the BLASTP command of BLAST+ to compare the antibody sequence with the publicly available database operated on Kabat, Chothia or IMGT methods to identify the most similar annotation sequences. Each of these methods has designed a unique residue numbering scheme, according to which the hypervariable region residues are numbered, and then the start and end of each of the six CDRs are determined according to certain key positions. After alignment with the most similar annotation sequence, for example, CDR can be extrapolated from the annotation sequence to the non-annotation sequence, thereby identifying CDR. Suitable tools / databases are: e.g. Kabat database, Kabatman, Scalinger, IMGT, Abnum.

[0257] Suitably, the IL-33 axis antagonist is an anti-IL-33 antibody or antigen-binding fragment comprising a heavy chain variable region (HCVR or VH) and a light chain variable region (LCVR or VL) pair selected from Table 1.

[0258] Thus, suitably, in one example, a method of treating a subject having respiratory distress or preventing respiratory distress in a subject at risk of respiratory distress is provided, the method comprising administering to the subject an effective amount of an anti-IL-33 antibody or antigen-binding fragment comprising a heavy chain variable region and a light chain variable region pair selected from Table 1, preferably 33_640087-7B / Torekizumab, wherein the IL-33 / sST2 level in a sample obtained from the subject is greater than or equal to a reference level of about 25 pg / ml.

[0259] Thus, suitably, in one example, a method of treating a subject having respiratory distress or preventing respiratory distress in a subject at risk of respiratory distress is provided, wherein the method comprises: measuring the level of IL-33 / sST2 in a sample obtained from the subject; and if the level of IL-33 / sST2 in the sample is greater than or equal to a reference level of about 25 pg / ml, administering to the subject an effective amount of an anti-IL-33 antibody or antigen-binding fragment comprising a heavy chain variable region and a light chain variable region pair selected from Table 1, preferably 33_640087-7B / torezimab.

[0260] Thus, suitably, in one example, a method of selecting a subject having respiratory distress or at risk of respiratory distress for treatment with an anti-IL-33 antibody or antigen-binding fragment comprising a heavy chain variable region and a light chain variable region pair selected from Table 1, preferably 33_640087-7B / Torekizumab is provided, the method comprising: measuring the level of IL-33 / sST2 in a sample obtained from the subject; and if the level of IL-33 / sST2 in the sample is greater than or equal to a reference level of about 25 pg / ml, selecting the subject for said treatment.

[0261] Thus, suitably, in one example, a method of determining whether a subject having respiratory distress or at risk of respiratory distress is likely to respond to treatment with an anti-IL-33 antibody or antigen-binding fragment comprising a heavy chain variable region and a light chain variable region pair selected from Table 1, preferably 33_640087-7B / Torekizumab is provided, the method comprising: measuring the level of IL-33 / sST2 in a sample obtained from the subject; and if the measured level of IL-33 / sST2 in the sample is greater than or equal to the reference level, determining that the subject is likely to respond to the treatment.

[0262] Suitably, the anti-IL33 antibody or antigen-binding fragment thereof comprises a HCVR / VH of the sequence of SEQ ID NO:1 and a LCVR / VL of the sequence of SEQ ID NO:19.

[0263] Suitably, the anti-IL33 antibody or antigen-binding fragment thereof comprises a HCVR / VH of the sequence of SEQ ID NO:7 and a LCVR / VL of the sequence of SEQ ID NO:25.

[0264] Suitably, the anti-IL33 antibody or antigen-binding fragment thereof comprises a HCVR / VH of the sequence of SEQ ID NO:11 and a LCVR / VL of the sequence of SEQ ID NO:29.

[0265] Suitably, the anti-IL33 antibody or antigen-binding fragment thereof comprises a HCVR / VH of the sequence of SEQ ID NO:13 and a LCVR / VL of the sequence of SEQ ID NO:31.

[0266] Suitably, the anti-IL33 antibody or antigen-binding fragment thereof comprises a HCVR / VH of the sequence of SEQ ID NO:16 and a LCVR / VL of the sequence of SEQ ID NO:34.

[0267] Suitably, the anti-IL33 antibody or antigen-binding fragment thereof comprises a HCVR / VH of the sequence of SEQ ID NO: 17 and a LCVR / VL of the sequence of SEQ ID NO: 35.

[0268] Suitably, the anti-IL33 antibody or antigen-binding fragment thereof comprises a HCVR / VH of the sequence of SEQ ID NO: 18 and a LCVR / VL of the sequence of SEQ ID NO: 36.

[0269] Thus, suitably, the IL-33 axis antagonist is a binding molecule which may, for example, comprise three CDRs in the heavy chain variable region independently selected from SEQ ID NOs: 1, 7, 11, 13, 16, 17 and 18.

[0270] Suitably, the IL-33 axis antagonist is a binding molecule comprising three CDRs in the heavy chain variable region according to SEQ ID NO:1.

[0271] Suitably, the IL-33 axis antagonist is a binding molecule that comprises three CDRs in the light chain variable region independently selected from SEQ ID NOs: 19, 25, 29, 31, 34, 35 and 36.

[0272] Suitably, the IL-33 axis antagonist is a binding molecule comprising three CDRs in the light chain variable region according to SEQ ID NO:19.

[0273] Thus, suitably, the IL-33 axis antagonist is a binding molecule that may, for example, comprise 3 CDRs in the heavy chain variable region independently selected from SEQ ID NOs: 1, 7, 11, 13, 16, 17 and 18 and, for example, comprise 3 CDRs in the light chain variable region independently selected from SEQ ID NOs: 19, 25, 29, 31, 34, 35 and 36.

[0274] Thus, suitably, the IL-33 axis antagonist is a binding molecule comprising 3 CDRs in the heavy chain variable region according to SEQ ID NO:1 and 3 CDRs in the light chain variable region according to SEQ ID NO:19.

[0275] Thus, suitably, the IL-33 axis antagonist is a binding molecule that may comprise a variable heavy domain (VH) and a variable light domain (VL), the variable heavy domain having VH CDRs 1-3 having sequences of SEQ ID NOs: 37, 38 and 39, respectively, wherein one or more VH CDRs have 3 or fewer single amino acid substitutions, insertions and / or deletions.

[0276] Thus, suitably, the IL-33 axis antagonist is a binding molecule comprising a VH domain comprising VHCDRs 1-3 of SEQ ID NO: 37, SEQ ID NO: 38 and SEQ ID NO: 39, respectively.

[0277] Thus, suitably, the IL-33 axis antagonist is a binding molecule comprising a VH domain comprising VH CDRs 1-3 consisting of SEQ ID NO: 37, SEQ ID NO: 38 and SEQ ID NO: 39, respectively.

[0278] Thus, suitably, the IL-33 antagonist is a binding molecule that may comprise a variable heavy domain (VH) and a variable light domain (VL) having VL CDRs 1-3 having sequences of SEQ ID NOs: 40, 41 and 42, respectively, wherein one or more VLCDRs have 3 or fewer single amino acid substitutions, insertions and / or deletions.

[0279] Thus, suitably the IL-33 axis antagonist is a binding molecule comprising a VL domain comprising VLCDRs 1-3 of SEQ ID NO: 40, SEQ ID NO: 41 and SEQ ID NO: 42, respectively.

[0280] Thus, suitably, the IL-33 axis antagonist is a binding molecule comprising a VL domain comprising VLCDRs 1-3 consisting of SEQ ID NO: 40, SEQ ID NO: 41 and SEQ ID NO: 42, respectively.

[0281] Thus, suitably, the IL-33 axis antagonist is a binding molecule that may comprise a VHCDR1 having the sequence of SEQ ID NO:37, a VHCDR2 having the sequence of SEQ ID NO:38, a VHCDR3 having the sequence of SEQ ID NO:39, a VLCDR1 having the sequence of SEQ ID NO:40, a VLCDR2 having the sequence of SEQ ID NO:41 and a VLCDR3 having the sequence of SEQ ID NO:42.

[0282] Thus, suitably, the IL-33 axis antagonist is an antibody or binding fragment thereof comprising a VH and a VL, wherein the HCVR / VH has an amino acid sequence that is at least 90%, such as 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the HCVR / VH according to SEQ ID NOs: 1, 7, 11, 13, 16, 17 and 18.

[0283] Thus, suitably, the IL-33 axis antagonist is an antibody or binding fragment thereof comprising a VH and a VL, wherein the HCVR / VH has an amino acid sequence that is at least 90%, such as 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the HCVR / VH according to SEQ ID NO: 1.

[0284] Thus, suitably, the IL-33 axis antagonist is an antibody or binding fragment thereof comprising VH and VL, wherein the HCVR / VH disclosed above has a sequence in which 1, 2, 3 or 4 amino acids in the framework are deleted, inserted and / or independently substituted with different amino acids.

[0285] Thus, suitably, the IL-33 axis antagonist is an antibody or binding fragment thereof comprising a VH and a VL, wherein the LCVR / VL has an amino acid sequence that is at least 90%, such as 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the LCVR / VL according to SEQ ID NOs: 19, 25, 29, 31, 34, 35 and 36.

[0286] Thus, suitably, the IL-33 axis antagonist is an antibody or binding fragment thereof comprising a VH and a VL, wherein the LCVR / VL has an amino acid sequence that is at least 90%, such as 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the LCVR / VL according to SEQ ID NO: 19.

[0287] Thus, suitably, the IL-33 axis antagonist is an antibody or binding fragment thereof comprising VH and VL, wherein the LCVR / VL disclosed above has a sequence in which 1, 2, 3 or 4 amino acids in the framework are independently deleted, inserted and / or substituted with different amino acids.

[0288] Thus, suitably, the IL-33 axis antagonist is an anti-IL-33 antibody or binding fragment thereof comprising a VH and a VL, wherein the VH has an amino acid sequence that is at least 90%, such as 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the HCVR / VH according to SEQ ID NOs: 1, 7, 11, 13, 16, 17 and 18, and the VL has an amino acid sequence that is at least 90%, such as 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the LCVR / VL according to SEQ ID NOs: 19, 25, 29, 31, 34, 35 and 36.

[0289] Thus, suitably, the IL-33 axis antagonist is an anti-IL-33 antibody or binding fragment thereof comprising a VH and a VL, wherein the HCVR / VH has an amino acid sequence consisting of SEQ ID NOs: 1, 7, 11, 13, 16, 17 and 18, and the LCVR / VL has an amino acid sequence consisting of SEQ ID NOs: 19, 25, 29, 31, 34, 35 and 36.

[0290] Thus, suitably, the IL-33 axis antagonist is an anti-IL-33 antibody or binding fragment thereof comprising a VH and a VL, wherein the HCVR / VH has an amino acid sequence consisting of SEQ ID NO: 1, and the LCVR / VL has an amino acid sequence consisting of SEQ ID NO: 19. Suitably, in such examples, the IL-33 axis antagonist is 33_640087-7B, also known as torelizumab.

[0291] Effective amount and administration

[0292] The IL-33 axis antagonists in the medical uses and methods described herein can be administered to a subject in the form of a pharmaceutical composition.

[0293] Suitably, any reference herein to "an IL-33 axis antagonist" may also refer to a pharmaceutical composition comprising an IL-33 axis antagonist. Suitably, a pharmaceutical composition may comprise one or more IL-33 axis antagonists in combination.

[0294] Suitably, the IL-33 axis antagonist may be administered in a pharmaceutically effective amount for the in vivo treatment of respiratory distress as defined herein in terms of medical uses and methods of treatment.

[0295] Suitably, a "pharmaceutically effective amount" or "therapeutically effective amount" of an IL-33 axis antagonist is understood to mean an amount sufficient to achieve effective binding to a target molecule within the IL-33 axis and achieve a beneficial effect (e.g., improving symptoms of a disease or condition such as respiratory distress as described herein in the medical uses / methods).

[0296] Suitably, the IL-33 axis antagonist or pharmaceutical composition thereof can be administered to humans or other animals in an amount sufficient to produce a therapeutic effect according to the above-mentioned treatment methods / medical uses.

[0297] A suitable dose of an IL-33 axis antagonist or a pharmaceutical composition thereof that may constitute a "pharmaceutically effective amount" or a "therapeutically effective amount" may be calculated by a skilled person using known techniques. In one example, a suitable dose may be about 300 mg.

[0298] Suitably, the IL-33 axis antagonist or pharmaceutical composition thereof can be administered to such humans or other animals in conventional dosage forms prepared by combining the IL-33 axis antagonist with one or more conventional pharmaceutically acceptable carriers or diluents according to known techniques.

[0299] Those skilled in the art will recognize that the form and characteristics of the pharmaceutically acceptable carrier or diluent are determined by the amount of active ingredient combined therewith, the route of administration and other well-known variables. Those skilled in the art will also know that a cocktail comprising one or more species of IL-33 axis antagonists may prove particularly effective.

[0300] The amount of the IL-33 axis antagonist that can be combined with the carrier material to produce a single dosage form will vary depending on the subject being treated and the particular mode of administration. Suitably, the IL-33 axis antagonist can be administered as a single dose, multiple doses, or in the form of an infusion over a defined period of time. Suitably, the dosage regimen can also be adjusted to provide the optimal desired response (e.g., a therapeutic or preventive response).

[0301] Suitably, the IL-33 axis antagonist will be formulated to facilitate administration and promote stability of the active IL-33 axis antagonist.

[0302] Suitably, the pharmaceutical composition is formulated to contain a pharmaceutically acceptable non-toxic sterile carrier, such as physiological saline, non-toxic buffer, preservatives and the like.

[0303] Suitable formulations for use in the methods of treatment disclosed herein are described in Remington's Pharmaceutical Sciences (Mack Publishing Co.) 16th Edition (1980).

[0304] In some examples, the IL-33 axis antagonist is formulated as a liquid. In some examples, the liquid formulation comprises the following: 20 mM L-histidine / L-histidine-hydrochloride, 220 mM L-arginine-hydrochloride, 0.03% (weight / volume) polysorbate 80, pH 5.5. In some examples, the formulation comprises 150 mg / ml IL-33 axis antagonist.

[0305] Methods of administering an IL-33 axis antagonist or a pharmaceutical composition thereof to a subject in need thereof are well known or readily determined by one skilled in the art.

[0306] Suitably, the route of administration of the IL-33 axis antagonist or its pharmaceutical composition can be, for example, oral, parenteral, by inhalation or topical administration. Suitably, the term parenteral as used herein includes, for example, intravenous, intraarterial, intraperitoneal, intramuscular, subcutaneous, rectal or vaginal administration.

[0307] Suitably, the IL-33 axis antagonist or pharmaceutical composition thereof may be orally administered in an acceptable dosage form including, for example, capsules, tablets, aqueous suspensions or solutions.

[0308] Suitably, the IL-33 axis antagonist or pharmaceutical composition thereof may be administered by nasal aerosol or inhalation.

[0309] In one example, the IL-33 axis antagonist or pharmaceutical composition thereof is administered intravenously.

[0310] In one example, the IL-33 axis antagonist or its pharmaceutical composition is administered at a dose of 300 mg to 600 mg, e.g., 350 mg, 400 mg, 450 mg, 500 mg, 550 mg, 600 mg. In one example, the IL-33 axis antagonist or its pharmaceutical composition is administered intravenously, suitably at a dose of 300 mg to 600 mg (i.e., using a steady dose rather than a weight-dependent dose). In one example, the IL-33 axis antagonist or its pharmaceutical composition is administered intravenously at a dose of 300 mg.

[0311] In one example, the IL-33 axis antagonist or a pharmaceutical composition thereof is administered after the subject is hospitalized. In one example, within 12, 24, 48, or 36 hours of the subject's hospitalization. In one example, within 36 hours of the subject's hospitalization. Suitably, the subject's hospitalization can be considered to be admitted to a hospital.

[0312] In one example, the IL-33 axis antagonist or pharmaceutical composition thereof is administered up to about 14 days after the onset of symptoms of the respiratory viral infection.

[0313] The dosage regimen utilized in the present disclosure may include administering only a single dose of an IL-33 axis antagonist or a pharmaceutical composition thereof, or may include multiple doses (particularly two doses). In a specific example, the therapy disclosed herein includes administering a single dose of an IL-33 axis antagonist or a pharmaceutical composition thereof to a subject. That is, the treatment methods disclosed herein include administering a single dose of an IL-33 axis antagonist or a pharmaceutical composition thereof during therapy.

[0314] When multiple doses of the antibody are administered, the doses are appropriately spaced, i.e., a gap of appropriate length is left between the doses. In one example, the IL-33 axis antagonist or its pharmaceutical composition is administered approximately once a week, once every two weeks, once every four weeks, once every 6 weeks, or once every 8 weeks, and may be administered appropriately after the first dose. Suitably, the first dose may be within 36 hours of the subject's hospitalization. Typically, when multiple doses are administered in the present disclosure, each dose has the same amount of antibody. In one example, the IL-33 axis antagonist or its pharmaceutical composition is administered in a first dose and an optional second dose, wherein the second dose is about two weeks after the first dose. In some cases, the dosage regimen includes administering a first dose, followed by an optional second dose two weeks later, depending on the subject's clinical condition / progress. Suitably, the first dose may be administered within 36 hours of the subject's hospitalization. Suitably, the first dose may be administered up to about 14 days after the onset of symptoms of respiratory viral infection. In one example, the IL-33 axis antagonist or its pharmaceutical composition is administered in a single dose.

[0315] In one example, the IL-33 axis antagonist or a pharmaceutical composition thereof is administered intravenously at a dose of 300 mg within 36 hours of hospitalization of the subject. Suitably, it may be a single dose.

[0316] In one example, the IL-33 axis antagonist or a pharmaceutical composition thereof is administered intravenously in a subject at a dose of 300 mg up to about 14 days after the onset of symptoms of respiratory viral infection. Suitably, it may be a single dose. BRIEF DESCRIPTION OF THE DRAWINGS

[0317] Certain elements of the present disclosure will now be described by way of example with reference to the following drawings, in which:

[0318] Figure 1 : Shows patient recruitment in the ACCORD Phase 2a study during two periods.

[0319] Figure 2: Shows measurements of IL-33 / sST2 in patients during the ACCORD Phase 2a study. The number of patients treated with SoC versus the combination of SoC and torelizumab who died or had respiratory failure on day 29 of the study is shown as (a) overall, (b) grouped by low IL-33 / sST2 baseline levels below a reference value, or (c) grouped by high IL-33 / sST2 baseline levels equal to or above a reference value.

[0320] The present disclosure will now be described with reference to the following non-limiting examples, in which:

[0321] Example

[0322] Higher baseline IL-33 / sST2 levels are predictive biomarkers for identifying responders to IL-33 axis antagonists

[0323] Serum samples from patients with SARS-CoV-2 infection were obtained from patients participating in the Phase 2a ACCORD study (EudraCT number: 2020-001736-95, Wilkinson et al., 2020). Figure 1 As shown, patients were recruited during two time periods spanning the pandemic.

[0324] Patients were randomized and received standard of care (SoC) alone or in combination with anti-IL-33 antibody (torezumab) treatment (300 mg IV and optional second dose if invasive ventilation was performed on day 15) over a period of 29 days. The 300 mg IV dose was administered by the following procedure: 2 ml of torelezumab was diluted with 8 ml of saline to a total volume of 10 ml and administered to the patient via IV push over 1-2 minutes using an IV-line filter, followed by a 5 ml saline IV flush.

[0325] As the understanding of the SARS-CoV-2 virus deepened, SoC changed in the two time periods of the ACCORD study. The SoC used during each time period is shown in Table 2 below. The SoC therapy in the second time period of the ACCORD study more accurately reflects current best practices.

[0326] Table 2 - SoC

[0327]

[0328]

[0329] Sera from patients dosed with torelizumab + standard of care (n=46 as baseline, n=37 on day 5, n=10 on day 10) and SoC alone (n=37 as baseline, n=23 on day 5, n=10 on day 10) were measured for IL-33 / sST2 at a 1:4 dilution.

[0330] All serum samples were stored in aliquots at -80°C after collection.

[0331] At MSD (Gaithersburg, USA), we used Serum samples obtained from patients were subjected to MSD S-PLEX using the antibody pairs described in Table 3. To measure the levels of IL-33 / sST2 in serum.

[0332] Note that, as explained above, any other assay method available in the art could have been used to measure IL-33 / sST2 levels in serum samples.

[0333] Table 3 - Antibody pairs used for IL-33 / sST2 assay

[0334]

[0335] Table 4-MSD S-PLEX Estimated lower limit of detection (LLOD)

[0336]

[0337] The estimated LLOD was calculated as the concentration off the standard curve that produced a signal 2.5 standard deviations higher than diluent alone (buffer only).

[0338] The custom MSD S-PLEX IL-33 / sST2 complex assay was prepared and validated by Mesoscale Discovery (MSD) and performed according to the manufacturer's instructions. Unless otherwise specified, all incubations required plate shaking at room temperature (RT). As specified, the plates were washed 3x with wash buffer (phosphate buffered saline (PBS) / 0.05% Tween-20). The biotin-coated capture mAb (Table 5) was diluted in diluent 100 (MSD) with S-Plex coating reagent (Table 5). The assay plate (MSD) was coated with 50 μl / well of coating solution and incubated for 1 h. The blocking reagent (1x final concentration) was prepared by diluting the S-Plex Blocker reagent (MSD) in diluent 101 (MSD). The recombinant IL-33 / sST2 complex standard curve was generated by diluting the stock solution in diluent 100 (Table 5) to the highest standard concentration and performing a 4-fold serial dilution. 25 μl blocking reagent is added to all wells and 25 μl standards and samples are added to the wells and incubated for 1.5 h. TURBO-enhanced solution is prepared by diluting the TURBO-enhanced labeled detection mAb stock solution (Table 5) to a working concentration in diluent 3 (MSD). Wash the plate, add 50 μl of TURBO-enhanced detection mAb solution to each well and incubate for 1 h. Wash the plate, add 50 μl of enhanced solution (MSD) to each well and incubate for 30 minutes. Wash the plate, add 50 μl of detection solution (MSD) to each well and incubate for 1 h at 26 ° C. Wash the plate and add 150 μl of 1x read buffer A (MSD) to each well. Read the plate on an MSD MESO SECTORS600 instrument.

[0339] Table 5 - Concentrations of antibodies and IL-33 / sST2 standards

[0340] Reagents IL-33 / ST2 complex assay Biotin-coated capture Ab (μg / ml) 0.25 TURBO-enhanced detection Ab (μg / ml) 0.1 Highest Standard (Unit / ml)* 1000

[0341] *Data for IL-33 / sST2 complexes are expressed in units / ml; for the IL-33 / sST2 standard this can be approximated as pg / ml if 100% complex formation is assumed.

[0342] The MSD S-PLEX assay is sensitive enough to determine pg / ml levels of IL-33 / sST2 in patient serum.

[0343] Based on the median value of baseline IL-33 / sST2, a subgroup analysis of the endpoint "death or respiratory failure on day 29" was performed. The median value at baseline was 30.15 U / ml, and the subgroups were defined as IL-33 low: baseline IL-33 / sST2 <30.15 U / ml; IL-33 high: baseline IL-33 / sST2>=30.15 U / ml.

[0344] For each treatment in each subgroup, the proportion of subjects who died or were in respiratory failure on day 29 was calculated, and the relative risk (torezumab: placebo) and 80% confidence interval were calculated for each subgroup. In addition, a logistic regression model was fitted to each subgroup, adjusting for age (continuous) and baseline severity (WHO score of "3 or 4" versus "5"). From the logistic regression model, the odds ratio (torezumab: placebo) of death or respiratory failure on day 29 and 80% confidence interval were calculated for each subgroup.

[0345] Using this assay, it was determined that those patients with high baseline serum levels of IL-33 / sST2 equal to or above 30.15 pg / ml were significantly less likely to die or have respiratory failure after 29 days when treated with torelizumab, as shown in Tables 6 and Figure 2 as shown in .

[0346] Such patients form a subgroup that may respond well to IL-33 axis antagonist treatment, thereby providing a way to stratify and select patients in respiratory distress for treatment with IL-33 axis antagonists. These treatments are well suited for subjects in respiratory distress who are hospitalized for viral lower respiratory tract infections and require supplemental oxygen. These subjects are particularly at risk of death and or progression to the need for invasive mechanical ventilation (IMV) or ECMO.

[0347] Table 6

[0348]

[0349] Sequences other than those in Table 1

[0350] IL-33 axis antagonist binding molecule (Torekizumab):

[0351] VH CDR 1-3:

[0352] VH CDR1 SEQ ID NO 37: SYAMS

[0353] VH CDR2 SEQ ID NO 38:GISAIDQSTYYADSVKG

[0354] VH CDR3 SEQ ID NO 39: QKFMQLWGGGLRYPFGY

[0355] VL CDR 1-3:

[0356] VL CDR1 SEQ ID NO 40:SGEGMGDKYAA

[0357] VL CDR2 SEQ ID NO 41: RDTKRPS

[0358] VL CDR3 SEQ ID NO 42: GVIQDNTGV

[0359] Anti-IL-33 / sST2 Antibody (AB1070008):

[0360] AB1070008 VH according to SEQ ID NO:43

[0361] QVQLQQSGPELVKPGASVKTSCKASGYSFTSYYIHWVKQRPGQGLEWIGWIYPGSGNTKYNEKFKGKATLTADTSSSTAFMQLSSLTSEDSAVYYCASGFHYYGRMDYWGQGTTLTVSS

[0362] AB1070008 VL according to SEQ ID NO:44

[0363] DIQMTQSPSSLSASLGERVSLTCRASQEISGYLSWLQQKPDGTIKRLIYSTSTLDSGVPKSFSGSRSGSDYSLTISSLESEDFADYYCLQYASSPWTFGGGTKLEIK

[0364] AB1070008 VHCDR 1-3:

[0365] VH CDR1 SEQ ID NO:45: SYYIH

[0366] VH CDR2 SEQ ID NO:46WIYPGSGNTKYNEKFK

[0367] VH CDR3 SEQ ID NO:47GFHYYGRMDY

[0368] AB1070008 VLCDR 1-3:

[0369] VL CDR1 SEQ ID NO:48:RASQEISGYLS

[0370] VL CDR2 SEQ ID NO:49: STSTLDS

[0371] VL CDR3 SEQ ID NO:50:LQYASSPWT

[0372] Toreqimab heavy chain sequence (SEQ ID NO: 51):

[0373] EVQLLESGGGLVQPGGSLRLSCAASGFTFSSYAMSWVRQAPGKGLEWVSGISAIDQSTYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARQKFMQLWGGGLRYPFGYWGQGTMVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK

[0374] Torreticumab light chain sequence (SEQ ID NO:52):

[0375] SYVLTQPPSVSVSPGQTASITCSGEGMGDKYAAWYQQKPGQSPVLVIYRDTKRPSGIPERFSGSNSGNTATLTISGTQAMDEADYYCGVIQDNTGVFGGGTKLTVLGQPKAAPSVTLFPPSSEELQANKATLVCLISDFYPGAVTVAWKADSSPVKAGVETTTPSKQSNNKYAASSYLSLTPEQWKSHRSYSCQVTHEGSTVEKTVAPTECS

Claims

1. A method for treating a subject having respiratory distress or preventing respiratory distress in a subject at risk of respiratory distress, the method comprising administering to the subject an effective amount of an anti-IL-33 antibody or an antigen-binding fragment thereof, wherein the level of IL-33 / sST2 in a sample obtained from the subject has been determined to be greater than or equal to a reference level of 25 pg / ml, wherein the anti-IL-33 antibody or antigen-binding fragment thereof comprises a heavy chain variable region (VH) and a light chain variable region (VL), the heavy chain variable region having VHCDRs 1-3 of SEQ ID NO: 37, SEQ ID NO: 38, and SEQ ID NO: 39, respectively, and the light chain variable region having VLCDRs 1-3 of SEQ ID NO: 40, SEQ ID NO: 41, and SEQ ID NO: 42, respectively.

2. A method for preventing acute respiratory failure in a subject at risk of acute respiratory failure, the method comprising administering to the subject an effective amount of an anti-IL-33 antibody or an antigen-binding fragment thereof, wherein the IL-33 / sST2 level in a sample obtained from the subject has been determined to be greater than or equal to a reference level of 25 pg / ml, wherein the anti-IL-33 antibody or antigen-binding fragment thereof comprises a heavy chain variable region and a light chain variable region, the heavy chain variable region having VHCDRs 1-3 of SEQ ID NO: 37, SEQ ID NO: 38, and SEQ ID NO: 39, respectively, and the light chain variable region having VLCDRs 1-3 of SEQ ID NO: 40, SEQ ID NO: 41, and SEQ ID NO: 42, respectively.

3. The method according to claim 1 or 2, further comprising the following steps: Measuring the level of IL-33 / sST2 in a sample obtained from the subject, and administering an effective amount of the anti-IL-33 antibody or antigen-binding fragment thereof to the subject if the level of IL-33 / sST2 in the sample obtained from the subject is greater than or equal to a reference level of 25 pg / ml.

4. A method of selecting a subject having or at risk of having respiratory distress for treatment with an anti-IL-33 antibody or antigen-binding fragment thereof, the method comprising: measuring the level of IL-33 / sST2 in a sample obtained from the subject; and if the IL-33 / sST2 level in the sample is greater than or equal to a reference level of 25 pg / ml, selecting the subject for the treatment, wherein the anti-IL-33 antibody or fragment thereof comprises a heavy chain variable region and a light chain variable region, the heavy chain variable region having VHCDR 1-3 of SEQ ID NO: 37, SEQ ID NO: 38 and SEQ ID NO: 39, respectively, and the light chain variable region having VLCDR 1-3 of SEQ ID NO: 40, SEQ ID NO: 41 and SEQ ID NO: 42, respectively.

5. A method of determining whether a subject having or at risk of having respiratory distress is likely to respond to treatment with an anti-IL-33 antibody or antigen-binding fragment thereof, the method comprising: measuring the level of IL-33 / sST2 in a sample obtained from the subject; And if the measured level of IL-33 / sST2 in the sample is greater than or equal to the reference level of 25 pg / ml, determining that the subject is likely to respond to the treatment, wherein the anti-IL-33 antibody or fragment thereof comprises a heavy chain variable region and a light chain variable region, the heavy chain variable region having VHCDR 1-3 of SEQ ID NO: 37, SEQ ID NO: 38 and SEQ ID NO: 39, respectively, and the light chain variable region having VLCDR1-3 of SEQ ID NO: 40, SEQ ID NO: 41 and SEQ ID NO: 42, respectively.

6. The method according to any preceding claim, wherein the reference level is 26 pg / ml, 27 pg / ml, 28 pg / ml, 29 pg / ml or 30 pg / ml, preferably wherein the reference level is 30.15 pg / ml.

7. The method according to any preceding claim, wherein the sample is a whole blood sample, a serum sample, a plasma sample or a combination thereof.

8. The method of claim 7, wherein the sample is a serum sample.

9. A method according to any preceding claim, wherein the respiratory distress is acute respiratory failure.

10. The method of claim 9, wherein the acute respiratory failure is type 1 or type 2 acute respiratory failure.

11. The method of claim 10, wherein the acute respiratory failure is type 1 acute respiratory failure.

12. The method of any one of claims 9 to 11, wherein the acute respiratory failure is caused by a disease, disorder, condition or infection selected from the group consisting of pneumonia, acute respiratory distress syndrome (ARDS), chronic obstructive pulmonary disease (COPD), asthma, bronchitis, bronchiectasis, emphysema, heart failure, myocardial ischemia, mitral stenosis, pulmonary edema, pulmonary embolism, thromboembolism, cystic fibrosis, amyotrophic lateral sclerosis, muscular dystrophy, Guillain-Barré syndrome, myasthenia gravis, poliomyelitis, polymyositis, botulism, hypokalemia, hypophosphatemia, myxedema, hypothyroidism, sepsis, stroke, acute pancreatitis, blood transfusion, reperfusion, drug or alcohol overdose, acute lung injury, chest trauma, viral or bacterial infection, inhalation injury (caused by inhalation of smoke, fumes or chemicals), aspiration and drowning.

13. The method according to any one of claims 9 to 11, wherein the acute respiratory failure is caused by bacterial, fungal or viral infection, preferably viral respiratory tract infection, more preferably SARS-Cov-2 infection.

14. A method according to any preceding claim, wherein the subject has COVID-19.

15. The method according to any preceding claim, wherein the subject has pneumonia, or is suspected of having pneumonia.

16. The method according to any preceding claim, wherein the subject has, or is suspected of having, viral pneumonia.

17. The method of claim 15 or 16, wherein the viral pneumonia is caused by influenza A virus, influenza B virus, respiratory syncytial virus, human parainfluenza virus, adenovirus, metapneumovirus, SARS-COV, Middle East respiratory syndrome virus (MERS-CoV), Hantavirus, herpes simplex virus, varicella-zoster virus, measles virus, rubella virus, cytomegalovirus or smallpox virus or dengue virus.

18. The method of claim 17, wherein the viral pneumonia is caused by influenza A virus, influenza B virus, respiratory syncytial virus, or human parainfluenza virus.

19. The method of any preceding claim, wherein the subject has or is at risk of acute respiratory failure caused by COVID-19 and / or viral pneumonia.

20. The method of any preceding claim, wherein the subject has or is at risk of Type 1 or Type 2 acute respiratory failure caused by COVID-19 and / or viral pneumonia.

21. The method according to any preceding claim, wherein the subject has tested positive for SARS-Cov-2 infection.

22. The method of any preceding claim, wherein the subject has a viral lower respiratory tract infection or disease.

23. The method according to any preceding claim, wherein the anti-IL-33 antibody or antigen-binding fragment thereof comprises a heavy chain variable region (VH) according to SEQ ID NO: 1 and a light chain variable region (VL) according to SEQ ID NO.

19.

24. The method of any preceding claim, wherein the IL-33 axis antagonist is torelikizumab.

25. The method of any preceding claim, wherein the subject requires supplemental oxygen or ventilation.

26. The method according to any preceding claim, wherein the subject is hospitalized.

27. The method of any preceding claim, wherein the subject has a viral lower respiratory tract infection or disease, is hospitalized and requires supplemental oxygen or ventilation.

28. The method according to any preceding claim, wherein the subject was hospitalized prior to the method according to any one of claims 1 to 27.

29. The method of any one of claims 3-28, wherein measuring the level of IL-33 / sST2 in a sample obtained from the subject comprises performing an assay on the sample obtained from the subject to determine the level of IL-33 / sST2.

30. The method of claim 29, wherein the assay is an immunoassay.

31. The method of any one of claims 3-30, wherein measuring the level of IL-33 / sST2 in a sample obtained from the subject comprises the following steps: (i) contacting the sample with one or more binding molecules capable of binding to IL-33 / sST2 under conditions sufficient for the formation of a complex, and (ii) detecting the level of IL-33 / sST2 complex in the sample.

32. The method of claim 31, further comprising step (iii) contacting the complex with one or more reporter molecules capable of binding to the one or more complexes.

33. The method of claim 31 or 32, wherein the one or more binding molecules and the one or more reporter molecules are antibodies or antigen-binding fragments thereof.

34. The method of claim 33, wherein the one or more binding molecules are anti-IL-33 / sST2 antibodies or antigen-binding fragments thereof, and wherein the one or more reporter molecules are anti-IL-33 / sST2-binding molecule complex antibodies or antigen-binding fragments thereof.

35. The method of claim 34, wherein the anti-IL-33 / sST2 antibody or antigen-binding fragment thereof comprises a heavy chain variable region having VHCDRs 1-3 of SEQ ID NO: 45, SEQ ID NO: 46, and SEQ ID NO: 47, respectively, and a light chain variable region having VLCDRs 1-3 of SEQ ID NO: 48, SEQ ID NO: 49, and SEQ ID NO: 50, respectively.

36. The method of claim 34 or 35, wherein the anti-IL-33 / sST2 antibody or antigen-binding fragment thereof comprises a heavy chain variable region (VH) according to SEQ ID NO: 43 and a light chain variable region (VL) according to SEQ ID NO:

44.

37. A method of reducing the likelihood of death and / or acute respiratory failure in a subject having or at risk of having respiratory distress, the method comprising administering to the subject an effective amount of an anti-IL-33 antibody or antigen-binding fragment thereof, wherein the level of IL-33 / sST2 in a sample obtained from the subject has been determined to be greater than or equal to a reference level of 25 pg / ml, wherein the anti-IL-33 antibody or antigen-binding fragment thereof comprises a heavy chain variable region and a light chain variable region, the heavy chain variable region having VHCDRs 1-3 of SEQ ID NO: 37, SEQ ID NO: 38, and SEQ ID NO: 39, respectively, and the light chain variable region having VLCDRs 1-3 of SEQ ID NO: 40, SEQ ID NO: 41, and SEQ ID NO: 42, respectively.

38. The method of claim 37, wherein the subject has a viral lower respiratory tract infection or disease, is hospitalized and requires supplemental oxygen or ventilation.

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