Treatment of acute respiratory failure

Abstract

The present disclosure provides a method of treating or preventing acute respiratory distress syndrome (ARDS) in a subject suffering from or at risk of developing ARDS, such as a subject suffering from a viral pulmonary infection in need of oxygenation. The method comprises administering to the subject an anti-IL-33 antibody in a dose of from 250 mg to 350 mg. The method may also include preventing progression of the subject to invasive mechanical ventilation (IMV) or extracorporeal membrane pulmonary oxygenation (ECMO).

Description

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This application claims the benefit of U.S. Provisional Patent Application No. 63 / 371,936 filed on August 19, 2022 and U.K. Patent Application No. 2213964.6 filed on September 23, 2022 under 35 U.S.C. §119(e), and the entire text of each of these patents is incorporated herein by reference for all purposes.

[0003] References to sequence listings 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 "IL33-440-WO-PCT Sequence Listing" created on August 17, 2023 and has a size of 13,464 bytes. Technical Field

[0005] The present disclosure relates to the treatment of acute respiratory failure with anti-IL33 antibodies, particularly tozorakimab. Background Art

[0006] Acute respiratory viral diseases are of great global public health importance and continue to cause more than 1.5 million deaths each year. Immune-mediated damage caused by dysregulated inflammatory responses that lead to the development of acute respiratory distress syndrome (ARDS) is a major contributing factor to the severity of lung damage and the adverse prognosis of respiratory viral diseases. Over the past few decades, several pandemic respiratory viruses, including influenza A H1N1 and H5N1 and the new coronaviruses MERS-CoV, SARS-CoV, and SARS-CoV-2 have caused significantly higher ARDS frequencies and mortality rates compared to seasonal viruses. The COVID-19 pandemic has caused more than 6 million deaths (as of September 2022) and has increased the need to develop new effective treatments to prevent and treat virus-induced ARDS and / or acute respiratory failure (ARF).

[0007] WO 2021 / 204707 discloses the treatment and prevention of ARDS using IL-33 antagonists, including anti-IL-33 antibodies. Torezimab is included in the ACCORD-2 Phase II clinical trial for the treatment of COVID-19 (Wilkinson et al., Trials 21:691, 2020). Summary of the invention

[0008] In a first aspect, the present disclosure provides a method of treating or preventing acute respiratory distress syndrome (ARDS) in a subject having ARDS or at risk of developing ARDS, the method comprising administering to the subject a dose of 250 mg to 350 mg of an anti-IL-33 antibody, wherein the antibody comprises:

[0009] (a) a heavy chain variable region comprising: a VHCDR1 comprising the sequence of SEQ ID NO: 1, a VHCDR2 comprising the sequence of SEQ ID NO: 2, and a VHCDR3 comprising the sequence of SEQ ID NO: 3; and

[0010] (b) a light chain variable region comprising: a VLCDR1 comprising the sequence of SEQ ID NO:4, a VLCDR2 comprising the sequence of SEQ ID NO:5, and a VLCDR3 comprising the sequence of SEQ ID NO:6.

[0011] In a second aspect, the present disclosure provides a method of treating or preventing acute respiratory failure (ARF) in a subject having or at risk of developing ARF, the method comprising administering to the subject a dose of 250 mg to 350 mg of an anti-IL-33 antibody, wherein the antibody comprises:

[0012] (a) a heavy chain variable region comprising: a VHCDR1 comprising the sequence of SEQ ID NO: 1, a VHCDR2 comprising the sequence of SEQ ID NO: 2, and a VHCDR3 comprising the sequence of SEQ ID NO: 3; and

[0013] (b) a light chain variable region comprising: a VLCDR1 comprising the sequence of SEQ ID NO:4, a VLCDR2 comprising the sequence of SEQ ID NO:5, and a VLCDR3 comprising the sequence of SEQ ID NO:6.

[0014] In a third aspect, the present disclosure provides a method of reducing the risk of a subject requiring invasive mechanical ventilation (IMV) or extracorporeal membrane oxygenation (ECMO), wherein the subject suffers from ARDS and / or ARF or is at risk of developing ARDS and / or ARF, the method comprising administering to the subject a dose of 250 mg to 350 mg of an anti-IL-33 antibody, wherein the antibody comprises:

[0015] (a) a heavy chain variable region comprising: a VHCDR1 comprising the sequence of SEQ ID NO: 1, a VHCDR2 comprising the sequence of SEQ ID NO: 2, and a VHCDR3 comprising the sequence of SEQ ID NO: 3; and

[0016] (b) a light chain variable region comprising: a VLCDR1 comprising the sequence of SEQ ID NO:4, a VLCDR2 comprising the sequence of SEQ ID NO:5, and a VLCDR3 comprising the sequence of SEQ ID NO:6.

[0017] In a fourth aspect, the present disclosure provides a method of reducing the risk of a subject having ARDS and / or ARF or at risk of developing ARDS and / or ARF requiring admission to an intensive care unit (ICU), the method comprising administering to the subject a dose of 250 mg to 350 mg of an anti-IL-33 antibody, wherein the antibody comprises:

[0018] (a) a heavy chain variable region comprising: a VHCDR1 comprising the sequence of SEQ ID NO: 1, a VHCDR2 comprising the sequence of SEQ ID NO: 2, and a VHCDR3 comprising the sequence of SEQ ID NO: 3; and

[0019] (b) a light chain variable region comprising: a VLCDR1 comprising the sequence of SEQ ID NO:4, a VLCDR2 comprising the sequence of SEQ ID NO:5, and a VLCDR3 comprising the sequence of SEQ ID NO:6.

[0020] In a fifth aspect, the present disclosure provides a method for reducing the duration of hospitalization of a subject having ARDS and / or ARF or at risk of developing ARDS and / or ARF, the method comprising administering to the subject a dose of 250 mg to 350 mg of an anti-IL-33 antibody, wherein the antibody comprises:

[0021] (a) a heavy chain variable region comprising: a VHCDR1 comprising the sequence of SEQ ID NO: 1, a VHCDR2 comprising the sequence of SEQ ID NO: 2, and a VHCDR3 comprising the sequence of SEQ ID NO: 3; and

[0022] (b) a light chain variable region comprising: a VLCDR1 comprising the sequence of SEQ ID NO:4, a VLCDR2 comprising the sequence of SEQ ID NO:5, and a VLCDR3 comprising the sequence of SEQ ID NO:6.

[0023] In a sixth aspect, the present disclosure provides a method of treating a subject having ARDS and / or ARF or at risk of developing ARDS and / or ARF and requiring supplemental oxygen therapy, the treatment reducing the required duration of the supplemental oxygen therapy, the method comprising administering to the subject a dose of 250 mg to 350 mg of an anti-IL-33 antibody, wherein the antibody comprises:

[0024] (a) a heavy chain variable region comprising: a VHCDR1 comprising the sequence of SEQ ID NO: 1, a VHCDR2 comprising the sequence of SEQ ID NO: 2, and a VHCDR3 comprising the sequence of SEQ ID NO: 3; and

[0025] (b) a light chain variable region comprising: a VLCDR1 comprising the sequence of SEQ ID NO:4, a VLCDR2 comprising the sequence of SEQ ID NO:5, and a VLCDR3 comprising the sequence of SEQ ID NO:6.

[0026] In a seventh aspect, the present disclosure provides a method for preventing or reducing the risk of respiratory failure in a subject hospitalized for viral lung infection or suspected viral lung infection, the method comprising administering to the subject a dose of 250 mg to 350 mg of an anti-IL-33 antibody, wherein the antibody comprises:

[0027] (a) a heavy chain variable region comprising: a VHCDR1 comprising the sequence of SEQ ID NO: 1, a VHCDR2 comprising the sequence of SEQ ID NO: 2, and a VHCDR3 comprising the sequence of SEQ ID NO: 3; and

[0028] (b) a light chain variable region comprising: a VLCDR1 comprising the sequence of SEQ ID NO:4, a VLCDR2 comprising the sequence of SEQ ID NO:5, and a VLCDR3 comprising the sequence of SEQ ID NO:6.

[0029] In an eighth aspect, the present disclosure provides a method of treating a subject hospitalized with a viral lung infection or suspected viral lung infection, the method comprising administering to the subject a dose of 250 mg to 350 mg of an anti-IL-33 antibody, wherein the antibody comprises:

[0030] (a) a heavy chain variable region comprising: a VHCDR1 comprising the sequence of SEQ ID NO: 1, a VHCDR2 comprising the sequence of SEQ ID NO: 2, and a VHCDR3 comprising the sequence of SEQ ID NO: 3; and

[0031] (b) a light chain variable region comprising: a VLCDR1 comprising the sequence of SEQ ID NO:4, a VLCDR2 comprising the sequence of SEQ ID NO:5, and a VLCDR3 comprising the sequence of SEQ ID NO:6.

[0032] In a related aspect, the disclosure provides an anti-IL-33 antibody for use in treating or preventing ARDS or ARF in a subject, wherein the antibody, treatment or prevention, ARDS, ARF and / or subject are as defined above.

[0033] In a related aspect, the disclosure provides use of an anti-IL-33 antibody in the manufacture of a medicament for treating or preventing ARDS or ARF in a subject, wherein the antibody, treatment or prevention, ARDS, ARF and / or subject are as defined above.

[0034] In a related aspect, the present disclosure provides a pharmaceutical composition comprising an anti-IL-33 antibody for treating or preventing ARDS or ARF in a subject, wherein the antibody, treatment or prevention, ARDS, ARF and / or subject are as defined above.

[0035] In a related aspect, the disclosure provides an anti-IL-33 antibody for use in treating or preventing respiratory failure in a subject hospitalized with a viral lung infection or suspected viral lung infection, wherein the treatment comprises administering to the subject a dose of 250 mg to 350 mg of the anti-IL-33 antibody, and wherein the antibody comprises:

[0036] (a) a heavy chain variable region comprising: a VHCDR1 comprising the sequence of SEQ ID NO: 1, a VHCDR2 comprising the sequence of SEQ ID NO: 2, and a VHCDR3 comprising the sequence of SEQ ID NO: 3; and

[0037] (b) a light chain variable region comprising: a VLCDR1 comprising the sequence of SEQ ID NO:4, a VLCDR2 comprising the sequence of SEQ ID NO:5, and a VLCDR3 comprising the sequence of SEQ ID NO:6.

[0038] In a related aspect, the present disclosure provides an anti-IL-33 antibody for use in treating a viral lung infection or suspected viral lung infection in a subject, wherein the subject is hospitalized for the viral lung infection or suspected viral lung infection, wherein the treatment comprises administering to the subject a dose of 250 mg to 350 mg of the anti-IL-33 antibody, and wherein the antibody comprises:

[0039] (a) a heavy chain variable region comprising: a VHCDR1 comprising the sequence of SEQ ID NO: 1, a VHCDR2 comprising the sequence of SEQ ID NO: 2, and a VHCDR3 comprising the sequence of SEQ ID NO: 3; and

[0040] (b) a light chain variable region comprising: a VLCDR1 comprising the sequence of SEQ ID NO:4, a VLCDR2 comprising the sequence of SEQ ID NO:5, and a VLCDR3 comprising the sequence of SEQ ID NO:6. DETAILED DESCRIPTION

[0041] The present disclosure relates to the use of anti-IL-33 antibodies in treating or preventing diseases and conditions, including acute respiratory distress syndrome (ARDS), acute respiratory failure (ARF), and confirmed or suspected viral lung infections.

[0042] As used herein, the term "IL-33" refers to interleukin 33, in particular mammalian interleukin-33 protein, typically human IL-33 protein with UniProt accession number O95760. This entity is not a single species, but exists in several forms with different functional activities, such as a full-length form and a proteolytically processed form or an oxidized form and a reduced form. Considering the rapid oxidation of the reduced form in vivo and in vitro, the IL-33 generally referred to in the prior art may be most relevant to the detection of the oxidized form. The terms "IL-33" and "IL-33 polypeptide" and "IL-33 protein" are used interchangeably herein.

[0043] IL-33 is a pleiotropic nuclear alarmin cytokine from the IL-1 superfamily. The full-length, reduced form of IL-33 (IL-33 红色 ) is released from damaged epithelial and endothelial barrier cells and alerts the immune system to tissue damage. IL-33 drives lung inflammation through its receptor ST2, which is expressed by several inflammatory cell types, including mast cells, type 1 and type 2 innate lymphocytes, macrophages, and endothelial cells. The IL-33 / ST2 signaling pathway causes these cell types to produce inflammatory cytokines such as IL-6 and granulocyte-macrophage colony stimulating factor.

[0044] IL-33 is known to be released in response to a variety of viral pathogens, which together cause most severe viral lung infections and lower airway infections, including influenza, RSV, HRV, and SARS-CoV-2. Animal models of acute and chronic lung injury are similarly associated with elevated IL-33 and upregulation of type 1 / 2 cytokines (e.g., IL-6), and preclinical studies have shown that IL-33 blockade can reduce inflammation and improve lung function and symptoms (Allinne et al., J Allergy Clin Immunol. 2019, 144 (6): 1624-37.e10). IL-33 is released by lung epithelial cells infected with human respiratory viruses.

[0045] The term "antibody" is used in the broadest sense and encompasses various antibody structures, including but not limited to monoclonal antibodies, polyclonal antibodies, multispecific antibodies (eg, bispecific antibodies), and antibody fragments, so long as they exhibit the desired antigen-binding activity.

[0046] In some cases, the antibodies used herein can be monoclonal antibodies (MAbs); recombinant; chimeric; human; antibody variants, including single chains; and / or bispecifics; or derivatives thereof. Antibody antigen-binding fragments include those portions of antibodies that bind to epitopes on polypeptides of interest. Examples of such fragments include Fab fragments and F(ab') fragments produced by enzymatic cleavage of full-length antibodies. Other binding fragments include those produced by recombinant DNA technology (e.g., expressing a recombinant plasmid containing a nucleic acid sequence encoding an antibody variable region).

[0047] Monoclonal antibodies can be modified for use as therapeutic or diagnostic agents. "Monoclonal antibody" or "monoclonal antibody composition" as used herein refers to polypeptides, including antibodies, bispecific antibodies, etc., which have substantially the same amino acid sequence or are derived from the same genetic source. The term also includes antibody molecule preparations composed of single molecules. Monoclonal antibody compositions show a single binding specificity and affinity for a specific epitope. One case is a "chimeric" antibody, in which a portion of the heavy chain (H) and / or light chain (L) is identical or homologous to the corresponding sequence in an antibody derived from a specific species or belonging to a specific antibody class or subclass, while the remaining chain is identical or homologous to the corresponding sequence in an antibody derived from another species or belonging to another antibody class or subclass. Fragments of such antibodies are also included as long as they exhibit the desired biological activity. See U.S. Patent No. 4,816,567; Morrison et al., 1985, Proc.Natl.Acad.Sci.81:6851-55.

[0048] Suitably, full length antibodies are used herein (that is, not antibody fragments or derivatives). Suitably, antibodies used herein are monoclonal antibodies. Suitably, antibodies used herein are human. Suitably, human monoclonal antibodies are used.

[0049] The antibodies used herein suitably comprise: a heavy chain variable region comprising: a VHCDR1 comprising a sequence of SEQ ID NO: 1, a VHCDR2 comprising a sequence of SEQ ID NO: 2, and a VHCDR3 comprising a sequence of SEQ ID NO: 3; and a light chain variable region comprising: a VLCDR1 comprising a sequence of SEQ ID NO: 4, a VLCDR2 comprising a sequence of SEQ ID NO: 5, and a VLCDR3 comprising a sequence of SEQ ID NO: 6. However, in some cases, the CDR sequences may be modified or altered relative to those defined in SEQ ID NOs: 1-6. For example, VHCDR1, VHCDR2, VHCDR3, VLCDR1, VLCDR2, and / or VLCDR3 may each comprise a sequence modified by 1 to 3 amino acid substitutions, deletions, and / or additions relative to SEQ ID NOs: 1-6.

[0050] The antibody used herein may comprise a heavy chain variable region comprising the sequence shown in SEQ ID NO: 7, or an amino acid sequence having at least 80%, 85%, 90% or 95% sequence identity thereto. When a modified heavy chain variable region relative to SEQ ID NO: 7 is used, it is preferred that the heavy chain CDR sequences are as shown in SEQ ID NO: 1-3, but they may be modified or altered as shown above.

[0051] The antibody used herein may comprise a light chain variable region comprising the sequence shown in SEQ ID NO: 8, or an amino acid sequence having at least 80%, 85%, 90% or 95% sequence identity thereto. When a modified light chain variable region relative to SEQ ID NO: 8 is used, it is preferred that the light chain CDR sequences are as shown in SEQ ID NO: 4-6, but they may be modified or altered as shown above.

[0052] Suitably, the antibody or antigen-binding fragment comprises: a heavy chain comprising the sequence shown in SEQ ID NO:7, or an amino acid sequence having at least 80%, 85%, 90% or 95% sequence identity thereto; and a light chain variable region comprising the sequence shown in SEQ ID NO:8, or an amino acid sequence having at least 80%, 85%, 90% or 95% sequence identity thereto.

[0053] As used herein, the term "sequence identity" or "identity" refers to a property of sequences that measures their similarity or relationship. The term "sequence identity" or "identity" as used in the present disclosure means the percentage of pairwise identical residues in terms of the number of residues in the longer of the two sequences after (homologous) alignment of the sequence of a protein or polypeptide of the present disclosure with the sequence in question. Sequence identity is measured by dividing the number of identical amino acid residues by the total number of residues and multiplying the product by 100.

[0054] The skilled person will recognize that available computer programs, such as BLAST (Altschul et al., Nucleic Acids Res, 1997), BLAST2 (Altschul et al., J Mol Biol, 1990), FASTA (using the method of Pearson and Lipman (1988)), TBLASTN program of Altschul et al. (1990) supra, GAP (Wisconsin GCG package, Accelerys Inc, San Diego USA) and Smith-Waterman (Smith and Waterman, J Mol Biol, 1981), are used to determine sequence identity using standard parameters. Sequence identity percentages can be determined, for example, herein using the BLASTP program 2.2.5 version of November 16, 2002 (Altschul et al., Nucleic Acids Res, 1997). In this case, the homology percentage is based on the alignment of the complete protein or peptide sequence including the peptide sequence (matrix: BLOSUM 62; gap cost: 11.1; cutoff value set to 10 -3 ), suitably using the wild-type protein scaffold as a reference in paired comparisons. Homology percentage is calculated as the number of "positives" (homologous amino acids) shown as a result in the BLASTP program output divided by the percentage of the total number of amino acids selected for comparison by the program. Sequence identity is usually defined with reference to the algorithm GAP (Wisconsin GCG package, Accelerys Inc, San Diego USA). GAP uses the Needleman and Wunsch algorithm to align two complete sequences, maximizing the number of matches and minimizing the number of gaps, which are spaces in the alignment as a result of amino acid addition or deletion. Typically, default parameters are used, with a gap creation penalty equal to 12 and a gap extension penalty equal to 4.

[0055] Specifically, to determine whether the amino acid residues of the amino acid sequence of the anti-IL-33 antibody are different from those of another antibody sequence, a skilled person can use means and methods well known in the art, such as alignment, manual alignment or by using a computer program such as BLAST 2.0 (standing for Basic Local Alignment Search Tool, or Clustal Omega), or any other suitable program suitable for producing sequence alignments.

[0056] When a full length antibody is used, it may be of any isotype or subclass thereof. Suitably, the antibody is an IgG, such as an IgG1, IgG2, IgG3 or IgG4 antibody. Suitably, the antibody is an IgG 1.

[0057] Most suitably, the antibody used in the therapy according to the present disclosure is torelizumab, as disclosed in WO2016 / 156440, which is incorporated herein by reference. Torelizumab is also known in the art as MEDI3506 and 33_640087_7B. The light chain of torelizumab has the amino acid sequence shown in SEQ ID NO:9, and the heavy chain of torelizumab has the amino acid sequence shown in SEQ ID NO:10.

[0058] Torezumab is a fully human IgG1 monoclonal antibody that is being developed for the treatment of, inter alia, chronic obstructive pulmonary disease (COPD). Torezumab binds to the human reduced form of IL-33 (IL-33 红色 ) binds and prevents IL-33 红色 Binds to its receptor ST2. Torezumab binds to human IL-33 with an exceptionally high affinity of approximately 30 fM and completely neutralizes endogenous IL-33 红 The full-length form and all mature forms of IL33 (Scott et al., ERS International Congress 2022, Barcelona (ES), Abstract OA2254). 红色 In combination, torelizumab effectively inhibited ST2-dependent inflammatory responses in several primary human cells and in an in vivo model of allergen-driven lung epithelial injury. ox ) Signaling occurs via the RAGE / EGFR pathway. Torelizumab does not bind to IL-33 ox , but can prevent IL-33 oxidation and IL-33 via the RAGE / EGFR complex ox Dependent signaling and mimics the mechanism of action of ST2 (Scott et al., supra). oxInhibition of signaling can improve airway epithelial repair and reverse airway epithelial dysfunction, including mucus hypersecretion, in respiratory diseases (Scott et al., supra).

[0059] In some instances, the anti-IL-33 antibody has similar or identical pharmacokinetic (pK) characteristics in humans as torelikizumab.

[0060] In particular, the anti-IL-33 antibody may have a half-life similar to or the same as torelgimab in humans. When administered at a dose of 30 mg Q2W, an anti-IL-33 antibody having a half-life similar to or the same as torelgimab in humans may have a half-life of about 10 days to about 20 days, about 12 days to about 15 days, or about 12.7 days. When administered at a dose of 100 mg Q2W, an anti-IL-33 antibody having a half-life similar to or the same as torelgimab in humans may have a half-life of about 10 days to about 20 days, about 12 days to about 15 days, or about 13.2 days. When administered at a dose of 300 mg Q2W, an anti-IL-33 antibody having a half-life similar to or the same as torelgimab in humans may have a half-life of about 10 days to about 20 days, about 12 days to about 15 days, or about 14.8 days.

[0061] In some cases, the IL-33 antibody can competitively inhibit the binding of IL-33 to torelqimab (torelqimab is referred to as 33_640087-7B in WO2016 / 156440). WO2016 / 156440 discloses that 33_640087-7B (torelqimab) binds to redlL-33 with particularly high affinity and attenuates ST-2 and RAGE-dependent IL-33 signaling. If an antibody specifically binds to a given epitope to the extent that it blocks the binding of a reference antibody to the epitope to some extent, the antibody is considered to competitively inhibit the binding of a reference antibody to the epitope. Competitive inhibition can be determined by any method known in the art, for example, solid phase assays such as competitive ELISA assays, dissociation enhanced lanthanide fluorescence immunoassays ( Perkin Elmer) and radioligand binding assays. For example, a technician can determine whether an antibody competes for binding to IL-33 by using an in vitro competitive binding assay, such as the HTRF assay described in paragraphs 881-886 of WO2016 / 156440, which is incorporated herein by reference. For example, a technician can label torelqimab with a donor fluorophore and mix multiple concentrations with a fixed concentration of redIL-33 sample labeled with an acceptor fluorophore. Subsequently, the fluorescence resonance energy transfer between the donor and acceptor fluorophores in each sample can be measured to determine the binding characteristics. In order to illustrate competitive binding antibody molecules, a technician can first mix different concentrations of test binding molecules with a fixed concentration of labeled torelqimab antibodies. When the mixture is incubated with labeled IL-33, a reduction in the FRET signal compared to a positive control of only labeled antibody will indicate competitive binding to IL-33. It can be considered that the antibody competitively inhibits the binding of the reference antibody to a given epitope by at least 90%, at least 80%, at least 70%, at least 60%, or at least 50%.

[0062] Therapy disclosed herein includes administering a dose of anti-IL-33 antibody to a subject. The dose is in the range of 250mg-350mg (i.e., using a steady dose rather than a weight-dependent dose). In some cases, the dose may be in the range of 260mg-340mg, 270mg-330mg, 225mg-325mg, 280mg-320mg, 285mg-315mg, 290mg-310mg or 295mg-305mg. Suitably, the dose is 300mg or about 300mg. As shown in the examples below, it has been found that such doses of torelqi monoclonal antibody can effectively reduce respiratory failure or death in patients hospitalized for COVID-19.

[0063] The dosage regimen utilized in the present disclosure may include administering only a single dose of the antibody, or may include multiple doses (particularly two doses). In certain cases, the therapy disclosed herein includes administering a single dose of the antibody to the subject. That is, the therapeutic methods disclosed herein include administering a single dose of the antibody during the therapy.

[0064] 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. For example, a gap of at least one week, or two weeks, three weeks, or four weeks, six weeks, or eight weeks may be left between each dose. Typically, when multiple doses are administered in the present disclosure, each dose has the same amount of antibody. In particular cases, the therapy of the present disclosure includes administering two doses of the antibody to the subject, wherein the second dose is administered at least one week after the first dose, and is suitably administered two weeks after the first dose. In some cases, the dosage regimen includes administering a first dose, followed by the optional administration of a second dose two weeks later, depending on the clinical condition / progress of the subject.

[0065] In one instance, the first dose of the antibody is administered after the subject has been hospitalized. In one instance, the first dose of the antibody is administered within 12 hours, 24 hours, 48 ​​hours, or 36 hours of the subject's hospitalization. In one instance, the subject is administered within 36 hours of hospitalization. Suitably, the subject's hospitalization can be considered an admission. In one instance, the first dose of the antibody is administered up to about 14 days after the onset of symptoms of respiratory viral infection.

[0066] In one instance, a method of treatment according to the present disclosure comprises administering a single dose. In one instance, a method of treatment according to the present disclosure comprises administering a single 300 mg dose of the antibody (torezumab) to the subject.

[0067] The antibody may be administered to the subject by any suitable route. Suitably, the antibody is administered intravenously.

[0068] In one instance, a treatment method according to the present disclosure comprises administering a single 300 mg dose of the antibody (torezumab) intravenously to a subject.

[0069] In one instance, a treatment method according to the present disclosure comprises administering a single 300 mg dose of the antibody (torezumab) intravenously to a subject within 36 hours of hospitalization.

[0070] In one instance, a treatment method according to the present disclosure comprises administering a single 300 mg dose of the antibody (torezumab) intravenously to a subject up to about 14 days after the onset of symptoms of a respiratory viral infection.

[0071] The antibody can be administered in a pharmaceutical composition. The pharmaceutical composition can be formulated with suitable carriers, excipients, and other agents that provide suitable transfer, delivery, tolerance, etc. Many formulations can be found in formulas known to all pharmaceutical chemists: Remington's Pharmaceutical Sciences, Mack Publishing Company, Easton, PA. Therefore, in addition to the active ingredient (i.e., the anti-IL-33 antibody), the pharmaceutical composition may also contain a pharmaceutically acceptable excipient, carrier, buffer, stabilizer, or other substance well known to those skilled in the art. Such substances should be non-toxic and should not interfere with the efficacy of the active ingredient. The precise nature of the carrier or other substance will depend on the route of administration, which can be by injection, such as intravenous or subcutaneous injection.

[0072] For intravenous injection, the pharmaceutical composition may be a parenterally acceptable aqueous solution which is pyrogen-free and has suitable pH, isotonicity and stability.

[0073] The pharmaceutical composition can be a liquid preparation or a lyophilized preparation reconstructed before use. As an excipient for a lyophilized preparation, for example, sugar alcohol or sugar (such as mannitol or glucose) can be used. In the case of a liquid preparation, the pharmaceutical composition is generally provided in the form of a container with a defined volume, including sealed and sterilized plastic or glass vials, ampoules and syringes, and provided in the form of a large volume container such as a bottle. Suitably, in the methods described herein, the pharmaceutical composition is a liquid preparation. Suitably, the liquid pharmaceutical composition is provided in a vial. Suitably, the anti-IL-33 antibody can be present in a pharmaceutical composition at a concentration of 100mg / ml to 200mg / ml, more suitably 150mg / ml. In particular, when using an antibody dose of 300mg, the antibody (particularly torelqi monoclonal antibody) can be provided in a 150mg / ml liquid composition of 2ml.

[0074] Suitably, the anti-IL-33 antibody may be buffered to a pH of 5.2 to 5.7, most suitably 5.5 (eg ± 0.1). The choice of such a pH confers significant stability to the pharmaceutical composition.

[0075] It should be understood that reference to a "pharmaceutically acceptable excipient" includes reference to any excipient conventionally used in pharmaceutical compositions. Such excipients may typically include one or more surfactants, inorganic or organic salts, stabilizers, diluents, solubilizers, reducing agents, antioxidants, chelating agents, preservatives, and the like.

[0076] Suitably, the surfactant is present in the pharmaceutical composition in an amount of 0.001% to 0.1% (w / w).Suitably, the surfactant is polysorbate-80 (PS-80).

[0077] Anti-IL-33 (particularly torelizumab) may be provided in a pharmaceutical composition comprising L-histidine and / or L-histidine hydrochloride, L-arginine hydrochloride and polysorbate 80. The composition may particularly comprise 20 mM ± 10% L-histidine / L-histidine hydrochloride, such as 20 mM ± 2.5%, 5% or 7.5% L-histidine / L-histidine hydrochloride. That is, L-histidine / L-histidine hydrochloride may be present in the composition at a concentration of 18 mM-22 mM, 18.5 mM-21.5 mM, 19 mM-21 mM or 19.5 mM-20.5 mM, suitably at a concentration of 20 mM.

[0078] The composition may particularly comprise 220 mM ± 10% L-arginine hydrochloride, such as 220 mM ± 2.5%, 5% or 7.5% L-arginine hydrochloride. For example, L-arginine hydrochloride may be present in the composition at a concentration of 200 mM-240 mM, 205 mM-235 mM, 210 mM-230 mM or 215 mM-225 mM, suitably at a concentration of 220 mM.

[0079] The composition may particularly comprise 0.03% w / v ± 10% polysorbate 80, such as 0.03% w / v ± 2.5%, 5% or 7.5% polysorbate 80. For example, polysorbate 80 may be present in the composition at a concentration of 0.027%-0.033%, 0.028%-0.032% or 0.029%-0.031% w / v, suitably at a concentration of 0.03% w / v.

[0080] The pH of the composition may be 5.2-5.7, 5.3-5.6 or 5.4-5.5, suitably 5.5.

[0081] In a particular case, the pharmaceutical composition comprises 20 mM L-histidine / L-histidine hydrochloride, 220 mM L-arginine hydrochloride and 0.03% polysorbate 80, and has a pH of 5.5. Suitably, the pharmaceutical composition further comprises 150 mg / ml torelgi monoclonal antibody. When the composition comprises 150 mg / ml torelgi monoclonal antibody, a 300 mg dose of the antibody can be administered in 2 ml of the composition.

[0082] After administering the antibody to the subject, a saline solution, particularly a saline flush, may be administered to the subject. When the antibody is administered intravenously, a saline flush is preferably included to flush out the IV line. A saline solution is a sterile physiological solution. Suitably, the saline solution comprises 0.9% w / v ± 10% NaCl, such as 0.9% w / v ± 2.5%, 5% or 7.5% NaCl. Suitably, the pH of the saline solution is 5.5 ± 0.1. Suitably, the saline solution comprises 0.9% w / v NaCl and has a pH of 5.5. The saline flush may have any suitable volume required to flush the IV line, for example 2 ml-10 ml, such as 2 ml-8 ml, 3 ml-7 ml or 4 ml-6 ml, suitably 5 ml.

[0083] As described above, some aspects of the present disclosure relate to treating a subject suffering from ARDS and / or ARF or at risk of developing ARDS and / or ARF. Acute respiratory distress syndrome (ARDS) is a life-threatening condition in which the lungs do not function properly. It is caused by damage to the capillary walls from illness or physical injury such as major trauma. This causes the walls to become leaky, leading to the accumulation of fluid and the eventual collapse of the air sacs, making it impossible for the lungs to exchange oxygen and carbon dioxide. Acute respiratory failure (ARF) is a term commonly used with ARDS, but it is a broader term that refers to lung failure caused by any cause, such as chronic obstructive pulmonary disease (COPD).

[0084] Suitably, a subject suffering from ARDS and / or ARF may be defined as a subject who is unable to be adequately ventilated to supply sufficient oxygen to the blood and organs throughout the body.

[0085] Suitably, a subject with ARDS and / or ARF has one or more of the following symptoms: higher than normal respiratory rate, low blood oxygen concentration, dyspnea, shortness of breath, low blood pressure, higher than normal heart rate, chest pain, changes in skin color, sweating, wheezing, confusion, and fatigue. Suitably, ARDS and / or ARF may be defined as a subject having at least one of the following symptoms: higher than normal respiratory rate, low blood oxygen concentration, dyspnea, shortness of breath, and may additionally include one or more of the following symptoms: low blood pressure, higher than normal heart rate, chest pain, changes in skin color, sweating, wheezing, confusion, and fatigue.

[0086] Suitably, subjects at risk of ARDS and / or ARF may develop one or more of the following symptoms: higher than normal respiratory rate, low blood oxygen concentration, dyspnea, shortness of breath, hypotension, higher than normal heart rate, chest pain, skin color changes, sweating, wheezing, confusion and fatigue. Suitably, subjects at risk of ARDS and / or ARF may have few such symptoms, or no such symptoms, but may be at risk of developing further symptoms. Suitably, subjects at risk of ARDS and / or ARF may have diseases, disorders, conditions or infections associated with ARDS and / or ARF or that may cause ARDS and / or ARF as identified elsewhere herein.

[0087] Suitably, the subject suffering from ARDS and / or ARF can be a subject requiring oxygen or a subject requiring ventilation. In one case, the subject suffering from ARDS and / or ARF is a subject requiring oxygen supplementation or ventilation. In one case of any Therapeutic Method described herein, the subject requires oxygen supplementation or ventilation.

[0088] In one instance, the subject has, or is at risk of, acute respiratory failure (ARF). In one instance, the subject has, or is at risk of, hypoxemic (Type 1) acute respiratory failure. In one instance, the subject has, or is at risk of, hypercapnic (Type 2) acute respiratory failure.

[0089] Suitably, a subject at risk of ARDS and / or ARF may be a subject having any one or more of the above symptoms, 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.

[0090] Suitably, acute respiratory failure (ARF) may be caused by a condition, disease, disorder or infection, such as a bacterial infection or a viral 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.

[0091] Bacterial or viral respiratory infections associated with ARDS and / or ARF can be selected from the group consisting of tonsillitis, scarlet fever, pharyngitis, laryngitis, diphtheria, pharyngalgia, Lemmiere syndrome, tularemia, plague, enterocolitis, colds, influenza, mononucleosis, HIV infection, pneumonia, appropriate viral pneumonia, bronchitis, psittacosis, SARS, MERS, and COVID-19. In one embodiment, the viral respiratory infection is a viral lower respiratory tract infection or disease.

[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 instance, the subject suffers from ARDS and / or ARF caused by pneumonia, suitably viral pneumonia. In one instance, the subject suffers from or has pneumonia, suitably viral pneumonia. In one instance, the subject is at risk of pneumonia or viral pneumonia.

[0094] In one case, 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 cases, 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 cases, pneumonia is caused by influenza A virus, influenza B virus, respiratory syncytial virus or human parainfluenza virus.

[0095] Thus suitably, in some cases, the subject suffers from or has COVID-19 and viral pneumonia. In some cases, wherein the viral pneumonia is caused by infection with COVID-19 or SARS-CoV-2. In some cases, the subject suffers from COVID-19 and is at risk of viral pneumonia.

[0096] ARDS or ARF in a subject may be of any cause, for example, ARDS or ARF may be caused by pneumonia, 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, aspiration, and / or drowning.

[0097] In a specific instance, the subject has (ie, has been diagnosed with) or is suspected of having a viral lung infection (ie, a viral infection of the lungs). In a specific instance, the subject has (ie, has been diagnosed with) or is suspected of having a viral lower respiratory tract infection or disease.

[0098] The diagnosis of viral lung infection can be carried out by any means known in the art, such as nucleic acid amplification test (e.g., using PCR or RT-PCR) or antigen test (e.g., using lateral flow test device). "Diagnosis" herein means positive confirmation of viral infection by test (e.g., laboratory test). Diagnosed viral lung infection can be compared with suspected lung infection. If the examining physician believes that the subject has a lung infection (e.g., due to signs or symptoms at the time of statement) but has not yet confirmed this by diagnostic tests (e.g., because of waiting for test results, the test is unavailable or failed, or when the infectious agent cannot be identified), the subject has a suspected lung infection. Generally speaking, when a subject has or is suspected of having a viral lung infection, the viral lung infection is the cause of ARDS or ARF treated according to the present disclosure, or the viral lung infection is putting the subject at risk of developing ARDS or ARF.

[0099] As noted above, in certain aspects of the disclosure, the subject has or is suspected of having a viral lung infection.

[0100] A viral lung infection can be caused by any known viral respiratory pathogen. For example, a viral lung infection can be caused by a coronavirus, such as SARS-CoV, MERS-CoV, or SARS-CoV-2 (the causative agent of COVID-19). In a specific instance, the viral lung infection is caused by SARS-CoV-2, i.e., the subject has COVID-19. In another instance, the viral lung infection is not caused by SARS-CoV-2, i.e., a virus other than SARS-CoV-2 is the causative agent of the infection.

[0101] In another specific case of the present disclosure, the viral lung infection is caused by an influenza virus. Any influenza virus may be the cause, particularly influenza A or influenza B. The influenza A virus may be a seasonal influenza subtype, such as a seasonal H1N1 or H3N2 subtype. Alternatively, the influenza A virus may be a non-human (e.g., avian) strain or a pandemic strain, such as H5Nx (e.g., H5N1) or H7N9.

[0102] In another specific aspect of the present disclosure, the viral lung infection is caused by respiratory syncytial virus (RSV). In another aspect, the viral lung infection is caused by human metapneumovirus (HMPV).

[0103] In other cases, viral lung infections are caused by human parainfluenza virus, adenovirus, hantavirus, herpes simplex virus, varicella-zoster virus, measles virus, rubella virus, cytomegalovirus, smallpox virus, or dengue virus.

[0104] The subject may be hospitalized when the anti-IL-33 antibody is administered. That is, the subject may be in a hospital. Hospitalization is typically due to the fact that the subject suffers from ARDS or ARF or due to a condition that puts them at risk of developing ARDS or ARF. In the case where the subject has or is suspected of having a viral lung infection, the subject is typically hospitalized due to a (suspected) viral lung infection (indeed, some aspects of the present disclosure relate to the treatment of subjects hospitalized for a viral lung infection). In one case, the subject is hospitalized.

[0105] In one embodiment of any of the methods 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 one embodiment of any of the methods described herein, the subject has a viral lower respiratory tract infection, is hospitalized and requires supplemental oxygen or ventilation.

[0106] When a subject is hospitalized due to ARDS or ARF or a condition that places them at risk of developing ARDS or ARF (such as a viral lung infection), it is preferred that the anti-IL-33 antibody is administered within 36 hours of the subject's admission to the hospital (that is, the anti-IL-33 antibody is suitably administered to the subject no more than 36 hours after the subject is admitted to the hospital). Suitably, the anti-111-33 antibody is administered to the subject within 30 hours, 24 hours, 18 hours, 12 hours or 6 hours of the subject's admission to the hospital.

[0107] When the subject has a viral lung infection and is at risk of respiratory failure (e.g., ARDS or ARF) due to the infection, it is preferred that the anti-IL-33 antibody is administered to the subject up to about 14 days after the onset of symptoms of the viral infection. Early symptoms of viral respiratory infections are well known and include, for example, coughing, sneezing, sore throat and / or fever. Suitably, the anti-IL-33 antibody is administered to the subject no more than 14 days after the onset of the first symptoms of viral lung infection. In other cases, the anti-IL-33 antibody is administered to the subject no more than 13 days, 12 days, 11 days, 10 days, 9 days, 8 days, 7 days, 6 days, 5 days, 4 days, or 3 days after the onset of the first symptoms of viral infection.

[0108] Typically, the subject suffers from hypoxemia and therefore requires supplemental oxygen (i.e., oxygen therapy). Hypoxemia is a condition in which there is a lack of oxygen in the arterial blood. Hypoxemia can be easily diagnosed by a physician. In certain cases, hypoxemia is diagnosed when the subject has the following conditions: (i) having an SpO2 (oxygen saturation) of 94% or less in room air (i.e., air with atmospheric levels of O2, as opposed to oxygen-enriched air); (ii) receiving oxygen therapy, but SpO2 is less than 94% before starting oxygen therapy; and / or receiving at least (e.g., more than) 6L / min of supplemental oxygen and / or non-invasive ventilation. In some cases, hypoxemia is diagnosed when the subject has SpO2≤90% or has SpO2≤92% and one or both of the following: (i) at the discretion of the investigator, radiographic infiltrations on a chest X-ray / CT scan are consistent with viral lung infection; or (ii) using accessory muscles of respiration or a respiratory rate of >22 / minute.

[0109] As will be appreciated from the above, the subject is suitably a human patient.

[0110] Therapy disclosed herein can reduce the risk of respiratory failure (such as ARDS and / or ARF) in the risk of subjects developing respiratory failure (such as ARDS and / or ARF). For example, therapy disclosed herein can reduce the risk of respiratory failure (such as ARDS and / or ARF) of such subjects by at least 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45% or 50%. Similarly, therapy disclosed herein can reduce the risk of pneumonia in subjects, for example, by at least 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45% or 50%. The therapies disclosed herein can reduce the risk of developing respiratory failure, ARDS, ARF and / or pneumonia by a specified amount within a specified period of time after administration of the anti-IL-33 antibody (or a first dose of the anti-IL-33 antibody), for example, within a period of 14 days, 28 days, 42 days, 56 days or 60 days after administration of the anti-IL-33 antibody, in particular within a period of 28 days or 60 days after administration of the anti-IL-33 antibody.

[0111] Therapies disclosed herein can improve the survival prospects of subjects with respiratory failure (e.g., ARDS and / or ARF) or at risk of developing respiratory failure (e.g., ARDS and / or ARF). For example, therapies disclosed herein can reduce the risk of such subjects dying from respiratory failure (e.g., ARDS and / or ARF) by at least 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, or 50%. In particular, the therapies disclosed herein can therefore reduce the risk of a subject dying from respiratory failure (e.g., ARDS or ARF) within a period of, for example, 14 days, 28 days, 42 days, 56 days, or 60 days after administration of an anti-IL-33 antibody, particularly within 28 days or 60 days after administration of an anti-IL-33 antibody.

[0112] That is, the therapy disclosed herein can treat or prevent respiratory failure, such as ARDS and / or ARF, in a subject. In the case of a subject suffering from respiratory failure or at risk of respiratory failure due to a viral lung infection, the therapy disclosed herein can be considered to treat a viral lung infection. The therapy disclosed herein can also limit the severity of the respiratory failure (such as ARDS and / or ARF) of the subject, so that less hospital treatment or less intensive or invasive hospital treatment is required. In particular, they can reduce the demand for care in an intensive care unit (ICU), and / or reduce the demand for invasive mechanical ventilation (IMV) or extracorporeal membrane oxygenation (ECMO).

[0113] In particular, the therapies disclosed herein can reduce the risk of requiring IMV and / or ECMO in a subject suffering from ARDS and / or ARF or at risk of developing ARDS and / or ARF by at least 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45% or 50%. In particular, the therapies disclosed herein can therefore reduce the risk of requiring IMV and / or ECMO in a subject for a period of, for example, 14 days, 28 days, 42 days, 56 days or 60 days after administration of an anti-IL-33 antibody, in particular 28 days or 60 days after administration of an anti-IL-33 antibody.

[0114] Therapies disclosed herein can reduce the risk of requiring admission to an intensive care unit (ICU) for a subject suffering from ARDS and / or ARF or at risk of developing ARDS and / or ARF by at least 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, or 50%. In particular, therapies disclosed herein can therefore reduce the risk of requiring admission to an ICU for a subject within a period of, for example, 14 days, 28 days, 42 days, 56 days, or 60 days after administration of an anti-IL-33 antibody, particularly 28 days or 60 days after administration of an anti-IL-33 antibody.

[0115] If a subject with ARDS and / or ARF or at risk of developing ARDS and / or ARF needs to be admitted to the ICU, the therapy disclosed herein can reduce the duration of the subject's need to stay in the ICU, particularly by at least 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45% or 50%. Alternatively, the therapy disclosed herein can reduce the duration of the subject's need to stay in the ICU by at least 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days or 10 days. In this case, the required stay period of the subject in the ICU can be the average required stay period of a group of subjects in the ICU, all of whom suffer from ARDS and / or ARF or are at risk of developing ARDS and / or ARF. This reduction in the required ICU stay period can be, for example, 14 days, 28 days, 42 days, 56 days or 60 days after the administration of the anti-IL-33 antibody, particularly within a period of 28 days or 60 days after the administration of the anti-IL-33 antibody.

[0116] Similarly, the therapy disclosed herein can increase the number of days that a subject with ARDS and / or ARF or at risk of developing ARDS and / or ARF survives and is outside the ICU in 60 days after administering an anti-IL-33 antibody. The number of days that the subject survives and is outside the ICU can be increased by at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% or 100% or more. Alternatively, the number of days that the subject survives and is outside the ICU can be increased by at least 5 days, 10 days, 15 days, 20 days, 25 days, 30 days, 35 days, 40 days, 45 days, 50 days or 55 days. In this case, the number of days that the subject survives and is outside the ICU can be the average number of days for a group of subjects, all of whom suffer from ARDS and / or ARF or are at risk of developing ARDS and / or ARF.

[0117] Therapies disclosed herein can increase the number of days that a subject with ARDS and / or ARF or at risk of developing ARDS and / or ARF survives and does not need oxygen supplementation within 60 days after administration of an anti-IL-33 antibody. The number of days that a subject survives and does not need oxygen supplementation can be increased by at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% or 100% or more. Alternatively, the number of days that a subject survives and does not need oxygen supplementation can be increased by at least 5 days, 10 days, 15 days, 20 days, 25 days, 30 days, 35 days, 40 days, 45 days, 50 days or 55 days. In this case, the number of days that a subject survives and does not need oxygen supplementation can be the average number of days for a group of subjects, all of whom suffer from ARDS and / or ARF or are at risk of developing ARDS and / or ARF.

[0118] Relatedly, the therapies disclosed herein can reduce the duration of supplemental oxygen therapy required by subjects suffering from ARDS and / or ARF or at risk of developing ARDS and / or ARF and requiring supplemental oxygen therapy, particularly by at least 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45% or 50%. Alternatively, the therapies disclosed herein can reduce the duration of supplemental oxygen therapy required by at least 2 days, 4 days, 6 days, 8 days, 10 days, 12 days, 14 days, 16 days, 18 days or 20 days. In this case, the duration of supplemental oxygen therapy required by the subject can be the average required duration of oxygen therapy for a group of subjects, all of whom suffer from ARDS and / or ARF or are at risk of developing ARDS and / or ARF. This reduction in the required duration of supplemental oxygen therapy can be, for example, 14 days, 28 days, 42 days, 56 days or 60 days after administration of the anti-IL-33 antibody, particularly within a period of 28 days or 60 days after administration of the anti-IL-33 antibody.

[0119] As used herein, the terms "oxygen therapy," "supplemental oxygen," and "oxygen supplementation therapy" are used interchangeably.

[0120] Therapies disclosed herein can reduce the duration of hospitalization required by subjects suffering from ARDS and / or ARF or at risk of developing ARDS and / or ARF, in particular by at least 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45% or 50%. Alternatively, the therapy disclosed herein can reduce the required duration of hospitalization by at least 2 days, 4 days, 6 days, 8 days, 10 days, 12 days, 14 days, 16 days, 18 days or 20 days. In this case, the duration of hospitalization required by the subject can be the average required duration of hospitalization for a group of subjects, all of whom suffer from ARDS and / or ARF or are at risk of developing ARDS and / or ARF. This reduction in the required duration of hospitalization can be within a period of, for example, 14 days, 28 days, 42 days, 56 days or 60 days after administration of the anti-IL-33 antibody, in particular within a period of 28 days or 60 days after administration of the anti-IL-33 antibody.

[0121] Therapies disclosed herein can increase the chance of survival to hospital discharge in subjects suffering from ARDS and / or ARF or at risk of developing ARDS and / or ARF, for example, by at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% or 100% or more. This increase in the chance of survival to hospital discharge in subjects can be within a period of, for example, 14 days, 28 days, 42 days, 56 days or 60 days after administration of the anti-IL-33 antibody, particularly within a period of 28 days or 60 days after administration of the anti-IL-33 antibody.

[0122] Therapies disclosed herein can reduce the risk of subjects who are initially discharged alive from a hospital with ARDS and / or ARF or are at risk of developing ARDS and / or ARF requiring re-admission within 28 or 60 days of administration of an anti-IL-33 antibody. This risk can be reduced, for example, by at least 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, or 50%.

[0123] When the subject has a viral lung infection caused by SARS-CoV-2 (i.e., the subject has COVID-19), the therapies disclosed herein can reduce or prevent disease progression as defined by the WHO 10-point clinical progression scale for COVID-19, or cause an improvement in the subject's condition as defined by the clinical progression scale. For example, treatment can increase the chance that the subject will have a score of less than 7, 6, 5, 4, or 3 as defined by the WHO 10-point clinical progression scale for COVID-19 on day 28 or day 60 after administration of the anti-IL-33 antibody, or cause the subject to reach a score of less than 7, 6, 5, 4, or 3 according to the scale more quickly. The WHO 10-point clinical progression scale for COVID-19 is as follows:

[0124]

[0125]

[0126] When treatment with IL-33 antibodies in the manner described above reduces the risk associated with ARDS / ARF or improves recovery from ARDS / ARF, the reduction or improvement is compared to a control patient population suffering from the same condition as the subject but not administered the anti-IL-33 antibody (or fragment thereof). In addition to the anti-IL-33 antibody, the control patient population also received standard care for the condition. That is, in addition to the anti-IL-33 antibody, the control patient population received the same medical care as the subject. Therefore, the improvement in the above clinical outcome is a direct result of administering the antibody (or fragment thereof) to the subject.

[0127] The present disclosure can be further understood by reference to the following non-limiting examples and accompanying figures. BRIEF DESCRIPTION OF THE DRAWINGS

[0128] Figure 1 - Study Design of a Phase III, multicenter, randomized, double-blind, parallel-group, placebo-controlled study to evaluate the efficacy and safety of torelizumab (MEDI3506) in patients hospitalized with viral lung infections requiring supplemental oxygen (TILIA).

[0129] Example

[0130] Example 1 - ACCORD2: Evaluating the efficacy and safety of multiple candidate agents for the treatment of COVID-19 in hospitalized patients A comprehensive, multicenter, seamless, 2-phase adaptive randomization platform study

[0131] Study Design

[0132] The objective of the study was to evaluate the efficacy and safety of torelizumab 300 mg IV plus SoC compared with SoC alone in hospitalized adults with SARS-CoV-2 (COVID-19) infection with an 8-point WHO Ordinal Clinical Progression Scale score of 3, 4, or 5 (see Table 1).

[0133] In this study, MEDI3506 (torezumab) was administered to patients as a single 300 mg IV. If the patient became invasively ventilated on or before Day 15 but after randomization and remained invasively ventilated on Day 15, a second dose of 300 mg IV torelizumab was administered. Based on a 4-week good laboratory practice toxicology study, a dose of 300 mg torelizumab IV was predicted to have a >47-fold safety margin for both the maximum observed concentration and the area under the concentration-time curve (AUC) for exposure at a level where no adverse effects were observed (150 mg / kg).

[0134] In total, 103 patients were randomized to torelgi plus standard of care (SoC) (n=56) or SoC alone (n=47). After the end of the torelgi substudy, three patients who received SoC alone were randomized, and 2 patients were randomized to torelgi plus SoC but without medication; these patients were excluded from the safety analysis set and the full analysis set. One patient received one dose of torelgi, but did not have any post-baseline ordinal scale data, so it was excluded from the full analysis set. In total, 98 patients in the safety analysis set received torelgi plus SoC (n=54) or SoC alone (n=44).

[0135] In the safety analysis set, demographic characteristics were well balanced between treatment arms. Most patients were male (for torelizumab plus SoC vs. SoC alone: ​​37 patients [68.5%] vs. 29 patients [65.9%]) and were middle-aged and elderly (mean [SD] for torelizumab plus SoC vs. SoC alone: ​​55.4 years [12.51] vs. 58.0 years [13.90]). The percentage of patients with diabetes and ≥2 comorbidities in the torelizumab plus SoC arm (diabetes: 22 patients [40.7%]; ≥2 comorbidities: 21 patients [38.9%]) was higher than in the SoC arm alone (diabetes: 13 patients [29.5%]; ≥2 comorbidities: 13 patients [29.5%]). The standard of care evolved during the study treatment period, with the addition of dexamethasone and remdesivir and the late addition of tocilizumab. The primary endpoint of time to sustained clinical response was defined as an improvement of ≥2 points on the ordinal scale by discharge on day 29 or when deemed suitable for discharge, whichever came first. The WHO 8-point ordinal clinical progression scale was used as recommended by the WHO at the time of study design (Table 1).

[0136]

[0137] Table 1: WHO 8-point ordinal clinical progression scale, source: (WHO, 2020)

[0138] Study Results

[0139] Primary End Point

[0140] No statistically significant differences were observed between the treatment arms based on the hazard ratios for time to sustained clinical response (Table 2).

[0141] The observed benefit of torelikimab was not in speed of discharge, as many patients were successfully treated quickly, but in the prevention of morbidity or mortality in those who could not be discharged quickly (see "Key secondary endpoints" below).

[0142] parameter Torecimab plus SoC (N=53) Individual SoCs (N=44) Patients examined, n (%) 11(20.8) 12(27.3) Median time of reaction, days (80% Cl) 8(7.00,9.00) 9.5(7.00,13.00) <![CDATA[Hazard ratio (80% CI) c > 0.96(0.700,1.306) NA One-sided p-value 0.4267 NA

[0143] Table 2 - Duration of Clinical Response to Day 29 (Full Analysis Set)

[0144] a Patients who died before day 29 or had no response by day 29 were censored on day 29.

[0145] bKaplan-Meier product limit estimates are provided, with 80% Cl calculated according to Brookmeyer and Crowley.

[0146] c Hazard ratios were calculated from the Cox-proportional hazards model after adjustment for age, treatment, and binary baseline ordinal score as covariates. A hazard ratio > 1 indicated a treatment effect in favor of torelizumab.

[0147] Cl = confidence interval.

[0148] Key Secondary End Points

[0149] For the secondary endpoint of death or respiratory failure by day 29, respiratory failure was defined as a score of 6 or 7 on the ordinal scale. Patients in the torelaxumab plus SoC arm had lower odds of death or respiratory failure by day 29 compared with SoC alone (Table 3).

[0150] Patients in the torelikimab arm had lower mortality by day 29 in the torelikimab plus SoC arm compared to SoC alone (Table 4).

[0151] In relative terms, patients had an approximately 1 / 3 reduction in risk for both endpoints. Although neither finding showed a statistically significant difference, this was a small pilot study to identify a potential treatment and was not prospectively powered for these endpoints. These findings suggest the potential for clinically meaningful benefit of torelizumab and indicate that further study is warranted.

[0152] parameter Torecimab plus SoC (N=53) SoC (N=44) Death or respiratory failure by day 29 Yes, n(%) 9(17.0％) 11(25.0％) No, n(%) 44(83.0％) 33(75.0％) Odds ratio (80% CI) 0.55(0.272,1.123) NA P-value 0.2835 NA

[0153] Table 3 - Death or respiratory failure by day 29 (full analysis set)

[0154] a Calculated from logistic regression models adjusted for age and baseline severity.

[0155] Cl = confidence interval; NA = not applicable; SoC = standard of care.

[0156]

[0157] Table 4 - Mortality to Day 29 (Full Analysis Set)

[0158] a Calculated from logistic regression models adjusted for age and baseline severity.

[0159] Cl = confidence interval; NA = not applicable; SoC = standard of care.

[0160] Example 2 - Evaluation of torelizumab (MEDI3506) in hospitalized patients with viral lung infections requiring oxygen supplementation A phase III, multicenter, randomized, double-blind, parallel-group, placebo-controlled study of the efficacy and safety of TILIA in patients with Study.

[0161] Overall study design

[0162] This is a Phase III, multicenter, randomized, double-blind, parallel-group, placebo-controlled study to evaluate the efficacy and safety of torelizumab in reducing the risk of progression to acute respiratory distress syndrome or death in patients hospitalized for viral lung infection requiring supplemental oxygen.

[0163] The primary outcome is the proportion of participants who die or progress to invasive mechanical ventilation (IMV) / extracorporeal membrane oxygenation (ECMO) by day 28. The study intervention will be administered on day 1. Patient status will be recorded daily while in the hospital. Upon discharge, participants will be followed up by telephone on days 14 and 28. A final in-person visit will be conducted on day 60.

[0164] The study initially planned to randomize approximately 2352 participants (i.e., 1176 per treatment arm), but the final sample size will be determined by the number of events. Randomization will be stratified by the known virus positivity rate (SARS-CoV-2 vs. other viruses vs. uncertain viruses) and region at randomization. The study will be recruited until approximately 375 primary endpoint events are observed in participants with confirmed virus positivity rates from baseline samples (known before or after randomization). It is expected that at least 60% of the participants will have a confirmed positive virus test at randomization, with the intention of having at least approximately 75% of virus-positive cases (including retrospectively confirmed cases) in the study population as a whole. Participants will be randomized to receive 300 mg toreqi monoclonal antibody or matching placebo at a ratio of 1: 1, administered intravenously (IV injection) within 36 hours after admission.

[0165] Participants will receive a single dose of the study intervention (torezumab 300 mg or placebo) administered via IV injection, followed by a 5 mL saline flush.

[0166] Participants' vital signs and the WHO Clinical Progress Scale were assessed and recorded once daily during hospitalization.

[0167] Study interventions are given in addition to SoC treatment. Study participants will continue to receive SoC based on local guidance throughout the study period.

[0168] Figure 1 A schematic diagram of the study design is shown.

[0169] Dose rationalization

[0170] Torelizumab will be administered to participants as a single 300 mg IV injection, followed by a 5 mL saline flush.

[0171] The nonclinical and clinical safety and efficacy data generated by torelikimab support a positive risk / benefit ratio for the clinical program in adults hospitalized with acute viral infections requiring supplemental oxygen and who are at risk of developing ARDS.

[0172] This dose and route of administration was tested in addition to SoC in the ACCORD-2 study of patients with COVID-19 and showed a numerical reduction of 32% in the proportion of participants who had died or had experienced respiratory failure by day 29 compared to SoC alone (Example 1). In this study, there were no safety findings that would preclude further development of the drug. In addition, a single 300 mg IV injection of torelizumab was the highest dose tested for the first time in a human single ascending dose study in healthy participants with a history of mild atopy, with a good safety and tolerability profile.

[0173] Goals, Endpoints, and Measurables

[0174] The goals and endpoints are presented in Table 5 .

[0175]

[0176]

[0177] Table 5: Objectives and endpoints

[0178] a Statistical analysis of multiple controls will also be performed using the full analysis set.

[0179] b Relevant intercurrent events other than death included receipt of additional treatment, changes in background treatment, or changes in care setting.

[0180] c All secondary endpoints except PK were analyzed in the confirmed virus-positive analysis set and the full analysis set.

[0181] ADA = antidrug antibodies; AE = adverse event; ECG = electrocardiogram; ED = emergency department; ECMO = extracorporeal membrane oxygenation; ER = emergency room; HRCU = health care resource utilization; ICU = intensive care unit; IMV = intermodal ventilation; PK = pharmacokinetics; SAE = serious adverse event; SoC = standard of care; WHO = World Health Organization.

[0182] Study Group

[0183] Inclusion criteria

[0184] Participants were eligible for inclusion in the study only if all of the following criteria applied: Age:

[0185] 1. Adult participants were ≥18 years old when signing the ICF.

[0186] Participant Type and Disease Characteristics:

[0187] 2. Patients hospitalized with viral lung infection. NOTE: Suspected viral etiology is acceptable to meet this criterion.

[0188] 3. Hypoxemia requiring supplemental oxygen therapy, consistent with disease progression scores of 5 and 6 on the WHO Clinical Progression Scale. Note: Hypoxemia is defined as SpO2 ≤ 90% or SpO2 ≤ 92% and one or both of the following:

[0189] a. Radiographic infiltrates on chest X-ray / CT scan consistent with viral lung infection, at the investigator's discretion.

[0190] b. Use of accessory muscles of breathing or respiratory rate >22 / minute.

[0191] Note: Patients receiving oxygen >6 L / min or non-invasive ventilation will be considered to have met this inclusion criterion regardless of SpO2 levels. Documented pre-hospitalization SpO2 (related to the episode) is acceptable, e.g. from an ambulance report.

[0192] 4. ≤ 36 hours since admission.

[0193] 5. ≤ 14 days since onset of respiratory viral infection symptoms.

[0194] Exclusion criteria

[0195] Participants were excluded from the study if any of the following criteria applied:

[0196] Medical conditions

[0197] 1. Known fungal or parasitic lung infection, aspiration lung infection, lung abscess, or pulmonary sepsis. Bacterial co-infection is permitted unless, in the opinion of the investigator, the bacterial infection limits the severity of the participant's condition.

[0198] 2. Hypoxemia caused primarily by extrapulmonary damage (e.g., multiple organ failure, shock, or sepsis) or by lung damage of non-infectious etiology (e.g., trauma, chemical injury, etc.).

[0199] 3. IMV / ECMO is ongoing or about to occur at the time of randomization.

[0200] 4. Any coexisting condition that, in the opinion of the investigator, may result in death within 3 months after randomization.

[0201] 5. Expected to recover and be discharged from hospital within 24 hours of randomization.

[0202] 6. Active TB disease defined as requiring current treatment.

[0203] 7. Known unstable cardiovascular disease that, in the investigator's judgment, may put participants at risk or negatively affect study outcomes (e.g., unstable chronic heart failure NYHA III-IV, myocardial infarction or stroke within the last 3 months, or uncontrolled ventricular arrhythmia).

[0204] 8. Known absolute neutrophil count ≤1.0x 109 / L.

[0205] 9. Known untreated HIV. Known history of active hepatitis B or C (treated and controlled hepatitis allowed).

[0206] 10. Known history of active severe inflammatory bowel disease or colitis (including Crohn's disease or ulcerative colitis).

[0207] 11. The following malignant tumors:

[0208] a. Solid tumors with metastasis (stage IV).

[0209] b. Lymphoma / leukemia not in complete remission.

[0210] c. Malignancy treated with chemotherapy and / or immunomodulatory drugs within the past 2 months.

[0211] 12. Transplant patients at risk for organ rejection, or those receiving long-term immunosuppressive therapy for transplantation. Treatment with corticosteroids is permitted.

[0212] 13. Any condition that is unstable in the opinion of the Investigator, including but not limited to cardiovascular, gastrointestinal, hepatic, renal, neurological, musculoskeletal, infectious (including risk factors for viral lung infection), endocrine, metabolic, hematological, immune, psychiatric or major physical impairment, and can:

[0213] - Affects the safety of participants throughout the study,

[0214] - influence the research findings or their interpretation,

[0215] - Impedes the participant's ability to complete the full duration of the study.

[0216] Previous / concomitant therapy

[0217] 14. Use long-term oxygen therapy for pre-existing conditions.

[0218] 15. Long-term treatment with TNF inhibitors, Janus kinase inhibitors or interferon-γ. A wash-out period of 4 weeks or 5 half-lives (whichever is longer) is required before enrollment.

[0219] 16. Currently being treated with any study drug. A washout period of 4 weeks or half-life (whichever is longer) is required before enrollment.

[0220] 17. Participants who have previously received torelizumab.

[0221] 18. Known medical history:

[0222] - Allergy to any other biological therapy,

[0223] - Severe reaction to any medication including biologic agents or human gamma globulin therapy

[0224] - Allergy or reaction to any component of the study intervention formulation.

[0225] sequence

[0226]

Claims

1. A method of treating or preventing acute respiratory distress syndrome (ARDS) in a subject having or at risk of developing ARDS, the method comprising administering to the subject a dose of 250 mg to 350 mg of an anti-IL-33 antibody, wherein the antibody comprises: (a) a heavy chain variable region comprising a VHCDR1 having the sequence of SEQ ID NO: 1, a VHCDR2 having the sequence of SEQ ID NO: 2, and a VHCDR3 having the sequence of SEQ ID NO: 3; and (b) a light chain variable region comprising a VLCDR1 having the sequence of SEQ ID NO:4, a VLCDR2 having the sequence of SEQ ID NO:5, and a VLCDR3 having the sequence of SEQ ID NO:

6.

2. A method of treating or preventing acute respiratory failure (ARF) in a subject having or at risk of developing ARF, the method comprising administering to the subject a dose of 250 mg to 350 mg of an anti-IL-33 antibody, wherein the antibody comprises: (a) a heavy chain variable region comprising a VHCDR1 having the sequence of SEQ ID NO: 1, a VHCDR2 having the sequence of SEQ ID NO: 2, and a VHCDR3 having the sequence of SEQ ID NO: 3; and (b) a light chain variable region comprising a VLCDR1 having the sequence of SEQ ID NO:4, a VLCDR2 having the sequence of SEQ ID NO:5, and a VLCDR3 having the sequence of SEQ ID NO:

6.

3. A method of reducing the risk of a subject requiring invasive mechanical ventilation (IMV) or extracorporeal membrane oxygenation (ECMO), wherein the subject suffers from or is at risk of developing ARDS and / or ARF, the method comprising administering to the subject an anti-IL-33 antibody at a dose of 250 mg to 350 mg, wherein the antibody comprises: (a) a heavy chain variable region comprising a VHCDR1 having the sequence of SEQ ID NO: 1, a VHCDR2 having the sequence of SEQ ID NO: 2, and a VHCDR3 having the sequence of SEQ ID NO: 3; and (b) a light chain variable region comprising a VLCDR1 having the sequence of SEQ ID NO:4, a VLCDR2 having the sequence of SEQ ID NO:5, and a VLCDR3 having the sequence of SEQ ID NO:

6.

4. A method of reducing the risk of requiring admission to an intensive care unit (ICU) in a subject having ARDS and / or ARF or at risk of developing ARDS and / or ARF, the method comprising administering to the subject a dose of 250 mg to 350 mg of an anti-IL-33 antibody, wherein the antibody comprises: (a) a heavy chain variable region comprising a VHCDR1 having the sequence of SEQ ID NO: 1, a VHCDR2 having the sequence of SEQ ID NO: 2, and a VHCDR3 having the sequence of SEQ ID NO: 3; and (b) a light chain variable region comprising a VLCDR1 having the sequence of SEQ ID NO:4, a VLCDR2 having the sequence of SEQ ID NO:5, and a VLCDR3 having the sequence of SEQ ID NO:

6.

5. A therapeutic method for reducing the duration of hospitalization of a subject having ARDS and / or ARF or at risk of developing ARDS and / or ARF, the method comprising administering to the subject a dose of 250 mg to 350 mg of an anti-IL-33 antibody, wherein the antibody comprises: (a) a heavy chain variable region comprising a VHCDR1 having the sequence of SEQ ID NO: 1, a VHCDR2 having the sequence of SEQ ID NO: 2, and a VHCDR3 having the sequence of SEQ ID NO: 3; and (b) a light chain variable region comprising a VLCDR1 having the sequence of SEQ ID NO:4, a VLCDR2 having the sequence of SEQ ID NO:5, and a VLCDR3 having the sequence of SEQ ID NO:

6.

6. A method of treating a subject having ARDS and / or ARF or at risk of developing ARDS and / or ARF and requiring supplemental oxygen therapy, said treatment reducing the required duration of said supplemental oxygen therapy, said method comprising administering to said subject a dose of 250 mg to 350 mg of an anti-IL-33 antibody, wherein said antibody comprises: (a) a heavy chain variable region comprising a VHCDR1 having the sequence of SEQ ID NO: 1, a VHCDR2 having the sequence of SEQ ID NO: 2, and a VHCDR3 having the sequence of SEQ ID NO: 3; and (b) a light chain variable region comprising a VLCDR1 having the sequence of SEQ ID NO:4, a VLCDR2 having the sequence of SEQ ID NO:5, and a VLCDR3 having the sequence of SEQ ID NO:

6.

7. The method of any one of claims 1 to 6, wherein the anti-IL-33 antibody comprises: a heavy chain variable region comprising the sequence of SEQ ID NO: 7 or an amino acid sequence having at least 80% sequence identity thereto; and A light chain variable region comprising the sequence of SEQ ID NO: 8 or an amino acid sequence having at least 80% sequence identity thereto.

8. The method of claim 7, wherein the anti-IL-33 antibody is torelizumab.

9. The method of any one of claims 1 to 8, wherein the anti-IL-33 antibody is administered to the subject intravenously.

10. The method according to any one of claims 1 to 9, wherein the dose of the anti-IL-33 antibody is 300 mg.

11. The method of any one of claims 1 to 10, wherein a single dose of the anti-IL-33 antibody is administered to the subject.

12. The method of any one of claims 1 to 11, wherein the subject has or is suspected of having a viral lung infection.

13. The method of any one of claims 1 to 12, wherein the subject has or is suspected of having a viral lower respiratory tract infection or disease.

14. The method of claim 12 or 13, wherein the viral lung infection is caused by a coronavirus such as SARS-CoV-2.

15. The method of claim 12 or 13, wherein the viral lung infection is not a SARS-CoV-2 infection.

16. The method of claim 12 or 13, wherein the viral infection is caused by an influenza virus, such as influenza A virus or influenza B virus.

17. The method of claim 12 or 13, wherein the viral lung infection is caused by RSV.

18. The method of claim 12 or 13, wherein the viral lung infection is caused by human metapneumovirus (HMPV).

19. The method according to any one of claims 1 to 18, wherein the subject is hospitalized.

20. The method of claim 19, wherein the subject is hospitalized due to the viral lung infection or suspected viral lung infection.

21. The method of claim 19 or claim 20, wherein the subject is hospitalized due to a viral lower respiratory tract infection or disease or suspected viral lower respiratory tract infection or disease.

22. The method of any one of claims 19, 20 or 21, wherein the anti-IL-33 antibody is administered to the subject up to about 36 hours after the subject is admitted to the hospital.

23. The method of any one of claims 12 to 22, wherein the anti-IL-33 antibody is administered to the subject up to about 14 days after the onset of symptoms of a viral lung infection in the subject.

24. The method of any one of claims 1 to 23, wherein the subject requires supplemental oxygen or ventilation.

25. The method of any one of claims 1 to 24, wherein the subject suffers from hypoxemia and requires supplemental oxygen.

26. The method of any one of claims 1 to 25, wherein the subject has a viral lower respiratory tract infection or disease, is hospitalized and requires supplemental oxygen or ventilation.

27. The method of claim 24 or 25, wherein the subject: (i) SpO2 ≤ 94% in room air; (ii) SpO2 ≤ 94% before initiation of oxygen therapy; and / or (iii) receiving supplemental oxygen and / or non-invasive ventilation >6 L / min.

28. The method of claim 24 or 25, wherein the subject has: (i) SpO2 ≤ 90%, or (ii) SpO2 ≤ 92% and one or both of the following: radiographic infiltrates on chest X-ray / CT scan consistent with viral lung infection or use of accessory muscles of breathing or respiratory rate > 22 / min, as judged by the investigator.

29. The method of any one of claims 1 to 28, wherein the anti-IL-33 antibody is torelakinumab and is administered in a solution comprising: (a) 20 mM ± 10% L-histidine / L-histidine hydrochloride; (b) 220 mM ± 10% L-arginine hydrochloride; and (c) 0.03% ± 10% w / v polysorbate 80; and the pH of the solution is 5.5; Suitably wherein the solution comprises 150 mg / ml torelikimab.

30. The method of any one of claims 1 to 29, wherein after administration of the anti-IL-33 antibody, a saline rinse is administered to the subject, optionally wherein the saline rinse comprises 0.9% ± 10% w / v NaCl and has a pH of 5.5, optionally wherein the saline rinse is 5 ml of saline rinse.

31. The method according to any one of claims 1 to 30, wherein the treatment reduces the risk of the subject developing ARDS or pneumonia, particularly within 28 days or 60 days after administration of the anti-IL-33 antibody.

32. The method according to any one of claims 1 to 31, wherein the treatment reduces the risk of death of the subject within 28 days or 60 days after administration of the anti-IL-33 antibody, particularly reduces the risk of death of the subject from ARDS within said time frame.

33. The method of any one of claims 1 to 32, wherein the treatment reduces the risk of the subject requiring ICU admission or requiring invasive mechanical ventilation (IMV) or extracorporeal membrane oxygenation (ECMO) within 28 days or 60 days after administration of the anti-IL-33 antibody; and / or reduces the duration of ICU admission, IMV or ECMO required within 28 days or 60 days after administration of the anti-IL-33 antibody.

34. The method of any one of claims 1 to 33, wherein the treatment increases the number of days that the subject is alive and outside the ICU within 60 days after administration of the anti-IL-33 antibody, and / or increases the number of days that the subject is alive and does not require supplemental oxygen within 60 days after administration of the anti-IL-33 antibody.

35. The method of any one of claims 1 to 34, wherein the treatment reduces the duration of supplemental oxygen administration required by the subject within 28 days or 60 days after administration of the anti-IL-33 antibody.

36. The method of any one of claims 1 to 35, wherein the treatment reduces the length of hospitalization required for the subject, and / or increases the chance that the subject will survive discharge from the hospital within 28 days or 60 days after administration of the anti-IL-33 antibody.

37. The method of any one of claims 1 to 36, wherein the treatment reduces the risk of the subject being readmitted to the hospital following discharge within 28 days or 60 days following administration of the anti-IL-33 antibody.

38. The method of any one of claims 1 to 37, wherein the treatment reduces or prevents disease progression as defined by the WHO 10-point Clinical Progression Scale for COVID-19, or causes an improvement in the subject's condition as defined by the Clinical Progression Scale, for example, wherein the treatment increases the chance that the subject will have a score of less than 7, 6, 5, 4, or 3 as defined by the WHO 10-point Clinical Progression Scale for COVID-19 on day 28 or day 60 after administration of the anti-IL-33 antibody, or causes the subject to reach a score of less than 7, 6, 5, 4, or 3 according to the scale more quickly.

39. An anti-IL-33 antibody for use in treating or preventing ARDS or ARF in a subject, wherein the antibody, treatment or prevention, ARDS, ARF and / or subject are as defined in any one of claims 1 to 38.

40. Use of an anti-IL-33 antibody in the manufacture of a medicament for treating or preventing ARDS or ARF in a subject, wherein the antibody, treatment or prevention, ARDS, ARF and / or subject are as defined in any one of claims 1 to 38.

41. A pharmaceutical composition comprising an anti-IL-33 antibody for treating or preventing ARDS or ARF in a subject, wherein the antibody, treatment or prevention, ARDS, ARF and / or subject are as defined in any one of claims 1 to 38.

42. A method of preventing or reducing the risk of acute respiratory failure or ARDS in a subject hospitalized with a viral lung infection or suspected viral lung infection, the method comprising administering to the subject a dose of 250 mg to 350 mg of an anti-IL-33 antibody, wherein the antibody comprises: (a) a heavy chain variable region comprising a VHCDR1 having the sequence of SEQ ID NO: 1, a VHCDR2 having the sequence of SEQ ID NO: 2, and a VHCDR3 having the sequence of SEQ ID NO: 3; and (b) a light chain variable region comprising a VLCDR1 having the sequence of SEQ ID NO:4, a VLCDR2 having the sequence of SEQ ID NO:5, and a VLCDR3 having the sequence of SEQ ID NO:

6.

43. A method of treating a subject hospitalized with a viral lung infection or suspected viral lung infection, the method comprising administering to the subject a dose of 250 mg to 350 mg of an anti-IL-33 antibody, wherein the antibody comprises: (a) a heavy chain variable region comprising a VHCDR1 having the sequence of SEQ ID NO: 1, a VHCDR2 having the sequence of SEQ ID NO: 2, and a VHCDR3 having the sequence of SEQ ID NO: 3; and (b) a light chain variable region comprising a VLCDR1 having the sequence of SEQ ID NO:4, a VLCDR2 having the sequence of SEQ ID NO:5, and a VLCDR3 having the sequence of SEQ ID NO:

6.

44. The method of claim 43, wherein the subject requires the use of supplemental oxygen.

45. The method of claim 42 or 43, wherein the anti-IL-33 antibody, administration, viral lung infection, subject and / or treatment is as defined in any one of claims 7 to 11, 14 to 18 or 22 to 37.

46. ​​An anti-IL-33 antibody for use in treating or preventing respiratory failure in a subject hospitalized with a viral lung infection or suspected viral lung infection, wherein the treatment comprises administering to the subject a dose of 250 mg to 350 mg of the anti-IL-33 antibody, and wherein the antibody comprises: (a) a heavy chain variable region comprising a VHCDR1 having the sequence of SEQ ID NO: 1, a VHCDR2 having the sequence of SEQ ID NO: 2, and a VHCDR3 having the sequence of SEQ ID NO: 3; and (b) a light chain variable region comprising a VLCDR1 having the sequence of SEQ ID NO:4, a VLCDR2 having the sequence of SEQ ID NO:5, and a VLCDR3 having the sequence of SEQ ID NO:

6.

47. An anti-IL-33 antibody for use in treating a viral lung infection or suspected viral lung infection in a subject, wherein the subject is hospitalized for the viral lung infection or suspected viral lung infection, wherein the treatment comprises administering to the subject a dose of 250 mg to 350 mg of the anti-IL-33 antibody, and wherein the antibody comprises: (a) a heavy chain variable region comprising a VHCDR1 having the sequence of SEQ ID NO: 1, a VHCDR2 having the sequence of SEQ ID NO: 2, and a VHCDR3 having the sequence of SEQ ID NO: 3; and (b) a light chain variable region comprising a VLCDR1 having the sequence of SEQ ID NO:4, a VLCDR2 having the sequence of SEQ ID NO:5, and a VLCDR3 having the sequence of SEQ ID NO:

6.

48. An anti-IL-33 antibody for use according to claim 42 or 43, wherein the anti-IL-33 antibody, administration, viral lung infection, subject and / or treatment is as defined in any one of claims 7 to 11, 14 to 18 or 22 to 37.

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