Treatment of acute respiratory failure

Abstract

The present disclosure provides a method for treating or preventing acute respiratory distress syndrome (ARDS) in a subject suffering from or at risk of developing ARDS, such as a subject with a viral lung infection requiring supplemental oxygen. The method comprises administering to the subject a dose of 250 to 350 mg of an anti-IL-33 antibody. The method may further comprise preventing the subject from progressing to invasive mechanical ventilation (IMV) or extracorporeal membrane oxygenation (ECMO).

Description

[Technical Field]

[0001] (CROSS-REFERENCE TO RELATED APPLICATIONS) This application claims the benefit under 35 U.S.C. §119(e) of U.S. Provisional Patent Application No. 63 / 371,936, filed August 19, 2022, and of UK Patent Application No. 2213964.6, filed September 23, 2022, which are hereby incorporated by reference in their entireties for all purposes.

[0002] (Reference to electronically submitted sequence listing) This application incorporates by reference the Sequence Listing submitted herewith in computer readable form (CRF) as a text file entitled "IL33-440-WO-PCT Sequence Listing," created on August 17, 2023, and having a size of 13,464 bytes.

[0003] FIELD OF THE INVENTION The present disclosure relates to the treatment of acute respiratory failure with anti-IL33 antibodies, particularly tozorakimab. [Background technology]

[0004] Acute respiratory viral diseases are of great public health importance worldwide, continuing to cause more than 1.5 million deaths annually. Immune-mediated damage resulting from a dysregulated inflammatory response leading to the development of acute respiratory distress syndrome (ARDS) is a major contributor to the severity of lung injury and poor prognosis in respiratory viral diseases. Over the past few decades, several epidemic respiratory viruses, including influenza A H1N1 and H5N1 and the novel coronaviruses MERS-CoV, SARS-CoV, and SARS-CoV-2, have caused significantly higher rates of ARDS and mortality compared with seasonal viruses. The COVID-19 pandemic has caused more than 6 million deaths (as of September 2022), further increasing the need for the development of new and effective therapies to prevent and treat virus-induced ARDS and / or acute respiratory failure (ARF).

[0005] WO 2021 / 204707 discloses the treatment and prevention of ARDS using IL-33 antagonists, including anti-IL-33 antibodies. Tozorakimab was 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

[0006] In a first aspect, the disclosure provides a method of treating or preventing acute respiratory distress syndrome (ARDS) in a subject suffering from or at risk of developing ARDS, the method comprising administering to the subject a dose of 250-350 mg of an anti-IL-33 antibody, wherein the antibody: (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; (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.

[0007] In a second aspect, the disclosure provides a method for treating or preventing acute respiratory failure (ARF) in a subject suffering from or at risk of developing ARF, the method comprising administering to the subject a dose of 250-350 mg of an anti-IL-33 antibody, wherein the antibody: (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; (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.

[0008] In a third aspect, the present disclosure provides a method of treatment for reducing the risk of requiring invasive mechanical ventilation (IMV) or extracorporeal membrane oxygenation (ECMO) in a subject having or at risk of developing ARDS and / or ARF, the method comprising administering to the subject a dose of 250 to 350 mg of an anti-IL-33 antibody, wherein the antibody: (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; (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.

[0009] In a fourth aspect, the present disclosure provides a method of treatment for reducing the risk of a subject having 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 250-350 mg of an anti-IL-33 antibody, wherein the antibody: (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; (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.

[0010] In a fifth aspect, the present disclosure provides a method of treatment for reducing the length of hospitalization in a subject having or at risk of developing ARDS and / or ARF, the method comprising administering to the subject a dose of 250 to 350 mg of an anti-IL-33 antibody, wherein the antibody: (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; (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 sixth aspect, the disclosure provides a method of treating a subject having or at risk of developing ARDS and / or ARF and requiring supplemental oxygen therapy, wherein the treatment reduces the duration of the need for supplemental oxygen therapy, the method comprising administering to the subject a dose of 250-350 mg of an anti-IL-33 antibody, wherein the antibody: (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; (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.

[0012] In a seventh aspect, the present disclosure provides a method of treatment for preventing or reducing the risk of respiratory failure in a subject hospitalized for treatment of a viral pulmonary infection or suspected viral pulmonary infection, the method comprising administering to the subject a dose of 250 to 350 mg of an anti-IL-33 antibody, wherein the antibody: (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; (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.

[0013] In an eighth aspect, the present disclosure provides a method of treating a subject hospitalized with a viral pulmonary infection or suspected viral pulmonary infection, the method comprising administering to the subject a dose of 250 to 350 mg of an anti-IL-33 antibody, wherein the antibody: (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; (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 related aspect, the present 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.

[0015] In a related aspect, the disclosure provides for the use of an anti-IL-33 antibody in the manufacture of a medicament for the treatment or prevention of ARDS or ARF in a subject, wherein the antibody, treatment or prevention, ARDS, ARF, and / or subject are as defined above.

[0016] In a related aspect, the disclosure provides a pharmaceutical composition comprising 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.

[0017] In a related aspect, the disclosure provides an anti-IL-33 antibody for use in treating or preventing respiratory failure in a subject hospitalized for treatment of a viral pulmonary infection or suspected viral pulmonary infection, the treatment comprising administering to the subject a dose of 250 to 350 mg of an anti-IL-33 antibody, wherein the antibody: (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; (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.

[0018] In a related aspect, the disclosure provides an anti-IL-33 antibody for use in treating a viral pulmonary infection or suspected viral pulmonary infection in a subject who is hospitalized for treatment due to a viral pulmonary infection or suspected viral pulmonary infection, the treatment comprising administering to the subject a dose of 250 to 350 mg of an anti-IL-33 antibody, wherein the antibody: (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; (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 OF THE INVENTION

[0019] The present disclosure relates to the use of anti-IL-33 antibodies in the treatment or prevention of diseases and conditions, including acute respiratory distress syndrome (ARDS), acute respiratory failure (ARF), and diagnosed or suspected viral pulmonary infections.

[0020] As used herein, the term "IL-33" refers to interleukin-33, particularly mammalian interleukin-33 protein, generally the human IL-33 protein having UniProt accession number O95760. This entity is not a single species, but instead exists in several forms with different functional activities, e.g., full-length, as well as proteolytically processed or oxidized and reduced forms. Given the rapid oxidation of the reduced form in vivo and in vitro, prior art references to IL-33 are generally likely to relate most to detection of the oxidized form. The terms "IL-33," "IL-33 polypeptide," and "IL-33 protein" are used interchangeably herein.

[0021] IL-33 is a pleiotropic nuclear alarmin cytokine from the IL-1 superfamily. The full-length, reduced form of IL-33 (IL-33 red IL-33 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 lymphoid cells, macrophages, and endothelial cells. The IL-33 / ST2 signaling pathway leads to the production of proinflammatory cytokines, such as IL-6 and granulocyte-macrophage colony-stimulating factor, by these cell types.

[0022] IL-33 is known to be released in response to multiple viral pathogens, including influenza, RSV, HRV, and SARS-CoV-2, which are collectively responsible for the majority of severe viral lung and lower respiratory tract infections. 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 indicate that IL-33 blockade can attenuate 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.

[0023] The term "antibody" is used in the broadest sense and encompasses a variety of antibody structures, including, but not limited to, monoclonal antibodies, polyclonal antibodies, multispecific antibodies (e.g., bispecific antibodies), and antibody fragments, so long as they exhibit the desired antigen-binding activity.

[0024] In some examples, an antibody as used herein may be monoclonal (MAb); recombinant; chimeric; human; antibody variants including single chain and / or bispecific; or derivatives thereof. Antibody antigen-binding fragments include the portion of an antibody that binds to an epitope on a polypeptide of interest. Examples of such fragments include Fab and F(ab') fragments produced by enzymatic cleavage of full-length antibodies. Other binding fragments include those produced by recombinant DNA techniques, such as expression of recombinant plasmids containing nucleic acid sequences encoding antibody variable regions.

[0025] Monoclonal antibodies can be modified for use as therapeutic or diagnostic agents. As used herein, "monoclonal antibody" or "monoclonal antibody composition" refers to polypeptides, including antibodies, bispecific antibodies, etc., having substantially identical amino acid sequences or derived from the same genetic source. The term also includes preparations of antibody molecules of a single molecular composition. A monoclonal antibody composition exhibits a single binding specificity and affinity for a particular epitope. One example is a "chimeric" antibody in which a portion of the heavy (H) and / or light (L) chain is identical to or homologous to corresponding sequences in antibodies from a particular species or belonging to a particular antibody class or subclass, while the remainder of the chains is identical to or homologous to corresponding sequences in antibodies from another species or belonging to another antibody class or subclass. Fragments of such antibodies are also included, so 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.

[0026] Preferably, full-length antibodies are used herein (i.e., not antibody fragments or derivatives). Preferably, antibodies used herein are monoclonal antibodies. Preferably, antibodies used herein are human. Preferably, human monoclonal antibodies are used.

[0027] The antibodies used herein preferably comprise 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 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. However, in some examples, the CDR sequences may be modified or changed relative to those defined in SEQ ID NOs: 1 to 6. For example, VHCDR1, VHCDR2, VHCDR3, VLCDR1, VLCDR2, and / or VLCDR3 may comprise sequences modified by one to three amino acid substitutions, deletions, and / or additions relative to SEQ ID NOs: 1 to 6, respectively.

[0028] The antibodies used herein may comprise a heavy chain variable region comprising the sequence set forth in SEQ ID NO: 7, or an amino acid sequence having at least 80, 85, 90, or 95% sequence identity thereto. When a heavy chain variable region modified relative to SEQ ID NO: 7 is used, the heavy chain CDR sequences are preferably as set forth in SEQ ID NOs: 1-3, although they may be modified or altered as set forth above.

[0029] The antibodies used herein may comprise a light chain variable region comprising the sequence set forth in SEQ ID NO: 8, or an amino acid sequence having at least 80, 85, 90, or 95% sequence identity thereto. When a light chain variable region modified relative to SEQ ID NO: 8 is used, the light chain CDR sequences are preferably as set forth in SEQ ID NOs: 4-6, although they may be modified or altered as set forth above.

[0030] Preferably, the antibody or antigen-binding fragment comprises a heavy chain comprising the amino acid sequence set forth in SEQ ID NO:7 or having at least 80, 85, 90, or 95% sequence identity thereto, and a light chain variable region comprising the amino acid sequence set forth in SEQ ID NO:8 or having at least 80, 85, 90, or 95% sequence identity thereto.

[0031] As used herein, the term "sequence identity" or "identity" refers to a property of sequences that measures their similarity or relationship. As used in this disclosure, the term "sequence identity" or "identity" refers to the percentage of pairwise identical residues, relative to the number of residues in the longer of the two sequences, after (homologous) alignment of a protein or polypeptide sequence 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.

[0032] Those skilled in the art will be aware of available computer programs for determining sequence identity using standard parameters, 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)), the TBLASTN program, Altschul et al. (1990) supra, GAP (Wisconsin GCG package, Accelerys Inc., San Diego, USA), and Smith-Waterman (Smith and Waterman, J. Mol. Biol., 1981). The percentage of sequence identity herein can be determined, for example, using the program BLASTP, version 2.2.5, November 16, 2002 (Altschul et al., Nucleic Acids Res., 1997). In this case, the percentage of homology is based on the alignment of the entire protein or polypeptide sequence containing the polypeptide sequence (matrix: BLOSUM 62; gap cost: 11.1; cutoff value: 10 -3), preferably using the wild-type protein scaffold as a reference in pairwise comparisons. It is calculated as a percentage of the number of "positives" (homologous amino acids) shown as a result of the BLASTP program output divided by the total number of amino acids selected by the program for alignment. Sequence identity is generally 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 resulting from the addition or deletion of amino acids. Generally, default parameters are used, with a gap creation penalty equal to 12 and a gap extension penalty equal to 4.

[0033] Specifically, to determine whether amino acid residues in the amino acid sequence of an anti-IL-33 antibody differ from another antibody sequence, one skilled in the art can use means and methods well known in the art, e.g., alignment, either manually or by using a computer program such as BLAST 2.0, which stands for Basic Local Alignment Search Tool, or Clustal Omega, or any other suitable program suitable for generating sequence alignments.

[0034] When a full-length antibody is used, it can be of any isotype or subclass thereof. Preferably, the antibody is an IgG, such as an IgG1, IgG2, IgG3, or IgG4 antibody. Preferably, the antibody is an IgG1.

[0035] Most preferably, the antibody used in the therapy according to the present disclosure is tozorakimab, which is disclosed in WO 2016 / 156440, which is incorporated herein by reference. Tozorakimab is also known in the art as MEDI3506 and 33_640087_7B. The light chain of tozorakimab has the amino acid sequence set forth in SEQ ID NO:9, and the heavy chain of tozorakimab has the amino acid sequence set forth in SEQ ID NO:10.

[0036] Tozolaximab is a fully human IgG1 monoclonal antibody being developed specifically for the treatment of chronic obstructive pulmonary disease (COPD). Tozolaximab is a human reduced form of IL-33 (IL-33 red ) and binds to IL-33 red Tozorakimab binds to human IL-33 with exceptionally high affinity of approximately 30 fM and inhibits endogenous IL-33. red It completely neutralizes the full-length and all mature forms of IL33 (Scott et al., ERS International Congress 2022, Barcelona (ES), Abstract OA2254). red By binding to ST2, tozolaximab potently inhibits ST2-dependent inflammatory responses in several primary human cells and in an allergen-driven in vivo model of lung epithelial injury. The oxidized form of IL-33 (IL-33) that cannot bind to ST2 is also involved. ox ) signals through the RAGE / EGFR pathway. Tozorakimab inhibits IL-33 ox However, it cannot bind to IL-33, but it inhibits IL-33 via oxidation and the RAGE / EGFR complex. ox This prevents ST2-dependent signaling and mimics the mechanism of action of ST2 (Scott et al., supra). ox Inhibition of signaling can improve airway epithelial repair function and reverse airway epithelial dysfunction in respiratory diseases, including mucus hypersecretion (Scott et al., supra).

[0037] In some instances, the anti-IL-33 antibody has similar or the same pharmacokinetic (pK) characteristics as tozolaximab in humans.

[0038] In particular, anti-IL-33 antibodies may have a half-life in humans similar to or the same as that of tozolaximab. Anti-IL-33 antibodies having a half-life similar to or the same as tozolaximab in humans may have a half-life of about 10 to about 20 days, about 12 to about 15 days, or about 12.7 days when administered at a dose of 30 mg Q2W. Anti-IL-33 antibodies having a half-life similar to or the same as tozolaximab in humans may have a half-life of about 10 to about 20 days, about 12 to about 15 days, or about 13.2 days when administered at a dose of 100 mg Q2W. Anti-IL-33 antibodies having a half-life similar to or the same as tozolaximab in humans may have a half-life of about 10 to about 20 days, about 12 to about 15 days, or about 14.8 days when administered at a dose of 300 mg Q2W.

[0039] In some instances, an IL-33 antibody can competitively inhibit the binding of IL-33 to tozolaximab (tozolaximab is referred to as 33_640087-7B in WO 2016 / 156440). WO 2016 / 156440 discloses that 33_640087-7B (tozolaximab) binds to redIL-33 with particularly high affinity and attenuates both ST-2- and RAGE-dependent IL-33 signaling. An antibody is said to competitively inhibit the binding of a reference antibody to a given epitope if it specifically binds to that epitope to the extent that it blocks, to some extent, the binding of the reference antibody to that epitope. Competitive inhibition can be determined by any method known in the art, such as a solid-phase assay, such as a competitive ELISA assay, a dissociation-promoting lanthanide fluorescence immunoassay (DELFIA®, Perkin Elmer), or a radioligand binding assay. For example, one skilled in the art can determine whether an antibody competes for binding to IL-33 by using an in vitro competitive binding assay (e.g., the HTRF assay described in paragraphs 881-886 of WO 2016 / 156440, incorporated herein by reference). For example, one skilled in the art can label tozolaximab with a donor fluorophore and mix multiple concentrations with a fixed concentration sample of acceptor fluorophore-labeled redIL-33. Subsequently, fluorescence resonance energy transfer between the donor fluorophore and acceptor fluorophore in each sample can be measured to confirm the binding characteristics. To identify competitively binding antibody molecules, one skilled in the art can first mix various concentrations of a test binding molecule with a fixed concentration of labeled tozolaximab antibody. A decrease in FRET signal when the mixture is incubated with labeled IL-33 compared to a positive control of labeled antibody only indicates competitive binding to IL-33. An antibody may be said to competitively inhibit binding of a reference antibody to a given epitope by at least 90%, at least 80%, at least 70%, at least 60%, or at least 50%.

[0040] Therapies disclosed herein include administering a dose of an anti-IL-33 antibody to a subject. The dose is in the range of 250-350 mg (i.e., a flat dose is used rather than a weight-dependent dose). In some cases, the dose may be in the range of 260-340 mg, 270-330 mg, 225-325 mg, 280-320 mg, 285-315 mg, 290-310 mg, or 295-305 mg. Preferably, the dose is at or about 300 mg. Such doses of tozolaximab have been found to be effective in reducing respiratory failure or death in subjects hospitalized with COVID-19, as shown in the Examples below.

[0041] The dosing regimen utilized in the present disclosure may include administration of only a single dose of the antibody, or may include multiple doses (particularly two doses). In certain examples, the therapy of the present disclosure includes administration of a single dose of the antibody to a subject. That is, the therapeutic methods disclosed herein include administering a single dose of the antibody over the course of therapy.

[0042] When multiple doses of antibody are administered, the doses are appropriately spaced apart, i.e., a gap of appropriate length is left between doses.For example, there may be a gap of at least 1 week, or 2, 3, 4, 6, or 8 weeks between each dose.Generally, when multiple doses are administered in the present disclosure, each dose contains the same amount of antibody.In certain examples, the therapy of the present disclosure includes administering two doses of antibody to a subject, and the second dose is administered at least 1 week after the first dose, preferably 2 weeks after the first dose.In some examples, the dosing regimen includes administering the first dose, followed by the optional administration of the second dose 2 weeks later, depending on the clinical condition / progression of the subject.

[0043] In one example, the first dose of the antibody is administered after the subject is hospitalized. In one example, the first dose of the antibody is administered within 12, 24, 48, or 36 hours of the subject's hospitalization. In one example, the first dose of the antibody is administered within 36 hours of the subject's hospitalization. Preferably, the subject's hospitalization can be considered admission to a hospital. In one example, the first dose of the antibody is administered up to about 14 days after the onset of symptoms of a respiratory viral infection.

[0044] In one example, a method of treatment according to the present disclosure includes administering a single dose. In one example, a method of treatment according to the present disclosure includes administering a single 300 mg dose of an antibody (tozorakimab) to a subject.

[0045] The antibody may be administered to the subject by any suitable route. Preferably, the antibody is administered intravenously.

[0046] In one example, a method of treatment according to the present disclosure involves administering a single 300 mg dose of antibody (tozorakimab) intravenously to a subject.

[0047] In one example, a method of treatment according to the present disclosure involves administering a single 300 mg dose of antibody (tozorakimab) intravenously to a subject within 36 hours of hospitalization.

[0048] In one example, a method of treatment according to the present disclosure comprises administering a single 300 mg dose of the antibody (tozorakimab) intravenously to a subject up to about 14 days after the onset of symptoms of a respiratory viral infection.

[0049] The antibody may be administered in a pharmaceutical composition. The pharmaceutical composition may be formulated with suitable carriers, excipients, and other agents that provide suitable transport, delivery, tolerance, etc. Many formulations can be found in the formulary known to every pharmacist: Remington's Pharmaceutical Sciences, Mack Publishing Company, Easton, PA. Thus, in addition to the active ingredient (i.e., anti-IL-33 antibody), a pharmaceutical composition may contain pharmaceutically acceptable excipients, carriers, buffers, stabilizers, or other materials 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 materials will depend on the route of administration, which may be by injection, for example, intravenous or subcutaneous.

[0050] For intravenous injection, the pharmaceutical composition may be a parenterally acceptable aqueous solution that is pyrogen-free and has suitable pH, isotonicity, and stability.

[0051] The pharmaceutical composition may be a liquid formulation or a lyophilized formulation to be reconstituted before use. For example, sugar alcohols or sugars (e.g., mannitol or glucose) can be used as excipients for lyophilized formulations. In the case of a liquid formulation, the pharmaceutical composition is typically provided in the form of a container having a defined volume, including a sealed, sterilized plastic or glass vial, an ampoule, and a syringe, as well as in the form of a large-volume container such as a bottle. Preferably, in the methods described herein, the pharmaceutical composition is a liquid formulation. Preferably, the liquid pharmaceutical composition is provided in a vial. Preferably, the anti-IL-33 antibody may be present in the pharmaceutical composition at a concentration of 100 mg / mL to 200 mg / mL, more preferably 150 mg / mL. In particular, when a 300 mg antibody dose is used, the antibody (particularly tozolaximab) may be provided in 2 mL of a 150 mg / mL liquid composition.

[0052] Preferably, the anti-IL-33 antibody can be buffered to a pH of 5.2 to 5.7, most preferably 5.5 (for example, ±0.1). Selecting such a pH confers significant stability to the pharmaceutical composition.

[0053] It will 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, solubilizing agents, reducing agents, antioxidants, chelating agents, preservatives, etc.

[0054] Preferably, the surfactant is present in the pharmaceutical composition in an amount of 0.001% to 0.1% (w / w). Preferably, the surfactant is polysorbate-80 (PS-80).

[0055] An anti-IL-33 antibody (particularly tozolaximab) may be provided in a pharmaceutical composition containing L-histidine and / or L-histidine hydrochloride, L-arginine hydrochloride, and polysorbate 80. The composition may particularly contain 20 mM ± 10% L-histidine / L-histidine hydrochloride, for example, 20 mM ± 2.5%, 5%, or 7.5% L-histidine / L-histidine hydrochloride. That is, L-histidine / L-histidine hydrochloride may be present in the composition at a concentration of 18 to 22, 18.5 to 21.5, 19 to 21, or 19.5 to 20.5 mM, preferably at a concentration of 20 mM.

[0056] The composition may particularly comprise 220 mM ± 10% L-arginine hydrochloride, e.g., 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 200-240, 205-235, 210-230, or 215-225 mM, preferably at a concentration of 220 mM.

[0057] The composition may in particular comprise 0.03% w / v ± 10% polysorbate 80, for example 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, preferably at a concentration of 0.03% w / v.

[0058] The composition may have a pH of 5.2 to 5.7, 5.3 to 5.6, or 5.4 to 5.5, preferably 5.5.

[0059] In a specific example, the pharmaceutical composition comprises 20 mM L-histidine / L-histidine hydrochloride, 220 mM L-arginine hydrochloride, and 0.03% polysorbate 80, and has a pH of 5.5. Preferably, the pharmaceutical composition also comprises 150 mg / mL tozolaximab. When the composition comprises 150 mg / mL tozolaximab, a 300 mg dose of the antibody can be administered in 2 mL of the composition.

[0060] Following administration of the antibody to the subject, the subject may be administered a saline solution, particularly a saline flush. When the antibody is administered intravenously, it is preferable to include a saline flush to flush the IV line. The saline solution is a sterile physiological solution. Preferably, the saline solution contains 0.9% w / v ± 10% NaCl, e.g., 0.9% w / v ± 2.5%, 5%, or 7.5% NaCl. Preferably, the saline solution has a pH of 5.5 ± 0.1. Preferably, the saline solution contains 0.9% w / v NaCl and has a pH of 5.5. The saline flush may have any suitable volume necessary to flush the IV line, for example, 2 to 10 mL, e.g., 2 to 8, 3 to 7, or 4 to 6 mL, preferably 5 mL.

[0061] Some aspects of the present disclosure are directed to treating subjects suffering from or at risk of developing ARDS and / or ARF, as described above. Acute respiratory distress syndrome (ARDS) is a life-threatening condition in which the lungs are unable to function properly. It is caused by damage to the capillary walls, either by disease or physical injury, such as severe trauma. This results in the walls becoming leaky, fluid accumulation, and eventually the air sacs collapsing, preventing the lungs from exchanging oxygen and carbon dioxide. Acute respiratory failure (ARF), a term often used alongside ARDS, is a broader term that refers to lung failure from any cause, such as chronic obstructive pulmonary disease (COPD).

[0062] Preferably, a subject suffering from ARDS and / or ARF may be defined as a subject who is unable to be adequately ventilated to provide sufficient oxygen to the blood and systemic organs.

[0063] Preferably, a subject suffering from ARDS and / or ARF has one or more of the following symptoms: higher than normal breathing rate, low blood oxygen level, difficulty breathing, shortness of breath, low blood pressure, higher than normal heart rate, chest pain, skin color change, sweating, wheezing, confusion, and fatigue. Preferably, ARDS and / or ARF can be defined as a subject having at least one of the following symptoms: higher than normal breathing rate, low blood oxygen level, difficulty breathing, shortness of breath, and can further include one or more of the following symptoms: low blood pressure, higher than normal heart rate, chest pain, skin color change, sweating, wheezing, confusion, and fatigue.

[0064] Preferably, a subject at risk for ARDS and / or ARF is likely to develop one or more of the following symptoms: higher than normal respiratory rate, low blood oxygen levels, difficulty breathing, shortness of breath, low blood pressure, higher than normal heart rate, chest pain, changes in skin color, sweating, wheezing, confusion, and fatigue. Preferably, a subject at risk for ARDS and / or ARF has few or no such symptoms, but may be at risk for developing additional symptoms. Preferably, a subject at risk for ARDS and / or ARF may have a disease, disorder, condition, or infection identified elsewhere herein that is associated with or may lead to ARDS and / or ARF.

[0065] Preferably, the subject suffering from ARDS and / or ARF may be a subject requiring oxygen or a subject requiring ventilation. In one example, the subject suffering from ARDS and / or ARF is a subject requiring supplemental oxygen or ventilation. In one example of any of the treatment methods described herein, the subject requires supplemental oxygen or ventilation.

[0066] In one example, the subject has or is at risk for acute respiratory failure (ARF). In one example, the subject has or is at risk for hypoxemic (type 1) acute respiratory failure. In one example, the subject has or is at risk for hypercapnic (type 2) acute respiratory failure.

[0067] Preferably, a subject at risk for 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 levels, difficulty breathing, shortness of breath, low blood pressure, higher than normal heart rate, chest pain, changes in skin color, sweating, wheezing, confusion, and fatigue.

[0068] Preferably, the acute respiratory failure (ARF) may be caused by a condition, disease, disorder, or infection, such as a bacterial or viral lung infection. Preferably, the condition, disease, disorder, or infection is a respiratory disease. Preferably, the respiratory disease is a disease affecting the trachea, bronchi, bronchioles, alveolar ducts, and / or alveoli.

[0069] The bacterial or viral respiratory infection associated with ARDS and / or ARF may be selected from tonsillitis, scarlet fever, pharyngitis, laryngitis, diphtheria, angina, Lemmiere's syndrome, tularemia, plague, enteritis, colds, influenza, mononucleosis, HIV infection, pneumonia, preferably viral pneumonia, bronchitis, psittacosis, SARS, MERS, and COVID-19. In one example, the viral respiratory infection is a viral lower respiratory tract infection or disease.

[0070] Preferably, such infections may be caused by the following bacteria or viruses: Streptococcus species, Arcanobacterium haemolyticum, Neisseria gonorrhoeae, Corynebacterium diphtheriae, Fusobacterium necrophorum, Francisella tulareniss, Yersinia pestis, Yersinia enterocolitica, adenovirus species, herpes simplex virus (HSV), HIV, coxsackievirus species, coronavirus species, rhinovirus species, influenza A or B virus, parainfluenza virus, bocapablovirus species, metapneumovirus species, respiratory syncytial virus (RSV), Epstein-Barr virus, cytomegalovirus species, Mycoplasma pneumoniae, Chlamydophla pneumoniae, and Chlamydophla psittaci.

[0071] In one example, the subject suffers from ARDS and / or ARF caused by pneumonia, preferably viral pneumonia. In one example, the subject suffers from or has pneumonia, preferably viral pneumonia. In one example, the subject is at risk of pneumonia or viral pneumonia.

[0072] In one example, the viral pneumonia is caused by COVID-19, preferably resulting from infection with a coronavirus, which may be selected from any of those listed above, preferably infection with SARS-CoV-2. In some examples, the pneumonia is caused by influenza virus A, influenza virus B, 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, the pneumonia is caused by influenza virus A, influenza virus B, respiratory syncytial virus, or human parainfluenza virus.

[0073] Thus, preferably, in some instances, the subject suffers from or has both COVID-19 and viral pneumonia. In some instances, the viral pneumonia is caused by COVID-19 or SARS-CoV-2 infection. In some instances, the subject has COVID-19 and is at risk for viral pneumonia.

[0074] ARDS or ARF in a subject can have any cause, for example, ARDS or ARF can 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-Barré syndrome, myasthenia gravis, poliomyelitis, polymyositis, botulism, hypokalemia, hypophosphatemia, myxedema, hypothyroidism, sepsis, stroke, acute pancreatitis, blood transfusion, reperfusion, drug or alcohol overdose, chest trauma, viral or bacterial infection, airway injury, aspiration, and / or drowning.

[0075] In certain instances, the subject has (i.e., has been diagnosed with) or is suspected of having a viral pulmonary infection (i.e., a viral infection of the lungs). In certain instances, the subject has (i.e., has been diagnosed with) or is suspected of having a viral lower respiratory tract infection or disease.

[0076] Diagnosis of viral pulmonary infections can be made by any means known in the art, such as nucleic acid amplification tests (e.g., using PCR or RT-PCR) or antigen tests (e.g., using a lateral flow test device). As used herein, "diagnosis" refers to positive confirmation of a viral infection by a test, e.g., a clinical trial. A diagnosed viral pulmonary infection can be contrasted with a suspected pulmonary infection. A subject is suspected of having a pulmonary infection when the examining physician believes the subject has a pulmonary infection (e.g., due to signs or symptoms at the time of presentation) but has not confirmed this with a diagnostic test, for example, because test results are awaited, comparisons are unavailable or failed, or the infectious agent cannot be identified. Generally, when a subject has or is suspected of having a viral pulmonary infection, the viral pulmonary infection is the cause of, or puts the subject at risk for developing, ARDS or ARF, which are treated according to the present disclosure.

[0077] As noted above, in certain aspects of the present disclosure, the subject has or is suspected of having a viral pulmonary infection.

[0078] The viral pulmonary infection can be caused by any known viral respiratory pathogen. For example, the viral pulmonary 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 particular example, the viral pulmonary infection is caused by SARS-CoV-2, i.e., the subject has COVID-19. In another example, the viral pulmonary infection is not caused by SARS-CoV-2, i.e., a virus other than SARS-CoV-2 is the causative agent of the infection.

[0079] In another specific example of the present disclosure, the viral pulmonary infection is caused by an influenza virus. Any influenza virus, particularly influenza A or B virus, can be the cause. The influenza A virus can be a seasonal influenza subtype, such as seasonal H1N1 or H3N2 subtype. Alternatively, the influenza A virus can be a non-human (e.g., avian) strain or a pandemic strain, such as H5Nx (e.g., H5N1) or H7N9.

[0080] In another specific example of the present disclosure, the viral pulmonary infection is caused by respiratory syncytial virus (RSV). In another example, the viral pulmonary infection is caused by human metapneumovirus (HMPV).

[0081] In other examples, the viral pulmonary infection is caused by human parainfluenza virus, adenovirus, hantavirus, herpes simplex virus, varicella zoster virus, measles virus, rubella virus, cytomegalovirus, smallpox virus, or dengue virus.

[0082] The subject may be hospitalized at the time the anti-IL-33 antibody is administered. That is, the subject may be in a hospital. Hospitalization generally results from the fact that the subject has ARDS or ARF, or a condition that places the subject at risk for developing ARDS or ARF. A subject is generally hospitalized with (suspected of) a viral lung infection if the subject has or is suspected of having a viral lung infection (indeed, some aspects of the present disclosure are directed to treating subjects hospitalized with a viral lung infection). In one example, the subject is hospitalized.

[0083] In one example of any of the methods described herein, the subject has or is suspected of having a viral lower respiratory tract infection and may optionally be hospitalized and / or may optionally require supplemental oxygen or ventilation. In one example of any of the methods described herein, the subject has a viral lower respiratory tract infection, is hospitalized, and requires supplemental oxygen or ventilation.

[0084] If the subject is hospitalized due to ARDS or ARF, or a condition that places the subject at risk for developing ARDS or ARF (e.g., a viral lung infection), the anti-IL-33 antibody is preferably administered within 36 hours of the subject's admission to the hospital (i.e., the anti-IL-33 antibody is suitably administered to the subject within 36 hours of the subject's admission to the hospital). Preferably, the anti-IL-33 antibody is administered to the subject within 30, 24, 18, 12, or 6 hours of the subject's admission to the hospital.

[0085] When a subject has a viral pulmonary infection and is at risk of respiratory failure (e.g., ARDS or ARF) due to the infection, the anti-IL-33 antibody is preferably 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. Preferably, the anti-IL-33 antibody is administered to the subject within 14 days after the onset of the first symptom of the viral pulmonary infection. In other examples, the anti-IL-33 antibody is administered to the subject within 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, or 3 days after the onset of the first symptom of the viral pulmonary infection.

[0086] Generally, a subject has hypoxemia and therefore requires supplemental oxygen (i.e., oxygen therapy). Hypoxemia is a condition in which arterial blood is deficient in oxygen. Hypoxemia can be easily diagnosed by a physician. In certain instances, hypoxemia is diagnosed when a subject has an SpO2 (blood oxygen saturation) of 94% or less on room air (i.e., air with atmospheric levels of O2, as opposed to oxygen-enriched air), (ii) is receiving oxygen therapy but had an SpO2 of less than 94% before the start of oxygen therapy, and / or (iii) is receiving at least 6 L / min (e.g., more than 6 L / min) of supplemental oxygen / or non-invasive ventilation. In some instances, hypoxemia is diagnosed when a subject has an SpO2 of 90% or less, or an SpO2 of 92%, and one or both of the following: (i) radiographic infiltrates on a chest X-ray / CT scan compatible with a viral lung infection, as determined by the investigator, or (ii) accessory muscle use or a respiratory rate of >22 / min.

[0087] As will be appreciated from the above, the subject is preferably a human patient.

[0088] The therapies disclosed herein can reduce the risk of a subject at risk of respiratory failure, e.g., ARDS and / or ARF, developing respiratory failure, e.g., ARDS and / or ARF. For example, the therapies disclosed herein can reduce the risk of such a subject developing respiratory failure, e.g., ARDS and / or ARF, by at least 5, 10, 15, 20, 25, 30, 35, 40, 45, or 50%. Similarly, the therapies disclosed herein can reduce the risk of a subject developing pneumonia, for example, by at least 5, 10, 15, 20, 25, 30, 35, 40, 45, or 50%. The therapies disclosed herein may reduce the risk of developing respiratory failure, ARDS, ARF, and / or pneumonia by the recited amounts for a particular period of time following administration of an anti-IL-33 antibody (or a first dose of an anti-IL-33 antibody), e.g., for a period of 14, 28, 42, 56, or 60 days following administration of an anti-IL-33 antibody, particularly for 28 or 60 days following administration of an anti-IL-33 antibody.

[0089] The therapies disclosed herein may improve the survival prospects of subjects suffering from or at risk of developing respiratory failure, e.g., ARDS and / or ARF. For example, the therapies disclosed herein may reduce the risk of such subjects dying from respiratory failure, e.g., ARDS or ARF, by at least 5, 10, 15, 20, 25, 30, 35, 40, 45, or 50%. In particular, the therapies disclosed herein may so reduce the risk of a subject dying from respiratory failure, e.g., ARDS or ARF, over a period of, e.g., 14, 28, 42, 56, or 60 days after administration of an anti-IL-33 antibody, particularly over a period of 28 or 60 days after administration of an anti-IL-33 antibody.

[0090] That is, the therapies disclosed herein can treat or prevent respiratory failure, such as ARDS and / or ARF, in a subject. In the situation of a subject suffering from or at risk of respiratory failure due to a viral pulmonary infection, the therapies disclosed herein can be considered to treat the viral pulmonary infection. The therapies disclosed herein can also limit the severity of respiratory failure, such as ARDS and / or ARF, in a subject, so that less hospitalization or intense or invasive hospitalization treatment is required. In particular, they can reduce the need for care in an intensive care unit (ICU) and / or reduce the need for invasive mechanical ventilation (IMV) or extracorporeal membrane oxygenation (ECMO).

[0091] In particular, the therapies disclosed herein may reduce the risk of requiring IMV and / or ECMO in a subject having 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 may so reduce the risk of a subject requiring IMV and / or ECMO over a period of, e.g., 14, 28, 42, 56, or 60 days after administration of an anti-IL-33 antibody, particularly over 28 or 60 days after administration of an anti-IL-33 antibody.

[0092] The therapies disclosed herein may reduce the risk of a subject having or at risk of developing ARDS and / or ARF requiring admission to an intensive care unit (ICU) by at least 5, 10, 15, 20, 25, 30, 35, 40, 45, or 50%. In particular, the therapies disclosed herein may so reduce the risk of a subject requiring ICU admission, for example, over a period of 14, 28, 42, 56, or 60 days after administration of an anti-IL-33 antibody, particularly over a period of 28 or 60 days after administration of an anti-IL-33 antibody.

[0093] When a subject having or at risk of developing ARDS and / or ARF requires admission to an ICU, the therapies disclosed herein may reduce the subject's required length of stay in the ICU, particularly by at least 5, 10, 15, 20, 25, 30, 35, 40, 45, or 50%. Alternatively, the therapies disclosed herein may reduce the subject's required length of stay in the ICU by at least 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 days. In this case, the subject's required ICU stay may be the average required ICU stay of a group of subjects all having or at risk of developing ARDS and / or ARF. Such a reduction in required ICU stay may be, for example, over a period of 14, 28, 42, 56, or 60 days after administration of the anti-IL-33 antibody, particularly 28 or 60 days after administration of the anti-IL-33 antibody.

[0094] Similarly, the therapies disclosed herein may increase the number of days a subject is alive and out of the ICU 60 days after administration of an anti-IL-33 antibody. The number of days a subject is alive and out of the ICU may increase by at least 10, 20, 30, 40, 50, 60, 70, 80, 90, or 100% or more. Alternatively, the number of days a subject is alive and out of the ICU may increase by at least 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, or 55 days. In this case, the number of days a subject is alive and out of the ICU may be the average number of days for a group of subjects who all have or are at risk of developing ARDS and / or ARF.

[0095] The therapies disclosed herein can increase the number of days a subject with or at risk of developing ARDS and / or ARF remains alive and free of supplemental oxygen 60 days after administration of an anti-IL-33 antibody. The number of days a subject remains alive and free of supplemental oxygen may be increased by at least 10, 20, 30, 40, 50, 60, 70, 80, 90, or 100% or more. Alternatively, the number of days a subject remains alive and free of supplemental oxygen may be increased by at least 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, or 55 days. In this case, the number of days a subject remains alive and free of supplemental oxygen may be the average number of days for a group of subjects who all have or are at risk of developing ARDS and / or ARF.

[0096] Relatedly, the therapies disclosed herein may reduce the duration of oxygen supplementation therapy in a subject who has or is at risk of developing ARDS and / or ARF and requires supplemental oxygen therapy, particularly by at least 5, 10, 15, 20, 25, 30, 35, 40, 45, or 50%. Alternatively, the therapies disclosed herein may reduce the duration of oxygen supplementation therapy by at least 2, 4, 6, 8, 10, 12, 14, 16, 18, or 20 days. In this case, the subject's duration of oxygen supplementation therapy may be the average duration of oxygen therapy requirement for a group of subjects all of whom have or are at risk of developing ARDS and / or ARF. Such a reduction in the duration of oxygen supplementation therapy requirement may be, for example, over a period of 14, 28, 42, 56, or 60 days after administration of an anti-IL-33 antibody, particularly 28 or 60 days after administration of an anti-IL-33 antibody.

[0097] As used herein, the terms "oxygen therapy," "supplemental oxygen," and "supplemental oxygen therapy" are interchangeable.

[0098] The therapies disclosed herein may reduce the duration of hospitalization in a subject having or at risk of developing ARDS and / or ARF, particularly by at least 5, 10, 15, 20, 25, 30, 35, 40, 45, or 50%. Alternatively, the therapies disclosed herein may reduce the duration of hospitalization by at least 2, 4, 6, 8, 10, 12, 14, 16, 18, or 20 days. In this case, the subject's duration of hospitalization may be the average duration of hospitalization for a group of subjects all having or at risk of developing ARDS and / or ARF. Such a reduction in the duration of hospitalization may be, for example, over a period of 14, 28, 42, 56, or 60 days after administration of the anti-IL-33 antibody, particularly 28 or 60 days after administration of the anti-IL-33 antibody.

[0099] The therapies disclosed herein may increase the chances of a subject having or at risk of developing ARDS and / or ARF being discharged from the hospital alive, e.g., by at least 10, 20, 30, 40, 50, 60, 70, 80, 90, or 100% or more. Such an increase in the chances of a subject being discharged from the hospital alive may be, for example, over a period of 14, 28, 42, 56, or 60 days after administration of the anti-IL-33 antibody, particularly 28 or 60 days after administration of the anti-IL-33 antibody.

[0100] The therapies disclosed herein may reduce the risk of a subject who has or is at risk of developing ARDS and / or ARF and who is initially discharged alive from the hospital requiring readmission to the hospital within 28 or 60 days of administration of an anti-IL-33 antibody. Such risk may be reduced, for example, by at least 5, 10, 15, 20, 25, 30, 35, 40, 45, or 50%.

[0101] When a subject has a viral lung infection caused by SARS-CoV-2 (i.e., the subject has COVID-19), the therapies disclosed herein may reduce or prevent disease progression as defined by the WHO 10-point clinical progression scale for COVID-19, or may result in an improvement in the subject's condition as defined by the clinical progression scale. For example, the treatment may increase the likelihood of the subject having a score of less than 7, 6, 5, 4, or 3 according to the WHO 10-point clinical progression scale for COVID-19 at 28 or 60 days after administration of anti-IL-33, or may enable the subject to more quickly reach a score of less than 7, 6, 5, 4, or 3 according to the scale. The WHO 10-point clinical progression scale for COVID-19 is shown below:

[0102] [Table 1]

[0103] If treatment with an IL-33 antibody reduces the risk associated with ARDS / ARF or improves recovery from ARDS / ARF in the manner described above, the reduction or improvement occurs compared to a control patient population having the same condition as the subject but not administered the anti-IL-33 antibody (or fragment thereof). The control patient population receives standard treatment for the condition, except for the anti-IL-33 antibody. That is, the control patient population receives the same medical care as the subject, except for the anti-IL-33 antibody. Thus, the improvement in clinical outcomes described above is a direct result of administering the antibody (or fragment thereof) to the subject.

[0104] The present disclosure may be further understood from the following non-limiting examples and figures. [Brief explanation of the drawings]

[0105] [Figure 1]Study design (TILIA) of a Phase III, multicenter, randomized, double-blind, parallel-group, placebo-controlled study to evaluate the efficacy and safety of tozorakimab (MEDI3506) in patients hospitalized with viral pulmonary infections requiring supplemental oxygen. [Example]

[0106] Example 1 - ACCORD2: A Multicenter, Seamless, Phase 2 Adaptive Randomized Platform Study to Evaluate the Efficacy and Safety of Multiple Candidate Agents for the Treatment of COVID-19 in Hospitalized Patients research design The objective of the study was to evaluate the efficacy and safety of tozorakimab 300 mg IV plus SoC compared with SoC alone in hospitalized adults with SARS-CoV-2 (COVID-19) infection with a WHO 8-point ordinal clinical progression scale score of 3, 4, or 5 (see Table 1).

[0107] In this study, MEDI3506 (tozolaximab) was administered to patients as a single 300 mg IV dose. If a patient was invasively ventilated on or before Day 15 but after randomization and remained invasively ventilated on Day 15, they received a second dose of 300 mg IV tozolaximab. The 300 mg IV tozolaximab dose is predicted to have a >47-fold margin of safety for both the maximum observed concentration and the area under the concentration-time curve (AUC) relative to exposure at the no observed adverse effect level (150 mg / kg) based on a 4-week good laboratory practice toxicity study.

[0108] A total of 103 patients were randomized to either tozorakimab plus standard of care (SoC) (n = 56) or SoC alone (n = 47). Three patients in the SoC alone group were randomized after the tozorakimab substudy was completed, and two patients were randomized to tozorakimab plus SoC but did not receive it. These patients were excluded from the safety analysis and full analysis set. One patient received tozorakimab but did not have any post-baseline ordinal scale data and was therefore excluded from the full analysis set. A total of 98 patients in the safety analysis set received either tozorakimab plus SoC (n = 54) or SoC alone (n = 44).

[0109] In the safety analysis set, demographic characteristics were well balanced across treatment groups. The majority of patients were male (37 patients [68.5%] vs. 29 patients [65.9%] for tozoraximab plus SoC vs. SoC alone) and middle-aged or older (mean [SD] for tozoraximab plus SoC vs. SoC alone: ​​55.4 years [12.51] vs. 58.0 years [13.90]). A higher proportion of patients had diabetes and ≥2 comorbidities in the tozoraximab plus SoC group (diabetes: 22 patients [40.7%]; ≥2 comorbidities: 21 patients [38.9%]) compared with the SoC alone group (diabetes: 13 patients [29.5%]; ≥2 comorbidities: 13 patients [29.5%]). Standard care evolved during the study treatment period, with increased use of dexamethasone and remdesivir and the addition of tocilizumab later in the study. The primary endpoint of time to sustained clinical response was defined as a ≥2-point improvement on an ordinal scale by day 29 leading to discharge from the hospital or being deemed fit for discharge, whichever occurred first. The WHO 8-point ordinal clinical progress scale was used, as recommended by the WHO at the time the study was designed (Table 1).

[0110] [Table 2] Research results

[0111] Primary endpoint Based on the hazard ratios for time to sustained clinical response, no statistically significant differences were observed between treatment groups (Table 2).

[0112] The benefit of tozolaximab was observed not in the speed of hospital discharge, as many patients were able to be treated successfully promptly, but rather in the prevention of morbidity or mortality in patients who were unable to be discharged promptly (see "Key Secondary Endpoints" below).

[0113] [Table 3] a Patients who died before day 29 or who had not responded by day 29 were censored at day 29. b Kaplan-Meier product limit estimators are provided, and 80% CIs were calculated according to Brookmeyer and Crowley. c Hazard ratios were calculated from Cox proportional hazards models after adjusting for age, treatment, and binary baseline ordinal score as covariates. A hazard ratio >1 indicates a treatment effect in favor of tozorakimab. CI = confidence interval.

[0114] Key secondary endpoints 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 tozolaximab + SoC group had lower odds of death or respiratory failure by day 29 compared with SoC alone (Table 3).

[0115] Patients in the tozoraximab group had lower odds of mortality by day 29 in the tozoraximab + SoC group compared with SoC alone (Table 4).

[0116] On a relative basis, patients experienced approximately one-third of the risk for both endpoints. Neither finding was statistically significant; however, this was a small pilot study to identify potential treatments and did not prospectively measure these endpoints. These findings suggest the possibility of a clinically meaningful benefit with tozorakimab, and further study is warranted.

[0117] [Table 4] a Calculated from a logistic regression model adjusting for age and baseline severity. CI = confidence interval, NA = not applicable, SoC = standard of care.

[0118] [Table 5] a Calculated from a logistic regression model adjusting for age and baseline severity. CI = confidence interval, NA = not applicable, SoC = standard of care.

[0119] Example 2 - A Phase III, multicenter, randomized, double-blind, parallel-group, placebo-controlled study (TILA) to evaluate the efficacy and safety of tozolaximab (MEDI3506) in patients hospitalized with viral pulmonary infections requiring supplemental oxygen. Overall study design This is a Phase III, multicenter, randomized, double-blind, parallel-group, placebo-controlled study to evaluate the efficacy and safety of tozolaximab in patients hospitalized with viral lung infections requiring supplemental oxygen to reduce the risk of progression to acute respiratory distress syndrome or death.

[0120] The primary outcome is the proportion of participants who die or progress to invasive mechanical ventilation (IMV) / extracorporeal membrane oxygenation (ECMO) by day 28. Study interventions will occur 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 site visit will occur on day 60.

[0121] The study initially plans to randomize approximately 2,352 participants (i.e., 1,176 per treatment group), but the final sample size will be determined by the number of events. Randomization will be stratified by known viral positivity at randomization (SARS-CoV-2 vs. other viruses vs. indeterminate) and region. The study will accrue participants with a confirmed viral positivity from a baseline sample (known before or after randomization) until approximately 375 primary endpoint events are observed. At least 60% of participants are expected to have a confirmed positive viral test at randomization, which is intended to represent at least approximately 75% of all viral positivity cases (including retrospectively confirmed cases) in the study population. Participants will be randomized in a 1:1 ratio to receive tozolaximab 300 mg or matching placebo administered intravenously (IV infusion) within 36 hours of hospital admission.

[0122] Participants will receive a single dose of the study intervention (tozorakimab 300 mg or placebo) administered by IV injection, followed by a 5 mL saline flush.

[0123] Participants' vital signs and WHO Clinical Progression Scale will be assessed and recorded once daily during their hospital stay.

[0124] The study intervention will be administered in addition to SoC treatment, and participants will continue to receive SoC based on local guidelines throughout the study.

[0125] Figure 1 shows a schematic diagram of the study design.

[0126] Dose justification Tozorakimab will be administered to participants as a single 300 mg IV injection, followed by a 5 mL saline flush.

[0127] Preclinical and clinical safety and efficacy data generated with tozolaximab provide a positive risk / benefit ratio for the clinical program in adults hospitalized with acute viral infections requiring supplemental oxygen and at risk of developing ARDS.

[0128] This dose and route of administration, in addition to SoC, was tested in the ACCORD-2 study in patients with COVID-19 and demonstrated a 32% numerical reduction in the proportion of participants who died or experienced respiratory failure by day 29 relative to SoC alone (Example 1). There were no safety findings in this study that would preclude further development of this drug. Additionally, a single 300 mg IV injection of tozolaximab was the highest dose initially tested in a human single-ascending-dose study conducted in healthy participants with a history of mild atopy, with a favorable safety and tolerability profile.

[0129] Objectives, Endpoints, and Estimands The objectives and endpoints are shown in Table 5.

[0130] [Table 6] a Multiplicity-controlled statistical analyses will also be performed using the full analysis set. b In addition to death, associated complications include receiving additional treatment, changing background treatment, or changing care setting. c All secondary endpoints, except PK, will be analyzed in both the confirmed virus positive analysis set and the full analysis set. ADA = Anti-drug antibody, AE = Adverse event, ECG = Electrocardiogram, ED = Emergency department, ECMO = Extracorporeal membrane oxygenation, ER = Emergency room, HRCU = Healthcare resource utilization, ICU = Intensive care unit, IMV = Inter-module ventilation, PK = Pharmacokinetic, SAE = Serious adverse event, SoC = Standard of care, WHO = World Health Organization.

[0131] Study population Inclusion criteria Participants were eligible for inclusion in the study only if all of the following criteria applied: Age: 1. Adult participants aged 18 years or older at the time of signing the ICF. Participant type and disease characteristics: 2. Patients hospitalized with a viral pulmonary infection. Note: Suspicion of a viral etiology is acceptable to meet this criterion. Hypoxemia requiring treatment with O2 supplementation consistent with a WHO Clinical Progression Scale of Disease Progression scores of 3.5 and 6. Note: Hypoxemia is defined as SpO2 ≤ 90% or SpO2 ≤ 92% and one or both of the following: a. Radiographic infiltrates on chest x-ray / CT scan compatible with viral pulmonary infection as determined by the investigator. b. Accessory muscle use or respiratory rate >22 / min. Note: Patients receiving oxygen >6 L / min or noninvasive ventilation were considered to meet this inclusion criterion regardless of SpO2 level. Documented pre-hospital SpO2 (related to the episode), e.g., from the emergency department report, is acceptable. 4. Within 36 hours of admission to the hospital. 5. Within 14 days of the onset of symptoms of a respiratory viral infection.

[0132] Exclusion criteria Participants will be excluded from the study if any of the following criteria apply:

[0133] medical conditions 1. Known fungal or parasitic lung infection, aspiration pulmonary infection, lung abscess, or pulmonary sepsis. Bacterial co-infection is permitted as long as, in the investigator's opinion, the bacterial infection does not define the severity of the participant's condition. 2. Hypoxemia caused primarily by extrapulmonary injury (e.g., multiple organ failure, shock, or sepsis) or extrapulmonary insult of non-infectious etiology (e.g., trauma, chemical injury, etc.). 3. Ongoing or impending IMV / ECMO at the time of randomization. 4. Any coexisting condition that, in the investigator's opinion, is likely to result in death within 3 months of randomization. 5. Anticipated recovery and discharged from hospital within 24 hours of randomization. 6. Active tuberculosis defined as requiring current treatment. 7. Known unstable cardiovascular disease that, in the investigator's judgment, may place the participant at risk or adversely affect study outcome (e.g., unstable chronic heart failure NYHA III-IV, recent myocardial infarction or stroke within 3 months, or uncontrolled ventricular arrhythmias). 8. Known absolute neutrophil count ≤ 1.0 × 109 / L. 9. Known untreated HIV. Known history of active hepatitis B or C (treated and controlled hepatitis is acceptable). 10. Known history of active severe inflammatory bowel disease or colitis (including Crohn's disease or ulcerative colitis). 11. The following malignant tumors: a. Solid tumor with metastasis (stage IV). b. Lymphoma / leukemia not in complete remission. c. Malignant tumors treated with chemotherapy and / or immunomodulatory agents within the past 2 months. 12. Transplant patients at risk of organ rejection or receiving long-term immunosuppressive therapy for transplant. Corticosteroid therapy is permitted. 13. Any disorder that is not stable in the opinion of the investigator, including but not limited to cardiovascular, gastrointestinal, hepatic, renal, neurological, musculoskeletal, infectious (including risk factors for viral pulmonary infections), endocrine, metabolic, hematological, immune, psychiatric, or major somatic disorder; - Affecting the participant's safety throughout the study, -Affect the findings of the study or their interpretation; - May interfere with the participant's ability to complete the full duration of the study.

[0134] Upfront / concomitant therapy 14. Use of long-term oxygen therapy for pre-existing conditions. 15. Chronic treatment with TNF inhibitors, Janus kinase inhibitors, or interferon-gamma, with a washout period of 4 weeks or 5 half-lives (whichever is longer) required prior to enrollment. 16. Current treatment with any investigational drug, with a washout period of 4 weeks or half-life (whichever is longer) required prior to enrollment. 17. Participants who have previously received tozoraximab. 18. Known medical history of: - Anaphylaxis to any other biologic therapy, - Severe reaction to any drug, including biologic agents or human gamma globulin therapy, - Allergy or reaction to any component of the study intervention formulation.

[0135] [Table 7]

Claims

1. A pharmaceutical composition for treating or preventing acute respiratory distress syndrome (ARDS) in a subject who has ARDS or is at risk of developing ARDS, comprising an anti-IL-33 antibody, wherein the treatment or prevention comprises administering a dose of 250 to 350 mg of the anti-IL-33 antibody to the subject, and the anti-IL-33 antibody is (a) A heavy chain variable region including VHCDR1 having the sequence of SEQ ID NO: 1, VHCDR2 having the sequence of SEQ ID NO: 2, and VHCDR3 having the sequence of SEQ ID NO: 3, (b) The pharmaceutical composition comprising a light chain variable region having a sequence of sequence number 4, a VLCDR2 having a sequence of sequence number 5, and a VLCDR3 having a sequence of sequence number 6.

2. A pharmaceutical composition for treating or preventing acute respiratory failure (ARF) in a subject suffering from or at risk of developing ARF, comprising an anti-IL-33 antibody, wherein the treatment or prevention comprises administering a dose of 250 to 350 mg of the anti-IL-33 antibody to the subject, and the anti-IL-33 antibody is (a) A heavy chain variable region including VHCDR1 having the sequence of SEQ ID NO: 1, VHCDR2 having the sequence of SEQ ID NO: 2, and VHCDR3 having the sequence of SEQ ID NO: 3, (b) The pharmaceutical composition comprising a light chain variable region having a sequence of sequence number 4, a VLCDR2 having a sequence of sequence number 5, and a VLCDR3 having a sequence of sequence number 6.

3. The aforementioned anti-IL-33 antibody, A heavy chain variable region comprising the sequence of Sequence ID No. 7, or an amino acid sequence having at least 80% sequence identity thereto, A light chain variable region comprising the sequence of Sequence ID No. 8, or an amino acid sequence having at least 80% sequence identity thereto, A pharmaceutical composition according to claim 1 or 2, comprising:

4. The pharmaceutical composition according to claim 1 or 2, wherein the anti-IL-33 antibody is tozolakimab.

5. The pharmaceutical composition according to claim 1 or 2, wherein the anti-IL-33 antibody is administered intravenously to the subject.

6. The pharmaceutical composition according to claim 1 or 2, wherein the dose of the anti-IL-33 antibody is 300 mg.

7. The pharmaceutical composition according to claim 1 or 2, wherein a single dose of the anti-IL-33 antibody is administered to the subject.

8. The pharmaceutical composition according to claim 1 or 2, wherein the subject has or is suspected of having a viral lung infection.

9. The pharmaceutical composition according to claim 1 or 2, wherein the subject has or is suspected of having a viral lower respiratory tract infection or viral lower respiratory tract disease.

10. The aforementioned viral lung infection, (i) Caused by coronaviruses such as SARS-CoV-2, (ii) Is it not a SARS-CoV-2 infection? (iii) Caused by influenza viruses such as influenza virus A or influenza virus B, (iv) Caused by RSV, or (v) The pharmaceutical composition according to claim 8, which is caused by human metapneumovirus (HMPV).

11. The aforementioned subject is, (i) hospitalized or (ii) The pharmaceutical composition according to claim 8, wherein the patient is hospitalized and receiving treatment for a viral lung infection or suspected viral lung infection.

12. The pharmaceutical composition according to claim 11, wherein the subject is hospitalized and receiving treatment for (i) a viral lower respiratory tract infection or viral lower respiratory tract disease, or (ii) a suspected viral lower respiratory tract infection or viral lower respiratory tract disease.

13. The pharmaceutical composition according to claim 11, wherein the anti-IL-33 antibody is administered to the subject within approximately 36 hours after the subject is admitted to the hospital.

14. The pharmaceutical composition according to claim 8, wherein the anti-IL-33 antibody is administered to the subject within approximately 14 days after the onset of symptoms of viral lung infection in the subject.

15. The subject in question (i) requires oxygen supplementation or ventilation, (ii) The pharmaceutical composition according to claim 1 or 2, which has hypoxemia and requires oxygen supplementation.

16. The pharmaceutical composition according to claim 1 or 2, wherein the subject has a viral lower respiratory tract infection or viral lower respiratory tract disease, is hospitalized for treatment, and requires oxygen supplementation or ventilation.

17. A pharmaceutical composition for use in the treatment of a subject who is hospitalized and receiving treatment for a viral lung infection or suspected viral lung infection, comprising administering an anti-IL-33 antibody in a dose of 250 to 350 mg to the subject, wherein the anti-IL-33 antibody is (a) A heavy chain variable region including VHCDR1 having the sequence of SEQ ID NO: 1, VHCDR2 having the sequence of SEQ ID NO: 2, and VHCDR3 having the sequence of SEQ ID NO: 3, (b) The pharmaceutical composition comprising a light chain variable region having a sequence of sequence number 4, a VLCDR2 having a sequence of sequence number 5, and a VLCDR3 having a sequence of sequence number 6.

18. The anti-IL-33 antibody is A heavy chain variable region comprising the sequence of Sequence ID No. 7, or an amino acid sequence having at least 80% sequence identity thereto, A light chain variable region comprising the sequence of Sequence ID No. 8, or an amino acid sequence having at least 80% sequence identity thereto, A pharmaceutical composition according to claim 17, comprising:

19. The pharmaceutical composition according to claim 17, wherein the anti-IL-33 antibody is tozolakimab.

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