Treatment of chronic sinusitis with anti-TSLP antibodies

Abstract

The present disclosure relates generally to methods of treating chronic rhinosinusitis with or without nasal polyps using antibodies specific for thymic stromal lymphopoietin (TSLP).

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of priority to U.S. Provisional Patent Application Nos. 63 / 483,000, filed February 2, 2023, and 63 / 503,087, filed May 18, 2023, each of which is incorporated by reference in its entirety.

[0002] Incorporation by Reference of Electronically Submitted Materials A sequence listing, which is part of this disclosure, is submitted herewith as a text file. The name of the text file containing the sequence listing is "58714_SeqListing.xml", it was created on January 23, 2024, and it is 15,609 bytes in size. The contents of the sequence listing are incorporated herein by reference in their entirety.

[0003] The present disclosure relates generally to methods of treating chronic rhinosinusitis with or without nasal polyps using antibodies specific for thymic stromal lymphopoietin (TSLP). [Background technology]

[0004] Chronic rhinosinusitis with nasal polyposis (CRSwNP) is a chronic, heterogeneous inflammatory state of the nasal and sinonasal mucosa (Fokkens et al., 2020). While the underlying etiology of the disease is currently unknown, type 2 (T2)-driven inflammation has recently been shown to be a key process in CRSwNP, and therapeutic agents targeting T2 inflammation have demonstrated efficacy in CRSwNP (Gevaert et al., 2011; Bachert et al., 2016; Bachert et al., 2017; Bachert et al., 2019; Gevaert et al., 2020). CRSwNP is strongly associated with asthma based on epidemiological, pathophysiological, and clinical evidence, supporting the "united airway" concept for chronic inflammatory diseases of the upper and lower airways. Both diseases are co-morbid conditions (Hakansson K et al., 2015).

[0005] Compared to non-asthmatics, asthmatics have a higher prevalence of CRS and CRSwNP and a higher severity of sinusitis (Jarvis D et al., 2012; Seybt MW et al., 2007; Pearlman AN et al., 2009; Tint D et al., 2016; Settipane GA, 1977). Furthermore, asthmatic subjects with CRSwNP may have poorly controlled asthma, increased airway obstruction, and more severe lower airway inflammation compared to subjects without CRSwNP (Bilodeau L et al., 2010). Coexisting asthma in CRSwNP patients is associated with a lower quality of life (Alobid I et al., 2005; Ehnhage A et al., 2009). Mechanistically, both NP and severe eosinophilic asthma are considered to be diseases caused by type 2 (T2), and the inflammatory profile is similar between the upper airways in NP and the lower airways in asthma (Fokkens et al., 2020, Chaaban MR et al., 2013). As in asthma, the role of eosinophils is thought to be important in the pathology of NP in a high proportion of patients.

[0006] Nasal polyps are an area of ​​significant unmet medical need, particularly for the subset of NP patients who have exhausted current treatment options, including medical interventions (intranasal corticosteroids (INCS), systemic corticosteroids (SCS), and antibiotics) and surgical intervention. Both patients and healthcare professionals point to a greater need for novel therapies that reduce the need for repeated SCS or surgery for all NP patients. While surgery to remove polyps is still considered in patients whose symptoms are not controlled with corticosteroids, recurrence rates are high (approximately 40% 12 months after surgery), and repeat surgical intervention is often required. INCS continues after surgery; nevertheless, even when treated with currently available therapies, a proportion of patients experience recurrence after surgery, and these participants are at even higher risk of recurrence if they undergo further surgery (Fokkens et al., 2020; Orlandi RR et al., 2013; Agarwal et al., 2019; van der Veen et al., 2017).

[0007] Thymic stromal lymphopoietin (TSLP), an epithelial cell-derived cytokine produced in response to environmental and proinflammatory stimuli, leads to the activation of multiple inflammatory cells and downstream pathways (Soumelis et al., 2002; Allakhverdi et al., J Exp Med 2007;204:253-8). TSLP is elevated in the airways of asthmatics and correlates with the expression of Th2 cytokines and chemokines (Shikotra et al., J Allergy Clin Immunol 2012;129:104-11 e1-9) and disease severity (Ying et al., J Immunol 2005;174:8183-90; Ying, et al. J Immunol 2008;181:2790-8).

[0008] Tezepelumab (also known as AMG 157) (Gilliet, et al., J Exp Med 2003;197:1059-63) is a fully human monoclonal antibody (immunoglobulin G2λ) that targets thymic stromal lymphopoietin (TSLP), an epithelial cell-derived cytokine that promotes inflammatory responses to environmental stimuli through activity on multiple pathways, including but not limited to, activity on dendritic cells (Gilliet, et al., 2003; Soumelis et al., 2002; Reche, et al. J Immunol 2001;167:336-43) and mast cells (Allakhverdi et al., 2007). By binding to TSLP, tezepelumab prevents its interaction with the TSLP-receptor complex and inhibits multiple downstream inflammatory pathways. [Prior art documents] [Non-patent literature]

[0009] [Non-Patent Document 1] Fokkens et al. 2020 [Non-patent document 2] Gevaert et al. 2011 [Non-patent document 3] Bachert et al. 2016 [Non-patent document 4] Bachert et al. 2017 [Non-Patent Document 5] Bachert et al. 2019 [Non-patent document 6] Gevaert et al. 2020 [Non-Patent Document 7] Hakansson K et al 2015 [Non-patent document 8] Jarvis D et al 2012 [Non-Patent Document 9] Seybt MW et al 2007 [Non-Patent Document 10] Pearlman AN et al, 2009

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[0010] The anti-TSLP antibodies described herein address unmet needs in patients with chronic rhinosinusitis, with or without nasal polyps, for whom other medications fail to control symptoms. For example, antibody therapy may improve nasal polyp scores, improve anosmia, or reduce the need for surgery to remove polyps in patients with chronic sinusitis, and reduce the need for alternative therapies such as systemic corticosteroids.

[0011] The present disclosure provides, in part, a method for treating chronic sinusitis in a subject, the method comprising selecting a subject in need of treatment for chronic sinusitis and administering to the subject a therapeutically effective amount of an anti-TSLP antibody or antibody variant, wherein both binding sites of the antibody have identical binding affinity for TSLP, the antibody comprising: a. a light chain variable domain comprising: i. a light chain CDR1 sequence comprising the amino acid sequence set forth in SEQ ID NO:3; ii. a light chain CDR2 sequence comprising the amino acid sequence set forth in SEQ ID NO:4; iii. a light chain CDR3 sequence comprising the amino acid sequence set forth in SEQ ID NO:5; and b. a heavy chain variable domain comprising: i. a heavy chain CDR1 sequence comprising the amino acid sequence set forth in SEQ ID NO:6; ii. a heavy chain CDR2 sequence comprising the amino acid sequence set forth in SEQ ID NO:7; and iii. a heavy chain CDR3 sequence comprising the amino acid sequence set forth in SEQ ID NO:8, wherein the antibody specifically binds to the TSLP polypeptide set forth in amino acids 29 to 159 of SEQ ID NO:2, or both binding sites of the antibody have identical binding affinity for TSLP. ai) a sequence of amino acids at least 80% identical to SEQ ID NO: 12; ii) a sequence of amino acids encoded by a polynucleotide sequence at least 80% identical to SEQ ID NO: 11; iii) a sequence of amino acids encoded by a polynucleotide that hybridizes under moderately stringent conditions to the complement of the polynucleotide consisting of SEQ ID NO: 11; and b) a heavy chain variable domain selected from the group consisting of a sequence of amino acids at least 80% identical to SEQ ID NO: 10; ii) a sequence of amino acids encoded by a polynucleotide sequence at least 80% identical to SEQ ID NO: 9; iii) a sequence of amino acids encoded by a polynucleotide that hybridizes under moderately stringent conditions to the complement of the polynucleotide consisting of SEQ ID NO: 9; or c) the light chain variable domain of (a) and the heavy chain variable domain of (b), wherein the antibody specifically binds to the TSLP polypeptide represented by amino acids 29 to 159 of SEQ ID NO: 2.

[0012] Also provided is a method for treating chronic sinusitis in a subject, comprising administering a composition comprising an anti-TSLP antibody at a dose of 140 to 420 mg at intervals of every two weeks or every four weeks, wherein the antibody comprises: a. a light chain variable domain comprising: i. a light chain CDR1 sequence comprising the amino acid sequence set forth in SEQ ID NO:3; ii. a light chain CDR2 sequence comprising the amino acid sequence set forth in SEQ ID NO:4; iii. a light chain CDR3 sequence comprising the amino acid sequence set forth in SEQ ID NO:5; and b. a heavy chain variable domain comprising: i. a heavy chain CDR1 sequence comprising the amino acid sequence set forth in SEQ ID NO:6; ii. a heavy chain CDR2 sequence comprising the amino acid sequence set forth in SEQ ID NO:7; and iii. a heavy chain CDR3 sequence comprising the amino acid sequence set forth in SEQ ID NO:8, wherein the antibody specifically binds to the TSLP polypeptide set forth in amino acids 29 to 159 of SEQ ID NO:2, or both binding sites of the antibody have identical binding affinity for TSLP, and the antibody specifically binds to the TSLP polypeptide set forth in SEQ ID NO:12. a light chain variable domain selected from the group consisting of: a sequence of amino acids at least 80% identical to SEQ ID NO: 10; ii. a sequence of amino acids encoded by a polynucleotide sequence at least 80% identical to SEQ ID NO: 11; iii. a sequence of amino acids encoded by a polynucleotide that hybridizes under moderately stringent conditions to the complement of the polynucleotide consisting of SEQ ID NO: 11; and b. a sequence of amino acids at least 80% identical to SEQ ID NO: 10; ii. a sequence of amino acids encoded by a polynucleotide sequence at least 80% identical to SEQ ID NO: 9; iii. a heavy chain variable domain selected from the group consisting of: a sequence of amino acids at least 80% identical to SEQ ID NO: 10; ii. a sequence of amino acids encoded by a polynucleotide sequence at least 80% identical to SEQ ID NO: 9;

[0013] The present disclosure further provides a method for treating chronic sinusitis in a subject, the method comprising: selecting a subject in need of treatment for chronic sinusitis; and administering to the subject a composition comprising an anti-TSLP antibody at a dose of 140 to 420 mg every two weeks, wherein the antibody comprises: a. a light chain variable domain comprising: i. a light chain CDR1 sequence comprising the amino acid sequence set forth in SEQ ID NO: 3; ii. a light chain CDR2 sequence comprising the amino acid sequence set forth in SEQ ID NO: 4; and iii. a light chain CDR3 sequence comprising the amino acid sequence set forth in SEQ ID NO: 5; and b. a heavy chain variable domain comprising: i. a heavy chain CDR1 sequence comprising the amino acid sequence set forth in SEQ ID NO: 6; ii. a heavy chain CDR2 sequence comprising the amino acid sequence set forth in SEQ ID NO: 7; and iii. a heavy chain CDR3 sequence comprising the amino acid sequence set forth in SEQ ID NO: 8; wherein the antibody specifically binds to the TSLP polypeptide set forth in amino acids 29 to 159 of SEQ ID NO: 2.

[0014] Also provided is a method for treating chronic sinusitis in a subject, the method comprising: selecting a subject in need of treatment for chronic sinusitis; and administering to the subject a composition comprising an anti-TSLP antibody at a dose of 140-420 mg at biweekly intervals, wherein the antibody consists of: a. a sequence of amino acids at least 80% identical to SEQ ID NO:12; ii. a sequence of amino acids encoded by a polynucleotide sequence at least 80% identical to SEQ ID NO:11; or iii. a sequence of amino acids encoded by a polynucleotide that hybridizes under moderately stringent conditions to the complement of a polynucleotide consisting of SEQ ID NO:11. a light chain variable domain selected from the group consisting of: bi. a sequence of amino acids at least 80% identical to SEQ ID NO: 10; ii. a sequence of amino acids encoded by a polynucleotide sequence at least 80% identical to SEQ ID NO: 9; iii. a sequence of amino acids encoded by a polynucleotide that hybridizes under moderately stringent conditions to the complement of a polynucleotide consisting of SEQ ID NO: 9; or c. the light chain variable domain of (a) and the heavy chain variable domain of (b), wherein the antibody specifically binds to the TSLP polypeptide represented by amino acids 29 to 159 of SEQ ID NO: 2.

[0015] In various embodiments, the antibody is administered every four weeks. In various embodiments, the antibody is administered at a 140 mg dose or at a 420 mg dose every two weeks or every four weeks. In various embodiments, the antibody is administered at a 140 mg dose or at a 210 mg dose every two weeks or every four weeks.

[0016] In various embodiments, the antibody is administered at a dose of 210 mg every two weeks. In various embodiments, the antibody is administered at a dose of 210 mg every four weeks.

[0017] In various embodiments, the subject is also receiving corticosteroid treatment.

[0018] In various embodiments, a method for treating chronic sinusitis in a subject is provided, comprising selecting a subject in need of treatment for chronic sinusitis and administering to the subject a therapeutically effective amount of a systemic corticosteroid and an anti-TSLP antibody at a dose of 210 mg every two weeks, the antibody comprising: a. a light chain variable domain comprising: i. a light chain CDR1 sequence comprising the amino acid sequence set forth in SEQ ID NO:3; ii. a light chain CDR2 sequence comprising the amino acid sequence set forth in SEQ ID NO:4; and iii. a light chain CDR3 sequence comprising the amino acid sequence set forth in SEQ ID NO:5; and b. a heavy chain variable domain comprising: i. a heavy chain CDR1 sequence comprising the amino acid sequence set forth in SEQ ID NO:6; ii. a heavy chain CDR2 sequence comprising the amino acid sequence set forth in SEQ ID NO:7; and iii. a heavy chain CDR3 sequence comprising the amino acid sequence set forth in SEQ ID NO:8, wherein the antibody specifically binds to the TSLP polypeptide set forth in amino acids 29-159 of SEQ ID NO:2.

[0019] In various embodiments, a method for treating chronic sinusitis in a subject is provided, comprising selecting a subject in need of treatment for chronic sinusitis and administering to the subject a therapeutically effective amount of a systemic corticosteroid and an anti-TSLP antibody at a dose of 210 mg every two weeks, the antibody comprising: a. a light chain variable domain comprising: i. a light chain CDR1 sequence comprising the amino acid sequence set forth in SEQ ID NO:3; ii. a light chain CDR2 sequence comprising the amino acid sequence set forth in SEQ ID NO:4; and iii. a light chain CDR3 sequence comprising the amino acid sequence set forth in SEQ ID NO:5; and b. a heavy chain variable domain comprising: i. a heavy chain CDR1 sequence comprising the amino acid sequence set forth in SEQ ID NO:6; ii. a heavy chain CDR2 sequence comprising the amino acid sequence set forth in SEQ ID NO:7; and iii. a heavy chain CDR3 sequence comprising the amino acid sequence set forth in SEQ ID NO:8, wherein the antibody specifically binds to the TSLP polypeptide set forth in amino acids 29-159 of SEQ ID NO:2.

[0020] The present disclosure also provides a method for treating chronic sinusitis in a subject, the method comprising: selecting a subject in need of treatment for chronic sinusitis; and administering to the subject a composition comprising an anti-TSLP antibody at a dose of 210 mg every four weeks, wherein the antibody comprises: a. a light chain variable domain comprising: i. a light chain CDR1 sequence comprising the amino acid sequence set forth in SEQ ID NO:3; ii. a light chain CDR2 sequence comprising the amino acid sequence set forth in SEQ ID NO:4; and iii. a light chain CDR3 sequence comprising the amino acid sequence set forth in SEQ ID NO:5; and b. a heavy chain variable domain comprising: i. a heavy chain CDR1 sequence comprising the amino acid sequence set forth in SEQ ID NO:6; ii. a heavy chain CDR2 sequence comprising the amino acid sequence set forth in SEQ ID NO:7; and iii. a heavy chain CDR3 sequence comprising the amino acid sequence set forth in SEQ ID NO:8; wherein the antibody specifically binds to the TSLP polypeptide set forth in amino acids 29 to 159 of SEQ ID NO:2.

[0021] The present disclosure further provides a method for treating chronic sinusitis in a subject, the method comprising: selecting a subject in need of treatment for chronic sinusitis; and administering to the subject a composition comprising an anti-TSLP antibody at a dose of 210 mg every four weeks, the antibody comprising: a.i. a sequence of amino acids at least 80% identical to SEQ ID NO:12; ii. a sequence of amino acids encoded by a polynucleotide sequence at least 80% identical to SEQ ID NO:11; or iii. a sequence of amino acids encoded by a polynucleotide that hybridizes under moderately stringent conditions to the complement of a polynucleotide consisting of SEQ ID NO:11. a light chain variable domain selected from the group consisting of: bi. a sequence of amino acids at least 80% identical to SEQ ID NO: 10; ii. a sequence of amino acids encoded by a polynucleotide sequence at least 80% identical to SEQ ID NO: 9; iii. a sequence of amino acids encoded by a polynucleotide that hybridizes under moderately stringent conditions to the complement of a polynucleotide consisting of SEQ ID NO: 9; or c. the light chain variable domain of (a) and the heavy chain variable domain of (b), wherein the antibody specifically binds to the TSLP polypeptide represented by amino acids 29 to 159 of SEQ ID NO: 2.

[0022] In various embodiments, the light chain variable domain is set forth in SEQ ID NO:12 and the heavy chain variable domain is set forth in SEQ ID NO:10.

[0023] In various embodiments, the anti-TSLP antibody or antibody variant has substantially similar pK characteristics to tezepelumab in humans.

[0024] In various embodiments, the antibody or antibody variant is administered for at least 4 months, 6 months, 9 months, 1 year or more.

[0025] In various embodiments, the anti-TSLP antibody or antibody variant thereof is bivalent and is selected from the group consisting of a human antibody, a humanized antibody, a chimeric antibody, a monoclonal antibody, a recombinant antibody, an antigen-binding antibody fragment, a single-chain antibody, a monomeric antibody, a Fab fragment, an IgG1 antibody, an IgG2 antibody, an IgG3 antibody, and an IgG4 antibody.

[0026] In various embodiments, the anti-TSLP antibody is bivalent and is selected from the group consisting of a human antibody, a humanized antibody, a chimeric antibody, a monoclonal antibody, a recombinant antibody, an IgG1 antibody, an IgG2 antibody, an IgG3 antibody, and an IgG4 antibody.

[0027] In one embodiment, the anti-TSLP antibody variant is selected from the group consisting of a Fab fragment, a single domain antibody, and an scFv, wherein the dosage is adjusted so that the binding sites are equimolar to that administered by the bivalent antibody.

[0028] In various embodiments, the antibody is an IgG2 antibody.

[0029] In one embodiment, the antibody or antibody variant is a human or humanized antibody.

[0030] In various embodiments, the antibody is tezepelumab. In various embodiments, the anti-TSLP antibody is an IgG2 antibody having the full-length heavy and light chain amino acid sequences set forth in SEQ ID NOs: 13 and 14, respectively. In various embodiments, the anti-TSLP antibody is tezepelumab.

[0031] In various embodiments, the antibody or antibody variant is in a pharmaceutical composition that further comprises a pharmaceutically acceptable carrier or excipient.

[0032] In various embodiments, the antibody is an anti-TSLP antibody described in the art. Exemplary antibodies are further described in the detailed description.

[0033] In various embodiments, the subject is an adult. In various embodiments, the subject is a child or adolescent.

[0034] Additionally, administration of an anti-TSLP antibody or antibody variant provides for a reduction in the levels of Th2 cytokines in a subject.

[0035] In various embodiments, administration of an anti-TSLP antibody or antibody variant improves one or more of the following measures of chronic rhinosinusitis: Nasal Polyp Score (NPS), Nasal Congestion Score (NCS), anosmia, SinoNasal Outcome Test 22-item (SNOT-22), EuroQOL Quality of Life 5 Dimension 3-Level (EQ-5D-3L), Asthma Control Questionnaire (ACQ-6), Lund-Mackay score, modified Lund-Mackay score, incidence of nasal polyp surgery, and / or systemic corticosteroids (SCS).

[0036] In various embodiments, the NPS and / or NCS is reduced by 1, 2, or 3 points. In various embodiments, the subject has an NPS score of 0 (none) or 1 (mild) at 52 weeks post-treatment. In various embodiments, the subject has a starting NPS score of 2. In various embodiments, the subject has a starting NPS score of 3. In various embodiments, the subject has an NCS score of 0 (none) or 1 (mild) at 52 weeks post-treatment. In various embodiments, the subject has a starting NCS score of 2. In various embodiments, the subject has a starting NCS score of 3.

[0037] In various embodiments, anti-TSLP treatment modulates the levels of one or more of the following biomarkers of chronic sinusitis: cytokines, IgE, CCL17, CCL18, CCL22, and RNA transcriptional changes in the nasal epithelium. In various embodiments, anti-TSLP treatment reduces the levels of Th2 cytokines. In various embodiments, treatment modulates (reduces or alleviates) the level or activity of one or more of IL-4, IL-5, IL-13, IL-17, IL-22, IL-23, IL-31, or a combination thereof.

[0038] Provided herein is a method for treating chronic rhinosinusitis with nasal polyps in a subject, the method comprising selecting a subject in need of treatment for chronic rhinosinusitis with nasal polyps, and administering to the subject a composition comprising an anti-TSLP antibody at a dose of 210 mg every four weeks, wherein the antibody is Aa light chain variable domain, comprising: i. a light chain CDR1 sequence comprising the amino acid sequence set forth in SEQ ID NO: 3; ii. a light chain CDR2 sequence comprising the amino acid sequence set forth in SEQ ID NO: 4; iii. a light chain CDR3 sequence comprising the amino acid sequence set forth in SEQ ID NO: 5; and b. a heavy chain variable domain, comprising: i. a heavy chain CDR1 sequence comprising the amino acid sequence set forth in SEQ ID NO: 6; ii. a heavy chain CDR2 sequence comprising the amino acid sequence set forth in SEQ ID NO: 7; and iii. a heavy chain CDR3 sequence comprising the amino acid sequence set forth in SEQ ID NO: 8; or a light chain variable domain selected from the group consisting of: a sequence of amino acids at least 80% identical to SEQ ID NO: 12; ii. a sequence of amino acids encoded by a polynucleotide sequence at least 80% identical to SEQ ID NO: 11; iii. a sequence of amino acids encoded by a polynucleotide that hybridizes under moderately stringent conditions to the complement of the polynucleotide consisting of SEQ ID NO: 11; and b. a sequence of amino acids at least 80% identical to SEQ ID NO: 10; ii. a sequence of amino acids encoded by a polynucleotide sequence at least 80% identical to SEQ ID NO: 9; iii. a heavy chain variable domain selected from the group consisting of an amino acid sequence encoded by a polynucleotide that hybridizes under moderately stringent conditions to the complement of the polynucleotide consisting of SEQ ID NO: 9; or c. a light chain variable domain of (a) and a heavy chain variable domain of (b), wherein the antibody specifically binds to the TSLP polypeptide represented by amino acids 29 to 159 of SEQ ID NO: 2.

[0039] Further provided is a method for treating chronic sinusitis in a subject, the method comprising selecting a subject in need of treatment for chronic sinusitis and administering to the subject a composition comprising an anti-TSLP antibody at a dose of 140 to 420 mg at intervals of every two weeks or every four weeks, the antibody comprising: (a) a light chain variable domain comprising: i. a light chain CDR1 sequence comprising the amino acid sequence set forth in SEQ ID NO: 3; ii. a light chain CDR2 sequence comprising the amino acid sequence set forth in SEQ ID NO: 4; and iii. a light chain CDR3 sequence comprising the amino acid sequence set forth in SEQ ID NO: 5; and (b) a heavy chain variable domain comprising: i. a heavy chain CDR1 sequence comprising the amino acid sequence set forth in SEQ ID NO: 6; ii. a heavy chain CDR2 sequence comprising the amino acid sequence set forth in SEQ ID NO: 7; and iii. a heavy chain CDR3 sequence comprising the amino acid sequence set forth in SEQ ID NO: 8, wherein the antibody specifically binds to the TSLP polypeptide set forth in amino acids 29 to 159 of SEQ ID NO: 2, and the antibody is an IgG2 antibody.

[0040] In various embodiments, the light chain variable domain is set forth in SEQ ID NO:12 and the heavy chain variable domain is set forth in SEQ ID NO:10.

[0041] In various embodiments, the antibody is administered every four weeks. In various embodiments, the antibody is administered at a dose of 210 mg every two weeks or every four weeks.

[0042] In various embodiments, the antibody is administered at a dose of 210 mg every four weeks.

[0043] Also provided is a method for reducing the frequency of necessary surgery or systemic corticosteroids in a subject with chronic rhinosinusitis, with or without nasal polyps, comprising selecting a subject in need of treatment for chronic rhinosinusitis and administering to the subject a composition comprising an anti-TSLP antibody at a dose of 140 to 420 mg every two weeks, the antibody comprising: a. a light chain variable domain comprising: i. a light chain CDR1 sequence comprising the amino acid sequence set forth in SEQ ID NO:3; ii. a light chain CDR2 sequence comprising the amino acid sequence set forth in SEQ ID NO:4; and iii. a light chain CDR3 sequence comprising the amino acid sequence set forth in SEQ ID NO:5; and b. a heavy chain variable domain comprising: i. a heavy chain CDR1 sequence comprising the amino acid sequence set forth in SEQ ID NO:6; ii. a heavy chain CDR2 sequence comprising the amino acid sequence set forth in SEQ ID NO:7; and iii. a heavy chain CDR3 sequence comprising the amino acid sequence set forth in SEQ ID NO:8, wherein the antibody specifically binds to the TSLP polypeptide set forth in amino acids 29 to 159 of SEQ ID NO:2.

[0044] Also provided is a method for reducing the frequency of required surgery or systemic corticosteroids in a subject with chronic rhinosinusitis and nasal polyps, the method comprising: selecting a subject in need of treatment for chronic rhinosinusitis; and administering to the subject a composition comprising an anti-TSLP antibody at a dose of 140 to 420 mg every two weeks, the antibody comprising: a. a light chain variable domain comprising: i. a light chain CDR1 sequence comprising the amino acid sequence set forth in SEQ ID NO: 3; ii. a light chain CDR2 sequence comprising the amino acid sequence set forth in SEQ ID NO: 4; and iii. a light chain CDR3 sequence comprising the amino acid sequence set forth in SEQ ID NO: 5; and b. a heavy chain variable domain comprising: i. a heavy chain CDR1 sequence comprising the amino acid sequence set forth in SEQ ID NO: 6; ii. a heavy chain CDR2 sequence comprising the amino acid sequence set forth in SEQ ID NO: 7; and iii. a heavy chain CDR3 sequence comprising the amino acid sequence set forth in SEQ ID NO: 8, wherein the antibody specifically binds to the TSLP polypeptide set forth in amino acids 29 to 159 of SEQ ID NO: 2.

[0045] Further provided is a method for reducing the frequency of chronic sinusitis exacerbations in a subject, the method comprising: selecting a subject in need of treatment for chronic sinusitis; and administering to the subject a composition comprising an anti-TSLP antibody at a dose of 140 to 420 mg at biweekly intervals, the antibody comprising: a. a sequence of amino acids at least 80% identical to SEQ ID NO:12; ii. a sequence of amino acids encoded by a polynucleotide sequence at least 80% identical to SEQ ID NO:11; iii. a polynucleotide that hybridizes under moderately stringent conditions to the complement of a polynucleotide consisting of SEQ ID NO:11. a light chain variable domain selected from the group consisting of: a sequence of amino acids encoded by a polynucleotide sequence that is at least 80% identical to SEQ ID NO: 10; ii. a sequence of amino acids encoded by a polynucleotide sequence that is at least 80% identical to SEQ ID NO: 9; iii. a sequence of amino acids encoded by a polynucleotide that hybridizes under moderately stringent conditions to the complement of a polynucleotide consisting of SEQ ID NO: 9; or c. the light chain variable domain of (a) and the heavy chain variable domain of (b).

[0046] Also provided is a method for reducing the frequency of chronic sinusitis exacerbations in a subject, the method comprising: selecting a subject in need of treatment for chronic sinusitis; and administering to the subject a composition comprising an anti-TSLP antibody at a dose of 210 mg every four weeks, wherein the antibody comprises a light chain variable domain selected from the group consisting of: ai. a sequence of amino acids at least 80% identical to SEQ ID NO: 12; ii. a sequence of amino acids encoded by a polynucleotide sequence at least 80% identical to SEQ ID NO: 11; iii. a sequence of amino acids encoded by a polynucleotide that hybridizes under moderately stringent conditions to the complement of the polynucleotide consisting of SEQ ID NO: 11; and bi. a heavy chain variable domain selected from the group consisting of: a sequence of amino acids at least 80% identical to SEQ ID NO: 10; ii. a sequence of amino acids encoded by a polynucleotide sequence at least 80% identical to SEQ ID NO: 9; iii. a sequence of amino acids encoded by a polynucleotide that hybridizes under moderately stringent conditions to the complement of the polynucleotide consisting of SEQ ID NO: 9; or c. the light chain variable domain of (a) and the heavy chain variable domain of (b).

[0047] Also provided are methods for reducing a subject's SNOT-22 and / or Lund-Mackay score, comprising administering a composition comprising an anti-TSLP antibody at a dose of 140-420 mg at every two-week interval or at a dose of 210 mg at every four-week interval, wherein the antibody is selected from the group consisting of: a. a sequence of amino acids at least 80% identical to SEQ ID NO:12; ii. a sequence of amino acids encoded by a polynucleotide sequence at least 80% identical to SEQ ID NO:11; iii. a polynucleotide that hybridizes under moderately stringent conditions to the complement of a polynucleotide consisting of SEQ ID NO:11. a light chain variable domain selected from the group consisting of: a sequence of amino acids encoded by a polynucleotide sequence that is at least 80% identical to SEQ ID NO: 10; ii. a sequence of amino acids encoded by a polynucleotide sequence that is at least 80% identical to SEQ ID NO: 9; iii. a sequence of amino acids encoded by a polynucleotide that hybridizes under moderately stringent conditions to the complement of a polynucleotide consisting of SEQ ID NO: 9; or c. the light chain variable domain of (a) and the heavy chain variable domain of (b).

[0048] In various embodiments, the disclosure provides methods for reducing SNOT-22 and / or Lund-Mackay score in a subject, the method comprising administering a composition comprising an anti-TSLP antibody at a dose of 140-420 mg every two weeks or at a dose of 210 mg every four weeks, the antibody comprising: a. a light chain variable domain comprising: i. a light chain CDR1 sequence comprising the amino acid sequence set forth in SEQ ID NO:3; ii. a light chain CDR2 sequence comprising the amino acid sequence set forth in SEQ ID NO:4; and iii. a light chain CDR3 sequence comprising the amino acid sequence set forth in SEQ ID NO:5; and b. a heavy chain variable domain comprising: i. a heavy chain CDR1 sequence comprising the amino acid sequence set forth in SEQ ID NO:6; ii. a heavy chain CDR2 sequence comprising the amino acid sequence set forth in SEQ ID NO:7; and iii. a heavy chain CDR3 sequence comprising the amino acid sequence set forth in SEQ ID NO:8, wherein the antibody specifically binds to the TSLP polypeptide set forth in amino acids 29-159 of SEQ ID NO:2.

[0049] In various embodiments, the disclosure provides a method for reducing a subject's SNOT-22 domain score, comprising administering a composition comprising an anti-TSLP antibody at a dose of 140 to 420 mg every two weeks or at a dose of 210 mg every four weeks, wherein the antibody comprises: a. a light chain variable domain comprising: i. a light chain CDR1 sequence comprising the amino acid sequence set forth in SEQ ID NO:3; ii. a light chain CDR2 sequence comprising the amino acid sequence set forth in SEQ ID NO:4; and iii. a light chain CDR3 sequence comprising the amino acid sequence set forth in SEQ ID NO:5; and b. a heavy chain variable domain comprising: i. a heavy chain CDR1 sequence comprising the amino acid sequence set forth in SEQ ID NO:6; ii. a heavy chain CDR2 sequence comprising the amino acid sequence set forth in SEQ ID NO:7; and iii. a heavy chain CDR3 sequence comprising the amino acid sequence set forth in SEQ ID NO:8, wherein the antibody specifically binds to the TSLP polypeptide set forth in amino acids 29 to 159 of SEQ ID NO:2.

[0050] In various embodiments, the SNOT-22 domain is a nose domain, an ear / face domain, a sleep domain, a function domain, or an emotional domain. In various embodiments, administration improves one or more symptoms in a domain score selected from the following: need to blow nose, nasal blockage, sneezing, runny nose, cough, postnasal discharge, thick nasal discharge, decreased sense of smell / taste; ear fullness, dizziness, ear pain, facial pain / pressure; difficulty falling asleep, nighttime awakenings, poor nighttime sleep, tiredness upon waking, fatigue, decreased productivity, decreased concentration, irritability / restlessness / irritability, sadness, and panic.

[0051] In various embodiments, the antibody comprises a light chain variable domain selected from the group consisting of: ai. a sequence of amino acids at least 80% identical to SEQ ID NO: 12; ii. a sequence of amino acids encoded by a polynucleotide sequence at least 80% identical to SEQ ID NO: 11; iii. a sequence of amino acids encoded by a polynucleotide that hybridizes under moderately stringent conditions to the complement of the polynucleotide consisting of SEQ ID NO: 11; and bi. a sequence of amino acids at least 80% identical to SEQ ID NO: 10; ii. a sequence of amino acids encoded by a polynucleotide sequence at least 80% identical to SEQ ID NO: 9; iii. a sequence of amino acids encoded by a polynucleotide that hybridizes under moderately stringent conditions to the complement of the polynucleotide consisting of SEQ ID NO: 9; or c. a light chain variable domain of (a) and a heavy chain variable domain of (b).

[0052] In various embodiments, the light chain variable domain is set forth in SEQ ID NO:12 and the heavy chain variable domain is set forth in SEQ ID NO:10.

[0053] In various embodiments, the antibody is tezepelumab.

[0054] The administrations and types of antibodies and antibody variants described above are intended to apply to each of the methods contemplated herein.

[0055] In various embodiments, a pharmaceutical composition is provided comprising an antibody or antibody variant, and further comprising a pharmaceutically acceptable carrier or excipient.

[0056] In various embodiments, administration delays the time to chronic sinusitis exacerbation compared to a subject not receiving the anti-TSLP antibody or compared to the patient's baseline symptoms before treatment with the anti-TSLP antibody or antibody variant. An example of such an antibody is tezepelumab.

[0057] In various embodiments, administration delays the onset or time to nasal polyp surgery in subjects with chronic sinusitis compared to subjects not receiving the anti-TSLP antibody.

[0058] Administration of the TSLP antibody or antibody variant alone can be subcutaneous.

[0059] In various embodiments, administration reduces the frequency or level of co-administered therapy in a subject. Exemplary co-administered therapies are dupilumab, immunosuppressants or immunomodulators (e.g., systemic corticosteroids, cyclosporine, mycophenolate mofetil, interferon (IFN) gamma, Janus kinase inhibitors, azathioprine, methotrexate), anti-IL-13 antibodies, anti-IL-5 pathway antibodies (benralizumab, mepolizumab, reslizumab), or combinations thereof. For purposes of this description, "co-administration" encompasses administration of two such different molecules in the same syringe / autoinjector or in two different syringes / autoinjectors. The different molecules can also be administered at the same time or at different times.

[0060] In various embodiments, this administration reduces or eliminates the need for corticosteroid therapy.

[0061] In various embodiments, administration is subcutaneous or intravenous.

[0062] In various embodiments, the antibody is tezepelumab, or any of the antibodies described in the art, for example, in Table A, or in WO 20220226342A1, WO 20220226339A1, WO 2023098491A1, WO 2021155634A1, WO 2022166072A1, WO 2021043221A1, WO 2022184074A1, WO 2021104053A1, WO 2023116925A1, WO 2021155861 ... and other anti-TSLP antibodies or antibody variants described in US Pat. Nos. 2022116858A1, 2022117079A1, 2020244544A1, 2021152488A1, 2022253147A1, 2023070948A1, 2023142309A1, 2022095689A1, 2021115240A1, 2022166739A1, and 2019100111A1. Exemplary antibodies are further described in the detailed description. [Brief explanation of the drawings]

[0063] [Figure 1A] Baseline demographic and clinical characteristics of subjects with chronic rhinosinusitis with or without nasal polyps treated with anti-TSLP antibodies. [Figure 1B] Baseline demographic and clinical characteristics of subjects with chronic rhinosinusitis with or without nasal polyps treated with anti-TSLP antibodies. [Figure 2] LS mean change from baseline to week 52 in SNOT-22 scores in patients with a history of nasal polyps treated with anti-TSLP antibodies. [Figure 3] Mean change from baseline to week 52 in SNOT-22 scores in patients with any history of nasal polyps treated with anti-TSLP antibodies. [Figure 4] Improvement from baseline to week 52 in SNOT-22 domain scores with tezepelumab compared with placebo in patients with a history of NP. Placebo, n=57; tezepelumab 210 mg Q4W, n=65. n is the number of patients contributing to the analysis, i.e., the number of patients with baseline values ​​and non-missing independent variables included in the model. CI, confidence interval; LS, least squares; NP, nasal polyps; SNOT-22, Nasal Sinus Outcome Test-22. [Figure 5A] Change from baseline in SNOT-22 total and domain scores in patients with a history of NP. Figure 5A, % total score; Figure 5B, total score; Figure 5C, ear / face domain; Figure 5D, emotional domain; Figure 5E, functional domain; Figure 5F, nasal domain; Figure 5G, sleep domain. Baseline: placebo, n=62; tezepelumab, n=69. Week 28: placebo, n=57; tezepelumab, n=64. Week 52: placebo, n=53; tezepelumab, n=64. LS, least squares; NP, nasal polyps; Q4W, every 4 weeks; SE, standard error; SNOT-22, Nasal Sinus Outcome Test-22. [Figure 5B] Change from baseline in SNOT-22 total and domain scores in patients with a history of NP. Figure 5A, % total score; Figure 5B, total score; Figure 5C, ear / face domain; Figure 5D, emotional domain; Figure 5E, functional domain; Figure 5F, nasal domain; Figure 5G, sleep domain. Baseline: placebo, n=62; tezepelumab, n=69. Week 28: placebo, n=57; tezepelumab, n=64. Week 52: placebo, n=53; tezepelumab, n=64. LS, least squares; NP, nasal polyps; Q4W, every 4 weeks; SE, standard error; SNOT-22, Nasal Sinus Outcome Test-22. [Figure 5C]Change from baseline in SNOT-22 total and domain scores in patients with a history of NP. Figure 5A, % total score; Figure 5B, total score; Figure 5C, ear / face domain; Figure 5D, emotional domain; Figure 5E, functional domain; Figure 5F, nasal domain; Figure 5G, sleep domain. Baseline: placebo, n=62; tezepelumab, n=69. Week 28: placebo, n=57; tezepelumab, n=64. Week 52: placebo, n=53; tezepelumab, n=64. LS, least squares; NP, nasal polyps; Q4W, every 4 weeks; SE, standard error; SNOT-22, Nasal Sinus Outcome Test-22. [Figure 5D] Change from baseline in SNOT-22 total and domain scores in patients with a history of NP. Figure 5A, % total score; Figure 5B, total score; Figure 5C, ear / face domain; Figure 5D, emotional domain; Figure 5E, functional domain; Figure 5F, nasal domain; Figure 5G, sleep domain. Baseline: placebo, n=62; tezepelumab, n=69. Week 28: placebo, n=57; tezepelumab, n=64. Week 52: placebo, n=53; tezepelumab, n=64. LS, least squares; NP, nasal polyps; Q4W, every 4 weeks; SE, standard error; SNOT-22, Nasal Sinus Outcome Test-22. [Figure 5E] Change from baseline in SNOT-22 total and domain scores in patients with a history of NP. Figure 5A, % total score; Figure 5B, total score; Figure 5C, ear / face domain; Figure 5D, emotional domain; Figure 5E, functional domain; Figure 5F, nasal domain; Figure 5G, sleep domain. Baseline: placebo, n=62; tezepelumab, n=69. Week 28: placebo, n=57; tezepelumab, n=64. Week 52: placebo, n=53; tezepelumab, n=64. LS, least squares; NP, nasal polyps; Q4W, every 4 weeks; SE, standard error; SNOT-22, Nasal Sinus Outcome Test-22. [Figure 5F]Change from baseline in SNOT-22 total and domain scores in patients with a history of NP. Figure 5A, % total score; Figure 5B, total score; Figure 5C, ear / face domain; Figure 5D, emotional domain; Figure 5E, functional domain; Figure 5F, nasal domain; Figure 5G, sleep domain. Baseline: placebo, n=62; tezepelumab, n=69. Week 28: placebo, n=57; tezepelumab, n=64. Week 52: placebo, n=53; tezepelumab, n=64. LS, least squares; NP, nasal polyps; Q4W, every 4 weeks; SE, standard error; SNOT-22, Nasal Sinus Outcome Test-22. [Figure 5G] Change from baseline in SNOT-22 total and domain scores in patients with a history of NP. Figure 5A, % total score; Figure 5B, total score; Figure 5C, ear / face domain; Figure 5D, emotional domain; Figure 5E, functional domain; Figure 5F, nasal domain; Figure 5G, sleep domain. Baseline: placebo, n=62; tezepelumab, n=69. Week 28: placebo, n=57; tezepelumab, n=64. Week 52: placebo, n=53; tezepelumab, n=64. LS, least squares; NP, nasal polyps; Q4W, every 4 weeks; SE, standard error; SNOT-22, Nasal Sinus Outcome Test-22. [Figure 6A] Change from baseline to week 52 in SNOT-22 item of interest scores in patients with a history of NP. Figure 6A, decreased sense of smell / taste; Figure 6B, nasal congestion; Figure 6C, cough; Figure 6D, decreased productivity; Figure 6E, morning fatigue. n is the number of patients contributing to the analysis, i.e., the number of patients with baseline values ​​and non-missing independent variables included in the model. CI, confidence interval; LS, least squares; NP, nasal polyps; Q4W, every 4 weeks; SE, standard error; SNOT-22, Nasal and Sinus Outcome Test-22. [Figure 6B]Change from baseline to week 52 in SNOT-22 item of interest scores in patients with a history of NP. Figure 6A, decreased sense of smell / taste; Figure 6B, nasal congestion; Figure 6C, cough; Figure 6D, decreased productivity; Figure 6E, morning fatigue. n is the number of patients contributing to the analysis, i.e., the number of patients with baseline values ​​and non-missing independent variables included in the model. CI, confidence interval; LS, least squares; NP, nasal polyps; Q4W, every 4 weeks; SE, standard error; SNOT-22, Nasal and Sinus Outcome Test-22. [Figure 6C] Change from baseline to week 52 in SNOT-22 item of interest scores in patients with a history of NP. Figure 6A, decreased sense of smell / taste; Figure 6B, nasal congestion; Figure 6C, cough; Figure 6D, decreased productivity; Figure 6E, morning fatigue. n is the number of patients contributing to the analysis, i.e., the number of patients with baseline values ​​and non-missing independent variables included in the model. CI, confidence interval; LS, least squares; NP, nasal polyps; Q4W, every 4 weeks; SE, standard error; SNOT-22, Nasal and Sinus Outcome Test-22. [Figure 6D] Change from baseline to week 52 in SNOT-22 item of interest scores in patients with a history of NP. Figure 6A, decreased sense of smell / taste; Figure 6B, nasal congestion; Figure 6C, cough; Figure 6D, decreased productivity; Figure 6E, morning fatigue. n is the number of patients contributing to the analysis, i.e., the number of patients with baseline values ​​and non-missing independent variables included in the model. CI, confidence interval; LS, least squares; NP, nasal polyps; Q4W, every 4 weeks; SE, standard error; SNOT-22, Nasal and Sinus Outcome Test-22. [Figure 6E] Change from baseline to week 52 in SNOT-22 item of interest scores in patients with a history of NP. Figure 6A, decreased sense of smell / taste; Figure 6B, nasal congestion; Figure 6C, cough; Figure 6D, decreased productivity; Figure 6E, morning fatigue. n is the number of patients contributing to the analysis, i.e., the number of patients with baseline values ​​and non-missing independent variables included in the model. CI, confidence interval; LS, least squares; NP, nasal polyps; Q4W, every 4 weeks; SE, standard error; SNOT-22, Nasal and Sinus Outcome Test-22. [Figure 7-1] Sequences of TSLP and the anti-TSLP antibody tezepelumab. [Figure 7-2] Sequences of TSLP and the anti-TSLP antibody tezepelumab. DETAILED DESCRIPTION OF THE INVENTION

[0064] The use of anti-TSLP antibodies addresses an unmet need in patients with chronic rhinosinusitis (CRS) or chronic rhinosinusitis with nasal polyps (CRSwNP), for whom other medications may not control moderate to severe symptoms. Furthermore, treatment with anti-TSLP antibodies, such as tezepelumab, may eliminate periodic disease activity, allowing more patients to become steroid-free or reducing the need for steroids in the treatment of CRS and CRSwNP.

[0065] definition Unless otherwise stated, the following terms used in this Application, including the specification and claims, have the definitions set forth below.

[0066] As used in the specification and the appended claims, the indefinite articles "a" and "an" and the definite article "the" include plural and singular referents unless the context clearly dictates otherwise.

[0067] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. The following references provide those of ordinary skill in the art with general definitions of many of the terms used in this disclosure, but are not limited to: Singleton et al., DICTIONARY OF MICROBIOLOGY AND MOLECULAR BIOLOGY (2nd Ed. 1994); THE CAMBRIDGE DICTIONARY OF SCIENCE AND TECHNOLOGY (Walker Ed., 1988); THE GLOSSARY OF GENETICS, 5th Ed., R. Rieger et al. (Eds.), Springer Verlag (1991); and Hale & Marham, THE HARPER COLLINS DICTIONARY OF BIOLOGY (1991).

[0068] The term "about" or "approximately" refers to an acceptable error for a particular value as determined by one of ordinary skill in the art, which depends in part on how the value is measured or determined. In certain embodiments, the term "about" or "approximately" means within 1, 2, 3, or 4 standard deviations. In certain embodiments, the term "about" or "approximately" means within 30%, 25%, 20%, 15%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.5%, or 0.05% of a given value or range. Whenever the term "about" or "approximately" is placed before the first number in a series of two or more numbers, it is understood that the term "about" or "approximately" applies to each of the numbers in the series.

[0069] As used herein, the term "chronic sinusitis" refers to an inflammatory condition of the nasal and paranasal mucosa in which type 2 (T2)-induced inflammation is thought to be the primary process in CRS. Chronic sinusitis can be chronic sinusitis with nasal polyps (CRSwNP) or chronic sinusitis without nasal polyps (CRSsNP), and may be observed with or without co-morbid asthma / allergies, asthma, infections, and aspirin-sensitive exacerbated respiratory disease (AERD) or nonsteroidal anti-inflammatory drug-exacerbated respiratory disease (NSAID-ERD).

[0070] As used herein, the term "chronic sinusitis exacerbation" refers to a worsening of chronic sinusitis resulting in any of the following: the use of systemic corticosteroids or other adjunctive therapy for at least three days; a worsening of one or more symptoms or measures of chronic sinusitis described herein, and / or an increase or enlargement in the number, size, or severity of nasal polyps.

[0071] The term "exacerbation of chronic sinusitis" refers to new or increased symptoms and / or signs (examination) that may be related to a subject with chronic sinusitis with or without nasal polyps (subject-driven) or may be related to a patient diary alert (diary-driven).

[0072] As used herein, the term "cytokine" refers to one or more small (5-20 kD) proteins released by cells that have specific effects on cell-to-cell interaction and communication, or on cellular behavior, such as immune cell proliferation and differentiation. The functions of cytokines in the immune system include promoting the influx of circulating leukocytes and lymphocytes to sites of immunological encounter; stimulating the development and proliferation of B cells, T cells, peripheral blood mononuclear cells (PBMCs), and other immune cells; and providing antibacterial activity. Exemplary immune cytokines include, but are not limited to, IL-1, IL-2, IL-3, IL-4, IL-5, IL-6, IL-7, IL-9, IL-10, IL-12, IL-13, IL-15, IL-17A, IL-17F, IL-18, IL-21, IL-22, IL-23, IL-31, IL-33, interferons (including IFN alpha, beta, and gamma), tumor necrosis factors (including TNF alpha, beta), transforming growth factors (including TGF alpha, beta), granulocyte colony-stimulating factor (GCSF), granulocyte-macrophage colony-stimulating factor (GMCSF), and thymic stromal lymphopoietin (TSLP).

[0073] "T helper (Th)1 cytokines" or "Th1-specific cytokines" refer to cytokines expressed (intracellularly expressed and / or secreted) by Th1 T cells, including IFN-γ, TNF-α, and IL-12. "Th2 cytokines" or "Th2-specific cytokines" refer to cytokines expressed (intracellularly expressed and / or secreted) by Th2 T cells, including IL-4, IL-5, IL-13, and IL-10. "Th17 cytokines" or "Th17-specific cytokines" refer to cytokines expressed (intracellularly expressed and / or secreted) by Th17 T cells, including IL-17A, IL-17F, IL-22, and IL-21. Certain populations of Th17 cells express IFN-γ and / or IL-2 in addition to the Th17 cytokines listed herein. Polyfunctional CTL cytokines include IFN-γ, TNF-α, IL-2, and IL-17.

[0074] The term "specifically binds" refers to an antibody or polypeptide that is "antigen-specific," "selective binding agent," "specific binder," "specific for" or "immunoreactive" with an antigen, and binds to a target antigen with greater affinity than other antigens of similar sequence. As used herein, the agents are considered to specifically bind a target protein useful for identifying immune cell types, e.g., surface antigens (e.g., T cell receptor, CD3), cytokines (e.g., TSLP, IL-4, IL-5, IL-13, IL-17, IFN-g, TNF-a), etc. In various embodiments, an antibody specifically binds to a target antigen but can cross-react with orthologs in closely related species; for example, the antibody can be a human protein and also bind to a closely related primate protein.

[0075] The term "antibody" or "immunoglobulin" refers to a tetrameric glycoprotein consisting of two heavy chains and two light chains, each containing a variable region and a constant region. "Heavy chain" and "light chain" refer to substantially full-length canonical immunoglobulin light and heavy chains (see, e.g., Immunobiology, 5th Edition (Janeway and Travers et al., Eds., 2001)). Antigen-binding portions can be produced by recombinant DNA techniques or by enzymatic or chemical cleavage of intact antibodies. The term "antibody" includes monoclonal antibodies, polyclonal antibodies, chimeric antibodies, human antibodies, and humanized antibodies.

[0076] Antibody variants include antibody fragments and antibody-like proteins with altered structures in the canonical tetrameric antibody. Typically, antibody variants contain V regions with altered constant regions, or alternatively, optionally with the addition of V regions to the constant regions in a non-canonical manner. Examples include multispecific antibodies (e.g., bispecific antibodies with additional V regions), antibody fragments capable of binding to antigen (e.g., Fab', F'(ab)2, Fv, single-chain antibodies, diabodies), biparatopic peptides and recombinant peptides containing the above, so long as they exhibit the desired biological activity.

[0077] Antibody fragments include, inter alia, Fab, Fab', F(ab'), Fv, domain antibodies (dAbs), complementarity determining region (CDR) fragments, CDR-grafted antibodies, single-chain antibodies (scFv), single-chain antibody fragments, chimeric antibodies, nanobodies, small modular immunopharmaceuticals (SMIPs), antigen-binding domain immunoglobulin fusion proteins, single-domain antibodies (including camelized antibodies), VHH-containing antibodies, or variants or derivatives thereof, as well as antigen-binding portions of antibodies comprising a polypeptide comprising at least a portion of an immunoglobulin sufficient to confer specific antigen binding to the polypeptide, e.g., one, two, three, four, five, or six CDR sequences.

[0078] "Valency" refers to the number of antigen-binding sites on each antibody or antibody fragment that target an epitope. A typical full-length IgG molecule or F(ab)2 is "bivalent" in that it has two identical target-binding sites. "Monovalent" antibody fragments, such as F(ab)' or scFc, have a single antigen-binding site. Trivalent or tetravalent antigen-binding proteins can also be engineered to be multivalent.

[0079] A "monoclonal antibody" refers to an antibody obtained from a population of substantially homogeneous antibodies, i.e., the individual antibodies comprising the population are identical except for possible naturally occurring mutations that may be present in minor amounts.

[0080] The term "inhibiting TSLP activity" includes inhibiting any one or more of the following: binding of TSLP to its receptor; proliferation, activation, or differentiation of TSLPR-expressing cells in the presence of TSLP; inhibition of Th2 cytokine production in a polarization assay in the presence of TSLP; activation or maturation of dendritic cells in the presence of TSLP; and mast cell cytokine release in the presence of TSLP. See, e.g., U.S. Pat. No. 7,982,016 B2, column 6 and Example 8, and U.S. Patent Application Publication No. 2012 / 0020988 A1, Examples 7-10.

[0081] "Tezepelumab" refers to an antibody having the same amino acid sequence as INN tezepelumab-ekko. Tezepelumab also has the heavy and light chain amino acid sequences set forth in SEQ ID NOs: 13 and 14, respectively.

[0082] The term "sample" or "biological sample" refers to a specimen obtained from a subject for use in the present methods, and includes urine, whole blood, plasma, serum, saliva, sputum, skin or tissue biopsy, cerebrospinal fluid, peripheral blood mononuclear cells with in vitro stimulation, peripheral blood mononuclear cells without in vitro stimulation, intestinal lymphoid tissue with in vitro stimulation, intestinal lymphoid tissue without in vitro stimulation, intestinal lavage, bronchoalveolar lavage, nasal wash, and induced sputum.

[0083] The terms "treat," "treating," and "treatment" refer to the partial or complete elimination, reduction, inhibition, or amelioration, temporarily or permanently, of the clinical symptoms, onset, or progression of an event, disease, or condition associated with an inflammatory disorder described herein. As recognized in the relevant art, a drug used as a therapeutic agent can reduce the severity of a given pathology, but need not necessarily eliminate every occurrence of the disease to be considered a useful therapeutic agent. Similarly, a prophylactically administered treatment need not necessarily be completely effective in preventing the onset of symptoms to constitute a viable prophylactic agent. It is sufficient to merely reduce the impact of the disease (e.g., by reducing the number or severity of its symptoms, or by improving the effectiveness of another treatment, or by producing another beneficial effect), or reduce the likelihood that the disease will develop or worsen in the subject. One embodiment of the present invention relates to a method for measuring the effectiveness of a treatment, comprising administering a therapeutic agent to a patient in an amount and for a time sufficient to produce a sustained improvement over baseline in an indicator reflective of the severity of a particular disorder.

[0084] The term "therapeutically effective amount" refers to an amount of a therapeutic agent effective to ameliorate or alleviate the symptoms or signs of disease associated with a disease or disorder.

[0085] Chronic rhinosinusitis with nasal polyps (CRSwNP) Chronic rhinosinusitis with nasal polyposis (CRSwNP) is a chronic, heterogeneous inflammatory state of the nasal and sinonasal mucosa (Fokkens et al., 2020). While the underlying etiology of the disease is currently unknown, type 2 (T2)-driven inflammation has recently been shown to be a major process in CRSwNP, and therapeutic agents targeting T2 inflammation have demonstrated efficacy in CRSwNP (Gevaert et al., 2011, Bachert et al., 2016, Bachert et al., 2017, Bachert et al., 2019, Gevaert et al., 2020). Thymic stromal lymphopoietin (TSLP) is an epithelial cytokine released in response to airborne environmental triggers. TSLP drives T2 cytokine release from Th2 and ILC2 cells and may influence other immune cells present in NP tissues. TSLP levels are elevated in nasal polyp tissue from patients with CRSwNP compared with healthy sinus tissue or sinus tissue from patients with CRS without NP (Kimura S et al., 2011; Nagarkar DR et al., 2013). Thus, TSLP may play a role in the initiation and maintenance of CRSwNP, and blocking it is predicted to be beneficial for patients.

[0086] Currently available biologic treatments for NP have success rates ranging from approximately 40% to 60% (Gevaert et al., 2011; Bachert et al., 2016; Bachert et al., 2017; Bachert et al., 2019; Gevaert et al., 2020). There are two possible explanations for the lack of complete response to biologics. First, once polyps reach symptomatic size, reduction of inflammatory cells and / or inflammation may limit and reduce new growth, but may not be able to substantially reduce polyp size in the presence of persistent tissue fibrosis (Stevens et al., 2016). The contribution of TSLP to extracellular matrix (ECM) deposition may be indirect, as an initiator of the inflammatory process that drives fibrosis, or it may be direct, as TSLP has been shown to affect or be produced by lung fibroblasts (reviewed in Gauvreau et al., 2020). Furthermore, in CRSwNP, TSLP has been shown to indirectly stimulate fibroblasts via CST-1 (Kato et al., 2019) and induce periostin, a matricellular signaling protein demonstrated to regulate ECM structure and organization through its ability to bind to the ECM and promote collagen fibrillogenesis and cross-linking. This suggests that, in addition to its anti-inflammatory MOA, treatment with tezepelumab may potentially have anti-fibrotic effects that could result in improvement of CRSwNP. Because the kinetics of ECM turnover are known to be slow, the proposed 52-week treatment period would be necessary to allow sufficient time for ECM changes to occur. Continued improvement in NPS scores beyond week 24 can be expected based on this potential anti-fibrotic MOA for tezepelumab.

[0087] Second, there is a subset of CRSwNP patients who do not have T2-mediated disease. Subgroup analyses in the tezepelumab phase 2b and 3 trials in asthma patients (PATHWAY, NCT02054130 and NAVIGATOR, NCT03347279) showed that tezepelumab benefited participants with low and high baseline eosinophil counts and low and high baseline T2 profiles. These analyses suggest that tezepelumab, unlike other biologics currently available on the market for the treatment of severe asthma, is effective in patients with high and low T2 airway inflammation and may be effective in patients with low and high T2 CRSwNP. Tezepelumab is hypothesized to reduce asthma-associated anti-inflammatory responses (AAERs) by acting as an airway anti-inflammatory drug.

[0088] The eosinophilic (high type 2) endotype of CRSwNP is most common in the United States, Europe, and Japan, while the non-eosinophilic endotype is more frequent in other Asian countries (Lou H et al., 2018; Hull and Chandra, 2017; Fokkens et al., 2020; Shin SH et al., 2014; Chitsuthipakorn W et al., 2018).

[0089] Epidemiological, pathophysiological, and clinical evidence strongly links CRSwNP to asthma, supporting the "united airway" concept for chronic inflammatory diseases of the upper and lower airways. Both diseases are co-morbid conditions (Hakansson K et al., 2015). Compared with non-asthmatics, asthmatics have a higher prevalence of CRS and CRSwNP and higher severity of sinusitis (Jarvis et al., 2012; Seybt et al., 2007; Pearlman et al., 2009; Tint et al., 2016; Settipane 1977). Furthermore, asthmatic subjects with CRSwNP may have poorly controlled asthma, increased airway obstruction, and more severe lower airway inflammation compared to subjects without CRSwNP (Bilodeau et al., 2010). Concomitant asthma in patients with CRSwNP is associated with a lower quality of life (Alobid I et al., 2005, Ehnhage A et al., 2009). Mechanistically, both NP and severe eosinophilic asthma are considered diseases caused by type 2 (T2), and the inflammatory profile is similar between the upper airways in NP and the lower airways in asthma (Fokkens et al., 2020, Chaaban MR et al., 2013). As with asthma, the role of eosinophils is thought to be important in the pathology of NP in a high proportion of patients.

[0090] Asthma and CRSwNP share some pathophysiology and common comorbidities. A post-hoc analysis of patients with nasal polyps in the PATHWAY study population revealed that 15.2% of subjects had CRSwNP. Compared with placebo, asthma patients with NP treated with tezepelumab showed improvements in AERR, FEV1, and ACQ-6, as well as T2 inflammatory biomarkers, to a similar extent as non-NP asthma patients. These findings support the rationale for the broad efficacy of tezepelumab in asthma and its potential efficacy in CRSwNP (Emson C et al., 2020; Emson C et al., 2021).

[0091] Although the etiology of NP is still thought to be unknown, allergies, asthma, infections, and aspirin hypersensitivity (AERD) have all been associated with this complex, intractable disease in adults (Hull and Chandra 2017). Both NP and asthma are T2-driven disease processes characterized by eosinophil infiltrates in affected tissues, either polyps or airways. The inflammatory profile observed in asthma shares many features and similarities with the inflammation observed in NP patients, where eosinophils are the primary effector cells in the pathophysiology of both upper airway sinusitis and lower airway asthma (Hakansson K et al. 2015; Ediger et al. 2005).

[0092] Nasal polyps are recognized as the result of chronic inflammatory disease of the nasal mucosa. Their presence can cause long-term symptoms, including significant nasal obstruction, postnasal drip and nasal discharge, anosmia, and facial pain. These symptoms can significantly impact patients' quality of life. Patients with CRSwNP have been observed to have worse symptoms (as evidenced by higher Nasal and Sinus Outcome Test (SNOT)-22 scores), more severe disease on imaging (as evidenced by Lund-Mackay and modified LMK computed tomography [CT] scores), and require more frequent reoperations than patients with CRSsNP (Hull and Chandra 2017; Fokkens et al. 2020).

[0093] Nasal polyps are an area of ​​significant unmet medical need, particularly for the subset of NP patients who have exhausted current treatment options, including medical interventions (intranasal corticosteroids (INCS), systemic corticosteroids (SCS), and antibiotics) and surgical intervention. Both patients and healthcare professionals point to a greater need for novel therapies that reduce the need for repeated SCS or surgery for all NP patients. While surgery to remove polyps is still considered in patients whose symptoms are not controlled with corticosteroids, recurrence rates are high (approximately 40% 12 months after surgery), and repeat surgical intervention is often required. INCS continues after surgery; nevertheless, even when treated with currently available therapies, a proportion of patients experience recurrence after surgery, and these participants are at even higher risk of recurrence if they undergo further surgery (Fokkens et al., 2020; Orlandi RR et al., 2013; Agarwal et al., 2019; van der Veen et al., 2017).

[0094] Chronic rhinosinusitis without nasal polyps (CRSsNP) has also been detected in patients with allergic and non-allergic upper and lower respiratory tract diseases, epithelial cell disorders, immunodeficiency, autoimmune diseases, certain infections, a high incidence of abnormal biofilms, and congenital immune disorders (Cho et al., J Allergy Clin Immunol Pract. 2016 4(4):575-582). Characterization of subjects with CRSsNP is described in "Chronic Rhinosinusitis Without Nasal Polyps: Clinical Characteristics and Comorbid Diseases," The Journal of Allergy and Clinical Immunology: In Practice 2018.

[0095] Chronic sinusitis can be assessed using several objective and subjective scales, such as the Nasal Polyp Score and the Nasal Congestion Score. This scale allows the investigator to assess overall disease severity at a given time point and consists of a 4-point severity scale ranging from "clear" to severe disease (0 = no disease; 1 = mild; 2 = moderate disease; 3 = severe disease). The NPS is the sum of the left and right nostril scores (maximum 8), assessed by nasal endoscopy. The total NPS is graded based on polyp size, as described in Table 2.

[0096] Further measures of chronic sinusitis severity / improvement include the Nasal Polyp Symptom Diary (NPSD) and Nasal Polyp Symptom Screening Assessment (NPSSA), anosmia, Nasal and Sinus Outcome Test-22 (SNOT-22), EuroQOL Quality of Life 5 Dimension 3 Level (EQ-5D-3L), Asthma Control Questionnaire (ACQ-6), Lund-Mackay score, modified Lund-Mackay score, incidence of nasal polyp surgery, and / or systemic corticosteroids (SCS).

[0097] The Nasal Polyp Symptom Diary (NPSD) and Nasal Polyp Symptom Screening Assessment (NPSSA) are 11-item NP symptom diaries completed every morning throughout the screening, treatment, and follow-up periods. Participants are asked to reflect on their NP / nasal polyp experience over the past 24 hours when answering each question. Participants are asked to report their experience of NP symptoms (nasal congestion, nasal obstruction, runny nose, postnasal drip (mucus discharge down the throat), headache, facial pain, facial pressure, and loss of smell) and symptom impact (interference with sleep due to nasal symptoms, and interference with daily activities due to nasal symptoms). Participants report the severity and symptom impact of each symptom at their worst using a 4-point verbal rating scale (0 = none to 3 = severe). A total symptom score (TSS) is calculated by summing eight equally weighted symptom items. After the symptom and symptom impact items, a single item (yes or no) is provided to record INCS compliance.

[0098] The nasal congestion score (NCS) is recorded by an item on the NPSD, which asks participants to rate the severity of their worst nasal congestion over the past 24 hours using the following response options: 0 - none; 1 - mild; 2 - moderate; 3 - severe.

[0099] Anosmia is recorded by an item on the NPSD, in which participants are asked to rate the severity of their worst olfactory impairment over the past 24 hours using the following response options: 0 - none; 1 - mild; 2 - moderate; 3 - severe.

[0100] The SNOT-22 is a condition-specific health-related quality of life (HRQoL) assessment that records participant-reported physical problems, functional limitations, and emotional consequences of nasal and sinus conditions (Piccirillo et al., 2002; Hopkins et al., 2009). Patient-reported symptom severity and symptom impact are recorded on a 6-point scale (0—no problems to 5—worst possible problems). The total score is the sum of item scores and ranges from 0 to 110 (higher scores indicate poorer outcomes). A minimal clinically important difference (MCID) of 8.90 for individual score changes has been established as a clinically important improvement (Hopkins et al., 2009).

[0101] Asthma Control Questionnaire (Asthma / AERD / NSAID-ERD participants only): The Asthma Control Questionnaire (ACQ-6) is an assessment of asthma symptoms (nighttime awakenings, awakening symptoms, activity limitations, shortness of breath, wheezing, and short-acting beta-agonist use). Participants are asked to recall their level of asthma control during the past week by answering one question about bronchodilator use and five questions about symptoms. Questions are equally weighted and scored from 0 (completely controlled) to 6 (severely uncontrolled). The mean ACQ-6 score is the average of the responses. A mean score of ≤0.75 indicates well-controlled asthma, a score of 0.75 to <1.5 indicates partially controlled asthma, and a score of ≥1.5 indicates poorly controlled asthma (Juniper et al., 2006). An individual change of at least 0.5 is considered a clinically important improvement.

[0102] The University of Pennsylvania Odor Identification Test (UPSIT) is a quantitative test of olfactory function that uses microencapsulated odorants that are released by scratching a standardized odor-impregnated test booklet (Doty et al., 1984). Four booklets, each containing 10 odorants, are used in the test. Participants are asked to identify odors using a multiple-choice format that lists various possibilities. The test is forced-choice; participants must mark one of four options, even if the odor is not detected. Scoring is based on the number of correctly identified odors (score range 0–40).

[0103] The Patient Global Impression of Severity (PGI-S) is a single item designed to record participants' perception of the severity of their overall NP symptoms at the time of completion, using a 6-point categorical response scale (0 - no symptoms to 5 - very severe). The Patient Global Impression of Change (PGI-C) tool records participants' global assessment of their response to treatment since the first dose of IP. Participants are asked to report how much their health status has changed using a 7-point scale (1 - much improved to 7 - much worse).

[0104] The Work Productivity and Activity Impairment Questionnaire (WPAI, General Health Version 2.0) is a self-administered tool consisting of six questions addressing absenteeism, presenteeism (reduced efficiency at work), overall work productivity loss (absenteeism + presenteeism), and activity impairment. This validated tool records data for the past 7 days. WPAI outcomes are scored as percentage impairment, with higher percentages indicating greater impairment and lower productivity (Reilly et al. 1993).

[0105] The Lund-Mackay scoring system is used to provide a semiquantitative assessment of the paranasal sinuses on sinus CT scans (Lund and Mackay 1993). Based on the sinus CT images, five sinuses on each side (maxillary, anterior ethmoid, posterior ethmoid, sphenoid, and frontal sinuses) are scored.

[0106] The EuroQOL Quality of Life 5 Dimensions 3 Level (EQ-5D-3L) is a standardized tool for use as a measure of health-related quality of life (HRQoL) developed by EuroQol (Brooks, 1996). It defines health in terms of five dimensions: mobility, self-care, daily activities, pain / discomfort, and anxiety / depression. Each dimension has three ordinal levels of severity: 1: no problem, 2: some problem, and 3: severe problem. Overall health status is defined as a five-digit number.

[0107] TSLP Thymic stromal lymphopoietin (TSLP) is an epithelial cell-derived cytokine that is produced in response to proinflammatory stimuli and drives allergic inflammatory responses primarily through its activity on dendritic cells (Gilliet, J Exp Med. 197:1059-1067, 2003; Soumelis, Nat Immunol. 3:673-680, 2002; Reche, J Immunol. 167:336-343, 2001), mast cells (Allakhverdi, J Exp Med. 204:253-258, 2007), and CD34+ progenitor cells. 9 TSLP signals through a heterodimeric receptor consisting of the interleukin (IL)-7 receptor alpha (IL-7Rα) chain and the common gamma chain-like receptor (TSLPR) (Pandey, Nat Immunol. 1:59-64, 2000; Park, J Exp Med. 192:659-669 (2000)).

[0108] Data from other studies suggest that TSLP may promote airway inflammation through Th2-independent pathways, such as crosstalk between airway smooth muscle and mast cells (Allakhverdi et al., J Allergy Clin Immunol. 123(4):958-60, 2009; Shikotra et al., supra). TSLP may also promote the induction of T cells to differentiate into Th-17 cytokine-producing cells, resulting in increased neutrophilic inflammation commonly seen in more severe asthma (Tanaka et al., Clin Exp Allergy. 39(1):89-100, 2009). These data, along with other emerging evidence, suggest that blocking TSLP may play a role in suppressing multiple biological pathways, including but not limited to those involving Th2 cytokines (IL-4 / IL-13 / IL-5).

[0109] antibody Antibodies or antibody variants specific for TSLP are believed to be useful in the treatment of chronic sinusitis, including moderate or severe chronic sinusitis, chronic sinusitis with or without nasal polyps, and / or chronic sinusitis with or without asthma / AERD / NSAID-ERD.

[0110] Antibodies or antibody variants specific for TSLP are believed to be useful in the treatment of chronic sinusitis, including moderate or severe chronic sinusitis, chronic sinusitis with nasal polyps, and / or chronic sinusitis with or without asthma / AERD / NSAID-ERD.

[0111] Specific binding agents, such as antibodies and antibody variants or fragments, that bind to a target antigen, e.g., TSLP, are useful in the methods of the present disclosure. In one embodiment, the specific binding agent is an antibody. The antibody can be monoclonal (MAb); recombinant; chimeric; humanized, such as complementarity-determining region (CDR)-grafted; human; antibody variants, including single chains; and / or bispecifics; as well as fragments, mutants, or derivatives thereof. Antibody fragments include those portions of antibodies that bind to an epitope on a polypeptide of interest. Examples of such fragments include Fab and F(ab') fragments generated by enzymatic cleavage of full-length antibodies. Other binding fragments include fragments generated by recombinant DNA techniques, such as expression of recombinant plasmids containing nucleic acid sequences encoding antibody variable regions.

[0112] Monoclonal antibodies may be modified for use as therapeutic or diagnostic agents. One embodiment 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 derived from a particular species or belonging to a particular antibody class or subclass, while the remainder of the chain is identical to or homologous to corresponding sequences in antibodies derived 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. Pat. No. 4,816,567; Morrison et al., 1985, Proc. Natl. Acad. Sci. 81:6851-55.

[0113] In another embodiment, the monoclonal antibody is a "humanized" antibody. Methods for humanizing non-human antibodies are well known in the art. See U.S. Patent Nos. 5,585,089 and 5,693,762. Generally, a humanized antibody has one or more amino acid residues introduced into it from a non-human source. Humanization can be performed using methods described in the art, for example, by substituting at least a portion of a rodent complementarity-determining region for the corresponding region of a human antibody (Jones et al., 1986, Nature 321:522-25; Riechmann et al., 1998, Nature 332:323-27; Verhoeyen et al., 1988, Science 239:1534-36). For example, in CDR grafting, non-human CDR sequences are inserted into human framework regions (Lu et al. Journal of Biomedical Science (2020) 27:1).

[0114] Human antibodies and antibody variants (including antibody fragments) that bind to TSLP are also encompassed by the present disclosure. Human antibodies refer to antibodies made from human immunoglobulin sequences and containing human variable and constant regions. Such antibodies are produced by immunizing transgenic animals (e.g., mice) that are capable of producing a repertoire of human antibodies without producing endogenous immunoglobulins with a polypeptide antigen (i.e., having at least six consecutive amino acids), optionally conjugated to a carrier. See, e.g., Jakobovits et al., 1993, Proc. Natl. Acad. Sci. 90:2551-55; Jakobovits et al., 1993, Nature 362:255-58; Bruggermann et al., 1993, Year in Immuno. 7:33. See also PCT Application Nos. PCT / US96 / 05928 and PCT / US93 / 06926. Additional methods are described in U.S. Patent No. 5,545,807, PCT Application Nos. PCT / US91 / 245 and PCT / GB89 / 01207, and European Patent Nos. 546073B1 and 546073A1. Alternatively, "human" antibodies can be produced by synthetically producing human antibodies using human constant and framework regions. Human antibodies can also be produced by expression of recombinant DNA in host cells, or by expression in hybridoma cells as described herein, by using phage display libraries, or by cloning single B cells (Lu et al. Journal of Biomedical Science (2020) 27:1). It is understood that human, humanized, or chimeric antibodies may contain mutations or modifications that enhance antibody stability or extend antibody half-life, such as SEFL, YTE, and other modifications known in the art (see, e.g., Wang et al., Protein Cell. 2018 9:63-73).

[0115] Chimeric, CDR-grafted, and humanized antibodies and / or antibody variants are typically produced by recombinant methods. Nucleic acid encoding the antibody is introduced into a host cell and expressed using the materials and procedures described herein. In a preferred embodiment, the antibody is produced in a mammalian host cell, such as a CHO cell. Monoclonal (e.g., human) antibodies can be produced by expression of recombinant DNA in a host cell or in hybridoma cells as described herein. Additional mutations can be made in human, humanized, or chimeric antibodies to improve stability or half-life. Such mutations are known in the art.

[0116] Antibodies and antibody variants (including antibody fragments) useful in the methods of the present invention include anti-TSLP antibodies that comprise: a. a light chain variable domain comprising: i. a light chain CDR1 sequence comprising the amino acid sequence set forth in SEQ ID NO: 3; ii. a light chain CDR2 sequence comprising the amino acid sequence set forth in SEQ ID NO: 4; and iii. a light chain CDR3 sequence comprising the amino acid sequence set forth in SEQ ID NO: 5; and b. a heavy chain variable domain comprising: i. a heavy chain CDR1 sequence comprising the amino acid sequence set forth in SEQ ID NO: 6; ii. a heavy chain CDR2 sequence comprising the amino acid sequence set forth in SEQ ID NO: 7; and iii. a heavy chain CDR3 sequence comprising the amino acid sequence set forth in SEQ ID NO: 8, wherein the antibody or antibody variant specifically binds to the TSLP polypeptide set forth in amino acids 29 to 159 of SEQ ID NO: 2.

[0117] Also provided is an antibody or antibody variant comprising: a. a light chain variable domain selected from the group consisting of: a. a sequence of amino acids at least 80% identical to SEQ ID NO: 12; ii. a sequence of amino acids encoded by a polynucleotide sequence at least 80% identical to SEQ ID NO: 11; iii. a sequence of amino acids encoded by a polynucleotide that hybridizes under moderately stringent conditions to the complement of the polynucleotide consisting of SEQ ID NO: 11; and b. a sequence of amino acids at least 80% identical to SEQ ID NO: 10; ii. a sequence of amino acids encoded by a polynucleotide sequence at least 80% identical to SEQ ID NO: 9; iii. a heavy chain variable domain selected from the group consisting of: a sequence of amino acids at least 80% identical to SEQ ID NO: 9; or c. a light chain variable domain of (a) and a heavy chain variable domain of (b), wherein the antibody or antibody variant specifically binds to the TSLP polypeptide represented by amino acids 29 to 159 of SEQ ID NO: 2.

[0118] Tezepelumab is an exemplary anti-TSLP antibody having a.i. a light chain CDR1 sequence comprising the amino acid sequence set forth in SEQ ID NO:3; ii. a light chain CDR2 sequence comprising the amino acid sequence set forth in SEQ ID NO:4; iii. a light chain CDR3 sequence comprising the amino acid sequence set forth in SEQ ID NO:5, and b. a heavy chain variable domain comprising: i. a heavy chain CDR1 sequence comprising the amino acid sequence set forth in SEQ ID NO:6; ii. a heavy chain CDR2 sequence comprising the amino acid sequence set forth in SEQ ID NO:7, and iii. a heavy chain CDR3 sequence comprising the amino acid sequence set forth in SEQ ID NO:8.

[0119] Tezepelumab also comprises a light chain variable domain having the amino acid sequence set forth in SEQ ID NO:12, which is encoded by the polynucleotide sequence set forth in SEQ ID NO:11; and a heavy chain variable domain having the amino acid sequence set forth in SEQ ID NO:10, which is encoded by the polynucleotide sequence set forth in SEQ ID NO:9.

[0120] Tezepelumab is an IgG2 antibody. The full-length heavy and light chain sequences of tezepelumab, including the IgG2 chain, are set forth in SEQ ID NOs: 13 and 14, respectively.

[0121] Exemplary sequences for tezepelumab are set forth in U.S. Pat. No. 7,982,016, and include SEQ ID NOs: 13, 60, 105, 145, 173, 212; SEQ ID NOs: 361 and 363; and a light chain comprising a light chain variable domain comprising the amino acid sequence set forth in SEQ ID NO: 363 and a lambda light chain constant domain comprising the amino acid sequence set forth in SEQ ID NO: 369, and a heavy chain comprising a heavy chain variable domain comprising the amino acid sequence set forth in SEQ ID NO: 361 and an IgG2 heavy chain constant domain comprising the amino acid sequence set forth in SEQ ID NO: 365, which are incorporated herein by reference.

[0122] In various embodiments, anti-TSLP antibody derivatives for use in the methods are provided. Anti-TSLP antibody derivatives are described in WO 2022 / 226342 and WO 2022 / 226339, the entire contents of which are incorporated herein by reference. Exemplary derivatives include tezepelumab antibodies that may have modifications after purification or after prolonged storage of the antibody, including, but not limited to, isomerized derivatives, deamidated derivatives, oxidized derivatives, glycosylated derivatives, disulfide isoform derivatives, and / or high molecular weight (HMW) species or antibody fragments. Exemplary derivatives also can be variants having the amino acid sequences set forth in SEQ ID NOS: 13-36 of WO 2022 / 226342, as well as variants of SEQ ID NOS: 3-8 therein (e.g., containing residues identified in the anti-TSLP antibody tezepelumab CDRs (SEQ ID NOS: 3-8) or in the variable regions (SEQ ID NOS: 10 and 12) as potentially causing reduced stability, including CDRH1 M34, CDRH2 W52, CDRH2 D54, CDRH2 N57, CDRH2 D62, CDRH3 W102, FRH1 N25, FRH1 N26, CDRL2 D49, CDRL2 D50, FRL2 N65, CDRL3 W90, CDRL3 D91, CDRL3 S92, S93, S94, and / or CDRL3 D95).

[0123] In various embodiments, the anti-TSLP antibody or antibody variant thereof is bivalent and is selected from the group consisting of a human antibody, a humanized antibody, a chimeric antibody, a monoclonal antibody, a recombinant antibody, an antigen-binding antibody fragment, a single-chain antibody, a monomeric antibody, a Fab fragment, an IgG1 antibody, an IgG2 antibody, an IgG3 antibody, and an IgG4 antibody.

[0124] In various embodiments, the anti-TSLP antibody is bivalent and is selected from the group consisting of a human antibody, a humanized antibody, a chimeric antibody, a monoclonal antibody, a recombinant antibody, an IgG1 antibody, an IgG2 antibody, an IgG3 antibody, and an IgG4 antibody.

[0125] In various embodiments, the anti-TSLP antibody variant is selected from the group consisting of a Fab fragment, a single domain antibody, and an scFv, where the dosage is adjusted so that the binding sites are equimolar to that administered by the bivalent antibody.

[0126] The antibody is believed to be an IgG2 antibody. An exemplary sequence of the constant region of human IgG2 is available from the Uniprot database as Uniprot number P01859, and is incorporated herein by reference. Information, including sequence information, regarding the heavy and light chain constant regions of other antibodies is also publicly available through the Uniprot database, as well as other databases familiar to those skilled in the art of antibody engineering and antibody production.

[0127] In certain embodiments, antibody derivatives include tetrameric glycosylated antibodies in which the number and / or type of glycosylation sites are altered compared to the amino acid sequence of the parent polypeptide. In certain embodiments, variants contain more or fewer N-linked glycosylation sites than the native protein. Alternatively, substitutions that delete this sequence result in the removal of existing N-linked carbohydrate chains. Alternatively, one or more N-linked glycosylation sites (typically naturally occurring) are deleted, resulting in the rearrangement of N-linked carbohydrate chains, creating one or more new N-linked sites. Further preferred antibody variants include cysteine ​​mutants in which one or more cysteine ​​residues are deleted or substituted with another amino acid (e.g., serine) compared to the parent amino acid sequence. Cysteine ​​variants may be useful when antibodies must be refolded into a biologically active conformation, such as after isolation of insoluble inclusion bodies. Cysteine ​​variants generally have fewer cysteine ​​residues than the native protein, and typically have an even number to minimize interactions resulting from unpaired cysteines.

[0128] Desired amino acid substitutions (whether conservative or non-conservative) can be determined by one of skill in the art at the time such substitutions are desired. In certain embodiments, amino acid substitutions can be used to identify residues of antibodies that are important for human TSLP, to increase or decrease the affinity of the antibodies described herein for human TSLP, or to increase stability or extend half-life (e.g., YTE mutations).

[0129] According to certain embodiments, preferred amino acid substitutions are those that (1) reduce susceptibility to proteolysis, (2) reduce susceptibility to oxidation, (3) alter binding affinity for forming protein complexes, (4) alter binding affinity, and / or (5) confer or modify other physiochemical or functional properties to such polypeptides. According to certain embodiments, single or multiple amino acid substitutions (in certain embodiments, conservative amino acid substitutions) may be made within the naturally occurring sequence (in certain embodiments, portions of the polypeptide outside the domains that form intermolecular contacts). In certain embodiments, conservative amino acid substitutions may typically not substantially alter the structural features of the parent sequence (e.g., the substituted amino acid should not tend to disrupt helices present in the parent sequence or other types of secondary structure that characterize the parent sequence). Examples of art-recognized polypeptide secondary and tertiary structures are described in Proteins, Structures and Molecular Principles (Creighton, Ed., W.H. Freeman and Company, New York (1984)); Introduction to Protein Structure (C. Branden and J. Tooze, eds., Garland Publishing, New York, NY (1991)); and Thornton et al. Nature 354:105 (1991), each of which is incorporated herein by reference.

[0130] Administration method In one aspect, the methods of the disclosure comprise administering a therapeutic anti-TSLP antibody or antibody variant described herein, optionally in a pharmaceutically acceptable carrier or excipient. In certain embodiments, the pharmaceutical composition is a sterile composition.

[0131] Provided herein are methods for treating chronic sinusitis in a subject, including severe or moderate chronic sinusitis, chronic sinusitis with or without nasal polyps, and / or chronic sinusitis associated with asthma, AERD, or NSAID-ERD. In various embodiments, the method includes selecting a subject in need of treatment for chronic sinusitis and administering an anti-TSLP antibody described herein. In various embodiments, the chronic sinusitis is associated with nasal polyps. In various embodiments, the subject has moderate or severe asthma. In various embodiments, the subject has moderate asthma.

[0132] In various embodiments, the antibody is tezepelumab or another anti-TSLP antibody described in the art. Exemplary anti-TSLP antibodies include those described in WO 2017 / 042701, WO 2016 / 142426, WO 2010 / 017468, U.S. Patent Application Publication No. 20170066823, U.S. Patent Application Publication No. 20120020988, and U.S. Patent Application Publication No. 8637019, which are incorporated herein by reference, some of which are described in Table A below. In exemplary embodiments, the anti-TSLP antibody is an antibody selected from the group consisting of antibodies in Table A, as well as antibodies in WO 20220226342A1, WO 20220226339A1, WO 2023098491A1, WO 2021155634A1, WO 2022166072A1, WO 2021043221A1, WO 2022184074A1, WO 2021104053A1, WO 2023116925A1, and WO 2021155861A1, the disclosures of each of which are incorporated herein by reference. No. 2022116858A1, WO 2022117079A1, WO 2020244544A1, WO 2021152488A1, WO 2022253147A1, WO 2023070948A1, WO 2023142309A1, WO 2022095689A1, WO 2021115240A1, WO 2022166739A1, and WO 2019100111A1.

[0133] [Table 1]

[0134] [Table 2]

[0135] [Table 3]

[0136] [Table 4]

[0137] [Table 5]

[0138] [Table 6]

[0139] The subject of treatment is intended to be a human. The subject may be an adult, an adolescent, or a child.

[0140] Therapeutic antibody (or antibody variant) compositions can be delivered to a patient at multiple sites. Multiple administrations can occur simultaneously or can be administered over a period of time. In certain cases, it is beneficial to provide a continuous flow of therapeutic composition. Additional therapy can be administered periodically, for example, hourly, daily, weekly, every two weeks, every three weeks, monthly, every two months, or at longer intervals.

[0141] In various embodiments, the amount in a given dose of a therapeutic agent, such as a bivalent antibody having two TSLP binding sites, can vary depending on the characteristics of the disorder being treated as well as the size of the individual to whom the treatment is administered.

[0142] In an exemplary treatment, the anti-TSLP antibody or antibody variant is administered at a dose range of about 140 mg to about 420 mg per dose. In various embodiments, doses may be administered at about 140 mg, 210 mg, 280 mg, or 420 mg. In various embodiments, the anti-TSLP antibody or antibody variant may be administered at a dose of about 140, 150, 160, 170, 180, 190, 200, 210, 220, 230, 240, 250, 260, 270, 280, 290, 300, 310, 320, 330, 340, 350, 360, 370, 380, 390, 400, 410, or 420 mg per dose. These concentrates may be administered as a single dosage form or as multiple doses. The above doses may be administered every two weeks or every four weeks. In various embodiments, the anti-TSLP antibody or antibody variant is administered in a single dose of 210 mg every two weeks or every four weeks. In various embodiments, the anti-TSLP antibody or antibody variant is administered in a single dose of 210 mg every four weeks.

[0143] With respect to antibody variants, the amount of antibody variant should be such that the number of TSLP binding sites present in a dose has an equimolar number of TSLP binding sites relative to the canonical bivalent antibody described above.

[0144] The anti-TSLP antibody or antibody variant is administered every two weeks or every four weeks for at least four months, six months, nine months, one year, or more. In various embodiments, administration is subcutaneous or intravenous.

[0145] Treatment with an anti-TSLP antibody or antibody variant is provided to improve one or more of the following measures of chronic rhinosinusitis (with or without nasal polyps): Nasal Polyp Score (NPS), Nasal Congestion Score (NCS), anosmia, Nasal and Sinus Outcome Test-22 (SNOT-22), EuroQOL Quality of Life 5 Dimension 3 Level (EQ-5D-3L), Asthma Control Questionnaire (ACQ-6), Lund-Mackay score, modified Lund-Mackay score, incidence of nasal polyp surgery, and / or systemic corticosteroids (SCS).

[0146] In one embodiment, the administration improves one or more symptoms of chronic sinusitis including nasal congestion, nasal obstruction, runny nose, postnasal drip, mucus discharge down the throat, significant nasal blockage, runny nose, loss of smell, headache, facial pain, facial pressure, olfactory disturbance, asthma symptoms, disturbance of sleep due to nasal symptoms, and disturbance of daily activities due to nasal symptoms, optionally as measured by an electronic diary of the chronic sinusitis patient.

[0147] The improvement in score is considered to be related to the minimum clinically important difference (MCID) in symptom measurements for patients treated according to the methods herein, or the least squares mean difference compared to the placebo group. MCID refers to the smallest improvement considered therapeutically relevant by a patient or physician. See, for example, Cook et al., J Man Manip Ther. 2008;16(4):E82-E83; Phillips et al., Clin Otolaryngol 2018 43(5):1328-1334.

[0148] For example, clinically relevant improvements in nasal congestion score (NC) include an MCID of 0.5 to 1.2, e.g., 0.5, 0.6, 0.7, 0.8, 0.89, 0.9, 1.0, 1.1, or 1.2 or more, compared to baseline or untreated control levels. Clinically relevant improvements in nasal polyp score (NPS) include an MCID of 1 to 3, e.g., 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2.0, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, or 3.0, compared to baseline or untreated control levels. Clinically relevant improvements include a reduction in systemic corticosteroid and / or surgical treatment by an MCID of 60% to 90%, e.g., 60%, 65%, 70%, 75%, 80%, 85%, or 90%, compared to baseline or untreated control levels. Clinically relevant improvements include a reduction in the need for nasal surgery by an MCID of 60% to 90%, e.g., 60%, 65%, 70%, 75%, 80%, 85%, or 90%, compared to baseline or untreated control levels. Clinically relevant improvements in Lund-Mackay score include an MCID of 5 to 10, e.g., 5, 6, 7, 8, 9, or 10, compared to baseline or untreated control levels. Clinically relevant improvements in nasal and sinus symptoms (SNOT-22) include an MCID compared to baseline or untreated control levels of 15 to 30, e.g., 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30. Comparisons can be made over the entire treatment period, e.g., at week 28 or week 52 or later.

[0149] In various embodiments, the NPS or NCS score is reduced by 1 point, 2 points, or 3 points. In various embodiments, the subject has an NPS of 0 (none) or 1 (mild) at 52 weeks post-treatment.

[0150] In various embodiments, anti-TSLP treatment modulates the levels of one or more biomarkers of chronic rhinosinusitis, including cytokines, IgE, CCL17, CCL18, CCL22, and RNA transcriptional changes in the nasal epithelium. In various embodiments, anti-TSLP treatment reduces the levels of Th2 cytokines. In various embodiments, treatment modulates the levels or activity of IL-4, IL-5, IL-13, IL-17, IL-22, IL-23, IL-31, or a combination thereof.

[0151] Treatment also improves one or more symptoms of chronic rhinosinusitis as measured by the Nasal Polyps Symptom Diary (NPSD) and Nasal Polyps Symptom Screening Assessment (NPSSA). Symptoms include nasal congestion, stuffiness, runny nose, postnasal drip (mucus draining down the throat), headache, facial pain, facial pressure, and loss of smell. Symptom impacts include sleep disturbance due to nasal symptoms and daily activity disturbance due to nasal symptoms; and exercise capacity, self-care, daily activities, pain / discomfort, and anxiety / depression as measured by the EuroQOL Quality of Life 5 Dimension 3 Level (EQ-5D-3L).

[0152] In various embodiments, treatment with an anti-TSLP antibody delays the time to chronic sinusitis exacerbation or flare-up compared to subjects who do not receive the anti-TSLP antibody.

[0153] Also provided in the present disclosure is the administration of multiple agents, such as an antibody composition in combination with a second agent as described herein, including, but not limited to, an anti-inflammatory agent or an asthma therapy.

[0154] However, in various embodiments, this administration reduces the frequency or level of concurrent therapy in the subject. Exemplary concurrent therapies include, but are not limited to, systemic corticosteroids, dupilumab, immunosuppressants or immunomodulators (e.g., cyclosporine, mycophenolate mofetil, interferon (IFN) gamma, Janus kinase inhibitors, azathioprine, methotrexate), anti-IL-13 antibodies, anti-IL-5 pathway antibodies (benralizumab, mepolizumab, reslizumab), or combinations thereof. In various embodiments, this administration reduces or eliminates the need for corticosteroid therapy or other adjunctive therapies.

[0155] formulation In some embodiments, the present disclosure provides for the use of pharmaceutical compositions comprising a therapeutically effective amount of an anti-TSLP antibody or antibody variant together with a pharmaceutically acceptable diluent, carrier, solubilizer, emulsifier, preservative, and / or adjuvant. Additionally, the present disclosure provides methods for treating a subject by administering such pharmaceutical compositions.

[0156] In certain embodiments, acceptable formulation materials are preferably nontoxic to recipients at the dosages and concentrations employed. In certain embodiments, pharmaceutical compositions may contain formulation materials to modify, maintain, or preserve, for example, the pH, osmolality, viscosity, clarity, color, isotonicity, odor, sterility, stability, dissolution or release rate, adsorption, or permeability of the composition. In such embodiments, suitable formulation materials include, but are not limited to, amino acids (e.g., glycine, glutamine, asparagine, arginine, or lysine); antimicrobial agents; antioxidants (e.g., ascorbic acid, sodium sulfite, or sodium bisulfite); buffers (e.g., borate, bicarbonate, Tris-HCl, citrate, phosphate, or other organic acids); bulking agents (e.g., mannitol or glycine); chelating agents (e.g., ethylenediaminetetraacetic acid (EDTA)); complexing agents (e.g., caffeine, polyvinylpyrrolidone, beta-cyclodextrin, or hydroxypropyl-beta-cyclodextrin); fillers; monosaccharides; disaccharides; and other carbohydrates (e.g., glucose, sucrose, mannose, or dextrin); proteins (e.g., serum albumin, gelatin, or immunoglobulins); colors, flavors, and diluents; emulsifiers; hydrophilic polymers (e.g., polyvinylpyrrolidone, beta-cyclodextrin, or hydroxypropyl-beta-cyclodextrin). lydone); low molecular weight polypeptides; salt-forming counterions (e.g., sodium); preservatives (e.g., benzalkonium chloride, benzoic acid, salicylic acid, thimerosal, phenethyl alcohol, methylparaben, propylparaben, chlorhexidine, sorbic acid, or hydrogen peroxide); solvents (e.g., glycerin, propylene glycol, or polyethylene glycol); sugar alcohols (e.g., mannitol or sorbitol); suspending agents; surfactants or wetting agents (e.g., pluronic, PEG, sorbitan esters, polysorbates, e.g., polysorbate 20, polysorbate, Triton, tromethamine, lecithin, cholesterol, tyloxapar); stability enhancers (e.g., sucrose or sorbitol); tonicity enhancers (e.g., alkali metal halides, preferably sodium chloride or potassium chloride, mannitol sorbitol); delivery vehicles; diluents; excipients and / or pharmaceutical adjuvants.See REMINGTON'S PHARMACEUTICAL SCIENCES, 18th Edition, (AR Genrmo, ed.), 1990, Mack Publishing Company.

[0157] Suitable vehicles or carriers may be water for injection, saline solution, or artificial cerebrospinal fluid, optionally supplemented with other materials common in compositions for parenteral administration. Neutral buffered saline or saline mixed with serum albumin are further exemplary vehicles. In certain embodiments, the pharmaceutical composition comprises Tris buffer of about pH 7.0-8.5 or acetate buffer of about pH 4.0-5.5, and may further include sorbitol or a suitable substitute thereof.

[0158] Formulation components are preferably present in concentrations that are acceptable to the site of administration. In certain embodiments, a buffer is used to maintain the composition at physiological pH or slightly lower, typically within a pH range of about 4.5 to about 8, e.g., about 4.5, about 4.6, about 4.7, about 4.8, about 4.9, about 5.0, about 5.1, about 5.2, about 5.3, about 5.4, about 5.5, about 5.6, about 5.7, about 5.8, about 5.9, about 6.0, about 6.1, about 6.2, about 6.3, about 6.4, about 6.5, about 6.6, about 6.7, about 6.8, about 6.9, about 7.0, about 7.1, about 7.2, about 7.3, about 7.4, about 7.5, about 7.6, about 7.7, about 7.8, about 7.9, and about 8.0.

[0159] In various embodiments, the anti-TSLP antibody or antibody variant is in the form of a formulation containing one or more basic amino acids (e.g., arginine, histidine, or lysine) or salts thereof, or calcium or magnesium salts thereof, and a surfactant. In various embodiments, the formulation contains 0.005% (w / v) to about 0.015% (w / v) polysorbate 20 or polysorbate 80. In various embodiments, the pH of the formulation is 4.5 to 6.8. In various embodiments, the concentration of the antibody or antibody fragment in the formulation is greater than 110 mg / ml, e.g., about 110 mg / ml to about 250 mg / ml, e.g., about 140 mg / ml to about 250 mg / ml, about 160 mg / ml to about 250 mg / ml, or about 140 mg / ml to about 210 mg / ml, or about 180 mg / ml or about 210 mg / ml. The formulation can be stored at 2°C to 8°C or -20°C to -70°C. Exemplary formulations are described in commonly owned applications PCT / US2021 / 018561 and PCT / US2021 / 17880.

[0160] When parenteral administration is performed, the therapeutic composition for use may be provided in the form of a pyrogen-free, parenterally acceptable aqueous solution containing the desired anti-TSLP antibody in a pharmaceutically acceptable vehicle. A particularly suitable vehicle for parenteral injection is sterile distilled water, in which the antibody is formulated as a sterile, isotonic solution, properly preserved. In certain embodiments, the formulation may include a formulation of the desired molecule with an agent that can provide sustained or timed release of the product, such as injectable microspheres, bioerodible particles, polymeric compounds (such as polylactic acid or polyglycolic acid), beads, or liposomes, which can be delivered via depot injection. In certain embodiments, hyaluronic acid, which has the effect of enhancing duration in the circulation, may also be used. In certain embodiments, an implantable drug delivery device may be used to introduce the antibody. [Example]

[0161] Example 1 - Phase 3 Study to Evaluate the Effect of Tezepelumab in Chronic Rhinosinusitis with Nasal Polyposis (CRSwNP) The objective of this study is to investigate the efficacy and safety of tezepelumab in participants with severe chronic rhinosinusitis with nasal polyps (CRSwNP) with or without co-morbid asthma / AERD / NSAID-ERD, with a severity sufficient to require surgery (Total Nasal Polyp Score (NPS) ≥ 5 (at least 2 for each nostril)) despite documented prior treatment with systemic corticosteroids (SCS) or surgery for NP. The effect of tezepelumab 210 mg every 4 weeks (Q4W) on nasal polyps will be evaluated in addition to standard treatment with intranasal corticosteroids (INCS) over a 52-week treatment period and up to 24 weeks of post-treatment follow-up.

[0162] Approximately 400 participants worldwide will be randomized 1:1 to receive tezepelumab 210 mg or matching placebo.

[0163] Participants will be stratified by region, previous nasal polyp surgery, and co-morbid asthma / aspirin-induced respiratory disease (AERD) / nonsteroidal anti-inflammatory drug-exacerbated respiratory disease (NSAID-ERD). Randomization will be monitored to ensure that 50%-70% of the study population has co-morbid asthma / AERD / NSAID-ERD and at least 50% has previously undergone surgery for CRSwNP.

[0164] After enrollment, eligible participants will receive a standardized dose of intranasal mometasone furoate nasal spray (MFNS) or an equivalent INCS and enter a 5-week screening / run-in period. The equivalent dose should refer to the maximum dose of INCS approved in each country for CRSwNP. Participants who meet the eligibility criteria will be randomized at week 0 (day 0) to receive either placebo or tezepelumab 210 mg SC, starting at randomization (week 0) and every 4 weeks thereafter. An end-of-treatment (EOT) visit will occur at week 52.

[0165] After the 52-week treatment period, there will be two separate follow-up periods. Generally, the first 200 participants who complete the 52-week treatment period will have a 24-week investigational drug (IP) (tezepelumab)-free follow-up (FU) period. The final 200 participants will have a 12-week FU period without IP.

[0166] Endpoints and Evaluation The primary endpoints are shown in Table 1.

[0167] [Table 7]

[0168] Nasal Polyp Score (NPS): NPS is the sum of the left and right nostril scores (maximum 8) assessed by nasal endoscopy. The total NPS is graded based on polyp size as described in Table 2. Prior to nasal endoscopy, a combination of topical anesthetics and decongestants may be administered according to local medical practice.

[0169] [Table 8]

[0170] Secondary endpoints include those shown in Table 3.

[0171] [Table 9]

[0172] [Table 10]

[0173] Clinical Outcome Assessments. Participants will complete all patient-reported outcome measures (PROs) using a handheld ePRO device. The ePRO device will also be used to record symptoms (Nasal Polyps Symptom Screening Assessment) and Health-Related Quality of Life ((HRQoL)SNOT-22) screening data at Visit 1.

[0174] Participant compliance should be checked weekly (at a minimum) to ensure participants are completing assessments on schedule. It is important to monitor participants' diary compliance during the baseline period (study days -13 to 0) to ensure participants meet the criteria for randomization.

[0175] Nasal Polyp Symptom Diary (NPSD) and Nasal Polyp Symptom Screening Assessment (NPSSA): Participants complete the 11-item NP Symptom Diary (NPSD) every morning throughout the screening, treatment, and follow-up periods. Participants are asked to reflect on their NP / nasal polyp experience over the past 24 hours as they answer each question. Participants are asked to report their experience of NP symptoms (nasal congestion, nasal obstruction, runny nose, postnasal drip (mucus discharge down the throat), headache, facial pain, facial pressure, and loss of smell) and symptom impact (interference with sleep due to nasal symptoms, and interference with daily activities due to nasal symptoms). Participants report the severity and symptom impact of each symptom at their worst using a 4-point verbal rating scale (0 = none to 3 = severe). A total symptom score (TSS) is calculated by summing eight equally weighted symptom items. After the symptom and symptom impact items, a single item (yes or no) is given to record INCS compliance.

[0176] Nasal Congestion Score: The NC score (NCS) is recorded by an item on the NPSD that asks participants to rate the severity of their worst nasal congestion over the past 24 hours using the following response options: 0 - none; 1 - mild; 2 - moderate; 3 - severe. Baseline is the average of daily responses from day -13 to day 0. Biweekly (14-day) mean NCS is calculated if at least 8 days during each 14-day period have evaluable data.

[0177] Anosmia: Anosmia is recorded by an item on the NPSD, where participants are asked to rate the severity of their worst olfactory impairment over the past 24 hours using the following response options: 0 - none; 1 - mild; 2 - moderate; 3 - severe. Baseline is the average of daily responses from day -13 to day 0. Biweekly (14-day) mean anosmia is calculated if at least 8 days during each 14-day period have evaluable data.

[0178] The 22-item Nasal and Sinus Outcome Test (SNOT-22) is a condition-specific HRQoL assessment that records participant-reported physical problems, functional limitations, and emotional consequences of nasal and sinus conditions (Piccirillo et al., 2002; Hopkins et al., 2009). Patient-reported symptom severity and symptom impact over the past two weeks are recorded on a 6-point scale (0—no problems to 5—worst possible problems). The total score is the sum of the item scores and ranges from 0 to 110 (higher scores indicate poorer outcomes). A minimal clinically important difference (MCID) of 8.90 has been established for individual score changes (Hopkins et al., 2009).

[0179] The SNOT-22 test can be further divided into domains to provide a domain score. The domains and factors considered in the domain scores include: Nasal domain: need to blow nose, nasal congestion, sneezing, runny nose, coughing, postnasal drip, thick nasal discharge, and decreased sense of smell / taste; Ear / Face domain: ear fullness, dizziness, ear pain, facial pain / pressure; Sleep domain: difficulty falling asleep, nighttime awakenings, poor nighttime sleep, and tiredness upon awakening; Functional domain: fatigue, decreased productivity, and decreased concentration; Emotional domain: irritability / restlessness / irritability, sadness, and confusion (Khan et al., Laryngoscope. 2022 132(5):933-941). Each domain is scored on a scale of 0 to 5, with 0 being the worst.

[0180] Short-Form 36-Item Health Survey Version 2: The Short-Form 36-Item Health Survey Version 2 (Standard Recall) (SF-36v2) is a 36-item self-report questionnaire on functional health and well-being with a 4-week recall period (QualityMetric 2011). Responses to 35 of the 36 items are used to calculate an 8-domain profile of functional health and well-being score. The remaining items, called "health transition" items, ask participants to rate their current health status compared to their health status one year ago and are not used to calculate the domain score. The 8-domain profile consists of the following subscales: physical functioning (PF), role limitations due to physical health (RP), bodily pain (BP), general health perception (GH), vitality (VT), social functioning (SF), role limitations due to emotional problems (RE), and mental health (MH). Psychometrically based physical and mental health component summary scores (PCS and MCS, respectively) were calculated from the subscale scores to provide broader metrics of physical and mental HRQoL.

[0181] Two types of thresholds have been developed for the interpretation of SF-36v2 scores: the first type is suitable for comparing group mean scores and is commonly referred to as the MCID; the second type is suitable for interpreting change at the individual level and is referred to as the responder threshold or responder definition (QualityMetric 2011).

[0182] [Table 11]

[0183] Asthma Control Questionnaire (Asthma / AERD / NSAID-ERD participants only): The Asthma Control Questionnaire (ACQ-6) is an assessment of asthma symptoms (nighttime awakenings, awakening symptoms, activity limitations, shortness of breath, wheezing, and short-acting beta-agonist use). Participants are asked to recall their level of asthma control during the past week by answering one question about bronchodilator use and five questions about symptoms. Questions are equally weighted and scored from 0 (completely controlled) to 6 (severely uncontrolled). The mean ACQ-6 score is the average of the responses. A mean score of ≤0.75 indicates well-controlled asthma, a score of 0.75 to <1.5 indicates partially controlled asthma, and a score of ≥1.5 indicates poorly controlled asthma (Juniper et al., 2006). Individual changes of at least 0.5 are considered clinically important.

[0184] University of Pennsylvania Odor Identification Test: The University of Pennsylvania Odor Identification Test (UPSIT) is a quantitative test of olfactory function that uses microencapsulated odorants that are released by scratching a standardized odor-impregnated test booklet (Doty et al., 1984). Four booklets, each containing 10 odorants, are used in the test. Participants are asked to identify odors using a multiple-choice format that lists various possibilities. The test is forced-choice; participants must mark one of four options, even if the odor is not detected. Scoring is based on the number of correctly identified odors (score range 0–40).

[0185] Patient Global Impression of Severity and Change: The Patient Global Impression of Severity (PGI-S) is a single item designed to record the participant's perception of the overall severity of their NP symptoms at the time of completion using a 6-point categorical response scale (0 - no symptoms to 5 - very severe). The Patient Global Impression of Change (PGI-C) tool records the participant's global assessment of their response to treatment since the first dose of IP. Participants are asked to report how much their health status has changed using a 7-point scale (1 - much improved to 7 - much worse).

[0186] Work Productivity and Activity Impairment (WPAI) Questionnaire: The Work Productivity and Activity Impairment Questionnaire (WPAI, General Health Version 2.0) is a self-administered tool consisting of six questions addressing absenteeism, presenteeism (reduced efficiency at work), overall work productivity loss (absenteeism + presenteeism), and activity impairment. This validated tool records data for the past seven days. WPAI outcomes are scored as percentage impairment, with higher percentages indicating greater impairment and lower productivity (Reilly et al. 1993).

[0187] Sinus Computed Tomography: Computed tomography (CT) will be performed on all participants. A baseline CT scan referral should be provided at V2 (week 2) and should be performed after the nasal biopsy procedure (if applicable) at V2 only if the participant meets all eligibility criteria at V2, including confirmation of NPS score by a central reader. At V17 (EOT / IPD), a CT scan should be performed prior to the completion of the nasal biopsy procedure for participants in the nasal biopsy substudy.

[0188] For participants undergoing or planned surgery for NP during the treatment period, a CT scan should be performed at the IPD visit before the first NP surgery. For participants requiring SCS for the treatment of NP, a CT scan should be performed before the first course of SCS, if possible, and at week 52. For participants undergoing multiple NP surgeries and / or SCS treatment for NP, a CT scan should be performed before the first of either NP surgery or SCS treatment for NP. For participants who discontinue IP for other reasons, a CT scan should be performed at the IPD visit and at week 52 if the participant selects follow-up option 1 or 2. Sinus CT images will be used to derive the Lund-Mackay score (LMS) and Zinreich (modified Lund-Mackay) score based on visual assessment by an independent central reader, providing a quantitative estimate of the sinus severity score, which represents sinus disease burden.

[0189] Lund-Mackay score: The Lund-Mackay scoring system is used to provide a semiquantitative assessment of the paranasal sinuses on sinus CT scans (Lund and Mackay 1993). Based on the sinus CT images, a central radiologist scores the five paranasal sinuses on both sides (maxillary sinus, anterior ethmoid sinus, posterior ethmoid sinus, sphenoid sinus, and frontal sinus) as follows:

[0190] [Table 12]

[0191] The middle meatus complex is scored for the right and left sides.

[0192] [Table 13]

[0193] The maximum total score is 24.

[0194] Quantitative measurement of sinus disease burden on sinus computed tomography: Quantitative assessment of sinus CT image data is used to derive an objective measure of sinus disease burden called the Sinus Severity Score (Pallanch et al., 2013), which is defined as: Sinus severity score = sinus mucosal volume / (sinus mucosal volume + sinus air volume)*100%.

[0195] The following parameters are used to calculate the sinus severity score: (a) sinus air volume (mL); (b) sinus mucosa volume (mL). Image analysis is performed centrally.

[0196] Zinreich (Modified Lund Mackay) Score: In addition to the Lund Mackay scoring described above, the same CT images are also scored using the modified Lund Mackay (Zinreich) scoring system (Okushi et al., 2013; Likeness et al., 2014). All five paranasal sinuses on both sides (maxillary, anterior ethmoid, posterior ethmoid, sphenoid, and frontal sinuses) are scored based on the percentage of mucosal thickening opacification according to Table 7.

[0197] [Table 14]

[0198] Post-randomization nasal polyp surgery and / or use of SCS: Participants with NP surgery scheduled at the time of study enrollment and randomization should not be randomized (see Exclusion Criteria 15). After randomization, no surgery should be planned for the first 3 months unless it is urgent or deemed necessary by the physician.

[0199] Acute treatment of NP or other reasons is defined as requiring at least 3 consecutive days of treatment with systemic corticosteroids (SCS). (A single depot injection dose of corticosteroids is considered equivalent to a 3-day course of systemic corticosteroids.) A course of SCS is considered continuous if there are fewer than 7 days between treatment episodes.

[0200] If SCS is used for the treatment of NP for more than 3 consecutive days, a CT scan and nasal endoscopic evaluation of NPS should be performed before the first course of treatment with SCS (unless the subject has already undergone a CT scan before NP surgery after randomization).

[0201] If SCS use for treatment of any reason other than NP occurs near V10 (week 24) or V17 (week 52), the visit should be rescheduled for at least 2 weeks after the last dose of SCS.

[0202] Spirometry (Asthma / AERD / NSAID-ERD Participants Only): Pulmonary function (FEV1, FEF25–75%, and FVC) will be measured by spirometry at the study site using equipment provided by a central supplier. MasterScope is a system used within the site to perform and record procedures, including but not limited to spirometry, NPIF, and FeNO. Spirometry will be performed by the investigator or an authorized representative in accordance with American Thoracic Society / European Respiratory Society (ATS / ERS) guidelines or local guidelines (Graham et al., 2019). The MasterScope kit includes a spirometer handle used to record spirometry measurements at the site. The Global Lung Function Initiative (GLI) equation can be used to determine predicted normal values ​​(PNV), which are pre-programmed into the spirometer (Quanjer et al., 2012). FEV1, expressed as a percentage of PNV, is calculated as follows: FEV1% of PNV = (measured FEV1 / FEV1PNV) × 100

[0203] FeNO (participants with asthma / AERD / NSAID-ERD only): Airway inflammation will be assessed using a standardized single-breath FeNO test according to the SoA. The manufacturer's recommended single-breath technique will be followed (Alving et al., 2017). Participants will be asked if they have had a respiratory infection within 2 weeks prior to the measurement. FeNO measurement will be performed within 2 weeks of a respiratory infection. FeNO testing will be performed before spirometry. Participants should not use rescue SABA medications (e.g., albuterol / salbutamol) within 6 hours prior to the measurement. Inhaled BDs (including ICS / LABAs) should be withheld for the BD-specific duration of effect, as described in the spirometry section.

[0204] The NIOX VERO® Airway Inflammation Monitor is used to measure FeNO.

[0205] Nasal Peak Inspiratory Flow: Nasal peak inspiratory flow (NPIF) assessment represents a physiological measure of airflow through both nasal passages during forced inspiration, expressed in liters per minute. Nasal inspiration correlates most strongly with the participant's sense of obstruction and is the best validated technique for monitoring nasal airflow in clinical trials. A minimum of three and a maximum of eight NPIF efforts are performed by the participant, and all values ​​are recorded by the participant on the MasterScope, with the highest value used for assessment.

[0206] NPIF will be performed at enrollment / screening V1 (week -5), V3 (week 0), V7 (week 12), V10 (week 24), V13 (week 36), V17 (week 52), V19 (week 64), and V21 (week 76).

[0207] Nasal airflow is measured continuously and expressed in liters per minute. The best of three results with less than 10% variation is considered the best way to express the result (Scadding et al. 2011).

[0208] Asthma Exacerbation (Asthma / AERD / NSAID-ERD participants only): During the study, an asthma exacerbation is defined as a worsening of asthma leading to any of the following: A temporary bolus / burst of systemic corticosteroids (or a temporary increase in a stable background OCS dose) for at least 3 consecutive days to treat symptoms of asthma exacerbation; a single depot injected dose of corticosteroid is considered equivalent to a 3-day burst of systemic corticosteroids. Emergency room or urgent care visit due to asthma (as above) requiring systemic corticosteroids (defined as evaluation and treatment in an emergency department or urgent care center within 24 hours). Hospitalization for asthma (defined as admission to an inpatient facility and / or evaluation and treatment in a medical facility for 24 hours or more).

[0209] Participants must report in their eDiary any of the following: An increase in rescue medication use of 4 or more puffs on at least 2 consecutive days compared to average use during baseline or 12 puffs / day on any one day; and / or Use of additional nebulized beta-2 agonists for at least 2 consecutive days compared with average use during baseline, and / or An increase in asthma-related awakenings requiring rescue medication on 2 or more nights over a 7-day period compared to the mean during baseline, and / or asthma-related awakenings requiring rescue medication on 6 or more of the previous 7 nights (this criterion must be met on 2 consecutive days).

[0210] If an exacerbation event is not associated with a decline in at least one of the pre-specified objective measures, the investigator must justify the decision to define the event as an exacerbation and document it on the eCRF. Events not supported by any objective assessment will not be considered exacerbations as defined by the protocol.

[0211] The onset of an exacerbation is defined as the earliest of the date of initiation of systemic corticosteroids or the date of temporary increase in stable background OCS dose, the date of an ER or urgent care visit requiring systemic corticosteroids, or the date of hospitalization attributable to asthma. The end date of an exacerbation is defined as the latest of the last day of systemic corticosteroids or the last day of temporary increase in stable background OCS dose, the date of an ER or urgent care visit, or the date of hospital discharge.

[0212] If less than 7 days have elapsed between the end date of the asthma exacerbation and the start date of the new asthma exacerbation, the second event is considered a recurrence of a previous asthma exacerbation.

[0213] EQ-5D-3L. The EuroQOL Quality of Life 5 Dimensions 3 Levels (EQ-5D-3L) is a standardized tool developed by EuroQol (Brooks, 1996) for use as a measure of health-related quality of life (HRQoL). It defines health in terms of five dimensions: mobility, self-care, daily activities, pain / discomfort, and anxiety / depression. Each dimension has three ordinal levels of severity: 1: no problem, 2: some problem, and 3: severe problem. Overall health status is defined as a five-digit number. Participants are asked to indicate their current health status by selecting the most appropriate level for each of the five dimensions. The questionnaire also includes a VAS, where participants are asked to rate their current health status on a scale of 0 to 100, with 0 being the worst imaginable health state.

[0214] Patient Global Impression of Severity. The PGI-S is a single item designed to record the subject's perceived overall symptom severity at the time of completion on a 5-point categorical response scale (ranging from no symptoms to very severe).

[0215] Adverse Events: All adverse events observed by the investigator or reported by the subject occurring after the first dose of study drug through the end of the study / safety follow-up visit or 20 weeks after the last dose of study drug will be collected / reported.

[0216] Biomarkers Serum immunoglobulins. Levels of total immunoglobulin E (IgE) and assessment of the presence of allergen-specific IgE (IgE FEIA) will be collected at pre-specified scheduled visits prior to IP administration (pre-dose) according to the SoA and assessed by a central laboratory.

[0217] Nasal epithelial lining fluid samples are obtained at scheduled visits. Nasal epithelial lining fluid biomarkers are measured to evaluate tezepelumab pharmacology and assess changes in biomarkers related to CRSwNP, inflammation, and the TSLP pathway. Baseline and early post-dose levels of nasal epithelial lining fluid biomarkers can also be used to explore potential predictive biomarkers of response or exposure to tezepelumab. Specific biomarkers that may be analyzed include, but are not limited to, cytokines, chemokines, and inflammatory mediators related to CRSwNP and the TSLP pathway. Drug concentrations, if available, can also be measured in nasal epithelial lining fluid samples. If necessary, urea concentrations may be measured to correct for the dilution factor of nasal lining fluid samples.

[0218] Additionally, a nasal biopsy substudy will be conducted at selected sites for a total of approximately 60 participants. Nasal biopsies will be collected at V2 (week -2) and EOT (week 52) to evaluate the effect of tezepelumab on inflammatory cell infiltrates and gene expression by transcriptome profiling. At V2, the nasal biopsy should be performed after nasal epithelial lining fluid collection and before NPS assessment or CT scan. If a nasal biopsy sample cannot be collected at Visit 2, the participant should be excluded from the nasal biopsy substudy and may continue in the main study. In this case, NLF collection at Visit 2 and Staphylococcus A-enterotoxin-specific IgE status sampling at Visit 3 should not be performed. At EOT, the nasal biopsy should be performed after NPS assessment, nasal epithelial lining fluid collection, and CT scan. Nasal biopsy collection may be postponed for up to 7 days after the EOT visit only if the appropriate kit is not available at the time of the EOT visit.

[0219] Staphylococcus Aureus Characterization. Staphylococcus Aureus (S. aureus; Staph A) enterotoxin IgE will be performed only on participants in the nasal biopsy substudy. Staph A bacterial cultures from nasal swabs will be collected on all participants and evaluated by a central laboratory. These tests will be performed at scheduled visits according to the SoA.

[0220] Pharmacokinetic Evaluation: An approximately 5 mL whole blood sample will be collected for measurement of tezepelumab serum concentrations.

[0221] Pharmacodynamic Assessment. Venous blood samples will be collected from all subjects at outlined time points to determine the effect of tezepelumab on levels of circulating CCL17 (TARC) and CCL22 (MDC), which are downstream of TSLP signaling (Soumelis et al., 2002).

[0222] Pharmacogenetic evaluation. DNA analysis may be performed. These optional pharmacogenetic analyses focus on inherited genetic variations to assess their possible correlation with disease and / or response to therapies used in the study. The goals of this optional testing include the use of genetic markers to aid in the investigation of CRS with or without nasal polyps and / or to identify subjects who may have a positive or negative response to the investigational drug or therapy required by the protocol.

[0223] Antibody Testing Procedures: Bioanalytical testing for anti-tezepelumab antibodies may be performed if there are unexpected PK findings or safety-related concerns in the study population that require further investigation. Samples testing positive for anti-tezepelumab antibodies may be further characterized.

[0224] Blood Biomarkers: Blood samples (serum / plasma and whole blood) will be collected as indicated to assess changes in circulating biomarker levels that are elevated in subjects with CRS. Additional assays that may be performed on blood samples include measuring changes in mRNA transcripts following tezepelumab treatment.

[0225] statistical analysis For the primary endpoint, the treatment effect will be tested using a logistic regression model adjusting for covariates. From this model, odds ratios and 95% CIs will be reported comparing each tezepelumab dose group with placebo. In addition, the percentage of subjects in each treatment group with a response and the difference in the percentage of subjects responding between each tezepelumab dose group and placebo will be summarized with 95% confidence intervals.

[0226] Approximately 400 adult participants with severe CRSwNP (total NPS ≥ 5) and an inadequate response to standard therapy will be randomized 1:1 to receive tezepelumab 210 mg Q4W or matching placebo.

[0227] Endpoints of Interest: Changes from baseline in the co-primary endpoints NPS and biweekly mean NCS at week 52 will be measured, with the mean difference between the tezepelumab and placebo treatment groups used as the efficacy measure. Analyses of key secondary endpoints are described as follows: Changes from baseline in LMK, SNOT-22, anosmia, and NPSD TSS at week 52 will be analyzed using the methods described in the primary analysis approach for the co-primary endpoints.

[0228] The time to the first decision for surgery or SCS for NP during the 52-week treatment period was analyzed using a Cox proportional hazards model, adjusting for treatment, baseline comorbid asthma / AERD / NSAID-ERD status, previous surgery status, and region. The event of interest was the time to first SCS use or decision for nasal polyp surgery, whichever occurred first (if both occurred). The date of the decision to undergo NP surgery was used in the analysis instead of the actual date of NP surgery. If the decision date was missing, the actual date of NP surgery was used instead. Hazard ratios and corresponding 95% CIs and p-values ​​are presented. The proportion of participants who underwent surgery or SCS by week 52 was estimated using the Kaplan-Meier method. The same method was used to analyze the time to first surgery and the time to first SCS separately.

[0229] The proportion of participants achieving a maximum NPS ≤ 1 in each nostril will be analyzed as follows: at week 52, participants who achieved a maximum score of 1 (NPS ≤ 1) in each nostril without SCS or actual surgery before that time point will be defined as responders; otherwise, participants will be defined as non-responders. Participants who discontinued treatment before week 52 will be considered non-responders. The response variable in the model will be a binary responder status at week 52. A logistic regression model will be used with treatment group, region, baseline co-morbid asthma / AERD / NSAID-ERD status, and previous surgery status as factors, and baseline NPS as a covariate. Odds ratios, corresponding 95% CIs, and p-values ​​will be presented. The same logistic regression model will be used to analyze the proportion of participants achieving a maximum NPS ≤ 1 in each nostril and NPSD TSS response. Details of NPSD TSS response will be provided in SAP.

[0230] Analysis of the change from baseline in FEV1 at week 52 will also follow the method described in the primary analysis approach for the co-primary endpoint, but the population of interest will be the subset of participants with co-morbid asthma / AERD / NSAID-ERD. The model will include baseline value of FEV1 as a covariate and previous surgical status and region as factors.

[0231] result In the initial study (NAVIGATOR), patients (aged 12-80 years) were randomized 1:1 to receive tezepelumab 210 mg subcutaneously every 4 weeks for 52 weeks or placebo. Change from baseline to week 52 in SNOT-22 score (0 [no impairment] to 110 [maximum impairment]) was assessed in patients with a reported history of any NP, and patients were grouped by whether NP was reported within the 2 years prior to randomization. To be included, patients had to have experienced at least two documented asthma exacerbations (within the 12 months prior to the date of informed consent) that resulted in hospitalization, an emergency department visit requiring at least three consecutive days of systemic corticosteroid treatment, or the use of systemic corticosteroid treatment for at least three consecutive days.

[0232] Baseline demographic and clinical characteristics were generally balanced between subgroups (Figure 1A). Compared with patients without a history of NP, patients with any history of NP were less likely to be female (65.0% vs. 55.2%) or to have a positive fluorescent enzyme immunoassay test for any perennial aeroallergen (67.7% vs. 45.5%). Patients with any history of NP were more commonly reported to have had more than two exacerbations in the past 12 months (49.1% vs. 38.4%) and to have higher mean exhaled nitric oxide fraction levels (47.4 ppb vs. 39.2 ppb) and blood eosinophil counts (744.8 cells / μL vs. 289.4 cells / μL) at baseline compared with patients without a history of NP.

[0233] Further analysis is described in Figure 1B, which shows the SNOT scores and domain scores of enrolled subjects. Changes in SNOT-22 total scores (0 [no impairment] to 110 [maximum impairment]; minimal clinically important difference, 8.97) and domain scores were assessed from baseline to weeks 28 and 52 in patients with a history of NP. Patients with a history of NP had higher SNOT-22 total and domain scores at baseline than patients without a history of NP (Figure 1B).

[0234] Mean baseline SNOT-22 scores were similar in patients with a history of any NP who received tezepelumab or placebo (49.6 [n = 69] and 49.3 [n = 62], respectively). In patients with a history of any NP, the change from baseline in SNOT-22 scores was -21.29 for tezepelumab and -10.21 for placebo (LS mean difference, -11.08 [95% CI: -17.80, -4.35]) (Figure 2). Reductions from baseline in SNOT-22 scores were observed in those without NP within 2 years prior to randomization (tezepelumab, -23.40 [n = 32]; placebo, -8.15 [n = 22]; LS mean difference: -15.24 [95% CI: -28.36, -2.13]) and in those with NP within 2 years prior to randomization (tezepelumab, -20.10 [n = 37]; placebo, -10.55 [n = 40]; LS mean difference: -9.56 [95% CI: -18.19, -0.93]). Clinically important improvements in SNOT-22 scores compared with placebo were observed from the first postbaseline assessment (mean change from baseline to week 28: tezepelumab, -19.43; placebo, -7.43) (Figure 3).

[0235] When results were examined according to the chronology of NP history, a reduction from baseline in SNOT-22 scores was observed in those with NP within 2 years before randomization and in those with NP for more than 2 years before randomization (Figure 2). These results indicate that tezepelumab provided clinically meaningful improvements in sinusitis symptoms over 52 weeks compared with placebo in patients with severe uncontrolled asthma and a recent or recent history of co-morbid NP.

[0236] Tezepelumab reduced the numerical value of each SNOT-22 domain score compared with placebo from baseline to weeks 28 and 52 in patients with a history of NP (Figures 4 and 5). The percent change from baseline in the SNOT-22 total score was greater with tezepelumab than with placebo at both weeks 28 (LS mean difference: -26% [95% confidence interval (CI): -49, -3]) and 52 (LS mean difference: -28% [95% CI: -47, -9]) (Figure 5B). The SNOT-22 nasal domain was most significantly impaired at baseline, followed by sleep, function, emotion, and ear / face domains (Figures 5C–G). Tezepelumab reduced the following symptoms: decreased smell / taste, nasal congestion, cough, decreased productivity, and morning fatigue from baseline to week 52 compared with placebo. At week 52, the greatest improvements were seen in the sleep domain, followed by the nasal and functional domains. Tezepelumab reduced all five symptoms of greatest clinical concern. The greatest improvements were seen in decreased smell / taste, followed by nasal congestion, decreased productivity, morning fatigue, and cough (Figure 6).

[0237] Asthma-related clinical outcomes Tezepelumab reduced AAERs by 69% (95% CI: 50, 81) in patients with a history of CRSwNP and by 53% (95% CI: 42, 62) in patients without CRSwNP over 52 weeks compared with placebo. Baseline pre-bronchodilator FEV1 (mean, standard deviation [SD]) was similar in patients with a history of CRSwNP (tezepelumab, 1.91 [0.72] L; placebo, 1.84 [0.71] L) and patients without CRSwNP (tezepelumab, 1.81 [0.72] L; placebo, 1.85 [0.71] L). Tezepelumab treatment resulted in an improvement in pre-bronchodilator FEV1 compared with placebo in patients regardless of their history of CRSwNP. The LS mean difference (95% CI) in change in pre-bronchodilator FEV1 from baseline to week 52 was 0.20 (0.07, 0.32) L in patients with a history of CRSwNP and 0.12 (0.07, 0.17) in patients without a history.

[0238] Baseline ACQ-6 scores (mean [SD]) were similar in patients with a history of CRSwNP (tezepelumab, 2.86 [0.82]; placebo, 2.83 [0.86]) and those without (tezepelumab, 2.81 [0.81]; placebo, 2.79 [0.81]). Tezepelumab treatment resulted in improvements in ACQ-6 scores compared with placebo. The LS mean difference (95% CI) in the change in ACQ-6 score from baseline to week 52 was -0.63 (-0.95, -0.31) in patients with a history of CRSwNP and -0.27 (-0.41, -0.13) in patients without a history of CRSwNP. Baseline AQLQ(S)+12 scores (mean [SD]) were similar in patients with a history of CRSwNP (tezepelumab, 3.90 [0.99]; placebo, 3.84 [1.01]) and those without (tezepelumab, 3.86 [1.03]; placebo, 3.92 [1.00]). At week 52, improvement in AQLQ(S)+12 score with tezepelumab compared with placebo was greater in patients with a history of CRSwNP (LS mean difference [95% CI]: 0.77 [0.43, 1.12]) than in patients without a history of CRSwNP (LS mean difference [95% CI]: 0.25 [0.10, 0.40]). Baseline ASD scores (mean [SD]) were similar in patients with a history of CRSwNP (tezepelumab, 1.41 [0.68]; placebo, 1.44 [0.71]) and those without CRSwNP (tezepelumab, 1.39 [0.70]; placebo, 1.39 [0.69]). Tezepelumab improved ASD scores compared with placebo in patients with and without a history of CRSwNP; the LS mean differences (95% CI) for the change from baseline to week 52 were -0.32 (-0.51, -0.13) and -0.08 (-0.16, 0.01), respectively.

[0239] These results show that reductions were observed across all SNOT-22 domains, with the greatest reductions seen in the sleep, nasal, and functional domains. Tezepelumab improved the following symptoms over 52 weeks compared to placebo: decreased smell / taste, nasal congestion, cough, decreased productivity, and morning fatigue. These results demonstrate the efficacy of tezepelumab in improving sinusitis symptoms in patients with severe, uncontrolled asthma and a history of NP.

[0240] Numerous modifications and variations of the present invention as set forth in the illustrative examples above are expected to occur to those skilled in the art, and therefore only such limitations as are indicated in the appended claims should be placed on the present invention.

[0241] References Alobid et al., Allergy. 2005;60:452-458. Alving et al., Pulm Ther. 2017 3(1):207-218. Agarwal et al., Clin Rev Allergy Immunol 2019;doi 10.1007 / s12016-019-08734-z: May 10 [Epub ahead of print]. Bachert et al., JAMA. 2016;315(5):469-79. Bachert et al., Journal of Allergy and Clinical Immunology (2017), doi: 10.1016 / j.jaci.2017.05.044. Bachert et al., Lancet 2019. Available from: URL: https: / / doi.org / 10.1016 / S0140-6736(19)31881-1. Bilodeau et al., Rhinology. 2010;48:420-425. Chaaban et al., Am J Rhinol Allergy 2013;27:473-478. Chitsuthipakorn W et al., Curr Allergy Asthma Rep. 2018;18(9):46. Deal and Kountakis et al., Laryngoscope 2004;114:1932-1935. Doty et al., Physiology & Behavior (Monograph) 1984 32:489-502. Ediger et al., Clinical & Experimental Allergy, 35(3), 319-326. Ehnhage A et al., Allergy. 2009;64:762-769. Emson C et al., Am J Respir Crit Care Med 2020; 201:A4256. Emson et al ., Presented at: European Academy of Allergy and Clinical Immunology (EAACI) Digital Congress 2020. Emson et al., J Asthma Allergy. 2021;14:91-99. Fokkens et al., Rhinol Suppl 2020 58 Supplement S29 (1-464). Gauvreau et al., Expert opinion on therapeutic targets, 1-16. Gevaert et al., J Allergy Clin Immunol 2011; 128:989-95. Gevaert et al., Journal of Allergy and Clinical Immunology 2020. Graham et al., Am J Respir Crit Care Med. 2019;200(8):e70-e88. Hakansson et al., PLoS ONE 2015;10(7):e0127228. Hopkins et al., Clinical otolaryngology 2009;34(5):447-5. Hull and Chandra Otolaryngol Clin North Am 2017;50(1):61-81. Jarvis et al., Allergy. 2012;67:91-98. Juniper et al., Respir Med 2006; 100: 616- 621. Kato et al., Journal of Allergy and Clinical Immunology, 143(2), AB86. Kimura et al., Allergy Asthma Immunol Res. 2011;3(3):186-193. Lieberman et al., J Allergy Clin Immunol. 2010 Sep;126(3):477-80. e1-42. Likness et al., Otolaryngol Head Neck Surg. 2014 February ; 150(2): 305-311. Lou et al., Int Forum Allergy Rhinol. 2018 Nov;8(11):1218-1225. Lund and Mackay, Rhinology 1993;31(4):183-4. Nagarkar et al. J Allergy Clin Immunol. 2013;132(3):593-600 e512. Okushi et al., Auris Nasus Larynx 40 (2013) 548-553. Orlandi et al., Int Forum Allergy Rhinol 2016;6(Suppl. 1):S22-S209. Pallanch et al., Int Forum Allergy Rhinol 2013;3(12):963-72. Pearlman et al., Am J Rhinol Allergy. 2009;23:145-148. Piccirillo et al., Otolaryngology--Head and Neck Surgery. 2002;126(1);41-7. Quanjer et al. Multi ethnic reference values for spirometry for the 3-95 year age range: the global lung function 2012 equations. 2012 Dec;40(6):1324-43. QualityMetric, I. User’s manual for the SF-36v2 Health Survey (3 ed.). 2011. Lincoln, RI. Reilly et al., PharmacoEconomics 1993; 4(5): 353-365. Sampson et al., J Allergy Clin Immunol. 2006 Feb;117(2):391-7. Scadding et al., Clin Transl Allergy. 2011;1:1-39. Settipane et al., J Allergy Clin Immunol. 1977;59:17-21. Seybt et al., Ear Nose Throat J 2007;86:409-11. Shin et al., American journal of rhinology & allergy, 28(2), 95-98. Stevens et al., Clin Immunol Pract 2016;4(4):565-72. Tint et al., Curr Allergy Asthma Rep 2016;16:16. Tokunaga et al., Allergy 2015; 70: 995-1003. van der Veen et al. Allergy 2017;72:282-290.

Claims

1. 1. A method for treating chronic sinusitis in a subject, comprising selecting a subject in need of treatment for chronic sinusitis and administering to the subject a therapeutically effective amount of an anti-TSLP antibody or antibody variant, wherein the antibody: a. i. a light chain CDR1 sequence comprising the amino acid sequence set forth in SEQ ID NO:3; ii. a light chain CDR2 sequence comprising the amino acid sequence set forth in SEQ ID NO:4, and iii. A light chain CDR3 sequence comprising the amino acid sequence set forth in SEQ ID NO:5 a light chain variable domain comprising: b. i. a heavy chain CDR1 sequence comprising the amino acid sequence set forth in SEQ ID NO:6; ii. a heavy chain CDR2 sequence comprising the amino acid sequence set forth in SEQ ID NO: 7; and iii. A heavy chain CDR3 sequence comprising the amino acid sequence set forth in SEQ ID NO:8 a heavy chain variable domain comprising: wherein the antibody specifically binds to the TSLP polypeptide set forth in amino acids 29-159 of SEQ ID NO:

2.

2. 1. A method for treating chronic sinusitis in a subject, comprising selecting a subject in need of treatment for chronic sinusitis and administering to the subject a therapeutically effective amount of an anti-TSLP antibody or antibody variant, wherein the antibody: a. i. a sequence of amino acids at least 80% identical to SEQ ID NO: 12; ii. a sequence of amino acids encoded by a polynucleotide sequence at least 80% identical to SEQ ID NO: 11; iii. An amino acid sequence encoded by a polynucleotide that hybridizes under moderately stringent conditions to the complement of a polynucleotide consisting of SEQ ID NO:

11. a light chain variable domain selected from the group consisting of: b. i. a sequence of amino acids at least 80% identical to SEQ ID NO: 10; ii. a sequence of amino acids encoded by a polynucleotide sequence at least 80% identical to SEQ ID NO:9; iii. An amino acid sequence encoded by a polynucleotide that hybridizes under moderately stringent conditions to the complement of a polynucleotide consisting of SEQ ID NO:

9. a heavy chain variable domain selected from the group consisting of: or c. the light chain variable domain of (a) and the heavy chain variable domain of (b). wherein the antibody specifically binds to the TSLP polypeptide set forth in amino acids 29-159 of SEQ ID NO:

2.

3. 3. The method of claim 1 or 2, wherein the antibody is administered every two weeks or every four weeks.

4. The method of any one of claims 1 to 3, wherein the antibody is an IgG2 antibody.

5. The method of any one of claims 1 to 4, wherein the antibody is administered at a dose of 140 to 420 mg.

6. The method of any one of claims 1 to 5, wherein the antibody is administered at a dose of 210 mg.

7. The method of any one of claims 1 to 6, wherein the antibody is administered at a dose of 420 mg.

8. 1. A method for treating chronic sinusitis in a subject, comprising: selecting a subject in need of treatment for chronic sinusitis; and administering to the subject a composition comprising an anti-TSLP antibody at a dose of 210 mg every four weeks, wherein the antibody is a. i. a light chain CDR1 sequence comprising the amino acid sequence set forth in SEQ ID NO:3; ii. a light chain CDR2 sequence comprising the amino acid sequence set forth in SEQ ID NO:4; iii. A light chain CDR3 sequence comprising the amino acid sequence set forth in SEQ ID NO:5 a light chain variable domain comprising: b. i. a heavy chain CDR1 sequence comprising the amino acid sequence set forth in SEQ ID NO:6; ii. a heavy chain CDR2 sequence comprising the amino acid sequence set forth in SEQ ID NO: 7; and iii. A heavy chain CDR3 sequence comprising the amino acid sequence set forth in SEQ ID NO:8 a heavy chain variable domain comprising: wherein the antibody specifically binds to the TSLP polypeptide set forth in amino acids 29-159 of SEQ ID NO:

2.

9. 1. A method for treating chronic sinusitis in a subject, comprising: selecting a subject in need of treatment for chronic sinusitis; and administering to the subject a composition comprising an anti-TSLP antibody at a dose of 210 mg every four weeks, wherein the antibody is a. i. a sequence of amino acids at least 80% identical to SEQ ID NO: 12; ii. a sequence of amino acids encoded by a polynucleotide sequence at least 80% identical to SEQ ID NO: 11; iii. An amino acid sequence encoded by a polynucleotide that hybridizes under moderately stringent conditions to the complement of a polynucleotide consisting of SEQ ID NO:

11. a light chain variable domain selected from the group consisting of: b. i. a sequence of amino acids at least 80% identical to SEQ ID NO: 10; ii. a sequence of amino acids encoded by a polynucleotide sequence at least 80% identical to SEQ ID NO:9; iii. An amino acid sequence encoded by a polynucleotide that hybridizes under moderately stringent conditions to the complement of a polynucleotide consisting of SEQ ID NO:

9. a heavy chain variable domain selected from the group consisting of: or c. the light chain variable domain of (a) and the heavy chain variable domain of (b). wherein the antibody specifically binds to the TSLP polypeptide set forth in amino acids 29-159 of SEQ ID NO:

2.

10. 10. The method of any one of claims 1 to 9, wherein the light chain variable domain is set forth in SEQ ID NO: 12 and the heavy chain variable domain is set forth in SEQ ID NO:

10.

11. 11. The method of any one of claims 1 to 10, wherein the antibody is administered for a period of at least 4 months, 6 months, 9 months, 1 year or more.

12. The method of any one of claims 1 to 11, wherein the anti-TSLP antibody is selected from the group consisting of a monoclonal antibody, a recombinant antibody, an IgG1 antibody, an IgG2 antibody, an IgG3 antibody, and an IgG4 antibody.

13. The method of any one of claims 9 to 12, wherein the antibody is an IgG2 antibody.

14. The method of any one of claims 1 to 13, wherein the antibody is a human antibody.

15. 15. The method of any one of claims 1 to 14, comprising administering to a patient a pharmaceutical composition comprising said antibody or antibody variant and further comprising a pharmaceutically acceptable carrier or excipient.

16. The method according to any one of claims 1 to 15, wherein the chronic sinusitis is severe or moderate chronic sinusitis.

17. 17. The method of any one of claims 1 to 16, wherein the chronic sinusitis is accompanied by nasal polyps.

18. The method of any one of claims 1 to 17, wherein the subject has moderate asthma.

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

20. 20. The method of any one of claims 1 to 19, wherein the subject is a child or an adolescent.

21. 21. The method of any one of claims 1-20, wherein the administration results in an improvement in one or more measures of chronic sinusitis including Nasal Polyp Score (NPS), Nasal Congestion Score (NCS), anosmia, Nasal and Sinus Outcome Test-22 item (SNOT-22), EuroQOL Quality of Life 5 Dimension 3 Level (EQ-5D-3L), Asthma Control Questionnaire (ACQ-6), Lund-Mackay score, modified Lund-Mackay score, incidence of nasal polyp surgery, and / or systemic corticosteroids (SCS).

22. 22. The method of any one of claims 1-21, wherein said administering improves one or more symptoms of chronic sinusitis as measured by a patient's symptom diary.

23. 23. The method of any one of claims 1-22, wherein said administering improves one or more symptoms of chronic sinusitis selected from the group consisting of nasal congestion, nasal obstruction, runny nose, postnasal drip, mucus discharge down the throat, significant nasal blockage, runny nose, loss of smell, asthma symptoms, headache, facial pain, facial pressure, loss of smell, impaired sleep due to nasal symptoms, and impaired daily activities due to nasal symptoms.

24. 1. A method for treating chronic sinusitis in a subject, comprising: selecting a subject in need of treatment for chronic sinusitis; and administering to said subject a composition comprising an anti-TSLP antibody at a dose of 140-420 mg at biweekly intervals, said antibody comprising: a. i. a light chain CDR1 sequence comprising the amino acid sequence set forth in SEQ ID NO:3; ii. a light chain CDR2 sequence comprising the amino acid sequence set forth in SEQ ID NO:4, and iii. A light chain CDR3 sequence comprising the amino acid sequence set forth in SEQ ID NO:5 a light chain variable domain comprising: b. i. a heavy chain CDR1 sequence comprising the amino acid sequence set forth in SEQ ID NO:6; ii. a heavy chain CDR2 sequence comprising the amino acid sequence set forth in SEQ ID NO: 7; and iii. A heavy chain CDR3 sequence comprising the amino acid sequence set forth in SEQ ID NO:8 a heavy chain variable domain comprising: wherein the antibody specifically binds to the TSLP polypeptide set forth in amino acids 29-159 of SEQ ID NO:2, and the antibody is an IgG2 antibody.

25. 25. The method of claim 24, wherein the light chain variable domain is set forth in SEQ ID NO: 12 and the heavy chain variable domain is set forth in SEQ ID NO:

10.

26. 25. The method of claim 24, wherein the antibody is administered every four weeks.

27. 26. The method of claim 24 or 25, wherein the antibody is administered at a dose of 210 mg.

28. 28. The method of any one of claims 24 to 27, wherein the antibody is administered at a dose of 420 mg.

29. The method of any one of claims 1 to 28, wherein the antibody is tezepelumab.

30. 30. The method of claim 29, wherein the antibody is an IgG2 antibody and has the full-length heavy and light chain sequences set forth in SEQ ID NOs: 13 and 14, respectively.

31. 31. The method of any one of claims 1 to 30, wherein the antibody variant has substantially similar pK properties to human tezepelumab.

32. 1. A method for reducing the frequency of chronic sinusitis exacerbations in a subject, comprising: selecting a subject in need of treatment for chronic sinusitis; and administering to the subject a composition comprising an anti-TSLP antibody at a dose of 140-420 mg at intervals of every two weeks or every four weeks, wherein the antibody is a. i. a light chain CDR1 sequence comprising the amino acid sequence set forth in SEQ ID NO:3; ii. a light chain CDR2 sequence comprising the amino acid sequence set forth in SEQ ID NO:4, and iii. A light chain CDR3 sequence comprising the amino acid sequence set forth in SEQ ID NO:5 a light chain variable domain comprising: b. i. a heavy chain CDR1 sequence comprising the amino acid sequence set forth in SEQ ID NO:6; ii. a heavy chain CDR2 sequence comprising the amino acid sequence set forth in SEQ ID NO: 7; and iii. A heavy chain CDR3 sequence comprising the amino acid sequence set forth in SEQ ID NO:8 a heavy chain variable domain comprising: wherein the antibody specifically binds to the TSLP polypeptide set forth in amino acids 29-159 of SEQ ID NO:

2.

33. 1. A method for reducing the frequency of chronic sinusitis exacerbations in a subject, comprising: selecting a subject in need of treatment for chronic sinusitis; and administering to the subject a composition comprising an anti-TSLP antibody at a dose of 140-420 mg at intervals of every two weeks or every four weeks, wherein the antibody is a. i. a sequence of amino acids at least 80% identical to SEQ ID NO: 12; ii. a sequence of amino acids encoded by a polynucleotide sequence at least 80% identical to SEQ ID NO: 11; iii. An amino acid sequence encoded by a polynucleotide that hybridizes under moderately stringent conditions to the complement of a polynucleotide consisting of SEQ ID NO:

11. a light chain variable domain selected from the group consisting of: b. i. a sequence of amino acids at least 80% identical to SEQ ID NO: 10; ii. a sequence of amino acids encoded by a polynucleotide sequence at least 80% identical to SEQ ID NO:9; iii. An amino acid sequence encoded by a polynucleotide that hybridizes under moderately stringent conditions to the complement of a polynucleotide consisting of SEQ ID NO:

9. a heavy chain variable domain selected from the group consisting of: or c. the light chain variable domain of (a) and the heavy chain variable domain of (b). A method comprising:

34. 34. The method of claim 32 or 33, wherein the light chain variable domain is set forth in SEQ ID NO: 12 and the heavy chain variable domain is set forth in SEQ ID NO:

10.

35. 35. The method of any one of claims 32 to 34, wherein the antibody is administered every four weeks.

36. 35. The method of any one of claims 32-34, wherein the antibody is administered at a dose of 210 mg.

37. 35. The method of any one of claims 32-34, wherein the antibody is administered at a dose of 420 mg.

38. 38. The method of any one of claims 32-37, wherein the antibody is administered for a period of at least 4 months, 6 months, 9 months, 1 year or more.

39. 39. The method of any one of claims 32 to 38, wherein the anti-TSLP antibody is selected from the group consisting of a monoclonal antibody, a recombinant antibody, an IgG1 antibody, an IgG2 antibody, an IgG3 antibody, and an IgG4 antibody.

40. The method of any one of claims 32 to 39, wherein the antibody is an IgG2 antibody.

41. The method of any one of claims 32 to 40, wherein the antibody is a human antibody.

42. The method of any one of claims 32 to 41, wherein the antibody is tezepelumab.

43. 43. The method of any one of claims 32 to 42, comprising administering to a patient a pharmaceutical composition comprising said antibody or antibody variant, and further comprising a pharmaceutically acceptable carrier or excipient.

44. 44. The method of any one of claims 32-43, wherein said administering delays the time to chronic sinusitis exacerbation compared to a subject not administered the anti-TSLP antibody.

45. 45. The method of any one of claims 32-44, wherein said administering reduces the frequency or level of co-administered therapy in said subject.

46. 46. ​​The method of claim 45, wherein the co-administration therapy is selected from the group consisting of dupilumab, an immunosuppressant or immunomodulatory agent, a systemic corticosteroid, cyclosporine, mycophenolate mofetil, interferon (IFN) gamma, a Janus kinase inhibitor, azathioprine, methotrexate, an anti-IL-13 antibody, an anti-IL-5 pathway antibody, or a combination thereof.

47. 46. ​​The method of claim 45, wherein said administering reduces or eliminates the need for corticosteroid therapy.

48. 1. A method for reducing SNOT-22 and / or Lund-Mackay score in a subject, comprising administering a composition comprising an anti-TSLP antibody at a dose of 140-420 mg at biweekly intervals, wherein the antibody: a. i. a light chain CDR1 sequence comprising the amino acid sequence set forth in SEQ ID NO:3; ii. a light chain CDR2 sequence comprising the amino acid sequence set forth in SEQ ID NO:4, and iii. A light chain CDR3 sequence comprising the amino acid sequence set forth in SEQ ID NO:5 a light chain variable domain comprising: b. i. a heavy chain CDR1 sequence comprising the amino acid sequence set forth in SEQ ID NO:6; ii. a heavy chain CDR2 sequence comprising the amino acid sequence set forth in SEQ ID NO: 7; and iii. A heavy chain CDR3 sequence comprising the amino acid sequence set forth in SEQ ID NO:8 a heavy chain variable domain comprising: wherein the antibody specifically binds to the TSLP polypeptide set forth in amino acids 29-159 of SEQ ID NO:

2.

49. 1. A method for reducing SNOT-22 and / or Lund-Mackay score in a subject, comprising administering a composition comprising an anti-TSLP antibody at a dose of 140-420 mg at biweekly intervals, wherein the antibody: a. i. a sequence of amino acids at least 80% identical to SEQ ID NO: 12; ii. a sequence of amino acids encoded by a polynucleotide sequence at least 80% identical to SEQ ID NO: 11; iii. An amino acid sequence encoded by a polynucleotide that hybridizes under moderately stringent conditions to the complement of a polynucleotide consisting of SEQ ID NO:

11. a light chain variable domain selected from the group consisting of: b. i. a sequence of amino acids at least 80% identical to SEQ ID NO: 10; ii. a sequence of amino acids encoded by a polynucleotide sequence at least 80% identical to SEQ ID NO:9; iii. An amino acid sequence encoded by a polynucleotide that hybridizes under moderately stringent conditions to the complement of a polynucleotide consisting of SEQ ID NO:

9. a heavy chain variable domain selected from the group consisting of: or c. the light chain variable domain of (a) and the heavy chain variable domain of (b). A method comprising:

50. 1. A method of reducing a subject's SNOT-22 and / or Lund-Mackay score, comprising administering a composition comprising an anti-TSLP antibody at a dose of 210 mg every four weeks, wherein the antibody: a. i. a light chain CDR1 sequence comprising the amino acid sequence set forth in SEQ ID NO:3; ii. a light chain CDR2 sequence comprising the amino acid sequence set forth in SEQ ID NO:4, and iii. A light chain CDR3 sequence comprising the amino acid sequence set forth in SEQ ID NO:5 a light chain variable domain comprising: b. i. a heavy chain CDR1 sequence comprising the amino acid sequence set forth in SEQ ID NO:6; ii. a heavy chain CDR2 sequence comprising the amino acid sequence set forth in SEQ ID NO: 7; and iii. A heavy chain CDR3 sequence comprising the amino acid sequence set forth in SEQ ID NO:8 a heavy chain variable domain comprising: wherein the antibody specifically binds to the TSLP polypeptide set forth in amino acids 29-159 of SEQ ID NO:

2.

51. 1. A method of reducing a subject's SNOT-22 and / or Lund-Mackay score, comprising administering a composition comprising an anti-TSLP antibody at a dose of 210 mg every four weeks, wherein the antibody: a. i. a sequence of amino acids at least 80% identical to SEQ ID NO: 12; ii. a sequence of amino acids encoded by a polynucleotide sequence at least 80% identical to SEQ ID NO: 11; iii. An amino acid sequence encoded by a polynucleotide that hybridizes under moderately stringent conditions to the complement of a polynucleotide consisting of SEQ ID NO:

11. a light chain variable domain selected from the group consisting of: b. i. a sequence of amino acids at least 80% identical to SEQ ID NO: 10; ii. a sequence of amino acids encoded by a polynucleotide sequence at least 80% identical to SEQ ID NO:9; iii. An amino acid sequence encoded by a polynucleotide that hybridizes under moderately stringent conditions to the complement of a polynucleotide consisting of SEQ ID NO:

9. a heavy chain variable domain selected from the group consisting of: or c. the light chain variable domain of (a) and the heavy chain variable domain of (b). A method comprising:

52. 52. The method of any one of claims 48 to 51, wherein the light chain variable domain is set forth in SEQ ID NO: 12 and the heavy chain variable domain is set forth in SEQ ID NO:

10.

53. 53. The method of any one of claims 48-52, wherein the subject has a Nasal Polyp Score (NPS) of 0 or 1 after 52 weeks of treatment.

54. The method of any one of claims 32 to 53, wherein the anti-TSLP antibody is tezepelumab.

55. 55. The method of claim 54, wherein the antibody is an IgG2 antibody and has the full-length heavy and light chain sequences set forth in SEQ ID NOs: 13 and 14, respectively.

56. 56. The method of any one of claims 48 to 55, wherein the antibody is administered every four weeks.

57. The method of any one of claims 24 to 56, wherein the subject has chronic sinusitis.

58. 58. The method of claim 57, wherein the chronic sinusitis is severe or moderate chronic sinusitis.

59. 59. The method of any one of claims 1 to 58, wherein the administration is subcutaneous or intravenous.

60. 1. A method for treating chronic rhinosinusitis with nasal polyps in a subject, comprising: selecting a subject in need of treatment for chronic rhinosinusitis with nasal polyps; and administering to the subject a composition comprising an anti-TSLP antibody at a dose of 210 mg every four weeks, wherein the antibody is a. i. a light chain CDR1 sequence comprising the amino acid sequence set forth in SEQ ID NO:3; ii. a light chain CDR2 sequence comprising the amino acid sequence set forth in SEQ ID NO:4, and iii. A light chain CDR3 sequence comprising the amino acid sequence set forth in SEQ ID NO:5 a light chain variable domain comprising: b. i. a heavy chain CDR1 sequence comprising the amino acid sequence set forth in SEQ ID NO:6; ii. a heavy chain CDR2 sequence comprising the amino acid sequence set forth in SEQ ID NO: 7; and iii. A heavy chain CDR3 sequence comprising the amino acid sequence set forth in SEQ ID NO:8 a heavy chain variable domain comprising: A method comprising:

61. 1. A method for treating chronic rhinosinusitis with nasal polyps in a subject, comprising: selecting a subject in need of treatment for chronic rhinosinusitis with nasal polyps; and administering to the subject a composition comprising an anti-TSLP antibody at a dose of 210 mg every four weeks, wherein the antibody is a. i. a sequence of amino acids at least 80% identical to SEQ ID NO: 12; ii. a sequence of amino acids encoded by a polynucleotide sequence at least 80% identical to SEQ ID NO: 11; iii. An amino acid sequence encoded by a polynucleotide that hybridizes under moderately stringent conditions to the complement of a polynucleotide consisting of SEQ ID NO:

11. a light chain variable domain selected from the group consisting of: b. i. a sequence of amino acids at least 80% identical to SEQ ID NO: 10; ii. a sequence of amino acids encoded by a polynucleotide sequence at least 80% identical to SEQ ID NO:9; iii. An amino acid sequence encoded by a polynucleotide that hybridizes under moderately stringent conditions to the complement of a polynucleotide consisting of SEQ ID NO:

9. a heavy chain variable domain selected from the group consisting of: or c. the light chain variable domain of (a) and the heavy chain variable domain of (b). wherein the antibody specifically binds to the TSLP polypeptide set forth in amino acids 29-159 of SEQ ID NO:

2.

62. 62. The method of claim 60 or 61, wherein the light chain variable domain is set forth in SEQ ID NO: 12 and the heavy chain variable domain is set forth in SEQ ID NO:

10.

63. 63. The method of claim 62, wherein the antibody is an IgG2 antibody and has the full-length heavy and light chain sequences set forth in SEQ ID NOs: 13 and 14, respectively.

64. 64. The method of any one of claims 60 to 63, wherein the antibody or antibody variant is administered for a period of at least 4 months, 6 months, 9 months, 1 year or more.

65. 65. The method of any one of claims 60 to 64, wherein the anti-TSLP antibody is selected from the group consisting of a monoclonal antibody, a recombinant antibody, an IgG1 antibody, an IgG2 antibody, an IgG3 antibody, and an IgG4 antibody.

66. The method of any one of claims 60 to 65, wherein the antibody is an IgG2 antibody.

67. The method of any one of claims 60 to 66, wherein the antibody is a human antibody.

68. 68. The method of any one of claims 60 to 67, wherein the antibody is tezepelumab.

69. 1. A method for treating chronic sinusitis in a subject, comprising selecting a subject in need of treatment for chronic sinusitis and administering to the subject a therapeutically effective amount of an anti-TSLP antibody or antibody variant, wherein the anti-TSLP antibody or antibody variant is selected from the group consisting of antibodies and antibodies disclosed in WO 20220226342 A1, WO 20220226339 A1, WO 2023098491 A1, WO 2021155634 A1, WO 2022166072 A1, WO 2021043221 A1, WO 2022184074 A1, WO 2021104053 A1, WO 2023116 925 A1, 2021155861 A1, 2022116858 A1, 2022117079 A1, 2020244544 A1, 2021152488 A1, 2022253147 A1, 2023070948 A1, 2023142309 A1, 2022095689 A1, 2021115240 A1, 2022166739 A1, and 2019100111 A1 or shown in Table A.

70. 70. The method of any one of claims 60 to 69, comprising administering to a patient a pharmaceutical composition comprising said antibody or antibody variant and further comprising a pharmaceutically acceptable carrier or excipient.

71. 71. The method of any one of claims 60-70, wherein said administering delays the time to chronic sinusitis exacerbation compared to a subject not administered the anti-TSLP antibody.

72. 72. The method of any one of claims 60-71, wherein said administering reduces the frequency or level of co-administered therapy in said subject.

73. 73. The method of claim 72, wherein the co-administration therapy is selected from the group consisting of dupilumab, an immunosuppressant or immunomodulatory agent, a systemic corticosteroid, cyclosporine, mycophenolate mofetil, interferon (IFN) gamma, a Janus kinase inhibitor, azathioprine, methotrexate, an anti-IL-13 antibody, an anti-IL-5 pathway antibody, or a combination thereof.

74. 74. The method of claim 72 or 73, wherein said administering reduces or eliminates the need for corticosteroid therapy.

75. 75. The method of any one of claims 60-74, wherein the subject has a Nasal Polyp Score (NPS) of 0 or 1 after 52 weeks of treatment.

76. 76. The method of any one of claims 60-75, wherein the administration results in an improvement in one or more measures of chronic rhinosinusitis including Nasal Polyp Score (NPS), Nasal Congestion Score (NCS), anosmia, Nasal and Sinus Outcome Test-22 item (SNOT-22), EuroQOL Quality of Life 5 Dimension 3 Level (EQ-5D-3L), Asthma Control Questionnaire (ACQ-6), Lund-Mackay score, modified Lund-Mackay score, incidence of nasal polyp surgery, and / or systemic corticosteroids (SCS).

77. 77. The method of any one of claims 60-76, wherein said administering improves one or more symptoms of chronic sinusitis as measured by a patient's symptom diary.

78. 78. The method of any one of claims 60-77, wherein said administering improves one or more symptoms of chronic sinusitis selected from the group consisting of nasal congestion, nasal obstruction, runny nose, postnasal drip, mucus discharge down the throat, significant nasal blockage, runny nose, loss of smell, asthma symptoms, headache, facial pain, facial pressure, loss of smell, impaired sleep due to nasal symptoms, and impaired daily activities due to nasal symptoms.

79. 79. The method of any one of claims 60 to 78, wherein the chronic sinusitis is severe or moderate chronic sinusitis.

80. 80. The method of any one of claims 60 to 79, wherein the administration is subcutaneous or intravenous.

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