Chronic sinusitis treatment with anti-TSLP antibodies

Abstract

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

Description

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This application claims the benefit of priority to U.S. Provisional Patent Application No. 63 / 483,000, filed February 2, 2023, and U.S. Provisional Patent Application No. 63 / 503,087, filed May 18, 2023, which are incorporated herein by reference in their entireties.

[0003] Incorporation by Reference of Electronically Submitted Materials

[0004] The Sequence Listing, which forms part of this disclosure, is submitted as a text file along with the specification. The text file containing the Sequence Listing is named "58714_SeqListing.xml," was created on January 23, 2024, and is 15,609 bytes in size. The subject matter of the Sequence Listing is incorporated herein by reference in its entirety. Technical Field

[0005] The present disclosure generally relates to methods of treating chronic sinusitis with or without nasal polyps using antibodies specific for thymic stromal lymphopoietin (TSLP). Background Art

[0006] Chronic rhinosinusitis with nasal polyps (CRSwNP) is a chronic, heterogeneous inflammatory disorder of the nasal and paranasal mucosa (Fokkens et al. 2020). The underlying pathogenesis of the disease is currently unknown, but in recent years, type 2 (T2)-driven inflammation has been shown to be the main process in CRSwNP, and treatments targeting T2 inflammation have been shown to be effective in CRSwNP (Gevaert et al. 2011, Bachert et al. 2016, Bachert et al. 2017, Bachert et al. 2019, Gevaert et al. 2020). Through epidemiological, pathophysiological, and clinical evidence, CRSwNP is closely associated with asthma, supporting the concept of a "combined airway" of chronic inflammatory diseases of the upper and lower respiratory tract. Both diseases are comorbidities ( K et al. 2015).

[0007] Asthmatic patients have a higher prevalence of CRS and CRSwNP and more severe rhinosinusitis compared to non-asthmatic patients (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 can have worse asthma control, increased airway obstruction, and more severe lower airway inflammation compared to subjects without CRSwNP (Bilodeau L et al. 2010). Co-morbid asthma in CRSwNP patients is associated with reduced quality of life (Alobid I et al. 2005, Ehnhage A et al. 2009). Mechanistically, both NP and severe eosinophilic asthma are considered to be type 2 (T2) driven diseases, and the inflammatory features between the upper airways in NP and the lower airways in asthma are similar (Fokkens et al. 2020, Chaaban MR et al. 2013). As with asthma, the role of eosinophils is considered important in the pathology of NP in a high proportion of patients.

[0008] Nasal polyposis represents a serious unmet medical need area, especially for a subset of NP patients who have exhausted current treatment options, including medical interventions (intranasal corticosteroids (INCS), systemic corticosteroids (SCS) and antibiotics) and surgical interventions. Both patients and healthcare professionals point to a greater need for new therapies that reduce the need for repeated SCS or surgery in all NP patients. For patients whose symptoms cannot be controlled with corticosteroids, surgical resection of polyps is still considered, but the recurrence rate is high (about 40% at 12 months post-surgery) and often requires repeated surgical intervention. Despite the continuation of INCS post-surgery, a proportion of patients will experience post-surgical recurrence even with treatment using currently available therapies, and if these participants undergo further surgery, their risk of recurrence is even higher (Fokkens et al. 2020, Orlandi RR et al. 2013, Agarwal et al. 2019, van der Veen et al. 2017).

[0009] Thymic stromal lymphopoietin (TSLP) is an epithelial cell-derived cytokine produced in response to environmental and pro-inflammatory stimuli that leads to activation of multiple inflammatory cells and downstream pathways (Soumelis et al., 2002; Allakhverdi et al., J Exp Med 2007; 204:253-8). TSLP is increased in the airways of asthmatic patients and correlates with Th2 cytokine and chemokine expression (Shikotra et al., J Allergy Clin Immunol 2012; 129:104-11el-9) and disease severity (Ying et al., J Immunol 2005; 174:8183-90; Ying et al. J Immunol 2008; 181:2790-8).

[0010] Tezepelumab (also known as AMG 157) (Gilliet, et al., J Exp Med 2003; 197:1059-63) is a fully human monoclonal antibody (immunoglobulin G2l) targeting thymic stromal lymphopoietin (TSLP), an epithelial cell-derived cytokine that promotes inflammatory responses to environmental stimuli through its 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. SUMMARY

[0011] The anti-TSLP antibodies described herein address unmet needs in patients with chronic rhinosinusitis with or without nasal polyps, where other medications can not control symptoms. For example, antibody therapy can improve nasal polyp scores, olfactory loss, or reduce the need for surgical polyp removal in patients with chronic rhinosinusitis, as well as reduce the need for alternative therapies such as systemic corticosteroids.

[0012] The disclosure provides, in part, a method for treating chronic rhinosinusitis in a subject, the method comprising selecting a subject in need of treatment for chronic rhinosinusitis, administering to the subject a therapeutically effective amount of an anti-TSLP antibody or antibody variant, wherein the two binding sites of the antibody have the same binding to TSLP, and 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 a TSLP polypeptide as set forth in amino acids 29-159 of SEQ ID NO: 2; or wherein the two binding sites of the antibody have the same binding to TSLP, and the antibody comprises: a. a light chain variable domain selected from the group consisting of: i. an amino acid sequence that is at least 80% identical to SEQ ID NO: 12; ii. an amino acid sequence encoded by a polynucleotide sequence that is at least 80% identical to SEQ ID NO: 11; iii. an amino acid sequence encoded by a polynucleotide that hybridizes to the complement of a polynucleotide consisting of SEQ ID NO: 11 under moderately stringent conditions; and b. a heavy chain variable domain selected from the group consisting of: i. an amino acid sequence that is at least 80% identical to SEQ ID NO: 10; ii. an amino acid sequence encoded by a polynucleotide sequence that is at least 80% identical to SEQ ID NO: 9; iii. an amino acid sequence encoded by a polynucleotide that hybridizes to the complement of a polynucleotide consisting of SEQ ID NO: 9 under moderately stringent conditions; or c. the light chain variable domain of (a) and the heavy chain variable domain of (b), wherein the antibody specifically binds to a TSLP polypeptide as set forth in amino acids 29-159 of SEQ ID NO: 2.

[0013] Also provided is a method for treating chronic rhinosinusitis in a subject, the method comprising administering a composition comprising an anti-TSLP antibody at a dose of 140 mg to 420 mg at intervals of every 2 weeks or every 4 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 a TSLP polypeptide as set forth in amino acids 29-159 of SEQ ID NO:2; or wherein the two binding sites of the antibody have the same binding to TSLP, and the antibody comprises: a. a light chain variable domain selected from the group consisting of: i. an amino acid sequence that is at least 80% identical to SEQ ID NO: 12; ii. an amino acid sequence encoded by a polynucleotide sequence that is at least 80% identical to SEQ ID NO: 11; iii. an amino acid sequence encoded by a polynucleotide that hybridizes to the complement of a polynucleotide consisting of SEQ ID NO: 11 under moderately stringent conditions; and b. a heavy chain variable domain selected from the group consisting of: i. an amino acid sequence that is at least 80% identical to SEQ ID NO: 10; ii. an amino acid sequence encoded by a polynucleotide sequence that is at least 80% identical to SEQ ID NO: 9; iii. an amino acid sequence encoded by a polynucleotide that hybridizes to the complement of a polynucleotide consisting of SEQ ID NO: 9 under moderately stringent conditions; or c. the light chain variable domain of (a) and the heavy chain variable domain of (b), wherein the antibody specifically binds to a TSLP polypeptide as set forth in amino acids 29-159 of SEQ ID NO:2.

[0014] The disclosure further provides a method for treating chronic rhinosinusitis in a subject, the method comprising selecting a subject in need of treatment for chronic rhinosinusitis, administering to the subject a composition comprising an anti-TSLP antibody at a dose of 140 mg to 420 mg at intervals of every 2 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 a TSLP polypeptide as set forth in amino acids 29-159 of SEQ ID NO:2.

[0015] The disclosure further provides a method for treating chronic rhinosinusitis in a subject, the method comprising selecting a subject in need of treatment for chronic rhinosinusitis, administering to the subject a composition comprising an anti-TSLP antibody at a dose of 140 mg to 420 mg at intervals of every 2 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 a TSLP polypeptide as set forth in amino acids 29-159 of SEQ ID NO:2.

[0016] In embodiments, the antibody is administered every 4 weeks. In embodiments, the antibody is administered every 2 weeks or every 4 weeks at a dose of 140 mg or at a dose of 420 mg. In embodiments, the antibody is administered every 2 weeks or every 4 weeks at a dose of 140 mg or at a dose of 210 mg.

[0017] In various embodiments, the antibody is administered at a dose of 210 mg every 2 weeks. In various embodiments, the antibody is administered at a dose of 210 mg every 4 weeks.

[0018] In various embodiments, the subject is also receiving a corticosteroid therapy.

[0019] In various embodiments, a method for treating chronic rhinosinusitis in a subject is provided, the method comprising selecting a subject in need of treatment for chronic rhinosinusitis, administering to the subject a therapeutically effective amount of a systemic corticosteroid and a composition comprising an anti-TSLP antibody at a dose of 210 mg at intervals of every 2 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 a TSLP polypeptide as set forth in amino acids 29-159 of SEQ ID NO:2.

[0020] In various embodiments, a method for treating chronic rhinosinusitis in a subject is provided, the method comprising selecting a subject in need of treatment for chronic rhinosinusitis, administering to the subject a therapeutically effective amount of a systemic corticosteroid and a composition comprising an anti-TSLP antibody at a dose of 210 mg at intervals of every 2 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 a TSLP polypeptide as set forth in amino acids 29-159 of SEQ ID NO:2.

[0021] The present disclosure also provides a method for treating chronic rhinosinusitis in a subject, the method comprising selecting a subject in need of treatment for chronic rhinosinusitis, administering to the subject a composition comprising an anti-TSLP antibody at a dose of 210 mg at an interval of every 4 weeks, wherein the two antibodies 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; 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 a TSLP polypeptide as set forth in amino acids 29-159 of SEQ ID NO:2.

[0022] The present disclosure further provides a method for treating chronic rhinosinusitis in a subject, the method comprising selecting a subject in need of treatment for chronic rhinosinusitis, administering to the subject a composition comprising an anti-TSLP antibody at a dose of 210 mg at an interval of every 4 weeks, wherein the antibody comprises: a. a light chain variable domain selected from the group consisting of: i. an amino acid sequence that is at least 80% identical to SEQ ID NO: 12; ii. an amino acid sequence encoded by a polynucleotide sequence that is 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; and b. a heavy chain variable domain selected from the group consisting of: i. an amino acid sequence that is at least 80% identical to SEQ ID NO: 10; ii. an amino acid sequence encoded by a polynucleotide sequence that is 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; or c. the light chain variable domain of (a) and the heavy chain variable domain of (b), wherein the antibody specifically binds to a TSLP polypeptide as set forth in amino acids 29-159 of SEQ ID NO:2.

[0023] In 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.

[0024] In various embodiments, the anti-TSLP antibody or variant has substantially similar pK characteristics in humans as tezepelumab.

[0025] In various embodiments, the antibody or antibody variant is administered for a period of at least 4 months, 6 months, 9 months, 1 year, or longer.

[0026] In various embodiments, the anti-TSLP antibody or antibody variant thereof is bivalent and 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 IgGl antibody, an IgG2 antibody, an IgG3 antibody, and an IgG4 antibody.

[0027] In various embodiments, the anti-TSLP antibody is bivalent and selected from the group consisting of: a human antibody, a humanized antibody, a chimeric antibody, a monoclonal antibody, a recombinant antibody, an IgGl antibody, an IgG2 antibody, an IgG3 antibody, and an IgG4 antibody.

[0028] In one embodiment, the anti-TSLP antibody variant is selected from the group consisting of: a Fab fragment, a single domain antibody, a scFv, wherein the dose is adjusted such that these binding sites are equimolar relative to the binding sites of the bivalent antibody dosed.

[0029] In various embodiments, the antibody is an IgG2 antibody.

[0030] In one embodiment, the antibody or antibody variant is a human or humanized antibody.

[0031] In various embodiments, the antibody is tezepelumab. In various embodiments, the anti-TSLP antibody is an IgG2 antibody having 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.

[0032] In various embodiments, the antibody or antibody variant is further in a pharmaceutical composition further comprising a pharmaceutically acceptable carrier or excipient.

[0033] In various embodiments, the antibody is an anti-TSLP antibody described in the art. Exemplary antibodies are further described in the DETAILED DESCRIPTION.

[0034] In various embodiments, the subject is an adult. In various embodiments, the subject is a child or adolescent.

[0035] Further provided is that administration of the anti-TSLP antibody or antibody variant reduces the level of Th2 cytokines in the subject.

[0036] In various embodiments, administering the 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), olfactory loss, Sino-Nasal Outcome Test 22 (SNOT-22), EuroQOL Quality of Life 5-Dimension 3-Level Version (EQ-5D-3L), Asthma Control Questionnaire (ACQ-6), Lund-Mackay Score, Modified Lund-Mackay Score, incidence of nasal polyp surgery, and / or systemic corticosteroid (SCS).

[0037] 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 week 52 after treatment. In various embodiments, the subject has an initial NPS score of 2. In various embodiments, the subject has an initial NPS score of 3. In various embodiments, the subject has an NCS score of 0 (none) or 1 (mild) at week 52 after treatment. In various embodiments, the subject has an initial NCS score of 2. In various embodiments, the subject has an initial NCS score of 3.

[0038] In various embodiments, treatment with the anti-TSLP modulates the level of one or more of the following biomarkers of chronic rhinosinusitis: cytokines, IgE, CCL17, CCL18, CCL22, and RNA transcription changes in the nasal epithelium. In various embodiments, treatment with the anti-TSLP reduces the level of Th2 cytokines. In various embodiments, the treatment modulates (reduces or mitigates) the level or activity of IL-4, IL-5, IL-13, IL-17, IL-22, IL-23, IL-31, or one or more combinations thereof.

[0039] Provided herein are methods for treating chronic rhinosinusitis with nasal polyps in a subject, comprising selecting a subject in need of treatment for chronic rhinosinusitis with nasal polyps, administering to the subject a composition comprising an anti-TSLP antibody at an interval of every 4 weeks at a dose of 210 mg, wherein the antibody comprises

[0040] A. 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; or

[0041] B. a. a light chain variable domain selected from the group consisting of: i. an amino acid sequence at least 80% identical to SEQ ID NO: 12; ii. an amino acid sequence 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 to the complement of a polynucleotide consisting of SEQ ID NO: 11 under moderately stringent conditions; and b. a heavy chain variable domain selected from the group consisting of: i. an amino acid sequence at least 80% identical to SEQ ID NO: 10; ii. an amino acid sequence 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 to the complement of a polynucleotide consisting of SEQ ID NO: 9 under moderately stringent conditions; or c. the light chain variable domain of (a) and the heavy chain variable domain of (b), wherein the antibody specifically binds to a TSLP polypeptide as set forth in amino acids 29-159 of SEQ ID NO: 2.

[0042] Further provided is a method for treating chronic rhinosinusitis in a subject, the method comprising selecting a subject in need of treatment for chronic rhinosinusitis, administering to the subject a composition comprising an anti-TSLP antibody at a dose of 140 to 420 mg at intervals of every 2 weeks or every 4 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 a TSLP polypeptide as set forth in amino acids 29-159 of SEQ ID NO: 2, wherein the antibody is an IgG2 antibody.

[0043] In 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.

[0044] In embodiments, the antibody is administered every 4 weeks. In embodiments, the antibody is administered at a dose of 210 mg every 2 weeks or every 4 weeks.

[0045] In embodiments, the antibody is administered at a dose of 210 mg every 4 weeks.

[0046] Also provided is a method of reducing the frequency of required surgery or systemic corticosteroids in a subject having chronic rhinosinusitis with or without nasal polyps, the method comprising selecting a subject in need of treatment for chronic rhinosinusitis, administering to the subject a composition comprising an anti-TSLP antibody at a dose of 140 mg to 420 mg at 2-week intervals, 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 antigen binding protein specifically binds to a TSLP polypeptide as set forth in amino acids 29-159 of SEQ ID NO:2.

[0047] Also provided is a method of reducing the frequency of required surgery or systemic corticosteroids in a subject having chronic rhinosinusitis with nasal polyps, the method comprising selecting a subject in need of treatment for chronic rhinosinusitis, administering to the subject a composition comprising an anti-TSLP antibody at a dose of 140 mg to 420 mg at 2-week intervals, 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 antigen binding protein specifically binds to a TSLP polypeptide as set forth in amino acids 29-159 of SEQ ID NO:2.

[0048] Further provided is a method of reducing the frequency of exacerbations of chronic rhinosinusitis in a subject, the method comprising selecting a subject in need of treatment for chronic rhinosinusitis, administering to the subject a composition comprising an anti-TSLP antibody at a dose of 140 mg to 420 mg at intervals of every 2 weeks, wherein the antibody comprises: a. a light chain variable domain selected from the group consisting of: i. an amino acid sequence at least 80% identical to SEQ ID NO: 12; ii. an amino acid sequence 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 to the complement of a polynucleotide consisting of SEQ ID NO: 11 under moderately stringent conditions; and b. a heavy chain variable domain selected from the group consisting of: i. an amino acid sequence at least 80% identical to SEQ ID NO: 10; ii. an amino acid sequence 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 to the complement of a polynucleotide consisting of SEQ ID NO: 9 under moderately stringent conditions; or c. the light chain variable domain of (a) and the heavy chain variable domain of (b).

[0049] Further provided is a method of reducing the frequency of exacerbations of chronic rhinosinusitis in a subject, the method comprising selecting a subject in need of treatment for chronic rhinosinusitis, administering to the subject a composition comprising an anti-TSLP antibody at a dose of 140 mg to 420 mg at intervals of every 2 weeks, wherein the antibody comprises: a. a light chain variable domain selected from the group consisting of: i. an amino acid sequence at least 80% identical to SEQ ID NO: 12; ii. an amino acid sequence 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 to the complement of a polynucleotide consisting of SEQ ID NO: 11 under moderately stringent conditions; and b. a heavy chain variable domain selected from the group consisting of: i. an amino acid sequence at least 80% identical to SEQ ID NO: 10; ii. an amino acid sequence 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 to the complement of a polynucleotide consisting of SEQ ID NO: 9 under moderately stringent conditions; or c. the light chain variable domain of (a) and the heavy chain variable domain of (b).

[0050] Also provided are methods for reducing SNOT-22 and / or Lund-Mackay scores in a subject, comprising administering a composition comprising an anti-TSLP antibody at a dose of 140 mg to 420 mg at an interval of every 2 weeks, or at a dose of 210 mg at an interval of every 4 weeks, wherein the antibody comprises: a. a light chain variable domain selected from the group consisting of: i. an amino acid sequence at least 80% identical to SEQ ID NO: 12; ii. an amino acid sequence 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 to the complement of a polynucleotide consisting of SEQ ID NO: 11 under moderately stringent conditions; and b. a heavy chain variable domain selected from the group consisting of: i. an amino acid sequence at least 80% identical to SEQ ID NO: 10; ii. an amino acid sequence 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 to the complement of a polynucleotide consisting of SEQ ID NO: 9 under moderately stringent conditions; or c. the light chain variable domain of (a) and the heavy chain variable domain of (b).

[0051] In various embodiments, the present disclosure provides a method for reducing SNOT-22 and / or Lund-Mackay scores in a subject, comprising administering a composition comprising an anti-TSLP antibody at a dose of 140 mg to 420 mg at an interval of every 2 weeks, or at a dose of 210 mg at an interval of every 4 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 antigen binding protein specifically binds a TSLP polypeptide as set forth in amino acids 29-159 of SEQ ID NO: 2.

[0052] In various embodiments, the disclosure provides a method for reducing SNOT-22 domain score in a subject, the method comprising administering a composition comprising an anti-TSLP 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, at a dose of 140 mg to 420 mg at an interval of every 2 weeks, or at a dose of 210 mg at an interval of every 4 weeks, wherein the antigen binding protein specifically binds to a TSLP polypeptide as set forth in amino acids 29-159 of SEQ ID NO:2.

[0053] In various embodiments, the SNOT-22 domain is a nasal domain, an ear / facial domain, a sleep domain, a function domain, or an emotion domain. In various embodiments, the administration improves one or more symptoms selected from the group consisting of: need to blow nose, congestion, sneezing, runny nose, cough, post-nasal drainage, thick nasal drainage, decreased sense of smell / taste; ear fullness, dizziness, ear pain, facial pain / pressure; difficulty falling asleep, waking at night, inadequate nighttime sleep, waking up tired; fatigue, decreased productivity, decreased concentration, sad / depressed / irritable, sad, and embarrassed.

[0054] In various embodiments, the antibody comprises: a. a light chain variable domain selected from the group consisting of: i. an amino acid sequence that is at least 80% identical to SEQ ID NO: 12; ii. an amino acid sequence encoded by a polynucleotide sequence that is at least 80% identical to SEQ ID NO: 11; iii. an amino acid sequence encoded by a polynucleotide that hybridizes under medium stringency conditions to the complement of a polynucleotide consisting of SEQ ID NO: 11; and b. a heavy chain variable domain selected from the group consisting of: i. an amino acid sequence that is at least 80% identical to SEQ ID NO: 10; ii. an amino acid sequence encoded by a polynucleotide sequence that is at least 80% identical to SEQ ID NO: 9; iii. an amino acid sequence encoded by a polynucleotide that hybridizes under medium stringency 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).

[0055] 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.

[0056] In various embodiments, the antibody is tezepelumab.

[0057] It is provided that the above-mentioned dosing and antibody and antibody variant types apply to the various methods contemplated herein.

[0058] In various embodiments, a pharmaceutical composition is provided comprising an antibody or antibody variant and further comprising a pharmaceutically acceptable carrier or excipient.

[0059] In various embodiments, the administration delays the time to exacerbation of chronic rhinosinusitis compared to subjects who do not receive an anti-TSLP antibody or the patient’s baseline symptoms prior to treatment with an anti-TSLP antibody or antibody variant. Examples of such antibodies include tezepelumab.

[0060] In various embodiments, the administration delays the incidence or time to surgery for nasal polyps in subjects with chronic rhinosinusitis compared to subjects who do not receive an anti-TSLP antibody.

[0061] The administration of the TSLP antibody or antibody variant alone can be subcutaneous.

[0062] In various embodiments, the administration reduces the frequency or level of co-administered therapy in the subject. Exemplary co-administered therapies are dupilumab, immunosuppressive or immunomodulatory drugs (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. “Co-administration” for this purpose encompasses administration of the two different molecules described above in the same syringe / auto-injector or two different syringes / auto-injectors. The different molecules described above can also be administered simultaneously or at different times.

[0063] In various embodiments, the administration reduces or eliminates the need for corticosteroid therapy.

[0064] In various embodiments, the administration is subcutaneous or intravenous.

[0065] In various embodiments, the antibody is tezepelumab or another anti-TSLP antibody or antibody variant described in the art, e.g., in Table A or WO 20220226342A1, WO 20220226339A1, WO 2023098491A1, WO 2021155634A1, WO 2022166072A1, WO 2021043221A1, WO 2022184074A1, WO 2021104053A1, WO 2023116925A1, WO 2021155861A1, WO 2022116858A1, WO 2022117079A1, WO 2020244544A1, WO 2021152488A1, WO 2022253147A1, WO 2023070948A1, WO 2023142309A1, WO 2022095689A1, WO 2021115240A1, WO 2022166739A1, and WO 2019100111A1. Exemplary antibodies are further described in the DETAILED DESCRIPTION. BRIEF DESCRIPTION OF DRAWINGS

[0066] Figure 1A and Figure 1B Baseline demographics and clinical characteristics of patients with or without nasal polyps who received anti-TSLP antibody treatment for chronic rhinosinusitis.

[0067] Figure 2 Mean change from baseline to week 52 in SNOT-22 scores for patients with a history of nasal polyps who received anti-TSLP antibody treatment.

[0068] Figure 3 Mean change from baseline to week 52 in SNOT-22 scores for patients with any history of nasal polyps who received anti-TSLP antibody treatment.

[0069] Figure 4 Improvement from baseline to week 52 in SNOT-22 domain scores for patients with a history of NP for tezepelumab compared with placebo. Placebo, n=57; tezepelumab 210 mg Q4W, n=65. n is the number of patients who contributed to the analysis, i.e., the number of patients with a baseline value and non-missing values for the independent variables included in the model. CI, confidence interval; LS, least squares; NP: nasal polyps; SNOT-22, Sinusitis Outcomes Test-22.

[0070] Figures 5A-5G Change from baseline in SNOT-22 total scores and domain scores for 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; Tezelumab, n = 69. Week 28: Placebo, n = 57; Tezelumab, n = 64. Week 52: Placebo, n = 53; Tezelumab, n = 64. LS, least squares; NP, nasal polyposis; Q4W, every 4 weeks; SE, standard error; SNOT-22, Sinus Nasal Outcome Test-22.

[0071] Figures 6A-6E Change from baseline to week 52 in the SNOT-22 item scores of interest in patients with a history of NP. Figure 6A , decreased sense of smell / taste; Figure 6B , nasal congestion; Figure 6C ,cough; Figure 6D , productivity declines; Figure 6E , fatigue upon waking. n is the number of patients contributing to the analysis, that is, the number of patients with baseline values ​​and nonmissing independent variables included in the model. CI, confidence interval; LS, least squares; NP, nasal polyps; Q4W, every 4 weeks; SE, standard error; SNOT-22, nasosinusoidal Outcome Test-22.

[0072] Figure 7 .Sequences of TSLP and the anti-TSLP antibody tezelumab. DETAILED DESCRIPTION

[0073] The use of anti-TSLP antibodies addresses an unmet need in patients with chronic rhinosinusitis (CRS) or chronic rhinosinusitis with nasal polyps (CRSwNP), whose moderate to severe symptoms may not be controlled by other medications. Furthermore, treatment with anti-TSLP antibodies, such as tezelumab, may eliminate regular disease activity, allowing more patients to become steroid-free or reduce the need for steroid use in the treatment of CRS and CRSwNP.

[0074] definition

[0075] Unless otherwise stated, the following terms used in this application, including the specification and claims, have the definitions given below.

[0076] As used in the specification and the appended claims, the indefinite articles "a," "an," and "the" include plural as well as singular referents unless the context clearly dictates otherwise.

[0077] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as is commonly understood by one of ordinary skill in the art to which this disclosure belongs. The following references provide one of ordinary skill with a general definition of many of the terms used in this disclosure: Singleton et al., DICTIONARY OF MICROBIOLOGY AND MOLECULAR BIOLOGY (2d 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).

[0078] The term“about” or“approximately” means an acceptable error for the particular value as determined by one of ordinary skill in the art to which the value pertains, 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” precedes the first numerical value in a series of two or more numerical values, the term“about” or“approximately” is understood to apply to every numerical value in the series.

[0079] The term“chronic rhinosinusitis” as used herein refers to an inflammatory condition of the nasal and paranasal mucosa that is considered to be primarily driven by type 2 (T2) inflammation, which is the main process of CRS. Chronic rhinosinusitis can be chronic rhinosinusitis with nasal polyps (CRSwNP) or without nasal polyps (CRSsNP), and can also be associated with or without co-morbid asthma / allergy, asthma, infection, and aspirin-exacerbated respiratory disease (AERD) or nonsteroidal anti-inflammatory drug-exacerbated respiratory disease (NSAID-ERD).

[0080] The term“chronic rhinosinusitis exacerbation” as used herein refers to a worsening of chronic rhinosinusitis that results in any one of: use of systemic corticosteroids or other adjunctive therapy for at least 3 days; worsening of one or more symptoms or measures of chronic rhinosinusitis described herein, and / or growth or enlargement of the number, size, or severity of nasal polyps.

[0081] The term "worsening of chronic rhinosinusitis" refers to new or increased symptoms and / or signs (examinations) that can be associated with subjects having chronic rhinosinusitis with or without nasal polyps (subject-driven) or with patient daily diary alerts (diary-driven).

[0082] The term "cytokine" as used herein refers to one or more small (5-20 kD) proteins released by cells that have specific effects on cell-to-cell interactions 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 into sites of immune challenge; stimulating the development and proliferation of B cells, T cells, peripheral blood mononuclear cells (PBMCs), and other immune cells; and providing antimicrobial 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, IL17A, IL-17F, IL-18, IL-21, IL-22, IL-23, IL-31, IL-33, interferons (including IFN a, b, and g), tumor necrosis factors (including TNF a, b), transforming growth factors (including TGF a, b), granulocyte colony-stimulating factor (GCSF), granulocyte macrophage colony-stimulating factor (GMCSF), and thymic stromal lymphopoietin (TSLP).

[0083] "Helper T cell (Th) 1 cytokine" or "Thl -specific cytokine" refers to a cytokine expressed (intracellularly and / or secreted) by Thl T cells and includes IFN-g, TNF-a, and IL-12. "Th2 cytokine" or "Th2-specific cytokine" refers to a cytokine expressed (intracellularly and / or secreted) by Th2 T cells, including IL-4, IL-5, IL-13, and IL-10. "Thl 7 cytokine" or "Thl 7-specific cytokine" refers to a cytokine expressed (intracellularly and / or secreted) by Thl 7 T cells, including IL-17A, IL-17F, IL-22, and IL-21. In addition to the Thl 7 cytokines listed herein, certain populations of Thl 7 cells also express IFN-g and / or IL-2. Multifunctional CTL cytokines include IFN-g, TNF-a, IL-2, and IL-17.

[0084] The term "specifically binds" is "antigen specific," "has specificity for an antigen," "selective binding agent," "specific binding agent," "antigen target," or "immunologically reactive with an antigen" means that the antibody or polypeptide binds to a target antigen with greater affinity than to other antigens of similar sequence. Provided herein are agents that specifically bind to target proteins 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 homologs of closely related species, e.g., an antibody can be a human protein and also binds closely related primate proteins.

[0085] The term "antibody" or "immunoglobulin" refers to a tetrameric glycoprotein consisting of two heavy chains and two light chains each containing a variable and a constant region. "Heavy chain" and "light chain" refer to the light and heavy chains of an essentially full-length standard immunoglobulin (see, e.g., Immunobiology, 5thEdition (Janeway and Travers, et al. eds., 2001)). Antigen binding moieties 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.

[0086] Antibody variants include antibody fragments and antibody-like proteins that vary from the standard tetrameric antibody structure. Typically, antibody variants include V regions that vary from constant regions, or alternatively, V regions that are optionally added to constant regions in a non-standard fashion. Examples include multispecific antibodies (e.g., bispecific antibodies with additional V regions), antibody fragments that can bind antigen (e.g., Fab', F'(ab)2, Fv, single chain antibodies, diabodies), biparatopic peptides and recombinant peptides comprising the foregoing, so long as they exhibit the desired biological activity.

[0087] Antibody fragments include antigen binding portions of antibodies, including, inter alia, Fab, Fab', F(ab')2, 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, and polypeptides that contain at least a portion of an immunoglobulin that is sufficient to confer antigen-specific binding to a polypeptide, such as one, two, three, four, five, or six CDR sequences, so long as the antibody retains the desired biological activity.

[0088] "Valency" refers to the number of antigen binding sites on each antibody or antibody fragment that targets an epitope. A typical full-length IgG molecule or F(ab)2 is "bivalent" because it has two identical target binding sites. "Monovalent" antibody fragments, such as F(ab)' or scFc, have a single antigen binding site. Tri- or tetra-valent antigen binding proteins can also be engineered to be multivalent.

[0089] The term "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 can be present in minor amounts.

[0090] The term "inhibiting TSLP activity" includes inhibiting any one or more of: TSLP binding to its receptor; proliferation, activation or differentiation of cells expressing TSLPR in the presence of TSLP; inhibition of Th2 cytokine production in the presence of TSLP in a polarization assay; dendritic cell activation or maturation in the presence of TSLP; and mast cell cytokine release in the presence of TSLP. See, e.g., Column 6 and Example 8 of U.S. Patent 7982016B2, and Examples 7-10 of US 2012 / 0020988A1.

[0091] "Tezepelumab" refers to an antibody having the same amino acid sequence as the INN Tezepelumab-ekko. Tezepelumab also has heavy and light chain amino acid sequences set forth in SEQ ID NOs: 13 and 14, respectively.

[0092] The term "sample" or "biological sample" refers to a sample obtained from a subject for use in the methods of the present application, and includes urine, whole blood, plasma, serum, saliva, sputum, skin or tissue biopsy, cerebrospinal fluid, peripheral blood mononuclear cells with ex vivo stimulation, peripheral blood mononuclear cells without ex vivo stimulation, gut-associated lymphoid tissue with ex vivo stimulation, gut-associated lymphoid tissue without ex vivo stimulation, intestinal lavage fluid, bronchoalveolar lavage fluid, nasal lavage fluid, and induced sputum.

[0093] The terms "treat," "treating," and "treatment" refer to the temporary or permanent, partial or complete, elimination, reduction, suppression, or amelioration of a clinical symptom, manifestation, or progression of an event, disease, or condition associated with an inflammatory disorder as described herein. As recognized in the relevant art, a drug used as a therapeutic agent can reduce the severity of an established disease state, but need not eliminate every manifestation of the disease to be considered a useful therapeutic agent. Similarly, a treatment administered prophylactically need not be completely effective in preventing the onset of a disorder to be a viable prophylactic agent. It is sufficient to merely reduce the impact of the disease (e.g., by reducing the number of its symptoms or reducing the severity of its symptoms, or by increasing the effectiveness of another treatment, or by producing another beneficial effect), or to reduce the likelihood that the disease will occur or worsen in a subject. One embodiment of the present application relates to a method for determining therapeutic efficacy, the method comprising administering to a patient a therapeutic agent in an amount and for a time sufficient to cause sustained improvement beyond the baseline of an indicator reflective of the severity of a particular disorder.

[0094] The term "therapeutically effective amount" refers to an amount of a therapeutic agent effective to improve or alleviate a symptom or indication associated with a disease or disorder.

[0095] Chronic rhinosinusitis with nasal polyps (CRSwNP)

[0096] Chronic rhinosinusitis with nasal polyps (CRSwNP) is a chronic heterogeneous inflammatory disorder of the nasal and paranasal mucosa (Fokkens et al. 2020). The underlying pathogenesis of this disease is currently not well understood, but in recent years, type 2 (T2)-driven inflammation has been shown to be the main process in CRSwNP, and treatments targeting T2 inflammation have proven effective 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 airway environmental triggers. TSLP can drive the release of T2 cytokines from Th2 and ILC2 cells and have an impact on other immune cells present in NP tissue. TSLP levels are elevated in nasal polyp tissue in patients with CRSwNP compared to healthy sinus tissue or patients with CRS without NP (Kimura S et al. 2011, Nagarkar DR et al. 2013). Thus, TSLP can play a role in the initiation and persistence of CRSwNP and blocking is predicted to be beneficial to patients.

[0097] Current biotherapies available for NP have a success rate of only about 40% to 60% (Gevaert et al. 2011, Bachert et al. 2016, Bachert et al. 2017, Bachert et al. 2019, Gevaert et al. 2020). The lack of complete response with biologies has two possible explanations. First, when polyps become large enough to be symptomatic, the reduction of inflammatory cells and / or inflammation can limit and reduce new growth, but can not significantly reduce polyp size in the face of persistent tissue fibrosis (Stevens et al. 2016). The contribution of TSLP to extracellular matrix (ECM) deposition can be indirect, as an initiator of the inflammatory processes that drive fibrosis, or direct, as TSLP has been shown to have an effect on or be produced by lung fibroblasts (reviewed in Gauvreau et al. 2020). Furthermore, in CRSwNP, TSLP has been shown to indirectly stimulate fibroblasts through periostin induced by CST-1 (Kato et al. 2019); this periostin is a matrix cell signaling protein that modulates ECM structure and organization through its ability to bind ECM and promote collagen fibril formation and cross-linking. This suggests that, in addition to an anti-inflammatory MOA, treatment with tezepelumab can potentially have an anti-fibrotic effect, which can lead to improvement in CRSwNP. The kinetics of ECM turnover are known to be slow, so a suggested 52-week treatment period is needed if sufficient time is needed for ECM to change. Based on this potential anti-fibrotic MOA of tezepelumab, it is expected that NPS scores will continue to improve after Week 24.

[0098] Second, there is a subset of CRSwNP patients who do not have T2-mediated disease. Subgroup analyses of the tezepelumab Phase 2b study and Phase 3 study in asthma patients (PATHWAY, NCT02054130 and NAVIGATOR, NCT03347279) showed that tezepelumab was beneficial to participants with low and high baseline eosinophil counts and low and high baseline T2 distribution. These analyses suggest that, unlike other biologies currently on the market for the treatment of severe asthma, tezepelumab is effective in both T2-high and T2-low airway inflammation patients and can be effective in both T2-low and T2-high CRSwNP. It is hypothesized that tezepelumab reduces AAER in asthma by acting as an anti-inflammatory in the airways.

[0099] The eosinophilic (type 2 high) endotype of CRSwNP is most common in the US, Europe, and Japan, while the non-eosinophilic endotype is more common 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).

[0100] By epidemiological, pathophysiological, and clinical evidence, CRSwNP is closely related to asthma, supporting the concept of a “united airway” for chronic inflammatory diseases of the upper and lower airways. Both diseases are comorbidities K et al. 2015). Asthmatic patients have a higher prevalence of CRS and CRSwNP and more severe rhinosinusitis compared to non-asthmatic patients (Jarvis et al. 2012, Seybt et al. 2007, Pearlman et al., 2009, Tint et al. 2016, Settipane 1977). Furthermore, asthmatic subjects with CRSwNP can have worse asthma control, increased airway obstruction, and more severe lower airway inflammation compared to subjects without CRSwNP (Bilodeau et al. 2010). Co-morbid asthma in CRSwNP patients is associated with reduced quality of life (Alobid I et al. 2005, Ehnhage A et al. 2009). Mechanistically, both NP and severe eosinophilic asthma are considered to be type 2 (T2)-driven diseases, and the inflammatory profile between the upper airway of NP and the lower airway of asthma are similar (Fokkens et al. 2020, Chaaban MR et al. 2013). As with asthma, the role of eosinophils is considered important to the pathology of NP in a high proportion of patients.

[0101] Asthma and CRSwNP share some pathophysiology and common comorbidities. Post-hoc analysis of the PATHWAY study population showed that 15.2% of subjects had co-morbid CRSwNP. NP asthmatic patients receiving tezepelumab treatment had a comparable degree of improvement in AERR, FEV1, ACQ-6, and T2 inflammation biomarkers compared to non-NP asthmatic patients compared to placebo. These findings support the rationale for the broad effect of tezepelumab on asthma and potential efficacy in CRSwNP. (Emson C et al., 2020; Emson C et al., 2021).

[0102] The etiology of NP is still unclear, but allergy, asthma, infection, and aspirin sensitivity (AERD) are all associated with this complex and refractory disease in adults (Hull and Chandra 2017). Both NP and asthma are T2-driven disease processes characterized by eosinophilic infiltration in the affected tissue (polyp or airway). The inflammatory profile observed in asthma shares many features and similarities with the inflammation in NP patients, where eosinophils are the main effector cells in the pathophysiology of both upper airway rhinosinusitis and lower airway asthma K et al. 2015; Ediger et al. 2005).

[0103] Nasal polyposis is considered to be the result of chronic inflammatory disease of the nasal mucosa. The presence of polyps causes long-term symptoms such as significant nasal obstruction, postnasal drip and nasal discharge, loss of smell and facial pain. These symptoms can greatly affect the patient’s quality of life. Patients with CRSwNP have been observed to have more severe symptoms (as evidenced by higher Sinus Nasal 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 revision surgery than patients with CRSsNP (Hull and Chandra 2017; Fokkens et al. 2020).

[0104] Nasal polyposis represents a serious unmet area of medical need, particularly for a subset of NP patients who have exhausted current treatment options, including medical interventions (intranasal corticosteroids (INCS), systemic corticosteroids (SCS) and antibiotics) and surgical interventions. There is a strong need for new therapies, reducing the need for repeated SCS or surgery for all NP patients, identified by both patients and healthcare professionals. For patients whose symptoms are not controlled by corticosteroids, surgical removal of polyps is still considered, but with a high rate of recurrence (approximately 40% at 12 months post-surgery) and often requiring repeated surgical intervention. Despite the continuation of INCS post-surgery, there is a subset of patients who experience post-surgical recurrence even with treatment using currently available therapies, and if these participants undergo further surgery, their risk of recurrence is even higher (Fokkens et al. 2020, Orlandi RR et al. 2013, Agarwal et al. 2019, van der Veen et al. 2017).

[0105] Chronic rhinosinusitis without nasal polyps (CRSsNP) has also been detected in patients with allergic and non-allergic upper and lower airway diseases, epithelial cell diseases, immune deficiencies, autoimmune diseases, certain infectious diseases, abnormal biological membrane incidence, and patients with congenital immune deficiencies (Cho et al., J Allergy Clin Immunol Pract. 2016 4(4):575-582). The characteristics of subjects with CRSsNP are described in “Chronic Rhinosinusitis Without Nasal Polyps: Clinical Characteristics And Comorbid Diseases”, The Journal Of Allergy And Clinical Immunology: In Practice 2018.

[0106] Chronic rhinosinusitis can be assessed using several objective and subjective measures, such as the nasal polyp score and the nasal congestion score. These measures enable the researchers to assess the overall disease severity at a given time point and include a 4-point severity scale from none to severe disease (0 = none; 1 = mild; 2 = moderate disease; 3 = severe disease). The NPS is the sum of the right and left nostril scores assessed by endoscopy (max 8). The total NPS is graded according to the polyp size as described in Table 2.

[0107] Other measures of chronic rhinosinusitis severity / improvement include the nasal polyp symptom diary (NPSD) and the nasal polyp symptom screening assessment (NPSSA), olfactory loss, the Sino-Nasal Outcome Test 22 (SNOT-22), the EuroQOL Quality of Life 5-Dimensions 3-Level version (EQ-5D-3L), the Asthma Control Questionnaire (ACQ-6), the Lund-Mackay score, the modified Lund-Mackay score, the incidence of nasal polyp surgery and / or systemic corticosteroids (SCS).

[0108] The nasal polyp symptom diary (NPSD) and the nasal polyp symptom screening assessment (NPSSA) is an 11-item NP symptom diary that should be completed every morning throughout the screening, treatment, and follow-up period. Participants are asked to consider 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 congestion, rhinorrhea, postnasal drip (mucus running down the back of the throat), headache, facial pain, facial pressure, and olfactory difficulty) and symptom impact (sleep difficulties due to nasal symptoms and difficulties with daily activities due to nasal symptoms). Participants report the severity of each symptom and the symptom impact at its worst using a 4-point verbal rating scale (0 - none to 3 - severe). The total symptom score (TSS) is calculated by taking the sum of the 8 equally weighted symptom items. Following the symptom and symptom impact items, a single item will be administered to obtain INCS adherence (yes or no).

[0109] The nasal congestion score (NCS) is obtained from an item in the NPSD, asking participants to rate the severity of the worst nasal congestion over the past 24 hours using the following response options: 0 - none; 1 - mild; 2 - moderate; 3 - severe.

[0110] Olfactory loss is obtained from an item in the NPSD, asking participants to rate the severity of the worst olfactory difficulty over the past 24 hours using the following response options: 0 - none; 1 - mild; 2 - moderate; 3 - severe.

[0111] SNOT-22 is a health-related quality of life (HRQoL) assessment for specific conditions that captures participant-reported physical problems, functional limitations, and emotional consequences of rhinologic conditions (Piccirillo et al. 2002; Hopkins et al. 2009). Patient-reported symptom severity and symptom impact are captured by 6-point scales (0 - no problem to 5 - problem as bad as possible). The total score is the sum of the item scores, ranging from 0 to 110 (with higher scores indicating worse outcomes). A minimal clinically important difference (MCID) of 8.90 in individual score change has been identified (Hopkins et al. 2009) as clinically meaningful improvement.

[0112] Asthma Control Questionnaire (for asthma / AERD / NSAID-ERD participants only): The Asthma Control Questionnaire (ACQ-6) is an assessment of asthma symptoms (night awakenings, waking symptoms, activity limitation, shortness of breath, wheeze, and short-acting beta-agonist use). Participants are asked to recall their level of asthma control over the previous week by answering one bronchodilator use question and 5 symptom questions. The 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 good asthma control, a score of between 0.75 and <1.5 indicates partial asthma control, and a score of >1.5 indicates poor asthma control (Juniper et al. 2006). An individual change of at least 0.5 is considered a clinically meaningful improvement.

[0113] The University of Pennsylvania Smell Identification Test (UPSIT) is a quantitative test of olfactory function that uses microencapsulated odorants released by scraping a standardized odor-impregnated test booklet (Doty et al. 1984). The test uses four booklets, each with 10 odorants. Participants are asked to identify the odor using a multiple-choice format listing different possibilities. The test is forced choice, i.e., participants are asked to mark one of the four alternatives even if no odor is perceived. Scores are based on the number of odors correctly identified (score range 0 to 40).

[0114] Patient Global Severity Impression (PGI-S) is a single item designed to capture participant perception of overall NP symptom severity at completion using a 6-point categorical response scale (0 - no symptoms to 5 - very severe). The Patient Global Change Impression (PGI-C) instrument captures participant’s overall assessment of treatment response since the first dose of IP. Participants are asked to report the degree of change in their health status using a 7-point scale (1 - much better to 7 - much worse).

[0115] The Work Productivity and Activity Impairment Questionnaire (WPAI, Universal Health Version 2.0) is a self-administered instrument consisting of six questions addressing absenteeism, presenteeism (reduced productivity at work), overall work productivity loss (absenteeism plus presenteeism), and activity impairment. This validated instrument collects data from the previous 7 days. WPAI outcomes are scored as a percentage of impairment, with higher percentages indicating greater impairment and lower productivity (Reilly et al. 1993).

[0116] The Lund-Mackay scoring system is used to provide a semiquantitative assessment of the sinuses using sinus CT scans (Lund and Mackay 1993). Based on the sinus CT images, the five sinuses on each side (maxillary, anterior ethmoid, posterior ethmoid, sphenoid, and frontal) are scored.

[0117] The EuroQOL Quality of Life 5 Dimensions 3 Levels version (EQ-5D-3L) is a standardized instrument for measuring health-related quality of life (HRQoL) developed by EuroQol (Brooks, 1996). It defines health along five dimensions: mobility, self-care, usual activities, pain / discomfort, and anxiety / depression. Each dimension has three ordinal severity levels: 1, no problems; 2, some problems; and 3, severe problems. Overall health status is defined as a 5-digit number.

[0118] TSLP

[0119] 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 composed 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).

[0120] Data from other studies suggest that TSLP can cause airway inflammation via pathways that are not Th2 dependent, such as cross-talk between airway smooth muscle and mast cells (Allakhverdi et al., J Allergy Clin Immunol. 123(4):958-60, 2009; Shikotra et al., supra). TSLP can also promote the differentiation of T cells into Th-17-cytokine producing cells, leading to an increase in neutrophilic inflammation that is common in more severe asthma (Tanaka et al., Clin Exp Allergy. 39(1):89-100, 2009). These data and other emerging evidence suggest that blocking TSLP can be useful in suppressing multiple biological pathways, including but not limited to those involving Th2 cytokines (IL-4 / 13 / 5).

[0121] Antibodies

[0122] It is provided that a TSLP-specific antibody or antibody variant can be used to treat chronic rhinosinusitis, including moderate or severe chronic rhinosinusitis, chronic rhinosinusitis with or without nasal polyps, and / or chronic rhinosinusitis with or without asthma / AERD / NSAID-ERD.

[0123] It is provided that a TSLP-specific antibody or antibody variant can be used to treat chronic rhinosinusitis, including moderate or severe chronic rhinosinusitis, chronic rhinosinusitis with nasal polyps, and / or chronic rhinosinusitis with or without asthma / AERD / NSAID-ERD.

[0124] Specific binding agents such as antibodies and antibody variants or fragments that bind to a target antigen, e.g., TSLP, can be used in the methods of the disclosure. In one embodiment, the specific binding agent is an antibody. These antibodies can be monoclonal antibodies (MAbs); recombinant antibodies; chimeric antibodies; humanized antibodies, such as complementarity determining region (CDR) grafted antibodies; human antibodies; antibody variants, including single chain; and / or bispecific; as well as fragments; variants; or derivatives thereof. Antibody fragments include those portions of antibodies that bind to the epitope of the polypeptide of interest. Examples of such fragments include Fab and F(ab') fragments produced by enzymatic cleavage of full-length antibodies. Other binding fragments include those produced by recombinant DNA techniques, such as recombinant plasmids containing nucleic acid sequences encoding the variable regions of antibodies.

[0125] Monoclonal antibodies can 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 with or homologous to a corresponding sequence in an antibody that is derived from a particular species or belongs to a particular antibody class or subclass, while the remainder of the chain(s) is identical with or homologous to a corresponding sequence in an antibody that is derived from another species or belongs to another antibody class or subclass. Also included are fragments of such antibodies as long as they exhibit the desired biological activity. See, e.g., U.S. Patent No. 4,816,567; Morrison et al., 1985, Proc. Natl. Acad. Sci. 81 :6851-55.

[0126] In another embodiment, the monoclonal antibody is a “humanized” antibody. Methods for humanizing non-human antibodies are well known in the art. See, e.g., 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, e.g., using methods described in the art (Jones et al., 1986, Nature 321 :522-25; Riechmann et al., 1998, Nature 332:323-27; Verhoeyen et al., 1988, Science 239:1534-36), by replacing at least a portion of an antibody’s corresponding region with at least a portion of a rodent’s complementarity determining region. For example, by CDR grafting, non-human CDR sequences are inserted into human framework regions (Lu et al. Journal of Biomedical Science (2020) 27:1).

[0127] The present disclosure also encompasses human antibodies and antibody variants (including antibody fragments) that bind to TSLP. Human antibodies refer to antibodies produced by human immunoglobulin sequences and comprising human variable and constant regions. Such antibodies are produced using transgenic animals (e.g., mice) that are capable of producing a repertoire of human antibodies when endogenous immunoglobulin production is disabled, by immunization with a polypeptide antigen (i.e., having at least 6 contiguous amino acids), optionally in combination with an adjuvant. 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. Other 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 made by using human constant and framework regions and synthetic manufacture of human antibodies. Human antibodies can also be produced by expression of recombinant DNA in host cells, or by expression in hybridoma cells as described herein, using phage display libraries, or by single B cell cloning (Lu et al. Journal of Biomedical Science (2020) 27: 1). It is provided that the human, humanized, or chimeric antibody can comprise mutations or modifications that enhance antibody stability or prolong 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).

[0128] Chimeric, CDR-grafted, and humanized antibodies and / or antibody variants are typically produced by recombinant methods. Nucleic acids encoding the antibodies are introduced into host cells and expressed using the materials and procedures described herein. In preferred embodiments, the antibodies are produced in mammalian host cells, such as CHO cells. Monoclonal (e.g., human) antibodies can be produced by expression of recombinant DNA in host cells or by expression in hybridoma cells as described herein. Additional mutations can be made to the human, humanized, or chimeric antibodies to improve stability or half-life. Such mutations are known in the art.

[0129] Antibodies and antibody variants (including antibody fragments) useful in the methods of the application comprise an anti-TSLP 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 or antibody variant specifically binds to a TSLP polypeptide as set forth in amino acids 29-159 of SEQ ID NO:2.

[0130] Also provided is an antibody or antibody variant comprising: a. a light chain variable domain selected from the group consisting of: i. an amino acid sequence that is at least 80% identical to SEQ ID NO: 12; ii. an amino acid sequence encoded by a polynucleotide sequence that is at least 80% identical to SEQ ID NO: 11; iii. an amino acid sequence encoded by a polynucleotide that hybridizes to the complement of a polynucleotide consisting of SEQ ID NO: 11 under moderately stringent conditions; and b. a heavy chain variable domain selected from the group consisting of: i. an amino acid sequence that is at least 80% identical to SEQ ID NO: 10; ii. an amino acid sequence encoded by a polynucleotide sequence that is at least 80% identical to SEQ ID NO: 9; iii. an amino acid sequence encoded by a polynucleotide that hybridizes to the complement of a polynucleotide consisting of SEQ ID NO: 9 under moderately stringent conditions; or c. the light chain variable domain of (a) and the heavy chain variable domain of (b), wherein the antibody or antibody variant specifically binds to a TSLP polypeptide as set forth in amino acids 29-159 of SEQ ID NO:2.

[0131] Tesidolumab is an exemplary anti-TSLP antibody having: a. 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 containing: 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.

[0132] Tesidolumab also comprises a light chain variable domain having the amino acid sequence set forth in SEQ ID NO: 12; 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 encoded by the polynucleotide sequence set forth in SEQ ID NO: 9.

[0133] Tesidolumab is an IgG2 antibody. The sequences of the full length heavy and light chains of tesidolumab comprising IgG2 chains are set forth in SEQ ID NOs: 13 and 14, respectively.

[0134] Exemplary sequences of tesidolumab are also set forth in U.S. Patent 7,982,016, 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 is incorporated herein by reference.

[0135] In various embodiments, anti-TSLP antibody derivatives are provided for use in the methods. Anti-TSLP antibody derivatives are described in International Patent Publication Nos. WO 2022 / 226342 and WO 2022 / 226339, which are incorporated herein by reference in their entirety. Exemplary derivatives include tezelumab antibodies that may have modifications after antibody purification or long-term storage, 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 can also be variants having the amino acid sequences shown in SEQ ID NOs: 13-36 of WO 2022 / 226342, as well as variants of SEQ ID NOs: 3-8 therein, for example, including residues identified as possible sources of reduced stability in the anti-TSLP antibody tezelumab CDRs (SEQ ID NOs: 3-8) or variable regions (SEQ ID NOs: 10 and 12), 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.

[0136] 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.

[0137] 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.

[0138] In various embodiments, the anti-TSLP antibody variant is selected from the group consisting of: a Fab fragment, a single domain antibody, a scFv, wherein the dose is adjusted such that the binding sites are equimolar to the binding sites of the administered bivalent antibody.

[0139] It is provided that the antibody is an IgG2 antibody. An exemplary sequence of a human IgG2 constant region is available from the Uniprot database under Uniprot number P01859, which is incorporated herein by reference. Information including sequence information on other antibody heavy and light chain constant regions is also publicly available via the Uniprot database and other databases well known in the art of antibody engineering and production.

[0140] In certain embodiments, antibody derivatives include tetrameric, glycosylated antibodies in which the number and / or type of glycosylation sites is altered as compared to the amino acid sequence of the parent polypeptide. In certain embodiments, the variant contains a greater or lesser number of N-linked glycosylation sites than the native protein. Alternatively, substitutions of this sequence will remove an existing N-linked carbohydrate chain. Also provided are rearrangements of the N-linked carbohydrate chain in which one or more N-linked glycosylation sites (typically those that are naturally occurring) are eliminated and one or more new N-linked sites are created. Additional preferred antibody variants include cysteine variants in which one or more cysteine residues are deleted or substituted for another amino acid (e.g., serine) as compared to the parent amino acid sequence. Cysteine variants can be useful when the antibody 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 so that interactions caused by unpaired cysteines are minimized.

[0141] Desired amino acid substitutions, whether conservative or non-conservative, can be determined by one of skill in the art when such substitutions are desired. In certain embodiments, amino acid substitutions can be used to identify important residues of an antibody against human TSLP, to increase or decrease the affinity of the antibody for human TSLP described herein, or to increase stability or to prolong half-life (e.g., YTE mutations).

[0142] According to certain embodiments, preferred amino acid substitutions are those that: (1) decrease susceptibility to proteolysis; (2) decrease susceptibility to oxidation; (3) alter binding affinity for forming protein complexes; (4) alter binding affinity and / or (4) confer or alter other physicochemical or functional properties on such polypeptides. According to certain embodiments, single or multiple amino acid substitutions (in certain embodiments, conservative amino acid substitutions) can be made in the naturally occurring sequence (in certain embodiments, in the portion of the polypeptide outside of the one or more domains forming intermolecular contacts). In certain embodiments, conservative amino acid substitutions typically do not substantially alter the structural properties of the parent sequence (e.g., the substitution amino acid should not tend to break helices present in the parent sequence, or disrupt other types of secondary structure characteristic of 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, N.Y. (1991)); and Thornton et al. Nature 354:105 (1991), each of which is incorporated herein by reference.

[0143] Methods of administration

[0144] In one aspect, the methods of the disclosure include the step of 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.

[0145] Provided herein are methods for treating chronic rhinosinusitis or chronic rhinosinusitis (including severe or moderate chronic rhinosinusitis, chronic rhinosinusitis with or without nasal polyps, and / or chronic rhinosinusitis with asthma, AERD, or NSAID-ERD) in a subject. In various embodiments, the method includes selecting a subject in need of treatment for chronic rhinosinusitis, and administering an anti-TSLP antibody described herein. In various embodiments, the chronic rhinosinusitis is accompanied by nasal polyps. In various embodiments, the subject has moderate or severe asthma. In various embodiments, the subject has moderate asthma.

[0146] 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, US20170066823, US20120020988, and US 8637019, the disclosures of which are incorporated herein by reference, some of which are described in Table A below. In exemplary aspects, the anti-TSLP antibody is selected from the antibodies of Table A and the antibodies or antibody fragments described in WO 20220226342A1, WO 20220226339A1, WO 2023098491A1, WO 2021155634A1, WO 2022166072A1, WO 2021043221A1, WO 2022184074A1, WO 2021104053A1, WO 2023116925A1, WO 2021155861A1, WO 2022116858A1, WO 2022117079A1, WO 2020244544A1, WO 2021152488A1, WO 2022253147A1, WO 2023070948A1, WO 2023142309A1, WO 2022095689A1, WO 2021115240A1, WO 2022166739A1, and WO 2019100111A1, the disclosures of each of which are incorporated herein by reference.

[0147] Table A

[0148]

[0149]

[0150]

[0151]

[0152]

[0153]

[0154]

[0155] It is provided that the subject to be treated is a human. The subject can be an adult, adolescent, or child.

[0156] Therapeutic antibody (or antibody variant) compositions can be delivered to the patient at multiple positions. Multiple administrations can be performed simultaneously or can be administered over a period of time. In some cases, it is beneficial to provide a continuous flow of therapeutic compositions. Other therapies can be administered periodically, for example, hourly, daily, weekly, every 2 weeks, every 3 weeks, monthly, every two months or with longer time intervals.

[0157] In various embodiments, the amount of therapeutic agent (eg, a bivalent antibody having two TSLP binding sites) in a given dose can vary depending on the size of the individual to whom the therapy is being administered and the characteristics of the condition being treated.

[0158] In exemplary treatments, 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, the dose can be about 140 mg, 210 mg, 280 mg, or 420 mg. In various embodiments, the anti-TSLP antibody or antibody variant can 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 concentrations can be administered in a single dosage form or in multiple doses. The above doses are 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 every four weeks in a single dose of 210 mg.

[0159] For antibody variants, the amount of antibody variant should be such that the number of TSLP binding sites in the dose is equimolar to the number of TSLP binding sites of the standard bivalent antibody described above.

[0160] It is provided that the anti-TSLP antibody or antibody variant is administered every 2 weeks or every 4 weeks for a period of at least 4 months, 6 months, 9 months, 1 year or longer. In various embodiments, the administration is subcutaneous or intravenous.

[0161] Treatment with an anti-TSLP antibody or antibody variant is provided to improve one or more of the following measures of chronic sinusitis (with or without nasal polyps): nasal polyp score (NSP), nasal congestion score (NCS), loss of smell, Sinus Nasal Outcome Test 22-item (SNOT-22), EuroQOL Quality of Life 5 Dimensions 3 Levels Version (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).

[0162] In one embodiment, administration improves one or more symptoms of chronic sinusitis including nasal obstruction, nasal congestion, runny nose, postnasal drip, mucus running down the throat, significant nasal obstruction, nasal discharge, loss of smell, headache, facial pain, facial pressure, difficulty smelling, asthma symptoms, difficulty sleeping due to nasal symptoms, difficulty performing daily activities due to nasal symptoms, optionally as measured by a chronic sinusitis patient electronic diary.

[0163] Improvements in scores were considered to be related to the minimal clinically important difference (MCID) or least squares mean difference in symptom measures in patients treated according to the methods herein compared to the placebo group. The MCID is the smallest improvement that a patient or physician considers to be therapeutically meaningful. 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.

[0164] For example, a clinically relevant improvement in nasal congestion score (NC) comprises an MCID of between 0.5 and 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 a baseline or untreated control level. A clinically relevant improvement in nasal polyp score (NPS) comprises an MCID of between 1 and 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 a baseline or untreated control level. Clinically relevant improvements include a reduction in the need for systemic corticosteroids and / or surgery compared to baseline or untreated control levels with an MCID of between 60% and 90%, e.g., 60%, 65%, 70%, 75%, 80%, 85%, 90%. Clinically relevant improvements include a reduction in the need for nasal surgery compared to baseline or untreated control levels with an MCID of between 60% and 90%, e.g., 60%, 65%, 70%, 75%, 80%, 85%, 90%. Clinically relevant improvements in the Lund Mackey score (NC) include an MCID of between 5 and 10, e.g., 5, 6, 7, 8, 9, or 10, compared to baseline or untreated control levels. A clinically relevant improvement in sinus symptoms (SNOT-22) includes an MCID of between 15 and 30, e.g., 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30, compared to a baseline or untreated control level. Comparisons can be made throughout the treatment period, e.g., at week 28 or week 52 or thereafter.

[0165] In various embodiments, the NPS or NCS score is reduced by 1, 2, or 3 points. In various embodiments, the subject has an NPS of 0 (none) or 1 (mild) at week 52 after treatment.

[0166] In various embodiments, treatment with an anti-TSLP modulates the level of one or more biomarkers of chronic rhinosinusitis, including cytokine, IgE, CCL17, CCL18, CCL22, and RNA transcription changes in nasal epithelium. In various embodiments, treatment with an anti-TSLP reduces the level of Th2 cytokines. In various embodiments, the treatment modulates the level or activity of IL-4, IL-5, IL-13, IL-17, IL-22, IL-23, IL-31, or a combination thereof.

[0167] The treatment also improves one or more symptoms of chronic rhinosinusitis, as measured by the Nasal Polyp Symptom Diary (NPSD) and the Nasal Polyp Symptom Screening Assessment (NPSSA). Symptoms include nasal congestion, nasal discharge, postnasal drip (mucus running down the back of the throat), headache, facial pain, facial pressure, and difficulty smelling) and symptom impact (difficulty sleeping due to nasal symptoms and difficulty with daily activities due to nasal symptoms); activity, self-care, daily activities, pain / discomfort, and anxiety / depression, as measured by the EuroQOL Quality of Life 5-Dimension 3-Level Version (EQ-5D-3L).

[0168] In various embodiments, treatment with an anti-TSLP antibody delays the time to exacerbation or onset of chronic rhinosinusitis compared to subjects who do not receive an anti-TSLP antibody.

[0169] Also provided in the disclosure are administration of various agents, such as antibody compositions in combination with a second agent described herein, including but not limited to anti-inflammatory agents or asthma therapies.

[0170] However, it is provided that, in various embodiments, the administration reduces the frequency or level of a co-administered therapy in the subject. Exemplary co-administered therapies include, but are not limited to, systemic corticosteroids, dupilumab, immunosuppressive or immunomodulatory drugs (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 a combination thereof. In various embodiments, the administration reduces or eliminates the need for corticosteroid therapy or other adjunctive therapy.

[0171] Formulations

[0172] In some embodiments, the disclosure provides uses of pharmaceutical compositions comprising a therapeutically effective amount of an anti-TSLP antibody or antibody variant and a pharmaceutically acceptable diluent, carrier, solubilizer, emulsifier, preservative, and / or adjuvant. In addition, the disclosure provides methods of treating a subject by administering such pharmaceutical compositions.

[0173] In certain embodiments, acceptable formulation materials are preferably nontoxic to recipients at the dosages and concentrations employed. In certain embodiments, a pharmaceutical composition can contain formulation materials for modifying, maintaining, or preserving, for example, the pH, osmolarity, viscosity, clarity, color, isotonicity, odor, sterility, stability, release, absorption, or penetration of the composition. In such embodiments, suitable formulation materials include, but are not limited to, amino acids (such as glycine, glutamine, asparagine, arginine, or lysine); antimicrobials; antioxidants (such as ascorbic acid, sodium sulfite or sodium hydrogen-sulfite); buffers (such as borate, bicarbonate, Tris-HCl, citrates, phosphates, or other organic acids); bulking agents (such as mannitol or glycine); chelating agents (such as ethylenediaminetetraacetic acid (EDTA)); complexing agents (such as caffeine, polyvinylpyrrolidone, beta-cyclodextrin, or hydroxypropyl-beta-cyclodextrin); fillers; monosaccharides; disaccharides; and other carbohydrates (such as glucose, sucrose, mannitol, or dextrins); proteins (such as serum albumin, gelatin, or immunoglobulins); coloring, flavoring and diluting agents; emulsifying agents; hydrophilic polymers (such as polyvinylpyrrolidone); low molecular weight polypeptides; salt-forming counterions (such as sodium); preservatives (such as benzalkonium chloride, benzoic acid, salicylic acid, thimerosal, phenethyl alcohol, methyl paraben, propyl paraben, chlorhexidine, sorbic acid, or hydrogen peroxide); solvents (such as glycerin, propylene glycol, or polyethylene glycol); sugar alcohols (such as mannitol or sorbitol); suspending agents; surfactants or wetting agents (such as pluronics, PEG, sorbitan, polysorbate (such as polysorbate 20, polysorbate), triton, tromethamine, lecithin, cholesterols, tyloxapal); stability enhancing agents (such as sucrose or sorbitol); tonicity enhancing agents (such as alkali metal halides, preferably sodium or potassium chloride, mannitol, sorbitol); delivery vehicles; diluents; excipients and / or pharmaceutical adjuvants. See REMINGTON'S PHARMACEUTICAL SCIENCES, 18thEdition, (A. R. Genrmo, Ed.), 1990, Mack Publishing Company.

[0174] Suitable vehicles or carriers can be water for injection, a solution of physiological saline or artificial cerebrospinal fluid, possibly supplemented with other substances commonly used in parenteral compositions. Neutral buffered saline or saline mixed with serum albumin are further exemplary vehicles. In particular embodiments, the pharmaceutical composition comprises a Tris buffer at about pH 7.0-8.5 or an acetate buffer at about pH 4.0-5.5, and can further include sorbitol or suitable substitutes thereof.

[0175] The formulation components are preferably present in amounts that are acceptable to the site of administration. In certain embodiments, a buffer is used to maintain the composition at physiological or slightly lower pH, typically in the pH range of about 4.5 to about 8. Inclusion of 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.

[0176] In various embodiments, the anti-TSLP antibody or antibody variant is in a formulation containing one or more basic amino acids (e.g., arginine, histidine, or lysine) or salts thereof, or calcium or magnesium salts, and a surfactant. In various embodiments, the formulation comprises 0.005% (w / v) to about 0.015% (w / v) polysorbate 20 or polysorbate 80. In various embodiments, the pH of the formulation is between 4.5 and 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 co-owned applications PCT / US2021 / 018561 and PCT / US2021 / 17880.

[0177] When parenteral administration is carried out, the therapeutic composition used can be provided in the form of a pyrogen-free, parenterally acceptable aqueous solution, comprising the desired anti-TSLP antibody in a pharmaceutically acceptable vehicle. One especially suitable vehicle for parenteral injection is sterile, distilled water in which the antibody is formulated as a sterile, isotonic solution. In certain embodiments, the preparation can involve formulation of the desired molecule with an agent that provides controlled or sustained release of the product that can be delivered via depot injection, such as injectable microspheres, biodegradable polymers, polymer compounds such as polylactic acid or polyglycolic acid, beads, or liposomes. In certain embodiments, hyaluronic acid can also be used, which has the effect of promoting the duration of circulation. In certain embodiments, implantable drug delivery devices can be used to introduce the antibody.

[0178] Example

[0179] Example 1 - Phase 3 study to evaluate the efficacy of tezepelumab in chronic rhinosinusitis with nasal polyps (CRSwNP)

[0180] 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, consistent with a need for surgery (Nasal Polyps Total Score (NPS) > 5 (at least 2 in each nostril), despite documentation of systemic corticosteroid (SCS) therapy or prior NP surgery. The efficacy of 210 mg tezepelumab every 4 weeks (Q4W) on nasal polyps is evaluated over a 52-week treatment period and up to a 24-week post-treatment follow-up period, on top of standard-of-care treatment with intranasal corticosteroids (INCS).

[0181] Approximately 400 participants are randomized in a roughly 1 : 1 ratio to receive 210 mg tezepelumab or matching placebo.

[0182] Participants are stratified by region, prior nasal polyp surgery, and co-morbid asthma / aspirin -induced respiratory disease (AERD) / non-steroidal anti-inflammatory drug- exacerbated respiratory disease (NSAID-ERD). Randomization is monitored to ensure that 50-70% of the study population will have co-morbid asthma / AERD / NSAID-ERD, and at least 50% have had prior CRSwNP surgery.

[0183] After enrollment, eligible participants receive a standardized dose of intranasal mometasone furoate nasal spray (MFNS) or an equivalent INCS and will enter a 5-week screening / run-in period. Equivalent dose shall mean the highest approved national INCS dose for CRSwNP. Eligible participants will be randomized at Week 0 (Day 0) to receive placebo or tezepelumab 210 mg SC starting at randomization (Week 0) and then every 4 weeks thereafter. The end of treatment (EOT) visit will be conducted at Week 52.

[0184] After the 52-week treatment period, there will be two different follow-up periods. The first 200 participants who complete the 52-week treatment period will have a 24-week follow-up (FU) period without any investigational product (IP) (tezepelumab). The last 200 participants will have a 12-week FU period without any IP.

[0185] Endpoints and assessments

[0186] The primary endpoints are shown in Table 1.

[0187] Table 1. Primary endpoints

[0188]

[0189] Nasal polyp score (NPS): NPS is the sum of the right and left nostril scores assessed by intranasal endoscopy (max 8). The total NPS is graded according to the size of the polyps as described in Table 2. Local anesthetic and decongestant agents can be applied topically prior to the endoscopy according to local medical practice.

[0190] Table 2. Endoscopic NPS within each nostril

[0191]

[0192] Secondary endpoints include the endpoints shown in Table 3.

[0193] Table 3. Secondary endpoints

[0194]

[0195]

[0196] BD bronchodilator; FEV1 at 1st second 1用力 FVC forced vital capacity; LMK Lund MacKay score; NPS nasal polyp score; NCS nasal congestion score; SCS systemic corticosteroid; SNOT-22 sino-nasal outcome test

[0197] Clinical Outcome Assessments. Participants complete all patient-reported outcome assessments (PROs) using a hand-held ePRO device. The ePRO device is used to capture the symptom (Nasal Polyp Symptom Screening Assessment) and health-related quality of life [(HRQoL) SNOT-22] screening data at Visit 1.

[0198] Participants should be checked (at least) weekly for compliance to ensure that participants complete assessments as scheduled. During the baseline period (study Days -13 to 0), it is important to monitor participant compliance with the diary to ensure that participants meet the eligibility criteria for randomization.

[0199] Nasal Polyp Symptom Diary (NPSD) and Nasal Polyp Symptom Screening Assessment (NPSSA): Participants will complete an 11-item NP symptom diary (NPSD) each morning throughout the screening, treatment, and follow-up periods. Participants are asked to consider 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, rhinorrhea, postnasal drip (mucus running down the back of the throat), headache, facial pain, facial pressure, and difficulty smelling) and symptom impact (difficulty sleeping due to nasal symptoms and difficulty with daily activities due to nasal symptoms). Participants report the severity of each symptom and the symptom impact at its worst using a 4-point verbal rating scale (0 - none to 3 - severe). The total symptom score (TSS) is calculated by summing the 8 equally weighted symptom items. Following the symptom and symptom impact items, a single item will be administered to capture INCS compliance (yes or no).

[0200] Nasal Congestion Score: The NC score (NCS) is captured by an item in the NPSD asking participants to rate the severity of the worst nasal congestion over the past 24 hours using the following response options: 0 - none; 1 - mild; 2 - moderate; 3 - severe. The baseline will be the average of the daily responses from Days -13 to 0. If there are at least 8 days of evaluable data in each 14-day period, then the average NCS will be calculated every 2 weeks (14 days).

[0201] Olfactory Loss: Olfactory loss is captured by an item in the NPSD asking participants to rate the severity of the worst difficulty smelling over the past 24 hours using the following response options: 0 - none; 1 - mild; 2 - moderate; 3 - severe. The baseline will be the average of the daily responses from Days -13 to 0. If there are at least 8 days of evaluable data in each 14-day period, then the average olfactory loss will be calculated every 2 weeks (14 days).

[0202] Nasal outcomes test 22: The SNOT-22 is a HRQoL assessment for specific conditions that captures participants’ reports of physical problems, functional limitations, and emotional consequences of their nasal and sinus conditions (Piccirillo et al. 2002; Hopkins et al. 2009). The severity of symptoms and impact of symptoms reported by patients over the past 2 weeks are captured by 6-point scales (0 - no problem to 5 - problem as bad as possible). The total score is the sum of the item scores, ranging from 0 to 110 (higher scores indicate worse outcomes). The minimum clinically important difference (MCID) for individual score change has been established as 8.90 (Hopkins et al. 2009).

[0203] The SNOT-22 test can be further divided into domains to provide domain scores. The domains and factors considered in the domain scores include: nasal domain: need to blow nose, congestion, sneezing, runny nose, cough, post-nasal drainage, thick nasal drainage, decreased sense of smell / taste; ear / face domain: ear fullness, dizziness, ear pain, facial pain / pressure; sleep domain: difficulty falling asleep, waking at night, not enough sleep at night, waking up tired; function domain: fatigue, decreased productivity, decreased concentration; emotional domain: sad / depressed / irritable, sadness, embarrassment (Khan et al., Laryngoscope. 2022 132(5):933-941). Each domain is scored on a 0-5 scale, with 0 being the lowest.

[0204] 36-item short-form health survey, version 2: The 36-item short-form health survey, version 2 (standard recall) (SF-36v2) is a 36-item self-report survey of 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 scores. The remaining item, termed the “health transition” item, asks participants to rate their current health in comparison to their health 1 year ago and is not used to calculate domain scores. The 8-domain profile consists of the following subscales: physical functioning (PF), role limitations due to physical health (RP), bodily pain (BP), general health perceptions (GH), vitality (VT), social functioning (SF), emotional problems due to role limitations (RE), and mental health (MH). Psychometrically-based physical and mental health component summary scores (PCS and MCS, respectively) are calculated from the subscale scores to give a broader measure of physical and mental HRQoL.

[0205] Two types of thresholds have been developed for interpreting SF-36v2 scores. The first type is applicable to comparing group mean scores and is generally referred to as the MCID. The second type is applicable to interpreting change at the individual level and is referred to as the responder threshold or responder definition (QualityMetric 2011).

[0206] Table 4. Thresholds and summary measures for the SF-36v2 Scal4e

[0207]

[0208] BP bodily pain; GH general health perception; MCS mental component summary; MH mental health; PCS physical component summary; PF physical functioning; RE emotional problems; RP role limitations due to physical health; SF social functioning; VT vitality

[0209] Asthma Control Questionnaire (for asthma / AERD / NSAID-ERD participants only): The Asthma Control Questionnaire (ACQ-6) is an assessment of asthma symptoms (night waking, waking symptoms, activity limitation, breathlessness, wheeze, and short-acting beta agonist use). Participants are asked to recall their level of asthma control over the previous week by answering one bronchodilator use question and 5 symptom questions. 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 good asthma control, a score of between 0.75 and <1.5 indicates partial asthma control, and a score of >1.5 indicates poor asthma control (Juniper et al. 2006). An individual change of at least 0.5 is considered clinically meaningful.

[0210] University of Pennsylvania Smell Identification Test: The University of Pennsylvania Smell Identification Test (UPSIT) is a quantitative test of olfactory function that uses microencapsulated odorants released by scraping a standardized odor-impregnated test booklet (Doty et al. 1984). The test uses four booklets, each with 10 odorants. Participants are asked to identify the odor using a multiple-choice format listing different possibilities. The test is forced choice, i.e., participants are asked to mark one of the four alternatives even if no odor is perceived. Scoring is based on the number of odors correctly identified (score range 0 to 40).

[0211] Patient Global Severity and Change Impressions: The Patient Global Severity Impression (PGI-S) is a single item designed to capture the participant’s perception of the overall NP symptom severity at completion using a 6-point categorical response scale (0 - not at all to 5 - very severe). The Patient Global Change Impression (PGI-C) instrument captures the participant’s overall assessment of response to treatment since the first dose of IP. Participants are asked to report the degree of change in their health status using a 7-point scale (1 - much better to 7 - much worse).

[0212] Work Productivity and Activity Impairment (WPAI) Questionnaire: The Work Productivity and Activity Impairment Questionnaire (WPAI, General Health 2.0 version) is a self-administered instrument consisting of 6 questions that address absenteeism, presenteeism (reduced efficiency while at work), overall work productivity loss (absenteeism plus presenteeism), and activity impairment. This validated instrument captures data over the past 7 days. WPAI outcomes are scored as a percentage of impairment, with higher percentages indicating greater impairment and lower productivity (Reilly et al. 1993).

[0213] Nasal Sinus Computed Tomography: All participants will undergo computed tomography (CT). A referral for baseline CT scan should be provided at V2 (week -2) and must be performed at V2 after nasal biopsy procedure (as applicable) only if the participant is in compliance with all eligibility criteria at V2, including central reader confirmation of NPS score. At V17 (EOT / IPD), a CT scan should be performed prior to nasal biopsy procedure in nasal biopsy sub-study participants.

[0214] For participants who receive or plan to receive NP surgery during the treatment period, a CT scan should be performed prior to the first NP surgery at the IPD visit. For participants who require SCS for NP, a CT scan should be performed prior to the first course of SCS and at week 52 if possible. For participants who receive multiple NP surgeries and / or SCS for NP, a CT scan should be performed prior to the first NP surgery or SCS for NP. For participants who discontinue IP for other reasons, if the participant elects follow-up option 1 or 2, a CT scan should be performed at the IPD visit and at week 52. The sinus CT images are used to derive the Lund-Mackay score (LMS) and Zinreich (modified Lund-Mackay) score from independent central reader visual assessment and for quantitative estimation of the Sinus Disease Severity Score, which represents the burden of sinus disease.

[0215] Lund-Mackay Score: The Lund-Mackay scoring system is used to provide a semi-quantitative assessment of the sinuses by sinus CT scan (Lund and Mackay 1993). Based on the sinus CT images, a central radiologist scores each side of the five sinuses (maxillary, anterior ethmoid, posterior ethmoid, sphenoid, and frontal) as follows:

[0216] Table 5. Lund-Mackay Score

[0217] Score CT scan assessment 0 No abnormality 1 Partial opacity 2 Complete opacity

[0218] The ostiomeatal complex is scored on both the left and right sides.

[0219] 5Table 6. Osteomeatal Complex Score

[0220] Score CT scan assessment 0 No occlusion 2 Occlusion

[0221] The maximum total score is 24.

[0222] Quantitative measures of burden of sinus disease by paranasal sinus computed tomography: Quantitative assessment of paranasal sinus CT image data will be used to derive an objective measure of burden of sinus disease, termed the paranasal sinus severity score (Pallanch et al. 2013). This is defined as:

[0223] Paranasal sinus severity score = paranasal sinus mucosa volume / (paranasal sinus mucosa volume + paranasal sinus air volume) * 100%.

[0224] The following parameters are used to calculate the paranasal sinus severity score: (a) paranasal sinus air volume (mL);

[0225] (b) paranasal sinus mucosa volume (mL). Image analysis is performed centrally.

[0226] Zinreich (modified Lund Mackay) score: In addition to the Lund Mackay score described above, the same CT images are scored using the modified Lund Mackay (Zinreich) scoring system (Okushi et al. 2013, Likness et al. 2014). According to Table 7, all five sinuses on each side (maxillary, anterior ethmoid, posterior ethmoid, sphenoid, and frontal) are scored based on the percentage of opacity due to mucosal thickening.

[0227] Table 7. Modified Lund Mackay (Zinreich) score

[0228]

[0229]

[0230] NP surgery and / or SCS use after randomization: Participants who plan to undergo NP surgery at the time of study entry and randomization should not be randomized (refer to exclusion criterion 15). After randomization, surgery should not be planned for the first 3 months unless in an emergency situation or deemed necessary by the physician.

[0231] Rescue treatment for NP or other reasons is defined as requiring treatment with systemic corticosteroids (SCS) for at least 3 consecutive days (a single injectable dose of corticosteroid will be considered equivalent to a 3-day course of systemic corticosteroids). An SCS course is considered to be ongoing if the treatment interval is less than 7 days.

[0232] If SCS is used for treatment of NPs for > 3 consecutive days, a CT scan and endoscopic evaluation of NPs should be performed prior to the first course of SCS treatment (unless the subject has already had a CT scan after randomization prior to NP surgery).

[0233] If SCS is used for treatment of NPs for > 3 consecutive days, a CT scan and endoscopic evaluation of NPs should be performed prior to the first course of SCS treatment (unless the subject has already had a CT scan after randomization prior to NP surgery).

[0234] Spirometry (Asthma / AERD / NSAID-ERD participants only): Lung function (FEVi, FEF 25-75%, and FVC) will be measured by spirometry at the study site using equipment provided by the central vendor. MasterScope is a system used in the field to perform and record the results of procedures, including but not limited to spirometry, NPIF, and FeNO. Spirometry will be performed by the investigator or authorized representative according to the American Thoracic Society / European Respiratory Society (ATS / ERS) guidelines or local guidelines (Graham et al. 2019). The MasterScope kit will include a spirometer handle for recording spirometry values in the field. Global Lung Function Initiative (GLI) equations can be used to determine the predicted normal value (PNV) and are preprogrammed into the spirometer (Quanjer et al. 2012), FEVi expressed as a percentage of PNV is calculated as follows:

[0235] FEVi% of PNV = (measured FEVi / FEVi PNV) x 100

[0236] FeNO (Asthma / AERD / NSAID-ERD participants only): Standardized single-breath FeNO testing will be used to assess airway inflammation according to the SoA. The single-breath exhalation technique recommended by the manufacturer will be followed (Alving et al. 2017). Participants will be asked if they have had a respiratory tract infection within 2 weeks prior to measurement. FeNO measurements will be performed within 2 weeks after a respiratory tract infection. FeNO testing will be performed prior to spirometry. Participants should not use their rescue SABA medication (e.g., albuterol / ventolin) within 6 hours of measurement. Inhaled BD (including ICS / LABA) should be withheld for the duration of the BD-specific action duration as described in the spirometry section.

[0237] NIOX The NIOX is used to measure FeNO.

[0238] Nasal Peak Inspiratory Flow: Nasal peak inspiratory flow (NPIF) assessment represents a physiological measurement of the air flow through both nasal cavities during forced inspiration, expressed in liters / minute. Nasal inspiration is most correlated with the perception of obstruction and is the best validated technique to monitor nasal flow in clinical trials. Participants will perform at least three, up to eight NPIF efforts; participants will record all values on MasterScope and use the highest value for assessment.

[0239] NPIF will be performed at Enrollment / Screening VI (week -5), V3 (week 0), V7 (week 12), V10 (week 24), V13 (week 36), V17 (week 52), V19 (week 64), V21 (week 76).

[0240] Nasal flow is expressed in liters / minute and measured continuously. The best of 3 outcomes with a variability of less than 10% is considered the best way to express the result (Scadding et al. 2011).

[0241] Asthma exacerbations (applicable only to asthma / AERD / NSAID-ERD participants): During the study, an asthma exacerbation will be defined as an asthma worsening resulting in any of the following:

[0242] • At least 3 consecutive days of temporary bolus / flare systemic corticosteroids (or temporary increase in stable OCS background dose) to treat symptoms of asthma exacerbation; a single injectable dose of corticosteroid will be considered equivalent to 3 days of flare of systemic corticosteroids.

[0243] • Emergency room or urgent care visit for asthma requiring systemic corticosteroids (as described above) (defined as < 24 hours of evaluation and treatment in the emergency department or urgent care center).

[0244] • Hospitalization for asthma (defined as admission to an inpatient facility and / or evaluation and treatment > 24 hours in a medical facility).

[0245] Participants will be required to report in the e-diary any of the following:

[0246] • At least 2 consecutive days of increased rescue medication use of 4 or more puffs compared to the average amount used during the baseline period, or 12 puffs / day on any day, and / or;

[0247] • At least 2 consecutive days of additional use of nebulized beta2 agonists compared to the average amount used during the baseline period, and / or;

[0248] • 2 or more nights of awakening for asthma requiring rescue medication within 7 days compared to the average during the baseline period, and / or > 6 of the previous 7 nights of awakening for asthma requiring rescue medication (this criterion should be met for 2 consecutive days).

[0249] If the exacerbation is not associated with worsening of at least 1 pre-specified objective measure, the investigator must justify the decision to define the event as an exacerbation and document this in the eCRF. Events not supported by any objective assessment will not be considered exacerbations per protocol definition.

[0250] The start of an exacerbation is defined as the date of initiation of systemic corticosteroids or the date of temporary increase in stable OCS background dose, the date of ER or urgent care visit requiring systemic corticosteroids, or the date of hospitalization for asthma, whichever occurs earliest. The end of an exacerbation is defined as the date of last systemic corticosteroids or the date of last temporary increase in stable OCS background dose, the date of ER or urgent care visit, or the date of hospital discharge, whichever occurs latest.

[0251] If less than 7 days have elapsed since the end date of an asthma exacerbation and the start date of a new asthma exacerbation, the second event will be considered a relapse of the prior asthma exacerbation

[0252] EQ-5D-3L. The EuroQol 5-dimension 3-level version of health-related quality of life (EQ-5D-3L) is a standardized tool to measure health-related quality of life (HRQoL) and was developed by EuroQol (Brooks, 1996). It defines health from 5 dimensions: mobility, self-care, usual activities, pain / discomfort, and anxiety / depression. Each dimension has 3 ordinal severity levels: 1, no problems; 2, some problems; 3, problems severe. Overall health status is defined as a 5-digit number. Participants will be asked to indicate his / her current health status by selecting the most appropriate level in each of the 5 dimensions. The questionnaire also includes a VAS, where participants will be asked to rate their current health status using a 0 to 100 scale, where 0 is the worst health status imaginable.

[0253] Patient global severity impression. PGI-S is a single item designed to capture the subject’s perception of the overall symptom severity at completion using a 5-point categorical response scale (no symptoms to very severe symptoms).

[0254] 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 should be collected / reported.

[0255] Biomarkers

[0256] Serum immunoglobulins. Based on SoA, total immunoglobulin E (IgE) levels and the presence of allergen-specific IgE (IgEFEIA) will be collected before IP administration (predose) at prespecified scheduled visits and evaluated by a central laboratory.

[0257] Nasal epithelial lining fluid samples will be obtained at scheduled visits. Nasal epithelial lining fluid biomarkers will be measured to assess the pharmacology of tezelumab and to evaluate changes in biomarkers associated with CRSwNP, inflammation, and the TSLP pathway. Baseline and early post-dose levels of nasal epithelial lining fluid biomarkers may also be used to explore potential predictive biomarkers of response or exposure to tezelumab. Specific biomarkers that may be analyzed include, but are not limited to, cytokines, chemokines, and inflammatory mediators associated with CRSwNP and the TSLP pathway. If feasible, drug concentration may also be measured in the nasal epithelial lining fluid sample. If appropriate, urea concentration may be measured to correct for the dilution factor of the nasal lining fluid sample.

[0258] In addition, a nasal biopsy substudy will be conducted at selected sites in a total of approximately 60 participants. Nasal biopsies will be collected at V2 (Week -2) and EOT (Week 52) to assess the effects of tezelumab on inflammatory cell infiltration and gene expression by transcriptomic analysis. At V2, a nasal biopsy should be performed after nasal epithelial lining fluid (NELF) collection and before NPS assessment or CT scan. If a nasal biopsy sample cannot be obtained at Visit 2, the participant should be withdrawn from the nasal biopsy substudy and may continue in the main study. In this case, NLF should not be collected at Visit 2, and a Staph A-enterotoxin-specific IgE status sample should not be collected at Visit 3. At EOT, a nasal biopsy should be performed after NPS assessment, NELF collection, and CT scan. Collection of the nasal biopsy sample may be delayed for up to 7 days after the EOT visit only if appropriate test kits are not available at the time of the EOT visit.

[0259] Staphylococcus aureus characterization. Staphylococcus aureus (S. aureus; Staph A) enterotoxin IgE will be performed only in the nasal biopsy substudy participants. Staph A bacterial cultures will be collected from nasal swabs of all participants and evaluated by a central laboratory. These tests will be performed at scheduled visits according to the SoA.

[0260] Pharmacokinetic Assessment: Approximately 5 mL of whole blood samples were collected for measurement of serum concentrations of tezelumab.

[0261] Pharmacodynamic Assessment Venous blood samples were collected from all subjects at the outlined time points to determine the effect of tezelumab on the levels of circulating CCL17 (TARC) and CCL22 (MDC), which are downstream of TSLP signaling (Soumelis et al., 2002).

[0262] Pharmacogenetic assessments. DNA analysis can be performed. These optional pharmacogenetic analyses focus on genetic genetic variations to assess their possible relevance to the disease and / or responsiveness to the therapies used in the study. Optional study objectives include using genetic markers to help study CRS with or without nasal polyps and / or to identify subjects who can have a positive or negative response to the study product or regimen requiring therapy.

[0263] Antibody testing procedures: If there are unexpected PK findings or safety-related issues in the study population that require further investigation, bioanalytical testing for anti-tesidolumab antibodies can be performed. Samples positive for anti-tesidolumab antibodies can be further characterized.

[0264] Blood biomarkers: Blood samples (serum / plasma and whole blood) will be collected as instructed for the assessment of changes in circulating biomarker levels elevated in CRS subjects. Additional assays that can be performed on blood samples include measurement of changes in mRNA transcripts following tesidolumab treatment.

[0265] Statistical analysis

[0266] For the primary endpoint, a logistic regression model adjusted for covariates will be used to test the treatment effect. From this model, the odds ratio and 95% CI comparing each tesidolumab dose group to placebo will be reported. In addition, the percentage of subjects responding in each treatment group and the difference in the percentage of responding subjects between each tesidolumab dose group and placebo will be summarized with 95% confidence intervals.

[0267] Approximately 400 adult participants with severe CRSwNP (total NPS > 5) and inadequate response to standard-of-care treatment will be randomized in a 1 : 1 ratio to tesidolumab 210 mg Q4W or matching placebo.

[0268] Endpoints of interest: The change from baseline in the co-primary primary endpoint NPS and mean NCS every two weeks at Week 52 will be measured, and the difference in the mean values between the tesidolumab and placebo treatment groups will be used as a measure of efficacy. The analysis of key secondary endpoints is described below: the change from baseline in LMK, SNOT-22, olfactory loss, and NPSD TSS at Week 52 will be analyzed using the methods described in the primary analysis of the co-primary endpoints.

[0269] The time to first decision for NP surgery or SCS during the 52-week treatment period will be analyzed using a Cox proportional hazards model, adjusting for treatment, baseline comorbid asthma / AERD / NSAID-ERD status, prior surgery status, and region. The event of interest is the time to first use of SCS or decision for nasal polyp surgery, whichever is earlier. The date of decision for NP surgery will be used for analysis, not the actual date of NP surgery analysis. If the date of decision is missing, the actual date of NP surgery will be used. Hazard ratios and corresponding 95% CIs and p-values will be given. The proportion of participants who received surgery or SCS by Week 52 will be estimated using the Kaplan-Meier method. The same method will be used to analyze the time to first surgery and the time to first SCS, respectively.

[0270] The proportion of participants with maximum NPS < 1 per nostril will be analyzed as follows: Participants with a maximum score of 1 (NPS < 1) per nostril at Week 52 who did not have SCS or actual surgery at or before that time point will be defined as responders, otherwise the participant will be defined as non-responders. Participants who discontinue treatment prior to Week 52 will be considered non-responders. The response variable in the model will be the binary responder status at Week 52. A logistic regression model will be used, with treatment group, region, baseline comorbid asthma / AERD / NSAID-ERD status, and prior surgery status as factors, and baseline NPS as a covariate. Odds ratios, corresponding 95% CIs, and p-values will be given. The same logistic regression model will also be used to analyze the proportion of participants with maximum NPS < 1 per nostril and NPSD TSS response. Details of the NPSD TSS response will be provided in the SAP.

[0271] The analysis of change in FEV1 from baseline at Week 52 will also follow the methods described in the primary analysis for the common primary endpoint; however, the population of interest will be the subset of participants with comorbid asthma / AERD / NSAID-ERD. The model includes FEV1 baseline value as a covariate and prior surgery status and region as factors.

[0272] Results

[0273] In the initial study (NAVIGATOR), patients (12-80 years of age) were randomized 1 : 1 to subcutaneous injections of tezepelumab 210 mg or placebo every 4 weeks for 52 weeks. Changes in SNOT-22 scores (0 [no impairment] to 110 [maximal impairment]) from baseline to Week 52 were assessed in patients with any reported history of NP, stratified by whether NP was reported in the 2 years prior to randomization. Enrolled patients must have experienced at least two documented exacerbations of asthma (within 12 months prior to the informed consent date) that resulted in hospitalization, emergency department visit requiring treatment with systemic corticosteroids for at least 3 consecutive days, or treatment with systemic corticosteroids for at least 3 consecutive days.

[0274] Baseline demographics and clinical characteristics were generally balanced across subgroups Figure 1A ). Fewer female patients (65.0% vs 55.2%) or patients who were positive for any perennial aeroallergen by fluorescent enzyme immunoassay (67.7% vs 45.5%) had any history of NP compared with patients without a history of NP. Patients with any history of NP had more than twice as many exacerbations in the past 12 months (49.1% vs 38.4%) and higher mean fractional exhaled nitric oxide levels (47.4 ppb vs 39.2 ppb) and blood eosinophil counts at baseline (744.8 cells / pL vs 289.4 cells / pL) compared with patients without a history of NP.

[0275] Further analyses, as shown in Figure 1B , demonstrated SNOT scores and domain scores in enrolled subjects. Changes in SNOT-22 total scores (0 [no impairment] to 110 [maximal impairment]; minimal clinically important difference, 8.97) and domain scores from baseline to Week 28 and Week 52 were assessed in patients with a history of NP. Patients with a history of NP had higher SNOT-22 total scores and domain scores at baseline than patients without a history of NP Figure 1B .

[0276] Mean baseline SNOT-22 scores were similar in patients with any history of NP who received tezepelumab or placebo (49.6 [n = 69] and 49.3 [n = 62], respectively). In patients with any history of NP, the change from baseline in SNOT-22 scores with tezepelumab was -21.29 and with placebo was -10.21 (LS mean difference, -11.08 [95% Cl: -17.80, -4.35]).( Figure 2). Among patients without (tezepelumab, -23.40 [n=32]; placebo, -8.15 [n=22]; LS mean difference: -15.24 [95% CI: -28.36, -2.13]) and with NP (tezepelumab, -20.10 [n=37]; placebo, -10.55 [n=40]; LS mean difference: -9.56 [95% CI: -18.19, -0.93]) within 2 years prior to randomization, a decrease in SNOT-22 scores from baseline was observed. Clinically meaningful improvements in SNOT-22 scores from the first post-baseline timepoint assessment were observed compared with placebo (mean change from baseline to Week 28: tezepelumab, -19.43; placebo, -7.43) Figure 3

[0277] When examining results according to NP history timeline, a decrease in SNOT-22 scores from baseline was observed in patients with NP within 2 years prior to randomization and in patients with NP more than 2 years prior to randomization Figure 2 ). These results demonstrate that tezepelumab provided clinically meaningful improvements in sinus symptoms over 52 weeks in patients with severe, uncontrolled asthma and a long-term or recent comorbid NP history compared with placebo.

[0278] In patients with a history of NP, tezepelumab numerically reduced each SNOT-22 domain score from baseline to Week 28 and Week 52 compared with placebo Figure 4 and 5). Tezepelumab produced a greater percent change from baseline in SNOT-22 total score than placebo at Week 28 (LS mean difference: -26% [95% confidence interval (CI): -49, -3]) and Week 52 (LS mean difference: -28% [95% CI: -47, -9]) Figure 5B ). The SNOT-22 nasal domain was most severely impaired at baseline, followed by sleep, function, emotional, and ear / facial domains Figure 5C -G). Tezepelumab reduced the following symptoms from baseline to Week 52 compared with placebo: decreased sense of smell / taste, nasal congestion, cough, decreased productivity, and wake up tired. The sleep domain improved the most at Week 52, followed by the nasal and function domains. Tezepelumab reduced all five symptoms of greatest clinical interest. The improvement in decreased sense of smell / taste was the greatest, followed by nasal congestion, decreased productivity, wake up tired, and cough (Figure 6).

[0279] Asthma-related clinical outcomes

[0280] ​Trekizumab 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 compared with placebo over 52 weeks. Baseline pre-bronchodilator FEV1 (mean, standard deviation [SD]) was similar in patients with (trekizumab, 1.91 [0.72] L; placebo, 1.84 [0.71] L) and without (trekizumab, 1.81 [0.72] L; placebo, 1.85 [0.71] L) a history of CRSwNP. Treatment with trekizumab improved pre-bronchodilator FEV1 compared with placebo in patients with and without a history of CRSwNP. The LS mean difference (95% CI) in change from baseline to Week 52 in pre-bronchodilator FEV1 was 0.20 (0.07, 0.32) L in patients with a history of CRSwNP and 0.12 (0.07, 0.17) L in patients without CRSwNP.

[0281] Baseline ACQ-6 scores (mean [SD]) were similar for patients with (dupilumab, 2.86 [0.82]; placebo, 2.83 [0.86]) and without (dupilumab, 2.81 [0.81]; placebo, 2.79 [0.81]) a history of CRSwNP. Dupilumab treatment improved ACQ-6 scores compared with placebo. The LS mean change (95% CI) in ACQ-6 scores from baseline to Week 52 was -0.63 (-0.95, -0.31) for patients with and -0.27 (-0.41, -0.13) for patients without a history of CRSwNP. Baseline AQLQ(S)+12 scores (mean [SD]) were similar for patients with (dupilumab, 3.90 [0.99]; placebo, 3.84 [1.01]) and without (dupilumab, 3.86 [1.03]; placebo, 3.92 [1.00]) a history of CRSwNP. At Week 52, dupilumab produced greater improvement in AQLQ(S)+12 scores in patients with (LS mean difference [95% CI]: 0.77 [0.43, 1.12]) than in patients without (LS mean difference [95% CI]: 0.25 [0.10, 0.40]) a history of CRSwNP compared with placebo. Baseline ASD scores (mean [SD]) were similar for patients with (dupilumab, 1.41 [0.68]; placebo, 1.44 [0.71]) and without (dupilumab, 1.39 [0.70]; placebo, 1.39 [0.69]) a history of CRSwNP. Dupilumab improved ASD scores in patients with and without a history of CRSwNP compared with placebo; the LS mean change (95% CI) from baseline to Week 52 was -0.32 (-0.51, -0.13) and -0.08 (-0.16, 0.01), respectively.

[0282] These results show that a numerical decrease was observed in all SNOT-22 domains, with the greatest magnitude of decrease observed in the sleep, nasal, and functional domains. Dupilumab improved the following symptoms over 52 weeks compared with placebo: decreased sense of smell / taste, nasal congestion, cough, decreased productivity, and fatigue on wakening. These results demonstrate the efficacy of dupilumab in improving sinusitis symptoms in patients with severe, uncontrolled asthma and a history of NP.

[0283] It is expected that one of ordinary skill, having the benefit of the benefit of the foregoing disclosure, can effect numerous modifications thereto and changes therein without departing from the application in its broader aspects. Therefore, the only qualified limitations are those reflected in the claims, and equivalents thereto.

[0284] References

[0285] Alobid et al.,Allergy.2005;60:452–458.

[0286] Alving et al.,Pulm Ther.2017 3(1):207-218.

[0287] Agarwal et al.,Clin Rev Allergy Immunol 2019;doi 10.1007 / s12016-019-08734-z:May 10[Epub ahead of print].

[0288] Bachert et al.,JAMA.2016;315(5):469-79.

[0289] Bachert et al.,Journal of Allergy and Clinical Immunology(2017),doi:10.1016 / j.jaci.2017.05.044.

[0290] Bachert et al.,Lancet 2019.Available from:URL:https: / / doi.org / 10.1016 / S0140-6736(19)31881-1.

[0291] Bilodeau et al.,Rhinology.2010;48:420–425.

[0292] Chaaban et al.,Am J Rhinol Allergy 2013;27:473–478.

[0293] Chitsuthipakorn W et al.,Curr Allergy Asthma Rep.2018;18(9):46.

[0294] Deal and Kountakis et al.,Laryngoscope 2004;114:1932–1935.

[0295] Doty et al.,Physiology&Behavior(Monograph)1984 32:489-502.

[0296] Ediger et al., Clinical & Experimental Allergy, 35(3), 319-326.

[0297] Ehnhage A et al., Allergy. 2009; 64: 762-769.

[0298] Emson C et al., Am J Respir Crit Care Med 2020; 201 :A4256.

[0299] Emson et al., Presented at: European Academy of Allergy and Clinical Immunology (EAACI) Digital Congress 2020.

[0300] Emson et al., J Asthma Allergy. 2021; 14: 91-99.

[0301] Fokkens et al., Rhinol Suppl 2020 58 Supplement S29 (1-464).

[0302] Gauvreau et al., Expert opinion on therapeutic targets, 1-16.

[0303] Gevaert et al., J Allergy Clin Immunol 2011; 128: 989-95.

[0304] Gevaert et al., Journal of Allergy and Clinical Immunology 2020.

[0305] Graham et al., Am J Respir Crit Care Med. 2019; 200(8):e70-e88.

[0306] et al., PLoS ONE 2015; 10(7): e0127228.

[0307] Hopkins et al., Clinical otolaryngology 2009; 34(5): 447-5.

[0308] Hull and Chandra Otolaryngol Clin North Am 2017; 50(1): 61-81.

[0309] Jarvis et al., Allergy. 2012; 67: 91-98.

[0310] Juniper et al., Respir Med 2006; 100: 616-621.

[0311] Kato et al., Journal of Allergy and Clinical Immunology, 143(2), AB86.

[0312] Kimura et al., Allergy Asthma Immunol Res. 2011; 3(3): 186-193.

[0313] Lieberman et al., J Allergy Clin Immunol. 2010 Sep; 126(3): 477-80.el-42.

[0314] Likness et al., Otolaryngol Head Neck Surg. 2014 February; 150(2): 305-311.

[0315] Lou et al., Int Forum Allergy Rhinol. 2018 Nov; 8(11): 1218-1225.

[0316] Lund and Mackay, Rhinology 1993; 31(4): 183-4.

[0317] Nagarkar et al. J Allergy Clin Immunol. 2013; 132(3): 593-600 e512.

[0318] Okushi et al., Auris Nasus Larynx 40 (2013) 548-553.

[0319] Orlandi et al., Int Forum Allergy Rhinol 2016; 6(Suppl. 1): S22-S209.

[0320] Pallanch et al., Int Forum Allergy Rhinol 2013; 3(12): 963-72.

[0321] Pearlman et al., Am J Rhinol Allergy. 2009; 23: 145-148.

[0322] Piccirillo et al., Otolaryngology--Head and Neck Surgery. 2002; 126(1); 41-7.

[0323] 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.

[0324] QualityMetric, I. User's manual for the SF-36v2 Health Survey (3ed.). 2011. Lincoln, RI.

[0325] Reilly et al., PharmacoEconomics 1993; 4(5): 353-365.

[0326] Sampson et al., J Allergy Clin Immunol. 2006 Feb; 117(2): 391-7.

[0327] Scadding et al., Clin Transl Allergy. 2011; 1: 1-39.

[0328] Settipane et al., J Allergy Clin Immunol. 1977; 59: 17-21.

[0329] Seybt et al., Ear Nose Throat J 2007; 86: 409-11.

[0330] Shin et al., American journal of rhinology & allergy, 28(2), 95-98.

[0331] Stevens et al., Clin Immunol Pract 2016; 4(4): 565-72.

[0332] Tint et al., Curr Allergy Asthma Rep 2016; 16: 16.

[0333] Tokunaga et al., Allergy 2015; 70: 995-1003.

[0334] van der Veen et al. Allergy 2017; 72: 282-290.

Claims

1. 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 the antibody comprises: a. A light chain variable domain comprising: i. a light chain CDR1 sequence comprising the amino acid sequence shown in SEQ ID NO: 3; ii. a light chain CDR2 sequence comprising the amino acid sequence shown in SEQ ID NO: 4; iii. a light chain CDR3 sequence comprising the amino acid sequence shown in SEQ ID NO: 5; and b. A heavy chain variable domain comprising: i. a heavy chain CDR1 sequence comprising the amino acid sequence shown in SEQ ID NO: 6; ii. a heavy chain CDR2 sequence comprising the amino acid sequence shown in SEQ ID NO: 7, and iii. A heavy chain CDR3 sequence comprising the amino acid sequence shown in SEQ ID NO: 8, wherein the antibody specifically binds to the TSLP polypeptide shown in amino acids 29-159 of SEQ ID NO:

2.

2. 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 the antibody comprises: a. a light chain variable domain selected from the group consisting of: i. an amino acid sequence having at least 80% identity with SEQ ID NO: 12; ii. an amino acid sequence encoded by a polynucleotide sequence having at least 80% identity to SEQ ID NO: 11; iii. an amino acid sequence encoded by a polynucleotide that hybridizes under moderately stringent conditions to the complementary sequence of the polynucleotide consisting of SEQ ID NO: 11; and b. a heavy chain variable domain selected from the group consisting of: i. an amino acid sequence having at least 80% identity with SEQ ID NO: 10; ii. an amino acid sequence encoded by a polynucleotide sequence having at least 80% identity 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; 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 as shown in amino acids 29-159 of SEQ ID NO:

2.

3. The method of claim 1 or 2, wherein the antibody is administered every 2 weeks or every 4 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 between 140 and 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. 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 4 weeks, wherein the antibody comprises a. A light chain variable domain comprising: i. a light chain CDR1 sequence comprising the amino acid sequence shown in SEQ ID NO: 3; ii. a light chain CDR2 sequence comprising the amino acid sequence shown in SEQ ID NO: 4; iii. a light chain CDR3 sequence comprising the amino acid sequence shown in SEQ ID NO: 5; and b. A heavy chain variable domain comprising: i. a heavy chain CDR1 sequence comprising the amino acid sequence shown in SEQ ID NO: 6; ii. a heavy chain CDR2 sequence comprising the amino acid sequence shown in SEQ ID NO: 7, and iii. A heavy chain CDR3 sequence comprising the amino acid sequence shown in SEQ ID NO: 8, wherein the antibody specifically binds to the TSLP polypeptide shown in amino acids 29-159 of SEQ ID NO:

2.

9. 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 4 weeks, wherein the antibody comprises a. a light chain variable domain selected from the group consisting of: i. an amino acid sequence having at least 80% identity with SEQ ID NO: 12; ii. an amino acid sequence encoded by a polynucleotide sequence having at least 80% identity to SEQ ID NO: 11; iii. an amino acid sequence encoded by a polynucleotide that hybridizes under moderately stringent conditions to the complementary sequence of the polynucleotide consisting of SEQ ID NO: 11; and b. a heavy chain variable domain selected from the group consisting of: i. an amino acid sequence having at least 80% identity with SEQ ID NO: 10; ii. an amino acid sequence encoded by a polynucleotide sequence having at least 80% identity 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; 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 as shown in amino acids 29-159 of SEQ ID NO:

2.

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

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

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

14. The method of any one of the preceding claims, wherein the antibody is a human antibody.

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

16. The method of any one of the preceding claims, wherein the chronic sinusitis is severe or moderate chronic sinusitis.

17. The method of any one of the preceding claims, wherein the chronic sinusitis with nasal polyps.

18. The method of any one of the preceding claims, wherein the subject suffers from moderate asthma.

19. The method of any one of the preceding claims, wherein the subject is an adult.

20. The method of any one of the preceding claims, wherein the subject is a child or adolescent.

21. The method of any of the preceding claims, wherein the administration improves one or more measures of chronic sinusitis including Nasal Polyp Score (NSP), Nasal Congestion Score (NCS), Loss of smell, Sinus Nasal Outcome Test 22 Item (SNOT-22), EuroQOL Quality of Life 5 Dimensions 3 Levels Version (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. The method of any one of the preceding claims, wherein the administration improves one or more symptoms of chronic sinusitis as measured by a patient symptom diary.

23. The method of any one of the preceding claims, wherein the administration improves one or more symptoms of chronic sinusitis selected from the group consisting of nasal obstruction, nasal congestion, runny nose, postnasal drip, mucus running down the throat, significant nasal obstruction, nasal discharge, loss of smell, asthma symptoms, headache, facial pain, facial pressure, difficulty smelling, difficulty sleeping due to nasal symptoms, difficulty performing daily activities due to nasal symptoms.

24. 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 2 weeks, wherein the antibody comprises a. A light chain variable domain comprising: i. a light chain CDR1 sequence comprising the amino acid sequence shown in SEQ ID NO: 3; ii. a light chain CDR2 sequence comprising the amino acid sequence shown in SEQ ID NO: 4; iii. a light chain CDR3 sequence comprising the amino acid sequence shown in SEQ ID NO: 5; and b. A heavy chain variable domain comprising: i. a heavy chain CDR1 sequence comprising the amino acid sequence shown in SEQ ID NO: 6; ii. a heavy chain CDR2 sequence comprising the amino acid sequence shown in SEQ ID NO: 7, and iii. A heavy chain CDR3 sequence comprising the amino acid sequence shown in SEQ ID NO: 8, wherein the antibody specifically binds to the TSLP polypeptide shown in amino acids 29-159 of SEQ ID NO: 2, wherein the antibody is an IgG2 antibody.

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. The method of claim 24, wherein the antibody is administered every 4 weeks.

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

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 of the preceding claims, wherein the antibody is tezelumab.

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. The method of any of the preceding claims, wherein the antibody variant has a substantially similar pK profile as tezelumab in humans.

32. A method of reducing the frequency of exacerbations of 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 mg to 420 mg at intervals of every 2 weeks or every 4 weeks, wherein the antibody comprises a. A light chain variable domain comprising: i. a light chain CDR1 sequence comprising the amino acid sequence shown in SEQ ID NO: 3; ii. a light chain CDR2 sequence comprising the amino acid sequence shown in SEQ ID NO: 4; iii. a light chain CDR3 sequence comprising the amino acid sequence shown in SEQ ID NO: 5; and b. A heavy chain variable domain comprising: i. a heavy chain CDR1 sequence comprising the amino acid sequence shown in SEQ ID NO: 6; ii. a heavy chain CDR2 sequence comprising the amino acid sequence shown in SEQ ID NO: 7, and iii. A heavy chain CDR3 sequence comprising the amino acid sequence shown in SEQ ID NO: 8, wherein the antigen binding protein specifically binds to the TSLP polypeptide shown in amino acids 29-159 of SEQ ID NO:

2.

33. A method of reducing the frequency of exacerbations of 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 mg to 420 mg at intervals of every 2 weeks or every 4 weeks, wherein the antibody comprises a. a light chain variable domain selected from the group consisting of: i. an amino acid sequence having at least 80% identity with SEQ ID NO: 12; ii. an amino acid sequence encoded by a polynucleotide sequence having at least 80% identity to SEQ ID NO: 11; iii. an amino acid sequence encoded by a polynucleotide that hybridizes under moderately stringent conditions to the complementary sequence of the polynucleotide consisting of SEQ ID NO: 11; and b. a heavy chain variable domain selected from the group consisting of: i. an amino acid sequence having at least 80% identity with SEQ ID NO: 10; ii. an amino acid sequence encoded by a polynucleotide sequence having at least 80% identity to SEQ ID NO: 9; iii. 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. the light chain variable domain of (a) and the heavy chain variable domain of (b).

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. The method of any one of claims 32 to 34, wherein the antibody is administered every 4 weeks.

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

37. The method of any one of claims 32 to 34, wherein the dose is 420 mg.

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

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 IgGl 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 tezelumab.

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

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

45. The method of any one of claims 32 to 45, wherein the administration reduces the frequency or level of a co-administered therapy in the subject.

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

47. The method of claim 45, wherein the administration reduces or eliminates the need for corticosteroid therapy.

48. A method for reducing the SNOT-22 and / or Lund-Mackay score of a subject, the method comprising administering a composition comprising an anti-TSLP antibody at a dose of 140 mg to 420 mg at intervals of 2 weeks, wherein the antibody comprises a. A light chain variable domain comprising: i. a light chain CDR1 sequence comprising the amino acid sequence shown in SEQ ID NO: 3; ii. a light chain CDR2 sequence comprising the amino acid sequence shown in SEQ ID NO: 4; iii. a light chain CDR3 sequence comprising the amino acid sequence shown in SEQ ID NO: 5; and b. A heavy chain variable domain comprising: i. a heavy chain CDR1 sequence comprising the amino acid sequence shown in SEQ ID NO: 6; ii. a heavy chain CDR2 sequence comprising the amino acid sequence shown in SEQ ID NO: 7, and iii. A heavy chain CDR3 sequence comprising the amino acid sequence shown in SEQ ID NO: 8, wherein the antigen binding protein specifically binds to the TSLP polypeptide shown in amino acids 29-159 of SEQ ID NO:

2.

49. A method for reducing a subject's SNOT-22 and / or Lund-Mackay score, the method comprising administering a composition comprising an anti-TSLP antibody at a dose of 140 mg to 420 mg at intervals of 2 weeks, wherein the antibody comprises a. a light chain variable domain selected from the group consisting of: i. an amino acid sequence having at least 80% identity with SEQ ID NO: 12; ii. an amino acid sequence encoded by a polynucleotide sequence having at least 80% identity to SEQ ID NO: 11; iii. an amino acid sequence encoded by a polynucleotide that hybridizes under moderately stringent conditions to the complementary sequence of the polynucleotide consisting of SEQ ID NO: 11; and b. a heavy chain variable domain selected from the group consisting of: i. an amino acid sequence having at least 80% identity with SEQ ID NO: 10; ii. an amino acid sequence encoded by a polynucleotide sequence having at least 80% identity to SEQ ID NO: 9; iii. 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. the light chain variable domain of (a) and the heavy chain variable domain of (b).

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

2.

51. A method for reducing the SNOT-22 and / or Lund-Mackay score of a subject, the method comprising administering a composition comprising an anti-TSLP antibody at a dose of 210 mg every 4 weeks, wherein the antibody comprises a. a light chain variable domain selected from the group consisting of: i. an amino acid sequence having at least 80% identity with SEQ ID NO: 12; ii. an amino acid sequence encoded by a polynucleotide sequence having at least 80% identity to SEQ ID NO: 11; iii. an amino acid sequence encoded by a polynucleotide that hybridizes under moderately stringent conditions to the complementary sequence of the polynucleotide consisting of SEQ ID NO: 11; and b. a heavy chain variable domain selected from the group consisting of: i. an amino acid sequence having at least 80% identity with SEQ ID NO: 10; ii. an amino acid sequence encoded by a polynucleotide sequence having at least 80% identity to SEQ ID NO: 9; iii. 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. the light chain variable domain of (a) and the heavy chain variable domain of (b).

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. The method of any one of claims 48 to 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 32-53, wherein the anti-TSLP antibody is tezelumab.

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. The method of any one of claims 48-55, wherein the antibody is administered every 4 weeks.

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

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

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

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

8.

61. A method for treating chronic sinusitis with nasal polyps in a subject, the method comprising selecting a subject in need of treatment for chronic sinusitis with nasal polyps, and administering to the subject a composition comprising an anti-TSLP antibody at a dose of 210 mg every 4 weeks, wherein the antibody comprises a. a light chain variable domain selected from the group consisting of: i. an amino acid sequence having at least 80% identity with SEQ ID NO: 12; ii. an amino acid sequence encoded by a polynucleotide sequence having at least 80% identity to SEQ ID NO: 11; iii. an amino acid sequence encoded by a polynucleotide that hybridizes under moderately stringent conditions to the complementary sequence of the polynucleotide consisting of SEQ ID NO: 11; and b. a heavy chain variable domain selected from the group consisting of: i. an amino acid sequence having at least 80% identity with SEQ ID NO: 10; ii. an amino acid sequence encoded by a polynucleotide sequence having at least 80% identity 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; or c. the light chain variable domain of (a) and the heavy chain variable domain of (b), The antibody specifically binds to the TSLP polypeptide represented by amino acids 29-159 of SEQ ID NO:

2.

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. 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. 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 longer.

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 IgGl 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. The method of any one of claims 60 to 67, wherein the antibody is tezelumab.

69. 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 the anti-TSLP antibody or antibody variant is described in WO 20220226342A1, WO 20220226339A1, WO 2023098491A1, WO2021155634A1, WO 2022166072A1, WO 2021043221A1, WO 2022184074A1, WO 2021104053A1, WO 2023116925A1, WO 2021155861A1, WO 2022116858A1, WO 2022117079A1, WO2020244544A1, WO 2021152488A1, WO 2022253147A1, WO 2023070948A1, WO2023142309A1, WO 2022095689A1, WO 2021115240A1, WO 2022166739A1 and WO 2019100111A1 or listed in Table A.

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

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

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

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

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

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

76. The method of any one of claims 60 to 75, wherein the administration improves one or more measures of chronic sinusitis including Nasal Polyp Score (NSP), Nasal Congestion Score (NCS), Loss of smell, Sinus Nasal Outcome Test 22 Item (SNOT-22), EuroQOL Quality of Life 5 Dimensions 3 Levels Version (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. The method of any one of claims 60 to 76, wherein the administration improves one or more symptoms of chronic sinusitis as measured by a patient symptom diary.

78. The method of any one of claims 60 to 77, wherein the administration improves one or more symptoms of chronic sinusitis selected from the group consisting of nasal obstruction, nasal congestion, runny nose, postnasal drip, mucus running down the throat, significant nasal obstruction, nasal discharge, loss of smell, asthma symptoms, headache, facial pain, facial pressure, difficulty smelling, difficulty sleeping due to nasal symptoms, difficulty performing daily activities due to nasal symptoms.

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

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

Images