Treatment of asthma with Anti-TSLP antibody

Abstract

To provide antibody therapies for asthma including severe asthma, eosinophilic asthma and non / low eosinophilic asthma.SOLUTION: The disclosure provides a method for treating asthma in a subject comprising administering a therapeutically effective amount of an anti-TSLP antibody or antibody variant in a dose of 70 mg to 280 mg every 2 weeks, where both binding sites of the antibody have identical binding to TSLP, and the antibody comprises: a) a light chain variable domain comprising light chain CDR1, CDR2, CDR3 comprising amino acid sequences set forth in SEQ ID NO:3, SEQ ID NO:4 and SEQ ID NO:5 respectively; and b) a heavy chain variable domain comprising heavy chain CDR1, CDR2 and CDR3 comprising amino acid sequences set forth in SEQ ID NO:6, SEQ ID NO:7 and SEQ ID NO:8 respectively, where the antibody specifically binds to a TSLP polypeptide corresponding to amino acids 29-159 of SEQ ID NO:2.SELECTED DRAWING: None

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of priority to U.S. Provisional Patent Application No. 62 / 484,864, filed April 12, 2017, U.S. Provisional Patent Application No. 62 / 553,477, filed September 1, 2017, and U.S. Provisional Patent Application No. 62 / 553,575, filed September 1, 2017, each of which is incorporated by reference in its entirety.

[0002] The present disclosure relates generally to methods of treating asthma, including severe asthma, eosinophilic asthma, and non- / hypoeosinophilic asthma, using antibodies specific for thymic stromal lymphopoietin (TSLP). [Background technology]

[0003] Asthma affects an estimated 315 million people worldwide. 1 Of these, approximately 10-15% have severe asthma 2 and as many as 60% have poorly controlled disease. 3 These patients suffer from a significant impairment in quality of life and are at risk for recurrent severe exacerbations. Asthma treatments, including the combination of long-acting beta-2 agonists (LABAs) and inhaled corticosteroids (ICS), may not provide adequate disease control, especially in patients with severe disease. 2、4、5 The heterogeneous response to asthma treatment may be related in part to differences in patterns of airway inflammation and resistance to corticosteroids. 2、5、6 Alternative treatments that inhibit specific molecular targets, including immunoglobulin E (IgE), interleukin-4, interleukin-5, interleukin-13, and their respective receptors, have been shown to be beneficial for patients with asthma not adequately controlled with optimal ICS / LABA therapy. 7~18

[0004] Thymic stromal lymphopoietin (TSLP), an epithelial cell-derived cytokine produced in response to environmental and proinflammatory stimuli, leads to the activation of multiple inflammatory cells and downstream pathways. 19、20 TSLP is increased in the airways of asthmatic patients and suppresses the expression of Th2 cytokines and chemokines 21 and correlates with disease severity. 22、23 Although TSLP is central to the regulation of Th2 immunity, it may also play an important role in other pathways of inflammation and thus may be associated with multiple asthma phenotypes.

[0005] Tezepelumab is a human immunoglobulin G2 (IgG2) monoclonal antibody (mAb) that binds to TSLP and prevents its interaction with the TSLP-receptor complex. In a proof-of-concept study in patients with mild atopic asthma, tezepelumab was shown to inhibit early and late asthmatic responses and suppress biomarkers of Th2 inflammation after inhaled allergen exposure. 24 This disclosure describes a randomized, placebo-controlled, dose-ranging trial of tezepelumab in patients with inadequate disease control on medium- to high-dose ICS / LABA. [Prior art documents] [Non-patent literature]

[0006] [Non-Patent Document 1] To T, Stanojevic S, Moores G, et al. BMC Public Health 2012;12:204. [Non-patent document 2] Chung KF, Wenzel SE, Brozek JL, et al. Eur Respir J 2014;43:343-73. [Non-patent document 3] Pavord ID, et al., NPJ Prim Care Respir Med 2017;27:17. [Non-patent document 4] Bateman ED, et al. Am J Respir Crit Care Med 2004;170:836-44.

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[0007] The anti-TSLP antibodies described herein address an unmet need for asthma patients whose moderate-to-severe asthma is not controlled by other medications. For example, antibody therapy can improve asthma in patients with low eosinophils (EOS) and provide more robust exacerbation reduction in patients with high EOS.

[0008] The present disclosure provides a method for treating asthma in a subject, comprising administering a therapeutically effective amount of an anti-TSLP antibody or antibody variant at a dose of 70 mg to 280 mg every two weeks, wherein both binding sites of the antibody have identical binding affinity for TSLP, and the antibody comprises: 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 variable domain comprising the light chain CDR3 sequence comprising the amino acid sequence set forth in SEQ ID NO:5; and b. 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 variable domain comprising the heavy chain CDR3 sequence comprising the amino acid sequence set forth in SEQ ID NO:8, wherein the antibody specifically binds to the TSLP polypeptide set forth in amino acids 29 to 159 of SEQ ID NO:2.

[0009] Also disclosed is a method for treating asthma in a subject, comprising administering a therapeutically effective amount of an anti-TSLP antibody or antibody variant at a dose of 70 mg to 280 mg at biweekly intervals, wherein both binding sites of the antibody have identical binding affinity for TSLP, and the antibody is selected from the group consisting of: a. an amino acid sequence having at least 80% identity to 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 complement of a polynucleotide consisting of SEQ ID NO: 11. Also contemplated are methods comprising a light chain variable domain selected from the group consisting of: an amino acid sequence having at least 80% identity to 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. a heavy chain variable domain selected from the group consisting of an amino acid sequence encoded by a polynucleotide that hybridizes under moderately stringent conditions to the complement of a polynucleotide consisting of SEQ ID NO: 9; or c. a light chain variable domain of (a) and a heavy chain variable domain of (b), wherein the antibody specifically binds to a TSLP polypeptide represented by amino acids 29 to 159 of SEQ ID NO: 2.

[0010] In various embodiments, the antibody or antibody variant is administered every four weeks.

[0011] In various embodiments, the antibody or antibody variant is administered at a dose of 70 mg, at a dose of 210 mg, or at a dose of 280 mg, every two weeks, or every four weeks.

[0012] The present disclosure also provides a method for treating asthma in a subject, comprising administering a therapeutically effective amount of an anti-TSLP antibody or antibody variant at a dose of 210 mg every four weeks, wherein both binding sites of the antibody have identical binding affinity for TSLP, and the antibody comprises: 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 variable domain comprising a light chain CDR3 sequence comprising the amino acid sequence set forth in SEQ ID NO:5; and bi. 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 variable domain comprising a heavy chain CDR3 sequence comprising the amino acid sequence set forth in SEQ ID NO:8, wherein the antibody specifically binds to the TSLP polypeptide set forth in amino acids 29-159 of SEQ ID NO:2.

[0013] The present disclosure further provides a method of treating asthma in a subject, comprising administering a therapeutically effective amount of an anti-TSLP antibody or antibody variant at a dose of 210 mg every four weeks, wherein both binding sites of the antibody have identical binding affinity for TSLP, and the antibody is selected from the group consisting of: ai. an amino acid sequence having at least 80% identity to 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 complement of a polynucleotide consisting of SEQ ID NO:11. and a light chain variable domain selected from the group consisting of: an amino acid sequence having at least 80% identity to 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. a heavy chain variable domain selected from the group consisting of an amino acid sequence encoded by a polynucleotide that hybridizes under moderately stringent conditions to the complement of a polynucleotide consisting of SEQ ID NO: 9; or c. a light chain variable domain of (a) and a heavy chain variable domain of (b), wherein the antibody specifically binds to a TSLP polypeptide represented by amino acids 29 to 159 of SEQ ID NO: 2.

[0014] In various embodiments, the anti-TSLP antibody variants have pK characteristics in humans that are substantially similar to those of tezepelumab.

[0015] In various embodiments, the antibody or antibody variant is administered for at least 4 months, 6 months, 9 months, 1 year or more.

[0016] 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 bispecific antibody, a trispecific antibody, a tetraspecific antibody, a Fab fragment, an IgG1 antibody, an IgG2 antibody, an IgG3 antibody, and an IgG4 antibody.

[0017] In one embodiment, the anti-TSLP antibody variant is selected from the group consisting of a diabody, a triabody, a tetrabody, a Fab fragment, a single domain antibody, and an scFv, wherein the dosage is adjusted so that the binding sites are equimolar to that administered by the bivalent antibody.

[0018] In various embodiments, the antibody is an IgG2 antibody.

[0019] In one embodiment, the antibody or antibody variant is a human antibody.

[0020] In various embodiments, the antibody is tezepelumab, which is an IgG2 antibody having full-length heavy and light chain amino acid sequences set forth in SEQ ID NOs: 105 and 106, respectively.

[0021] In various embodiments, the antibody or antibody variant further comprises a pharmaceutically acceptable carrier or excipient.

[0022] In various embodiments, the asthma is severe asthma. The asthma is eosinophilic or noneosinophilic asthma, and optionally the asthma is further considered to be hypoeosinophilic asthma.

[0023] The data presented herein demonstrate that anti-TSLP antibodies substantially affect two key markers of inflammation in asthma: blood eosinophil counts and exhaled nitric oxide levels. The data indicate that anti-TSLP antibodies reduce the levels of both inflammatory markers, reduce asthma exacerbation rates, improve lung function regardless of asthma phenotype (eosinophilic (allergic and non-allergic) and non-eosinophilic / hypoeosinophilic asthma), and block at least two key inflammatory pathways in asthma. Thus, anti-TSLP antibodies can treat patients with either asthma phenotype: eosinophilic (allergic and non-allergic) or non-eosinophilic / hypoeosinophilic asthma. Accordingly, provided herein are methods for treating patients with hypoeosinophilic asthma, comprising administering an anti-TSLP antibody described herein. Also contemplated are methods for treating asthmatic subjects characterized by a low Th2 profile, comprising administering an anti-TSLP antibody. In various embodiments, the antibody is tezepelumab or another anti-TSLP antibody described in the art. Exemplary antibodies are further described in the detailed description.

[0024] In various embodiments, the subject is an adult. In various embodiments, the subject is a child or adolescent.

[0025] Administration of an anti-TSLP antibody or antibody variant is believed to reduce eosinophils in the blood, sputum, bronchoalveolar fluid, or lungs of a subject.

[0026] Furthermore, administration of an anti-TSLP antibody or antibody variant is believed to shift cell numbers in a subject from a high Th2 population to a low Th low population.

[0027] In various embodiments, administration of the anti-TSLP antibody or antibody variant improves one or more measures of asthma in a subject selected from the group consisting of forced expiratory volume (FEV), FEV1 reversibility, forced vital capacity (FVC), FeNO, Asthma Control Questionnaire-6 score, and AQLQ(S)+12 score.

[0028] In one embodiment, the administration improves one or more symptoms of asthma as assessed by an asthma symptom diary.

[0029] Further provided is a method for treating asthma in a subject, comprising administering a therapeutically effective amount of an anti-TSLP antibody or antibody variant at a dose of 70 to 280 mg every two weeks, wherein both binding sites of the antibody have identical binding affinity for TSLP, and the antibody comprises: 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 variable domain comprising a light chain CDR3 sequence comprising the amino acid sequence set forth in SEQ ID NO:5; and b. 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 variable domain comprising a heavy chain CDR3 sequence comprising the amino acid sequence set forth in SEQ ID NO:8, wherein the antibody specifically binds to the TSLP polypeptide set forth in amino acids 29 to 159 of SEQ ID NO:2, and the antibody is an IgG2 antibody.

[0030] In various embodiments, the IgG2 antibody is administered every two weeks or every four weeks.

[0031] In various embodiments, the IgG2 antibody is administered every two weeks or every four weeks at a dose of 70 mg, 210 mg, or 280 mg.

[0032] Also provided is a method for reducing the frequency of asthma exacerbations in a subject, comprising administering a therapeutically effective amount of an anti-TSLP antibody or antibody variant at a dose of 70 mg to 280 mg every two weeks, wherein both binding sites of the antibody have identical binding affinity for TSLP, and the antibody comprises: a. a light chain CDR1 sequence comprising the amino acid sequence of SEQ ID NO:3; ii. a light chain CDR2 sequence comprising the amino acid sequence of SEQ ID NO:4; iii. a light chain CDR3 sequence comprising the amino acid sequence of SEQ ID NO:5; and b. a heavy chain variable domain comprising a heavy chain CDR1 sequence comprising the amino acid sequence of SEQ ID NO:6; ii. a heavy chain CDR2 sequence comprising the amino acid sequence of SEQ ID NO:7; and iii. a heavy chain CDR3 sequence comprising the amino acid sequence of SEQ ID NO:8, wherein the antigen-binding protein specifically binds to the TSLP polypeptide represented by amino acids 29 to 159 of SEQ ID NO:2.

[0033] Further, a method for reducing the frequency of asthma exacerbations in a subject is provided, comprising administering a therapeutically effective amount of an anti-TSLP antibody or antibody variant at a dose of 70 mg to 280 mg at biweekly intervals, wherein both binding sites of the antibody have identical binding affinity for TSLP, and the antibody is selected from the group consisting of: a. an amino acid sequence having at least 80% identity to 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 sequence having at least 80% identity to SEQ ID NO: 11; and a light chain variable domain selected from the group consisting of: an amino acid sequence encoded by a polynucleotide sequence having at least 80% identity to 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. a heavy chain variable domain selected from the group consisting of an amino acid sequence encoded by a polynucleotide that hybridizes under moderately stringent conditions to the complement of a polynucleotide consisting of SEQ ID NO: 9; or c. a light chain variable domain of (a) and a heavy chain variable domain of (b).

[0034] The administrations and antibodies and antibody variants described above are believed to apply to each of the methods contemplated herein.

[0035] In various embodiments, the antibody or antibody variant further comprises a pharmaceutically acceptable carrier or excipient.

[0036] In various embodiments, administration delays the time to an asthma exacerbation compared to a subject not receiving the anti-TSLP antibody.

[0037] In various embodiments, administration reduces the frequency or concentration of the subject's concomitant therapy, which optionally is an inhaled corticosteroid (ICS), a long-acting beta-agonist (LABA), a leukotriene receptor antagonist (LTRA), a long-acting antimuscarinic agent (LAMA), a chromone, a short-acting beta-agonist (SABA), and theophylline or an oral corticosteroid.

[0038] In various embodiments, administration eliminates the need for corticosteroid treatment.

[0039] In various embodiments, administration is subcutaneous or intravenous.

[0040] Also provided herein is a method for treating chronic obstructive pulmonary disease (COPD), comprising administering a therapeutically effective amount of an anti-TSLP antibody or antibody variant at a dose of 70 mg to 280 mg every two weeks, wherein both binding sites of the antibody have identical binding affinity for TSLP, and the antibody comprises: 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 variable domain comprising the light chain CDR3 sequence comprising the amino acid sequence set forth in SEQ ID NO:5; and b. 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 variable domain comprising the heavy chain CDR3 sequence comprising the amino acid sequence set forth in SEQ ID NO:8, wherein the antigen-binding protein specifically binds to the TSLP polypeptide set forth in amino acids 29 to 159 of SEQ ID NO:2.

[0041] Also disclosed is a method for treating chronic obstructive pulmonary disease (COPD) in a subject, comprising administering a therapeutically effective amount of an anti-TSLP antibody or antibody variant at a dose of 70 mg to 280 mg at biweekly intervals, wherein both binding sites of the antibody have identical binding affinity for TSLP, and the antibody is selected from the group consisting of: a. an amino acid sequence having at least 80% identity to 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 that hybridizes under moderately stringent conditions to the complement of a polynucleotide consisting of SEQ ID NO: 11. a light chain variable domain selected from the group consisting of an amino acid sequence encoded by a polynucleotide having at least 80% identity to 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. a heavy chain variable domain selected from the group consisting of an amino acid sequence encoded by a polynucleotide that hybridizes under moderately stringent conditions to the complement of a polynucleotide consisting of SEQ ID NO: 9; or c. a light chain variable domain of (a) and a heavy chain variable domain of (b).

[0042] Also provided herein is a method for reducing a subject's ACQ-6 score, comprising administering a therapeutically effective amount of an anti-TSLP antibody or antibody variant at a dose of 70 mg to 280 mg every two weeks, wherein both binding sites of the antibody have identical binding affinity for TSLP, and the antibody comprises: 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 variable domain comprising a light chain CDR3 sequence comprising the amino acid sequence set forth in SEQ ID NO:5; and b. 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 variable domain comprising 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 the TSLP polypeptide set forth in amino acids 29 to 159 of SEQ ID NO:2.

[0043] Furthermore, a method for reducing ACQ-6 score in a subject is provided, comprising administering a therapeutically effective amount of an anti-TSLP antibody or antibody variant at a dose of 70 mg to 280 mg at biweekly intervals, wherein both binding sites of the antibody have identical binding affinity for TSLP, and the antibody is selected from the group consisting of: a. an amino acid sequence having at least 80% identity to 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 sequence having at least 80% identity to SEQ ID NO: 11 under moderately stringent conditions; a light chain variable domain selected from the group consisting of an amino acid sequence encoded by a polynucleotide having at least 80% identity to 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. a heavy chain variable domain selected from the group consisting of an amino acid sequence encoded by a polynucleotide that hybridizes under moderately stringent conditions to the complement of a polynucleotide consisting of SEQ ID NO: 9; or c. a light chain variable domain of (a) and a heavy chain variable domain of (b).

[0044] Provided herein are methods for reducing the ACQ-6 score in a subject with a low eosinophil profile, comprising administering a therapeutically effective amount of an anti-TSLP antibody or antibody variant, wherein the antibody or antibody variant binds to TSLP and inhibits TSLP activity. Also provided are methods for reducing the ACQ-6 score in a subject with a low Th2 profile, comprising administering a therapeutically effective amount of an anti-TSLP antibody or antibody variant, wherein the antibody or antibody variant binds to TSLP and inhibits TSLP activity.

[0045] Also contemplated are methods for treating asthma in a subject, including severe asthma, eosinophilic or noneosinophilic asthma, and hypoeosinophilic asthma, comprising administering a therapeutically effective amount of an anti-TSLP antibody or antibody variant, wherein the antibody or antibody variant binds to TSLP and inhibits TSLP activity.

[0046] In various embodiments, the subject has an eosinophil count of less than 250 cells / μL at the start of treatment.

[0047] Also provided is a method for treating asthma in a subject with a Th2-low profile, comprising administering a therapeutically effective amount of an anti-TSLP antibody or antibody variant, wherein the antibody or antibody variant binds to TSLP and inhibits TSLP activity.

[0048] In various embodiments, the subject has a Th2 profile with IgE of 100 IU / ml or less or an eosinophil count of less than 140 cells / μL at the time of diagnosis.

[0049] In various embodiments, the antibody is tezepelumab or another anti-TSLP antibody described in the art, e.g., in Table A. Exemplary antibodies are further described in the detailed description. The present invention provides, for example, the following items. (Item 1) 1. A method of treating asthma in a subject, comprising administering a therapeutically effective amount of an anti-TSLP antibody or antibody variant at a dose of 70 mg to 280 mg at biweekly intervals, wherein both binding sites of the antibody have identical binding affinity for TSLP, and the antibody: ai 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 variable domain comprising a light chain CDR3 sequence comprising the amino acid sequence set forth in SEQ ID NO: 5; and bi 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 method in which the antibody specifically binds to a TSLP polypeptide represented by amino acids 29 to 159 of SEQ ID NO: 2, wherein the antibody comprises a heavy chain variable domain comprising a heavy chain CDR3 sequence comprising the amino acid sequence represented by SEQ ID NO: 8. (Item 2) 1. A method of treating asthma in a subject, comprising administering a therapeutically effective amount of an anti-TSLP antibody or antibody variant at a dose of 70 mg to 280 mg at biweekly intervals, wherein both binding sites of the antibody have identical binding affinity for TSLP, and the antibody: ai an amino acid sequence having at least 80% identity to 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. a light chain variable domain selected from the group consisting of an amino acid sequence encoded by a polynucleotide that hybridizes under moderately stringent conditions to the complement of the polynucleotide consisting of SEQ ID NO: 11; and bi an amino acid sequence having at least 80% identity to 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. a heavy chain variable domain selected from the group consisting of amino acid sequences encoded by a polynucleotide that hybridizes under moderately stringent conditions to the complement of a polynucleotide consisting of SEQ ID NO: 9; or c. a light chain variable domain of (a) and a heavy chain variable domain of (b), wherein the antibody specifically binds to a TSLP polypeptide represented by amino acids 29 to 159 of SEQ ID NO: 2. (Item 3) 3. The method of item 1 or 2, wherein the antibody or antibody variant is administered every 4 weeks. (Item 4) 4. The method of any one of items 1 to 3, wherein the antibody or antibody variant is administered at a dose of 70 mg. (Item 5) 4. The method of any one of items 1 to 3, wherein the antibody or antibody variant is administered at a dose of 210 mg. (Item 6) 4. The method of any one of items 1 to 3, wherein the antibody or antibody variant is administered at a dose of 280 mg. (Item 7) 1. A method of treating asthma in a subject comprising administering a therapeutically effective amount of an anti-TSLP antibody or antibody variant at a dose of 210 mg every four weeks, wherein both binding sites of the antibody have identical binding affinity for TSLP, and the antibody: ai 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 variable domain comprising a light chain CDR3 sequence comprising the amino acid sequence set forth in SEQ ID NO: 5; and bi 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 method in which the antibody specifically binds to a TSLP polypeptide represented by amino acids 29 to 159 of SEQ ID NO: 2, wherein the antibody comprises a heavy chain variable domain comprising a heavy chain CDR3 sequence comprising the amino acid sequence represented by SEQ ID NO: 8. (Item 8) 1. A method of treating asthma in a subject comprising administering a therapeutically effective amount of an anti-TSLP antibody or antibody variant at a dose of 210 mg every four weeks, wherein both binding sites of the antibody have identical binding affinity for TSLP, and the antibody: ai an amino acid sequence having at least 80% identity to 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. a light chain variable domain selected from the group consisting of an amino acid sequence encoded by a polynucleotide that hybridizes under moderately stringent conditions to the complement of the polynucleotide consisting of SEQ ID NO: 11; and bi an amino acid sequence having at least 80% identity to 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. a heavy chain variable domain selected from the group consisting of amino acid sequences encoded by a polynucleotide that hybridizes under moderately stringent conditions to the complement of a polynucleotide consisting of SEQ ID NO: 9; or c. a light chain variable domain of (a) and a heavy chain variable domain of (b), wherein the antibody specifically binds to a TSLP polypeptide represented by amino acids 29 to 159 of SEQ ID NO: 2. (Item 9) 9. The method of any one of items 1 to 8, wherein the antibody or antibody variant is administered for at least 4 months, 6 months, 9 months, 1 year or more. (Item 10) The method of any one of Aspects 1 to 9, wherein 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 bispecific antibody, a trispecific antibody, a tetraspecific antibody, a Fab fragment, an IgG1 antibody, an IgG2 antibody, an IgG3 antibody, and an IgG4 antibody. (Item 11) The method of claim 8, wherein the anti-TSLP antibody variant is selected from the group consisting of a bispecific antibody, a trispecific antibody, a tetraspecific antibody, a Fab fragment, a single domain antibody, and an scFv, and the dosage is adjusted so that the binding sites are equimolar to that administered by the bivalent antibody. (Item 12) 12. The method according to any one of items 1 to 11, wherein the antibody is an IgG2 antibody. (Item 13) 13. The method according to any one of items 1 to 12, wherein the antibody or antibody mutant is a human antibody. (Item 14) 14. The method of any one of items 1 to 13, wherein the antibody or antibody variant further comprises a pharmaceutically acceptable carrier or excipient. (Item 15) 15. The method according to any one of items 1 to 14, wherein the asthma is severe asthma. (Item 16) 16. The method according to any one of items 1 to 15, wherein the asthma is eosinophilic or non-eosinophilic asthma. (Item 17) 17. The method according to any one of items 1 to 16, wherein the asthma is hypoeosinophilic asthma. (Item 18) 18. The method of any one of items 1 to 17, wherein the subject is an adult. (Item 19) 19. The method of any one of items 1 to 18, wherein the subject is a child or an adolescent. (Item 20) 20. The method of any one of items 1 to 19, wherein the administration reduces eosinophils in the blood, sputum, bronchoalveolar fluid, or lungs of the subject. (Item 21) 21. The method of any one of items 1 to 20, wherein said administering changes the number of cells in said subject from a high Th2 population to a low Th2 population. (Item 22) 22. The method of any one of items 1 to 21, wherein the administration improves one or more of the subject's asthma measures selected from the group consisting of forced expiratory volume (FEV), FEV1 reversibility, forced vital capacity (FCV), FeNO, Asthma Control Questionnaire-6 score, and AQLQ(S)+12 score. (Item 23) 23. The method of any one of items 1 to 22, wherein said administration improves one or more symptoms of asthma as assessed by an asthma symptom diary. (Item 24) 1. A method of treating asthma in a subject, comprising administering a therapeutically effective amount of an anti-TSLP antibody or antibody variant at a dose of 70-280 mg at biweekly intervals, wherein both binding sites of the antibody have identical binding affinity for TSLP, and the antibody: ai 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 variable domain comprising a light chain CDR3 sequence comprising the amino acid sequence set forth in SEQ ID NO: 5; and bi 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 method comprising an antibody comprising a heavy chain variable domain comprising a heavy chain CDR3 sequence comprising the amino acid sequence of SEQ ID NO: 8, wherein the antibody specifically binds to the TSLP polypeptide represented by amino acids 29 to 159 of SEQ ID NO: 2, and the antibody is an IgG2 antibody. (Item 25) 25. The method of item 24, wherein the antibody is administered every four weeks. (Item 26) 26. The method of item 24 or 25, wherein the antibody is administered at a dose of 70 mg. (Item 27) 26. The method of any one of items 24 to 25, wherein the antibody is administered at a dose of 210 mg. (Item 28) 26. The method of any one of items 24 to 25, wherein the antibody is administered at a dose of 280 mg. (Item 29) 29. The method of any one of items 1 to 28, wherein the antibody is tezepelumab. (Item 30) 30. The method of item 29, wherein the antibody is an IgG2 antibody and has full-length heavy and light chain sequences as set forth in SEQ ID NOs: 105 and 106, respectively. (Item 31) 31. The method of any one of items 1 to 30, wherein the antibody variant has pK characteristics substantially similar to human tezepelumab. (Item 32) 1. A method for reducing the frequency of asthma exacerbations in a subject, comprising administering a therapeutically effective amount of an anti-TSLP antibody or antibody variant at a dose of 70 mg to 280 mg at biweekly intervals, wherein both binding sites of the antibody have identical binding affinity for TSLP, and the antibody: ai 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 variable domain comprising a light chain CDR3 sequence comprising the amino acid sequence set forth in SEQ ID NO: 5; and bi 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 method comprising: a heavy chain variable domain comprising 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 set forth in amino acids 29 to 159 of SEQ ID NO: 2. (Item 33) 1. A method for reducing the frequency of asthma exacerbations in a subject, comprising administering a therapeutically effective amount of an anti-TSLP antibody or antibody variant at a dose of 70 mg to 280 mg at biweekly intervals, wherein both binding sites of the antibody have identical binding affinity for TSLP, and the antibody: ai an amino acid sequence having at least 80% identity to 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. a light chain variable domain selected from the group consisting of an amino acid sequence encoded by a polynucleotide that hybridizes under moderately stringent conditions to the complement of the polynucleotide consisting of SEQ ID NO: 11; and bi an amino acid sequence having at least 80% identity to 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. a heavy chain variable domain selected from the group consisting of an amino acid sequence encoded by a polynucleotide that hybridizes under moderately stringent conditions to the complement of a polynucleotide consisting of SEQ ID NO: 9; or c. a light chain variable domain of (a) and a heavy chain variable domain of (b). (Item 34) 34. The method of any one of paragraphs 32 or 33, wherein the antibody or antibody variant is administered every four weeks. (Item 35) 34. The method of any one of paragraphs 32 or 33, wherein the antibody or antibody variant is administered at a dose of 70 mg. (Item 36) 34. The method of any one of paragraphs 32 or 33, wherein the antibody or antibody variant is administered at a dose of 210 mg. (Item 37) 34. The method of any one of paragraphs 32 or 33, wherein the antibody or antibody variant is administered at a dose of 280 mg. (Item 38) 38. The method of any one of items 32 to 37, wherein the antibody or antibody variant is administered for at least 4 months, 6 months, 9 months, 1 year or more. (Item 39) 39. The method of any one of Aspects 32 to 38, wherein the anti-TSLP antibody or antibody mutant 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 bispecific antibody, a trispecific antibody, a tetraspecific antibody, a Fab fragment, an IgG1 antibody, an IgG2 antibody, an IgG3 antibody, and an IgG4 antibody. (Item 40) 40. The method according to any one of items 32 to 39, wherein the antibody or antibody mutant is an IgG2 antibody. (Item 41) 41. The method according to any one of items 32 to 40, wherein the antibody or antibody mutant is a human antibody. (Item 42) 42. The method of any one of items 32 to 41, wherein the antibody or antibody variant further comprises a pharmaceutically acceptable carrier or excipient. (Item 43) 43. The method of any one of items 32 to 42, wherein the administration delays the time to asthma exacerbation compared to a subject not administered the anti-TSLP antibody. (Item 44) 44. The method of any one of items 32 to 43, wherein the administration reduces the frequency or level of the subject's concurrent therapy. (Item 45) 45. The method of item 44, wherein the co-administration therapy is an inhaled corticosteroid (ICS), a long-acting beta-2 agonist (LABA), a leukotriene receptor antagonist (LTRA), a long-acting antimuscarinic agent (LAMA), a cromone, a short-acting beta-2 agonist (SABA), and theophylline or an oral corticosteroid. (Item 46) 45. The method of claim 44, wherein said administration eliminates the need for corticosteroid treatment. (Item 47) 1. A method for treating chronic obstructive pulmonary disease (COPD), comprising administering a therapeutically effective amount of an anti-TSLP antibody or antibody variant at a dose of 70 mg to 280 mg every two weeks, wherein both binding sites of the antibody have identical binding affinity for TSLP, and the antibody: ai 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 variable domain comprising a light chain CDR3 sequence comprising the amino acid sequence set forth in SEQ ID NO: 5; and bi 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 method comprising: a heavy chain variable domain comprising 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 set forth in amino acids 29 to 159 of SEQ ID NO: 2. (Item 48) 1. A method of treating chronic obstructive pulmonary disease (COPD) in a subject, comprising administering a therapeutically effective amount of an anti-TSLP antibody or antibody variant at a dose of 70 mg to 280 mg every two weeks, wherein both binding sites of the antibody have identical binding affinity for TSLP, and the antibody: ai an amino acid sequence having at least 80% identity to 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. a light chain variable domain selected from the group consisting of an amino acid sequence encoded by a polynucleotide that hybridizes under moderately stringent conditions to the complement of the polynucleotide consisting of SEQ ID NO: 11; and bi an amino acid sequence having at least 80% identity to 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. a heavy chain variable domain selected from the group consisting of an amino acid sequence encoded by a polynucleotide that hybridizes under moderately stringent conditions to the complement of a polynucleotide consisting of SEQ ID NO: 9; or c. a light chain variable domain of (a) and a heavy chain variable domain of (b). (Item 49) The method according to any one of Items 1 to 48, wherein the administration is subcutaneous or intravenous. (Item 50) 1. A method for reducing ACQ-6 score in a subject, comprising administering a therapeutically effective amount of an anti-TSLP antibody or antibody variant at a dose of 70 mg to 280 mg every two weeks, wherein both binding sites of the antibody have identical binding affinity for TSLP, and the antibody: ai 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 variable domain comprising a light chain CDR3 sequence comprising the amino acid sequence set forth in SEQ ID NO: 5; and bi 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 method comprising: a heavy chain variable domain comprising a heavy chain CDR3 sequence comprising the amino acid sequence set forth in SEQ ID NO:8; and an antigen-binding protein that specifically binds to a TSLP polypeptide set forth in amino acids 29 to 159 of SEQ ID NO:2. (Item 51) 1. A method for reducing ACQ-6 score in a subject, comprising administering a therapeutically effective amount of an anti-TSLP antibody or antibody variant at a dose of 70 mg to 280 mg every two weeks, wherein both binding sites of the antibody have identical binding affinity for TSLP, and the antibody: ai an amino acid sequence having at least 80% identity to 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. a light chain variable domain selected from the group consisting of an amino acid sequence encoded by a polynucleotide that hybridizes under moderately stringent conditions to the complement of the polynucleotide consisting of SEQ ID NO: 11; and bi an amino acid sequence having at least 80% identity to 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. a heavy chain variable domain selected from the group consisting of an amino acid sequence encoded by a polynucleotide that hybridizes under moderately stringent conditions to the complement of a polynucleotide consisting of SEQ ID NO: 9; or c. a light chain variable domain of (a) and a heavy chain variable domain of (b). (Item 52) The method according to any one of Items 1 to 51, wherein the administration is subcutaneous or intravenous. (Item 53) A method for treating asthma in a subject with a non-eosinophilic or low-eosinophilic profile, comprising administering a therapeutically effective amount of an anti-TSLP antibody or antibody variant, wherein the antibody or antibody variant binds to TSLP and inhibits TSLP activity. (Item 54) The method of claim 53, wherein the anti-TSLP antibody or anti-TSLP antibody variant is selected from the antibodies listed in Table A: [Table 2-1] [Table 2-2] [Table 2-3] [Table 2-4] [Table 2-5] [Table 2-6] [Table 2-7] (Item 55) 55. The method of any one of items 32 to 54, wherein the anti-TSLP antibody is tezepelumab. (Item 56) 56. The method of item 55, wherein the antibody is an IgG2 antibody and has full-length heavy and light chain sequences as set forth in SEQ ID NOs: 105 and 106, respectively. (Item 57) 57. The method of any one of items 32 to 56, wherein the antibody variant has pK characteristics substantially similar to human tezepelumab. (Item 58) 56. The method of any one of paragraphs 53, 54, or 55, wherein the subject has an eosinophil count of less than 250 cells / μL at the start of treatment. (Item 59) A method for treating asthma in a subject with a low Th2 profile, comprising administering a therapeutically effective amount of an anti-TSLP antibody or antibody variant, wherein the antibody or antibody variant binds to TSLP and inhibits TSLP activity. (Item 60) 60. The method of item 59, wherein the subject has a Th2 profile with IgE of 100 IU / ml or less or an eosinophil count of less than 140 cells / μL at the time of diagnosis. (Item 61) 61. The method of item 59 or 60, wherein the antibody or antibody variant is selected from the antibodies listed in Table A. (Item 62) 61. The method of item 59 or 60, wherein the antibody is tezepelumab. (Item 63) 63. The method of item 62, wherein the antibody is an IgG2 antibody and has full-length heavy and light chain sequences as set forth in SEQ ID NOs: 105 and 106, respectively. (Item 64) A method for reducing the ACQ-6 score in a subject with a low eosinophil profile, comprising administering a therapeutically effective amount of an anti-TSLP antibody or antibody variant, wherein the antibody or antibody variant binds to TSLP and inhibits TSLP activity. (Item 65) 65. The method of claim 64, wherein the anti-TSLP antibody or anti-TSLP antibody variant is selected from the antibodies listed in Table A. (Item 66) 65. The method of claim 64, wherein the anti-TSLP antibody is tezepelumab. (Item 67) 67. The method of item 66, wherein the antibody is an IgG2 antibody and has full-length heavy and light chain sequences as set forth in SEQ ID NOs: 105 and 106, respectively. (Item 68) 67. The method of any one of paragraphs 64, 65, or 66, wherein the subject has an eosinophil count of less than 250 cells / μL at the start of treatment. (Item 68) A method for reducing the ACQ-6 score in a subject with a low Th2 profile, comprising administering a therapeutically effective amount of an anti-TSLP antibody or antibody variant, wherein the antibody or antibody variant binds to TSLP and inhibits TSLP activity. (Item 69) 69. The method of item 68, wherein the subject has a Th2 profile with IgE of 100 IU / ml or less or an eosinophil count of less than 140 cells / μL at the time of diagnosis. (Item 70) 70. The method of item 68 or 69, wherein the antibody or antibody variant is selected from the antibodies listed in Table A. (Item 71) 70. The method of item 68 or 69, wherein the antibody is tezepelumab. (Item 72) 72. The method of claim 71, wherein the antibody is an IgG2 antibody and has full-length heavy and light chain sequences as set forth in SEQ ID NOs: 105 and 106, respectively. (Item 73) Both binding sites of the antibody have the same binding affinity for TSLP, and the antibody ai 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 variable domain comprising a light chain CDR3 sequence comprising the amino acid sequence set forth in SEQ ID NO: 5; and bi 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. The method of any one of Aspects 53 to 72, wherein the antibody comprises a heavy chain variable domain comprising a heavy chain CDR3 sequence comprising the amino acid sequence set forth in SEQ ID NO: 8, and the antibody specifically binds to the TSLP polypeptide set forth in amino acids 29 to 159 of SEQ ID NO: 2. (Item 74) Both binding sites of the antibody have the same binding affinity for TSLP, and the antibody ai an amino acid sequence having at least 80% identity to 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. a light chain variable domain selected from the group consisting of an amino acid sequence encoded by a polynucleotide that hybridizes under moderately stringent conditions to the complement of the polynucleotide consisting of SEQ ID NO: 11; and bi an amino acid sequence having at least 80% identity to 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. a heavy chain variable domain selected from the group consisting of amino acid sequences encoded by a polynucleotide that hybridizes under moderately stringent conditions to the complement of a polynucleotide consisting of SEQ ID NO: 9; or c. the light chain variable domain of (a) and the heavy chain variable domain of (b), wherein the antibody specifically binds to the TSLP polypeptide represented by amino acids 29 to 159 of SEQ ID NO: 2. (Item 75) 75. The method of any one of items 53 to 74, wherein the antibody or antibody variant is administered every four weeks. (Item 76) 76. The method according to any one of items 53 to 75, wherein the administration is subcutaneous or intravenous. [Brief explanation of the drawings]

[0050] [Figure 1A] Figures 1A-1D show the effect of antibody treatment at different doses on various assessments of asthma symptoms: Figure 1A shows asthma exacerbation rate; Figure 1B shows change from baseline in post-bronchodilator FEV1; Figure 1C shows change from baseline in ACQ-6; and Figure 1D shows change from baseline in AQLQ score. [Figure 1B] Figures 1A-1D show the effect of antibody treatment at different doses on various assessments of asthma symptoms: Figure 1A shows asthma exacerbation rate; Figure 1B shows change from baseline in post-bronchodilator FEV1; Figure 1C shows change from baseline in ACQ-6; and Figure 1D shows change from baseline in AQLQ score. [Figure 1C] Figures 1A-1D show the effect of antibody treatment at different doses on various assessments of asthma symptoms: Figure 1A shows asthma exacerbation rate; Figure 1B shows change from baseline in post-bronchodilator FEV1; Figure 1C shows change from baseline in ACQ-6; and Figure 1D shows change from baseline in AQLQ score. [Figure 1D] Figures 1A-1D show the effect of antibody treatment at different doses on various assessments of asthma symptoms: Figure 1A shows asthma exacerbation rate; Figure 1B shows change from baseline in post-bronchodilator FEV1; Figure 1C shows change from baseline in ACQ-6; and Figure 1D shows change from baseline in AQLQ score. [Figure 2A-2B] Figures 2A-2B show the effect of antibody treatment in patients receiving glucocorticoids. Figure 2A: The line within the square represents the median, the diamond represents the mean, the box represents the 25th-75th percentile, and the whiskers represent the range (highest and lowest values). Figure 2B: Histogram of baseline inhaled glucocorticoid dose (fluticasone equivalents). [Figure 3] Figure 3 shows Kaplan-Meier curves for time to first asthma exacerbation by week 52 in the intention-to-treat population. *P values ​​are nominal and not adjusted for multiplicity. [Figure 4A] Figures 4A-4B show the time course of peripheral blood eosinophils (cells / µl) (Figure 4A) and total IgE (IU / ml) (Figure 4B) from baseline in the intention-to-treat population. [Figure 4B] Figures 4A-4B show the time course of peripheral blood eosinophils (cells / µl) (Figure 4A) and total IgE (IU / ml) (Figure 4B) from baseline in the intention-to-treat population. [Figure 5] FIG. 5 shows the change from baseline in exhaled nitric oxide levels (FENO) in treated subjects. [Figure 6A] Figures 6A-6B show the annualized rate of asthma exacerbations (Figure 6A) and change from baseline in exhaled nitric oxide (FENO) levels by baseline biomarker status at week 52 (Figure 6B). Figure 6A shows a nominal two-sided P value of less than 0.05 for comparisons with the placebo group. A clinically significant cutoff of 24 ppb was used for FeNO subpopulation analysis. High type 2 helper T (Th2) status was defined as an IgE level greater than 100 IU per milliliter and a blood eosinophil count greater than or equal to 140 cells per microliter. Low Th2 status was defined as an IgE level less than or equal to 100 IU per milliliter or a blood eosinophil count less than 140 cells per microliter. [Figure 6B]Figures 6A-6B show the annualized rate of asthma exacerbations (Figure 6A) and change from baseline in exhaled nitric oxide (FENO) levels by baseline biomarker status at week 52 (Figure 6B). Figure 6A shows a nominal two-sided P value of less than 0.05 for comparisons with the placebo group. A clinically significant cutoff of 24 ppb was used for FeNO subpopulation analysis. High type 2 helper T (Th2) status was defined as an IgE level greater than 100 IU per milliliter and a blood eosinophil count greater than or equal to 140 cells per microliter. Low Th2 status was defined as an IgE level less than or equal to 100 IU per milliliter or a blood eosinophil count less than 140 cells per microliter. [Figure 7-1] Figure 7 (Table 1A) shows the inclusion and exclusion criteria for subjects. [Figure 7-2] Figure 7 (Table 1A) shows the inclusion and exclusion criteria for subjects. [Figure 7-3] Figure 7 (Table 1A) shows the inclusion and exclusion criteria for subjects. [Figure 7-4] Figure 7 (Table 1A) shows the inclusion and exclusion criteria for subjects. [Figure 8-1] Figure 8 (Table 1B) shows the baseline demographic and clinical characteristics in the intention-to-treat population. [Figure 8-2] Figure 8 (Table 1B) shows the baseline demographic and clinical characteristics in the intention-to-treat population. [Figure 8-3] Figure 8 (Table 1B) shows the baseline demographic and clinical characteristics in the intention-to-treat population. [Figure 9-1] FIG. 9 (Table 2) shows the reduction in annualized asthma exacerbation rate and change from baseline in FEV1, ACQ and AQLQ in eosinophil subpopulations <250 cells / μl and ≧250 cells / μl. [Figure 9-2] FIG. 9 (Table 2) shows the reduction in annualized asthma exacerbation rate and change from baseline in FEV1, ACQ and AQLQ in eosinophil subpopulations <250 cells / μl and ≧250 cells / μl. [Figure 9-3] FIG. 9 (Table 2) shows the reduction in annualized asthma exacerbation rate and change from baseline in FEV1, ACQ and AQLQ in eosinophil subpopulations <250 cells / μl and ≧250 cells / μl. [Figure 10] Figure 10 (Table 3) shows the change from baseline in ACQ-6 (week 50) and AQLQ(S)+12 (week 48) for the intention-to-treat population. [Figure 11-1] Figure 11 (Table 4) shows the reduction in annualized asthma exacerbation rate and change from baseline in FEV1 (Week 52), ACQ-6 (Week 50), and AQLQ(S)+12 (Week 48) in patient subpopulations: Th2 status, serum periostin. [Figure 11-2] Figure 11 (Table 4) shows the reduction in annualized asthma exacerbation rate and change from baseline in FEV1 (Week 52), ACQ-6 (Week 50), and AQLQ(S)+12 (Week 48) in patient subpopulations: Th2 status, serum periostin. [Figure 11-3] Figure 11 (Table 4) shows the reduction in annualized asthma exacerbation rate and change from baseline in FEV1 (Week 52), ACQ-6 (Week 50), and AQLQ(S)+12 (Week 48) in patient subpopulations: Th2 status, serum periostin. [Figure 11-4] Figure 11 (Table 4) shows the reduction in annualized asthma exacerbation rate and change from baseline in FEV1 (Week 52), ACQ-6 (Week 50), and AQLQ(S)+12 (Week 48) in patient subpopulations: Th2 status, serum periostin. [Figure 11-5] Figure 11 (Table 4) shows the reduction in annualized asthma exacerbation rate and change from baseline in FEV1 (Week 52), ACQ-6 (Week 50), and AQLQ(S)+12 (Week 48) in patient subpopulations: Th2 status, serum periostin. [Figure 12-1]Figure 12 (Table 5) shows the reduction in annualized asthma exacerbation rate and change from baseline in FEV1 (Week 52), ACQ-6 (Week 50), and AQLQ(S)+12 (Week 48) in patient subpopulations: FENO, allergic status, current post-BD reversibility. [Figure 12-2] Figure 12 (Table 5) shows the reduction in annualized asthma exacerbation rate and change from baseline in FEV1 (Week 52), ACQ-6 (Week 50), and AQLQ(S)+12 (Week 48) in patient subpopulations: FENO, allergic status, current post-BD reversibility. [Figure 12-3] Figure 12 (Table 5) shows the reduction in annualized asthma exacerbation rate and change from baseline in FEV1 (Week 52), ACQ-6 (Week 50), and AQLQ(S)+12 (Week 48) in patient subpopulations: FENO, allergic status, current post-BD reversibility. [Figure 12-4] Figure 12 (Table 5) shows the reduction in annualized asthma exacerbation rate and change from baseline in FEV1 (Week 52), ACQ-6 (Week 50), and AQLQ(S)+12 (Week 48) in patient subpopulations: FENO, allergic status, current post-BD reversibility. [Figure 12-5] Figure 12 (Table 5) shows the reduction in annualized asthma exacerbation rate and change from baseline in FEV1 (Week 52), ACQ-6 (Week 50), and AQLQ(S)+12 (Week 48) in patient subpopulations: FENO, allergic status, current post-BD reversibility. [Figure 12-6] Figure 12 (Table 5) shows the reduction in annualized asthma exacerbation rate and change from baseline in FEV1 (Week 52), ACQ-6 (Week 50), and AQLQ(S)+12 (Week 48) in patient subpopulations: FENO, allergic status, current post-BD reversibility. [Figure 12-7] Figure 12 (Table 5) shows the reduction in annualized asthma exacerbation rate and change from baseline in FEV1 (Week 52), ACQ-6 (Week 50), and AQLQ(S)+12 (Week 48) in patient subpopulations: FENO, allergic status, current post-BD reversibility. [Figure 13-1]Figure 13 (Table 6) shows the change from baseline in post-BD FEV1 and pre- and post-BD forced vital capacity at week 52 in the intention-to-treat population. [Figure 13-2] Figure 13 (Table 6) shows the change from baseline in post-BD FEV1 and pre- and post-BD forced vital capacity at week 52 in the intention-to-treat population. [Figure 13-3] Figure 13 (Table 6) shows the change from baseline in post-BD FEV1 and pre- and post-BD forced vital capacity at week 52 in the intention-to-treat population. [Figure 14-1] Figure 14 (Table 7) shows the annualized rate of severe asthma exacerbations, time to first asthma exacerbation / severe asthma exacerbation, and proportion of patients with ≥1 asthma exacerbation at week 52 in the intention-to-treat population. [Figure 14-2] Figure 14 (Table 7) shows the annualized rate of severe asthma exacerbations, time to first asthma exacerbation / severe asthma exacerbation, and proportion of patients with ≥1 asthma exacerbation at week 52 in the intention-to-treat population. [Figure 14-3] Figure 14 (Table 7) shows the annualized rate of severe asthma exacerbations, time to first asthma exacerbation / severe asthma exacerbation, and proportion of patients with ≥1 asthma exacerbation at week 52 in the intention-to-treat population. [Figure 15] Figure 15 (Table 8) is a post-hoc analysis of the reduction in annualized asthma exacerbation rate through week 52 stratified by blood eosinophil count <400 cells / μl vs. ≧400 cells / μl. [Figure 16-1] Figure 16 (Table 9) shows the reduction in annualized asthma exacerbation rate through week 52, stratified by patients on medium or high dose inhaled glucocorticoid therapy and patients on maintenance oral glucocorticoid therapy. [Figure 16-2] Figure 16 (Table 9) shows the reduction in annualized asthma exacerbation rate through week 52, stratified by patients on medium or high dose inhaled glucocorticoid therapy and patients on maintenance oral glucocorticoid therapy. [Figure 17-1]Figure 17 (Table 10) shows the reduction in annualized asthma exacerbation rate through week 52, stratified by number of previous asthma exacerbations and smoking history*. [Figure 17-2] Figure 17 (Table 10) shows the reduction in annualized asthma exacerbation rate through week 52, stratified by number of previous asthma exacerbations and smoking history*. [Figure 18-1] Figure 18 (Table 11) shows the change from baseline in Medimmune ASMA scores at week 52. [Figure 18-2] Figure 18 (Table 11) shows the change from baseline in Medimmune ASMA scores at week 52. [Figure 18-3] Figure 18 (Table 11) shows the change from baseline in Medimmune ASMA scores at week 52. [Figure 18-4] Figure 18 (Table 11) shows the change from baseline in Medimmune ASMA scores at week 52. [Figure 19-1] Figure 19 (Table 12) shows all treatment-emergent serious adverse events in the as-treated population. [Figure 19-2] Figure 19 (Table 12) shows all treatment-emergent serious adverse events in the as-treated population. [Figure 19-3] Figure 19 (Table 12) shows all treatment-emergent serious adverse events in the as-treated population. [Figure 19-4] Figure 19 (Table 12) shows all treatment-emergent serious adverse events in the as-treated population. [Figure 19-5] Figure 19 (Table 12) shows all treatment-emergent serious adverse events in the as-treated population. DETAILED DESCRIPTION OF THE INVENTION

[0051] The use of anti-TSLP antibodies addresses an unmet need in asthma patients whose moderate-to-severe asthma cannot be controlled with other medications. For example, the anti-TSLP antibody tezepelumab can reduce exacerbations in both low-eosinophil (EOS) and high-eosinophil (EOS) patients. Furthermore, treatment with tezepelumab may eliminate daily disease activity, enabling more patients to become steroid-free or reducing the need for steroids in asthma treatment.

[0052] definition Unless otherwise stated, the following terms used in this Application, including the specification and claims, have the definitions given below.

[0053] As used in the specification and the appended claims, the indefinite articles "a" and "an" and the definite article "the" include plural and singular referents unless the context clearly dictates otherwise.

[0054] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. The following references provide those of ordinary skill in the art with general definitions of many of the terms used in this disclosure, but are not limited to: Singleton et al., DICTIONARY OF MICROBIOLOGY AND MOLECULAR BIOLOGY (2d Ed. 1994); THE CAMBRIDGE DICTIONARY OF SCIENCE AND TECHNOLOGY (Walker Ed., 1988); THE GLOSSARY OF GENETICS, 5th Ed., R. Riegeret al. (Eds.), Springer Verlag (1991); and Hale & Marham, THE HARPER COLLINS DICTIONARY OF BIOLOGY (1991).

[0055] The term "about" or "approximately" refers to an acceptable error for a particular value as determined by one of ordinary skill in the art, which depends in part on how the value is measured or determined. In certain embodiments, the term "about" or "approximately" means within 1, 2, 3, or 4 standard deviations. In certain embodiments, the term "about" or "approximately" means within 30%, 25%, 20%, 15%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.5%, or 0.05% of a given value or range. Whenever the term "about" or "approximately" precedes a first value in a series of two or more values, it is understood that the term "about" or "approximately" applies to each of the values ​​in the series.

[0056] As used herein, the term "asthma" refers to allergic, non-allergic, eosinophilic, and non-eosinophilic asthma.

[0057] As used herein, the term "allergic asthma" refers to asthma induced by one or more inhaled allergens. Such patients have positive IgE fluorescent enzyme immunoassay (FEIA) levels to one or more allergens that induce an asthmatic response.

[0058] Most allergic asthma is usually associated with Th2-type inflammation.

[0059] The term "non-allergic asthma" refers to patients who have low eosinophils, low Th2, or low IgE at the time of diagnosis. Patients with "non-allergic asthma" usually have a negative IgE fluorescent enzyme immunoassay (FEIA), which reacts to an allergen panel that includes allergens specific to the region. In addition to low IgE, these patients often have low or no eosinophil counts and low Th2 counts at the time of diagnosis.

[0060] As used herein, the term "severe asthma" refers to asthma that requires intensive treatment (e.g., GINA Steps 4 and 5) to maintain good control or that does not achieve good control despite intensive treatment (GINA, Global Strategy for Asthma Management and Prevention. Global Initiative for Asthma (GINA) December 2012).

[0061] As used herein, the term "eosinophilic asthma" refers to asthma patients with a screening blood eosinophil count of ≧250 cells / μL. "Hypoeosinophilic" asthma refers to asthma patients with blood or serum counts of less than 250 cells / uL.

[0062] As used herein, the term "Th2-type inflammation" refers to subjects with a screening blood eosinophil count of ≧140 cells / μL and a screening total serum IgE level of >100 IU / mL (Corren et al, N Engl J Med. 22;365(12):1088-98, 2011). A "high Th2" asthma population or profile refers to subjects with IgE >100 IU / mL and a blood eosinophil count of ≧140 cells / μL. A "low Th2" asthma population refers to subjects with IgE <100 IU / mL and a blood eosinophil count ≦140 cells / μL.

[0063] As used herein, "high FeNO" (exhaled nitric oxide concentration) refers to a baseline FeNO measurement equal to or greater than the median for all randomized subjects in the study. High FeNO refers to an FeNO level of 24 or greater.

[0064] As used herein, the term "high serum periostin levels" refers to patients with baseline serum periostin levels equal to or greater than the median for all randomized subjects in a study. Periostin has been shown to be involved in certain aspects of allergic inflammation, including eosinophil recruitment, airway remodeling, and development of a Th2 phenotype (Li et al., Respir Res. 16(1):57, 2015).

[0065] As used herein, the term "current forced expiratory volume in 1 second (FEV1) reversibility after a bronchodilator (BD)" refers to a post-BD change in FEV1 of ≧12% and ≧200 mL.

[0066] As used herein, the term "asthma exacerbation" refers to a worsening of asthma resulting in any of the following: use of systemic corticosteroids for at least three days; a single depot injection dose of corticosteroids is considered equivalent to a three-day course of systemic corticosteroids; subjects receiving maintenance OCS are eligible for a temporary doubling of the maintenance dose for at least three days; an emergency room visit for asthma that required systemic corticosteroids (as above); or hospitalization for asthma. Additional measures related to asthma exacerbations have also been tested to determine efficacy. These include asthma exacerbation-related hospitalization (i.e., severe asthma exacerbation), time to first asthma exacerbation, and the proportion of subjects with one or more asthma exacerbations / severe asthma exacerbations.

[0067] The term "asthma exacerbation" refers to new or increased symptoms and / or signs (laboratory or pulmonary function) that may be related to the subject (subject-driven) or to daily asthma diary alerts via the ePRO device (diary-driven). Thresholds for asthma exacerbation include a ≥ 30% decrease in morning peak flow compared to baseline on at least two of three consecutive days (the last seven days of the run-in period), and / or a ≥ 50% increase in rescue medication compared to average use in the previous week (at least two more puffs or one new or additional beta-2 agonist inhalation) on at least two of three consecutive days, and / or nighttime awakenings due to asthma requiring rescue medication use on at least two of three consecutive nights, and / or an increase in the total asthma symptom score (sum of daytime [evening assessment] and nighttime [morning assessment]) of at least 2 units above the screening / run-in period average (the last 10 days of the screening / run-in period) or the highest possible score (daily score of 6) on at least two of three consecutive days.

[0068] As used herein, the term "cytokine" refers to one or more small (5-20 kD) proteins released by cells that have specific effects on cell-to-cell interaction and communication, or on cellular behavior, such as immune cell proliferation and differentiation. The functions of cytokines in the immune system include promoting the influx of circulating leukocytes and lymphocytes to sites of immunological encounter; stimulating the development and proliferation of B cells, T cells, peripheral blood mononuclear cells (PBMCs), and other immune cells; and providing antibacterial activity. Exemplary immune cytokines include, but are not limited to, IL-1, IL-2, IL-3, IL-4, IL-5, IL-6, IL-7, IL-9, IL-10, IL-12, IL-13, IL-15, IL-17A, IL-17F, IL-18, IL-21, IL-22, interferons (including IFN alpha, beta, and gamma), tumor necrosis factors (including TNF alpha, beta), transforming growth factors (including TGF alpha, beta), granulocyte colony-stimulating factor (GCSF), granulocyte-macrophage colony-stimulating factor (GMCSF), and thymic stromal lymphopoietin (TSLP).

[0069] "T helper (Th) 1 cytokines" or "Th1-specific cytokines" refer to cytokines that stimulate the T1 "Th2 cytokines" or "Th2-specific cytokines" refer to cytokines expressed (intracellularly and / or secreted) by Th2 T cells, including IL-4, IL-5, IL-13, and IL-10. "Th17 cytokines" or "Th17-specific cytokines" refer to cytokines expressed (intracellularly and / or secreted) by Th17 T cells, including IL-17A, IL-17F, IL-22, and IL-21. Certain populations of Th17 cells express IFN-g and / or IL-2 in addition to the Th17 cytokines listed herein. Polyfunctional CTL cytokines include IFN-g, TNF-g, IL-2, and IL-17.

[0070] The term "specifically binds" refers to an antibody or polypeptide that is "antigen-specific," "specific," "selective binding agent," "specific binder," "antigen target," or "immunoreactive" to the antigen and binds to the target antigen with greater affinity than other antigens of similar sequence. As used herein, the agents are considered to specifically bind to a target protein that is useful for identifying immune cell types, e.g., surface antigens (e.g., T cell receptor, CD3), cytokines (e.g., TSLP, IL-4, IL-5, IL-13, IL-17, IFN-g, TNF-a), etc. In various embodiments, an antibody specifically binds to a target antigen but can cross-react with orthologs in closely related species; for example, the antibody can be a human protein and also bind to a closely related primate protein.

[0071] The term "antibody" or "immunoglobulin" refers to a tetrameric glycoprotein consisting of two heavy chains and two light chains, each containing a variable region and a constant region. "Heavy chain" and "light chain" refer to the light and heavy chains of substantially full-length canonical immunoglobulins (see, e.g., Immunobiology, 5 th Edition (Janeway and Travers et al., Eds., 2001). Antigen-binding portions may 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.

[0072] Antibody variants include antibody fragments and antibody-like proteins with alterations in the structure of a canonical tetrameric antibody. Typically, antibody variants contain V regions with alterations in the constant regions, or alternatively, optionally by adding V regions to the constant regions in a non-canonical manner. Examples include multispecific antibodies (e.g., bispecific antibodies with extra V regions), antibody fragments capable of binding to antigen (e.g., Fab', F'(ab)2, Fv, single-chain antibodies, diabodies), biparatopic peptides and recombinant peptides containing the above, so long as they exhibit the desired biological activity.

[0073] Antibody fragments include, inter alia, Fab, Fab', F(ab'), Fv, domain antibodies (dAbs), complementarity determining region (CDR) fragments, CDR-grafted antibodies, single-chain antibodies (scFv), fragments of single-chain antibodies, chimeric antibodies, diabodies, triabodies, tetrabodies, minibodies, linear antibodies; chelating recombinant antibodies, tribodies or bibodies, intrabodies, nanobodies, small modular immunopharmaceuticals (SMIPs), antigen-binding domain immunoglobulin fusion proteins, single domain antibodies (including camelized antibodies), VHH-containing antibodies, or variants or derivatives thereof, as well as polypeptides comprising at least a portion of an immunoglobulin sufficient to confer specific antigen binding on the polypeptide, e.g., the antigen-binding portion of an antibody comprising one, two, three, four, five, or six CDR sequences, so long as the antibody retains the desired biological activity.

[0074] "Valency" refers to the number of antigen-binding sites on each antibody or antibody fragment that target an epitope. A typical full-length IgG molecule or F(ab)2 is "bivalent" in that it has two identical target-binding sites. "Monovalent" antibody fragments, such as F(ab)' or scFc, have a single antigen-binding site. Trivalent or tetravalent antigen-binding proteins can also be engineered to be multivalent.

[0075] A "monoclonal antibody" refers to an antibody obtained from a population of substantially homogeneous antibodies, i.e., the individual antibodies comprising the population are identical except for possible naturally occurring mutations that may be present in minor amounts.

[0076] The term "inhibiting TSLP activity" includes inhibition of any one or more of the following: binding of TSLP to its receptor; proliferation, activation, or differentiation of TSLPR-expressing cells in the presence of TSLP; inhibition of Th2 cytokine production in a polarization assay in the presence of TSLP; activation or maturation of dendritic cells in the presence of TSLP; and mast cell cytokine release in the presence of TSLP. See, e.g., U.S. Pat. No. 7,982,016 B2, column 6 and Example 8, and U.S. Patent Application Publication No. 2012 / 0020988 A1, Examples 7-10.

[0077] The term "sample" or "biological sample" refers to a specimen obtained from a subject for use in the present methods, and includes urine, whole blood, plasma, serum, saliva, sputum, tissue biopsy, cerebrospinal fluid, peripheral blood mononuclear cells with in vitro stimulation, peripheral blood mononuclear cells without in vitro stimulation, intestinal lymphoid tissue with in vitro stimulation, intestinal lymphoid tissue without in vitro stimulation, intestinal lavage, bronchioloalveolar lavage, nasal wash, and induced sputum.

[0078] The terms "treat," "treating," and "treatment" refer to the temporary or permanent, partial or complete elimination, reduction, inhibition, or amelioration of the clinical symptoms, onset, 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 a given pathology, but need not eliminate every symptom 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 condition to constitute a viable prophylactic agent. It is sufficient to merely reduce the impact of the disease (e.g., by reducing the number or severity of its symptoms, or by increasing the effectiveness of another treatment, or by producing another beneficial effect), or reduce the likelihood that the disease will develop or worsen in the subject. One embodiment of the present invention relates to a method for determining the effectiveness of a treatment, comprising administering a therapeutic agent to a patient in an amount and for a time sufficient to induce a sustained improvement over baseline in an indicator reflective of the severity of a particular disorder.

[0079] The term "therapeutically effective amount" refers to an amount of a therapeutic agent effective to ameliorate or alleviate the symptoms or signs of disease associated with a disease or disorder.

[0080] asthma Asthma is a chronic inflammatory disorder of the airways. In the United States, asthma accounts for an estimated 1.1 million outpatient visits, 1.6 million emergency department visits, 444,000 hospitalizations (Defrances et al, 2008, available at http: / / www.cdc.gov / nchs / data / nhsr / nhsr005.pdf), and 3,500 deaths each year. In susceptible individuals, asthmatic inflammation causes recurrent episodes of wheezing, shortness of breath, chest tightness, and coughing. The etiology of asthma is multifactorial and involves genetic-environmental mechanisms. 1、2 It is influenced by both natural and environmental allergens, the latter being thought to be the major cause. 2、3 The majority of cases occur when a person becomes hypersensitive to an allergen (atopy). Atopy is characterized by increased Th2 cell and Th2 cytokine expression and increased IgE production. Approximately 10 million patients in the United States are thought to suffer from allergy-induced asthma. Despite available treatment options, asthma remains a major health problem. Approximately 300 million people worldwide currently suffer from asthma, and by 2020, it is expected that 400 million people will suffer from asthma (Partridge, Eur Resp Rev. 16:67-72, 2007).

[0081] Inhalation of allergens in atopic asthmatics induces several symptoms of asthma, including reversible airflow obstruction, airway hyperresponsiveness, and eosinophilic and basophilic airway inflammation. Allergen inhalation challenge has become the predominant model of asthma in many species (Bates et al., Am J Physiol Lung Cell Mol Physiol. 297(3):L401-10, 2009; Diamant et al., J Allergy Clin Immunol. 132(5):1045-1055, 2013).

[0082] Various subtypes of asthma have been identified that are resistant to steroid treatment. Eosinophils are key inflammatory cells in allergic asthma, characteristically mediated by Th2 CD4+ T cells. Neutrophilic airway inflammation is associated with corticosteroid treatment of severe asthma and can be mediated by Th1 or Th17 T cells (Mishra et al., Dis. Model. Mech. 6:877-888, 2013).

[0083] Diagnostic and assessment measures for asthma include:

[0084] Airway inflammation is assessed using a standardized single-breath exhaled nitric oxide (FeNO) test (American Thoracic Society; ATS, Am J Respir Crit Care Med. 171(8):912-30, 2005). For example, subjects inhale to total lung capacity through a NIOX MINO® Airway Inflammation Monitor and then exhale at 50 mL / sec for 10 seconds (assisted by visual and auditory cues).

[0085] Spirometry will be performed according to ATS / European Respiratory Society (ERS) guidelines (Miller et al., Eur Respir J. 26(1):153-61, 2005). For example, multiple forced expiratory efforts (at least three but no more than eight) will be performed in each spirometry session, and two best efforts that meet the ATS / ERS acceptability and reproducibility criteria will be recorded. Best efforts will be based on the highest FEV1. The maximum FEV1 of the two best efforts will be used for analysis. Both absolute measurements (for FEV1 and FVC) and percentages of predicted normal values ​​will be recorded using appropriate reference values. The highest FVC will also be reported, regardless of the effort with which it occurred (even if the effort did not result in the highest FEV1).

[0086] Post-bronchodilator (post-BD) spirometry testing is assessed after the subject has completed pre-BD spirometry. Maximal bronchodilation is induced using a SABA such as albuterol (90 μg metered dose) or salbutamol (100 μg metered dose) or equivalent spacer device for up to eight total puffs (Sorkness et al., J Appl Physiol. 104(2):394-403, 2008). The highest pre-BD and post-BD FEV1 obtained after four, six, or eight puffs is used to determine and analyze reversibility. The reversibility algorithm is as follows: % reversibility=(FEV1 after BD-FEV1 before BD)×100 / FEV1 before BD

[0087] Home peak flow testing for peak expiratory flow rate (PEFR) will be performed using a peak flow meter twice daily, in the morning upon awakening and in the evening before going to bed, from the morning of visit 2 (week 4) through week 64. If possible, outpatient pulmonary function measurements should be performed at least 6 hours after the last dose of SABA rescue medication.

[0088] The asthma diary includes daily assessments of: asthma symptoms; rescue medication inhalation; nighttime awakenings due to asthma requiring rescue medication use, asthma-related activity limitations, asthma-related stress, and background medication compliance. The asthma diary is completed every morning and evening. The ePRO device has triggers to alert the subject to signs of asthma worsening.

[0089] The Asthma Control Questionnaire (ACQ)-6 is a patient-reported questionnaire that assesses asthma symptoms (i.e., nighttime awakenings, awakening symptoms, activity limitations, shortness of breath, wheezing), daily rescue bronchodilator use, and FEV1 (Juniper et al., Oct 1999). The ACQ-6 is a shortened version of the ACQ that omits the FEV1 measurement from the original ACQ score. Questions are equally weighted and scored from 0 (completely controlled) to 6 (almost uncontrolled). The mean ACQ score is the average of the responses. A mean score of ≤0.75 indicates well-controlled asthma, a score of 0.75 to ≤1.5 indicates partially controlled asthma, and a score >1.5 indicates uncontrolled asthma (Juniper et al., Respir Med. 100(4):616-21, 2006). An individual change of at least 0.5 is considered clinically significant (Juniper et al, Respir Med. 99(5):553-8, 2005).

[0090] The Asthma Quality of Life Questionnaire, Standardized (AQLQ[S]) + 12 (AQLQ(S) + 12) is a 32-item questionnaire that assesses the HRQoL experienced by asthma patients (Juniper et al., Chest. 115(5):1265-70, May 1999). The questionnaire includes four separate domains: symptoms, activity limitations, emotional functioning, and environmental stimuli. Subjects are asked to recall their experiences over the past two weeks and score each of the 32 questions on a 7-point scale ranging from 7 (no impairment) to 1 (severe impairment). A total score is calculated as the average response to all questions. The four individual domain scores (symptoms, activity limitations, emotional functioning, and environmental stimuli) are the average of the responses to the questions in each domain. An improvement of 0.5 in both the total score and the individual domain scores was identified as a minimally important change, and a score change of ≥ 1.5 was identified as a major significant change (Juniper et al., J Clin Epidemiol. 47(1):81-7, 1994).

[0091] TSLP Thymic stromal lymphopoietin (TSLP) is an epithelial cell-derived cytokine that is produced in response to proinflammatory stimuli and drives allergic inflammatory responses primarily through its activity on dendritic cells (Gilliet, J Exp Med. 197:1059-1067, 2003; Soumelis, Nat Immunol. 3:673-680, 2002; Reche, J Immunol. 167:336-343, 2001), mast cells (Allakhverdi, J Exp Med. 204:253-258, 2007), and CD34+ progenitor cells. 9 TSLP signals through a heterodimeric receptor consisting of the interleukin (IL)-7 receptor alpha (IL-7Rα) chain and the common gamma chain-like receptor (TSLPR) (Pandey, Nat Immunol. 1:59-64, 2000; Park, J Exp Med. 192:659-669 (2000)).

[0092] Human TSLP mRNA 10、11 and protein levels 11 is increased in the airways of asthmatic individuals compared to controls, and the magnitude of this expression correlates with the severity of the disease. 10 Recent studies have demonstrated an association between single nucleotide polymorphisms in the human TSLP gene locus and protection from asthma, atopic asthma, and airway hyperresponsiveness, suggesting that differential regulation of TSLP gene expression may influence disease susceptibility. 1、12、13 These data suggest that targeting TSLP may inhibit multiple biological pathways involved in asthma.

[0093] Early preclinical studies of TSLP suggested that after TSLP is released from airway epithelial or stromal cells, it activates mast cells, dendritic cells, and T cells to release Th2 cytokines (e.g., IL-4 / IL-13 / IL-5). Recently published human data showed a good correlation between tissue TSLP gene and protein expression, Th2 gene signature scores, and tissue eosinophils in severe asthma. Therefore, anti-TSLP targeted therapy may be effective for asthma patients with Th2-type inflammation (Shikotra et al., J Allergy Clin Immunol. 129(1):104-11, 2012).

[0094] Data from other studies suggest that TSLP may promote airway inflammation through Th2-independent pathways, such as crosstalk between airway smooth muscle and mast cells (Allakhverdi et al., J Allergy Clin Immunol. 123(4):958-60, 2009; Shikotra et al., supra). TSLP may also promote the induction of T cells to differentiate into Th-17 cytokine-producing cells, resulting in increased neutrophilic inflammation commonly seen in more severe asthma (Tanaka et al., Clin Exp Allergy. 39(1):89-100, 2009). These data and other emerging evidence suggest that blocking TSLP may help suppress multiple biological pathways, including, but not limited to, those involving Th2 cytokines (IL-4 / IL-13 / IL-5).

[0095] antibody Antibodies or antibody variants specific for TSLP are believed to be useful in the treatment of asthma, including severe asthma, eosinophilic asthma, non-eosinophilic / hypoeosinophilic asthma, and other forms of asthma described herein.

[0096] Specific binding agents, such as antibodies and antibody variants or fragments, that bind to a target antigen, e.g., TSLP, are useful in the methods of the invention. In one embodiment, the specific binding agent is an antibody. The antibody can be monoclonal (MAb); recombinant; chimeric; humanized, such as complementarity-determining region (CDR)-grafted; human; antibody variants, including single chain; and / or bispecific; as well as fragments, variants, or derivatives thereof. Antibody fragments include those portions of an antibody that bind to an epitope on a polypeptide of interest. Examples of such fragments include Fab and F(ab') fragments generated by enzymatic cleavage of full-length antibodies. Other binding fragments include fragments generated by recombinant DNA techniques, such as expression of recombinant plasmids containing nucleic acid sequences encoding antibody variable regions.

[0097] 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 to or homologous to corresponding sequences in antibodies derived from a particular species or belonging to a particular antibody class or subclass, while the remainder of the chain is identical to or homologous to corresponding sequences in antibodies derived from another species or belonging to another antibody class or subclass. Fragments of such antibodies are also included, so long as they exhibit the desired biological activity. See U.S. Pat. No. 4,816,567; Morrison et al., 1985, Proc. Natl. Acad. Sci. 81:6851-55.

[0098] In another embodiment, the monoclonal antibody is a "humanized" antibody. Methods for humanizing non-human antibodies are well known in the art. See U.S. Patent Nos. 5,585,089 and 5,693,762. Generally, a humanized antibody has one or more amino acid residues introduced into it from a non-human source. Humanization can be performed, for example, by substituting at least a portion of a rodent complementarity-determining region for the corresponding region of a human antibody 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).

[0099] Human antibodies and antibody variants (including antibody fragments) that bind to TSLP are also encompassed by the present invention. Using transgenic animals (e.g., mice) capable of producing a repertoire of human antibodies without endogenous immunoglobulin production, such antibodies can be produced by immunization with a polypeptide antigen (i.e., having at least six consecutive amino acids), optionally conjugated to a carrier. See, e.g., Jakobovits et al., 1993, Proc. Natl. Acad. Sci. 90:2551-55; Jakobovits et al., 1993, Nature 362:255-58; Bruggermann et al., 1993, Year in Immuno. 7:33. See also PCT Application Nos. PCT / US96 / 05928 and PCT / US93 / 06926. Further methods are described in U.S. Patent No. 5,545,807, PCT Applications Nos. PCT / US91 / 245 and PCT / GB89 / 01207, and EP 546073B1 and EP 546073A1. Human antibodies can also be produced by the expression of recombinant DNA in host cells or by expression in hybridoma cells as described herein.

[0100] Chimeric, CDR-grafted, and humanized antibodies and / or antibody variants are typically produced by recombinant methods. Nucleic acid encoding the antibody is introduced into a host cell and expressed using the materials and procedures described herein. In a preferred embodiment, the antibody is produced in a mammalian host cell, such as a CHO cell. Monoclonal (e.g., human) antibodies can be produced by expression of recombinant DNA in a host cell or by expression in hybridoma cells as described herein.

[0101] Antibodies and antibody variants (including antibody fragments) useful in the present methods include anti-TSLP antibodies, which comprise a light chain variable domain comprising: 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 bi. 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 variable domain comprising the heavy chain CDR3 sequence comprising the amino acid sequence set forth in SEQ ID NO: 8, and this antibody or antibody variant specifically binds to the TSLP polypeptide set forth in amino acids 29 to 159 of SEQ ID NO: 2.

[0102] ai. an amino acid sequence having at least 80% identity to 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 complement of a polynucleotide consisting of SEQ ID NO: 11; and bi. an amino acid sequence having at least 80% identity to 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. a heavy chain variable domain selected from the group consisting of amino acid sequences encoded by a polynucleotide that hybridizes under moderately stringent conditions to the complement of a polynucleotide consisting of SEQ ID NO: 9; or c. an antibody or antibody variant comprising the light chain variable domain of (a) and the heavy chain variable domain of (b), which antibody or antibody variant specifically binds to the TSLP polypeptide represented by amino acids 29 to 159 of SEQ ID NO: 2.

[0103] Tezepelumab is an exemplary anti-TSLP antibody having a heavy chain variable domain comprising: 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 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;

[0104] Tezepelumab also comprises a light chain variable domain having the amino acid sequence set forth in SEQ ID NO:12, which is encoded by the polynucleotide sequence set forth in SEQ ID NO:11; and a heavy chain variable domain having the amino acid sequence set forth in SEQ ID NO:10, which is encoded by the polynucleotide sequence set forth in SEQ ID NO:9.

[0105] Tezepelumab is an IgG2 antibody. The full-length heavy and light chain sequences of tezepelumab, including the IgG2 chain, are set forth in SEQ ID NOs: 105 and 106, respectively.

[0106] 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 bispecific antibody, a trispecific antibody, a tetraspecific antibody, a Fab fragment, an IgG1 antibody, an IgG2 antibody, an IgG3 antibody, and an IgG4 antibody.

[0107] In various embodiments, the anti-TSLP antibody variant is selected from the group consisting of a diabody, a triabody, a tetrabody, a Fab fragment, a single domain antibody, and an scFv, and the dosage is adjusted so that the binding sites are equimolar to that administered by the bivalent antibody.

[0108] The antibody or antibody variant is considered to be an IgG2 antibody. An exemplary sequence of a human IgG2 constant region is available from the Uniprot database as Uniprot number P01859, and is incorporated herein by reference. Information, including sequence information, for the heavy and light chain constant regions of other antibodies is also publicly available via the Uniprot database and other databases familiar to those skilled in the art of antibody engineering and production.

[0109] In certain embodiments, antibody derivatives include tetrameric glycosylated antibodies in which the number and / or type of glycosylation sites are altered compared to the amino acid sequence of the parent polypeptide. In certain embodiments, the variants contain more or fewer N-linked glycosylation sites than the native protein. Alternatively, substitutions that delete this sequence remove existing N-linked carbohydrate chains. Also provided are rearrangements of N-linked carbohydrate chains, in which one or more N-linked glycosylation sites (typically those of natural origin) are deleted and one or more new N-linked sites are created. Further preferred antibody variants include cysteine ​​variants in which one or more cysteine ​​residues have been deleted or substituted with another amino acid (e.g., serine) 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, usually an even number to minimize interactions resulting from unpaired cysteines.

[0110] Desired amino acid substitutions (whether conservative or non-conservative) can be determined by one of skill in the art at the time such substitutions are desired. In certain embodiments, amino acid substitutions can be used to identify key residues of antibodies to human TSLP or to increase or decrease the affinity of the antibodies to human TSLP described herein.

[0111] According to certain embodiments, preferred amino acid substitutions are those that (1) reduce susceptibility to proteolysis, (2) reduce susceptibility to oxidation, (3) alter binding affinity for forming protein complexes, (4) alter binding affinity, and / or (5) confer or modify other physiochemical or functional properties to such polypeptides. According to certain embodiments, single or multiple amino acid substitutions (in certain embodiments, conservative amino acid substitutions) may be made in the naturally occurring sequence (in certain embodiments, in portions of the polypeptide outside the domains that form intermolecular contacts). In certain embodiments, conservative amino acid substitutions typically may not substantially alter the structural features of the parent sequence (e.g., the substituted amino acid will not tend to disrupt helices present in the parent sequence or other types of secondary structure that characterize the parent sequence). Art-recognized examples of polypeptide secondary and tertiary structure are described in Proteins, Structures and Molecular Principles (Creighton, Ed., W.H. Freeman and Company, New York (1984)); Introduction to Protein Structure (C. Branden and J. Tooze, eds., Garland Publishing, New York, NY (1991)); and Thornton et al. Nature 354:105 (1991), each of which is incorporated herein by reference.

[0112] Administration method In one aspect, the methods of the disclosure comprise administering a therapeutic anti-TSLP antibody or antibody variant described herein, optionally in a pharmaceutically acceptable carrier or excipient. In certain embodiments, the pharmaceutical composition is a sterile composition.

[0113] Contemplated herein is a method for treating asthma in a subject, including severe asthma, eosinophilic or non-eosinophilic asthma, and hypoeosinophilic asthma.Surprisingly, it has been found herein that treatment with anti-TSLP antibodies is effective in reducing asthma symptoms in eosinophil-free / hypoeosinophilic populations, as well as in hypereosinophilic populations.Also contemplated is a method for reducing the frequency of asthma exacerbations in a subject.

[0114] Also contemplated herein are methods of treating asthma in subjects with a high Th2 asthma profile or a low Th2 asthma profile. TSLP antagonists that inhibit the binding of the TSLP protein to its receptor complex, similar to the antibodies described herein, are believed to effectively treat low eosinophilic asthma populations. Similarly, TSLP antagonists that inhibit the binding of TSLP to its receptor complex are believed to be effective in treating low Th2 asthma populations.

[0115] Provided herein are methods of treating patients with hypoeosinophilic asthma, comprising administering an anti-TSLP antibody. Also contemplated are methods of treating asthma subjects characterized by a low Th2 profile, comprising administering an anti-TSLP antibody. In various embodiments, the antibody is tezepelumab or another anti-TSLP antibody described in the art. Exemplary anti-TSLP antibodies include those described in WO 2017 / 042701, WO 2016 / 142426, WO 2010 / 017468, U.S. Patent Application Publication No. 20170066823, U.S. Patent Application Publication No. 20120020988, and U.S. Patent No. 8,637,019, all of which are incorporated by reference herein, some of which are listed in Table A below. In exemplary aspects, the anti-TSLP antibody is selected from the antibodies in Table A.

[0116] [Table 1-1]

[0117] [Table 1-2]

[0118] [Table 1-3]

[0119] [Table 1-4]

[0120] [Table 1-5]

[0121] [Table 1-6]

[0122] [Table 1-7]

[0123] Also contemplated are methods for treating chronic obstructive pulmonary disease (COPD) in a subject, comprising administering an anti-TSLP antibody or antibody variant.

[0124] The subject to be treated is considered to be a human. The subject may be an adult, an adolescent, or a child.

[0125] Therapeutic antibody (or antibody variant) compositions can be delivered to a patient at multiple sites. Multiple administrations can be given simultaneously or over a period of time. In certain cases, it is beneficial to provide a continuous flow of therapeutic composition. Additional treatments can be administered on an extended period basis, for example, hourly, daily, weekly, biweekly, triweekly, monthly, or at longer intervals.

[0126] In various embodiments, the amount of therapeutic agent in a given dose, such as a bivalent antibody having two TSLP binding sites, can vary depending on the size of the individual being treated and the characteristics of the disorder being treated.

[0127] In an exemplary treatment, the anti-TSLP antibody or antibody variant is administered in a dose range of about 70 mg to about 280 mg per daily dose. For example, doses may be administered at about 70 mg, 210 mg, or 280 mg. In various embodiments, the anti-TSLP antibody or antibody variant may be administered at a dose of 70, 80, 90, 100, 110, 120, 130, 140, 150, 160, 10, 180, 190, 200, 210, 220, 230, 240, 250, 260, 270, or 280 mg per administration. These concentrates may be administered in single or multiple doses. The above doses may be administered every two weeks or every four weeks. In various embodiments, the anti-TSLP antibody or antibody variant is administered in a single 70 mg dose every two weeks or every four weeks. In various embodiments, the anti-TSLP antibody or antibody variant is administered in a single dose of 210 mg every two weeks or every four weeks. In various embodiments, the anti-TSLP antibody or antibody variant is administered in a single dose of 280 mg every two weeks or every four weeks.

[0128] For antibody variants, the amount of antibody variant should be such that the number of TSLP binding sites present in a dose has an equimolar number of TSLP binding sites relative to the canonical bivalent antibody described above.

[0129] It is contemplated that the anti-TSLP antibody or antibody variant is administered every two weeks or every four weeks for at least four months, six months, nine months, one year, or more. In various embodiments, administration is subcutaneous or intravenous.

[0130] Treatment with an anti-TSLP antibody or antibody variant is believed to reduce eosinophils in a subject's blood, sputum, bronchoalveolar fluid, or lungs. Administration is also believed to shift a subject's cell count from a high Th2 population to a low Th2 population. Furthermore, administration of an anti-TSLP antibody or antibody variant is believed to improve one or more measures of asthma in a subject selected from the group consisting of forced expiratory volume (FEV), FEV1 reversibility, forced vital capacity (FVC), FeNO, Asthma Control Questionnaire-6 score, and AQLQ(S)+12 score.

[0131] Improvement in asthma may be assessed as one or more of the following: reduction in AER (annualized exacerbation rate), reduction in asthma hospitalizations / severe exacerbations, change (increase) from baseline in time to first asthma exacerbation (after initiation of treatment with anti-TSLP antibody), reduction in the proportion of subjects with one or more asthma exacerbations or severe exacerbations compared to placebo over the course of treatment, e.g., 52 weeks, change (increase) from baseline in FEV1 and FVC (pre-bronchodilator and post-bronchodilator), change (decrease) in blood or sputum eosinophils (or lung eosinophils if biopsy or BAL fluid is available) from baseline, change (decrease) in FeNO from baseline, change (decrease) in IgE from baseline, improvement in asthma symptoms and control as assessed by the ACQ and variants, AQLQ and variants, SGRQ, and asthma symptom diary PRO, change (decrease) in SGRQ, rescue medication use, reduction in systemic corticosteroid use, reduction in blood Th2 / Th1 cell ratio. Most / all of these assessments should be in the overall population and subpopulations, including high and low eosinophils (high >250, low <250), allergic and non-allergic, high and low Th2, high and low periostin (relative to the median), and high and low FeNO (high >24 or low <24).

[0132] Treatment also improves one or more asthma symptoms as assessed by an asthma symptom diary, including, but not limited to, daytime and nighttime symptom frequency and severity, activity avoidance and limitation, asthma-related stress and fatigue, and use of rescue asthma medications, and other measures of asthma control as assessed by the Asthma Control Questionnaire (ACQ-6) with abbreviated FEV1.

[0133] In various embodiments, treatment with an anti-TSLP antibody delays the time to asthma exacerbation compared to subjects not receiving the anti-TSLP antibody.

[0134] The present disclosure also contemplates the administration of multiple agents, such as an antibody composition in combination with a second agent described herein, including, but not limited to, an anti-inflammatory agent or an asthma treatment.

[0135] However, in various embodiments, its administration is expected to reduce the frequency or level of concurrent therapy in a subject. Exemplary concurrent therapies include, but are not limited to, inhaled corticosteroids (ICS), long-acting beta-agonists (LABAs), leukotriene receptor antagonists (LTRAs), long-acting antimuscarinics (LAMAs), chromones, short-acting beta-agonists (SABAs), and theophylline or oral corticosteroids. In various embodiments, its administration eliminates the need for corticosteroid therapy.

[0136] formulation In some embodiments, the present disclosure contemplates the use of pharmaceutical compositions comprising a therapeutically effective amount of an anti-TSLP antibody or antibody variant, together with a pharmaceutically acceptable diluent, carrier, solubilizer, emulsifier, preservative, and / or adjuvant. Additionally, the present disclosure provides methods of treating a subject by administering such pharmaceutical compositions.

[0137] In certain embodiments, acceptable formulation materials are preferably nontoxic to recipients at the dosages and concentrations employed. In certain embodiments, pharmaceutical compositions may contain formulation materials to modify, maintain, or preserve, for example, the pH, osmolality, viscosity, clarity, color, isotonicity, odor, sterility, stability, dissolution or release rate, adsorption, or permeability of the composition. In such embodiments, suitable formulation materials include amino acids (such as glycine, glutamine, asparagine, arginine, or lysine); antimicrobial agents; antioxidants (such as ascorbic acid, sodium sulfite, or sodium bisulfite); buffers (such as borate, bicarbonate, Tris-HCl, citrate, phosphate, 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, mannose, or dextrin); proteins (such as serum albumin, gelatin, or immunoglobulins); colors, flavors, and diluents; emulsifiers; hydrophilic polymers (such as polyvinylpyrrolidone); low molecular weight polypeptides; salt formation agents. These include, but are not limited to, counterions (such as sodium); preservatives (such as benzalkonium chloride, benzoic acid, salicylic acid, thimerosal, phenethyl alcohol, methylparaben, propylparaben, 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 esters, polysorbate 20, polysorbates, Triton, tromethamine, lecithin, cholesterol, tyloxapar); stability enhancers (such as sucrose or sorbitol); tonicity enhancers (such as alkali metal halides, preferably sodium or potassium chloride, mannitol, sorbitol, etc.); delivery vehicles; diluents; excipients and / or pharmaceutical adjuvants.See REMINGTON'S PHARMACEUTICAL SCIENCES, 18th Edition, (AR Genrmo, ed.), 1990, Mack Publishing Company.

[0138] Suitable vehicles or carriers may be water for injection, saline, or artificial cerebrospinal fluid, which may be supplemented with other materials common in compositions for parenteral administration. Neutral buffered saline or saline mixed with serum albumin are further exemplary vehicles. In certain embodiments, the pharmaceutical composition comprises Tris buffer of about pH 7.0-8.5 or acetate buffer of about pH 4.0-5.5, and may further include sorbitol or a suitable substitute thereof.

[0139] Formulation components are preferably present in concentrations that are acceptable to the site of administration. In certain embodiments, buffering agents are used to maintain the composition at physiological pH or slightly lower, typically within a pH range of about 5 to about 8, including 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.

[0140] In various embodiments, the anti-TSLP antibody or antibody variant is present in a formulation containing sodium acetate and one or more of proline, sucrose, polysorbate 20, or polysorbate 80. In various embodiments, the formulation has a pH of 4.9 to 6.0 and contains 1 to 50 mM sodium acetate, 3 to 9% (wt / vol) sucrose, and 0.015% (wt / vol) ± 0.005% (wt / vol) polysorbate 20 or polysorbate 80. Optionally, the antibody or antibody fragment is at a concentration of 70 mg / ml. The formulation may be stored at -20°C to -70°C.

[0141] When parenteral administration is contemplated, the therapeutic composition for use may be provided in the form of a pyrogen-free, parenterally acceptable aqueous solution containing the desired anti-TSLP antibody in a pharmaceutically acceptable vehicle. A particularly suitable vehicle for parenteral injection is sterile distilled water, in which the antibody is formulated as a properly preserved, sterile, isotonic solution. In certain embodiments, the preparation may involve formulation of the desired molecule with an agent, such as injectable microspheres, biodegradable particles, polymeric compounds (such as polylactic acid or polyglycolic acid), beads, or liposomes, which may provide sustained or sustained release of the product, which may be delivered via depot injection. In certain embodiments, hyaluronic acid, which has the effect of enhancing duration in the circulation, may also be used. In certain embodiments, an implantable drug delivery device may be used to introduce the antibody. [Example]

[0142] This anti-TSLP antibody is the first epithelial-targeted product with potential unprecedented efficacy in patients with both non-eosinophilic and eosinophilic asthma. The high EOS population comprises approximately 50-70% of patients with severe asthma.

[0143] This example describes a multicenter, placebo-controlled, parallel-group, double-blind, Phase 2 study conducted at 108 study sites across 12 countries. Eligible patients were 18-75 years of age and had received either medium-dose (250-500 μg daily fluticasone by dry powder inhaler or equivalent) or high-dose (>500 μg daily fluticasone by dry powder inhaler or equivalent) inhaled glucocorticoids (severe asthma) at least 6 months prior to enrollment. 24Patients were current nonsmokers (≥6 months, <10 pack-year smoking history) with inadequately controlled asthma despite combined treatment with a LABA (per the GINA 2012 guidelines defining asthma). Patients were also required to have a history of at least two asthma exacerbations leading to systemic glucocorticoid treatment or one severe exacerbation leading to hospitalization within the 12 months prior to study entry. Additional eligibility criteria included a pre-bronchodilator forced expiratory volume in 1 second (FEV1) of at least 40% and ≤80% predicted, a post-bronchodilator reversibility of at least 12% and at least 200 ml, and a 6-item Asthma Control Questionnaire (ACQ-6) score of at least 1.5 during screening (range 0–6, with lower scores indicating better disease control; minimal clinically important difference is 0.5). 26 Exclusion criteria included clinically significant lung disease other than asthma. A complete list of inclusion and exclusion criteria is shown in Table 1A.

[0144] Patients were randomly assigned (in a 1:1:1:1 ratio) to receive one of three different doses of subcutaneous (SC) tezepelumab (a bivalent antibody with a binding site identical to TSLP) or placebo according to a central interactive voice response or web response system. Randomization was stratified by location (Japan or other parts of the world), blood eosinophil count measured in the local laboratory (≥250 cells / μl or <250 cells / μl), and dose level of inhaled glucocorticoid (medium or high based on the GINA 2012 guidelines). 26 Patients receiving oral glucocorticoid maintenance therapy were assigned to the high-dose inhaled glucocorticoid stratum. Tezepelumab and placebo were prepared by site staff who were aware of the study group assignment and were not involved in the study evaluation. The study medications were similar in appearance and were administered by staff who were unaware of the study group assignment. Background asthma control medication was maintained at a stable dose throughout the treatment period.

[0145] procedure Patients were assigned to receive tezepelumab 70 mg every 4 weeks (Q4W, low dose), 210 mg Q4W (medium dose), or 280 mg every 2 weeks (Q2W, high dose) administered SC throughout the study, or placebo Q2W. To maintain blinding, patients randomized to the Q4W regimen received placebo at interim visits.

[0146] Pre- and post-bronchodilator exhaled nitric oxide (Fe ) concentrations were measured throughout the 5-week screening period. NO Baseline measurements were obtained for spirometry assessment of asthma (asthma spirometry), blood eosinophil count, ACQ-6 score, and Asthma Quality of Life Questionnaire (Standardized) (AQLQ[S]+12 [hereafter referred to as AQLQ]) 27 scores for people aged 12 years and older. ACQ-6 score, AQLQ score, and asthma symptom score (reflecting daytime severity, daytime frequency, and nighttime severity; ranging from 0 [no symptoms] to 4 [worst possible symptoms]) were recorded electronically. Safety was monitored at each study site from enrollment through the 64-week follow-up.

[0147] Endpoints and Evaluation The primary efficacy endpoint was the annualized asthma exacerbation rate (AER) at week 52. An asthma exacerbation was defined as a worsening of asthma symptoms that led to either: 1) the use of systemic glucocorticoids (oral or injectable) or, in the case of stable maintenance therapy with oral glucocorticoids, a doubling of the dose for 3 or more days; 2) an asthma-related emergency department visit that led to systemic glucocorticoid treatment; or 3) an asthma-related hospitalization. An asthma exacerbation was defined as any new or increased symptom or sign that was either of concern to the patient or associated with an asthma diary-driven alert.

[0148] Secondary endpoints included changes from baseline in pre- and post-bronchodilator FEV1 (increasing values ​​indicate improvement in lung function; minimal clinically important difference is 100-200 ml), ACQ-6 score, AQLQ score, asthma symptom score, and forced vital capacity (FVC), as well as the annualized rate of severe asthma exacerbations at week 52; time to first asthma exacerbation, time to first severe asthma exacerbation; percentage of patients with at least one asthma exacerbation, and percentage of patients with at least one severe asthma exacerbation.

[0149] The primary and secondary endpoints (change from baseline in pre-bronchodilator FEV1, ACQ-6 score, AQLQ score, and asthma symptom score) were also assessed by blood eosinophil count (≥250 or <250 cells per microliter), Th2 status (high [IgE level >100 IU per milliliter and blood eosinophil count ≥140 cells per microliter] or low [IgE level ≤100 IU per milliliter or blood eosinophil count <140 cells per microliter]), and eosinophil count (≥250 or <250 cells per microliter). 30 FENO levels (based on baseline median and clinically significant cutoff of 24 ppb); 31 Prespecified subpopulations were also assessed according to serum periostin levels (high or low based on median baseline levels), current (as indicated at screening) post-bronchodilator FEV1 reversibility, and allergic status (defined by a positive or negative fluorescent enzyme immunoassay for IgE at baseline).

[0150] The primary endpoint was also stratified according to the dose level of inhaled glucocorticoids (medium or high dose), the presence or absence of oral glucocorticoid maintenance therapy, and the number of asthma exacerbations in the past 12 months (prespecified subgroup analyses). Post-hoc analyses included stratification of the primary endpoint according to baseline blood eosinophil count (<400 or ≥400 cells per microliter) and patient smoking history.

[0151] statistical analysis Efficacy analyses were based on the intention-to-treat (ITT) population, consisting of patients who underwent randomization and received at least one dose of tezepelumab or placebo, and analyzed according to randomized study arm. Safety analyses were based on the as-treated population, including all patients who received at least one dose of tezepelumab or placebo, and patients were evaluated according to the study drug they received.

[0152] For the primary efficacy endpoint, to detect a 40% lower annualized asthma exacerbation rate in each tezepelumab dose group compared with the placebo group with 80% power, 138 patients per study arm were required, assuming an annualized asthma exacerbation rate of 0.7 in the placebo group and a negative binomial distribution parameter of 0.7, a two-sided alpha of 0.1, and an expected information loss due to dropouts of 10%.

[0153] The primary efficacy endpoint of annualized rate of asthma exacerbations was analyzed using a negative binomial model, with study arm, baseline blood eosinophil count (≥250 or <250 cells / μl), and baseline glucocorticoid dose level (medium or high dose) included in the model. Continuous secondary endpoints were analyzed using a mixed-effects model for repeated measures analysis. Time-to-first-event variables were analyzed using a Cox proportional hazards model. Categorical variables were analyzed using Pearson's chi-square test.

[0154] The primary endpoint was tested sequentially to control the type I overall error rate to 0.1. Strata were high-dose tezepelumab (280 mg Q2W) vs. placebo, medium-dose tezepelumab (210 mg Q4W) vs. placebo, and low-dose tezepelumab (70 mg Q4W) vs. placebo. No adjustment for multiplicity of secondary endpoints was applied. Nominal P values ​​are shown. All analyses were performed using SAS version 9.3.

[0155] result patient Analysis A, primary analysis after database lock, including all study sites: Overall, 918 subjects were screened, and 584 patients were randomized: 145 to low-dose tezepelumab (70 mg Q4W), 145 to medium-dose tezepelumab (210 mg Q4W), 146 to high-dose tezepelumab (280 mg Q2W), and 148 to placebo. Among patients receiving tezepelumab or placebo and included in the intention-to-treat population, 391 (89.7%) and 139 (93.9%) completed treatment, respectively. Baseline and clinical characteristics were similar between groups.

[0156] The dose ranges of inhaled glucocorticoids for patients at baseline are shown in Figures 2A and 2B. The median dose of fluticasone administered by dry powder inhaler or equivalent in the medium-dose inhaled glucocorticoid stratum was 400 μg per day in 73 patients in the placebo group, 71 in the low-dose tezepelumab group, 70 in the medium-dose group, and 72 in the high-dose group; the median dose of fluticasone administered by dry powder inhaler or equivalent in the high-dose inhaled glucocorticoid stratum was 1000 μg per day in 75, 74, 75, and 74 patients in the respective study groups.

[0157] Primary endpoint Treatment with tezepelumab resulted in 52-week annualized asthma exacerbation rates of 0.25, 0.18, and 0.22 in the low-, medium-, and high-dose groups, respectively, compared with 0.67 in the placebo group. Thus, exacerbation rates were 61% (90% confidence interval [CI], 39-75; P < 0.001), 72% (90% CI, 54-83; P < 0.001), and 66% (90% CI, 46-79; P < 0.001) lower in the tezepelumab group than in the placebo group, respectively (Table 2 and Figure 1A). The types of asthma exacerbations used in the primary analysis are shown in Table 1B.

[0158] Secondary endpoints The annualized asthma exacerbation rate was lower in the tezepelumab group than in the placebo group, regardless of baseline eosinophil count or other measures of Th2 status (Figure 2A; Figure 6; Table 2; Table 4, and Tables 5, 7, 9, and 10). Among patients in the medium-dose inhaled glucocorticoid stratum, low-, medium-, and high-dose tezepelumab resulted in annualized asthma exacerbation rates of 0.19, 0.14, and 0.20 exacerbations at week 52, respectively, compared with 0.37 exacerbations with placebo. These rates in the tezepelumab group were 49% (95% CI, -14 to 77; P = 0.10), 62% (95% CI, 8 to 84; P = 0.03), and 47% (95% CI, 41 to 76; P = 0.13) lower than those in the placebo group, respectively. Among patients in the high-dose inhaled glucocorticoid stratum, low-, medium-, and high-dose tezepelumab resulted in annualized asthma exacerbation rates of 0.32, 0.23, and 0.24 exacerbations at week 52, respectively, compared with 0.96 exacerbations with placebo. These rates in the tezepelumab groups were 67% (95% CI, 35-84; P = 0.002), 76% (95% CI, 49-89; P < 0.001), and 75% (95% CI, 47-88; P < 0.001) lower than those in the placebo group (Table 9). When patients were stratified according to the number of asthma exacerbations in the past 12 months, annualized asthma exacerbation rates were lower in some, but not all, tezepelumab groups than in the placebo group, and this remained true in post-hoc analyses according to smoking history (Table 10).

[0159] The time to first asthma exacerbation was longer in the tezepelumab group than in the placebo group. The risk of an exacerbation was 35% (hazard ratio [HR] 0.65, 95% CI 0.40, 1.04; P = 0.07), 53% (HR 0.47, 95% CI 0.28, 0.80; P = 0.004), and 43% (HR 0.57, 95% CI 0.35-0.93; P = 0.02) lower in the low-, medium-, and high-dose tezepelumab groups, respectively, compared with the placebo group (Figure 3 and Table 7).

[0160] In the overall population, the change from baseline in pre-BD FEV1 at week 52 was 0.12 L (95% CI 0.02-0.21, P = 0.01), 0.111 L (95% CI 0.02-0.21, P = 0.02), and 0.15 L (95% CI 0.06-0.25, P = 0.002) greater in the low-, medium-, and high-dose tezepelumab groups than in the placebo group, respectively (Table 2 and Figure 1B). Similar differences were observed when pre-BD FEV1 was measured as a percent of predicted (Table 2). Treatment effects were observed as early as week 4 (the first time point assessed) and sustained throughout the study (Figure 1B, Table 2).

[0161] The effect of tezepelumab on additional secondary endpoints, including the percentage of patients with at least one asthma exacerbation, the percentage of patients with at least one severe asthma exacerbation, the annualized rate of severe asthma exacerbations, the time to first severe asthma exacerbation, and the change from baseline in post-bronchodilator FEV1, FVC, ACQ-6 score, AQLQ score, and asthma symptom score, are shown in Table 2 and Figures 1C and 1D, and Tables 3, 5, 6, and 12. The effect of tezepelumab on secondary endpoints by subgroup (pre-bronchodilator FEV1, ACQ-6 score, AQLQ score, asthma symptom score) is shown in Tables 2, 4, 5, and 12.

[0162] Biomarkers Substantial and sustained reductions in blood eosinophils and FeNO were observed in all tezepelumab-treated groups, beginning at week 4 (the first time point assessed) and sustained over time (Figures 4, 5, and 6). Progressive reductions were also observed in serum total IgE in all tezepelumab groups (Figure 4A).

[0163] Safety and tolerability The overall incidence of AEs among subjects was similar between treatment groups (Table 3). Overall, 62.2% of patients in the placebo group, 65.5% of patients in the low-dose tezepelumab group, 64.1% of patients in the medium-dose tezepelumab group, and 61.6% of patients in the high-dose tezepelumab group reported at least one adverse event, with 12.2%, 11.7%, 9.0%, and 12.3%, respectively, reporting at least one serious adverse event. When asthma-related adverse events were removed from the above analysis, the overall incidence of adverse events was similar between study groups. A complete list of serious adverse events is shown in Table 12.

[0164] Of the three serious adverse events related to the study drug, two occurred in the same patient in the low-dose tezepelumab group (pneumonia and stroke) and one occurred in the medium-dose tezepelumab group (Guillain-Barré syndrome). The discontinuation rate due to adverse events was 1.1% in patients receiving tezepelumab (5 patients, including 2 in the medium-dose group and 3 in the high-dose group) and 0.7% in the placebo group (1 patient). One patient in the low-dose tezepelumab group died 8 weeks after the end of the treatment period due to a treatment-related serious adverse event (stroke in the same patient as above).

[0165] Injection site reactions after a 1 mL injection occurred in 3.4% of patients in the placebo group, 2.8% of patients in the low-dose tezepelumab group, 2.8% of patients in the medium-dose group, and 1.4% of patients in the high-dose group. The rates after a 1.5 mL injection were 2.7%, 2.1%, 2.8%, and 3.4% in the respective groups. No anaphylactic reactions related to the study drug were reported. Post-baseline, positive antidrug antibodies were detected in 13 of 148 patients (8.8%) in the placebo group, 7 of 144 patients (4.9%) in the low-dose tezepelumab group, 0 of 144 patients in the medium-dose group, and 3 of 143 patients (2.1%) in the high-dose group. No neutralizing antibodies were detected.

[0166] Analysis B: Final analysis after database lock, including all study sites: In Analysis B, 145 patients were assigned to low-dose tezepelumab (70 mg Q4W), 145 to medium-dose tezepelumab (210 mg Q4W), 146 to high-dose tezepelumab (280 mg Q2W), and 148 to placebo. Among patients receiving tezepelumab or placebo and included in the intention-to-treat population, 391 (89.7%) and 139 (93.9%) completed treatment, respectively. Baseline and clinical characteristics were similar between groups.

[0167] In Analysis B, patient dose ranges for inhaled glucocorticoids at baseline were similar to those in Analysis A. The median fluticasone administered by dry powder inhaler or equivalent in the medium-dose inhaled glucocorticoid stratum was 400 μg per day in 73 patients in the placebo group, 71 in the low-dose tezepelumab group, 70 in the medium-dose group, and 72 in the high-dose group, and the median fluticasone administered by dry powder inhaler or equivalent in the high-dose inhaled glucocorticoid stratum was 1000 μg per day in 75, 74, 75, and 74 patients in the respective study arms.

[0168] Primary endpoint Treatment with tezepelumab resulted in annualized asthma exacerbation rates at week 52 of 0.26, 0.19, and 0.22 in the low-, medium-, and high-dose groups, respectively, compared with 0.67 in the placebo group. Thus, exacerbation rates were 61% (90% confidence interval [CI], 39-75; P < 0.001), 71% (90% CI, 53-82; P < 0.001), and 66% (90% CI, 47-79; P < 0.001) lower in the tezepelumab group than in the placebo group, respectively (Table 2 and Figure 1A). The types of asthma exacerbations used in the primary analysis are listed in Table 1B.

[0169] Secondary endpoints The annualized asthma exacerbation rate was lower in the tezepelumab group than in the placebo group, regardless of baseline eosinophil count or other measures of Th2 status (Figure 2A; Table 2; Tables 4, 5, 7, 9, and 10). Among patients in the medium-dose inhaled glucocorticoid stratum, low-, medium-, and high-dose tezepelumab resulted in annualized asthma exacerbation rates of 0.19, 0.15, and 0.20 exacerbations at week 52, respectively, compared with 0.38 exacerbations with placebo. These rates in the tezepelumab group were 51% (95% CI, -8 to 78; P = 0.08), 60% (95% CI, 5 to 83; P = 0.04), and 49% (95% CI, -13 to 77; P = 0.10) lower than those in the placebo group, respectively. Among patients in the high-dose inhaled glucocorticoid stratum, low-, medium-, and high-dose tezepelumab resulted in annualized asthma exacerbation rates of 0.33, 0.23, and 0.24 exacerbations at week 52, respectively, compared with 0.96 exacerbations with placebo. These rates in the tezepelumab groups were 66% (95% CI, 33-83; P = 0.002), 76% (95% CI, 49-89; P < 0.001), and 75% (95% CI, 47-88; P < 0.001) lower than those in the placebo group (Table 9). When patients were stratified according to the number of asthma exacerbations in the past 12 months, annualized asthma exacerbation rates were lower in some, but not all, tezepelumab groups than in the placebo group, and this remained true in post-hoc analyses according to smoking history (Table 10).

[0170] The time to first asthma exacerbation was longer in the tezepelumab group than in the placebo group. The risk of an exacerbation was 34% (hazard ratio [HR] 0.66, 95% CI 0.41, 1.05; P = 0.08), 54% (HR 0.46, 95% CI 0.27, 0.78; P = 0.003), and 45% (HR 0.55, 95% CI 0.34-0.90; P = 0.02) lower in the low-, medium-, and high-dose tezepelumab groups, respectively, compared with the placebo group (Figure 3 and Table 7).

[0171] In the overall population, the change from baseline in pre-BD FEV1 at week 52 was 0.12 L (95% CI 0.02-0.21, P = 0.01), 0.11 L (95% CI 0.02-0.20, P = 0.02), and 0.15 L (95% CI 0.06-0.25, P = 0.002) greater in the low-, medium-, and high-dose tezepelumab groups than in the placebo group, respectively (Table 2 and Figure 1B). Similar differences were observed when pre-BD FEV1 was measured as a percent of predicted (Table 2). Treatment effects were observed as early as week 4 (the first time point assessed) and sustained throughout the study (Figure 1B, Table 2).

[0172] The effects of tezepelumab on additional secondary endpoints in Analysis B—including the percentage of patients with at least one asthma exacerbation, the percentage of patients with at least one severe asthma exacerbation, the annualized rate of severe asthma exacerbations, the time to first severe asthma exacerbation, and the change from baseline in post-bronchodilator FEV1, FVC, ACQ-6 score, AQLQ score, and asthma symptom score—were consistent with those in Analysis A discussed above, resulting in Table 2 and Figures 1C and 1D, and Tables 3, 5, 6, and 12. The effects of tezepelumab on secondary endpoints (pre-bronchodilator FEV1, ACQ-6 score, AQLQ score, and asthma symptom score) by subgroup are shown in Tables 2, 4, 5, and 12.

[0173] Biomarkers Substantial and sustained reductions in blood eosinophils and FeNO were observed in all tezepelumab-treated groups, beginning at week 4 (the first time point assessed) and sustained over time (Figures 2 and 4). Progressive reductions were also observed in serum total IgE in all tezepelumab groups (Figure 2B).

[0174] Safety and tolerability The overall subject incidence of AEs in Analysis B was consistent with Analysis A and similar between treatment groups (Table 3). Overall, 62.2% of patients in the placebo group, 66.2% of patients in the low-dose tezepelumab group, 64.8% of patients in the medium-dose tezepelumab group, and 61.6% of patients in the high-dose tezepelumab group reported at least one adverse event, with 12.2%, 11.7%, 9.0%, and 12.3%, respectively, reporting at least one serious adverse event. When asthma-related adverse events were removed from the above analysis, the overall incidence of adverse events was similar between study groups. A complete list of serious adverse events is shown in Table 12.

[0175] Of the three serious adverse events related to the study drug, two occurred in the same patient in the low-dose tezepelumab group (pneumonia and stroke) and one occurred in the medium-dose tezepelumab group (Guillain-Barré syndrome). The discontinuation rate due to adverse events was 1.1% in patients receiving tezepelumab (5 patients, including 2 in the medium-dose group and 3 in the high-dose group) and 0.7% in the placebo group (1 patient). One patient in the low-dose tezepelumab group died 8 weeks after the end of the treatment period due to a treatment-related serious adverse event (stroke in the same patient as above).

[0176] In Analysis B, injection site reactions after a 1 mL injection occurred in 3.4% of patients in the placebo group, 2.8% of patients in the low-dose tezepelumab group, 2.8% of patients in the medium-dose group, and 1.4% of patients in the high-dose group. The rates after a 1.5 mL injection were 2.7%, 2.1%, 2.8%, and 3.4% in the respective groups. No anaphylactic reactions related to the study drug were reported. Post-baseline, positive antidrug antibodies were detected in 13 of 148 patients (8.8%) in the placebo group, 7 of 144 patients (4.9%) in the low-dose tezepelumab group, 1 of 140 patients (0.7%) in the medium-dose group, and 3 of 142 patients (2.1%) in the high-dose group. No neutralizing antibodies were detected.

[0177] In summary, the overall results of Analysis A and Analysis B were consistent.

[0178] Analysis C, single-site results omitted after data lock. Based on the study sponsor's concerns about data integrity at one clinical site enrolled in the phase 2 study, data from Analysis B were reanalyzed after data lock, omitting patients from this site. In this secondary analysis, 367 (89.1%) and 129 (93.5%) patients received tezepelumab or placebo and were included in the intention-to-treat population, respectively, and completed treatment. Baseline and clinical characteristics were similar between groups. Analysis C is consistent with the results of the previous analysis.

[0179] In Analysis C, 138 patients were assigned to low-dose tezepelumab (70 mg Q4W), 137 to medium-dose tezepelumab (210 mg Q4W), 137 to high-dose tezepelumab (280 mg Q2W), and 138 to placebo. Of patients receiving tezepelumab or placebo and included in the intention-to-treat population (excluding patients at excluded centers), 367 (89.1%) and 129 (93.5%), respectively, completed treatment. Baseline and clinical characteristics were similar between groups.

[0180] The dose ranges of inhaled glucocorticoids for patients at baseline in Analysis B were similar to those in Analyses A and B, as shown in Figures 2A and 2B. The median fluticasone administered by dry powder inhaler or equivalent in the medium-dose inhaled glucocorticoid stratum was 400 μg per day in 73 patients in the placebo group, 67 in the low-dose tezepelumab group, 70 in the medium-dose group, and 71 in the high-dose group; the median fluticasone administered by dry powder inhaler or equivalent in the high-dose inhaled glucocorticoid stratum was 1000 μg per day in 65, 71, 67, and 66 patients in the respective study arms.

[0181] Primary endpoint Treatment with tezepelumab resulted in 52-week annualized asthma exacerbation rates of 0.27, 0.20, and 0.23 in the low-, medium-, and high-dose groups, respectively, compared with 0.72 in the placebo group. Thus, exacerbation rates were 62% (90% confidence interval [CI], 42-75; P < 0.001), 71% (90% CI, 54-82; P < 0.001), and 66% (90% CI, 47-79; P < 0.001) lower in the tezepelumab group than in the placebo group, respectively. The types of asthma exacerbations used in the primary analysis are listed in Table 1B.

[0182] Secondary endpoints The annualized asthma exacerbation rate was lower in the tezepelumab group than in the placebo group, regardless of baseline eosinophil count or other measures of Th2 status. Among patients in the medium-dose inhaled glucocorticoid stratum, low-, medium-, and high-dose tezepelumab resulted in annualized asthma exacerbation rates of 0.20, 0.15, and 0.20 exacerbations at week 52, respectively, compared with 0.38 exacerbations with placebo. These rates in the tezepelumab group were 48% (95% CI, -15 to 76; P = 0.11), 60% (95% CI, 5 to 83; P = 0.04), and 48% (95% CI, -14 to 76; P = 0.10) lower than those in the placebo group, respectively. Among patients in the high-dose inhaled glucocorticoid stratum, low-, medium-, and high-dose tezepelumab resulted in annualized asthma exacerbation rates of 0.35, 0.26, and 0.27 exacerbations at week 52, respectively, compared with 1.12 exacerbations with placebo. These rates in the tezepelumab groups were 70% (95% CI, 41-84; P = < 0.001), 77% (95% CI, 52-89; P < 0.001), and 76% (95% CI, 50-88; P < 0.001) lower than those in the placebo group, respectively. When patients were stratified according to the number of asthma exacerbations in the past 12 months, annualized asthma exacerbation rates were lower in some, but not all, tezepelumab groups than in the placebo group, and this remained true in post-hoc analyses according to smoking history.

[0183] The time to first asthma exacerbation was longer in the tezepelumab group than in the placebo group. The risk of an exacerbation was 38% (hazard ratio [HR] 0.62, 95% CI 0.39, 0.99; P = 0.04), 55% (HR 0.45, 95% CI 0.26, 0.75; P = 0.002), and 46% (HR 0.54, 95% CI 0.33-0.88; P = 0.01) lower in the low-, medium-, and high-dose tezepelumab groups, respectively, compared with the placebo group.

[0184] In the analyzed population, the change from baseline in pre-BD FEV1 at week 52 was 0.12 L (95% CI 0.02-0.22, P = 0.02), 0.13 L (95% CI 0.03-0.23, P = 0.01), and 0.15 L (95% CI 0.05-0.25, P = 0.002) greater in the low-, medium-, and high-dose tezepelumab groups than in the placebo group, respectively. Similar differences were observed when pre-BD FEV1 was measured as a percent of predicted (Table 2). Treatment effects were observed as early as week 4 (the first time point assessed) and were sustained throughout the study.

[0185] The effects of tezepelumab on additional secondary endpoints in Analysis C—including the percentage of patients with at least one asthma exacerbation, the percentage of patients with at least one severe asthma exacerbation, the annualized rate of severe asthma exacerbations, the time to first severe asthma exacerbation, and the change from baseline in post-bronchodilator FEV1, FVC, ACQ-6 score, AQLQ score, and asthma symptom score—were consistent with those in Analyses A and B discussed above. The effects of tezepelumab on subgroup secondary endpoints (pre-bronchodilator FEV1, ACQ-6 score, AQLQ score, and asthma symptom score) were also consistent with those in Analyses A and B above.

[0186] Biomarkers Substantial and sustained reductions in blood eosinophils and FeNO were observed in all tezepelumab-treated groups, beginning at week 4 (the first time point assessed) and sustained over time. Progressive reductions were also observed in serum total IgE in all tezepelumab groups.

[0187] Safety and tolerability The overall subject incidence of AEs in Analysis C was similar between treatment groups. Overall, 65.9% of patients in the placebo group, 67.4% of patients in the low-dose tezepelumab group, 65.7% of patients in the medium-dose tezepelumab group, and 65.0% of patients in the high-dose tezepelumab group reported at least one adverse event, with 13.0%, 12.3%, 9.5%, and 13.1%, respectively, reporting at least one serious adverse event. When asthma-related adverse events were removed from the above analysis, the overall incidence of adverse events was similar between the study groups.

[0188] Of the three serious adverse events related to the study drug, two occurred in the same patient in the low-dose tezepelumab group (pneumonia and stroke) and one occurred in the medium-dose tezepelumab group (Guillain-Barré syndrome). The discontinuation rate due to adverse events was 1.2% in patients receiving tezepelumab (5 patients, including 2 in the medium-dose group and 3 in the high-dose group) and 0.7% in the placebo group (1 patient). One patient in the low-dose tezepelumab group died 8 weeks after the end of the treatment period due to a treatment-related serious adverse event (stroke in the same patient as above).

[0189] In Analysis C, injection site reactions after a 1 mL injection occurred in 3.6% of patients in the placebo group, 2.9% of patients in the low-dose tezepelumab group, 2.9% of patients in the medium-dose group, and 1.5% of patients in the high-dose group. The rates after a 1.5 mL injection were 2.9%, 2.2%, 2.9%, and 3.6% in the respective groups. No anaphylactic reactions related to the study drug were reported. Post-baseline, positive antidrug antibodies were detected in 13 of 138 patients (9.4%) in the placebo group, 5 of 136 patients (3.7%) in the low-dose tezepelumab group, 1 of 131 patients (0.8%) in the medium-dose group, and 3 of 131 patients (2.3%) in the high-dose group. No neutralizing antibodies were detected.

[0190] In summary, the overall results of Assay A, Assay B and Assay C were consistent.

[0191] Interestingly, a re-examination of the effects of anti-TSLP therapy on different high-eosinophil and aeosinophil / hypoeosinophilic patients showed that treatment with anti-TSLP therapy was highly effective in both the high- and low-eosinophilic patient populations, but this was unexpected in the low-eosinophilic population. Table 2 and Figure 3 show that anti-TSLP treatment significantly reduced exacerbation rates in both the high-eosinophil and low-eosinophilic populations.

[0192] A subject's eosinophil cell concentration is a marker of Th2 inflammation in the subject. Given this association between eosinophils and Th2 concentration, study subjects were also divided into populations based on relative Th2 concentration, e.g., Th2-high or -low, at the start of treatment to test the efficacy of the antibody. Results demonstrated that anti-TSLP treatment was highly effective in both high- and low-Th2 patient populations. Table 4 shows that anti-TSLP treatment significantly reduced exacerbation rates in both high- and low-Th2 populations, but even more so in low-Th2 patients.

[0193] Consideration Treatment with tezepelumab resulted in significantly lower annualized asthma exacerbation rates than placebo among patients with asthma uncontrolled despite treatment with a LABA and medium- to high-dose inhaled glucocorticoids. Some, but not all, secondary outcomes were better with tezepelumab than with placebo. Treatment effects were observed soon after treatment initiation and were maintained throughout the trial. The incidence of adverse events was similar in the tezepelumab and placebo groups, and levels of discontinuation, regardless of whether they were asthma-related, were similar.

[0194] Tezepelumab reduced blood eosinophil counts, FeNO concentrations, and serum total IgE concentrations; changes in eosinophil counts and FeNO levels occurred rapidly, concomitant with changes in clinical endpoints, beginning at week 4. These findings were consistent with the results of a previous allergen challenge study in patients with mild asthma, in which tezepelumab suppressed increases in sputum and blood eosinophils and FeNO levels after allergen challenge. 24These changes in biomarker concentrations indicate that TSLP is an important upstream regulator of Th2 activation and / or function, affecting the interleukin-4, interleukin-5, and interleukin-13 pathways, and that inhibition of TSLP may have broader physiological effects than individual Th2 cytokine inhibitors. Furthermore, the epithelial cell-derived cytokines interleukin-25 and interleukin-33 may cooperate with TSLP to initiate and amplify Th2 inflammation, although the interplay between these cytokines requires further study. 32、33

[0195] Tezepelumab was well tolerated at all doses, with no increase in reported infections compared with placebo.

[0196] The observed improvement in disease control after tezepelumab treatment highlights the potential pathogenic role of TSLP across a wide range of asthma phenotypes. Nonallergic factors, including cigarette smoke, diesel particles, and viruses, have been shown to induce the release of TSLP, leading to the activation of non-Th2 inflammatory responses in asthma. 34-37 Cell types activated by TSLP and potentially involved in these pathways include mast cells, basophils, natural killer T cells, group 2 innate lymphoid cells, and potentially neutrophils and interleukin-17 cells. 20,36~39

[0197] These data provide the first clinical evidence that inhibition of TSLP results in a lower annualized rate of asthma exacerbations than in the absence of such inhibition, independent of baseline eosinophil counts or other Th2 biomarkers, and leads to better outcomes with respect to other clinical endpoints among patients with uncontrolled asthma receiving LABAs and medium- to high-dose inhaled glucocorticoids. These findings highlight the potential benefit of targeting upstream cytokines such as TSLP, which may affect disease activity more broadly than inhibiting a single downstream pathway.

[0198] Numerous modifications and variations of the present invention, as set forth in the illustrative examples above, are expected to occur to those skilled in the art, and therefore only such limitations as are set forth in the appended claims should be placed on the invention.

[0199] References 1.To T, Stanojevic S, Moores G, et al. BMC Public Health 2012;12:204. 2.Chung KF, Wenzel SE, Brozek JL, et al. Eur Respir J 2014;43:343-73. 3.Pavord ID, et al., NPJ Prim Care Respir Med 2017;27:17. 4.Bateman ED, et al. Am J Respir Crit Care Med 2004;170:836-44. 5.GINA Report. Global strategy for asthma management and prevention. August 2014. http: / / www.ginaasthma.org2014. 6.Woodruff PG, et al. Am J Respir Crit Care Med 2009;180:388-95. 7. Wenzel SE. Am J Respir Cell Mol Biol 2016;55:1-4. 8. Froidure A, et al., Eur Respir J 2016;47:304-19. 9. Sweden L, et al. Pharmacol Ther 2017;169:13-34. 10.Brightling C, Berry M, Amrani Y. J Allergy Clin Immunol 2008;121:5-10; quiz 1-2. 11. Ortega HG, Liu MC, Pavord ID, et al. N Engl J Med 2014;371:1198-207. 12. XOLAIR® (omalizumab): Highlights of Prescribing Information 2016. (In https: / / www.gene.com / download / pdf / xolair_prescribing.pdf.) 13. Bleecker ER, FitzGerald JM, Chanez P, et al. The Lancet 2016;388:2115-27. 14. FitzGerald JM, Bleecker ER, Nair P, et al. The Lancet 2016;388:2128-41. 15. Wenzel S, Castro M, Corren J, et al. Lancet 2016;388:31-44. 16. Castro M, et al. Lancet Respir Med 2015; Epub, doi:10.1016 / S2213-2600(15)00042-9. 17. Brightling CE, Chanez P, Leigh R, et al. Lancet Respir Med 2015;3:692-701. 18. Bel EH, Wenzel SE, Thompson PJ, et al. N Engl J Med 2014;371:1189-97. 19. Soumelis V, Reche PA, Kanzler H, et al. Nat Immunol 2002;3:673-80. 20. Allakhverdi Z, Comeau MR, Jessup HK, et al J Exp Med 2007;204:253-8. 21.Shikotra A, Choy DF, Ohri CM, et al. J Allergy Clin Immunol 2012;129:104-11 e1-9. 22.Ying S, O'Connor B, Ratoff J, et al. J Immunol 2005;174:8183-90. 23.Ying S, O'Connor B, Ratoff J, et al. J Immunol 2008;181:2790-8. 24.Gauvreau GM, O'Byrne PM, Boulet LP, et al.N Engl J Med 2014;370:2102-10. 25.Juniper EF, O'Byrne PM, Guyatt GH, Ferrie PJ, King DR. Eur Respir J 1999;14:902-7. 26.Global Stratgey for Asthma Management and Prevention 2012. 2012,http: / / ginasthma.org / において.) 27.Juniper EF, Buist AS, Cox FM, Ferrie PJ, King DR. Chest 1999;115:1265-70. 28.Corren J, Lemanske RF, Hanania NA, et al. N Engl J Med 2011;365:1088-98. 29.Dweik RA, Boggs PB, Erzurum SC, et al.. Am J Respir Crit Care Med 2011;184:602-15. 30.Hanania NA, Wenzel S, Rosen K, et al.. Am J Respir Crit Care Med 2013;187:804-11. 31.Tabrizi M, Bornstein GG, Suria H. AAPS J 2010;12:33-43. 32.Paul WE, Zhu J. Nat Rev Immunol 2010;10:225-35. 33.Gavala ML, Bashir H, Gern JE. Curr Allergy Asthma Rep 2013;13:298-307. 34.Nakamura Y, Miyata M, Ohba T, et al. J Allergy Clin Immunol 2008;122:1208-14.35.Bleck B, et al., Journal of clinical immunology 2008;28:147-56. 36.Lee HC, Headley MB, Loo YM, et al. J Allergy Clin Immunol 2012;130:1187-96 e5. 37.Calven J, Yudina Y, Hallgren O, et al. J Innate Immun 2012;4:86–99. 38.Nagata Y, et al., Int Arch Allergy Immunol 2007;144:305-14. 39.Kim BS, Siracusa MC, Saenz SA, et al. Sci Transl Med 2013;5:170ra16.

Claims

[Claim 1] The invention as described in the drawings.

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