Asthma treatment with anti-TSLP antibodies

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 of related applications This application claims priority to U.S. Provisional Patent Application No. 62 / 484,864 filed on 12 April 2017, U.S. Provisional Patent Application No. 62 / 553,477 filed on 1 September 2017, and U.S. Provisional Patent Application No. 62 / 553,575 filed on 1 September 2017, all of which are incorporated herein by reference.

[0002] This disclosure relates to a method for treating asthma, including severe asthma, eosinophilic asthma, and non / hypeoeosinophilic asthma, using antibodies that are generally specific to thymic interstitial lymphocyte necrosis factor (TSLP). [Background technology]

[0003] An estimated 315 million people worldwide suffer from asthma. 1 Of these, approximately 10-15% have severe asthma. 2 They have a condition where 60% of them have a disease that is not well controlled. 3 These patients experience a significant impairment in their quality of life and are at risk of 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 for patients with severe illness. 2、4、5 Heterogeneous responses to asthma treatment may be partly related to differences in airway inflammation patterns and resistance to corticosteroids. 2、5、6 Alternative therapies 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 asthma patients whose condition is 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 inflammatory stimuli, results in the activation of multiple inflammatory cells and downstream pathways. 19、20 TSLP is increased in the airways of asthma patients and is correlated with the expression of Th2 cytokines and chemokines 21 as well as disease severity. 22、23 TSLP is central to the regulation of Th2 immunity, but it can 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 trial of patients with mild atopic asthma, tezepelumab was shown to inhibit early and late asthma 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 for whom disease control is inadequate with medium to high doses of ICS / LABA. [[ID=…]]

Prior Art Documents

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[0007] The anti-TSLP antibodies described herein address the unmet needs of asthma patients whose moderate to severe asthma cannot be controlled with other medications. For example, antibody therapy may improve asthma in patients with low eosinophil (EOS) levels and provide a more potent reduction in exacerbations in patients with high EOS levels.

[0008] This disclosure provides a method for treating asthma in a subject, comprising administering a therapeutically effective amount of anti-TSLP antibody or antibody variant at doses of 70 mg to 280 mg at intervals of two weeks, wherein both binding sites of the antibody have the same binding affinity to TSLP, and the antibody comprises a light chain CDR1 sequence containing the amino acid sequence shown in ai SEQ ID NO: 3; ai SEQ ID NO: 4; ai SEQ ID NO: 4; ai SEQ ID NO: 5; ai SEQ ID NO: 45; ai SEQ ID NO: 6; ai SEQ ID NO: 7; ai SEQ ID NO: 7; and ai SEQ ID NO: 8; ai SEQ ID NO: 8; and ai SEQ ID NO: 8; and provides a method for specifically binding the antibody to the TSLP polypeptide shown in amino acids 29 to 159 of SEQ ID NO: 2.

[0009] Furthermore, a method for treating asthma in a subject, comprising administering a therapeutically effective amount of anti-TSLP antibody or antibody variant at doses of 70 mg to 280 mg at intervals of two weeks, wherein both binding sites of the antibody have the same binding affinity to TSLP, and the antibody comprises 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; and iii) an amino acid sequence encoded by a polynucleotide that hybridizes under moderately stringent conditions with a polynucleotide complement of the polynucleotide consisting of SEQ ID NO: 11. A heavy chain variable domain selected from the group consisting of: a selected light chain variable domain and an amino acid sequence having at least 80% identity with bi. Sequence ID No. 10; ii. An amino acid sequence encoded by a polynucleotide sequence having at least 80% identity with Sequence ID No. 9; iii. An amino acid sequence encoded by a polynucleotide that hybridizes with a polynucleotide complement of Sequence ID No. 9 under moderately stringent conditions; or c. A method is also envisioned in which the antibody comprises the light chain variable domain of (a) and the heavy chain variable domain of (b), and the antibody specifically binds to the TSLP polypeptide represented by amino acids 29-159 of Sequence 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, 210 mg, or 280 mg every two weeks or every four weeks.

[0012] The disclosure also provides a method for treating asthma in a subject, comprising administering a therapeutically effective dose of an anti-TSLP antibody or antibody variant at a dose of 210 mg at intervals of four weeks, wherein both binding sites of the antibody have the same binding affinity to TSLP, and the antibody comprises a light chain CDR1 sequence containing the amino acid sequence shown in SEQ ID NO: 3; a light chain CDR2 sequence containing the amino acid sequence shown in SEQ ID NO: 4; a light chain variable domain containing the light chain CDR3 sequence containing the amino acid sequence shown in SEQ ID NO: 5; and a heavy chain CDR1 sequence containing the amino acid sequence shown in SEQ ID NO: 6; a heavy chain CDR2 sequence containing the amino acid sequence shown in SEQ ID NO: 7; and a heavy chain variable domain containing the heavy chain CDR3 sequence containing the amino acid sequence shown in SEQ ID NO: 8, wherein the antibody specifically binds to the TSLP polypeptide shown in amino acids 29-159 of SEQ ID NO: 2.

[0013] The disclosure further relates to a method for treating asthma in a subject, comprising administering a therapeutically effective dose of an anti-TSLP antibody or antibody variant at a dose of 210 mg at intervals of four weeks, wherein both binding sites of the antibody have identical binding affinity to 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; and iii) an amino acid sequence encoded by a polynucleotide that hybridizes under moderately stringent conditions with a polynucleotide complement of the polynucleotide consisting of SEQ ID NO: 11. The present invention provides a method for specifically binding an antibody to the TSLP polypeptide represented by amino acids 29-159 of SEQ ID NO: 2, comprising the light chain variable domain and the heavy chain variable domain of (a) and the heavy chain variable domain of (b), wherein the antibody comprises 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 29-159 of SEQ ID NO: 2.

[0014] In various embodiments, anti-TSLP antibody variants have pK properties substantially similar to tezeperumab in humans.

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

[0016] In various embodiments, the anti-TSLP antibody or its antibody variant is bivalent and is selected from the group consisting of human antibodies, humanized antibodies, chimeric antibodies, monoclonal antibodies, recombinant antibodies, antigen-binding antibody fragments, single-chain antibodies, monomeric antibodies, bispecific antibodies, triplicate antibodies, quadruplespecific antibodies, Fab fragments, IgG1 antibodies, IgG2 antibodies, IgG3 antibodies, and IgG4 antibodies.

[0017] In one embodiment, the anti-TSLP antibody variant is selected from the group consisting of bispecificity antibodies, triplicity antibodies, quadruplicity antibodies, Fab fragments, single-domain antibodies, and scFv, where the dose is adjusted so that the binding site is equimolar to that of when administered by a 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 tezeperumab. In various embodiments, tezeperumab is an IgG2 antibody having full-length heavy-chain and light-chain amino acid sequences, as shown by 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, asthma is severe asthma. Asthma can be eosinophilic or noneosinophilic asthma, and in some cases, it can be further considered to be hypoeosinophilic asthma.

[0023] The data presented herein demonstrate that anti-TSLP antibodies substantially affect two key markers of asthmatic inflammation: blood eosinophil count and exhaled nitric oxide concentration. These data show that anti-TSLP antibodies reduce levels of both inflammatory markers, decrease asthma exacerbation rates, improve lung function regardless of asthmatic phenotype (eosinophilic (allergic and non-allergic) and non-eosinophilic / hypeoeosinophilic asthma), and block at least two key inflammatory pathways in asthma. Therefore, anti-TSLP antibodies can treat patients with asthmatic phenotypes: eosinophilic (allergic and non-allergic) or non-eosinophilic / hypeoeosinophilic asthma. Accordingly, this specification provides a method for treating patients with hypoeosinophilic asthma, comprising administering the anti-TSLP antibodies described herein. Furthermore, a method for treating asthmatic subjects characterized by a low Th2 profile, comprising administering anti-TSLP antibodies, is also envisioned. In various embodiments, the antibody is tezeperumab or another anti-TSLP antibody described in the art. Exemplary antibodies are further described in the detailed description.

[0024] In various embodiments, the subjects are adults. In various embodiments, the subjects are children or adolescents.

[0025] Administration of anti-TSLP antibodies or antibody variants is thought to reduce eosinophils in the subject's blood, sputum, bronchoalveolar fluid, or lungs.

[0026] Furthermore, administration of anti-TSLP antibodies or antibody variants is thought to alter the cell count of subjects from high-Th2 populations to low-Th populations.

[0027] In various embodiments, administration of an anti-TSLP antibody or antibody variant improves one or more measures of asthma in the subject, selected from the group consisting of forced expiratory capacity (FEV1), 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 asthma symptoms as assessed by an asthma symptom diary.

[0029] Furthermore, a method for treating a subject's asthma is provided, comprising administering a therapeutically effective amount of anti-TSLP antibody or antibody variant at doses of 70-280 mg at intervals of two weeks, wherein both binding sites of the antibody have the same binding affinity to TSLP, and the antibody comprises a light chain CDR1 sequence containing the amino acid sequence shown in ai SEQ ID NO: 3; ii. a light chain CDR2 sequence containing the amino acid sequence shown in SEQ ID NO: 4; iii. a light chain variable domain containing the amino acid sequence shown in SEQ ID NO: 5; and bi a heavy chain CDR1 sequence containing the amino acid sequence shown in SEQ ID NO: 6; ii. a heavy chain CDR2 sequence containing the amino acid sequence shown in SEQ ID NO: 7; and iii. a heavy chain variable domain containing the amino acid sequence shown in SEQ ID NO: 8, wherein the antibody specifically binds to the TSLP polypeptide shown in amino acids 29-159 of SEQ ID NO: 2, 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 in doses of 70 mg, 210 mg, or 280 mg.

[0032] Furthermore, a method is provided to reduce the frequency of asthma exacerbations in a subject, comprising administering a therapeutically effective amount of anti-TSLP antibody or antibody variant at doses of 70 mg to 280 mg at intervals of two weeks, wherein both binding sites of the antibody have the same binding affinity to TSLP, and the antibody comprises a light chain CDR1 sequence containing the amino acid sequence shown in ai SEQ ID NO: 3; ii. a light chain CDR2 sequence containing the amino acid sequence shown in SEQ ID NO: 4; iii. a light chain variable domain containing the light chain CDR3 sequence containing the amino acid sequence shown in SEQ ID NO: 5; and bi a heavy chain CDR1 sequence containing the amino acid sequence shown in SEQ ID NO: 6; ii. a heavy chain CDR2 sequence containing the amino acid sequence shown in SEQ ID NO: 7; and iii. a heavy chain variable domain containing the heavy chain CDR3 sequence containing the amino acid sequence shown in SEQ ID NO: 8, wherein the antigen-binding protein specifically binds to the TSLP polypeptide shown in amino acids 29 to 159 of SEQ ID NO: 2.

[0033] Furthermore, a method for reducing the frequency of asthma exacerbations in a subject, comprising administering a therapeutically effective dose of anti-TSLP antibody or antibody variant at doses of 70 mg to 280 mg at intervals of two weeks, wherein both binding sites of the antibody have identical binding affinity to TSLP, and the antibody comprises: 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; and iii) a polynucleotide that hybridizes under moderately stringent conditions with a polynucleotide complement consisting of SEQ ID NO: 11. A method is proposed comprising: a light chain variable domain selected from the group consisting of amino acid sequences encoded by a rheotide, and bi. an amino acid sequence having at least 80% identity with SEQ ID NO: 10; ii. an amino acid sequence encoded by a polynucleotide sequence having at least 80% identity with 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 with a polynucleotide complement of SEQ ID NO: 9 under moderately stringent conditions; or c. a method comprising the light chain variable domain of (a) and the heavy chain variable domain of (b).

[0034] The above-described administrations, antibodies, and antibody variants are considered applicable to each of the methods intended in this specification.

[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 asthma exacerbation compared to subjects who have not received anti-TSLP antibodies.

[0037] In various embodiments, administration reduces the frequency or concentration of the subject's concurrent therapies. Optional concurrent therapies include inhaled corticosteroids (ICS), long-acting β2-agonists (LABAs), leukotriene receptor antagonists (LTRAs), long-acting antimuscarinic agents (LAMAs), chromone, short-acting β2-agonists (SABAs), and theophylline or oral corticosteroids.

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

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

[0040] This specification also provides a method for treating chronic obstructive pulmonary disease (COPD), comprising administering a therapeutically effective amount of anti-TSLP antibody or antibody variant at doses of 70 mg to 280 mg at intervals of two weeks, wherein both binding sites of the antibody have the same binding affinity to TSLP, and the antibody comprises a light chain CDR1 sequence containing the amino acid sequence shown in ai SEQ ID NO: 3; ii. a light chain CDR2 sequence containing the amino acid sequence shown in SEQ ID NO: 4; iii. a light chain variable domain containing the amino acid sequence shown in SEQ ID NO: 5; and bi a heavy chain CDR1 sequence containing the amino acid sequence shown in SEQ ID NO: 6; ii. a heavy chain CDR2 sequence containing the amino acid sequence shown in SEQ ID NO: 7; and iii. a heavy chain variable domain containing the amino acid sequence shown in SEQ ID NO: 8, wherein the antigen-binding protein specifically binds to the TSLP polypeptide shown in amino acids 29 to 159 of SEQ ID NO: 2.

[0041] Furthermore, a method for treating chronic obstructive pulmonary disease (COPD) in a subject, comprising administering a therapeutically effective dose of anti-TSLP antibody or antibody variant at doses of 70 mg to 280 mg at intervals of two weeks, wherein both binding sites of the antibody have the same binding affinity to TSLP, and the antibody comprises: 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; and iii) a polynucleotide complementary that hybridizes under moderately stringent conditions. A method is provided comprising: a light chain variable domain selected from the group consisting of amino acid sequences encoded by a renucleotide, and bi. an amino acid sequence having at least 80% identity with sequence number 10; ii. an amino acid sequence encoded by a polynucleotide sequence having at least 80% identity with sequence number 9; iii. a heavy chain variable domain selected from the group consisting of amino acid sequences encoded by a polynucleotide that hybridizes with a complement of the polynucleotide of sequence number 9 under moderately stringent conditions; or c. a method comprising the light chain variable domain of (a) and the heavy chain variable domain of (b).

[0042] Furthermore, this specification provides a method for reducing the ACQ-6 score of a subject, comprising administering a therapeutically effective amount of anti-TSLP antibody or antibody variant at doses of 70 mg to 280 mg at intervals of two weeks, wherein both binding sites of the antibody have the same binding affinity to TSLP, and the antibody comprises a light chain CDR1 sequence containing the amino acid sequence shown in ai SEQ ID NO: 3; ii. a light chain CDR2 sequence containing the amino acid sequence shown in SEQ ID NO: 4; iii. a light chain variable domain containing the amino acid sequence shown in SEQ ID NO: 5; and bi a heavy chain CDR1 sequence containing the amino acid sequence shown in SEQ ID NO: 6; ii. a heavy chain CDR2 sequence containing the amino acid sequence shown in SEQ ID NO: 7; and iii. a heavy chain variable domain containing the amino acid sequence shown in SEQ ID NO: 8, wherein the antigen-binding protein specifically binds to the TSLP polypeptide shown in amino acids 29 to 159 of SEQ ID NO: 2.

[0043] Furthermore, a method for reducing a subject's ACQ-6 score, comprising administering a therapeutically effective dose of an anti-TSLP antibody or antibody variant at doses of 70 mg to 280 mg at intervals of two weeks, wherein both binding sites of the antibody have identical binding affinity to TSLP, and the antibody comprises: 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; and iii) a polynucleotide complementary to SEQ ID NO: 11, which hybridizes under moderately stringent conditions. A method is provided comprising: a light chain variable domain selected from the group consisting of amino acid sequences encoded by a renucleotide, and bi. an amino acid sequence having at least 80% identity with sequence number 10; ii. an amino acid sequence encoded by a polynucleotide sequence having at least 80% identity with sequence number 9; iii. a heavy chain variable domain selected from the group consisting of amino acid sequences encoded by a polynucleotide that hybridizes with a complement of the polynucleotide of sequence number 9 under moderately stringent conditions; or c. a method comprising the light chain variable domain of (a) and the heavy chain variable domain of (b).

[0044] This specification provides a method for reducing the ACQ-6 score of a subject having a low eosinophil profile, comprising administering a therapeutically effective dose of an anti-TSLP antibody or antibody variant, wherein the antibody or antibody variant that binds to TSLP inhibits TSLP activity. Furthermore, this specification provides a method for reducing the ACQ-6 score of a subject having a low Th2 profile, comprising administering a therapeutically effective dose of an anti-TSLP antibody or antibody variant, wherein the antibody or antibody variant that binds to TSLP inhibits TSLP activity.

[0045] Furthermore, the invention relates to a method 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 that binds to TSLP inhibits TSLP activity.

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

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

[0048] In various embodiments, the subject has an IgE Th2 profile 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 tezeperumab or another anti-TSLP antibody described in the art, for example, listed in Table A. Exemplary antibodies are further described in the detailed description. The present invention provides, for example, the following items. (Item 1) A method for treating asthma in a subject, comprising administering a therapeutically effective amount of anti-TSLP antibody or antibody variant at doses of 70 mg to 280 mg at intervals of two weeks, wherein both binding sites of the antibody have the same binding affinity to TSLP, and the antibody is Light chain CDR1 sequence containing the amino acid sequence shown in ai Sequence ID No. 3; ii. Light chain CDR2 sequence containing the amino acid sequence shown in Sequence ID No. 4; iii. A light chain variable domain containing a light chain CDR3 sequence containing the amino acid sequence shown in Sequence ID No. 5; and A heavy chain CDR1 sequence containing the amino acid sequence shown in bi_SEQ ID NO: 6; ii. A heavy chain CDR2 sequence containing the amino acid sequence shown in Sequence ID No. 7, and iii. A method comprising a heavy chain variable domain containing a heavy chain CDR3 sequence containing the amino acid sequence shown in SEQ ID NO: 8, wherein the antibody specifically binds to the TSLP polypeptide shown in amino acids 29-159 of SEQ ID NO: 2. (Item 2) A method for treating asthma in a subject, comprising administering a therapeutically effective amount of anti-TSLP antibody or antibody variant at doses of 70 mg to 280 mg at intervals of two weeks, wherein both binding sites of the antibody have the same binding affinity to TSLP, and the antibody is An amino acid sequence having at least 80% identity with ai-sequence number 12; ii. An amino acid sequence encoded by a polynucleotide sequence having at least 80% identity with SEQ ID NO: 11; iii. Light chain variable domains selected from the group consisting of amino acid sequences encoded by a polynucleotide that hybridizes with a polynucleotide complement of SEQ ID NO: 11 under moderately stringent conditions; and An amino acid sequence having at least 80% identity with bi-sequence number 10; ii. An amino acid sequence encoded by a polynucleotide sequence having at least 80% identity with 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 with a polynucleotide complement of SEQ ID NO: 9 under moderately stringent conditions; or c. A method comprising 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 29-159 of SEQ ID NO: 2. (Item 3) The method according to item 1 or 2, wherein the antibody or antibody variant is administered every four weeks. (Item 4) The method according to any one of items 1 to 3, wherein the antibody or antibody variant is administered in a dose of 70 mg. (Item 5) The method according to any one of items 1 to 3, wherein the antibody or antibody variant is administered in a dose of 210 mg. (Item 6) The method according to any one of items 1 to 3, wherein the antibody or antibody variant is administered in a dose of 280 mg. (Item 7) A method for treating asthma in a subject, comprising administering a therapeutically effective dose of an anti-TSLP antibody or antibody variant at a dose of 210 mg at intervals of four weeks, wherein both binding sites of the antibody have the same binding affinity to TSLP, and the antibody is Light chain CDR1 sequence containing the amino acid sequence shown in ai Sequence ID No. 3; ii. Light chain CDR2 sequence containing the amino acid sequence shown in Sequence ID No. 4; iii. A light chain variable domain containing a light chain CDR3 sequence containing the amino acid sequence shown in Sequence ID No. 5, and A heavy chain CDR1 sequence containing the amino acid sequence shown in bi_SEQ ID NO: 6; ii. A heavy chain CDR2 sequence containing the amino acid sequence shown in Sequence ID No. 7, and iii. A method comprising a heavy chain variable domain containing a heavy chain CDR3 sequence containing the amino acid sequence shown in SEQ ID NO: 8, wherein the antibody specifically binds to the TSLP polypeptide shown in amino acids 29-159 of SEQ ID NO: 2. (Item 8) A method for treating asthma in a subject, comprising administering a therapeutically effective dose of an anti-TSLP antibody or antibody variant at a dose of 210 mg at intervals of four weeks, wherein both binding sites of the antibody have the same binding affinity to TSLP, and the antibody is An amino acid sequence having at least 80% identity with ai-sequence number 12; ii. An amino acid sequence encoded by a polynucleotide sequence having at least 80% identity with SEQ ID NO: 11; iii. Light chain variable domains selected from the group consisting of amino acid sequences encoded by a polynucleotide that hybridizes with a polynucleotide complement of SEQ ID NO: 11 under moderately stringent conditions; and An amino acid sequence having at least 80% identity with bi-sequence number 10; ii. An amino acid sequence encoded by a polynucleotide sequence having at least 80% identity with 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 with a polynucleotide complement of SEQ ID NO: 9 under moderately stringent conditions; or c. A method comprising 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 29-159 of SEQ ID NO: 2. (Item 9) The antibody or antibody variant is administered for a period of at least 4 months, 6 months, 9 months, 1 year or longer, according to any one of items 1 to 8. (Item 10) The method according to any one of items 1 to 9, wherein the anti-TSLP antibody or its antibody variant is bivalent and selected from the group consisting of human antibodies, humanized antibodies, chimeric antibodies, monoclonal antibodies, recombinant antibodies, antigen-binding antibody fragments, single-chain antibodies, monomeric antibodies, bispecific antibodies, triplicate antibodies, quadruplespecific antibodies, Fab fragments, IgG1 antibodies, IgG2 antibodies, IgG3 antibodies, and IgG4 antibodies. (Item 11) The anti-TSLP antibody variant is selected from the group consisting of bispecific antibodies, triplicate antibodies, quadruplicate antibodies, Fab fragments, single-domain antibodies, and scFv, and the dose is adjusted so that the binding site is equimolar to that of when the bivalent antibody is administered, according to item 8. (Item 12) The method according to any one of items 1 to 11, wherein the antibody is an IgG2 antibody. (Item 13) The method according to any one of items 1 to 12, wherein the antibody or antibody variant is a human antibody. (Item 14) The method according to any one of items 1 to 13, wherein the antibody or antibody variant further comprises a pharmaceutically acceptable carrier or excipient. (Item 15) The aforementioned asthma is severe asthma, as described in any one of items 1 to 14. (Item 16) The method according to any one of items 1 to 15, wherein the asthma is eosinophilic or noneosinophilic asthma. (Item 17) The asthma is hypoeosinophilic asthma, as described in any one of items 1 to 16. (Item 18) The subject is an adult, and the method described in any one of items 1 to 17. (Item 19) The subject is a child or adolescent, as described in any one of items 1 to 18. (Item 20) The method according to 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) The method according to any one of items 1 to 20, wherein the administration alters the cell count of the subject from a high Th2 population to a low Th2 population. (Item 22) The administration is a method according to one of items 1 to 21, selected from the group consisting of forced expiratory volume (FEV1), FEV1 reversibility, forced vital capacity (FCV), FeNO, Asthma Control Questionnaire-6 score, and AQLQ(S)+12 score, which improves one or more of the subject's asthma scales. (Item 23) The administration described above is the method according to any one of items 1 to 22, which improves one or more symptoms of asthma as assessed by an asthma symptom diary. (Item 24) A method for treating asthma in a subject, comprising administering a therapeutically effective amount of anti-TSLP antibody or antibody variant at doses of 70-280 mg at intervals of two weeks, wherein both binding sites of the antibody have the same binding affinity to TSLP, and the antibody is Light chain CDR1 sequence containing the amino acid sequence shown in ai Sequence ID No. 3; ii. Light chain CDR2 sequence containing the amino acid sequence shown in Sequence ID No. 4; iii. A light chain variable domain containing a light chain CDR3 sequence containing the amino acid sequence shown in Sequence ID No. 5, and A heavy chain CDR1 sequence containing the amino acid sequence shown in bi_SEQ ID NO: 6; ii. A heavy chain CDR2 sequence containing the amino acid sequence shown in Sequence ID No. 7, and iii. A method comprising a heavy chain variable domain containing a heavy chain CDR3 sequence containing the amino acid sequence shown in SEQ ID NO: 8, wherein the antibody specifically binds to the TSLP polypeptide shown in amino acids 29-159 of SEQ ID NO: 2, and the antibody is an IgG2 antibody. (Item 25) The antibody is administered every four weeks, as described in item 24. (Item 26) The antibody is administered in a dose of 70 mg, as described in item 24 or 25. (Item 27) The antibody is administered in a dose of 210 mg, according to the method described in any one of items 24-25. (Item 28) The antibody is administered in a dose of 280 mg, according to the method described in any one of items 24-25. (Item 29) The method according to any one of items 1 to 28, wherein the antibody is tezepermab. (Item 30) The method according to item 29, wherein the antibody is an IgG2 antibody and has the full-length heavy chain and light chain sequences shown in SEQ ID NOs. 105 and 106, respectively. (Item 31) The antibody variant has pK properties substantially similar to those of human tezeperumab, according to the method described in any one of items 1 to 30. (Item 32) A method for reducing the frequency of asthma exacerbations in a subject, comprising administering a therapeutically effective dose of an anti-TSLP antibody or antibody variant at intervals of 2 weeks in doses of 70 mg to 280 mg, wherein both binding sites of the antibody have the same binding affinity to TSLP, and the antibody is Light chain CDR1 sequence containing the amino acid sequence shown in ai Sequence ID No. 3; ii. Light chain CDR2 sequence containing the amino acid sequence shown in Sequence ID No. 4; iii. A light chain variable domain containing a light chain CDR3 sequence containing the amino acid sequence shown in Sequence ID No. 5; and A heavy chain CDR1 sequence containing the amino acid sequence shown in bi_SEQ ID NO: 6; ii. A heavy chain CDR2 sequence containing the amino acid sequence shown in Sequence ID No. 7, and iii. A method comprising a heavy chain variable domain containing a heavy chain CDR3 sequence containing the amino acid sequence shown in SEQ ID NO: 8, wherein the antigen-binding protein specifically binds to the TSLP polypeptide shown in amino acids 29-159 of SEQ ID NO: 2. (Item 33) A method for reducing the frequency of asthma exacerbations in a subject, comprising administering a therapeutically effective dose of an anti-TSLP antibody or antibody variant at intervals of 2 weeks in doses of 70 mg to 280 mg, wherein both binding sites of the antibody have the same binding affinity to TSLP, and the antibody is An amino acid sequence having at least 80% identity with ai-sequence number 12; ii. An amino acid sequence encoded by a polynucleotide sequence having at least 80% identity with SEQ ID NO: 11; iii. Light chain variable domains selected from the group consisting of amino acid sequences encoded by a polynucleotide that hybridizes with a polynucleotide complement of SEQ ID NO: 11 under moderately stringent conditions; and An amino acid sequence having at least 80% identity with bi-sequence number 10; ii. An amino acid sequence encoded by a polynucleotide sequence having at least 80% identity with 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 with a polynucleotide complement of sequence number 9 under moderately stringent conditions; or c. A method comprising the light chain variable domain of (a) and the heavy chain variable domain of (b). (Item 34) The method according to either item 32 or 33, wherein the antibody or antibody variant is administered every four weeks. (Item 35) The method according to either item 32 or 33, wherein the antibody or antibody variant is administered in a dose of 70 mg. (Item 36) The method according to either item 32 or 33, wherein the antibody or antibody variant is administered in a dose of 210 mg. (Item 37) The method according to either item 32 or 33, wherein the antibody or antibody variant is administered in a dose of 280 mg. (Item 38) The method according to any one of items 32 to 37, wherein the antibody or antibody variant is administered for a period of at least 4 months, 6 months, 9 months, 1 year or longer. (Item 39) The method according to any one of items 32 to 38, wherein the anti-TSLP antibody or antibody variant is selected from the group consisting of human antibodies, humanized antibodies, chimeric antibodies, monoclonal antibodies, recombinant antibodies, antigen-binding antibody fragments, single-chain antibodies, monomeric antibodies, bispecific antibodies, triplicate antibodies, quadruplespecific antibodies, Fab fragments, IgG1 antibodies, IgG2 antibodies, IgG3 antibodies, and IgG4 antibodies. (Item 40) The method according to any one of items 32 to 39, wherein the antibody or antibody variant is an IgG2 antibody. (Item 41) The method according to any one of items 32 to 40, wherein the antibody or antibody variant is a human antibody. (Item 42) The method according to any one of items 32 to 41, further comprising the antibody or antibody variant as a pharmaceutically acceptable carrier or excipient. (Item 43) The method according to any one of items 32 to 42, wherein the administration delays the time to asthma exacerbation compared to subjects who have not been administered the anti-TSLP antibody. (Item 44) The method according to any one of items 32 to 43, wherein the administration reduces the frequency or level of concurrent therapy of the subject. (Item 45) The method according to item 44, wherein the concurrent administration therapy is an inhaled corticosteroid (ICS), a long-acting β2 agonist (LABA), a leukotriene receptor antagonist (LTRA), a long-acting antimuscarinic agent (LAMA), chromone, a short-acting β2 agonist (SABA), and theophylline or an oral corticosteroid. (Item 46) The aforementioned administration is the method described in item 44, which eliminates the need for corticosteroid treatment. (Item 47) A method for treating chronic obstructive pulmonary disease (COPD), comprising administering a therapeutically effective dose of an anti-TSLP antibody or antibody variant at a dose of 70 mg to 280 mg at intervals of two weeks, wherein both binding sites of the antibody have the same binding affinity to TSLP, and the antibody is Light chain CDR1 sequence containing the amino acid sequence shown in ai Sequence ID No. 3; ii. Light chain CDR2 sequence containing the amino acid sequence shown in Sequence ID No. 4; iii. A light chain variable domain containing a light chain CDR3 sequence containing the amino acid sequence shown in Sequence ID No. 5; and A heavy chain CDR1 sequence containing the amino acid sequence shown in bi_SEQ ID NO: 6; ii. A heavy chain CDR2 sequence containing the amino acid sequence shown in Sequence ID No. 7, and iii. A method comprising a heavy chain variable domain containing a heavy chain CDR3 sequence containing the amino acid sequence shown in SEQ ID NO: 8, wherein the antigen-binding protein specifically binds to the TSLP polypeptide shown in amino acids 29-159 of SEQ ID NO: 2. (Item 48) A method for treating chronic obstructive pulmonary disease (COPD) in a subject, comprising administering a therapeutically effective dose of an anti-TSLP antibody or antibody variant at intervals of two weeks in doses of 70 mg to 280 mg, wherein both binding sites of the antibody have the same binding affinity to TSLP, and the antibody is An amino acid sequence having at least 80% identity with ai-sequence number 12; ii. An amino acid sequence encoded by a polynucleotide sequence having at least 80% identity with SEQ ID NO: 11; iii. Light chain variable domains selected from the group consisting of amino acid sequences encoded by a polynucleotide that hybridizes with a polynucleotide complement of SEQ ID NO: 11 under moderately stringent conditions; and An amino acid sequence having at least 80% identity with bi-sequence number 10; ii. An amino acid sequence encoded by a polynucleotide sequence having at least 80% identity with 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 with a polynucleotide complement of sequence number 9 under moderately stringent conditions; or c. A method comprising the light chain variable domain of (a) and the heavy chain variable domain of (b). (Item 49) The administration is by subcutaneous or intravenous administration, as described in any one of items 1 to 48. (Item 50) A method for reducing a subject's ACQ-6 score, comprising administering a therapeutically effective dose of an anti-TSLP antibody or antibody variant at intervals of 2 weeks in doses of 70 mg to 280 mg, wherein both binding sites of the antibody have the same binding affinity to TSLP, and the antibody is Light chain CDR1 sequence containing the amino acid sequence shown in ai Sequence ID No. 3; ii. Light chain CDR2 sequence containing the amino acid sequence shown in Sequence ID No. 4; iii. A light chain variable domain containing a light chain CDR3 sequence containing the amino acid sequence shown in Sequence ID No. 5; and A heavy chain CDR1 sequence containing the amino acid sequence shown in bi_SEQ ID NO: 6; ii. A heavy chain CDR2 sequence containing the amino acid sequence shown in Sequence ID No. 7, and iii. A method by which an antigen-binding protein specifically binds to the TSLP polypeptide shown in amino acids 29-159 of SEQ ID NO: 8, comprising a heavy chain variable domain containing a heavy chain CDR3 sequence containing the amino acid sequence shown in SEQ ID NO: 8. (Item 51) A method for reducing a subject's ACQ-6 score, comprising administering a therapeutically effective dose of an anti-TSLP antibody or antibody variant at intervals of 2 weeks in doses of 70 mg to 280 mg, wherein both binding sites of the antibody have the same binding affinity to TSLP, and the antibody is An amino acid sequence having at least 80% identity with ai-sequence number 12; ii. An amino acid sequence encoded by a polynucleotide sequence having at least 80% identity with SEQ ID NO: 11; iii. Light chain variable domains selected from the group consisting of amino acid sequences encoded by a polynucleotide that hybridizes with a polynucleotide complement of SEQ ID NO: 11 under moderately stringent conditions; and An amino acid sequence having at least 80% identity with bi-sequence number 10; ii. An amino acid sequence encoded by a polynucleotide sequence having at least 80% identity with 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 with a polynucleotide complement of sequence number 9 under moderately stringent conditions; or c. A method comprising the light chain variable domain of (a) and the heavy chain variable domain of (b). (Item 52) The administration is by subcutaneous or intravenous administration, as described in any one of items 1 to 51. (Item 53) A method for treating asthma in a subject having a non-eosinophil profile or a hypoeosinophil profile, comprising administering a therapeutically effective amount of an anti-TSLP antibody or antibody variant, wherein the antibody or antibody variant that binds to TSLP inhibits TSLP activity. (Item 54) The anti-TSLP antibody or anti-TSLP antibody variant is selected from the antibodies listed in Table A, as described in item 53: [Table 2-1] [Table 2-2] [Table 2-3] [Table 2-4] [Table 2-5] [Table 2-6] [Table 2-7] (Item 55) The method according to any one of items 32 to 54, wherein the anti-TSLP antibody is tezepermab. (Item 56) The method according to item 55, wherein the antibody is an IgG2 antibody and has the full-length heavy chain and light chain sequences shown in SEQ ID NOs. 105 and 106, respectively. (Item 57) The antibody variant has pK properties substantially similar to those of human tezeperumab, according to the method described in any one of items 32 to 56. (Item 58) The method according to any one of items 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 having a low Th2 profile, comprising administering a therapeutically effective amount of an anti-TSLP antibody or antibody variant, wherein the antibody or antibody variant that binds to TSLP inhibits TSLP activity. (Item 60) The subject is described in item 59, and has a Th2 profile with an IgE level of 100 IU / ml or less or an eosinophil count of less than 140 cells / μL at the time of diagnosis. (Item 61) The antibody or antibody variant is selected from the antibodies listed in Table A, according to the method described in item 59 or 60. (Item 62) The antibody is tezeperumab, as described in item 59 or 60. (Item 63) The method according to item 62, wherein the antibody is an IgG2 antibody and has the full-length heavy chain and light chain sequences shown in SEQ ID NOs. 105 and 106, respectively. (Item 64) A method for reducing the ACQ-6 score of a subject having a low eosinophil profile, comprising administering a therapeutically effective amount of an anti-TSLP antibody or antibody variant, wherein the antibody or antibody variant that binds to TSLP inhibits TSLP activity. (Item 65) The anti-TSLP antibody or anti-TSLP antibody variant is selected from the antibodies listed in Table A, as described in item 64. (Item 66) The method described in item 64, wherein the anti-TSLP antibody is tezepermab. (Item 67) The method according to item 66, wherein the antibody is an IgG2 antibody and has the full-length heavy chain and light chain sequences shown in SEQ ID NOs. 105 and 106, respectively. (Item 68) The method according to any one of items 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 of a subject having a low Th2 profile, comprising administering a therapeutically effective amount of an anti-TSLP antibody or antibody variant, wherein the antibody or antibody variant that binds to TSLP inhibits TSLP activity. (Item 69) The subject is described in the method of item 68, wherein the subject has a Th2 profile with an IgE level of 100 IU / ml or less, or an eosinophil count of less than 140 cells / μL at the time of diagnosis. (Item 70) The antibody or antibody variant is selected from the antibodies listed in Table A, according to the method described in item 68 or 69. (Item 71) The antibody is tezepermab, as described in item 68 or 69. (Item 72) The method according to item 71, wherein the antibody is an IgG2 antibody and has the full-length heavy chain and light chain sequences shown in SEQ ID NOs. 105 and 106, respectively. (Item 73) Both binding sites of the antibody have the same binding affinity to TSLP, and the antibody is Light chain CDR1 sequence containing the amino acid sequence shown in ai Sequence ID No. 3; ii. Light chain CDR2 sequence containing the amino acid sequence shown in Sequence ID No. 4; iii. A light chain variable domain containing a light chain CDR3 sequence containing the amino acid sequence shown in Sequence ID No. 5; and A heavy chain CDR1 sequence containing the amino acid sequence shown in bi_SEQ ID NO: 6; ii. A heavy chain CDR2 sequence containing the amino acid sequence shown in Sequence ID No. 7, and iii. The method according to any one of items 53 to 72, wherein the antibody comprises a heavy chain variable domain comprising a heavy chain CDR3 sequence comprising the amino acid sequence shown in SEQ ID NO: 8, and the antibody specifically binds to the TSLP polypeptide shown in amino acids 29 to 159 of SEQ ID NO: 2. (Item 74) Both binding sites of the antibody have the same binding affinity to TSLP, and the antibody is An amino acid sequence having at least 80% identity with ai-sequence number 12; ii. An amino acid sequence encoded by a polynucleotide sequence having at least 80% identity with SEQ ID NO: 11; iii. Light chain variable domains selected from the group consisting of amino acid sequences encoded by a polynucleotide that hybridizes with a polynucleotide complement of SEQ ID NO: 11 under moderately stringent conditions; and An amino acid sequence having at least 80% identity with bi-sequence number 10; ii. An amino acid sequence encoded by a polynucleotide sequence having at least 80% identity with 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 with a polynucleotide complement of SEQ ID NO: 9 under moderately stringent conditions; or c. The method according to any one of items 53 to 72, comprising 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) The method according to any one of items 53 to 74, wherein the antibody or antibody variant is administered every four weeks. (Item 76) The method according to any one of items 53 to 75, wherein the administration is by subcutaneous or intravenous administration. [Brief explanation of the drawing]

[0050] [Figure 1A] Figures 1A-1D show the effects of antibody therapy at different doses on asthma symptoms using various evaluations. Figure 1A shows the rate of asthma exacerbations; Figure 1B shows the change from baseline in FEV1 after bronchodilator therapy; Figure 1C shows the change from baseline in ACQ-6; and Figure 1D shows the change from baseline in AQLQ score. [Figure 1B] Figures 1A-1D show the effects of antibody therapy at different doses on asthma symptoms using various evaluations. Figure 1A shows the rate of asthma exacerbations; Figure 1B shows the change from baseline in FEV1 after bronchodilator therapy; Figure 1C shows the change from baseline in ACQ-6; and Figure 1D shows the change from baseline in AQLQ score. [Figure 1C] Figures 1A-1D show the effects of antibody therapy at different doses on asthma symptoms using various evaluations. Figure 1A shows the rate of asthma exacerbations; Figure 1B shows the change from baseline in FEV1 after bronchodilator therapy; Figure 1C shows the change from baseline in ACQ-6; and Figure 1D shows the change from baseline in AQLQ score. [Figure 1D] Figures 1A-1D show the effects of antibody therapy at different doses on asthma symptoms using various evaluations. Figure 1A shows the rate of asthma exacerbations; Figure 1B shows the change from baseline in FEV1 after bronchodilator therapy; Figure 1C shows the change from baseline in ACQ-6; and Figure 1D shows the change from baseline in AQLQ score. [Figure 2A-2B] Figures 2A and 2B show the effects of antibody therapy in patients treated with glucocorticoids. Figure 2A: The line within the square represents the median, the diamond symbol represents the mean, the box represents the 25th to 75th percentile, and the whiskers represent the range (highest and lowest values). Figure 2B: Histogram of baseline inhaled glucocorticoid dose (fluticasone equivalent). [Figure 3] Figure 3 shows the Kaplan-Meier curves for time to first asthma exacerbation up to week 52 in the intention-to-treat group. *P values ​​are nominal values ​​and have not been 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] Figure 5 shows the change from baseline in exhaled nitric oxide concentration (FENO) of treated subjects. [Figure 6A] Figures 6A and 6B show the annualized rate of asthma exacerbations based on baseline biomarker status at week 52 (Figure 6A), and the change from baseline in exhaled nitric oxide (FENO) (Figure 6B). Figure 6A shows nominal two-sided P-values ​​of <0.05 for comparison with the placebo group. A clinically significant cutoff of 24 ppb was used for FeNO subpopulation analysis. High status with respect to type 2 helper T (Th2) cells was defined as IgE levels greater than 100 IU per milliliter and blood eosinophil counts greater than 140 cells per microliter, while low Th2 status was defined as IgE levels less than 100 IU per milliliter or blood eosinophil counts less than 140 cells per microliter. [Figure 6B]Figures 6A and 6B show the annualized rate of asthma exacerbations based on baseline biomarker status at week 52 (Figure 6A), and the change from baseline in exhaled nitric oxide (FENO) (Figure 6B). Figure 6A shows nominal two-sided P-values ​​of <0.05 for comparison with the placebo group. A clinically significant cutoff of 24 ppb was used for FeNO subpopulation analysis. High status with respect to type 2 helper T (Th2) cells was defined as IgE levels greater than 100 IU per milliliter and blood eosinophil counts greater than 140 cells per microliter, while low Th2 status was defined as IgE levels less than 100 IU per milliliter or blood eosinophil counts less than 140 cells per microliter. [Figure 7-1] Figure 7 (Table 1A) shows the selection and exclusion criteria for subjects. [Figure 7-2] Figure 7 (Table 1A) shows the selection and exclusion criteria for subjects. [Figure 7-3] Figure 7 (Table 1A) shows the selection and exclusion criteria for subjects. [Figure 7-4] Figure 7 (Table 1A) shows the selection and exclusion criteria for subjects. [Figure 8-1] Figure 8 (Table 1B) shows the baseline demographic and clinical characteristics of the intention-to-treat population. [Figure 8-2] Figure 8 (Table 1B) shows the baseline demographic and clinical characteristics of the intention-to-treat population. [Figure 8-3] Figure 8 (Table 1B) shows the baseline demographic and clinical characteristics of the intention-to-treat population. [Figure 9-1] Figure 9 (Table 2) shows the reduction in the annualized asthma exacerbation rate, as well as the changes from baseline in FEV1, ACQ, and AQLQ, in eosinophil subpopulations with <250 cells / μl and ≥250 cells / μl. [Figure 9-2] Figure 9 (Table 2) shows the reduction in the annualized asthma exacerbation rate, as well as the changes from baseline in FEV1, ACQ, and AQLQ, in eosinophil subpopulations with <250 cells / μl and ≥250 cells / μl. [Figure 9-3] Figure 9 (Table 2) shows the reduction in the annualized asthma exacerbation rate, as well as the changes from baseline in FEV1, ACQ, and AQLQ, in eosinophil subpopulations with <250 cells / μl and ≥250 cells / μl. [Figure 10] Figure 10 (Table 3) shows the changes from baseline in ACQ-6 (week 50) and AQLQ(S)+12 (week 48) for the intention-to-treat group. [Figure 11-1] Figure 11 (Table 4) shows the reduction in the annualized asthma exacerbation rate, as well as the changes from baseline in FEV1 (week 52), ACQ-6 (week 50), and AQLQ(S)+12 (week 48): Th2 status and serum periostin in a patient subgroup. [Figure 11-2] Figure 11 (Table 4) shows the reduction in the annualized asthma exacerbation rate, as well as the changes from baseline in FEV1 (week 52), ACQ-6 (week 50), and AQLQ(S)+12 (week 48): Th2 status and serum periostin in a patient subgroup. [Figure 11-3] Figure 11 (Table 4) shows the reduction in the annualized asthma exacerbation rate, as well as the changes from baseline in FEV1 (week 52), ACQ-6 (week 50), and AQLQ(S)+12 (week 48): Th2 status and serum periostin in a patient subgroup. [Figure 11-4] Figure 11 (Table 4) shows the reduction in the annualized asthma exacerbation rate, as well as the changes from baseline in FEV1 (week 52), ACQ-6 (week 50), and AQLQ(S)+12 (week 48): Th2 status and serum periostin in a patient subgroup. [Figure 11-5] Figure 11 (Table 4) shows the reduction in the annualized asthma exacerbation rate, as well as the changes from baseline in FEV1 (week 52), ACQ-6 (week 50), and AQLQ(S)+12 (week 48): Th2 status and serum periostin in a patient subgroup. [Figure 12-1]Figure 12 (Table 5) shows the reduction in the annualized asthma exacerbation rate, as well as the changes from baseline in FEV1 (week 52), ACQ-6 (week 50), and AQLQ(S)+12 (week 48) in a patient subgroup: FENO, allergic status, and current post-BD reversibility. [Figure 12-2] Figure 12 (Table 5) shows the reduction in the annualized asthma exacerbation rate, as well as the changes from baseline in FEV1 (week 52), ACQ-6 (week 50), and AQLQ(S)+12 (week 48) in a patient subgroup: FENO, allergic status, and current post-BD reversibility. [Figure 12-3] Figure 12 (Table 5) shows the reduction in the annualized asthma exacerbation rate, as well as the changes from baseline in FEV1 (week 52), ACQ-6 (week 50), and AQLQ(S)+12 (week 48) in a patient subgroup: FENO, allergic status, and current post-BD reversibility. [Figure 12-4] Figure 12 (Table 5) shows the reduction in the annualized asthma exacerbation rate, as well as the changes from baseline in FEV1 (week 52), ACQ-6 (week 50), and AQLQ(S)+12 (week 48) in a patient subgroup: FENO, allergic status, and current post-BD reversibility. [Figure 12-5] Figure 12 (Table 5) shows the reduction in the annualized asthma exacerbation rate, as well as the changes from baseline in FEV1 (week 52), ACQ-6 (week 50), and AQLQ(S)+12 (week 48) in a patient subgroup: FENO, allergic status, and current post-BD reversibility. [Figure 12-6] Figure 12 (Table 5) shows the reduction in the annualized asthma exacerbation rate, as well as the changes from baseline in FEV1 (week 52), ACQ-6 (week 50), and AQLQ(S)+12 (week 48) in a patient subgroup: FENO, allergic status, and current post-BD reversibility. [Figure 12-7] Figure 12 (Table 5) shows the reduction in the annualized asthma exacerbation rate, as well as the changes from baseline in FEV1 (week 52), ACQ-6 (week 50), and AQLQ(S)+12 (week 48) in a patient subgroup: FENO, allergic status, and current post-BD reversibility. [Figure 13-1]Figure 13 (Table 6) shows the changes from baseline in post-BD FEV1 and pre- and post-BD forced vital capacity at week 52 in the intention-to-treat group. [Figure 13-2] Figure 13 (Table 6) shows the changes from baseline in post-BD FEV1 and pre- and post-BD forced vital capacity at week 52 in the intention-to-treat group. [Figure 13-3] Figure 13 (Table 6) shows the changes from baseline in post-BD FEV1 and pre- and post-BD forced vital capacity at week 52 in the intention-to-treat group. [Figure 14-1] Figure 14 (Table 7) shows the annualized rate of severe asthma exacerbations, the time to the first asthma exacerbation / severe asthma exacerbation, and the percentage of patients who experienced one or more asthma exacerbations at week 52 in the intention-to-treat group. [Figure 14-2] Figure 14 (Table 7) shows the annualized rate of severe asthma exacerbations, the time to the first asthma exacerbation / severe asthma exacerbation, and the percentage of patients who experienced one or more asthma exacerbations at week 52 in the intention-to-treat group. [Figure 14-3] Figure 14 (Table 7) shows the annualized rate of severe asthma exacerbations, the time to the first asthma exacerbation / severe asthma exacerbation, and the percentage of patients who experienced one or more asthma exacerbations at week 52 in the intention-to-treat group. [Figure 15] Figure 15 (Table 8) shows a post-hoc analysis of the reduction in the annualized rate of asthma exacerbations up to week 52, stratified by blood eosinophil count <400 cells / μl versus ≥400 cells / μl. [Figure 16-1] Figure 16 (Table 9) shows the reduction in the annualized asthma exacerbation rate up to week 52, stratified by patients receiving moderate or high-dose inhaled glucocorticoid therapy and patients receiving maintenance oral glucocorticoid therapy. [Figure 16-2] Figure 16 (Table 9) shows the reduction in the annualized asthma exacerbation rate up to week 52, stratified by patients receiving moderate or high-dose inhaled glucocorticoid therapy and patients receiving maintenance oral glucocorticoid therapy. [Figure 17-1]Figure 17 (Table 10) shows the decrease in the annualized asthma exacerbation rate, stratified by the number of previous asthma exacerbations and smoking history*, up to week 52. [Figure 17-2] Figure 17 (Table 10) shows the decrease in the annualized asthma exacerbation rate, stratified by the number of previous asthma exacerbations and smoking history*, up to week 52. [Figure 18-1] Figure 18 (Table 11) shows the change from baseline in the Medimmune ASMA score at week 52. [Figure 18-2] Figure 18 (Table 11) shows the change from baseline in the Medimmune ASMA score at week 52. [Figure 18-3] Figure 18 (Table 11) shows the change from baseline in the Medimmune ASMA score at week 52. [Figure 18-4] Figure 18 (Table 11) shows the change from baseline in the Medimmune ASMA score at week 52. [Figure 19-1] Figure 19 (Table 12) shows all serious adverse events resulting from treatment in the as-treated group. [Figure 19-2] Figure 19 (Table 12) shows all serious adverse events resulting from treatment in the as-treated group. [Figure 19-3] Figure 19 (Table 12) shows all serious adverse events resulting from treatment in the as-treated group. [Figure 19-4] Figure 19 (Table 12) shows all serious adverse events resulting from treatment in the as-treated group. [Figure 19-5] Figure 19 (Table 12) shows all serious adverse events resulting from treatment in the as-treated group. [Modes for carrying out the invention]

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

[0052] definition Unless otherwise specified, the following terms used in this Application, including in the Specification and Claims, have the following definitions:

[0053] When used in the specification and the attached claims, the indefinite articles "a" and "an" and the definite article "the" include plural and singular referents unless the context explicitly indicates otherwise.

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

[0055] The terms “approximately” or “about” mean an acceptable error to a particular value as determined by those skilled in the art, which depends in part on how the value is measured or determined. In certain embodiments, the terms “approximately” or “about” mean within 1, 2, 3, or 4 standard deviations. In certain embodiments, the terms “approximately” or “about” mean within 30%, 25%, 20%, 15%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.5%, or 0.05% of a given number or range. Whenever the terms “approximately” or “about” precede a first number in a set of two or more numbers, it is understood that the terms “approximately” or “about” apply to each of those numbers in the set.

[0056] In this specification, the term "asthma" refers to allergic, non-allergic, eosinophilic, and non-eosinophilic asthma.

[0057] In this specification, the term “allergic asthma” refers to asthma induced by one or more inhaled allergens. Such patients have positive IgE fluorescence immunoassay (FEIA) levels for one or more allergens that trigger an asthmatic response.

[0058] Most allergic asthma cases are typically associated with Th2-type inflammation.

[0059] The term "non-allergic asthma" refers to patients with low eosinophil counts, low Th2 levels, or low IgE levels at the time of diagnosis. Patients with "non-allergic asthma" are typically negative on IgE fluorescence immunoassay (FEIA), which reacts to an allergen panel containing region-specific allergens. In addition to low IgE, these patients often have low or no eosinophil counts and low Th2 levels at the time of diagnosis.

[0060] In this specification, the term “severe asthma” refers to asthma that requires high-intensity treatment (e.g., GINA steps 4 and 5) to maintain good control, or asthma that fails to achieve good control despite high-intensity treatment. (GINA, Global Strategy for Asthma Management and Prevention. Global Initiative for Asthma (GINA), December 2012).

[0061] In this specification, 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 with a blood or serum count of less than 250 cells / μL.

[0062] In this specification, the term "Th2-type inflammation" refers to subjects with a screening serum 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). The "high Th2" asthma population or profile refers to subjects with IgE >100 IU / mL and a serum eosinophil count of ≥140 cells / μL. The "low Th2" asthma population refers to subjects with IgE <100 IU / mL and a serum eosinophil count of ≤140 cells / μL.

[0063] In this specification, "high FeNO" (exhaled nitric oxide concentration) refers to a baseline FeNO measurement value that is above the median of all subjects randomized in the study. High FeNO refers to an FeNO level of 24 or higher.

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

[0065] In this specification, the term "reversibility of current forced expiratory capacity (FEV1) in one second after bronchodilator (BD) administration" refers to a change in FEV1 after BD of ≥12% and ≥200 mL.

[0066] In this specification, the term “asthma exacerbation” refers to an asthma worsening that leads to any of the following: use of systemic corticosteroids for at least three days; a single depot dose of corticosteroids considered equivalent to a three-day course of systemic corticosteroids; for subjects receiving maintenance OCS, a temporary doubling of the maintenance dose for at least three days is eligible; emergency visits due to asthma requiring systemic corticosteroids (as above); or hospitalization due to asthma. Further measures related to asthma exacerbations have also been tested to determine efficacy. These include hospitalizations related to asthma exacerbations (i.e., severe asthma exacerbations), time to first asthma exacerbation, and the percentage of subjects who experienced 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) relating to the subject (subject-driven) or that may be related to daily asthma diary alerts via the ePRO device (diary-driven). The threshold for asthma exacerbation includes a decrease of ≥30% in morning peak flow compared to baseline on at least two consecutive days of three consecutive days (last seven days of the induction period), and / or an increase of ≥50% in rescue medication use compared to the average use of the previous week on at least two consecutive days of three consecutive days (at least two additional puffs or one new or additional β2 agonist inhalation), and / or nocturnal awakenings due to asthma requiring rescue medication on at least two consecutive nights of three consecutive nights, and / or an increase of at least two units in the total asthma symptom score (sum of daytime [evening assessment] and nighttime [morning assessment]) above the average of the screening / induction period (last ten days of the screening / induction period), or the best possible score (daily score of 6), on at least two consecutive days of three consecutive days.

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

[0069] "T helper (Th)1 cytokine" or "Th1-specific cytokine" refers to Th1 "Th2 cytokines" or "Th2-specific cytokines" refer to cytokines expressed (intracellularly and / or secreted) by T cells, including IFN-γ, TNF-α, and IL-12. "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-γ and / or IL-2 in addition to the Th17 cytokines listed herein. Multifunctional CTL cytokines include IFN-γ, TNF-α, IL-2, and IL-17.

[0070] The term "specifically binds" refers to an antibody or polypeptide that is "antigen-specific," "specific," "selective binder," "specific binder," "antigen target," or "immunoreactive" to an antigen and binds to the target antigen with higher affinity than other antigens with similar sequences. In this specification, the drug is considered to specifically bind to target proteins useful for identifying immune cell types, such as surface antigens (e.g., T cell receptor, CD3), cytokines (e.g., TSLP, IL-4, IL-5, IL-13, IL-17, IFN-γ, TNF-α), etc. In various embodiments, the antibody specifically binds to the target antigen but can cross-react with orthologues of closely related species; for example, the antibody may be a human protein and may also bind to closely related primate proteins.

[0071] The terms "antibody" or "immunoglobulin" refer 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 a canonical immunoglobulin at substantially full length (e.g., Immunobiology, 5). th See Edition (Janeway and Travers et al., Eds., 2001). The antigen-binding portion can be generated 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 that have structural changes in canonical tetrameric antibodies. Typically, antibody variants include a V region with a change in the constant region, or, alternatively, the addition of a V region to the constant region in a non-canonical manner. Examples include multispecific antibodies (e.g., bispecific antibodies with an extra V region), antibody fragments capable of binding to antigens (e.g., Fab', F'(ab)2, Fv, single-chain antibodies, bispecific antibodies), and biparatopic peptides and recombinant peptides that exhibit the above insofar as they exhibit the desired biological activity.

[0073] Antibody fragments include, in particular, Fab, Fab', F(ab')2, Fv, domain antibodies (dAb), complementarity-determining region (CDR) fragments, CDR-grafted antibodies, single-chain antibodies (scFv), single-chain antibody fragments, chimeric antibodies, bispecific antibodies, trispecific antibodies, quadruplespecific antibodies, minibodies, linear antibodies; chelated recombinant antibodies, tribodies or vibodies, 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 containing at least a portion of immunoglobulins sufficient to confer specific antigen binding to the polypeptide, such as antigen-binding moieties of antibodies containing 1, 2, 3, 4, 5, or 6 CDR sequences, insofar 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 targets 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 manipulated to become polyvalent.

[0075] A "monoclonal antibody" refers to an antibody obtained from a substantially homogeneous population of antibodies; that is, the individual antibodies that make up that population are identical except for naturally occurring mutations that may exist in small amounts.

[0076] The term "inhibit TSLP activity" includes inhibition of 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 polarization assays in the presence of TSLP; activation or maturation of dendritic cells in the presence of TSLP; and release of mast cell cytokines in the presence of TSLP. See, for example, U.S. Patent No. 7982016B2, column 6 and Example 8, and U.S. Patent Application Publication No. 2012 / 0020988A1, Examples 7-10.

[0077] The terms "sample" or "biological sample" refer to specimens obtained from a subject for use in this method, and include 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, bowel lavage, bronchioloalveolar lavage, nasal lavage, and induced sputum.

[0078] The terms “treat,” “treating,” and “treatment” refer to the temporary or permanent, partial or complete elimination, reduction, suppression, or improvement 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 fields, a drug used as a therapeutic agent may reduce the severity of a given condition, but it does not need to eliminate all symptoms of the disease to be considered a useful therapeutic agent. Similarly, a prophylactically administered treatment does not need to be completely effective in preventing the onset of a condition in order to constitute a viable prophylactic agent. It is sufficient if it merely reduces 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 by reducing the likelihood that the disease will develop or worsen in a 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 time sufficient to induce a sustained improvement above baseline in an index reflecting the severity of a particular disorder.

[0079] The term "therapeutic dose" refers to the amount of a drug that is effective in improving or alleviating the symptoms or signs of 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 room visits, 444,000 hospitalizations annually (Defrances et al, 2008, available at http: / / www.cdc.gov / nchs / data / nhsr / nhsr005.pdf), and 3,500 deaths. In susceptible individuals, asthmatic inflammation causes recurrent episodes of wheezing, shortness of breath, chest tightness, and cough. The etiology of asthma is multifactorial, involving genetic and environmental mechanisms. 1、2 It is influenced by both environmental allergens and the human body, but the latter is considered to be the more important cause. 2、3 The majority of cases occur when a person becomes hypersensitive to allergens (atopy). Atopy is characterized by increased Th2 cell and Th2 cytokine expression and increased IgE production. In the United States, it is estimated that approximately 10 million people suffer from allergy-induced asthma. Despite the availability of treatment options, asthma remains a major health problem. Globally, approximately 300 million people currently suffer from asthma, and this number is projected to reach 400 million by 2020 (Partridge, Eur Resp Rev.16:67-72, 2007).

[0081] Allergen inhalation in patients with atopic asthma can trigger several asthma symptoms, including reversible airflow obstruction, airway hyperresponsiveness, and eosinophilic and basophilic airway inflammation. Allergen inhalation challenge is a dominant 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 asthma subtypes have been identified that do not respond to steroid treatment. Eosinophils are important inflammatory cells in allergic asthma, characterized by their mediation by Th2-type CD4+ T cells. Neutrophilic airway inflammation is associated with corticosteroid treatment in severe asthma and can also be mediated by Th1-type or Th17-type T cells (Mishra et al., Dis. Model. Mech. 6:877-888, 2013).

[0083] The following are included in the diagnostic and evaluation scales for asthma:

[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, the subject inhales to total lung volume through a NIOX MINO® Airway Inflammation Monitor and then exhales at 50 mL / second for 10 seconds (assisted by visual and auditory cues).

[0085] Vital capacity measurements will be performed according to the 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 3 but no more than 8) will be performed in each vital capacity measurement session, and two best-effort measurements that meet the ATS / ERS acceptability and reproducibility criteria will be recorded. The best-effort measurements will be based on the highest FEV1. The maximum FEV1 of the two best-effort measurements will be used for analysis. Both absolute values ​​(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 that produced it (even if the effort did not result in the highest FEV1).

[0086] The post-BD (post-bronchodilator) vital capacity measurement test is evaluated after the subject has undergone a pre-BD vital capacity measurement. Maximum bronchiectasis is induced using a SABA such as albuterol (90 μg dose) or salbutamol (100 μg dose) or an equivalent spacer device for up to 8 total puffs (Sorkness et al, J Appl Physiol. 104(2):394-403, 2008). The best pre-BD and post-BD FEV1 obtained after 4, 6, or 8 puffs are used for reversibility determination and analysis. The reversibility algorithm is as follows: % reversibility=(FEV1 after BD-FEV1 before BD)×100 / FEV1 before BD

[0087] A home peak flow test for peak expiratory flow rate (PEFR) should be performed twice daily, in the morning upon waking and in the evening before bedtime, using a peak flow meter, from the morning of the second hospital visit (week 4) until week 64. If possible, outpatient pulmonary function tests should be performed at least 6 hours after the last administration 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; asthma-related activity limitations; asthma-related stress; and background medication compliance. The asthma diary is completed every morning and evening. The ePRO device has a trigger to alert the subject to signs of asthma exacerbation.

[0089] The Asthma Control Questionnaire (ACQ)-6 is a patient-reported questionnaire that assesses asthma symptoms (i.e., nighttime awakenings, symptoms upon waking, activity limitations, shortness of breath, wheezing), daily rescue bronchodilator use, and FEV1 (Juniper et al, Oct 1999). ACQ-6 is a shortened version of the ACQ, omitting FEV1 measurement from the original ACQ score. The questions are equally weighted and scored from 0 (fully controlled) to 6 (partially uncontrolled). The mean ACQ score is the average of the responses. A mean score ≤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). Individual changes of at least 0.5 are 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, Affective Functioning, and Environmental Irritation. Participants 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). The overall score is calculated as the average response to all questions. The scores for the four individual domains (Symptoms, Activity Limitations, Affective Functioning, and Environmental Irritation) are the average responses to the questions in each domain. An improvement of 0.5 in both the overall score and individual domain scores was identified as a minimally significant change, while a score change of ≥1.5 was identified as a large, significant change (Juniper et al, J Clin Epidemiol. 47(1):81-7, 1994).

[0091] TSLP Thymic stromal lymphocyte necrosis factor (TSLP) is an epithelial cell-derived cytokine produced in response to pro-inflammatory stimuli that 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 are transmitted via a heterodimer receptor consisting of an interleukin (IL)-7 receptor alpha (IL-7Rα) chain and a 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 It 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 10 Recent studies have demonstrated a link between single nucleotide polymorphisms (SNPs) at the human TSLP 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 nonclinical studies of TSLP suggested that after being released from airway epithelial or stromal cells, TSLP activates mast cells, dendritic cells, and T cells, leading to the release of Th2 cytokines (e.g., IL-4 / 13 / 5). Recent human data have shown a good correlation between tissue TSLP genes and protein expression, Th2 gene signature score, and tissue eosinophils in severe asthma. Therefore, anti-TSLP targeted therapy may be effective in 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 via 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, cited above). TSLP may also promote T cell induction and differentiation 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 / 13 / 5).

[0095] antibody Antibodies or antibody variants specific to TSLP are considered useful in the treatment of asthma, including severe asthma, eosinophilic asthma, noneosinophilic / hypeosinophilic asthma, and other forms of asthma as described herein.

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

[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 chain (H) and / or light chain (L) originates from a particular species or is identical or homologous to a corresponding sequence in an antibody belonging to a particular antibody class or subclass, and the remainder of the chain originates from another species or is identical or homologous to a corresponding sequence in an antibody belonging to another antibody class or subclass. Fragments of such antibodies are also included, insofar as they exhibit the desired biological activity. See U.S. Patent No. 4,816,567; Morrison et al., 1985, Proc. Natl. Acad. Sci. 81:6851-55.

[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 from a non-human source. Humanization can be carried out, for example, by substituting at least a portion of the complementarity-determining region of a rodent with 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 included in the present invention. Using genetically modified animals (e.g., mice) capable of producing a repertoire of human antibodies without producing endogenous immunoglobulins, such antibodies are produced by immunization with polypeptide antigens (i.e., having at least six consecutive amino acids) optionally conjugated to a carrier. See, for example, 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 publication 96 / 05928 and PCT application publication 93 / 06926. Further methods are described in U.S. Patent No. 5,545,807, PCT Application Publication No. 91 / 245 and PCT / GB89 / 01207, and European Patent No. 546073B1 and European Patent Publication No. 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. The nucleic acid encoding the antibody is introduced into a host cell and expressed using the materials and procedures described herein. In preferred embodiments, the antibody is produced in mammalian host cells, such as CHO cells. Monoclonal (e.g., human) antibodies may be produced by the expression of recombinant DNA in host cells or by expression in hybridoma cells as described herein.

[0101] The antibodies and antibody variants (including antibody fragments) useful in this method include an anti-TSLP antibody, which comprises a light chain CDR1 sequence containing the amino acid sequence shown in ai SEQ ID NO: 3; ai SEQ ID NO: 4; ai SEQ ID NO: 4; ai SEQ ID NO: 4; ai SEQ ID NO: 5; ai SEQ ID NO: 5; ai SEQ ID NO: 3; ai SEQ ID NO: 4; ai SEQ ID NO: 4; ai SEQ ID NO: 4; ai SEQ ID NO: 4; ai SEQ ID NO: 54; ai SEQ ID The antibody or antibody variant comprises a heavy chain variable domain including a heavy chain CDR1 sequence containing the amino acid sequence shown in SEQ ID NO: 6; a heavy chain CDR2 sequence containing the amino acid sequence shown in SEQ ID NO: 7; and a heavy chain CDR3 sequence containing the amino acid sequence shown in SEQ ID NO: 8. This antibody or antibody variant specifically binds to the TSLP polypeptide shown in amino acids 29-159 of SEQ ID NO: 2.

[0102] Furthermore, a light chain variable domain selected from the group consisting of: a. an amino acid sequence having at least 80% identity with SEQ ID NO: 12; ii. an amino acid sequence encoded by a polynucleotide sequence having at least 80% identity with SEQ ID NO: 11; iii. an amino acid sequence encoded by a polynucleotide that hybridizes with a complementary polynucleotide of SEQ ID NO: 11 under moderately stringent conditions; and A heavy chain variable domain selected from the group consisting of: bi. an amino acid sequence having at least 80% identity with SEQ ID NO: 10; ii. an amino acid sequence encoded by a polynucleotide sequence having at least 80% identity with SEQ ID NO: 9; iii. an amino acid sequence encoded by a polynucleotide that hybridizes with a polynucleotide complement of SEQ ID NO: 9 under moderately stringent conditions; or c. an antibody or antibody variant containing the light chain variable domain of (a) and the heavy chain variable domain of (b), wherein the antibody or antibody variant specifically binds to the TSLP polypeptide represented by amino acids 29-159 of SEQ ID NO: 2.

[0103] Tezeperumab is an exemplary anti-TSLP antibody having a light chain CDR1 sequence containing the amino acid sequence shown in ai SEQ ID NO: 3; ii. a light chain CDR2 sequence containing the amino acid sequence shown in SEQ ID NO: 4; iii. a light chain CDR3 sequence containing the amino acid sequence shown in SEQ ID NO: 5, and a heavy chain variable domain containing a heavy chain CDR1 sequence containing the amino acid sequence shown in bi SEQ ID NO: 6; ii. a heavy chain CDR2 sequence containing the amino acid sequence shown in SEQ ID NO: 7; and iii. a heavy chain CDR3 sequence containing the amino acid sequence shown in SEQ ID NO: 8.

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

[0105] Tezeperumab is an IgG2 antibody. The full-length heavy and light chain sequences of tezeperumab, including the IgG2 chain, are shown in SEQ ID NOs. 105 and 106, respectively.

[0106] In various embodiments, the anti-TSLP antibody or its antibody variant is bivalent and is selected from the group consisting of human antibodies, humanized antibodies, chimeric antibodies, monoclonal antibodies, recombinant antibodies, antigen-binding antibody fragments, single-chain antibodies, monomeric antibodies, bispecific antibodies, triplicate antibodies, quadruplespecific antibodies, Fab fragments, IgG1 antibodies, IgG2 antibodies, IgG3 antibodies, and IgG4 antibodies.

[0107] In various embodiments, the anti-TSLP antibody variant is selected from the group consisting of bispecificity antibodies, tripspecificity antibodies, quadrupspecificity antibodies, Fab fragments, single-domain antibodies, and scFv, and its dose is adjusted so that the binding site is equimolar to that of when administered by a bivalent antibody.

[0108] The antibody or antibody variant is considered to be an IgG2 antibody. An exemplary sequence of the 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 through the Uniprot database and other databases well known to technicians in the field 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 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 are deleted from or substituted with another amino acid (e.g., serine) compared to the parent amino acid sequence. Cysteine ​​variants may be useful when the antibody needs to be refolded into a biologically active conformation, such as after isolation of insoluble inclusion bodies. Cysteine ​​variants generally have fewer cysteine ​​residues than the native protein and usually have an even number to minimize interactions arising from unpaired cysteines.

[0110] The desired amino acid substitutions (whether conserved or non-conservative) can be determined by those skilled 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 against human TSLP, or to increase or decrease the affinity of antibodies against 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 protein complex formation, (4) alter binding affinity, and / or (4) confer or modify other physiological or functional properties to such polypeptide. According to certain embodiments, one or more amino acid substitutions (conservative amino acid substitutions in certain embodiments) may be made in naturally occurring sequences (in certain embodiments, portions of the polypeptide outside the domains that form intermolecular contacts). In certain embodiments, conservative amino acid substitutions typically do not substantially alter the structural features of the parent sequence (for example, the substituted amino acid would not tend to disrupt helices present in the parent sequence or other types of secondary structures that characterize the parent sequence). Examples of polypeptide secondary and tertiary structures recognized in the art are described in Proteins, Structures and Molecular Principles (Creighton, Ed., WH 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), which are incorporated herein by reference, respectively.

[0112] Method of administration In one embodiment, the method of this disclosure includes administering a therapeutic anti-TSLP antibody or antibody variant described herein, optionally encapsulated in a pharmaceutically acceptable carrier or excipient. In certain embodiments, the pharmaceutical composition is a sterile composition.

[0113] This specification envisions methods for treating asthma in subjects, including severe asthma, eosinophilic or noneosinophilic asthma, and hypoeosinophilic asthma. Surprisingly, it was found herein that treatment with anti-TSLP antibodies is effective in reducing asthma symptoms in the aeosinophilic / hypeosinophilic population as well as in the hypereosinophilic population. Furthermore, methods for reducing the frequency of asthma exacerbations in subjects are envisioned.

[0114] This specification also envisions methods for treating asthma in subjects with a high or low Th2 asthma profile. TSLP antagonists, which inhibit the binding of TSLP protein to its receptor complex, are considered to be effective in treating the low eosinophilic asthma population, similar to the antibodies described herein. Similarly, TSLP antagonists, which inhibit the binding of TSLP to its receptor complex, are considered to be effective in treating the low Th2 asthma population.

[0115] This specification provides a method for treating patients with hypoeosinophilic asthma, comprising administering an anti-TSLP antibody. Furthermore, a method for treating asthma subjects characterized by a low Th2 profile, comprising administering an anti-TSLP antibody, is envisioned. In various embodiments, the antibody is tezeperumab or another anti-TSLP antibody described in the art. Exemplary anti-TSLP antibodies include those described in International Publication No. 2017 / 042701, International Publication No. 2016 / 142426, International Publication No. 2010 / 017468, U.S. Patent Application Publication No. 20170066823, U.S. Patent Application Publication No. 20120020988, and U.S. Patent No. 8637019, some of which are listed in Table A below. In exemplary embodiments, 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] Furthermore, methods for treating chronic obstructive pulmonary disease (COPD) in subjects are being considered, including the administration of anti-TSLP antibodies or antibody variants.

[0124] The subjects being treated are expected to be human. The subjects may be adults, adolescents, or children.

[0125] Therapeutic antibody (or antibody variant) compositions can be delivered to the patient at multiple sites. Multiple doses may be administered simultaneously or over a period of time. In certain cases, it is beneficial to provide a continuous flow of the therapeutic composition. Additional treatments may be administered on a period-based basis, for example, hourly, daily, weekly, every two weeks, every three weeks, 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, may vary depending on the size of the individual being treated and the characteristics of the disorder being treated.

[0127] In exemplary treatments, the anti-TSLP antibody or antibody variant is administered in a dose range of approximately 70 mg to approximately 280 mg per day. For example, doses may be approximately 70 mg, 210 mg, or 280 mg. In various embodiments, the anti-TSLP antibody or antibody variant may be administered in doses 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 single dose. These concentrates may be administered as single doses or in repeated doses. The above doses are administered every two weeks or every four weeks. In various embodiments, the anti-TSLP antibody or antibody variant is administered as a single dose of 70 mg every two weeks or every four weeks. In various embodiments, the anti-TSLP antibody or antibody variant is administered as a single dose of 210 mg every two or four weeks. In various embodiments, the anti-TSLP antibody or antibody variant is administered as a single dose of 280 mg every two or four weeks.

[0128] Regarding antibody variants, the amount of the antibody variant should be such that the number of TSLP binding sites in the dose is equimolar to that of the canonical bivalent antibody.

[0129] The anti-TSLP antibody or antibody variant is expected to be administered every two weeks or every four weeks for a period of at least four months, six months, nine months, one year, or longer. In various embodiments, administration is subcutaneous or intravenous.

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

[0131] Improvement in asthma can be assessed by one or more of the following: a decrease in AER (annualized exacerbation rate), a decrease in hospitalizations / severe exacerbations due to asthma, a change from baseline in time to first asthma exacerbation (increase) (after initiation of treatment with anti-TSLP antibody), a decrease in the proportion of subjects with one or more asthma exacerbations or severe exacerbations over the course of treatment, e.g., over 52 weeks, compared to placebo, a change in FEV1 and FVC from baseline (increase) (before and after bronchodilator administration), a change from baseline in blood or sputum eosinophils (or pulmonary eosinophils if biopsy or BAL fluid is available) (decrease), a change from baseline in FeNO (decrease), a change from baseline in IgE (decrease), improvement in asthma symptoms and control as assessed by ACQ and modified versions, AQLQ and modified versions, SGRQ, and the Asthma Symptom Diary PRO, a change in rescue medication use (decrease), a decrease in systemic corticosteroid use, and a decrease in the blood Th2 / Th1 cell ratio. Most / all of these assessments should be performed in the whole population and subpopulations, including high and low eosinophil counts (high if ≥ 250, low if < 250), allergic and non-allergic, high and low Th2, high and low periostin (compared to the median), and high and low FeNO (≥ 24 or < 24).

[0132] Treatment also improves one or more asthma symptoms, as evaluated by an asthma symptom diary. Symptoms include the frequency and severity of daytime and nighttime symptoms, activity avoidance and limitation, asthma-related stress and fatigue, and use of rescue asthma medications), and other evaluations of asthma control as evaluated by an asthma control questionnaire (ACQ-6) omitting FEV1, but are not limited thereto.

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

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

[0135] However, in various embodiments, its administration is thought to reduce the frequency or level of co-administered treatment in a subject. Exemplary co-administered treatments include, but are not limited to, inhaled corticosteroids (ICS), long-acting β2 agonists (LABA), leukotriene receptor antagonists [LTRA], long-acting anti-muscarinic agents [LAMA], cromones, short-acting β2 agonists (SABA), and theophylline or oral corticosteroids. In various embodiments, its administration eliminates the need for corticosteroid treatment.

[0136] Formulations In some embodiments, the present disclosure contemplates the use of a pharmaceutical composition 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. Further, the present disclosure provides a method of treating a subject by administering such a pharmaceutical composition.

[0137] In certain embodiments, acceptable formulation materials are preferably nontoxic to the recipient at the dose and concentration used. In certain embodiments, the pharmaceutical composition may contain formulation materials for modifying, maintaining, or preserving, for example, the pH, molar osmotic pressure, viscosity, clarity, color, isotonicity, odor, sterility, stability, dissolution or release rate, or adsorption or permeability of the composition. In such embodiments, suitable formulation materials include amino acids (such as glycine, glutamine, asparagine, arginine, or lysine); antibacterial agents; antioxidants (such as ascorbic acid, sodium sulfite, or sodium bisulfite); buffering agents (such as borates, bicarbonates, tris-HCl, citrates, phosphates, or other organic acids); bulking agents (such as mannitol or glycine); chelating agents (such as ethylenediaminetetraacetic acid (EDTA)); complexing agents (such as caffeine, polyvinylpyrrolidone, beta-cyclodextrin, or hydroxypropyl-beta-cyclodextrin); fillers; monosaccharides; disaccharides; and other carbohydrates (such as glucose, sucrose, mannose, or dextrin); proteins (such as serum albumin, gelatin, or immunoglobulin); colorants, flavorings, and diluents; emulsifiers; hydrophilic polymers (such as polyvinylpyrrolidone); low molecular weight polypeptides; and salt formation agents. 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 Pluronic acid, PEG, sorbitan esters, polysorbate 20, polysorbate, Triton, tromethamine, lecithin, cholesterol, tyloxapal, etc.); stability enhancers (such as sucrose or sorbitol); isotonic enhancers (such as alkali metal halides, preferably sodium or potassium chloride, mannitol, or sorbitol); delivery vehicles; diluents; excipients and / or pharmaceutical adjuvants.See REMINGTON'S PHARMACEUTICAL SCIENCES, 18'' Edition, (ARGenrmo, ed.), 1990, Mack Publishing Company.

[0138] A suitable vehicle or carrier may be water for injection, saline solution, or artificial cerebrospinal fluid, and may be supplemented with other materials common in compositions for parenteral administration. Neutral buffered saline or saline solution mixed with serum albumin are further exemplary vehicles. In certain embodiments, the pharmaceutical composition comprises Tris buffer at approximately pH 7.0–8.5, or acetate buffer at approximately pH 4.0–5.5, and may further comprise sorbitol or a suitable substitute thereof.

[0139] The formulation components are preferably present at the administration site in an acceptable concentration. In certain embodiments, buffers are used to maintain the composition at a physiological pH or slightly lower, typically within a pH range of about 5 to about 8. These include 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% (weight / volume) sucrose, and 0.015% (weight / volume) ± 0.005% (weight / volume) polysorbate 20 or polysorbate 80. Optionally, the antibody or antibody fragment is present at a concentration of 70 mg / ml. The formulation can be stored at -20°C to -70°C.

[0141] Where parenteral administration is considered, the therapeutic composition for use may be provided in the form of a parenterally acceptable aqueous solution containing the desired anti-TSLP antibody in a pharmaceutically acceptable vehicle, and free of pyrogens. 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 include formulations of desired molecules containing the drug, such as injectable microspheres, biodegradable particles, polymeric compounds (such as polylactic acid or polyglycolic acid), beads, or liposomes, which may provide sustained or prolonged release of the product that can be delivered via accumulation injection. In certain embodiments, hyaluronic acid, which has the effect of increasing the duration of action in circulation, may also be used. In certain embodiments, an implantable drug delivery device may be used to introduce the antibody. [Examples]

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

[0143] This example describes a multicenter, placebo-controlled, parallel-group, double-blind Phase 2 trial conducted at 108 research sites across 12 countries. Eligible patients were 18–75 years of age and had received medium-dose (250–500 μg daily fluticasone via dry powder inhaler or equivalent) or high-dose (>500 μg daily fluticasone via dry powder inhaler or equivalent) inhaled glucorticoids (severe asthma) at least 6 months prior to enrollment. 24Participants were current non-smokers (≥6 months, <10 packs-years of smoking history) with asthma that was not adequately controlled despite treatment with LABA (as defined in the GINA 2012 guidelines). 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 12 months prior to participation in the trial. Additional eligibility criteria included a forced expiratory capacity (FEV1) of at least 40% and ≤80% of the predicted value before bronchodilator administration, reversibility of at least 12% and at least 200 ml after bronchodilator administration, and a score of at least 1.5 on the 6-item Asthma Control Questionnaire (ACQ-6) during screening (range 0-6, with lower scores indicating better disease control; minimum clinically significant difference 0.5). 26 Exclusion criteria included clinically significant lung diseases 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) tezeperumab (a bivalent antibody with the same binding site as TSLP) or placebo, according to a central interactive voice response or web-based response system. Randomization was stratified by location (Japan or other parts of the world), serum eosinophil count (≥250 cells / μl or <250 cells / μl) measured in a local laboratory, and inhaled glucocorticoid dose level (medium or high, according to GINA 2012 guidelines). 26 Patients receiving maintenance therapy with oral glucocorticoids were randomized to the high-dose inhaled glucocorticoid group. Tezeperumab and placebo were prepared by facility staff who were aware of the group assignment and were not involved in the evaluation of the trial. The investigational drugs were visually similar and administered by staff who were unaware of the group assignment. Background asthma control therapy was maintained at a stable dose throughout the treatment period.

[0145] procedure During the study period, patients were randomly assigned to receive tezeperumab 70 mg every 4 weeks (Q4W, low dose), 210 mg every 4 weeks (Q4W, medium dose), or 280 mg every 2 weeks (Q2W, high dose) via SC injection, or placebo every 2 weeks (Q2W). To maintain blinding, patients randomly assigned to the Q4W regimen received placebo at their mid-term visit.

[0146] Throughout the 5-week screening period, the exhaled nitric oxide concentration (Fe) before and after bronchodilator administration was measured. NO Baseline measurements were obtained for lung capacity measurement, blood eosinophil count, ACQ-6 score, and the standardized Asthma Quality of Life Questionnaire (AQLQ[S]+12 [hereinafter referred to as AQLQ]) 27 score for individuals 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 using electronic devices. Safety was monitored at each research facility from enrollment to 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 leading to any of the following: 1) use of systemic glucocorticoids (oral or injectable), or, in the case of maintenance therapy with oral glucocorticoids, doubling of the dose for three or more days; 2) emergency visit due to asthma leading to systemic glucocorticoid treatment; or 3) hospitalization due to asthma. An asthma exacerbation was defined as any new or exacerbated symptom or sign that is of concern to the patient or associated with an asthma diary-driven alert.

[0148] Secondary endpoints included changes from baseline in FEV1 (an increase in value indicates improved lung function; the minimum clinically important difference is 100-200 ml), ACQ-6 score, AQLQ score, asthma symptom score, forced vital capacity (FVC), and 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 (changes from baseline in pre-bronchodilator FEV1, ACQ-6 score, AQLQ score, and asthma symptom score) were also evaluated, as well as serum eosinophil count (≥250 or <250 cells per microliter), Th2 status (high [IgE level >100 IU per milliliter and serum eosinophil count ≥140 cells per microliter], or low [IgE level ≤100 IU per milliliter or serum eosinophil count <140 cells per microliter]), 30 FENO levels (based on baseline median and a clinically significant cutoff of 24 ppb), 31 In pre-specified subpopulations, serum periostin levels (high or low based on the median baseline level), current (as indicated during the screening period) FEV1 reversibility after bronchodilator use, and allergic status (defined as positive or negative IgE fluorescence immunoassay at baseline) were also evaluated.

[0150] The primary endpoint was also stratified according to the dose level of inhaled glucocorticoids (medium or high dose), whether or not oral glucocorticoid maintenance therapy was administered, and the number of asthma exacerbations in the past 12 months (pre-specified subgroup analysis). Post-hoc analyses included stratification of the primary endpoint according to baseline serum eosinophil count (<400 or ≥400 cells per microliter) and patient smoking history.

[0151] statistical analysis The efficacy analysis was conducted according to the randomized trial group, based on the intention-to-treat (ITT) population of patients who received randomization and at least one dose of tezepelumab or placebo. The safety analysis was based on the as-treated population and included all patients who received at least one dose of tezepelumab or placebo, and the patients were evaluated according to the investigational drug administered.

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

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

[0154] The primary endpoint was continuously tested to control the overall type I error rate at 0.1. The 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 was applied for the multiplicity of secondary endpoints. Nominal P values are shown. All analyses were performed using SAS version 9.3.

[0155] Results Patients Analysis A, a primary analysis after database lock-up, including all clinical trial sites: A total of 918 subjects were screened and 584 patients were randomized: 145 were assigned to low-dose tezeperumab (70 mg Q4W), 145 to medium-dose tezeperumab (210 mg Q4W), 146 to high-dose tezeperumab (280 mg Q2W), and 148 to placebo. Among patients receiving tezeperumab or placebo and included in the ITT population, 391 (89.7%) and 139 (93.9%) completed treatment, respectively. Baseline and clinical characteristics were similar between the groups.

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

[0157] Primary endpoints Treatment with tezeperumab resulted in annualized asthma exacerbation rates of 0.25, 0.18, and 0.22 in the low-dose, medium-dose, and high-dose groups, respectively, compared to 0.67 in the placebo group. Therefore, 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), respectively, lower in the tezeperumab groups than in the placebo group (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 tezeperumab group than in the placebo group, regardless of baseline eosinophil count or other assessment indicators of Th2 status (Figure 2A; Figure 6; Table 2; Tables 4 and 5, 7, 9 and 10). Among patients in the medium-dose inhaled glucocorticoid group, low-dose, medium-dose, and high-dose tezeperumab resulted in annualized asthma exacerbation rates of 0.19, 0.14, and 0.20 at week 52, compared to 0.37 in placebo. These rates in the tezeperumab group were 49% (95% CI, -14 to 77; P=0.10), 62% (95% CI, 8 to 84; P=0.03), and 47% (95% CI, 41-20 to 76; P=0.13), respectively, lower than the rate in the placebo group. Among patients in the high-dose inhaled glucocorticoid group, low-dose, medium-dose, and high-dose tezeperumab resulted in annualized asthma exacerbation rates of 0.32, 0.23, and 0.24 at week 52, compared to 0.96 in placebo. These rates in the tezeperumab 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), respectively, lower than the placebo group (Table 9). When patients were stratified according to the number of asthma exacerbations in the past 12 months, the annualized asthma exacerbation rates were lower than in the placebo group in some, but not all, tezeperumab groups, and this was also the case in a post-hoc analysis following smoking history (Table 10).

[0159] The time to the first asthma exacerbation was longer in the tezeperumab group than in the placebo group. The risk of 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-dose, medium-dose, and high-dose tezeperumab groups compared to the placebo group (Figure 3 and Table 7).

[0160] Across the entire population, the change from baseline in pre-BD FEV1 at week 52 was greater in the low-dose, medium-dose, and high-dose tezeperumab groups than in the placebo group by 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), respectively (Table 2 and Figure 1B). Similar differences were observed when pre-BD FEV1 was measured as a percentage of the predicted value (Table 2). The therapeutic effect was observed as early as week 4 (the first time point evaluated) and persisted throughout the study (Figure 1B, Table 2).

[0161] The effects of tezeperumab on further 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 the first severe asthma exacerbation, and the changes 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 in Tables 3, 5, 6, and 12. The effects of tezeperumab on subgroup-specific secondary endpoints (pre-bronchodilator FEV1, ACQ-6 score, AQLQ score, and asthma symptom score) are shown in Tables 2, 4, 5, and 12.

[0162] biomarkers Substantial and sustained decreases in serum eosinophils and FeNO were observed in all tezeperumab treatment groups, beginning at 4 weeks post-treatment (the first time point evaluated) and maintained over time (Figures 4, 5, and 6). Progression of the decrease was also observed in serum total IgE in all tezeperumab groups (Figure 4A).

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

[0164] Three serious adverse events related to the investigational drug occurred: two in the same patient in the low-dose tezeperumab group (pneumonia and stroke), and one in the medium-dose tezeperumab group (Guillain-Barré syndrome). The discontinuation rate due to adverse events was 1.1% in patients receiving tezeperumab (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 tezeperumab group died 8 weeks after the end of the treatment period due to a serious treatment-related 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% in the low-dose tezeperumab group, 2.8% in the medium-dose group, and 1.4% in the high-dose group. The rates after a 1.5 mL injection were 2.7%, 2.1%, 2.8%, and 3.4% in each group, respectively. No anaphylactic reactions related to the investigational drug were reported. After baseline, anti-drug antibody positivity was observed in 13 out of 148 patients (8.8%) in the placebo group, 7 out of 144 patients (4.9%) in the low-dose tezeperumab group, 0 out of 144 patients in the medium-dose group, and 3 out of 143 patients (2.1%) in the high-dose group. Neutralizing antibodies were not detected.

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

[0167] In Analysis B, the baseline dose range of inhaled glucocorticoids in patients was similar to that in Analysis A. The median fluticasone administered via a dry powder inhaler or equivalent to the medium-dose inhaled glucocorticoid group was 400 μg per day, with 73 patients in the placebo group, 71 in the low-dose tezepermab group, 70 in the medium-dose group, and 72 in the high-dose group. The median fluticasone administered via a dry powder inhaler or equivalent to the high-dose inhaled glucocorticoid group was 1000 μg per day, with 75, 74, 75, and 74 patients in the respective study groups.

[0168] Primary endpoints Treatment with tezeperumab resulted in annualized asthma exacerbation rates of 0.26, 0.19, and 0.22 exacerbations in the low-dose, medium-dose, and high-dose groups at week 52, compared to 0.67 exacerbations in the placebo group. Therefore, 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), respectively, lower in the tezeperumab groups than in the placebo group (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 tezeperumab group than in the placebo group, regardless of baseline eosinophil count or other assessment indicators of Th2 status (Figure 2A; Table 2; Tables 4 and 5, 7, 9 and 10). Among patients in the medium-dose inhaled glucocorticoid layer, low-dose, medium-dose, and high-dose tezeperumab resulted in annualized asthma exacerbation rates of 0.19, 0.15, and 0.20 at week 52, compared to 0.38 in placebo. These rates in the tezeperumab 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), respectively, lower than the rate in the placebo group. Among patients in the high-dose inhaled glucocorticoid group, low-dose, medium-dose, and high-dose tezeperumab resulted in annualized asthma exacerbation rates of 0.33, 0.23, and 0.24 at week 52, compared to 0.96 in placebo. These rates in the tezeperumab 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), respectively, lower than the placebo group (Table 9). When patients were stratified according to the number of asthma exacerbations in the past 12 months, the annualized asthma exacerbation rate was lower than in the placebo group in some, but not all, tezeperumab groups, and was also lower in a post-hoc analysis following smoking history (Table 10).

[0170] The time to the first asthma exacerbation was longer in the tezeperumab group than in the placebo group. The risk of 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-dose, medium-dose, and high-dose tezeperumab groups compared to the placebo group (Figure 3 and Table 7).

[0171] Across the entire population, the change from baseline in pre-BD FEV1 at week 52 was greater in the low-dose, medium-dose, and high-dose tezeperumab groups than in the placebo group by 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), respectively (Table 2 and Figure 1B). Similar differences were observed when pre-BD FEV1 was measured as a percentage of the predicted value (Table 2). The therapeutic effect was observed as early as week 4 (the first time point evaluated) and persisted throughout the study (Figure 1B, Table 2).

[0172] The effects of tezeperumab on further 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 the first severe asthma exacerbation, and the changes 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, yielding Table 2 and Figures 1C and 1D, and Tables 3, 5, 6, and 12. The effects of tezeperumab on subgroup-specific secondary endpoints (pre-bronchodilator FEV1, ACQ-6 score, AQLQ score, and asthma symptom score) are shown in Tables 2, 4, 5, and 12.

[0173] biomarkers Substantial and sustained decreases in serum eosinophils and FeNO were observed in all tezeperumab treatment groups, beginning at 4 weeks post-treatment (the first time point evaluated) and maintained over time (Figures 2 and 4). Progression of the decrease was also observed in serum total IgE in all tezeperumab groups (Figure 2B).

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

[0175] Three serious adverse events related to the investigational drug occurred: two in the same patient in the low-dose tezeperumab group (pneumonia and stroke), and one in the medium-dose tezeperumab group (Guillain-Barré syndrome). The discontinuation rate due to adverse events was 1.1% in patients receiving tezeperumab (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 tezeperumab group died 8 weeks after the end of the treatment period due to a serious treatment-related 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% in the low-dose tezeperumab group, 2.8% in the medium-dose group, and 1.4% in the high-dose group. The rates after a 1.5 mL injection were 2.7%, 2.1%, 2.8%, and 3.4% in each group, respectively. No anaphylactic reactions related to the investigational drug were reported. After baseline, anti-drug antibody positivity was observed in 13 out of 148 patients (8.8%) in the placebo group, 7 out of 144 patients (4.9%) in the low-dose tezeperumab group, 1 out of 140 patients (0.7%) in the medium-dose group, and 3 out of 142 patients (2.1%) in the high-dose group. Neutralizing antibodies were not detected.

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

[0178] Analysis C omitted single-site results after data locking. Based on the research sponsor's concerns regarding data integrity at one clinical site enrolled in the Phase 2 study, patients from this site were omitted, and the data from Analysis B was re-analyzed after data locking. In this secondary analysis, 367 (89.1%) and 129 (93.5%) of patients receiving tezeperumab or placebo and included in the ITT population completed treatment. Baseline and clinical characteristics were similar between the groups. Analysis C is consistent with the results of the previous analysis.

[0179] In Analysis C, 138 patients were randomly assigned to low-dose tezeperumab (70 mg Q4W), 137 to medium-dose tezeperumab (210 mg Q4W), 137 to high-dose tezeperumab (280 mg Q2W), and 138 to placebo. Of the patients who received tezeperumab or placebo and were included in the ITT population (excluding patients from omitted facilities), 367 (89.1%) and 129 (93.5%), respectively, completed treatment. Baseline and clinical characteristics were similar between the groups.

[0180] The baseline dose range of inhaled glucocorticoids for patients in Analysis B was similar to that of Analyses A and B, as shown in Figures 2A and 2B. The median fluticasone administered to the medium-dose inhaled glucocorticoid group via a dry powder inhaler or equivalent means was 400 μg per day, with 73 patients in the placebo group, 67 in the low-dose tezepermab group, 70 in the medium-dose group, and 71 in the high-dose group. The median fluticasone administered to the high-dose inhaled glucocorticoid group via a dry powder inhaler or equivalent means was 1000 μg per day, with 65, 71, 67, and 66 patients in the respective study groups.

[0181] Primary endpoints Treatment with tezeperumab resulted in annualized asthma exacerbation rates of 0.27, 0.20, and 0.23 exacerbations in the low-dose, medium-dose, and high-dose groups, respectively, compared to 0.72 exacerbations in the placebo group. Therefore, 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), respectively, lower in the tezeperumab groups than in the placebo group. 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 tezeperumab group than in the placebo group, regardless of baseline eosinophil count or other assessment indicators of Th2 status. Among patients in the intermediate-dose inhaled glucocorticoid group, low-dose, intermediate-dose, and high-dose tezeperumab resulted in annualized asthma exacerbation rates of 0.20, 0.15, and 0.20 at week 52, compared to 0.38 in placebo. These rates in the tezeperumab 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), respectively, lower than the rate in the placebo group. Among patients in the high-dose inhaled glucocorticoid group, low-dose, medium-dose, and high-dose tezeperumab resulted in annualized asthma exacerbation rates of 0.35, 0.26, and 0.27 at week 52, compared to 1.12 in the placebo group. These rates in the tezeperumab 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), respectively, lower than the placebo group. When patients were stratified according to the number of asthma exacerbations in the previous 12 months, the annualized asthma exacerbation rates were lower than in the placebo group in some, though not all, tezeperumab groups, and were also lower in the post-hoc analysis following smoking history.

[0183] The time to the first asthma exacerbation was longer in the tezeperumab group than in the placebo group. The risk of 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-dose, medium-dose, and high-dose tezeperumab groups compared to the placebo group.

[0184] In the analyzed population, the change from baseline in pre-BD FEV1 at week 52 was greater in the low-dose, medium-dose, and high-dose tezeperumab groups than in the placebo group by 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), respectively. Similar differences were observed when pre-BD FEV1 was measured as a percentage of the predicted value (Table 2). The treatment effect was observed as early as week 4 (the first time point evaluated) and persisted throughout the trial.

[0185] The effects of tezeperumab on further 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 the first severe asthma exacerbation, and the changes from baseline in post-bronchodilator FEV1, FVC, ACQ-6 score, AQLQ score, and asthma symptom score—were consistent with those of Analyses A and B discussed above. The effects of tezeperumab on subgroup-specific secondary endpoints (pre-bronchodilator FEV1, ACQ-6 score, AQLQ score, and asthma symptom score) were also consistent with those of Analyses A and B.

[0186] biomarkers A substantial and sustained decrease in serum eosinophils and FeNO was observed in all tezeperumab treatment groups, beginning at 4 weeks post-treatment (the first time point evaluated) and maintained over time. Progression of the decrease was also observed in serum total IgE in all tezeperumab groups.

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

[0188] Three serious adverse events related to the investigational drug occurred: two in the same patient in the low-dose tezeperumab group (pneumonia and stroke), and one in the medium-dose tezeperumab group (Guillain-Barré syndrome). The discontinuation rate due to adverse events was 1.2% in patients receiving tezeperumab (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 tezeperumab group died 8 weeks after the end of the treatment period due to a serious treatment-related 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% in the low-dose tezeperumab group, 2.9% in the medium-dose group, and 1.5% 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 investigational drug were reported. After baseline, anti-drug antibody positivity was observed in 13 out of 138 patients (9.4%) in the placebo group, 5 out of 136 patients (3.7%) in the low-dose tezeperumab group, 1 out of 131 patients (0.8%) in the medium-dose group, and 3 out of 131 patients (2.3%) in the high-dose group. Neutralizing antibodies were not detected.

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

[0191] Interestingly, a re-examination of the effects of anti-TSLP therapy in different hypereosinophilic and aneosinophilic / hypeosinophilic patient populations showed that anti-TSLP therapy was highly effective in both the hypereosinophilic and hypoeosinophilic patient populations, which was unexpected in the hypoeosinophilic population. Table 2 and Figure 3 show that anti-TSLP therapy significantly reduced the exacerbation rate in both the hypereosinophilic and hypoeosinophilic populations.

[0192] Eosinophil cell concentration in subjects is a marker of Th2 inflammation in the subjects. Considering this association between eosinophils and Th2 concentration, study subjects were also divided into groups based on relative Th2 concentration, e.g., high or low Th2 groups, at the start of treatment, and the efficacy of the antibody was tested. The results demonstrated that anti-TSLP treatment was highly effective in both high-Th2 and low-Th2 patient groups. Table 4 shows that anti-TSLP treatment significantly reduced the exacerbation rate in both high-Th2 and low-Th2 groups, but the reduction was even greater in low-Th2 patients.

[0193] Consideration Treatment with tezeperumab resulted in a significantly lower annualized asthma exacerbation rate compared to placebo in asthma patients whose condition was uncontrolled despite treatment with LABAs and moderate to high-dose inhaled glucocorticoids. Some, though not all, secondary outcomes were better with tezeperumab than with placebo. The therapeutic effect was observed soon after the start of treatment and was maintained throughout the trial. The incidence of adverse events was similar in the tezeperumab and placebo groups, and the level of discontinuation, regardless of whether the adverse event was asthma-related, was similar.

[0194] Tezeperumab reduced serum eosinophil count, FeNO concentration, and serum total IgE concentration; changes in eosinophil count and FeNO levels occurred rapidly from week 4, concurrently with changes in the clinical endpoint. These findings are consistent with previous allergen loading studies in patients with mild asthma (in which tezeperumab suppressed increases in sputum and serum eosinophils and FeNO after the allergen loading study). 24These changes in biomarker concentrations indicate that TSLP is a key upstream regulator of Th2 activation and / or function, influencing 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, interleukin-25 and interleukin-33, which are epithelial cell-derived cytokines, may work in conjunction with TSLP to initiate and amplify Th2 inflammation, but the interactions of these cytokines require further study. 32、33

[0195] Tezeperumab was well-tolerated in all dose groups, and there was no reported increase in infections compared to placebo.

[0196] The improvements observed in disease control after tezeperumab treatment highlight the potential pathogenic role of TSLP across the asthmatic phenotype. Non-allergic factors, including tobacco smoke, diesel particles, and viruses, have been shown to trigger TSLP release, leading to activation of non-Th2 inflammatory responses in asthma.34–37 Cell types that may be activated by TSLP and involved in these pathways include mast cells, basophils, natural killer T cells, group 2 innate lymphoid cells, and possibly neutrophils and interleukin-17 cells. 20,36~39

[0197] These data provide the first clinical evidence that TSLP inhibition results in a lower annualized rate of asthma exacerbations compared to the absence of such inhibition, independently of baseline eosinophil count or other Th2 biomarkers, and that other clinical endpoints are better among uncontrolled asthma patients receiving LABAs and moderate to high doses of inhaled glucocorticoids. These findings highlight the potential merits of targeting upstream cytokines such as TSLP, which may have a broader impact on disease activity than inhibition of a single downstream pathway.

[0198] Numerous modifications and variations of the present invention, as shown in the exemplary embodiments described above, are expected to be conceivable to those skilled in the art. Therefore, only the limitations set forth in the appended claims should be imposed on the present 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.Swedin 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 (registered trademark) (omalizumab): Highlights of Prescribing Information 2016. (In https: / / www.gene.com / download / pdf / xolair_prescribing.pdf.) 13. Bleecker ER, FitzGerald JM, Chanez P,<00​​​​​​​​​​​​​​​​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

1. A composition comprising an anti-TSLP antibody or its antigen-binding fragment for use in the treatment of chronic obstructive pulmonary disease (COPD) in a subject, characterized in that the anti-TSLP antibody or its antigen-binding fragment is administered at a dose of 210 mg to 280 mg at intervals of every two weeks or every four weeks, wherein both binding sites of the antibody have the same binding affinity to TSLP, and the antibody is, a. i. Light chain CDR1 sequence containing the amino acid sequence shown in Sequence ID No. 3; ii. A light chain CDR2 sequence containing the amino acid sequence shown in Sequence ID No. 4; and iii. Light chain CDR3 sequence containing the amino acid sequence shown in Sequence ID No. 5 Light chain variable domains including; and b. i. A heavy chain CDR1 sequence containing the amino acid sequence shown in Sequence ID No. 6; ii. A heavy chain CDR2 sequence containing the amino acid sequence shown in Sequence ID No. 7; and iii. Heavy chain CDR3 sequence containing the amino acid sequence shown in Sequence ID No. 8 Heavy chain variable domains including A composition comprising the anti-TSLP antibody or its antigen-binding fragment, wherein the anti-TSLP antibody or its antigen-binding fragment specifically binds to the TSLP polypeptide represented by amino acids 29 to 159 of SEQ ID NO:

2.

2. A composition comprising an anti-TSLP antibody or its antigen-binding fragment for use in the treatment of chronic obstructive pulmonary disease (COPD) in a subject, characterized in that the anti-TSLP antibody or its antigen-binding fragment is administered at a dose of 210 mg to 280 mg at intervals of two or four weeks, wherein both binding sites of the antibody have the same binding affinity to TSLP, and the antibody is, a. i. An amino acid sequence that is at least 80% identical to SEQ ID NO: 12; and ii. The amino acid sequence encoded by a polynucleotide sequence that is at least 80% identical to SEQ ID NO:

11. Light chain variable domains selected from the group consisting of; and b. i. An amino acid sequence that is at least 80% identical to SEQ ID NO: 10; and ii. The amino acid sequence encoded by a polynucleotide sequence that is at least 80% identical to SEQ ID NO: 9 Heavy chain variable domains selected from the group consisting of the following The light chain variable domain includes, i. Light chain CDR1 sequence containing the amino acid sequence shown in Sequence ID No. 3; ii. A light chain CDR2 sequence containing the amino acid sequence shown in Sequence ID No. 4; and iii. Light chain CDR3 sequence containing the amino acid sequence shown in Sequence ID No. 5 The heavy chain variable domain is i. A heavy chain CDR1 sequence containing the amino acid sequence shown in Sequence ID No. 6; ii. A heavy chain CDR2 sequence containing the amino acid sequence shown in Sequence ID No. 7; and iii. Heavy chain CDR3 sequence containing the amino acid sequence shown in Sequence ID No. 8 A composition containing the following:

3. The antibody or its antigen-binding fragment is administered every four weeks; and / or the antibody or its antigen-binding fragment is a) In a dose of 210 mg; or b) At a dose of 280 mg A composition according to any one of claims 1 or 2, characterized by being administered.

4. A composition comprising an anti-TSLP antibody or its antigen-binding fragment for use in the treatment of chronic obstructive pulmonary disease (COPD) in a subject, characterized in that the anti-TSLP antibody or its antigen-binding fragment is administered at a dose of 210 mg at intervals of four weeks, wherein both binding sites of the antibody have the same binding affinity to TSLP, and the antibody is, a. i. Light chain CDR1 sequence containing the amino acid sequence shown in Sequence ID No. 3; ii. A light chain CDR2 sequence containing the amino acid sequence shown in Sequence ID No. 4; and iii. Light chain CDR3 sequence containing the amino acid sequence shown in Sequence ID No. 5 Light chain variable domains including; and b. i. A heavy chain CDR1 sequence containing the amino acid sequence shown in Sequence ID No. 6; ii. A heavy chain CDR2 sequence containing the amino acid sequence shown in Sequence ID No. 7; and iii. Heavy chain CDR3 sequence containing the amino acid sequence shown in Sequence ID No. 8 Heavy chain variable domains including A composition comprising the above, wherein the antibody specifically binds to the TSLP polypeptide represented by amino acids 29 to 159 of SEQ ID NO:

2.

5. A composition comprising an anti-TSLP antibody or its antigen-binding fragment for use in the treatment of chronic obstructive pulmonary disease (COPD) in a subject, characterized in that the anti-TSLP antibody or its antigen-binding fragment is administered at a dose of 210 mg at intervals of four weeks, wherein both binding sites of the antibody have the same binding affinity to TSLP, and the antibody is, a. i. An amino acid sequence that is at least 80% identical to SEQ ID NO: 12; and ii. The amino acid sequence encoded by a polynucleotide sequence that is at least 80% identical to SEQ ID NO:

11. Light chain variable domains selected from the group consisting of; and b. i. An amino acid sequence that is at least 80% identical to SEQ ID NO: 10; and ii. The amino acid sequence encoded by a polynucleotide sequence that is at least 80% identical to SEQ ID NO: 9 Heavy chain variable domains selected from the group consisting of the following The light chain variable domain includes, i. Light chain CDR1 sequence containing the amino acid sequence shown in Sequence ID No. 3; ii. A light chain CDR2 sequence containing the amino acid sequence shown in Sequence ID No. 4; and iii. Light chain CDR3 sequence containing the amino acid sequence shown in Sequence ID No. 5 The heavy chain variable domain is i. A heavy chain CDR1 sequence containing the amino acid sequence shown in Sequence ID No. 6; ii. A heavy chain CDR2 sequence containing the amino acid sequence shown in Sequence ID No. 7; and iii. Heavy chain CDR3 sequence containing the amino acid sequence shown in Sequence ID No. 8 A composition comprising the above, wherein the antibody specifically binds to the TSLP polypeptide represented by amino acids 29 to 159 of SEQ ID NO:

2.

6. a) The antibody or its antigen-binding fragment is administered for a period of at least 4 months, 6 months, 9 months, 1 year or longer, and / or b) The TSLP antibody or its antigen-binding fragment is bivalent and selected from the group consisting of human antibody, humanized antibody, chimeric antibody, monoclonal antibody, recombinant antibody, antigen-binding antibody fragment, single-chain antibody, monomeric antibody, bispecific antibody, trispecific antibody, quadrispecific antibody, Fab fragment, IgG1 antibody, IgG2 antibody, IgG3 antibody, and IgG4 antibody. The composition according to any one of claims 1 to 5.

7. The composition according to claim 5, wherein the anti-TSLP antibody or its antigen-binding fragment is selected from the group consisting of a bispecific antibody, a triplicate antibody, a quadruplicate antibody, a Fab fragment, a single-domain antibody, and an scFv, and the dose is adjusted to be equimolar to that of when the binding site is administered by a bivalent antibody.

8. a) The antibody is an IgG2 antibody; b) The antibody or its antigen-binding fragment is a human antibody; c) The composition further comprises a pharmaceutically acceptable carrier or excipient; and / or d) The subject is an adult, The composition according to any one of claims 1 to 7.

9. a) The anti-TSLP antibody is tezeperumab; b) The antibody is an IgG2 antibody and has full-length heavy chain and light chain sequences as indicated by SEQ ID NOs. 105 and 106, respectively; and / or c) The anti-TSLP antibody or its antigen-binding fragment has pK properties substantially similar to tezeperumab in humans. The composition according to any one of claims 1 to 8.

10. The composition according to any one of claims 1 to 9, wherein the administration is subcutaneous or intravenous.

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