Methods for increasing forced expiratory volume in asthma patient using benralizumab

Abstract

To provide methods of increasing forced expiratory volume in one second (FEV1) in an asthma patient.SOLUTION: A method comprises subcutaneously administering an effective amount of benralizumab or an antigen-binding fragment thereof, which is about 2 mg to about 100 mg per dose every 4-12 weeks, where the patient uses a high-dose inhaled corticosteroid (ICS) or long-acting β2 agonist (LABA).SELECTED DRAWING: None

Description

[Background technology]

[0001] Sequence Listing Reference This application contains a Sequence Listing that has been submitted electronically in ASCII format and is incorporated by reference in its entirety. The ASCII copy, created on July 16, 2014, has the filename IL5R-604WO1_SL.txt and is 15,971 bytes in size.

[0002] background Over 300 million people worldwide suffer from asthma. Despite the use of long-acting bronchodilators and inhaled corticosteroids, asthma continues to account for a major proportion of morbidity worldwide (Masoli M, et al. Allergy 59:469-78 (2004)).

[0003] Recurrence after acute asthma exacerbation has been reported to range from 41-52% at 12 weeks, despite the use of systemic steroids at discharge (Lederle F, et al. Arch Int Med 147:2201-03 (1987)). Management of these patients has proven difficult to resolve due to the overwhelming disease or incompatibility and / or unwillingness to adhere to treatment. In one study of hospitalized patients, 50% of some life-threatening asthma patients had low compliance to systemic corticosteroids 7 days after discharge (Krishnan J, et al. AJRCCM 170:1281-85 (2004)). Many factors may be responsible for low compliance, including poor access to routine health care (especially in slum areas), lack of education or understanding of their disease, unwillingness to accept that their disease is chronic, or inability to receive medication.

[0004] A large body of evidence suggests that eosinophils are one of the main causative cells of asthmatic airway inflammation (James A. Curr Opin Pulm Med 11(1):1-6(2005)). Peripheral blood (PB) eosinophilia is a risk factor for acute asthma relapse (Janson C and Herala M. Resp Med 86(2):101-104(1992)). Patients with elevated peripheral blood eosinophilia had a 7.4 (confidence interval, 2.8-19.7) times higher risk of death from asthma compared with patients without eosinophilia (Ulrik C and Fredericksen J. Chest 108:10-15(1995)). Autopsy findings have identified two distinct pathogenic inflammatory mechanisms in fatal asthma (Restrepo R and Peters J. Curr Opin Pulm Med 14:13-23 (2008)). Neutrophil infiltration is more prominent in patients who die suddenly (within about 2 hours of onset of symptoms), whereas eosinophil infiltration is more prevalent in patients who die after a longer asthmatic crisis. Eosinophils in sputum and blood may also be increased in patients who present to the emergency department with an acute asthmatic episode (Bellido-Casado J, et al. Arch Bronconeumol 46(11):587-93 (2010)). Eosinophil-targeted therapy has been shown to reduce the number and severity of asthma exacerbations when compared with the use of clinical practice guidelines (Green R, et al. Lancet 360:1715-21 (2002); Haldar P, et al. NEJM 360:973-84 (2009)).

[0005] Benralizumab (MEDI-563) is a humanized monoclonal antibody (mAb) that binds to the alpha chain of the interleukin-5 receptor alpha (IL-5Rα) expressed on eosinophils and basophils. It induces apoptosis of these cells through antibody-dependent cellular cytotoxicity. A single intravenous (IV) dose of benralizumab in adults with mild asthma resulted in a long-lasting reduction in PB eosinophils, likely due to an effect on eosinophil / basophil bone marrow progenitor cells that express this target (Busse W, et al. JACI 125:1237-1244 e2 (2010)). Furthermore, a single dose of benralizumab significantly reduced blood eosinophil counts in patients presenting to the emergency department with severe asthma exacerbations, without affecting lung function (WO 13 / 066780).

[0006] Thus, because there is a strong unmet need to improve lung function, for example as measured by forced expiratory volume in 1 second (FEV1), in asthmatics, and because some asthmatics have an eosinophil component, we investigated the effect of benralizumab on forced expiratory volume in 1 second in adult patients. Summary of the Invention [Means for solving the problem]

[0007] The present application provides a method for increasing forced expiratory volume in one second (FEV1) in an asthma patient. In one embodiment, the method for increasing forced expiratory volume in one second (FEV1) in an asthma patient comprises administering an effective amount of benralizumab or an antigen-binding fragment thereof to the patient.

[0008] The present application also provides a method for treating asthma. In one embodiment, the method for treating asthma comprises administering an effective amount of benralizumab or an antigen-binding fragment thereof to an asthma patient having a pre-administration blood eosinophil count of at least 300 cells / μl.

[0009] In certain embodiments, a method for treating asthma comprises administering an effective amount of benralizumab, or an antigen-binding fragment thereof, to an asthma patient having a pre-dose forced expiratory volume in 1 second (FEV1) of at least 75% of predicted.

[0010] In certain embodiments, the method of treating asthma comprises administering at least two doses of benralizumab or an antigen-binding fragment thereof to an asthma patient.

[0011] In certain embodiments of the methods provided herein, administration increases the patient's FEV1. In some embodiments, administration increases the patient's FEV1 within 4 weeks of the first administration. In some embodiments, FEV1 increases by at least 0.1 L. In some embodiments, FEV1 increases by at least 0.13 L. In some embodiments, FEV1 increases by at least 0.2 L. In some embodiments, FEV1 increases by at least 0.25 L. In some embodiments, FEV1 increases by at least 0.50 L.

[0012] In certain embodiments of the methods provided herein, the asthma is eosinophilic asthma. In certain embodiments, the patient has a blood eosinophil count of at least 300 cells / μl.

[0013] In certain embodiments of the methods provided herein, the patient has a forced expiratory volume in 1 second (FEV1) of at least 75% of predicted value prior to administration. In certain embodiments, the patient has an Asthma Control Questionnaire score of at least 1.5 prior to administration. In certain embodiments, the patient uses high doses of inhaled corticosteroids (ICS). In certain embodiments, the patient uses long-acting beta2 agonists (LABAs). In certain embodiments, the patient has a history of exacerbations. In certain embodiments, the history of exacerbations includes at least two exacerbations in the year prior to administration of Benralizumab or an antigen-binding fragment thereof. In certain embodiments, the history of exacerbations includes six or fewer exacerbations in the year prior to administration of Benralizumab or an antigen-binding fragment thereof.

[0014] In certain embodiments of the methods provided herein, benralizumab or an antigen-binding fragment thereof is administered to the patient at least twice.

[0015] In some embodiments of the methods provided herein, benralizumab or an antigen-binding fragment thereof is administered at about 2 mg to about 100 mg per dose. In some embodiments, benralizumab or an antigen-binding fragment thereof is administered at about 20 mg per dose. In some embodiments, benralizumab or an antigen-binding fragment thereof is administered at about 30 mg per dose. In some embodiments, benralizumab or an antigen-binding fragment thereof is administered at about 100 mg per dose.

[0016] In certain embodiments of the methods provided herein, benralizumab or an antigen-binding fragment thereof is administered once every 4 to 12 weeks. In certain embodiments, benralizumab or an antigen-binding fragment thereof is administered once every 4 weeks. In certain embodiments, benralizumab or an antigen-binding fragment thereof is administered once every 8 weeks. In certain embodiments, benralizumab or an antigen-binding fragment thereof is administered once every 4 weeks for 12 weeks, and once every 8 weeks thereafter.

[0017] In some embodiments of the methods provided herein, Benralizumab or an antigen-binding fragment thereof is administered parenterally. In some embodiments, Benralizumab or an antigen-binding fragment thereof is administered subcutaneously.

[0018] In certain embodiments of the methods provided herein, benralizumab, or an antigen-binding fragment thereof, is administered in combination with corticosteroid therapy.

[0019] In one embodiment, a method for increasing forced expiratory volume in 1 second (FEV1) in an asthma patient comprises administering 20-100 mg of Benralizumab or an antigen-binding fragment thereof to a patient having a pre-administration blood eosinophil count of at least 300 cells / μl. In one embodiment, the method comprises administering 20 mg of Benralizumab or an antigen-binding fragment thereof. In one embodiment, 20 mg of Benralizumab is administered once every 4 weeks for 12 weeks and once every 8 weeks thereafter. In one embodiment, the method comprises administering 30 mg of Benralizumab or an antigen-binding fragment thereof. In one embodiment, 30 mg of Benralizumab is administered once every 4 weeks for 8 weeks and once every 8 weeks thereafter. In one embodiment, 30 mg of Benralizumab is administered once every 4 weeks. In one embodiment, the method comprises administering 100 mg of Benralizumab or an antigen-binding fragment thereof. In one embodiment, Benralizumab 100 mg is administered once every 4 weeks for 12 weeks, then once every 8 weeks.

[0020] In certain embodiments, a method of treating asthma in an asthma patient comprises administering to the patient a dose of at least 2 mg, but less than 100 mg, of Benralizumab or an antigen-binding fragment thereof. In certain embodiments, the method comprises administering 20 mg of Benralizumab or an antigen-binding fragment thereof. In certain embodiments, the method comprises administering 30 mg of Benralizumab or an antigen-binding fragment thereof. In certain embodiments, the method comprises administering a dose of at least 20 mg, but less than 100 mg, of Benralizumab or an antigen-binding fragment thereof. In certain embodiments, the method comprises administering a dose of at least 30 mg, but less than 100 mg, of Benralizumab or an antigen-binding fragment thereof. In certain embodiments, the method reduces the asthma exacerbation rate. In certain embodiments, the method reduces the annual asthma exacerbation rate. In certain embodiments, the administration is subcutaneous.

[0021] In certain embodiments of the provided methods, administration of benralizumab or an antigen-binding fragment thereof increases forced expiratory volume in 1 second (FEV1), as shown in Figures 2-9.

[0022] In one embodiment of the provided methods, administration of benralizumab or an antigen-binding fragment thereof increases forced expiratory volume in 1 second (FEV1), as shown in Examples 1-2. [Brief description of the drawings]

[0023] [Figure 1] Figure 1 shows the flow diagram of the study. [Diagram 2] FIG. 2 shows the change in forced expiratory volume in 1 second (FEV1) at 24 weeks after treatment with placebo, 2 mg Benralizumab, 20 mg Benralizumab or 100 mg Benralizumab in patients with less than 300 eosinophils / μl and patients with at least 300 eosinophils / μl. [Diagram 3] FIG. 3 shows the change in FEV1 at mid-term (week 24) and stage I (week 52) after treatment with placebo, 2 mg Benralizumab, 20 mg Benralizumab or 100 mg Benralizumab in patients with less than 300 eosinophils / μl and patients with at least 300 eosinophils / μl. [Figure 4] Figure 4 shows the change in FEV1 at mid-term (week 24) and stage I (week 52) after treatment with placebo, 2 mg benralizumab, 20 mg benralizumab or 100 mg benralizumab in patients using medium or high doses of inhaled corticosteroids (ICS). [Diagram 5] FIG. 5 shows the change in FEV1 at mid-term (week 24) and stage I (week 52) after treatment with placebo, 2 mg benralizumab, 20 mg benralizumab or 100 mg benralizumab in patients with less than 300 eosinophils / μl and using (i) medium dose or (ii) high dose ICS. [Figure 6]FIG. 6 shows the change in FEV1 at mid-term (week 24) and stage I (week 52) after treatment with placebo, 2 mg benralizumab, 20 mg benralizumab or 100 mg benralizumab in patients with at least 300 eosinophils / μl and using (i) medium or (ii) high dose ICS. [Figure 7A] 7A and 7B show the change in FEV1 in patients with different eosinophil counts. [Figure 7B] 7A and 7B show the change in FEV1 in patients with different eosinophil counts. [Figure 8] FIG. 8 shows the mean FEV1 over time for patients with at least 300 eosinophils / μl. [Figure 9] FIG. 9 shows the mean FEV1 over time for patients with less than 300 eosinophils / μl. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0024] It should be noted that an entity preceded by the term "a" or "an" refers to one or more of that entity, for example, "an anti-IL-5α antibody" is understood to mean one or more anti-IL-5α antibodies. Thus, the terms "a" (or "an"), "one or more," and "at least one" can be used synonymously herein.

[0025] Provided herein is a method for increasing forced expiratory volume in 1 second (FEV1) in an asthma patient, comprising administering an effective amount of benralizumab or an antigen-binding fragment thereof.

[0026] Information regarding Benralizumab (or a fragment thereof) for use in the methods provided herein can be found in US Patent Publication No. 2010 / 0291073A1, the disclosure of which is incorporated herein by reference in its entirety. Benralizumab and its antigen-binding fragments for use in the methods provided herein include a heavy chain and a light chain, or a heavy chain variable region and a light chain variable region. In further embodiments, Benralizumab or its antigen-binding fragments for use in the methods provided herein include any one of the amino acid sequences of SEQ ID NOs: 1-4. In certain embodiments, Benralizumab or its antigen-binding fragments for use in the methods provided herein include a light chain variable region comprising the amino acid sequence of SEQ ID NO: 1, and a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 3. In certain embodiments, Benralizumab or its antigen-binding fragments for use in the methods provided herein include a light chain comprising the amino acid sequence of SEQ ID NO: 2, and a heavy chain comprising the amino acid sequence of SEQ ID NO: 4. In certain embodiments, Benralizumab or an antigen-binding fragment thereof for use in the methods provided herein comprises a heavy chain variable region comprising the Kabat-defined CDR1, CDR2 and CDR3 sequences of SEQ ID NOs:7-9, and a light chain variable region comprising the Kabat-defined CDR1, CDR2 and CDR3 sequences of SEQ ID NOs:10-12. Those skilled in the art will be able to readily distinguish between Chothia-defined CDRs, Abm-defined CDRs, or other CDRs. In certain embodiments, Benralizumab or an antigen-binding fragment thereof for use in the methods provided herein comprises the variable heavy and variable light chain CDR sequences of the KM1259 antibody disclosed herein. U.S. Patent No. 6,018,032 is incorporated herein by reference in its entirety.

[0027] In one embodiment, benralizumab or an antigen-binding fragment thereof is administered to a patient who visits a hospital or ED with asthma. Given that benralizumab can lower or reduce eosinophil counts for 12 weeks or more (see US Patent Publication No. 2010 / 0291073), benralizumab or an antigen-binding fragment thereof can be administered only once or very infrequently while the patient still receives the benefit of increasing forced expiratory volume in one second (FEV1). In a further embodiment, the patient is further administered additional doses. Additional doses can be administered at various time intervals depending on other factors such as the patient's age, weight, ability to comply with physician's instructions, clinical evaluation, eosinophil counts (eosinophils in blood or sputum), eosinophil cationic protein (ECP) measurements, eosinophil-derived neurotoxin (EDN) measurements, major basic protein (MBP) measurements, and the judgment of the attending physician. The dosing interval can be every 4 weeks, every 5 weeks, every 6 weeks, every 8 weeks, every 10 weeks, every 12 weeks, or longer. In some embodiments, the dosing interval can be every 4 weeks, every 8 weeks, or every 12 weeks. In some embodiments, the single dose or the first dose is administered to the patient immediately after the asthma patient develops an acute exacerbation, for example, a mild, moderate, or severe exacerbation. For example, the single dose or the first dose of Benralizumab or an antigen-binding fragment thereof can be administered at the time of a clinic or hospital visit, but in the case of a very severe exacerbation within 1, 2, 3, 4, 5, 6, 7 days or more, for example within 7 days, after the acute exacerbation, the patient's condition is stabilized before administration of Benralizumab.

[0028] In some embodiments, Benralizumab or an antigen-binding fragment thereof is administered to a patient at least twice. In some embodiments, Benralizumab or an antigen-binding fragment thereof is administered to a patient at least three times, at least four times, at least five times, at least six times, or at least seven times. In some embodiments, Benralizumab or an antigen-binding fragment thereof is administered over 4 weeks, 8 weeks, 12 weeks, 24 weeks, or a year.

[0029] The amount of benralizumab or an antigen-binding fragment thereof administered to a patient will depend on various parameters such as the patient's age, weight, clinical evaluation, eosinophil count (blood or sputum eosinophils), eosinophil cationic protein (ECP) measurement, eosinophil-derived neurotoxin (EDN) measurement, major basic protein (MBP) measurement, and other factors such as the judgment of the attending physician. In some embodiments, the dose or administration interval is not dependent on sputum eosinophil levels.

[0030] In some embodiments, the patient is administered one or more doses of benralizumab or an antigen-binding fragment thereof, such as about 2 mg to about 100 mg, e.g., about 20 mg to about 100 mg, or about 30 mg to about 100 mg. In some embodiments, the patient is administered one or more doses of benralizumab or an antigen-binding fragment thereof, such as about 20 mg, about 30 mg, about 40 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, or about 100 mg. In some embodiments, the dose is about 20 mg. In some embodiments, the dose is about 30 mg. In some embodiments, the dose is about 100 mg.

[0031] In some embodiments, administration of benralizumab or an antigen-binding fragment thereof according to the methods provided herein is parenteral administration. For example, benralizumab or an antigen-binding fragment thereof can be administered by intravenous infusion or subcutaneous injection.

[0032] In some embodiments, benralizumab or an antigen-binding fragment thereof is administered by the methods provided herein in combination or in conjunction with another asthma therapy, including, but not limited to, inhaled corticosteroid therapy, long-acting or short-acting bronchodilator therapy, supplemental oxygen, or other standard therapies, such as those described in the NAEPP Guidelines. In some embodiments, the use of the methods provided herein, i.e., administration of benralizumab or an antigen-binding fragment thereof, provides adjunctive therapy to asthma patients with a history of exacerbations in situations where it is difficult to follow standard forms of asthma treatment management.

[0033] The methods provided herein can significantly increase forced expiratory volume in 1 second (FEV1) in asthma patients. The increase can be measured based on predicted FEV1 from a large patient population, based on FEV1 measured in a control population, or based on the individual patient's FEV1 prior to dosing. In some embodiments, the patient population is a group of patients who have experienced ≧2 exacerbations requiring oral systemic corticosteroids in the past year. In some embodiments, the patient population is a group of patients who have experienced ≧2 exacerbations requiring a systemic corticosteroid burst in the past year and ≦6 exacerbations requiring a systemic corticosteroid burst in the past year. In some embodiments, the patient population is a group of patients with eosinophil counts of at least 300 cells / μl.

[0034] In certain embodiments, the methods provided herein, i.e., administration of benralizumab or an antigen-binding fragment thereof, results in an increase in forced expiratory volume in 1 second (FEV1) over 24 weeks following administration of benralizumab or an antigen-binding fragment thereof, as compared to the patient's baseline FEV1. In certain embodiments, the patient can receive additional doses of benralizumab or an antigen-binding fragment thereof periodically, e.g., every 4 weeks, 5 weeks, 6 weeks, 8 weeks, 12 weeks, or at intervals determined based on other factors, such as the patient's age, weight, ability to comply with physician's instructions, clinical evaluation, eosinophil count (eosinophils in blood or sputum), eosinophil cationic protein (ECP) measurement, eosinophil-derived neurotoxin measurement (EDN), major basic protein (MBP) measurement, and the judgment of the attending physician. Using the methods provided herein, FEV1 can be increased by at least 0.05 L, at least 0.1 L, at least 0.13 L, at least 0.15 L, at least 0.20 L, at least 0.21 L, at least 0.22 L, at least 0.23 L, at least 0.24 L, at least 0.25 L, at least 0.30 L, at least 0.35 L, at least 0.40 L, at least 0.45 L, or at least 0.50 L over a 24 week period.

[0035] In other embodiments, the use of the methods provided herein, i.e., administration of benralizumab or an antigen-binding fragment thereof to an asthma patient, increases the patient's forced expiratory volume in one second (FEV1) for 52 weeks after administration of benralizumab or an antigen-binding fragment thereof. In some embodiments, the patient can receive additional doses of benralizumab or an antigen-binding fragment thereof periodically, for example, every 4 weeks, 5 weeks, 6 weeks, 8 weeks, 12 weeks, or at intervals determined based on other factors such as the patient's age, weight, ability to comply with physician's instructions, clinical evaluation, eosinophil count (eosinophils in blood or sputum), eosinophil cationic protein (ECP) measurement, eosinophil-derived neurotoxin measurement (EDN), major basic protein (MBP) measurement, and the judgment of the attending physician. In some embodiments, the intervals are every 4 weeks, 8 weeks, or 12 weeks. Use of the methods provided herein can result in an increase in forced expiratory volume in 1 second (FEV1) of at least 0.05 L, at least 0.1 L, at least 0.13 L, at least 0.15 L, at least 0.20 L, at least 0.21 L, at least 0.22 L, at least 0.23 L, at least 0.24 L, at least 0.25 L, at least 0.30 L, at least 0.35 L, at least 0.40 L, at least 0.45 L, or at least 0.50 L over a 24 week period.

[0036] In certain aspects, use of the methods provided herein, i.e., administration of benralizumab or an antigen-binding fragment thereof, increases forced expiratory volume in 1 second (FEV1) within 4 weeks, within 8 weeks, within 12 weeks, within 16 weeks, within 20 weeks, within 24 weeks, within 28 weeks, within 32 weeks, within 36 weeks, within 40 weeks, within 44 weeks, within 48 weeks, or within 52 weeks.

[0037] In certain aspects, use of the methods provided herein, i.e., administration of benralizumab or an antigen-binding fragment thereof to an asthma patient, increases forced expiratory volume in 1 second (FEV1), reduces annualized exacerbation rate, and / or improves asthma questionnaire scores (e.g., Asthma Control Questionnaire (ACQ)).

[0038] In some embodiments, the patient is "eosinophil positive," meaning that the patient is likely to have eosinophilic asthma.

[0039] In some embodiments, an asthma patient has a particular blood eosinophil count, e.g., prior to administration of benralizumab or an antigen-binding fragment thereof. Blood eosinophil count can be measured, e.g., by performing a complete blood count (CBC) with differential blood count.

[0040] In certain embodiments, the asthma patient has a blood eosinophil count of at least 300 / μl prior to administration of Benralizumab or an antigen-binding fragment thereof. In certain embodiments, the asthma patient has a blood eosinophil count of at least 350 / μl, at least 400 / μl, at least 450 / μl, or at least 500 / μl prior to administration of Benralizumab or an antigen-binding fragment thereof.

[0041] In certain embodiments, the asthma patient has a blood eosinophil count of less than 300 cells / μl prior to administration of Benralizumab or an antigen-binding fragment thereof. In certain embodiments, the asthma patient has a blood eosinophil count of at least 100 cells / μl, at least 150 cells / μl, at least 180 cells / μl, at least 200 cells / μl, or at least 250 cells / μl prior to administration of Benralizumab or an antigen-binding fragment thereof.

[0042] In certain embodiments, the asthma patient is prescribed or has been using a medium-dose inhaled corticosteroid (ICS) prior to administration of benralizumab or an antigen-binding fragment thereof, which can be a daily dose of at least 600 μg to 1,200 μg of budesonide, or an equivalent dose of another ICS.

[0043] In some embodiments, the asthma patient has been prescribed or has been using a high dose of ICS prior to administration of benralizumab or an antigen-binding fragment thereof. The high dose of ICS can be a daily dose of at least 1,200 μg of budesonide or an equivalent dose of another ICS. The high dose of ICS can also be a daily dose of more than 1,200 μg to 2000 μg of budesonide or an equivalent dose of another ICS.

[0044] In some embodiments, the asthma patient has been prescribed or has been using oral corticosteroids prior to administration of benralizumab or an antigen-binding fragment thereof. In some embodiments, administration of benralizumab or an antigen-binding fragment thereof reduces the asthma patient's use of oral corticosteroids. In some embodiments, administration reduces the asthma patient's use of oral corticosteroids by at least 50%.

[0045] In certain embodiments, the asthma patient has been prescribed or has been using a long-acting beta agonist (LABA) prior to administration of benralizumab or an antigen-binding fragment thereof.

[0046] In certain embodiments, the asthma patient has been prescribed or has been using both an ICS and a LABA prior to administration of benralizumab or an antigen-binding fragment thereof.

[0047] In certain embodiments, the asthma patient has a blood eosinophil count of at least 300 / μl and is using high doses of ICS prior to administration of benralizumab or an antigen-binding fragment thereof.

[0048] In certain aspects, the asthma patient has a forced expiratory volume in 1 second (FEV1) of at least 40% and less than 90% of predicted value prior to administration of Benralizumab or its antigen-binding fragment. In some embodiments, the FEV1 is greater than 70% of predicted value prior to administration of Benralizumab or its antigen-binding fragment. In some embodiments, the FEV1 is greater than 70% and less than 90% of predicted value prior to administration of Benralizumab or its antigen-binding fragment. In some embodiments, the FEV1 is at least 75% of predicted value prior to administration of Benralizumab or its antigen-binding fragment. In some embodiments, the FEV1 is at least 75% and less than 90% of predicted value prior to administration of Benralizumab or its antigen-binding fragment. In some embodiments, the FEV1 is at least 80% of predicted value prior to administration of Benralizumab or its antigen-binding fragment. In some embodiments, the FEV1 is at least 80% and less than 90% of predicted value prior to administration of Benralizumab or its antigen-binding fragment. EXAMPLES

[0049] Example 1: Patients and Methods (a) Patient Patients in the study were required to be 18-75 years old and weigh >45 kg but <150 kg (>100 lbs but <330 lbs). They also had to have a physician-diagnosed asthma diagnosis for at least 12 months prior to screening, and had to have used a physician-prescribed medium or high-dose inhaled corticosteroid (ICS) and a long-acting beta-agonist (LABA) daily, or any combination of medium or high-dose ICS / LABA in succession, for at least 12 months prior to screening. The medium and high doses of ICS defined in the study are shown in Table 1 below.

[0050] [Table 1]

[0051] Patients had to have been receiving stable doses of other asthma control medications for at least 30 days prior to screening. Patients also had to have had at least two, but not more than six, documented asthma exacerbations requiring the use of systemic corticosteroid bursts within the 12 months prior to screening. Patients also had to have a morning pre-bronchodilator forced expiratory volume in 1 second (FEV1) of at least 40% but less than 90% of predicted during the screening / run-in period (described below). Patients also had to meet one of the following criteria: a) Documented evidence within 36 months prior to randomization of reversible airflow limitation after bronchodilator use of ≥12% and ≥200 mL, or documented evidence within 36 months prior to randomization of a positive response to methacholine challenge [PC20 ≤8 mg / mL]; b)- At the 3-week screening visit, there was a post-bronchodilator increase in FEV1 of ≥ 12% and ≥ 200 mL; or c) If a) and b) were not met, but all other inclusion / exclusion criteria were met, patients with an FEV1 ≥ 1.5 L and ≥ 60% predicted at the -2 week screening visit were eligible to receive methacholine challenge at a site offering methacholine testing at the -2 week screening visit. Patients met this inclusion criterion if they had a positive response (PC20 ≤ 8 mg / mL).

[0052] Patients also had to have an Asthma Control Questionnaire (ACQ) score of at least 1.5 at least twice during the screening / run-in period.

[0053] Patients were not able to participate if they had been exposed to 10 or more packs of cigarettes per year before screening or had smoked within the previous 12 months, or if they had a health condition that, in the opinion of the investigator or medical monitor, would have prevented evaluation (e.g., eosinophilic lower airway disease other than asthma, chronic obstructive pulmonary disease (COPD), or cystic fibrosis). Patients were also not able to participate if they had received oral corticosteroid bursts or short-acting systemic corticosteroid therapy within 30 days before screening or during the screening / run-up period.

[0054] (b) Test Plan The study was a phase 2b, randomized, double-blind, placebo-controlled, dose-ranging, multicenter study in which asthma patients received multiple subcutaneous doses of benralizumab (ClinicalTrials.gov number: NCT01238861). Benralizumab was administered at doses of 2, 20, or 100 mg, and patients were followed for 1 year. A flow diagram of the study is shown in Figure 1.

[0055] There was a 3-week screening / run-in period before administration of benralizumab or placebo. During those 3 weeks, patients continued to use the same medium or high dose combination ICS / LABA product prior to study entry (ICS / LABA doses were required to be stable for 30 days prior to the 3-week screening / run-in period). Patients continued to use the same dose of ICS / LABA for the entire study period.

[0056] The administered Benralizumab composition contained Benralizumab (50 mg / mL), 10 mM histidine, 10 mM histidine hydrochloride monohydrate, 9% (wt / vol) trehalose dihydrate, and 0.004% (wt / vol) polysorbate 20, pH 6. The administered placebo composition contained 10 mM histidine, 10 mM histidine hydrochloride monohydrate, 9% (wt / vol) trehalose dihydrate, and 0.02% (wt / vol) polysorbate 20, pH 6.

[0057] Patients received two 1-ml subcutaneous (SC) injections of benralizumab or placebo every 4 weeks for the first three doses at weeks 1 (day 1), 4, and 8, and then every 8 weeks for the final four doses at weeks 16, 24, 32, and 40. After week 40, patients were followed for an additional 12 weeks (through week 52) for evaluation of acute exacerbations. Day 1 was the day the first dose of benralizumab or placebo was received.

[0058] Pulmonary function, as measured by change in airflow limitation over the study period (FEV1 and forced vital capacity (FVC) at the study site, and peak expiratory flow (PEF) and FEV1 at home), was assessed. Measurements at various time points, along with changes from baseline, were summarized using descriptive statistics. Changes from baseline in FEV1 and PEF were compared between the individual benralizumab and placebo groups using ANCOVA with treatment group and baseline values ​​as possible covariates.

[0059] Home peak flow testing for FEV1 and PEF was performed twice daily, in the morning after awakening and in the evening before going to bed, using an ePro device from the initial screening visit until the 52-week visit. Patients were checked for active participation in treatment at each visit until the 52-week visit. Patients were asked to perform the peak flow test each morning in a sitting or standing position, but in the same position for each test. At screening, each enrolled patient was provided with a home peak flow meter and instructions for recording the data.

[0060] In addition, spirometry was performed by the investigator or a qualified designee with equipment provided by a major vendor according to ATS / European Respiratory Society (ERS) guidelines (Miller et al, Eur Respir J 26:153-61 (2005)). Spirometry was performed in the morning between 6:00 AM and 11:00 AM at weeks -3, -2, -1, 1 (day 1), 4, 16, 24, 32, 40, and 52. On treatment days, spirometry tests were performed prior to administration of study article. All post-screening morning spirometry tests were requested to be completed between 6 and 11 AM and within ±1 hour of the time the screening spirometry was completed. For example, if screening spirometry was at 8:00 AM, then all subsequent spirometry tests had to be completed between 7:00 AM and 9:00 AM.

[0061] Multiple forced expiratory efforts (at least three, no more than eight) were performed at each office spirometry session, and the two best efforts that met American Thoracic Society / European Respiratory Society (ATS / ERS) acceptability and reproducibility criteria were recorded. The best effort was based on the highest FEV1. The maximum FEV1 of the two best efforts was used for analysis. Absolute measures (FEV1 and forced vital capacity (FVC)) and percentages of predicted normal values ​​(Hankinson et al., Am J Respir Crit Care Med 159:179-87(1999)) were recorded. Maximum forced vital capacity was also recorded, regardless of the effort that produced it (even if that effort did not result in a maximum FEV1). The preferred standard for predicted normal ranges is the National Health and Nutrition Examination Survey III (NHANES III). Indirect measures of air trapping were evaluated using data obtained by routine spirometry. Spirometry data will be substituted into the formula developed by Sorkness et al. (J Appl Physiol 104:394-403(2008)).

[0062] Reversibility of FEV1 with albuterol / salbutamol was measured after patients underwent pre-bronchodilator (pre-BD) spirometry at weeks -3, 1 (day 1), 16, 24, 32, 40, and 52. Maximal bronchodilation was induced by using a maximum of 8 total puffs, or 720 μg albuterol / salbutamol MDI, via the Aeorchamber (Sorkness et al., J Appl Physiol 104:394-403 (2008)).

[0063] After pre-BD spirometry, 4 puffs of albuterol / salbutamol MDI were administered, with a 30-second interval between each puff, and post-bronchodilator (post-BD) spirometry was performed 15–20 min later. An additional 2 puffs of albuterol / salmeterol were then administered, with a 30-second interval between each puff, and a second post-BD spirometry was performed 15–20 min later. Finally, if the incremental change in FEV1 after 6 puffs of albuterol / salbutamol was ≤5% of the FEV1 value after 4 puffs of albuterol / salbutamol, the last 2 puffs of albuterol / salmeterol were not administered. On the other hand, if the change was >5%, 2 puffs of albuterol / salmeterol were administered, with a 30-second interval between each puff, and a third post-BD spirometry was performed 15–20 min later.

[0064] The % difference comparing FEV1 after 6 puffs to FEV1 after 4 puffs was calculated as follows: % difference = (FEV1(6 puffs)-FEV1(4 puffs)) / FEV1(4 puffs) x 100

[0065] To determine reversibility, the maximum pre-BD and post-BD FEV1 was used and calculated as follows:

number

[0066] When applicable, methacholine inhalation challenges were completed in the morning ±1 hour before each assessment. Direct challenges using methacholine act directly on airway smooth muscle to cause airflow limitation and reduce FEV1. Methacholine inhalation challenges were performed using one of two ATS guideline-recommended methods: a 2-minute resting ventilation technique or a 5-breath dosimeter technique (American Thoracic Society, Am J Respir Crit Care Med. 161:309-329 (2000)). The same method was used for each patient. The best effort was the one that gave the highest FEV1 at each stage; maximum FVC and maximum peak flow were also recorded, even if they were obtained at an effort different from the highest FEV1. Only two efforts were required at each stage if two efforts were considered by the examiner or a qualified designee to be representative of the patient's ability to perform spirometry at that stage. In general, no more than three efforts (measurements) were performed at each stage to ensure that the patient maintained their ability to perform spirometry during the test.

[0067] Contraindications to methacholine stress testing include pregnancy, breast-feeding, FEV1 <1.5 L or <60% predicted, heart attack or stroke within the past 3 months, documented aortic aneurysm, uncontrolled hypertension (systolic >200 mmHg or diastolic >100 mmHg), anticholinesterase drug therapy for myasthenia gravis, respiratory infection within the past 6 weeks, acute asthma attack on the day of the test, oral corticosteroid burst within the past 30 minutes, or certain prohibited medications or foods.

[0068] The decline in FEV1 was calculated as a percentage of the best FEV1 determined at the saline stage. Positive or symptomatic patients received 2–4 puffs of albuterol / salbutamol and were observed until their FEV1 had recovered to at least 90% of their baseline (screening week -2) value. Patients with a decline in FEV1 >50% were rescued with albuterol and closely observed. Patients were not discharged from the clinic if their FEV1 had not recovered to at least 90% of their baseline (predilution) value without permission from the examiner or a qualified designee.

[0069] (c) Safety assessment Patients were monitored for adverse events after administration of placebo or benralizumab. Other evaluations included physical examinations, monitoring of vital signs, and laboratory measurements.

[0070] Example 2: Results (a) Enrolment and baseline characteristics Baseline characteristics of all randomized patients who received any dose of study product are shown below in Table 2. The mean dose for the ICS population was 1100 budesonide equivalents overall, 700 budesonide equivalents in the mid-dose stratum, and 1600 budesonide equivalents in the high-dose stratum.

[0071] [Table 2]

[0072] The baseline characteristics of randomized patients who received any study product and had a baseline eosinophil count of at least 300 cells / μl are shown in Table 3 below.

[0073] [Table 3]

[0074] (b) Validity The effect of benralizumab administration on FEV1 is shown in Figures 2-9. For example, the data in Figure 2 show that patients with blood eosinophil counts of at least 300 cells / μl who received 2, 20 or 100 mg of benralizumab had increased FEV1 by week 24. Similar results were observed at week 52 (Figure 3). The data in Figure 4 show that patients who received either medium or high doses of ICS had improved FEV1, but this improvement was greater in patients who received high doses of ICS. The data in Figure 5 compare the change in FEV1 in patients with blood eosinophil counts less than 300 cells / μl who were receiving medium doses of ICS with patients who were receiving high doses of ICS, and the data in Figure 6 compare the change in FEV1 in patients with blood eosinophil counts of at least 300 cells / μl who were receiving medium doses of ICS with patients who were receiving high doses of ICS. In patients with a blood eosinophil count of at least 300 cells / μl, we observed a greater improvement in FEV1 in patients receiving high doses of ICS (Figure 6). A more detailed analysis by eosinophil count is shown in Figure 7. As shown in Figures 8 and 9, the difference in FEV1 between patients receiving benralizumab and placebo could be observed as early as week 4. However, this difference was much larger in patients with a blood eosinophil count of at least 300 cells / μl.

[0075] (c) Safety Treatment-emergent adverse events (TEAEs) occurred approximately 10 percentage points more frequently in patients treated with benralizumab than in patients treated with placebo. Treatment-emergent severe adverse events (TE-SAEs) occurred with similar frequency in patients treated with benralizumab and placebo. In patients treated with benralizumab, TEAEs and TE-SAEs were not dose-related.

[0076] (d) Anti-drug antibodies The development of anti-drug antibodies to benralizumab showed an inverse relationship with dose, with the highest proportion of ADA-positive patients occurring at the 2 mg dose (see Table 4 below). The incidence of high titer ADA (≥ 400) was 12% and 9% in the 20 mg and 100 mg dose groups, respectively. High titer ADA, when present, was associated with reduced benralizumab concentrations and variable degrees of eosinophil recovery. The pharmacokinetic / pharmacodynamic (PK / PD) impact of high titer ADA was reduced with higher levels of drug exposure. No relationship was observed between TEAEs and ADA.

[0077] [Table 4]

[0078] Based on PK and immunological considerations, additional patient groups will receive a 30 mg dose of benralizumab. Some patients will receive a 30 mg dose of benralizumab every 4 weeks. Some patients will receive a 30 mg dose of benralizumab once every 4 weeks for three doses, then once every 8 weeks.

[0079] (e) Discussion This study shows that benralizumab improves lung function. Improvements were observed at all doses, with a clearly greater benefit at the 20 and 100 mg doses compared to the 2 mg dose. Furthermore, FEV1 appeared to improve more in patients receiving high-dose ICS / LABA than in patients receiving medium-dose ICS / LABA.

[0080] Example 3: Evaluation of additional doses Dose-effectiveness modeling was performed to identify an additional dose of Benralizumab that would reduce the annualized exacerbation rate and be safe and well tolerated. Modeling showed that approximately 30 mg was the lowest effective dose to achieve 90% of the maximum treatment effect. Thus, patients with uncontrolled asthma receive subcutaneous injections of 30 mg of Benralizumab or placebo. The 30 mg dose is administered (i) every 4 weeks, or (ii) every 4 weeks (three doses) for 8 weeks, and then every 8 weeks (i.e., every 8 weeks with an additional dose at week 4). To demonstrate that the 30 mg dose of Benralizumab reduces the annualized exacerbation rate, the number of exacerbations in patients receiving 30 mg of Benralizumab is compared to the number of exacerbations in patients receiving placebo. Additionally, to demonstrate that the 30 mg dose of Benralizumab is effective in reducing the annualized exacerbation rate in patients with baseline blood eosinophil counts of at least 300 cells / μl, the number of exacerbations in such patients is analyzed.

[0081] Those skilled in the art will recognize, or be able to ascertain using no more than routine experimentation, many equivalents to the specific embodiments of the disclosure described herein which equivalents are intended to be encompassed by the following claims.

[0082] Various publications are referenced herein, the disclosures of which are incorporated by reference in their entireties.

[0083] Although the present invention has been described in some detail by way of illustration and example for purposes of clarity of understanding, it will be apparent that certain changes and modifications can be practiced within the scope of the appended claims.

[0084] SEQ ID NO:1 >US20100291073_1 Sequence 1 of US Patent Application Publication No. 2010 / 0291073 Name of organism: Homo sapiens [ka] SEQ ID NO:2 >US20100291073_2 Sequence 2 of US Patent Application Publication No. 2010 / 0291073 Name of organism: Homo sapiens [ka] SEQ ID NO:3 >US20100291073_3 Sequence 3 of US Patent Application Publication No. 2010 / 0291073 Name of organism: Homo sapiens [ka] SEQ ID NO:4 >US20100291073_4 Sequence 4 of US Patent Application Publication No. 2010 / 0291073 Name of organism: Homo sapiens [ka] SEQ ID NO:5 >US20100291073_5 Sequence 5 of US Patent Application Publication No. 2010 / 0291073 Name of organism: Homo sapiens [ka] SEQ ID NO:6 >US20100291073_6 Sequence 6 of US Patent Application Publication No. 2010 / 0291073 Name of organism: Mus musculus [ka] SEQ ID NO:7-VH CDR1 [ka] SEQ ID NO:8-VH CDR2 [ka] SEQ ID NO:9-VH CDR3 [ka] SEQ ID NO:10-VL CDR1 [ka] SEQ ID NO:11-VL CDR2 [ka] SEQ ID NO:12-VL CDR3 [ka]

[0085] SEQUENCE LISTING <110> AstraZeneca AB <120> METHODS FOR INCREASING FORCED EXPIRATORY VOLUME IN ASTHMATICS USING BENRALIZUMAB <130> PA24-385 <150> US 61 / 864,948 <151> 2013-08-12 <160> 12 <170> PatentIn version 3.5 <210> 1 <211> 107 <212> PRT <213> Homo sapiens <400> 1 Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 1 5 10 15 Asp Arg Val Thr Ile Thr Cys Gly Thr Ser Glu Asp Ile Ile Asn Tyr 20 25 30 Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 35 40 45 Tyr His Thr Ser Arg Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro 65 70 75 80 Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Gly Tyr Thr Leu Pro Tyr 85 90 95 Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys 100 105 <210> 2 <211> 214 <212> PRT <213> Homo sapiens <400> 2 Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 1 5 10 15 Asp Arg Val Thr Ile Thr Cys Gly Thr Ser Glu Asp Ile Ile Asn Tyr 20 25 30 Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 35 40 45 Tyr His Thr Ser Arg Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro 65 70 75 80 Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Gly Tyr Thr Leu Pro Tyr 85 90 95 Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg Thr Val Ala Ala 100 105 110 Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly 115 120 125 Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala 130 135 140 Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln 145 150 155 160 Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser 165 170 175 Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr 180 185 190 Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser 195 200 205 Phe Asn Arg Gly Glu Cys 210 <210> 3 <211> 121 <212> PRT <213> Homo sapiens <400> 3 Glu Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala 1 5 10 15 Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr 20 25 30 Val Ile His Trp Val Arg Gln Arg Pro Gly Gln Gly Leu Ala Trp Met 35 40 45 Gly Tyr Ile Asn Pro Tyr Asn Asp Gly Thr Lys Tyr Asn Glu Arg Phe 50 55 60 Lys Gly Lys Val Thr Ile Thr Ser Asp Arg Ser Thr Ser Thr Val Tyr 65 70 75 80 Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Leu Cys 85 90 95 Gly Arg Glu Gly Ile Arg Tyr Tyr Gly Leu Leu Gly Asp Tyr Trp Gly 100 105 110 Gln Gly Thr Leu Val Thr Val Ser Ser 115 120 <210> 4 <211> 451 <212> PRT <213> Homo sapiens <400> 4 Glu Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala 1 5 10 15 Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr 20 25 30 Val Ile His Trp Val Arg Gln Arg Pro Gly Gln Gly Leu Ala Trp Met 35 40 45 Gly Tyr Ile Asn Pro Tyr Asn Asp Gly Thr Lys Tyr Asn Glu Arg Phe 50 55 60 Lys Gly Lys Val Thr Ile Thr Ser Asp Arg Ser Thr Ser Thr Val Tyr 65 70 75 80 Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Leu Cys 85 90 95 Gly Arg Glu Gly Ile Arg Tyr Tyr Gly Leu Leu Gly Asp Tyr Trp Gly 100 105 110 Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser 115 120 125 Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala 130 135 140 Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val 145 150 155 160 Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala 165 170 175 Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val 180 185 190 Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His 195 200 205 Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys 210 215 220 Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly 225 230 235 240 Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met 245 250 255 Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His 260 265 270 Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val 275 280 285 His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr 290 295 300 Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly 305 310 315 320 Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile 325 330 335 Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val 340 345 350 Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser 355 360 365 Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu 370 375 380 Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro 385 390 395 400 Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val 405 410 415 Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met 420 425 430 His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser 435 440 445 Pro Gly Lys 450 <210> 5 <211> 400 <212> PRT <213> Homo sapiens <400> 5 Asp Leu Leu Pro Asp Glu Lys Ile Ser Leu Leu Pro Pro Val Asn Phe 1 5 10 15 Thr Ile Lys Val Thr Gly Leu Ala Gln Val Leu Leu Gln Trp Lys Pro 20 25 30 Asn Pro Asp Gln Glu Gln Arg Asn Val Asn Leu Glu Tyr Gln Val Lys 35 40 45 Ile Asn Ala Pro Lys Glu Asp Asp Tyr Glu Thr Arg Ile Thr Glu Ser 50 55 60 Lys Cys Val Thr Ile Leu His Lys Gly Phe Ser Ala Ser Val Arg Thr 65 70 75 80 Ile Leu Gln Asn Asp His Ser Leu Leu Ala Ser Ser Trp Ala Ser Ala 85 90 95 Glu Leu His Ala Pro Pro Gly Ser Pro Gly Thr Ser Ile Val Asn Leu 100 105 110 Thr Cys Thr Thr Asn Thr Thr Glu Asp Asn Tyr Ser Arg Leu Arg Ser 115 120 125 Tyr Gln Val Ser Leu His Cys Thr Trp Leu Val Gly Thr Asp Ala Pro 130 135 140 Glu Asp Thr Gln Tyr Phe Leu Tyr Tyr Arg Tyr Gly Ser Trp Thr Glu 145 150 155 160 Glu Cys Gln Glu Tyr Ser Lys Asp Thr Leu Gly Arg Asn Ile Ala Cys 165 170 175 Trp Phe Pro Arg Thr Phe Ile Leu Ser Lys Gly Arg Asp Trp Leu Ala 180 185 190 Val Leu Val Asn Gly Ser Ser Lys His Ser Ala Ile Arg Pro Phe Asp 195 200 205 Gln Leu Phe Ala Leu His Ala Ile Asp Gln Ile Asn Pro Pro Leu Asn 210 215 220 Val Thr Ala Glu Ile Glu Gly Thr Arg Leu Ser Ile Gln Trp Glu Lys 225 230 235 240 Pro Val Ser Ala Phe Pro Ile His Cys Phe Asp Tyr Glu Val Lys Ile 245 250 255 His Asn Thr Arg Asn Gly Tyr Leu Gln Ile Glu Lys Leu Met Thr Asn 260 265 270 Ala Phe Ile Ser Ile Ile Asp Asp Leu Ser Lys Tyr Asp Val Gln Val 275 280 285 Arg Ala Ala Val Ser Ser Met Cys Arg Glu Ala Gly Leu Trp Ser Glu 290 295 300 Trp Ser Gln Pro Ile Tyr Val Gly Asn Asp Glu His Lys Pro Leu Arg 305 310 315 320 Glu Trp Phe Val Ile Val Ile Met Ala Thr Ile Cys Phe Ile Leu Leu 325 330 335 Ile Leu Ser Leu Ile Cys Lys Ile Cys His Leu Trp Ile Lys Leu Phe 340 345 350 Pro Pro Ile Pro Ala Pro Lys Ser Asn Ile Lys Asp Leu Phe Val Thr 355 360 365 Thr Asn Tyr Glu Lys Ala Gly Ser Ser Glu Thr Glu Ile Glu Val Ile 370 375 380 Cys Tyr Ile Glu Lys Pro Gly Val Glu Thr Leu Glu Asp Ser Val Phe 385 390 395 400 <210> 6 <211> 398 <212> PRT <213> Mus musculus <400> 6 Asp Leu Leu Asn His Lys Lys Phe Leu Leu Leu Pro Pro Val Asn Phe 1 5 10 15 Thr Ile Lys Ala Thr Gly Leu Ala Gln Val Leu Leu His Trp Asp Pro 20 25 30 Asn Pro Asp Gln Glu Gln Arg His Val Asp Leu Glu Tyr His Val Lys 35 40 45 Ile Asn Ala Pro Gln Glu Asp Glu Tyr Asp Thr Arg Lys Thr Glu Ser 50 55 60 Lys Cys Val Thr Pro Leu His Glu Gly Phe Ala Ala Ser Val Arg Thr 65 70 75 80 Ile Leu Lys Ser Ser His Thr Thr Leu Ala Ser Ser Trp Val Ser Ala 85 90 95 Glu Leu Lys Ala Pro Pro Gly Ser Pro Gly Thr Ser Val Thr Asn Leu 100 105 110 Thr Cys Thr Thr His Thr Val Val Ser Ser His Thr His Leu Arg Pro 115 120 125 Tyr Gln Val Ser Leu Arg Cys Thr Trp Leu Val Gly Lys Asp Ala Pro 130 135 140 Glu Asp Thr Gln Tyr Phe Leu Tyr Tyr Arg Phe Gly Val Leu Thr Glu 145 150 155 160 Lys Cys Gln Glu Tyr Ser Arg Asp Ala Leu Asn Arg Asn Thr Ala Cys 165 170 175 Trp Phe Pro Arg Thr Phe Ile Asn Ser Lys Gly Phe Glu Gln Leu Ala 180 185 190 Val His Ile Asn Gly Ser Ser Lys Arg Ala Ala Ile Lys Pro Phe Asp 195 200 205 Gln Leu Phe Ser Pro Leu Ala Ile Asp Gln Val Asn Pro Pro Arg Asn 210 215 220 Val Thr Val Glu Ile Glu Ser Asn Ser Leu Tyr Ile Gln Trp Glu Lys 225 230 235 240 Pro Leu Ser Ala Phe Pro Asp His Cys Phe Asn Tyr Glu Leu Lys Ile 245 250 255 Tyr Asn Thr Lys Asn Gly His Ile Gln Lys Glu Lys Leu Ile Ala Asn 260 265 270 Lys Phe Ile Ser Lys Ile Asp Asp Val Ser Thr Tyr Ser Ile Gln Val 275 280 285 Arg Ala Ala Val Ser Ser Pro Cys Arg Met Pro Gly Arg Trp Gly Glu 290 295 300 Trp Ser Gln Pro Ile Tyr Val Gly Lys Glu Arg Lys Ser Leu Val Glu 305 310 315 320 Trp His Leu Ile Val Leu Pro Thr Ala Ala Cys Phe Val Leu Leu Ile 325 330 335 Phe Ser Leu Ile Cys Arg Val Cys His Leu Trp Thr Arg Leu Phe Pro 340 345 350 Pro Val Pro Ala Pro Lys Ser Asn Ile Lys Asp Leu Pro Val Val Thr 355 360 365 Glu Tyr Glu Lys Pro Ser Asn Glu Thr Lys Ile Glu Val Val His Cys 370 375 380 Val Glu Glu Val Gly Phe Glu Val Met Gly Asn Ser Thr Phe 385 390 395 <210> 7 <211> 5 <212> PRT <213> Homo sapiens <400> 7 Ser Tyr Val Ile His 1 5 <210> 8 <211> 17 <212> PRT <213> Homo sapiens <400> 8 Tyr Ile Asn Pro Tyr Asn Asp Gly Thr Lys Tyr Asn Glu Arg Phe Lys 1 5 10 15 Gly <210> 9 <211> 12 <212> PRT <213> Homo sapiens <400> 9 Glu Gly Ile Arg Tyr Tyr Gly Leu Leu Gly Asp Tyr 1 5 10 <210> 10 <211> 11 <212> PRT <213> Homo sapiens <400> 10 Gly Thr Ser Glu Asp Ile Ile Asn Tyr Leu Asn 1 5 10 <210> 11 <211> 7 <212> PRT <213> Homo sapiens <400> 11 His Thr Ser Arg Leu Gln Ser 1 5 <210> 12 <211> 9 <212> PRT <213> Homo sapiens <400> 12 Gln Gln Gly Tyr Thr Leu Pro Tyr Thr 1 5

Claims

1. A pharmaceutical for use in a method for treating asthma by increasing forced expiratory volume in 1 second (FEV 1 ) in adult asthmatic patients, comprising: comprising an effective amount of benralizumab or an antigen-binding fragment thereof, a 30 mg dose of benralizumab or an antigen-binding fragment thereof is administered to the patient once every 4 weeks for 8 weeks, then once every 8 weeks; The administration increases FEV 1 in the patient.

2. The pharmaceutical composition of claim 1, wherein the administration increases FEV 1 in the asthma patient within 4 weeks of the first administration.

3. The pharmaceutical described in claim 1, wherein the asthma is eosinophilic asthma.

4. The pharmaceutical described in claim 1, wherein the patient has a blood eosinophil count of at least 300 cells / μl.

5. The method of claim 1, wherein the patient has a forced expiratory volume in 1 second (FEV 1 ) of at least 75% of the predicted value before administration.

6. The pharmaceutical composition of claim 1, wherein FEV 1 increases by at least 0.1 L.

7. The pharmaceutical described in claim 1, wherein the patient uses high-dose inhaled corticosteroids (ICS).

8. The pharmaceutical described in claim 1, wherein the patient uses a long-acting beta-2 agonist (LABA).

9. The pharmaceutical described in claim 1, wherein the patient has a history of exacerbation.

10. The pharmaceutical described in claim 1, wherein benralizumab or an antigen-binding fragment thereof is administered in addition to corticosteroid therapy.

Images