A method to increase forced vital capacity in asthma patients using benralitumab

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 Art

[0001] Reference to Sequence Listing This application includes a sequence listing submitted electronically in ASCII format, which is hereby incorporated by reference in its entirety. A copy of the ASCII created on July 16, 2014, has the file name IL5R-604WO1_SL.txt and a size of 15,971 bytes.

[0002] Background More than 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 the morbidity rate in the world (Masoli M, et al. Allergy 59:469-78 (2004)).

[0003] Recurrence after acute asthma exacerbation has been reported to be in the range of 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 been found to be difficult due to the disease being a serious intractable disease, or not being suitable for treatment and / or not willing to comply with treatment. In a study of inpatients, 50% of several fatal asthma patients had low compliance with systemic corticosteroids on the 7th day after discharge (Krishnan J, et al. AJRCCM 170:1281-85 (2004)). Many factors such as difficulty in accessing routine health management (especially in slum areas), lack of education or understanding about their disease, unwillingness to accept that their disease is chronic, or inability to receive drug treatment can be the cause of low compliance.

[0004] Numerous pieces of evidence implicitly suggest that eosinophils are one of the main causative cells of asthmatic airway inflammation (James A. Curr Opin Pulm Med 11(1):1-6 (2005)). Eosinophilia in peripheral blood (PB) 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 eosinophils had a 7.4 times higher risk (confidence interval, 2.8-19.7) of death from asthma compared to patients without elevated eosinophilia (Ulrik C and Fredericksen J. Chest 108:10-15 (1995)). Autopsy results identified two distinctly different pathogenic inflammatory mechanisms in fatal asthma (Restrepo R and Peters J. Curr Opin Pulm Med 14:13-23 (2008)). Neutrophil infiltration was more pronounced in patients who died suddenly (within approximately two hours of symptom onset), while eosinophil infiltration was more common in patients who died after a longer asthmatic crisis. Eosinophils in sputum and blood may also be elevated in patients who present to the emergency department due to the sudden onset of asthma symptoms (Bellido-Casado J, et al. Arch Bronconeumol 46(11):587-93 (2010)). Eosinophil-targeted therapies have been shown to reduce the frequency and severity of asthma exacerbations compared to the use of clinical 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 interleukin-5 receptor alpha (IL-5Rα) expressed on eosinophils and basophils. It induces apoptosis of these cells through antibody-dependent cell-mediated cytotoxicity. A single intravenous (IV) dose of Benralizumab in adults with mild asthma resulted in a prolonged decrease in eosinophils in the bone marrow, likely due to its effect on eosinophil / basophil myeloid progenitor cells expressing this target (Busse W, et al. JACI 125:1237-1244 e2 (2010)). Furthermore, a single dose of Benralizumab significantly reduced the serum eosinophil count in patients presenting to the emergency department due to severe asthma exacerbations, but without affecting lung function (International Publication No. 13 / 066780 pamphlet).

[0006] Thus, there is a strong, unmet need among asthma patients to improve lung function, such as that measured by forced expiratory volume in one second (FEV1). Furthermore, some asthma patients have eosinophilic components. Therefore, we investigated the effect of benralizumab on FEV1 in adult patients. [Overview of the Initiative] [Means for solving the problem]

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

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

[0009] In one embodiment, a method for treating asthma includes administering an effective dose of benralizumab or its antigen-binding fragment to an asthma patient whose pre-administration forced expiratory volume in one second (FEV1) is at least 75% of the predicted value.

[0010] In one embodiment, a method for treating asthma includes administering benralizumab or its antigen-binding fragment to an asthma patient at least twice.

[0011] In some embodiments of the method provided herein, administration increases the patient's FEV1. In some embodiments, administration increases the patient's FEV1 within 4 weeks from 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 one embodiment of the method provided herein, the asthma is eosinophilic asthma. In one embodiment, the patient's blood eosinophil count is at least 300 cells / μl.

[0013] In one embodiment of the method provided herein, the patient has a forced expiratory volume in one second (FEV1) of at least 75% of the predicted value prior to administration. In another embodiment, the patient has an asthma control questionnaire score of at least 1.5 prior to administration. In another embodiment, the patient uses a high-dose inhaled corticosteroid (ICS). In another embodiment, the patient uses a long-acting β2-agonist (LABA). In another embodiment, the patient has a history of exacerbations. In another embodiment, the history of exacerbations includes at least two exacerbations in the year prior to administration of Benralizumab or its antigen-binding fragment. In another embodiment, the history of exacerbations includes six or fewer exacerbations in the year prior to administration of Benralizumab or its antigen-binding fragment.

[0014] In one embodiment of the method provided herein, Benralizumab or its antigen-binding fragment is administered to the patient at least twice.

[0015] In some embodiments of the methods provided herein, Benralizumab or its antigen-binding fragment is administered in doses of approximately 2 mg to approximately 100 mg. In some embodiments, Benralizumab or its antigen-binding fragment is administered in doses of approximately 20 mg. In some embodiments, Benralizumab or its antigen-binding fragment is administered in doses of approximately 30 mg. In some embodiments, Benralizumab or its antigen-binding fragment is administered in doses of approximately 100 mg.

[0016] In some embodiments of the methods provided herein, Benralizumab or its antigen-binding fragment is administered once every 4 to 12 weeks. In some embodiments, Benralizumab or its antigen-binding fragment is administered once every 4 weeks. In some embodiments, Benralizumab or its antigen-binding fragment is administered once every 8 weeks. In some embodiments, Benralizumab or its antigen-binding fragment is administered once every 4 weeks for 12 weeks, and then once every 8 weeks thereafter.

[0017] In one embodiment of the method provided herein, Benralizumab or its antigen-binding fragment is administered parenterally. In another embodiment, Benralizumab or its antigen-binding fragment is administered subcutaneously.

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

[0019] In one embodiment, a method for increasing the forced expiratory volume in one second (FEV1) in asthma patients includes administering 20 to 100 mg of benralizumab or its antigen-binding fragment to patients with a pre-administration blood eosinophil count of at least 300 cells / μl. In another embodiment, the method includes administering 20 mg of benralizumab or its antigen-binding fragment. In another embodiment, 20 mg of benralizumab is administered once every four weeks for 12 weeks, and then once every eight weeks thereafter. In another embodiment, the method includes administering 30 mg of benralizumab or its antigen-binding fragment. In another embodiment, 30 mg of benralizumab is administered once every four weeks for 8 weeks, and then once every eight weeks thereafter. In yet another embodiment, 30 mg of benralizumab is administered once every four weeks. In yet another embodiment, the method includes administering 100 mg of benralizumab or its antigen-binding fragment. In one embodiment, Benralizumab 100 mg is administered once every four weeks for 12 weeks, and then once every eight weeks thereafter.

[0020] In some embodiments, a method for treating asthma in an asthma patient includes administering to the patient a dose of Benralizumab or its antigen-binding fragment in a dose of at least 2 mg and less than 100 mg. In some embodiments, the method includes administering 20 mg of Benralizumab or its antigen-binding fragment. In some embodiments, the method includes administering 30 mg of Benralizumab or its antigen-binding fragment. In some embodiments, the method includes administering a dose of at least 20 mg and less than 100 mg of Benralizumab or its antigen-binding fragment. In some embodiments, the method includes administering a dose of at least 30 mg and less than 100 mg of Benralizumab or its antigen-binding fragment. In some embodiments, the method reduces the rate of asthma exacerbations. In some embodiments, the method reduces the annual rate of asthma exacerbations. In some embodiments, the administration is subcutaneous.

[0021] In one embodiment of the method of provision, administration of benralizumab or its antigen-binding fragment increases the forced expiratory volume in one second (FEV1), as shown in Figures 2-9.

[0022] In one embodiment of the method of provision, administration of benralizumab or its antigen-binding fragment increases the forced expiratory volume in one second (FEV1), as shown in Examples 1-2. [Brief explanation of the drawing]

[0023] [Figure 1] Figure 1 shows the flowchart of the test. [Figure 2] Figure 2 shows the change in forced expiratory volume in one second (FEV1) at week 24 in patients with less than 300 eosinophils / μl and patients with at least 300 eosinophils / μl, after treatment with placebo, 2 mg benralizumab, 20 mg benralizumab, or 100 mg benralizumab. [Figure 3] Figure 3 shows the changes in FEV1 at the intermediate period (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 at least 300 eosinophils / μl. [Figure 4] Figure 4 shows the changes in FEV1 at the intermediate period (week 24) and stage I (week 52) after treatment with placebo, 2 mg benralizumab, 20 mg benralizumab, or 100 mg benralizumab in patients using moderate or high dose inhaled corticosteroids (ICS). [Figure 5] Figure 5 shows the changes in FEV1 at the intermediate period (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]Figure 6 shows the change in FEV1 at the intermediate stage (week 24) and stage I (week 52) after treating patients with at least 300 eosinophils / μl and using (i) medium dose, or (ii) high dose of ICS with placebo, 2 mg of Benralizumab, 20 mg of Benralizumab or 100 mg of Benralizumab. [Figure 7A] Figures 7A and 7B show the change in FEV1 with different eosinophil counts in patients. [Figure 7B] Figures 7A and 7B show the change in FEV1 with different eosinophil counts in patients. [Figure 8] Figure 8 shows the change in average FEV1 over time in patients with at least 300 eosinophils / μl. [Figure 9] Figure 9 shows the change in average FEV1 over time in patients with less than 300 eosinophils / μl.

Mode for Carrying Out the Invention

[0024] [[ID=十九]] [[ID=二十]]It should be noted that entities preceded by the term "a" or "an" refer to one or more of those entities. For example, "an anti-IL-5α antibody" is understood to mean one or more anti-IL-5α antibodies. Therefore, the terms "a" (or "an"), "one or more" and "at least one" can be used as synonyms in this specification. [[ID=二十一]] [[ID=二十二]]

[0025] [[ID=二十三]] [[ID=二十四]]Provided herein is a method for increasing the forced expiratory volume in one second (FEV1) in asthmatic patients. The provided method includes administering an effective amount of Benralizumab or an antigen-binding fragment thereof. [[ID=二十五]] [[ID=二十六]]

[0026] [[ID=二十七]] Information relating to Benralizumab (or its fragments) used in the methods provided herein can be found in U.S. Patent Application Publication No. 2010 / 0291073A1, the entire disclosure of which is incorporated herein by reference. Benralizumab and its antigen-binding fragments used 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 used in the methods provided herein include one of the amino acid sequences of SEQ ID NOs: 1 to 4. In certain embodiments, Benralizumab or its antigen-binding fragments used in the methods provided herein include a light chain variable region containing the amino acid sequence of SEQ ID NO: 1, and a heavy chain variable region containing the amino acid sequence of SEQ ID NO: 3. In certain embodiments, Benralizumab or its antigen-binding fragments used in the methods provided herein include a light chain containing the amino acid sequence of SEQ ID NO: 2, and a heavy chain containing the amino acid sequence of SEQ ID NO: 4. In certain embodiments, Benralizumab or its antigen-binding fragment used in the methods provided herein includes a heavy chain variable region containing the Kabat-defined CDR1, CDR2, and CDR3 sequences of SEQ ID NOs: 7-9, and a light chain variable region containing 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 CDRs as defined by Chothia, CDRs as defined by Abm, or other CDRs. In certain embodiments, Benralizumab or its antigen-binding fragment used in the methods provided herein includes the variable heavy chain 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, a patient presenting to a hospital or ED for asthma is administered benralizumab or its antigen-binding fragment. If benralizumab can reduce or decrease eosinophil counts for 12 weeks or longer (see U.S. Patent Application Publication No. 2010 / 0291073), benralizumab or its antigen-binding fragment may be administered only once or in very few doses, as long as the patient is still benefiting from increased forced expiratory volume in one second (FEV1). In a further embodiment, the patient may receive additional doses. Additional doses may be given at various time intervals depending on the patient's age, weight, ability to follow physician's instructions, clinical assessment, eosinophil count (eosinophils in blood or sputum), eosinophil cationic protein (ECP) levels, eosinophil-derived neurotoxin (EDN) levels, major basic protein (MBP) levels, and other factors such as the attending physician's judgment. The administration interval may be every 4 weeks, every 5 weeks, every 6 weeks, every 8 weeks, every 10 weeks, every 12 weeks, or longer intervals. In some embodiments, the administration interval may be every 4 weeks, every 8 weeks, or every 12 weeks. In some embodiments, a single dose or initial dose is administered to an asthma patient immediately after the patient experiences an acute exacerbation, e.g., a mild, moderate, or severe exacerbation. For example, a single dose or initial dose of Benralizumab or its antigen-binding fragment may be administered at a clinic or hospital visit, but in cases of very severe exacerbations occurring 1, 2, 3, 4, 5, 6, or 7 days or more after an acute exacerbation, e.g., within 7 days, the patient's symptoms should be stabilized before administering Benralizumab.

[0028] In some embodiments, Benralizumab or its antigen-binding fragment is administered to the patient at least twice. In some embodiments, the patient receives at least three, at least four, at least five, at least six, or at least seven doses. In some embodiments, Benralizumab or its antigen-binding fragment is administered over four weeks, eight weeks, twelve weeks, twenty-four weeks, or one year.

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

[0030] In some embodiments, the patient is administered one or more doses of Benralizumab or its antigen-binding fragment in a dose of approximately 2 mg to approximately 100 mg, for example, approximately 20 mg to approximately 100 mg, or approximately 30 mg to approximately 100 mg. In some embodiments, the patient is administered one or more doses of Benralizumab or its antigen-binding fragment in a dose of approximately 20 mg, approximately 30 mg, approximately 40 mg, approximately 50 mg, approximately 60 mg, approximately 70 mg, approximately 80 mg, approximately 90 mg, or approximately 100 mg. In some embodiments, the dose is approximately 20 mg. In some embodiments, the dose is approximately 30 mg. In some embodiments, the dose is approximately 100 mg.

[0031] In some embodiments, the administration of Benralizumab or its antigen-binding fragment by the method provided herein is parenteral administration. For example, Benralizumab or its antigen-binding fragment can be administered by intravenous infusion or subcutaneous injection.

[0032] In some embodiments, benralizumab or its antigen-binding fragment is administered in combination with or in conjunction with another asthma therapy by the method provided herein. Such therapies include, but are not limited to, inhaled corticosteroid therapy, long-acting or short-acting bronchodilator therapy, oxygen supplementation, or other standard therapies as described in, for example, the NAEPP Guidelines. In some embodiments, the use of the method provided herein, i.e., administration of benralizumab or its antigen-binding fragment, serves as an adjunct therapy for asthma patients with a history of exacerbations in situations where it is difficult to follow standard forms of asthma treatment management.

[0033] The method provided herein can significantly increase the forced expiratory volume in one second (FEV1) of asthma patients. The increase can be measured based on FEV1 predicted from a large patient population, based on FEV1 measured in a control population, or based on the FEV1 of individual patients before administration. In one embodiment, the patient population is a group of patients who have experienced ≥2 exacerbations requiring oral systemic corticosteroids in the past year. In another embodiment, 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 another embodiment, the patient population is a group of patients with an eosinophil count of at least 300 cells / μl.

[0034] In one embodiment, by the method provided herein, i.e., by administration of Benralizumab or its antigen-binding fragment, the patient's forced expiratory volume in one second (FEV1) increases over 24 weeks after administration of Benralizumab or its antigen-binding fragment compared to the patient's baseline FEV1. In one embodiment, the patient may receive additional doses of Benralizumab or its antigen-binding fragment regularly, 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 follow physician's instructions, clinical assessment, eosinophil count (eosinophils in blood or sputum), eosinophil cationic protein (ECP) measurement, eosinophil-derived neurotoxin (EDN) measurement, major basic protein (MBP) measurement, and the judgment of the attending physician. Using the method provided herein, FEV1 can be increased over 24 weeks 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.

[0035] In other embodiments, by using the method provided herein, i.e., by administering Benralizumab or its antigen-binding fragment to an asthma patient, the patient's forced expiratory volume in one second (FEV1) increases over 52 weeks after administration of Benralizumab or its antigen-binding fragment. In some embodiments, the patient may receive additional doses of Benralizumab or its antigen-binding fragment regularly, 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 follow physician's instructions, clinical assessment, eosinophil count (eosinophils in blood or sputum), eosinophil cationic protein (ECP) measurement, eosinophil-derived neurotoxin (EDN) measurement, major basic protein (MBP) measurement, and the judgment of the attending physician. In some embodiments, the interval is every 4 weeks, every 8 weeks, or every 12 weeks. By using the method provided herein, the forced expiratory volume in one second (FEV1) can be increased over 24 weeks 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.

[0036] In some embodiments, by using the method provided herein, i.e., by administering benralizumab or its antigen-binding fragment, the forced expiratory volume in one second (FEV1) increases within 4 weeks, 8 weeks, 12 weeks, 16 weeks, 20 weeks, 24 weeks, 28 weeks, 32 weeks, 36 weeks, 40 weeks, 44 weeks, 48 ​​weeks, or 52 weeks.

[0037] In one embodiment, the use of the method provided herein, i.e., by administering benralizumab or its antigen-binding fragment to an asthma patient, increases forced expiratory volume in one second (FEV1), reduces annual exacerbation rate, and / or improves asthma questionnaire scores (e.g., Asthma Control Questionnaire (ACQ)).

[0038] In some cases, a patient may be "eosinophil-positive," which means there is a high probability that the patient has eosinophilic asthma.

[0039] In one embodiment, asthma patients have a specific blood eosinophil count prior to administration of, for example, benralizumab or its antigen-binding fragment. The blood eosinophil count can be measured, for example, by performing a complete blood count (CBC) along with a blood cell classification.

[0040] In one embodiment, the asthma patient has a blood eosinophil count of at least 300 cells / μl prior to administration of Benralizumab or its antigen-binding fragment. In another embodiment, the asthma patient has a blood eosinophil count of at least 350 cells / μl, at least 400 cells / μl, at least 450 cells / μl, or at least 500 cells / μl prior to administration of Benralizumab or its antigen-binding fragment.

[0041] In one embodiment, the asthma patient has a blood eosinophil count of less than 300 cells / μl prior to administration of Benralizumab or its antigen-binding fragment. In another embodiment, 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 its antigen-binding fragment.

[0042] In some embodiments, asthma patients have been prescribed or have used a moderate dose of inhaled corticosteroid (ICS) prior to administration of benralizumab or its antigen-binding fragment. The moderate dose of ICS may be budesonide at a daily dose of at least 600 μg to 1,200 μg, or another ICS at an equivalent dose.

[0043] In some embodiments, asthma patients have been prescribed or have used high-dose intensive care units (ICS) prior to administration of benralizumab or its antigen-binding fragment. The high-dose ICS may be budesonide at a daily dose of at least 1,200 μg, or another ICS at an equivalent dose. The high-dose ICS may also be budesonide at a daily dose of more than 1,200 μg to 2,000 μg, or another ICS at an equivalent dose.

[0044] In one embodiment, asthma patients have been prescribed or have been using oral corticosteroids prior to the administration of benralizumab or its antigen-binding fragment. In another embodiment, administration of benralizumab or its antigen-binding fragment reduces the use of oral corticosteroids in asthma patients. In yet another embodiment, its administration reduces the use of oral corticosteroids in asthma patients by at least 50%.

[0045] In one embodiment, asthma patients have been prescribed or have used long-acting beta-agonists (LABAs) prior to administration of benralizumab or its antigen-binding fragment.

[0046] In one embodiment, asthma patients have been prescribed or have used both ICS and LABA prior to the administration of benralizumab or its antigen-binding fragment.

[0047] In one embodiment, an asthma patient has a blood eosinophil count of at least 300 cells / μl and is using a high dose of ICS prior to administration of benralizumab or its antigen-binding fragment.

[0048] In some embodiments, asthma patients have a forced expiratory volume in one second (FEV1) of at least 40% and less than 90% of the predicted value before administration of Benralizumab or its antigen-binding fragment. In some embodiments, FEV1 is greater than 70% of the predicted value before administration of Benralizumab or its antigen-binding fragment. In some embodiments, FEV1 is greater than 70% and less than 90% of the predicted value before administration of Benralizumab or its antigen-binding fragment. In some embodiments, FEV1 is at least 75% of the predicted value before administration of Benralizumab or its antigen-binding fragment. In some embodiments, FEV1 is at least 75% and less than 90% of the predicted value before administration of Benralizumab or its antigen-binding fragment. In some embodiments, FEV1 is at least 80% of the predicted value before administration of Benralizumab or its antigen-binding fragment. In some embodiments, FEV1 is at least 80% and less than 90% of the predicted value before administration of Benralizumab or its antigen-binding fragment. [Examples]

[0049] Example 1: Patient and Method (a) Patient Patients in this study were required to be between 18 and 75 years old and weigh between 45 kg and 150 kg (between 100 lbs and 330 lbs). They also had to have a physician's diagnosis of having had asthma for at least 12 months prior to screening, and had been using a physician-prescribed medium or high dose inhaled corticosteroid (ICS) and a long-acting beta-agonist (LABA) daily, or any combination of continuous medium or high dose ICS / LABA, daily for at least 12 months prior to screening. The medium and high doses of ICS as defined in this study are shown in Table 1 below.

[0050] [Table 1]

[0051] Other asthma control medications had to be administered stably to the patient for at least 30 days prior to screening. The patient had also experienced at least two, but no more than six, documented asthma exacerbations requiring systemic corticosteroid bursts within the 12 months prior to screening. Furthermore, during the screening / preparation period (described below), the patient's forced expiratory volume in one second (FEV1) before morning bronchodilator use had to be at least 40% and less than 90% of the predicted value. The patient also had to meet one of the following criteria: a) Documented evidence within 36 months prior to randomization that airflow limitation reversibility after bronchodilator use was ≥12% and ≥200 mL, or documented evidence within 36 months prior to randomization that there was a positive response to metacholine challenge [PC20 ≤ 8 mg / mL]; b) At the 3-week screening, FEV1 after bronchodilator use was ≥12% and there was an increase of ≥200 mL; or If criteria c)a) and b) were not met, but all other inclusion / exclusion criteria were met, patients with an FEV1 of ≥1.5L and ≥60% of the predicted value at the -2 week screening were eligible to receive a metacholine challenge at a location where a metacholine test could be performed at the -2 week screening. If the patient showed a positive response (PC20 ≤8 mg / mL), this inclusion criterion was met.

[0052] Patients were also required to take the Asthma Control Questionnaire (ACQ) score of at least 1.5 at least twice during the screening / preparation period.

[0053] Patients were ineligible to participate if they had been exposed to more than 10 packs of tobacco per year prior to screening, had smoked continuously within the past 12 months, or had a health condition that would interfere with the assessment in the judgment of the examiner or medical monitor (e.g., eosinophilic lower respiratory tract disease other than asthma, chronic obstructive pulmonary disease (COPD), or cystic fibrosis). They were also ineligible if they had received oral corticosteroid bursts or short-acting systemic corticosteroid therapy within 30 days prior to screening or during the screening / preparation period.

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

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

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

[0057] Patients received two 1 ml subcutaneous (SC) injections of either benralizumab or placebo: every four weeks for the first three doses in weeks 1 (day 1), 4, and 8; and every eight weeks for the last four doses in weeks 16, 24, 32, and 40. After 40 weeks, patients were followed for an additional 12 weeks (up to week 52) to assess for acute exacerbations. Day 1 was defined as the day the first dose of benralizumab or placebo was received.

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

[0059] Maximum flow rate (PEF) tests at home for FEV1 and PEF were performed twice daily, in the morning after waking and at night before going to bed, using an ePro device, from the initial screening until the 52-week visit. Patient active participation in treatment was checked at each visit until the 52-week visit. Patients were asked to perform the PEF test every morning in a seated or standing position, but in the same position for each test. At screening, each enrolled patient was provided with a home-use PEF meter and instructions for recording data.

[0060] Furthermore, spirometry was performed by examiners or qualified designated individuals using equipment provided by major vendors, in accordance with ATS / European Respiratory Society (ERS) guidelines (Miller et al, Eur Respir J 26:153-61 (2005)). Spirometry was performed in the mornings, from 6:00 AM to 11:00 AM, at weeks -3, -2, -1, 1 (day 1), 4, 16, 24, 32, 40, and 52. On treatment days, spirometry was performed before administration of the test product. All morning spirometry tests after screening were requested to be completed between 6:00 AM and 11:00 AM, and within ±1 hour of the completion time of the screening spirometry. For example, if the screening spirometry test was at 8:00 AM, all subsequent spirometry tests had to be completed between 7:00 AM and 9:00 AM.

[0061] At each spirometry session in the office, multiple forced expiratory efforts (at least 3, but no more than 8) were performed, and two best efforts meeting the American Thoracic Society / European Respiratory Society (ATS / ERS) acceptance and reproducibility criteria were recorded. The best effort was based on the highest FEV1. The maximum FEV1 from the two best efforts was used for analysis. Absolute values ​​(FEV1 and forced vital capacity (FVC)) and their percentages to the predicted normal range (Hankinson et al., Am J Respir Crit Care Med 159:179-87 (1999)) were recorded. The maximum forced vital capacity was also recorded, regardless of the effort that produced it (even if the effort did not result in the maximum FEV1). The preferred standard for the predicted normal range is the National Health and Nutrition Examination Survey III (NHANES III). We evaluated the indirect measurement of air trapping using data obtained from routine spirometry. The spirometry data were substituted into the formula developed by Sorkness et al. (J Appl Physiol 104:394-403 (2008)).

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

[0063] After pre-BD spirometry, four puffs of albuterol / salbutamol MDI were administered with a 30-second interval between puffs, and post-BD spirometry was performed 15-20 minutes later. Subsequently, two additional puffs of albuterol / salmeterol were administered with a 30-second interval between puffs, and a second post-BD spirometry was performed 15-20 minutes later. Finally, if the incremental change in FEV1 after six puffs of albuterol / salbutamol was ≤5% of the FEV1 value after four puffs of albuterol / salbutamol, the last two puffs of albuterol / salmeterol were not administered. On the other hand, if the change was >5%, two puffs of albuterol / salmeterol were administered with a 30-second interval between puffs, and a third post-BD spirometry was performed 15-20 minutes later.

[0064] The percentage difference between FEV1 after 6 puffs and FEV1 after 4 puffs was calculated as follows: % difference = (FEV1(6 puffs) - FEV1(4 puffs)) / FEV1(4 puffs) × 100

[0065] To determine reversibility, the maximum values ​​of FEV1 before and after BD were used and calculated as follows:

number

[0066] Where applicable, the metacholine inhalation challenge was completed in the morning, ±1 hour before each assessment. Direct challenge using metacholine acts directly on airway smooth muscle, causing airflow limitation and reducing FEV1. The metacholine inhalation challenge test was performed using either of the two ATS guideline recommended methods: 2 minutes of resting ventilation or 5 deep breaths dosimeter (American Thoracic Society, Am J Respir Crit Care Med. 161:309-329 (2000)). The same method was used for each individual patient. The best effort was defined as the one that yielded the highest FEV1 in each stage; maximum FVC and maximum peak flow rate were also recorded, even if they were obtained with different efforts than the highest FEV1. Only two efforts were required in each stage if the examiner or qualified designated person considered two efforts to be representative of the patient's ability to perform spirometry in that stage. In general, no more than three efforts (measurements) were performed in each stage to ensure the patient maintained the ability to perform spirometry throughout the test.

[0067] Contraindications for the metacholine loading test include pregnancy, breastfeeding, FEV1 <1.5L or <60% of the predicted value, heart attack or stroke within the past 3 months, aortic aneurysm with findings, uncontrolled hypertension (systolic >200 mmHg or diastolic >100 mmHg), ongoing anticholinesterase 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 days, or certain prohibited medications or foods.

[0068] The decrease in FEV1 was calculated as the percentage of the best FEV1 determined by the Saline stage. Positive or symptomatic patients received 2–4 puffs of albuterol / salbutamol and were observed until their FEV1 recovered to at least 90% of the baseline (-2 weeks screening) value. Patients with a decrease in FEV1 >50% were rescued with albuterol and carefully monitored. If FEV1 did not recover to at least 90% of the baseline (pre-dilution) value, the patient could not be discharged from the clinic without permission from the examiner or qualified designated person.

[0069] (c) Safety evaluation Adverse events were monitored after administration of placebo or benralizumab. Other evaluations included physical examination, monitoring of vital signs, and laboratory measurements.

[0070] Example 2: Results (a) Registration and baseline characteristics Table 2 below shows the baseline characteristics of all randomized patients who received some form of the test product. The mean dose in the ICS population was equivalent to 1100 budesonide overall, equivalent to 700 budesonide in the intermediate dose group, and equivalent to 1600 budesonide in the high dose group.

[0071] [Table 2]

[0072] Table 3 below shows the baseline characteristics of randomized patients who received some form of the test product and had a baseline eosinophil count of at least 300 cells / μl.

[0073] [Table 3]

[0074] (b) Effectiveness The effects of benralizumab administration on FEV1 are shown in Figures 2-9. For example, the data in Figure 2 shows that FEV1 increased by 24 weeks in patients with a blood eosinophil count of at least 300 cells / μl who received 2, 20, or 100 mg of benralizumab. Similar results were observed at 52 weeks (Figure 3). The data in Figure 4 shows that FEV1 improved in patients who received either medium-dose or high-dose ICS, but this improvement was greater in patients who received high-dose ICS. The data in Figure 5 compares the change in FEV1 in patients with a blood eosinophil count of less than 300 cells / μl who received medium-dose ICS and patients who received high-dose ICS, and the data in Figure 6 compares the change in FEV1 in patients with a blood eosinophil count of at least 300 cells / μl who received medium-dose ICS and patients who received high-dose ICS. In patients with a blood eosinophil count of at least 300 cells / μl, FEV1 was observed to be more significantly improved in patients receiving high-dose 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 those receiving 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 In patients treated with benralizumab, the incidence of treatment-dependent adverse events (TEAEs) was approximately 10 percentage points higher than in patients treated with placebo. Treatment-dependent severe adverse events (TE-SAEs) occurred at similar frequencies in patients treated with benralizumab and placebo. In patients treated with benralizumab, TEAEs and TE-SAEs were dose-dependent.

[0076] (d) Antidrug antibodies The generation of anti-drug antibodies against benralizumab showed an inverse relationship with dose, with the highest proportion of ADA-positive patients occurring at a dose of 2 mg (see Table 4 below). The incidence of high-titer ADA (≥400) was 12% in the 20 mg dose group and 9% in the 100 mg dose group, respectively. High-titer ADA, if present, was associated with decreased benralizumab concentration and varying degrees of eosinophil recovery. The pharmacokinetic / pharmacodynamic (PK / PD) effects of high-titer ADA decreased with higher levels of drug exposure. No relationship was observed between TEAE and ADA.

[0077] [Table 4]

[0078] Based on PK and immunological considerations, an additional patient group will be administered 30 mg of benralizumab. Some patients will receive 30 mg of benralizumab every four weeks. Other patients will receive 30 mg of benralizumab every four weeks for three doses, followed by every eight weeks thereafter.

[0079] (e) Discussion This study demonstrates that benralizumab improves lung function. Improvement was observed at all doses, but the benefits were clearly greater at the 20 and 100 mg doses compared to the 2 mg dose. Furthermore, FEV1 appeared to improve more significantly in patients receiving high doses of ICS / LABA than in patients receiving medium doses.

[0080] Example 3: Evaluation of additional dose To reduce the annual exacerbation rate and identify a safe and well-tolerated additional dose of Benralizumab, a dose-efficacy model was performed. The model showed that approximately 30 mg was the minimum effective dose to achieve 90% of the maximum therapeutic effect. Therefore, uncontrolled asthma patients receive either 30 mg of Benralizumab or placebo via subcutaneous injection. The 30 mg dose is administered (i) every 4 weeks, or (ii) every 4 weeks for 8 weeks (3 doses), and then every 8 weeks thereafter (i.e., every 8 weeks including an additional dose in week 4). To demonstrate that the 30 mg dose of Benralizumab reduces the annual exacerbation rate, the number of exacerbations in patients receiving 30 mg of Benralizumab is compared to that of patients receiving placebo. Furthermore, to demonstrate that the 30 mg dose of Benralizumab is effective in reducing the annual exacerbation rate in patients with a baseline serum eosinophil count of at least 300 cells / μl, the number of exacerbations in such patients was analyzed.

[0081] Those skilled in the art will recognize, or can confirm, through routine experiments below, many equivalents to certain aspects of the disclosure described herein. Such equivalents are intended to be covered in the following claims.

[0082] This specification references various publications, the entirety of which is incorporated by reference.

[0083] The present invention has been described in some detail above through explanations and examples for the purpose of ensuring a clear understanding, but it should be clear that certain changes and modifications can be made within the scope of the attached claims. The present invention also provides the following embodiments. [1] Forced expiratory volume in one second (FEV1) of asthma patients 1 A method for increasing the FEV1 of the patient, comprising administering an effective amount of benralizumab or its antigen-binding fragment to the asthma patient, wherein the administration increases the FEV1 of the patient. 1 A way to increase it. [2] A method for treating asthma, comprising administering an effective amount of benralizumab or an antigen-binding fragment thereof to an asthma patient, wherein the patient has a blood eosinophil count of at least 300 cells / μl prior to the administration. [3] A method for treating asthma, comprising administering an effective amount of benralizumab or an antigen-binding fragment thereof to an asthma patient, wherein the patient has a forced expiratory volume in one second (FEV1) of at least 75% of the predicted value prior to the administration. 1 A method having ). [4] A method for treating asthma, comprising administering benralizumab or an antigen-binding fragment thereof to an asthma patient at least twice. [5] The administration of the FEV1 of the patient 1 A method of increasing [2] to [4]. [6] The administration is performed on the FEV1 of the asthma patient. 1 A method of increasing the dose within four weeks of the first dose.[5] [7] The method according to any one of [1] or [3] to [6], wherein the asthma is eosinophilic asthma. [8] The patient having a blood eosinophil count of at least 300 cells / μl [1] or the method according to any one of [3] to [7]. [9] The patient had a forced expiratory volume in one second (FEV1) of at least 75% of the predicted value before the administration. 1 The method according to any one of [1], [2] or [4]-[8], having )

[10] The method according to any one of [1] to [9], wherein the patient has an asthma control questionnaire score of at least 1.5 prior to the administration.

[11] The method according to any one of [1]-[3] or [5]-

[10] , wherein the patient is administered benralizumab or its antigen-binding fragment at least twice.

[12] FEV1 of the patient after administration of benralizumab or its antigen-binding fragment 1 A method of increasing [1] or one of [6]-

[11] .

[13] The FEV 1 The method described in either [1] or [6]-

[12] increases by at least 0.1 L.

[14] The FEV 1 The method described in

[13] increases the volume by at least 0.13L.

[15] The FEV 1 A method that increases the volume by at least 0.2L

[14] .

[16] The FEV 1 The method described in

[15] increases the volume by at least 0.25L.

[17] The FEV 1 A method that increases the volume by at least 0.5L

[16] .

[18] The patient uses a high dose of inhaled corticosteroids (ICS) as described in any of the methods described in [1] to

[17] .

[19] The patient uses a long-acting β2-agonist (LABA) according to any of the methods described in [1] to

[18] .

[20] The patient has a history of exacerbation. [1] to

[19] The method described in any of the following [1] to

[19] .

[21] The method according to

[20] , wherein the exacerbation history includes at least two exacerbations in the year preceding the administration of benralizumab or its antigen-binding fragment.

[22] The exacerbation history includes six or fewer exacerbations in the year preceding the administration of benralizumab or its antigen-binding fragment, as described in

[20] or

[21] .

[23] The method according to any one of [1] to

[22] , wherein the benralizumab or antigen-binding fragment is administered in doses of approximately 2 mg to approximately 100 mg.

[24] The method according to

[23] , wherein the benralizumab or antigen-binding fragment is administered in a dose of approximately 20 mg.

[25] The method according to

[23] , wherein the benralizumab or its antigen-binding fragment is administered in a dose of approximately 30 mg.

[26] The method according to

[23] , wherein the benralizumab or antigen-binding fragment is administered at a dose of approximately 100 mg.

[27] The method according to any one of [1] to

[26] , wherein benralizumab or its antigen-binding fragment is administered once every 4 to 12 weeks.

[28] The method according to

[27] , wherein the benralizumab or antigen-binding fragment is administered once every four weeks.

[29] The method according to

[27] , wherein benralizumab or its antigen-binding fragment is administered once every 8 weeks.

[30] The method according to

[27] , wherein the benralizumab or antigen-binding fragment is administered once every four weeks for 12 weeks, and then once every eight weeks thereafter.

[31] The method according to any one of [1] to

[30] , wherein the benralizumab or its antigen-binding fragment is administered parenterally.

[32] The method according to

[31] , wherein the benralizumab or its antigen-binding fragment is administered subcutaneously.

[33] The method according to any one of [1] to

[32] , wherein benralizumab or its antigen-binding fragment is administered in addition to corticosteroid therapy.

[34] Forced expiratory volume in one second (FEV1) of asthma patients 1 A method for increasing the number of eosinophils in the blood, comprising administering 20 to 100 mg of benralizumab or an antigen-binding fragment thereof to the patient, wherein the patient has a blood eosinophil count of at least 300 cells / μl prior to the administration.

[35] The method according to

[34] , comprising administering 20 mg of benralizumab or its antigen-binding fragment.

[36] The method according to

[35] , wherein the benralizumab or its antigen-binding fragment is administered once every four weeks for 12 weeks, and then once every eight weeks thereafter.

[37] The method according to

[34] , comprising administering 30 mg of benralizumab or its antigen-binding fragment.

[38] The method according to

[37] , wherein the benralizumab or antigen-binding fragment is administered once every four weeks for eight weeks, and then once every eight weeks thereafter.

[39] The method according to

[37] , wherein benralizumab or its antigen-binding fragment is administered once every four weeks.

[40] The method according to

[34] , comprising administering 100 mg of benralitumab or its antigen-binding fragment.

[41] The method according to

[40] , wherein the benralizumab or antigen-binding fragment is administered once every four weeks for 12 weeks, and then once every eight weeks thereafter.

[42] A method for treating asthma in an asthma patient, comprising administering to the patient a dose of at least 2 mg and less than 100 mg of benralizumab or an antigen-binding fragment thereof.

[43] The method according to

[42] , wherein the benralizumab or its antigen-binding fragment is administered in a dose of 20 mg.

[44] The method according to

[42] , wherein the benralizumab or its antigen-binding fragment is administered in a dose of 30 mg.

[45] The method according to

[42] , wherein the benralizumab or antigen-binding fragment is administered in a dose of at least 20 mg and less than 100 mg.

[46] The method described in

[42] , wherein the benralizumab or antigen-binding fragment is administered in a dose of at least 30 mg and less than 100 mg.

[47] Administration of benralizumab or its antigen-binding fragment to the FEV1 of the asthma patient 1 A method of increasing any of the following

[42] -

[46] .

[48] ​​Administration of benralizumab or its antigen-binding fragments to the FEV1 of the asthma patient 1 A method by which the dose is increased within four weeks of the first dose.

[42] -

[47]

[49] The method according to any one of

[42] to

[48] , wherein the administration is performed subcutaneously.

[0084] Sequence ID: 1 >US20100291073_1 Sequence 1 of the specification of U.S. Patent Application Publication No. 2010 / 0291073: Organism name: Homo sapiens [ka] Sequence ID: 2 >US20100291073_2 Sequence 2 of the specification of U.S. Patent Application Publication No. 2010 / 0291073 Organism name: Homo sapiens [ka] Sequence ID: 3 >US20100291073_3 Sequence 3 of the specification of U.S. Patent Application Publication No. 2010 / 0291073: Organism name: Homo sapiens [ka] Sequence ID: 4 >US20100291073_4 Sequence 4 of the specification of U.S. Patent Application Publication No. 2010 / 0291073: Organism name: Homo sapiens [ka] Sequence ID: 5 >US20100291073_5 Sequence 5 of the specification of U.S. Patent Application Publication No. 2010 / 0291073: Organism name: Homo sapiens [ka] Sequence ID: 6 >US20100291073_6 Sequence 6 of the specification of U.S. Patent Application Publication No. 2010 / 0291073 Organism name: House mouse (Mus musculus) [ka] Sequence ID: 7-VH CDR1 [ka] Sequence ID: 8-VH CDR2 [ka] Sequence ID: 9-VH CDR3 [ka] Sequence ID: 10-VL CDR1 [ka] Sequence ID: 11-VL CDR2 [ka] Sequence ID: 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 product for use in a method of treating asthma by increasing the forced expiratory volume in one second (FEV1) in adult asthma patients, Containing an effective amount of benralizumab or its antigen-binding fragment, A dose of 30 mg of benralizumab or its antigen-binding fragment is administered to the patient once every four weeks for eight weeks, and then once every eight weeks thereafter. The aforementioned administration is a pharmaceutical agent that increases the patient's FEV1.

2. The pharmaceutical agent according to claim 1, wherein the administration increases the FEV 1 of the asthma patient within four weeks from the first administration.

3. The pharmaceutical product according to claim 1, wherein the asthma is eosinophilic asthma.

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

5. The pharmaceutical product according to claim 1, wherein the patient has a forced expiratory volume in one second (FEV1) of at least 75% of the predicted value before administration.

6. The pharmaceutical product according to claim 1, wherein FEV 1 increases by at least 0.1 L.

7. The pharmaceutical product according to claim 1, wherein the patient uses a high dose of inhaled corticosteroid (ICS).

8. The pharmaceutical product according to claim 1, wherein the patient uses a long-acting β2-agonist (LABA).

9. The pharmaceutical product according to claim 1, wherein the patient has a history of exacerbation.

10. The pharmaceutical product according to claim 1, wherein benralizumab or its antigen-binding fragment is administered in addition to corticosteroid therapy.

Images