Methods for treating or preventing asthma by administering IL-4R antagonists

Abstract

Methods are provided for treating or preventing asthma (e.g., allergic asthma, asthma associated with allergic bronchopulmonary aspergillosis (ABPA), moderate to severe asthma, persistent asthma, etc.) and related conditions (e.g., ABPA, ABPA comorbidity with asthma, ABPA comorbidity with cystic fibrosis (CF), ABPA comorbidity with both asthma and CF) in subjects. Methods are also provided for administering a therapeutic composition to a subject in need, said therapeutic composition comprising an interleukin-4 receptor (IL-4R) antagonist, such as an anti-IL-4R antibody or an antigen-binding fragment thereof.

Description

[0001] Cross-reference to related applications

[0002] This application claims priority to U.S. Provisional Application No. 63 / 004,084, filed April 2, 2020; U.S. Provisional Application No. 62 / 877,031, filed July 22, 2019; U.S. Provisional Application No. 62 / 874,747, filed July 16, 2019; and European Application No. 20315237.6, filed May 7, 2020; the contents of which are incorporated herein by reference in their entirety for all purposes. Technical Field

[0003] This invention relates to the treatment and / or prevention of asthma, such as allergic asthma, and related conditions such as allergic bronchopulmonary disease (ABPA). This invention relates to the administration of interleukin-4 receptor (IL-4R) antagonists to treat or prevent asthma in patients in need, such as allergic asthma, ABPA-related asthma, etc. This invention also relates to the administration of interleukin-4 receptor (IL-4R) antagonists to treat or prevent ABPA in patients in need, for example, ABPA comorbidity with asthma, ABPA comorbidity with cystic fibrosis, and / or ABPA comorbidity with both asthma and cystic fibrosis. Background Technology

[0004] Asthma is a chronic inflammatory airway disease characterized by airway hyperresponsiveness, acute and chronic bronchoconstriction, airway edema, and mucus blockage. The inflammatory components of asthma are thought to involve many cell types, including mast cells, eosinophils, T lymphocytes, neutrophils, epithelial cells, and their biological products. The most common symptoms in asthma patients are wheezing, shortness of breath, cough, and chest tightness. For most asthma patients, a regimen of controller therapy and bronchodilator therapy provides adequate long-term control. Inhaled corticosteroids (ICS) are considered the "gold standard" for controlling asthma symptoms, and inhaled beta2-agonists are currently the most effective bronchodilators available. Studies have shown that combination therapy with ICS and inhaled long-acting beta2-agonists (LABA) provides better asthma control than high-dose ICS alone. Therefore, combination therapy has become the recommended treatment for subjects whose asthma is not controlled by low-dose ICS alone.

[0005] Despite this, it is estimated that 5% to 10% of people with asthma still suffer from symptomatic disease despite receiving the maximum recommended treatment combination of anti-inflammatory and bronchodilator medications. Furthermore, this population of people with severe asthma accounts for up to 50% of total health costs due to hospitalizations, use of emergency services, and infrequent physician visits. Many people with severe asthma respond poorly to inhaled corticosteroids (ICS) due to multiple cellular and molecular mechanisms, and the need for new therapies in this population remains unmet. In addition, the long-term adverse effects of systemic and inhaled corticosteroids on bone metabolism, adrenal function, and childhood development have prompted attempts to minimize corticosteroid use. While most people with asthma manage it fairly well with existing treatments, those with severe uncontrolled asthma (e.g., severe corticosteroid-resistant asthma or steroid-intolerant asthma) have few treatment options that adequately control the disease. Unresponsiveness to therapy or lack of adherence to therapy results in uncontrolled asthma and ultimately, asthma exacerbations.

[0006] It is estimated that 45% of patients with severe asthma require systemic glucocorticoids to control their disease and prevent life-threatening exacerbations associated with an increased risk of permanent lung tissue damage, progressive fixed airway obstruction, and accelerated decline in lung function. However, systemic glucocorticoids act nonselectively and are associated with significant multi-organ toxicity and widespread immunosuppression. Safer and more effective targeted therapies are needed to prevent exacerbations and lung function impairment, improve asthma symptoms and control, and reduce or eliminate the need for oral glucocorticoids.

[0007] Despite maximal standard of care and control, approximately 20% of asthma patients have uncontrolled moderate to severe disease with recurrent exacerbations and persistent symptoms. This population has an increased risk of morbidity (especially exacerbations) and consumes significant healthcare resources. Despite maximal treatment, these patients have significantly reduced lung function and are destined for inevitable further loss of lung function. Currently, no approved therapies have shown promise in slowing this inevitable decline or consistently and meaningfully increasing lung function in these patients.

[0008] Type 2 hyperasthma is the most common type of persistent, uncontrolled asthma (Fahy (2015) Nat. Rev. Immunol. 15:57-65). It includes overlapping phenotypes of allergic asthma (characterized by increased expression of specific immunoglobulin E (IgE) against airborne allergens) and eosinophilic asthma (characterized by increased eosinophils in the blood and / or airways / tissues) (Fahy, ibid.; Campo et al. (2013) J. Investig. Allergol. Clin. Immunol. 23:76-88; Wenzel (2012) Clin Exp Allergy 42:650-8).

[0009] Allergic sensitization is a strong risk factor for the onset and severity of asthma in children and adults (Gough et al. (2015) Pediatr. Allergy Immunol. 26:431-437). Current allergic asthma therapies that address the symptoms and persistent inflammatory processes of the disease do not affect the underlying, dysregulated immune response and are therefore very limited in controlling the progression of allergic asthma (Dhami et al. (2017) Eur. J. Allergy Clin. Immunol. 72(12):1825-1848).

[0010] ABPA is an allergic lung disorder caused by a hypersensitivity reaction to Aspergillus species (e.g., Aspergillus fumigatus) that colonize the airways. ABPA most commonly occurs in subjects with asthma or cystic fibrosis.

[0011] The clinical features of ABPA include wheezing, dyspnea, worsening of breathing, bronchial hyperresponsiveness, hemoptysis or expectorative cough (with brown mucus plugs in 31% to 69% of patients), central bronchiectasis with mucus plugs and significantly elevated IgE levels, as well as eosinophilia in the blood and tissues.

[0012] Currently, there are no approved medications specifically for ABPA. The primary treatment is systemic corticosteroids, with antifungal drugs used as adjunctive therapy. However, due to limited efficacy or the significant side effects of corticosteroids, more than 50% of ABPA patients are not adequately treated or do not receive effective treatment. Therefore, there is a high unmet medical need among patients with ABPA.

[0013] Cystic fibrosis (CF), also known as cystic fibrosis, is a genetic disorder that primarily affects the lungs but can also affect the pancreas, liver, kidneys, and intestines. Long-term problems include difficulty breathing and frequent lung infections leading to coughing up mucus. Other signs and symptoms include sinus infections, slow growth, steatorrhea, clubbing of the fingers and toes, and male infertility. Subjects may experience varying degrees of symptoms.

[0014] CF is inherited in an autosomal recessive manner. It is caused by the presence of mutations in both copies of the gene for the cystic fibrosis transmembrane conduction regulation (CFTR) protein. Those with a single working copy are carriers and otherwise mostly normal. CFTR is involved in the production of sweat, digestive juices, and mucus. When CFTR is not functioning properly, normally thin secretions become thick. The condition is diagnosed through sweat tests and genetic testing. Screening is performed on newborns in some parts of the world.

[0015] There is no cure for cystic fibrosis. Lung infections are treated with antibiotics, which can be administered intravenously, by inhalation, or orally. Sometimes, azithromycin is used long-term. Inhaled hypertonic saline and salbutamol may also be helpful. If lung function continues to deteriorate, lung transplantation may be an option. Pancreatic enzyme replacement and fat-soluble vitamin supplementation are important, especially in younger individuals. The average life expectancy in developed countries is between 42 and 50 years. Although CF is a multi-organ disease, lung problems are a leading cause of morbidity and death. Other symptoms of CF include pancreatic insufficiency, intestinal obstruction, elevated electrolyte levels in sweat (the basis of the most common diagnostic tests), and male infertility. CF is most common in people of Nordic ancestry and affects approximately one in 2,500 to 4,000 newborns. About one in 25 people are carriers. While treatments for CF are available, more effective therapies are needed.

[0016] There is a need for novel targeted therapies for the treatment and / or prevention of asthma (e.g., allergic asthma, ABPA-related asthma, etc.) and disorders such as ABPA (including ABPA as a comorbidity of CF, ABPA as a comorbidity of asthma, and ABPA as a comorbidity of both asthma and CF). Summary of the Invention

[0017] According to one aspect, a method for treating a subject suffering from allergic asthma is provided. The method includes administering to the subject an antibody or antigen-binding fragment thereof that specifically binds to an interleukin-4 receptor (IL-4R), wherein the antibody or antigen-binding fragment comprises three heavy chain CDR sequences containing SEQ ID NO:3, 4, and 5, respectively, and three light chain CDR sequences containing SEQ ID NO:6, 7, and 8, respectively, and wherein the subject has a total serum IgE level of at least about 700 IU / mL.

[0018] In some exemplary embodiments, the subject has a baseline blood eosinophil count of at least about 150 cells / μl or at least about 300 cells / μl.

[0019] In some exemplary embodiments, the subject has a baseline exhaled nitric oxide (FeNO) level of at least about 25 ppb or at least about 20 ppb.

[0020] In some exemplary embodiments, the subject has an allergen-specific IgE level of at least about 0.35 kU / L.

[0021] In some exemplary embodiments, the allergen is selected from animals (e.g., dust mites (e.g., Dermatophagoides farinae or Dermatophagoides pteronyssinus), cockroaches, cats, or dogs), fungi (e.g., Alternaria alternata, Cladosporium herbarum, or Aspergillus fumigatus) and plants).

[0022] In some exemplary embodiments, the allergen is selected from cat dander, dog dander, German cockroach, and Oriental cockroach.

[0023] In some exemplary embodiments, the antibody or its antigen-binding fragment is administered to the subject as a loading dose, followed by multiple maintenance doses.

[0024] In some exemplary embodiments, the antibody or its antigen-binding fragment is administered using an auto-injector, needle and syringe or pen.

[0025] In some exemplary embodiments, the antibody or its antigen-binding fragment is administered once every two weeks (q2w).

[0026] In some exemplary embodiments, the loading dose is about 600 mg of the antibody or its antigen-binding fragment. In some exemplary embodiments, the loading dose is about 400 mg of the antibody or its antigen-binding fragment.

[0027] In some exemplary embodiments, each maintenance dose of the antibody or its antigen-binding fragment is about 300 mg of the antibody or its antigen-binding fragment.

[0028] In some exemplary embodiments, each maintenance dose of the antibody or its antigen-binding fragment is about 200 mg of the antibody or its antigen-binding fragment.

[0029] In some exemplary embodiments, a maintenance dose of the antibody or its antigen-binding fragment is administered for at least 24 weeks.

[0030] In some exemplary embodiments, a first maintenance dose of the antibody or its antigen-binding fragment is administered two weeks after the loading dose.

[0031] In some exemplary implementations, the treatment results in a reduction in annualized severe asthma exacerbations.

[0032] In some exemplary embodiments, the treatment results in an improvement in lung function, as measured by forced expiratory volume (FEV1) or forced expiratory flow rate at 25%-75% of lung volume (FEF25%-75%).

[0033] In some exemplary embodiments, the antibody or its antigen-binding fragment comprises a heavy chain variable region (HCVR) containing the sequence of SEQ ID NO:1 and a light chain variable region (LCVR) containing the sequence of SEQ ID NO:2.

[0034] In some exemplary embodiments, the antibody or its antigen-binding fragment comprises the heavy chain sequence of SEQ ID NO:9 and the light chain sequence of SEQ ID NO:10.

[0035] In some exemplary embodiments, the antibody is dupilumab.

[0036] In some exemplary embodiments, the subject suffers from moderate to severe uncontrolled allergic asthma.

[0037] In some exemplary embodiments, the subject exhibits comorbid cystic fibrosis. In some exemplary embodiments, the subject exhibits comorbid allergic asthma and comorbid cystic fibrosis.

[0038] In some exemplary embodiments, the subject is an adult. In some exemplary embodiments, the subject is a teenager. In some exemplary embodiments, the subject is a child.

[0039] According to another aspect, a method for treating a subject suffering from allergic asthma is provided, the method comprising administering to the subject an antibody or antigen-binding fragment thereof that specifically binds to an interleukin-4 receptor (IL-4R), wherein the antibody or antigen-binding fragment thereof comprises three heavy chain CDR sequences containing SEQ ID NO:3, 4 and 5, respectively, and three light chain CDR sequences containing SEQ ID NO:6, 7 and 8, respectively, and wherein the subject has a baseline blood eosinophil level of at least about 300 cells / μl.

[0040] In some exemplary embodiments, the subject has a baseline exhaled nitric oxide (FeNO) level of at least about 25 ppb or at least about 20 ppb.

[0041] In some exemplary embodiments, the subject has a total serum IgE level of at least about 700 IU / mL.

[0042] In some exemplary embodiments, the subject has an allergen-specific IgE level of at least about 0.35 kU / L.

[0043] In some exemplary embodiments, the allergen is selected from dust mites, cockroaches, cat dander, dog dander, house dust mites, Alternaria alternifolia, Cladosporium multiflorum, Aspergillus fumigatus, German cockroach, and Oriental cockroach.

[0044] In some exemplary embodiments, the antibody or its antigen-binding fragment is administered to the subject as a loading dose, followed by multiple maintenance doses.

[0045] In some exemplary embodiments, the antibody or its antigen-binding fragment is administered using an auto-injector, needle and syringe or pen.

[0046] In some exemplary embodiments, the antibody or its antigen-binding fragment is administered once every two weeks (q2w).

[0047] In some exemplary embodiments, the loading dose is about 600 mg of the antibody or its antigen-binding fragment. In some exemplary embodiments, the loading dose is about 400 mg of the antibody or its antigen-binding fragment.

[0048] In some exemplary embodiments, each maintenance dose of the antibody or its antigen-binding fragment is about 300 mg of the antibody or its antigen-binding fragment. In some exemplary embodiments, each maintenance dose of the antibody or its antigen-binding fragment is about 200 mg of the antibody or its antigen-binding fragment.

[0049] In some exemplary embodiments, a maintenance dose of the antibody or its antigen-binding fragment is administered for at least 24 weeks.

[0050] In some exemplary embodiments, a first maintenance dose of the antibody or its antigen-binding fragment is administered two weeks after the loading dose.

[0051] In some exemplary implementations, the treatment results in a reduction in annualized severe asthma exacerbations.

[0052] In some exemplary embodiments, the treatment results in an improvement in lung function, as measured by forced expiratory volume (FEV1) or forced expiratory flow rate at 25%-75% of lung volume (FEF25%-75%).

[0053] In some exemplary embodiments, the antibody or its antigen-binding fragment comprises a heavy chain variable region (HCVR) containing the sequence of SEQ ID NO:1 and a light chain variable region (LCVR) containing the sequence of SEQ ID NO:2.

[0054] In some exemplary embodiments, the antibody or its antigen-binding fragment comprises the heavy chain sequence of SEQ ID NO:9 and the light chain sequence of SEQ ID NO:10.

[0055] In some exemplary embodiments, the antibody is dupilumab.

[0056] In some exemplary embodiments, the subject suffers from moderate to severe uncontrolled allergic asthma.

[0057] In some exemplary embodiments, the subject exhibits comorbid cystic fibrosis. In some exemplary embodiments, the subject exhibits comorbid allergic asthma and comorbid cystic fibrosis.

[0058] In some exemplary embodiments, the subject is an adult. In some exemplary embodiments, the subject is a teenager. In some exemplary embodiments, the subject is a child.

[0059] According to another aspect, a method for treating a subject suffering from allergic asthma is provided, the method comprising administering to the subject an antibody or antigen-binding fragment thereof that specifically binds to an interleukin-4 receptor (IL-4R), wherein the antibody or antigen-binding fragment thereof comprises three heavy chain CDR sequences containing SEQ ID NO:3, 4 and 5 respectively and three light chain CDR sequences containing SEQ ID NO:6, 7 and 8 respectively, and wherein the subject has a baseline exhaled nitric oxide (FeNO) level of at least about 20 ppb.

[0060] In some exemplary embodiments, the subject has a baseline FeNO level of at least 25 ppb.

[0061] In some exemplary embodiments, the subject has a baseline blood eosinophil count of at least about 150 cells / μl. In some exemplary embodiments, the subject has a baseline blood eosinophil count of at least about 300 cells / μl.

[0062] In some exemplary embodiments, the subject has a total serum IgE level of at least about 700 IU / mL.

[0063] In some exemplary embodiments, the subject has an allergen-specific IgE level of at least about 0.35 kU / L.

[0064] In some exemplary embodiments, the allergen is selected from dust mites, cockroaches, cat dander, dog dander, house dust mites, Alternaria alternifolia, Cladosporium multiflorum, Aspergillus fumigatus, German cockroach, and Oriental cockroach.

[0065] In some exemplary embodiments, the antibody or its antigen-binding fragment is administered to the subject as a loading dose, followed by multiple maintenance doses.

[0066] In some exemplary embodiments, the antibody or its antigen-binding fragment is administered using an auto-injector, needle and syringe or pen.

[0067] In some exemplary embodiments, the antibody or its antigen-binding fragment is administered once every two weeks (q2w).

[0068] In some exemplary embodiments, the loading dose is about 600 mg of the antibody or its antigen-binding fragment. In some exemplary embodiments, the loading dose is about 400 mg of the antibody or its antigen-binding fragment.

[0069] In some exemplary embodiments, each maintenance dose of the antibody or its antigen-binding fragment is about 300 mg of the antibody or its antigen-binding fragment. In some exemplary embodiments, each maintenance dose of the antibody or its antigen-binding fragment is about 200 mg of the antibody or its antigen-binding fragment.

[0070] In some exemplary embodiments, a maintenance dose of the antibody or its antigen-binding fragment is administered for at least 24 weeks.

[0071] In some exemplary embodiments, a first maintenance dose of the antibody or its antigen-binding fragment is administered two weeks after the loading dose.

[0072] In some exemplary implementations, the treatment results in a reduction in annualized severe asthma exacerbations.

[0073] In some exemplary embodiments, the treatment results in an improvement in lung function, such as as measured by forced expiratory volume (FEV1) or by forced expiratory flow rate at 25%-75% of lung volume (FEF25%-75%).

[0074] In some exemplary embodiments, the antibody or its antigen-binding fragment comprises a heavy chain variable region (HCVR) containing the sequence of SEQ ID NO:1 and a light chain variable region (LCVR) containing the sequence of SEQ ID NO:2.

[0075] In some exemplary embodiments, the antibody or its antigen-binding fragment comprises the heavy chain sequence of SEQ ID NO:9 and the light chain sequence of SEQ ID NO:10.

[0076] In some exemplary embodiments, the antibody is dupilumab.

[0077] In some exemplary embodiments, the subject exhibits comorbid cystic fibrosis. In some exemplary embodiments, the subject exhibits comorbid allergic asthma and comorbid cystic fibrosis.

[0078] In some exemplary embodiments, the subject is an adult. In some exemplary embodiments, the subject is a teenager. In some exemplary embodiments, the subject is a child.

[0079] On the other hand, a method is provided for improving lung function in subjects suffering from allergic asthma, as measured by forced expiratory volume (FEV1) or forced expiratory flow rate at 25%-75% of lung volume (FEF25%-75%), the method comprising administering to the subject an antibody or antigen-binding fragment thereof that specifically binds to an interleukin-4 receptor (IL-4R), wherein the antibody or antigen-binding fragment thereof comprises three heavy chain CDR sequences containing SEQ ID NO:3, 4 and 5, respectively, and three light chain CDR sequences containing SEQ ID NO:6, 7 and 8, respectively, and wherein the subject has a total serum IgE level of at least about 700 IU / mL.

[0080] In some exemplary embodiments, the antibody or its antigen-binding fragment comprises a heavy chain variable region (HCVR) containing the sequence of SEQ ID NO:1 and a light chain variable region (LCVR) containing the sequence of SEQ ID NO:2.

[0081] In some exemplary embodiments, the antibody or its antigen-binding fragment comprises the heavy chain sequence of SEQ ID NO:9 and the light chain sequence of SEQ ID NO:10.

[0082] In some exemplary embodiments, the antibody is dupilumab.

[0083] In some exemplary embodiments, the subject suffers from moderate to severe uncontrolled allergic asthma.

[0084] In some exemplary embodiments, the subject exhibits comorbid cystic fibrosis. In some exemplary embodiments, the subject exhibits comorbid allergic asthma and comorbid cystic fibrosis.

[0085] In some exemplary embodiments, the subject is an adult. In some exemplary embodiments, the subject is a teenager. In some exemplary embodiments, the subject is a child.

[0086] On the other hand, a method for reducing annualized severe asthma exacerbations in subjects with allergic asthma is provided, the method comprising administering to the subject an antibody or antigen-binding fragment thereof that specifically binds to an interleukin-4 receptor (IL-4R), wherein the antibody or antigen-binding fragment thereof comprises three heavy chain CDR sequences containing SEQ ID NO:3, 4 and 5, respectively, and three light chain CDR sequences containing SEQ ID NO:6, 7 and 8, respectively, and wherein the subject has a total serum IgE level of at least about 700 IU / mL.

[0087] In some exemplary embodiments, the antibody or its antigen-binding fragment comprises a heavy chain variable region (HCVR) containing the sequence of SEQ ID NO:1 and a light chain variable region (LCVR) containing the sequence of SEQ ID NO:2.

[0088] In some exemplary embodiments, the antibody or its antigen-binding fragment comprises the heavy chain sequence of SEQ ID NO:9 and the light chain sequence of SEQ ID NO:10.

[0089] In some exemplary embodiments, the antibody is dupilumab.

[0090] In some exemplary embodiments, the subject suffers from moderate to severe uncontrolled allergic asthma.

[0091] In some exemplary embodiments, the subject exhibits comorbid cystic fibrosis. In some exemplary embodiments, the subject exhibits comorbid allergic asthma and comorbid cystic fibrosis.

[0092] In some exemplary embodiments, the subject is an adult. In some exemplary embodiments, the subject is a teenager. In some exemplary embodiments, the subject is a child.

[0093] On the other hand, a method is provided for improving Asthma Control Questionnaire-5 (ACQ-5) scores in subjects with allergic asthma, the method comprising administering to the subject an antibody or antigen-binding fragment thereof that specifically binds to an interleukin-4 receptor (IL-4R), wherein the antibody or antigen-binding fragment thereof comprises three heavy chain CDR sequences containing SEQ ID NO:3, 4 and 5, respectively, and three light chain CDR sequences containing SEQ ID NO:6, 7 and 8, respectively, and wherein the subject has a total serum IgE level of at least about 700 IU / mL.

[0094] In some exemplary embodiments, the antibody or its antigen-binding fragment comprises a heavy chain variable region (HCVR) containing the sequence of SEQ ID NO:1 and a light chain variable region (LCVR) containing the sequence of SEQ ID NO:2.

[0095] In some exemplary embodiments, the antibody or its antigen-binding fragment comprises the heavy chain sequence of SEQ ID NO:9 and the light chain sequence of SEQ ID NO:10.

[0096] In some exemplary embodiments, the antibody is dupilumab.

[0097] In some exemplary embodiments, the subject suffers from moderate to severe uncontrolled allergic asthma.

[0098] In some exemplary embodiments, the subject exhibits comorbid cystic fibrosis. In some exemplary embodiments, the subject exhibits comorbid allergic asthma and comorbid cystic fibrosis.

[0099] In some exemplary embodiments, the subject is an adult. In some exemplary embodiments, the subject is a teenager. In some exemplary embodiments, the subject is a child.

[0100] In another aspect, a method is provided for treating a subject suffering from allergic bronchopulmonary aspergillosis (ABPA), the method comprising administering to the subject an antibody or antigen-binding fragment thereof that specifically binds to an interleukin-4 receptor (IL-4R), wherein the antibody or antigen-binding fragment thereof comprises three heavy chain CDR sequences containing SEQ ID NO:3, 4 and 5, respectively, and three light chain CDR sequences containing SEQ ID NO:6, 7 and 8, respectively, wherein the subject has a total serum IgE level of at least about 1000 IU / mL.

[0101] In some exemplary embodiments, the subject has a baseline blood eosinophil count of at least about 500 cells / μl.

[0102] In some exemplary embodiments, the subject has an allergen-specific serum IgE level of at least about 0.35 kU / L. In some exemplary embodiments, the allergen is Aspergillus fumigatus.

[0103] In some exemplary embodiments, the antibody or its antigen-binding fragment is administered to the subject as a loading dose, followed by multiple maintenance doses.

[0104] In some exemplary embodiments, the antibody or its antigen-binding fragment is administered using an auto-injector, needle and syringe or pen.

[0105] In some exemplary embodiments, the antibody or its antigen-binding fragment is administered once every two weeks (q2w).

[0106] In some exemplary embodiments, the loading dose is about 600 mg of the antibody or its antigen-binding fragment. In some exemplary embodiments, the loading dose is about 400 mg of the antibody or its antigen-binding fragment.

[0107] In some exemplary embodiments, each maintenance dose of the antibody or its antigen-binding fragment is about 300 mg of the antibody or its antigen-binding fragment. In some exemplary embodiments, each maintenance dose of the antibody or its antigen-binding fragment is about 200 mg of the antibody or its antigen-binding fragment.

[0108] In some exemplary embodiments, a maintenance dose of the antibody or its antigen-binding fragment is administered for at least 24 weeks.

[0109] In some exemplary embodiments, a first maintenance dose of the antibody or its antigen-binding fragment is administered two weeks after the loading dose.

[0110] In some exemplary embodiments, the treatment results in a reduction in annualized severe asthma exacerbations. In some exemplary embodiments, the treatment results in improved lung function, as measured by forced expiratory volume (FEV1) or forced expiratory flow rate at 25%-75% of lung volume (FEF25%-75%). In some exemplary embodiments, the treatment results in a reduction in total serum IgE levels. In some exemplary embodiments, the treatment results in a reduction in serum Aspergillus fumigatus-specific IgE. In some exemplary embodiments, the treatment results in a reduction in one or more of TARC levels, eosinophil chemokine-3 levels, and peripheral blood eosinophil levels. In some exemplary embodiments, FeNO(ppb) is reduced.

[0111] In some exemplary embodiments, the antibody or its antigen-binding fragment comprises a heavy chain variable region (HCVR) containing the sequence of SEQ ID NO:1 and a light chain variable region (LCVR) containing the sequence of SEQ ID NO:2.

[0112] In some exemplary embodiments, the antibody or its antigen-binding fragment comprises the heavy chain sequence of SEQ ID NO:9 and the light chain sequence of SEQ ID NO:10.

[0113] In some exemplary embodiments, the antibody is dupilumab.

[0114] In some exemplary embodiments, the subject has moderate to severe uncontrolled asthma. In some exemplary embodiments, the subject exhibits comorbid cystic fibrosis. In some exemplary embodiments, the subject exhibits comorbid asthma and comorbid cystic fibrosis.

[0115] In some exemplary embodiments, the subject is an adult. In some exemplary embodiments, the subject is a teenager. In some exemplary embodiments, the subject is a child.

[0116] In another aspect, a method is provided for treating a subject suffering from allergic bronchopulmonary aspergillosis (ABPA), the method comprising administering to the subject an antibody or antigen-binding fragment thereof that specifically binds to an interleukin-4 receptor (IL-4R), wherein the antibody or antigen-binding fragment thereof comprises three heavy chain CDR sequences containing SEQ ID NO:3, 4 and 5, respectively, and three light chain CDR sequences containing SEQ ID NO:6, 7 and 8, respectively, and wherein the subject has an Aspergillus fumigatus-specific IgE level greater than 0.35 kU / L.

[0117] In some exemplary embodiments, the subject has a baseline blood eosinophil count of at least about 300 cells / μl.

[0118] In some exemplary embodiments, the subject has a total serum IgE level of at least about 1000 IU / mL.

[0119] In some exemplary embodiments, the subject has a baseline blood eosinophil count of at least about 500 cells / μl.

[0120] In some exemplary embodiments, the antibody or its antigen-binding fragment is administered to the subject as a loading dose, followed by multiple maintenance doses.

[0121] In some exemplary embodiments, the antibody or its antigen-binding fragment is administered using an auto-injector, needle and syringe or pen.

[0122] In some exemplary embodiments, the antibody or its antigen-binding fragment is administered once every two weeks (q2w).

[0123] In some exemplary embodiments, the loading dose is about 600 mg of the antibody or its antigen-binding fragment. In some exemplary embodiments, the loading dose is about 400 mg of the antibody or its antigen-binding fragment.

[0124] In some exemplary embodiments, each maintenance dose of the antibody or its antigen-binding fragment is about 300 mg of the antibody or its antigen-binding fragment.

[0125] In some exemplary embodiments, each maintenance dose of the antibody or its antigen-binding fragment is about 200 mg of the antibody or its antigen-binding fragment.

[0126] In some exemplary embodiments, a maintenance dose of the antibody or its antigen-binding fragment is administered for at least 24 weeks.

[0127] In some exemplary embodiments, a first maintenance dose of the antibody or its antigen-binding fragment is administered two weeks after the loading dose.

[0128] In some exemplary embodiments, the treatment results in a reduction in annualized severe asthma exacerbations. In some exemplary embodiments, the treatment results in improved lung function, as measured by forced expiratory volume (FEV1) or forced expiratory flow rate at 25%-75% of lung volume (FEF25%-75%). In some exemplary embodiments, the treatment results in a reduction in total serum IgE levels. In some exemplary embodiments, the treatment results in a reduction in serum Aspergillus fumigatus-specific IgE. In some exemplary embodiments, the treatment results in a reduction in one or more of TARC levels, eosinophil chemokine-3 levels, and peripheral blood eosinophil levels. In some exemplary embodiments, FeNO(ppb) is reduced.

[0129] In some exemplary embodiments, the antibody or its antigen-binding fragment comprises a heavy chain variable region (HCVR) containing the sequence of SEQ ID NO:1 and a light chain variable region (LCVR) containing the sequence of SEQ ID NO:2.

[0130] In some exemplary embodiments, the antibody or its antigen-binding fragment comprises the heavy chain sequence of SEQ ID NO:9 and the light chain sequence of SEQ ID NO:10.

[0131] In some exemplary embodiments, the antibody is dupilumab.

[0132] In some exemplary embodiments, the subject has moderate to severe uncontrolled asthma. In some exemplary embodiments, the subject exhibits comorbid cystic fibrosis. In some exemplary embodiments, the subject exhibits comorbid asthma and comorbid cystic fibrosis.

[0133] In some exemplary embodiments, the subject is an adult. In some exemplary embodiments, the subject is a teenager. In some exemplary embodiments, the subject is a child.

[0134] In another aspect, a method is provided for treating a subject suffering from allergic bronchopulmonary aspergillosis (ABPA), the method comprising administering to the subject an antibody or antigen-binding fragment thereof that specifically binds to an interleukin-4 receptor (IL-4R), wherein the antibody or antigen-binding fragment thereof comprises three heavy chain CDR sequences containing SEQ ID NO:3, 4 and 5, respectively, and three light chain CDR sequences containing SEQ ID NO:6, 7 and 8, respectively, and wherein the subject has a baseline blood eosinophil count of at least about 500 cells / μl.

[0135] In some exemplary embodiments, the subject has an allergen-specific serum IgE level of at least about 0.35 kU / L.

[0136] In some exemplary embodiments, the allergen is Aspergillus fumigatus.

[0137] In some exemplary embodiments, the subject has a total serum IgE level of at least about 1000 IU / mL.

[0138] In some exemplary embodiments, the antibody or its antigen-binding fragment is administered to the subject as a loading dose, followed by multiple maintenance doses.

[0139] In some exemplary embodiments, the antibody or its antigen-binding fragment is administered using an auto-injector, needle and syringe or pen.

[0140] In some exemplary embodiments, the antibody or its antigen-binding fragment is administered once every two weeks (q2w).

[0141] In some exemplary embodiments, the loading dose is about 600 mg of the antibody or its antigen-binding fragment. In some exemplary embodiments, the loading dose is about 400 mg of the antibody or its antigen-binding fragment.

[0142] In some exemplary embodiments, each maintenance dose of the antibody or its antigen-binding fragment is about 300 mg of the antibody or its antigen-binding fragment. In some exemplary embodiments, each maintenance dose of the antibody or its antigen-binding fragment is about 200 mg of the antibody or its antigen-binding fragment.

[0143] In some exemplary embodiments, a maintenance dose of the antibody or its antigen-binding fragment is administered for at least 24 weeks.

[0144] In some exemplary embodiments, a first maintenance dose of the antibody or its antigen-binding fragment is administered two weeks after the loading dose.

[0145] In some exemplary embodiments, the treatment results in a reduction in annualized severe asthma exacerbations. In some exemplary embodiments, the treatment results in improved lung function, as measured by forced expiratory volume (FEV1) or forced expiratory flow rate at 25%-75% of lung volume (FEF25%-75%). In some exemplary embodiments, the treatment results in a reduction in total serum IgE levels. In some exemplary embodiments, the treatment results in a reduction in serum Aspergillus fumigatus-specific IgE. In some exemplary embodiments, the treatment results in a reduction in one or more of TARC levels, eosinophil chemokine-3 levels, and peripheral blood eosinophil levels. In some exemplary embodiments, FeNO(ppb) is reduced.

[0146] In some exemplary embodiments, the antibody or its antigen-binding fragment comprises a heavy chain variable region (HCVR) containing the sequence of SEQ ID NO:1 and a light chain variable region (LCVR) containing the sequence of SEQ ID NO:2.

[0147] In some exemplary embodiments, the antibody or its antigen-binding fragment comprises the heavy chain sequence of SEQ ID NO:9 and the light chain sequence of SEQ ID NO:10.

[0148] In some exemplary embodiments, the antibody is dupilumab.

[0149] In some exemplary embodiments, the subject has moderate to severe uncontrolled asthma. In some exemplary embodiments, the subject exhibits comorbid cystic fibrosis. In some exemplary embodiments, the subject exhibits comorbid asthma and comorbid cystic fibrosis.

[0150] In some exemplary embodiments, the subject is an adult. In some exemplary embodiments, the subject is a teenager. In some exemplary embodiments, the subject is a child.

[0151] On the other hand, a method is provided for improving lung function in subjects with allergic bronchopulmonary aspergillosis (ABPA), as measured by forced expiratory volume (FEV1) or forced expiratory flow rate at 25%-75% of lung volume (FEF25%-75%), the method comprising administering to the subject an antibody or antigen-binding fragment thereof that specifically binds to an interleukin-4 receptor (IL-4R), wherein the antibody or antigen-binding fragment thereof comprises three heavy chain CDR sequences containing SEQ ID NO:3, 4 and 5, respectively, and three light chain CDR sequences containing SEQ ID NO:6, 7 and 8, respectively, and wherein the subject has a total serum IgE level of at least about 1000 IU / mL.

[0152] In some exemplary embodiments, the antibody or its antigen-binding fragment comprises a heavy chain variable region (HCVR) containing the sequence of SEQ ID NO:1 and a light chain variable region (LCVR) containing the sequence of SEQ ID NO:2.

[0153] In some exemplary embodiments, the antibody or its antigen-binding fragment comprises the heavy chain sequence of SEQ ID NO:9 and the light chain sequence of SEQ ID NO:10.

[0154] In some exemplary embodiments, the antibody is dupilumab.

[0155] In some exemplary embodiments, the subject has moderate to severe uncontrolled allergic asthma. In some exemplary embodiments, the subject exhibits comorbid cystic fibrosis. In some exemplary embodiments, the subject exhibits both comorbid asthma and comorbid cystic fibrosis.

[0156] In some exemplary embodiments, the subject is an adult. In some exemplary embodiments, the subject is a teenager. In some exemplary embodiments, the subject is a child.

[0157] On the other hand, a method is provided for reducing annualized severe asthma exacerbations in subjects with asthma associated with allergic bronchopulmonary aspergillosis (ABPA), the method comprising administering to the subject an antibody or antigen-binding fragment thereof that specifically binds to an interleukin-4 receptor (IL-4R), wherein the antibody or antigen-binding fragment thereof comprises three heavy chain CDR sequences containing SEQ ID NO:3, 4 and 5, respectively, and three light chain CDR sequences containing SEQ ID NO:6, 7 and 8, respectively, and wherein the subject has a total serum IgE level of at least about 1000 IU / mL.

[0158] In some exemplary embodiments, the antibody or its antigen-binding fragment comprises a heavy chain variable region (HCVR) containing the sequence of SEQ ID NO:1 and a light chain variable region (LCVR) containing the sequence of SEQ ID NO:2.

[0159] In some exemplary embodiments, the antibody or its antigen-binding fragment comprises the heavy chain sequence of SEQ ID NO:9 and the light chain sequence of SEQ ID NO:10.

[0160] In some exemplary embodiments, the antibody is dupilumab.

[0161] In some exemplary embodiments, the subject has moderate to severe uncontrolled allergic asthma. In some exemplary embodiments, the subject exhibits comorbid cystic fibrosis. In some exemplary embodiments, the subject exhibits both comorbid asthma and comorbid cystic fibrosis.

[0162] In some exemplary embodiments, the subject is an adult. In some exemplary embodiments, the subject is a teenager. In some exemplary embodiments, the subject is a child.

[0163] On the other hand, a method is provided to improve the Asthma Control Questionnaire-5 (ACQ-5) score in subjects with asthma associated with allergic bronchopulmonary aspergillosis (ABPA), the method comprising administering to the subject an antibody or antigen-binding fragment thereof that specifically binds to an interleukin-4 receptor (IL-4R), wherein the antibody or antigen-binding fragment thereof comprises three heavy chain CDR sequences containing SEQ ID NO:3, 4 and 5, respectively, and three light chain CDR sequences containing SEQ ID NO:6, 7 and 8, respectively, and wherein the subject has a total serum IgE level of at least about 1000 IU / mL.

[0164] In some exemplary embodiments, the antibody or its antigen-binding fragment comprises a heavy chain variable region (HCVR) containing the sequence of SEQ ID NO:1 and a light chain variable region (LCVR) containing the sequence of SEQ ID NO:2.

[0165] In some exemplary embodiments, the antibody or its antigen-binding fragment comprises the heavy chain sequence of SEQ ID NO:9 and the light chain sequence of SEQ ID NO:10.

[0166] In some exemplary embodiments, the antibody is dupilumab.

[0167] In some exemplary embodiments, the subject has moderate to severe uncontrolled allergic asthma. In some exemplary embodiments, the subject exhibits comorbid cystic fibrosis. In some exemplary embodiments, the subject exhibits both comorbid asthma and comorbid cystic fibrosis.

[0168] In some exemplary embodiments, the subject is an adult. In some exemplary embodiments, the subject is a teenager. In some exemplary embodiments, the subject is a child.

[0169] In another embodiment, a method is provided for treating a subject suffering from comorbid allergic bronchopulmonary aspergillosis (ABPA) and cystic fibrosis (CF), the method comprising administering to the subject an antibody or antigen-binding fragment thereof that specifically binds to an interleukin-4 receptor (IL-4R), wherein the antibody or antigen-binding fragment thereof comprises three heavy chain CDR sequences containing SEQ ID NO:3, 4, and 5, respectively, and three light chain CDR sequences containing SEQ ID NO:6, 7, and 8, respectively. In some embodiments, the subject has a total serum IgE level of at least about 1000 IU / mL.

[0170] In some exemplary embodiments, the subject has a baseline blood eosinophil count of at least about 500 cells / μl.

[0171] In some exemplary embodiments, the subject has an allergen-specific serum IgE level of at least about 0.35 kU / L. In some exemplary embodiments, the allergen is Aspergillus fumigatus.

[0172] In some exemplary embodiments, the antibody or its antigen-binding fragment is administered to the subject as a loading dose, followed by multiple maintenance doses.

[0173] In some exemplary embodiments, the antibody or its antigen-binding fragment is administered using an auto-injector, needle and syringe or pen.

[0174] In some exemplary embodiments, the antibody or its antigen-binding fragment is administered once every two weeks (q2w).

[0175] In some exemplary embodiments, the loading dose is about 600 mg of the antibody or its antigen-binding fragment. In some exemplary embodiments, each maintenance dose of the antibody or its antigen-binding fragment is about 300 mg of the antibody or its antigen-binding fragment.

[0176] In some exemplary embodiments, the loading dose is about 400 mg of the antibody or its antigen-binding fragment. In some exemplary embodiments, each maintenance dose of the antibody or its antigen-binding fragment is about 200 mg of the antibody or its antigen-binding fragment.

[0177] In some exemplary embodiments, a maintenance dose of the antibody or its antigen-binding fragment is administered for at least 24 weeks.

[0178] In some exemplary embodiments, a first maintenance dose of the antibody or its antigen-binding fragment is administered two weeks after the loading dose.

[0179] In some exemplary embodiments, the treatment results in an improvement in lung function, as measured by forced expiratory volume (FEV1) or forced expiratory flow rate at 25%-75% of lung volume (FEF25%-75%).

[0180] In some exemplary embodiments, treatment results in a decrease in one or both of total serum IgE levels and serum Aspergillus fumigatus-specific IgE levels. In some exemplary embodiments, treatment results in a decrease in one or more of TARC levels, eosinophil chemokine-3 levels, and peripheral blood eosinophil levels. In some exemplary embodiments, FeNO(ppb) is reduced.

[0181] In some exemplary embodiments, the antibody or its antigen-binding fragment comprises a heavy chain variable region (HCVR) containing the sequence of SEQ ID NO:1 and a light chain variable region (LCVR) containing the sequence of SEQ ID NO:2.

[0182] In some exemplary embodiments, the antibody or its antigen-binding fragment comprises the heavy chain sequence of SEQ ID NO:9 and the light chain sequence of SEQ ID NO:10.

[0183] In some exemplary embodiments, the antibody is dupilumab.

[0184] In some exemplary embodiments, the subject suffers from asthma. In some exemplary embodiments, the treatment results in a reduction in annualized asthma exacerbations.

[0185] In some exemplary embodiments, the subject is an adult. In some exemplary embodiments, the subject is a teenager. In some exemplary embodiments, the subject is a child.

[0186] In another aspect, a method is provided for treating a subject suffering from comorbid allergic bronchopulmonary aspergillosis (ABPA) and cystic fibrosis (CF), the method comprising administering to the subject an antibody or antigen-binding fragment thereof that specifically binds to an interleukin-4 receptor (IL-4R), wherein the antibody or antigen-binding fragment thereof comprises three heavy chain CDR sequences containing SEQ ID NO:3, 4 and 5, respectively, and three light chain CDR sequences containing SEQ ID NO:6, 7 and 8, respectively, and wherein the subject has an Aspergillus fumigatus-specific IgE level greater than 0.35 kU / L.

[0187] In some exemplary embodiments, the subject has a baseline blood eosinophil count of at least about 300 cells / μl. In some exemplary embodiments, the subject has a total serum IgE level of at least about 1000 IU / mL. In some exemplary embodiments, the subject has a baseline blood eosinophil count of at least about 500 cells / μl.

[0188] In some exemplary embodiments, the antibody or its antigen-binding fragment is administered to the subject as a loading dose, followed by multiple maintenance doses.

[0189] In some exemplary embodiments, the antibody or its antigen-binding fragment is administered using an auto-injector, needle and syringe or pen.

[0190] In some exemplary embodiments, the antibody or its antigen-binding fragment is administered once every two weeks (q2w).

[0191] In some exemplary embodiments, the loading dose is about 600 mg of the antibody or its antigen-binding fragment. In some exemplary embodiments, each maintenance dose of the antibody or its antigen-binding fragment is about 300 mg of the antibody or its antigen-binding fragment.

[0192] In some exemplary embodiments, the loading dose is about 400 mg of the antibody or its antigen-binding fragment. In some exemplary embodiments, each maintenance dose of the antibody or its antigen-binding fragment is about 200 mg of the antibody or its antigen-binding fragment.

[0193] In some exemplary embodiments, a maintenance dose of the antibody or its antigen-binding fragment is administered for at least 24 weeks.

[0194] In some exemplary embodiments, a first maintenance dose of the antibody or its antigen-binding fragment is administered two weeks after the loading dose.

[0195] In some exemplary embodiments, the treatment results in an improvement in lung function, as measured by forced expiratory volume (FEV1) or forced expiratory flow rate at 25%-75% of lung volume (FEF25%-75%).

[0196] In some exemplary embodiments, treatment results in a decrease in one or both of total serum IgE levels and serum Aspergillus fumigatus-specific IgE levels. In some exemplary embodiments, treatment results in a decrease in one or more of TARC levels, eosinophil chemokine-3 levels, and peripheral blood eosinophil levels. In some exemplary embodiments, FeNO(ppb) is reduced.

[0197] In some exemplary embodiments, the antibody or its antigen-binding fragment comprises a heavy chain variable region (HCVR) containing the sequence of SEQ ID NO:1 and a light chain variable region (LCVR) containing the sequence of SEQ ID NO:2.

[0198] In some exemplary embodiments, the antibody or its antigen-binding fragment comprises the heavy chain sequence of SEQ ID NO:9 and the light chain sequence of SEQ ID NO:10.

[0199] In some exemplary embodiments, the antibody is dupilumab.

[0200] In some exemplary embodiments, the subject suffers from asthma. In some exemplary embodiments, the treatment results in a reduction in annualized asthma exacerbations.

[0201] In some exemplary embodiments, the subject is an adult. In some exemplary embodiments, the subject is a teenager. In some exemplary embodiments, the subject is a child.

[0202] In another aspect, a method is provided for treating a subject suffering from comorbid allergic bronchopulmonary aspergillosis (ABPA) and cystic fibrosis (CF), the method comprising administering to the subject an antibody or antigen-binding fragment thereof that specifically binds to an interleukin-4 receptor (IL-4R), wherein the antibody or antigen-binding fragment thereof comprises three heavy chain CDR sequences containing SEQ ID NO:3, 4 and 5, respectively, and three light chain CDR sequences containing SEQ ID NO:6, 7 and 8, respectively, and wherein the subject has a baseline blood eosinophil count of at least about 500 cells / μl.

[0203] In some exemplary embodiments, the subject has an allergen-specific serum IgE level of at least about 0.35 kU / L. In some exemplary embodiments, the allergen is Aspergillus fumigatus.

[0204] In some exemplary embodiments, the subject has a total serum IgE level of at least about 1000 IU / mL.

[0205] In some exemplary embodiments, the antibody or its antigen-binding fragment is administered to the subject as a loading dose, followed by multiple maintenance doses.

[0206] In some exemplary embodiments, the antibody or its antigen-binding fragment is administered using an auto-injector, needle and syringe or pen.

[0207] In some exemplary embodiments, the antibody or its antigen-binding fragment is administered once every two weeks (q2w).

[0208] In some exemplary embodiments, the loading dose is about 600 mg of the antibody or its antigen-binding fragment. In some exemplary embodiments, each maintenance dose of the antibody or its antigen-binding fragment is about 300 mg of the antibody or its antigen-binding fragment.

[0209] In some exemplary embodiments, the loading dose is about 400 mg of the antibody or its antigen-binding fragment. In some exemplary embodiments, each maintenance dose of the antibody or its antigen-binding fragment is about 200 mg of the antibody or its antigen-binding fragment.

[0210] In some exemplary embodiments, a maintenance dose of the antibody or its antigen-binding fragment is administered for at least 24 weeks.

[0211] In some exemplary embodiments, a first maintenance dose of the antibody or its antigen-binding fragment is administered two weeks after the loading dose.

[0212] In some exemplary embodiments, the treatment results in an improvement in lung function, as measured by forced expiratory volume (FEV1) or forced expiratory flow rate at 25%-75% of lung volume (FEF25%-75%).

[0213] In some exemplary embodiments, treatment results in a decrease in one or both of total serum IgE levels and serum Aspergillus fumigatus-specific IgE levels. In some exemplary embodiments, treatment results in a decrease in one or more of TARC levels, eosinophil chemokine-3 levels, and peripheral blood eosinophil levels. In some exemplary embodiments, FeNO(ppb) is reduced.

[0214] In some exemplary embodiments, the antibody or its antigen-binding fragment comprises a heavy chain variable region (HCVR) containing the sequence of SEQ ID NO:1 and a light chain variable region (LCVR) containing the sequence of SEQ ID NO:2.

[0215] In some exemplary embodiments, the antibody or its antigen-binding fragment comprises the heavy chain sequence of SEQ ID NO:9 and the light chain sequence of SEQ ID NO:10.

[0216] In some exemplary embodiments, the antibody is dupilumab.

[0217] In some exemplary embodiments, the subject suffers from asthma. In some exemplary embodiments, the treatment results in a reduction in annualized asthma exacerbations.

[0218] In some exemplary embodiments, the subject is an adult. In some exemplary embodiments, the subject is a teenager. In some exemplary embodiments, the subject is a child.

[0219] In another aspect, a method for treating a subject suffering from allergic bronchopulmonary aspergillosis (ABPA) is provided, the method comprising administering to the subject an antibody or antigen-binding fragment thereof that specifically binds to an interleukin-4 receptor (IL-4R), wherein the antibody or antigen-binding fragment thereof comprises three heavy chain CDR sequences containing SEQ ID NO:3, 4 and 5, respectively, and three light chain CDR sequences containing SEQ ID NO:6, 7 and 8, respectively, wherein the subject has a total serum IgE level of at least about 1000 IU / mL, an Aspergillus fumigatus-specific IgE level greater than 0.35 kU / L, or a baseline blood eosinophil count of at least about 500 cells / μl.

[0220] In some exemplary embodiments, the subject has at least two of the following: a total serum IgE level of at least about 1000 IU / mL, an Aspergillus fumigatus-specific IgE level greater than 0.35 kU / L, and a baseline blood eosinophil count of at least about 500 cells / μl. In some exemplary embodiments, the subject has a total serum IgE level of at least about 1000 IU / mL, an Aspergillus fumigatus-specific IgE level greater than 0.35 kU / L, and a baseline blood eosinophil count of at least about 500 cells / μl.

[0221] In some exemplary embodiments, the antibody or its antigen-binding fragment is administered to the subject as a loading dose, followed by multiple maintenance doses. In some exemplary embodiments, the antibody or its antigen-binding fragment is administered using an autoinjector, needle, syringe, or pen. In some exemplary embodiments, the antibody or its antigen-binding fragment is administered every two weeks (q2w).

[0222] In some exemplary embodiments, the loading dose is about 600 mg of the antibody or its antigen-binding fragment. In some exemplary embodiments, each maintenance dose of the antibody or its antigen-binding fragment is about 300 mg of the antibody or its antigen-binding fragment.

[0223] In some exemplary embodiments, the loading dose is about 400 mg of the antibody or its antigen-binding fragment. In some exemplary embodiments, each maintenance dose of the antibody or its antigen-binding fragment is about 200 mg of the antibody or its antigen-binding fragment.

[0224] In some exemplary embodiments, a maintenance dose of the antibody or its antigen-binding fragment is administered for at least 24 weeks.

[0225] In some exemplary embodiments, a first maintenance dose of the antibody or its antigen-binding fragment is administered two weeks after the loading dose.

[0226] In some exemplary embodiments, the treatment results in an improvement in lung function, as measured by forced expiratory volume (FEV1) or forced expiratory flow rate at 25%-75% of lung volume (FEF25%-75%).

[0227] In some exemplary embodiments, treatment results in a decrease in one or both of total serum IgE levels and serum Aspergillus fumigatus-specific IgE levels. In some exemplary embodiments, treatment results in a decrease in one or more of TARC levels, eosinophil chemokine-3 levels, and peripheral blood eosinophil levels. In some exemplary embodiments, FeNO(ppb) is reduced.

[0228] In some exemplary embodiments, the antibody or its antigen-binding fragment comprises a heavy chain variable region (HCVR) containing the sequence of SEQ ID NO:1 and a light chain variable region (LCVR) containing the sequence of SEQ ID NO:2.

[0229] In some exemplary embodiments, the antibody or its antigen-binding fragment comprises the heavy chain sequence of SEQ ID NO:9 and the light chain sequence of SEQ ID NO:10.

[0230] In some exemplary embodiments, the antibody is dupilumab.

[0231] In some exemplary embodiments, the subject suffers from moderate to severe uncontrolled asthma. In some exemplary embodiments, the treatment results in a reduction in annualized severe asthma exacerbations.

[0232] In some exemplary embodiments, the subject exhibits comorbid asthma. In some exemplary embodiments, the subject exhibits comorbid cystic fibrosis. In some exemplary embodiments, the subject exhibits comorbid asthma and comorbid cystic fibrosis.

[0233] In some exemplary embodiments, the subject is an adult. In some exemplary embodiments, the subject is a teenager. In some exemplary embodiments, the subject is a child.

[0234] In another aspect, a method for treating a subject suffering from asthma is provided, the method comprising administering to the subject two or more doses of an antibody or antigen-binding fragment thereof that specifically binds to an interleukin-4 receptor (IL-4R), wherein the antibody or antigen-binding fragment thereof comprises three heavy chain CDR sequences containing SEQ ID NO:3, 4 and 5 respectively and three light chain CDR sequences containing SEQ ID NO:6, 7 and 8 respectively, and wherein a vaccine is further administered to the subject.

[0235] In some exemplary embodiments, the administration of the antibody or its antigen-binding fragment is temporarily suspended before the vaccine is administered.

[0236] In some exemplary embodiments, the vaccine is administered at least 7 days after the last administration of the antibody or its antigen-binding fragment to the subject. In some exemplary embodiments, the vaccine is administered between approximately 7 days and approximately 60 days after the last administration of the antibody or its antigen-binding fragment to the subject.

[0237] In some exemplary embodiments, the administration of the antibody or its antigen-binding fragment is resumed after the administration of the vaccine.

[0238] In some exemplary embodiments, the antibody or its antigen-binding fragment is administered between approximately 1 day and approximately 90 days after vaccine administration. In some exemplary embodiments, the antibody or its antigen-binding fragment is administered approximately 7 days after vaccine administration. In some exemplary embodiments, the antibody or its antigen-binding fragment is administered approximately 14 days after vaccine administration.

[0239] In some exemplary embodiments, the antibody or its antigen-binding fragment is administered approximately 21 days after the administration of the vaccine.

[0240] In some exemplary embodiments, administering the vaccine does not reduce the efficacy of the antibody or its antigen-binding fragment.

[0241] In some exemplary embodiments, the subject’s forced expiratory volume (FEV1) is approximately the same before and after administration of the vaccine.

[0242] In some exemplary embodiments, administration of the antibody or its antigen-binding fragment did not reduce vaccine efficacy in the subjects.

[0243] In some exemplary embodiments, the subject develops a protective neutralizing titer of serum after administration of the vaccine.

[0244] In some exemplary embodiments, the vaccine is a live vaccine. In some exemplary embodiments, the vaccine comprises an attenuated yellow fever virus. In some exemplary embodiments, the vaccine has specificity against the yellow fever virus.

[0245] In some exemplary embodiments, the antibody or its antigen-binding fragment comprises a heavy chain variable region (HCVR) containing the sequence of SEQ ID NO:1 and a light chain variable region (LCVR) containing the sequence of SEQ ID NO:2.

[0246] In some exemplary embodiments, the antibody or its antigen-binding fragment comprises the heavy chain sequence of SEQ ID NO:9 and the light chain sequence of SEQ ID NO:10.

[0247] In some exemplary embodiments, the antibody is dupilumab.

[0248] In some exemplary embodiments, the subject exhibits comorbid cystic fibrosis. In some exemplary embodiments, the subject exhibits comorbid asthma and comorbid cystic fibrosis.

[0249] In some exemplary embodiments, the subject is an adult. In some exemplary embodiments, the subject is a teenager. In some exemplary embodiments, the subject is a child.

[0250] In another aspect, a method for administering a vaccine to a subject is provided, wherein, before, during, or after administering the vaccine, at least one dose of an antibody or antigen-binding fragment thereof that specifically binds to an interleukin-4 receptor (IL-4R) is administered to the subject, wherein the antibody or antigen-binding fragment thereof comprises three heavy chain CDR sequences containing SEQ ID NO:3, 4, and 5, respectively, and three light chain CDR sequences containing SEQ ID NO:6, 7, and 8, respectively.

[0251] In some exemplary embodiments, the subject suffers from type 2 inflammatory disease. In some exemplary embodiments, the type 2 inflammatory disease is selected from one or any combination of the following: asthma, allergic rhinitis, chronic sinusitis with nasal polyps (CRSsNP), eosinophilic esophagitis (EoE), atopic dermatitis (AD), food and environmental allergies, aspirin-induced respiratory disease (AERD), and respiratory disease exacerbated by other nonsteroidal anti-inflammatory drugs (NSAIDs).

[0252] In some exemplary embodiments, the vaccine is administered to the subject approximately 1 day to approximately 90 days after the last dose of the antibody or its antigen-binding fragment.

[0253] In some exemplary embodiments, the antibody or its antigen-binding fragment comprises a heavy chain variable region (HCVR) containing the sequence of SEQ ID NO:1 and a light chain variable region (LCVR) containing the sequence of SEQ ID NO:2.

[0254] In some exemplary embodiments, the antibody or its antigen-binding fragment comprises the heavy chain sequence of SEQ ID NO:9 and the light chain sequence of SEQ ID NO:10.

[0255] In some exemplary embodiments, the antibody is dupilumab.

[0256] In some exemplary embodiments, the subject exhibits asthma. In some exemplary embodiments, the subject exhibits cystic fibrosis. In some exemplary embodiments, the subject exhibits comorbid asthma and comorbid cystic fibrosis.

[0257] In some exemplary embodiments, the subject is an adult. In some exemplary embodiments, the subject is a teenager. In some exemplary embodiments, the subject is a child.

[0258] Other embodiments will become clear from the following detailed description, drawings, tables and summary of the appended claims. Attached Figure Description

[0259] The foregoing and other features and advantages of the invention will be more fully understood from the following detailed description of illustrative embodiments, taken in conjunction with the accompanying drawings. This patent document contains at least one color drawing / photograph. Upon request and payment of the necessary fees, the Patent Office will provide copies of this patent having one or more color drawings / photographs.

[0260] Figures 1A-1E depict the effect of dupilumab on the annualized rate of severe exacerbations. Figure 1A shows that dupilumab reduced the overall annualized rate of severe exacerbations in both the overall allergic asthma subgroup and the overall asthma subgroup that did not meet the criteria for allergic asthma. Figure 1B depicts the effect of dupilumab in both the allergic asthma subgroup and the asthma subgroup that did not meet the criteria for allergic asthma, where subjects had a blood eosinophil level ≥150 cells / μL. Figure 1C depicts the effect of dupilumab in both the allergic asthma subgroup and the asthma subgroup that did not meet the criteria for allergic asthma, where subjects had a blood eosinophil level ≥300 cells / μL. Figure 1D depicts the effect of dupilumab in both the allergic asthma subgroup and the asthma subgroup that did not meet the criteria for allergic asthma, where subjects had a baseline blood FeNO level ≥25 ppb. Figure 1E depicts the effects of penicillin in the allergic asthma subgroup and the asthma subgroup that does not meet the criteria for allergic asthma, where subjects have serum total IgE >700 IU / mL. CI, confidence interval; FeNO, exhaled nitric oxide; ITT, intention-to-treat; q2w, every 2 weeks.

[0261] Figure 2 illustrates the effect of penicillin on FEV1(L) in the overall allergic asthma subgroup and the overall asthma subgroup that does not meet the criteria for allergic asthma. Figure 2A depicts the change in baseline FEV1 during the 52-week treatment period in the overall allergic asthma subgroup and illustrates the magnitude of the effect in the subgroups further defined by baseline blood eosinophil levels, FeNO levels, or baseline serum total IgE levels at week 12. Figure 2B depicts the change in baseline FEV1 during the 52-week treatment period in the overall asthma subgroup that does not meet the criteria for allergic asthma and illustrates the magnitude of the effect in the subgroups further defined by baseline blood eosinophil levels, FeNO levels, or baseline serum total IgE levels at week 12.

[0262] Figure 3 illustrates the effect of dupilumab on asthma control (as measured by ACQ-5) during a 52-week treatment period in the overall allergic asthma subgroup and the overall asthma subgroup that does not meet the criteria for allergic asthma. ACQ-5, 5-item Asthma Control Questionnaire; LS, least squares method; q2w, every 2 weeks; SE, standard error.

[0263] Figures 4A-4C depict the effects of dupilumab on various biomarkers. Figure 4A depicts the effect of dupilumab on serum total IgE levels. Figure 4B depicts the effect of dupilumab on FeNO levels. Figure 4C depicts the effect of dupilumab on serum TARC levels during a 52-week treatment period in the overall allergic asthma subgroup and the overall asthma subgroup that does not meet the criteria for allergic asthma (the exposed population). CI, confidence interval; FeNO, exhaled nitric oxide; q2w, every 2 weeks; TARC, thymus and activation regulation of chemokines.

[0264] Figures 5A-5H depict the effect of dupilumab on antigen-specific serum IgE levels during a 52-week treatment period in the allergic asthma subgroup. Figure 5A depicts the effect of dupilumab on antigen-specific serum IgE levels ≥0.35 kU / mL (exposed population) in the allergic asthma subgroup exposed to Aspergillus fumigatus. Figure 5B depicts the effect of dupilumab on antigen-specific serum IgE levels in the allergic asthma subgroup exposed to cat dander. Figure 5C depicts the effect of dupilumab on antigen-specific serum IgE levels in the allergic asthma subgroup exposed to house dust mites. Figure 5D depicts the effect of dupilumab on antigen-specific serum IgE levels in the allergic asthma subgroup exposed to house dust mites. Figure 5E depicts the effect of dupilumab on antigen-specific serum IgE levels in the allergic asthma subgroup exposed to dog dander. Figure 5F depicts the effect of moderate-dose pilumab on antigen-specific serum IgE levels in the allergic asthma subgroup exposed to German cockroaches. Figure 5G depicts the effect of moderate-dose pilumab on antigen-specific serum IgE levels in the allergic asthma subgroup exposed to *Alternaria tenuis* / *Alternata*. Figure 5H depicts the effect of moderate-dose pilumab on antigen-specific serum IgE levels in the allergic asthma subgroup exposed to *C. herbarum* / *Hormodendrum*. CI, confidence interval; q2w, every 2 weeks.

[0265] Figures 6A and 6B show the statistical analysis of patients with IgE ≥ 700 IU / ml. Figure 6A depicts the histogram of residuals used to ensure a normal distribution. Figure 6B depicts the qq plot showing a normal distribution.

[0266] Figure 7 depicts the annualized rate of severe exacerbations during the 52-week treatment period for patients with allergic bronchopulmonary aspergillosis (ABPA) in the intention-to-treat (ITT) population.

[0267] Figure 8 depicts the least squares (LS) mean change from baseline in the forced expiratory volume in one second (FEV1) before bronchodilator administration at weeks 24 and 52 in the ITT population.

[0268] Figure 9 depicts the total serum IgE levels at week 52 in a patient population exposed to Aspergillus fumigatus (Af).

[0269] Figure 10 depicts the total serum Af-specific IgE levels at week 52 in the patient population exposed to Af.

[0270] Figure 11 plots the absolute FeNO(ppb) levels at week 52 in the patient population exposed to Af.

[0271] Figure 12 illustrates, in graphical form, the effect of dupilumab q2w on annualized severe exacerbation rate during a 52-week treatment period in an ITT patient population with serological signs of ABPA.

[0272] Figure 13 illustrates, in graphical form, the effect of dupilumab q2w on pre-bronchodilator FEV1(L) during a 52-week treatment period in an ITT patient population with serological signs of ABPA.

[0273] Figure 14 illustrates, in graphical form, the effect of dupilumab q2w on ACQ-5 score during a 52-week treatment period in an ITT patient population with serological signs of ABPA.

[0274] Figures 15A-15B illustrate, in graphical form, the effects of dupilumab q2w on serum total IgE (IU / mL) (Figure 15A) and Aspergillus fumigatus-specific serum IgE (IU / mL) (Figure 15B) during a 52-week treatment period in exposed patients with serological signs of ABPA.

[0275] Figures 16A-16D illustrate, in graphical form, the effects of dupilumab q2w on type 2 biomarkers during a 52-week treatment period in exposed patients with serological signs of ABPA. FeNO (ppb) (Figure 16A), TARC (pg / mL) (Figure 16B), eosinophil chemokine-3 (pg / mL) (Figure 16C), and peripheral blood eosinophils (cells / μL) (Figure 16D).

[0276] Figures 17A-17B graphically depict the plaque reduction and neutralizing titer (PRNT) of neutralizing YFV-17D antibodies before and after vaccination. 50 Figure 17A depicts matched neutralizing titers for 23 patients who achieved pre-vaccination titers. Figure 17B depicts pre- and post-vaccination data for all patients. In Figure 17B, dupilumab concentrations were below the mean C. 谷Patients with a serum concentration of 37.4 mg / L are indicated by a black circle, while those with a serum concentration greater than 37.4 mg / L are indicated by a hollow circle. A titer <1:10 was defined as a negative serological reaction, and those values ​​were designated as "1". Figures 17A-17B show the serum protective yellow fever neutralizing titers of all 37 vaccinated patients after vaccination.

[0277] Figure 18 graphically depicts the increase in (log) PRNT titer compared to pre-titration dupilumab concentrations (pre-titration vs. post-titration). Pre-titration PK samples were collected from 15 of the 23 patients on the same day as YFV administration. All 13 patients with serum dupilumab concentrations >37.4 mg / L had serum protective PRNT titers after YFV. Twelve of these patients showed an increase in titer after vaccination, while one of the 13 patients did not show an increase but was already within the serum protective threshold at baseline. The fold change in PRNT titer levels for these patients is shown in Figure 18. Pre-titration <1:10, where 10 was used to calculate the fold increase in titer.

[0278] Figure 19 plots the mean absolute FEV1(L) before and after yellow fever vaccination in patients who received yellow fever vaccination in the LTS12551 study. Figure 19 shows that FEV1 was stable between the pre-YFV visit and the first visit after YFV administration. BL: baseline of the parental study; pre-YF: last visit before yellow fever vaccination; post-YF: first visit after yellow fever vaccination; FU: follow-up.

[0279] Figure 20 plots the mean change in FEV1(L) from baseline before and after yellow fever vaccination in patients who received yellow fever vaccination in the LTS12551 study. Figure 20 shows that FEV1 was stable between the pre-YFV administration visit and the first post-YFV administration visit. BL: Baseline of the parental study; Pre-YF: Last visit before yellow fever vaccination; Post-YF: First visit after yellow fever vaccination; FU: Follow-up. Detailed Implementation

[0280] Before describing the invention, it should be understood that the invention is not limited to the specific methods and experimental conditions described, as such methods and conditions are variable. It should also be understood that, because the scope of the invention will be limited only by the appended claims, the terminology used herein is for the purpose of describing particular embodiments only and is not intended to be restrictive.

[0281] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention pertains.

[0282] As used herein, the term “about” when used to refer to a specific numerical value means that the value may be approximately 1% closer to the stated value. For example, as used herein, the expression “about 100” includes 99 and 101 and all values ​​in between (e.g., 99.1, 99.2, 99.3, 99.4, etc.).

[0283] As used in this article, the terms “treat” and “treating” refer to the relief of symptoms, the temporary or permanent elimination of the cause of symptoms, or the prevention or mitigation of the symptoms of the mentioned obstacle or condition.

[0284] Although any methods and materials similar to or equivalent to those described herein may be used in the practice of this invention, typical methods and materials are now described. All publications mentioned herein are incorporated herein by reference in their entirety.

[0285] Methods for reducing the incidence of asthma and / or ABPA exacerbations

[0286] A method is provided for reducing the incidence of asthma (e.g., allergic asthma, ABPA-related asthma, moderate to severe asthma, persistent asthma, etc.) and / or ABPA (ABPA, asthma-related ABPA, CF-related ABPA, ABPA related to both asthma and CF, etc.) exacerbations in subjects in need, the method comprising administering to the subject a pharmaceutical composition comprising an IL-4R antagonist. According to some embodiments, the IL-4R antagonist is an antibody that specifically binds to IL-4R or an antigen-binding fragment thereof. Exemplary anti-IL-4R antibodies that can be used in the context of the methods characterized herein are described elsewhere herein.

[0287] As used herein, the term "asthma exacerbation" refers to an increase in the severity and / or frequency and / or duration of one or more symptoms or indicators of asthma (e.g., allergic asthma, ABPA-related asthma, moderate to severe asthma, persistent asthma, etc.). "Asthma exacerbation" also includes any deterioration in the subject's respiratory health that requires or can be treated with therapeutic interventions for asthma (e.g., steroid therapy, inhaled corticosteroid therapy, hospitalization, etc.). There are two types of asthma exacerbation events: out-of-control asthma (LOAC) events and severe exacerbation events.

[0288] As used herein, the expressions “exacerbation of allergic bronchopulmonary aspergillosis” or “ABPA exacerbation” mean an increase in the severity and / or frequency and / or duration of one or more symptoms or indicators of ABPA, including but not limited to wheezing, dyspnea, worsening of breathing, bronchial hyperresponsiveness, hemoptysis, expectorant cough (expulsion of sputum with brown mucus plugs), central bronchiectasis with mucus plugs, significantly elevated total IgE, significantly elevated Af-specific IgE, and histological eosinophilia.

[0289] According to certain implementations, ABPA exacerbation occurs in subjects with HLA-DR2 serotypes (e.g., subtypes HLA-DRB1*1501, *HLA-DRB1*1503, or *HLA-DRB1*1601) or HLA-DR5 serotypes (e.g., subtypes HLA-DRB1*1101, HLA-DRB1*1104, or HLA-DRB1*1202), optionally wherein the subjects have an increased susceptibility to ABPA upon exposure to Af compared to subjects who do not have one of these serotypes and / or subtypes.

[0290] According to certain implementation schemes, an out-of-control asthma (LOAC) event is defined as one or more of the following: (a) more than 6 additional doses of salbutamol / terbutaline or levosalbutamol / levosaline depressant inhaler (compared to baseline) over a 24-hour period for 2 consecutive days; (b) an increase in ICS greater than or equal to 4 times the dose at the second visit; and (c) use of systemic corticosteroids for more than or equal to 3 days; or (d) hospitalization or emergency room visit due to asthma requiring systemic corticosteroids.

[0291] In certain cases, asthma exacerbations (e.g., allergic asthma, ABPA-related asthma, moderate to severe asthma, persistent asthma, etc.) can be classified as “severe asthma exacerbations.” A severe asthma exacerbation (e.g., severe allergic asthma) is defined as an event requiring immediate intervention in the form of systemic or inhaled corticosteroids at a dose four or more times the dose used prior to the event. According to some implementation schemes, a severe asthma exacerbation (e.g., severe allergic asthma) is defined as an asthma exacerbation (e.g., allergic asthma, ABPA-related asthma, moderate to severe asthma, persistent asthma, etc.) requiring: systemic corticosteroids for 3 days or more, or hospitalization or emergency room visit due to asthma requiring systemic corticosteroids. Therefore, the general expression “asthma exacerbation” includes and encompasses the more specific subclasses of “severe asthma exacerbation.” Therefore, methods for reducing the incidence of moderate to severe asthma exacerbations in patients in need are included.

[0292] "Reduced incidence of asthma (e.g., allergic asthma, ABPA-related asthma, moderate to severe asthma, persistent asthma, etc.)" and / or "reduced incidence of ABPA exacerbations" means that a subject receiving a pharmaceutical composition containing an IL-4R antagonist experiences fewer asthma or ABPA exacerbations after treatment than before treatment (i.e., at least one fewer exacerbation), or does not experience an asthma exacerbation for at least 4 weeks (e.g., 4, 6, 8, 12, 14 weeks, or longer) after starting treatment with the pharmaceutical composition. "Reduced incidence of asthma and / or ABPA exacerbations" may alternatively mean that, after administration of the pharmaceutical composition, a subject is at least 10% less likely to experience an asthma exacerbation compared to a subject who did not receive the pharmaceutical composition (e.g., 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, or more).

[0293] A method is provided for reducing the incidence of asthma (e.g., allergic asthma, ABPA-related asthma, moderate to severe asthma, persistent asthma, etc.) and / or ABPA exacerbations in subjects in need, the method comprising administering a pharmaceutical composition comprising an IL-4R antagonist to the subject and administering one or more maintenance doses of an inhaled corticosteroid (ICS) and / or one or more maintenance doses of a second controller, such as a long-acting β-agonist (LABA) or a leukotriene receptor antagonist (LTA). Suitable ICS include, but are not limited to, fluticasone (e.g., fluticasone propionate, such as Flovent). TM ), budesonide, mometasone (e.g., mometasone furoate, e.g., Asmanex) TM ), flunisulfuron (e.g., Aerobid) TM ), dexamethasone acetate / phenobarbital / theophylline (e.g., Azmacort) TM ), beclomethasone dipropionate HFA (Qvar) TM Suitable LABAs include, but are not limited to, salmeterol (e.g., serevent). TM ), formoterol (e.g., Foradil) TM Suitable LTAs include, but are not limited to, Montelukast (e.g., Singulaire). TM ), Zalust (e.g., Accolate) TM )wait.

[0294] A method is provided for reducing the incidence of asthma (e.g., allergic asthma, ABPA-related asthma, moderate to severe asthma, persistent asthma, etc.) and / or ABPA exacerbations in subjects in need, the method comprising administering a pharmaceutical composition containing an IL-4R antagonist to the subject and administering one or more responsible medications to the subject to eliminate or reduce one or more asthma-related symptoms. Suitable responsible medications include, but are not limited to, short-acting β2-adrenergic receptor agonists, such as albuterol (i.e., salbutamol), for example, Proventil. TM Ventolin TM Xopenex TM etc.), piputerol (e.g., Maxair) TM ), metaproterenol (e.g., Alupent) TM )wait.

[0295] Methods for improving asthma-related and / or ABPA-related parameters

[0296] Methods for improving one or more asthma-related and / or ABPA-related parameters in subjects in need are also provided, wherein the methods involve administering a pharmaceutical composition comprising an IL-4R antagonist to the subject. A reduction in the incidence of asthma exacerbations and / or ABPA exacerbations (as described above) may be associated with improvements in one or more asthma-related and / or ABPA-related parameters; however, such an association is not necessarily observed in all cases.

[0297] Examples of “asthma-related parameters,” “ABPA-related asthma parameters,” and “allergic asthma-related parameters” include: (1) the percentage change in forced expiratory volume in one second (FEV1) from baseline (e.g., at week 12); (2) the percentage change in forced expiratory flow rate at 25%–75% lung volume from baseline (e.g., at week 12); (3) the annualized rate of asthma out-of-control events during the treatment period; (4) the annualized rate of severe exacerbations during the treatment period; (5) the time to an asthma out-of-control event during the treatment period; (6) the time to a severe exacerbation during the treatment period; (7) the time to an asthma out-of-control event throughout the study period; (8) the time to an asthma out-of-control event throughout the study period. (9) Time to severe exacerbation during the study period; (10) (e.g., at week 12) i) Morning and evening asthma symptom scores, ii) ACQ-5 scores, iii) AQLQ scores, iv) Morning and evening PEF, v) Number of inhalations of salbutamol / terbutaline or levosalbutamol / levosalbutamol / day for symptom relief; vi) Change in nighttime wakefulness from baseline; or (11) (e.g., at week 12 or week 24) i) 22-item nasal and sinus outcome test (SNOT-22), ii) Hospital anxiety and depression score (HADS), iii) Change in EuroQual questionnaire (EQ-5D-3L or EQ-5D-5L) from baseline. "Improvement in asthma-related parameters" means an increase in one or more of FEV1, AM PEF, or PM PEF from baseline and / or a decrease in one or more of daily salbutamol / levosalbutamol use, ACQ5 score, mean nocturnal wakefulness, or SNOT-22 score from baseline. As used herein, the term "baseline" for asthma-related parameters means the value of a patient's asthma-related parameter before or at the time of administration of a pharmaceutical composition containing an IL-4R antagonist.

[0298] To determine whether asthma-related parameters (e.g., allergic asthma-related) or ABPA-related asthma parameters have “improved,” the parameters are quantified at baseline and at time points following administration of the pharmaceutical composition described herein. For example, asthma-related parameters may be measured at days 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 14, or weeks 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, or longer after initial treatment with the pharmaceutical composition. The difference between the value of the parameter at a specific time point after the start of treatment and the value of the parameter at baseline is used to determine whether the asthma-related parameter has been "improved" (e.g., increased or decreased, depending on the specific parameter being measured).

[0299] As used herein, the term “acquire” or “acquiring” refers to the possession of a physical entity or value (e.g., a numerical value) by means of “direct acquisition” or “indirect acquisition” of a physical entity or value (e.g., an asthma-related parameter). “Direct acquisition” means performing a process (e.g., conducting a synthetic or analytical method) to obtain a physical entity or value. “Indirect acquisition” means receiving a physical entity or value from another party or source (e.g., a third-party laboratory that directly acquires the physical entity or value). Direct acquisition of a physical entity includes performing a process involving a physical change in a physical substance (e.g., a starting material). Exemplary changes include: creating a physical entity from two or more starting materials, shearing or crushing a substance, separating or purifying a substance, combining two or more separated entities into a mixture, or conducting a chemical reaction involving the breaking or formation of covalent or non-covalent bonds. Direct acquisition of a value includes performing a process involving a physical change in a sample or another substance; for example, performing an analytical process (sometimes referred to herein as “physical analysis”) that involves a physical change in a substance (e.g., a sample, analyte, or reagent).

[0300] Information obtained indirectly may be provided in the form of a report, for example, in paper or electronic form, such as from an online database or application (“App”). The report or information may be provided by, for example, a healthcare institution (such as a hospital or clinic); or a healthcare provider (such as a doctor or nurse).

[0301] Forced expiratory volume in one second (FEV1)According to certain implementation schemes, administration of an IL-4R antagonist to a patient results in an increase in forced expiratory volume in one second (FEV1) from baseline. Methods for measuring FEV1 are known in the art. For example, a spirometer conforming to the 2005 recommendations of the American Thoracic Society (ATS) / European Respiratory Society (ERS) can be used to measure a patient's FEV1. The ATS / ERS spirometry standards can be used as a guideline. Sphygmomanometer measurements are typically performed between 6:00 and 10:00 AM, at least 6 hours after discontinuation of salbutamol. Pulmonary function tests are typically performed in a seated position, and the highest FEV1 measurement (in liters) is recorded.

[0302] Such treatments are provided that result in an increase in FEV1 from baseline of at least 0.05 L at week 12 after initiation of treatment with a pharmaceutical composition containing an anti-IL-4R antagonist. For example, administration of an IL-4R antagonist to subjects in need results in an increase in FEV1 from baseline of approximately 0.05 L, 0.10 L, 0.12 L, 0.14 L, 0.16 L, 0.18 L, 0.20 L, 0.22 L, 0.24 L, 0.26 L, 0.28 L, 0.30 L, 0.32 L, 0.34 L, 0.36 L, 0.38 L, 0.40 L, 0.42 L, 0.44 L, 0.46 L, 0.48 L, 0.50 L, or more at week 12.

[0303] FEF 25%-75%.According to certain implementations, administration of an IL-4R antagonist to a patient results in an increase in FEF 25%–75% from baseline. Methods for measuring FEF are known in the art. For example, a patient's FEV1 can be measured using a spirometer conforming to the 2005 recommendations of the American Thoracic Society (ATS) / European Respiratory Society (ERS). FEF 25%–75% (forced expiratory flow rate between 25% and 75%) is the rate (in liters per second) at which an individual can expel the middle half of his or her forced expiratory volume (FVC) during maximal exhalation. This parameter relates to the average flow rate from 25% to 75% of the exhaled FVC. A subject's FEF 25%–75% provides information about small airway function, including the degree of small airway disease and / or inflammation. Changes in FEF 25%–75% are an early indication of obstructive lung disease. In some embodiments, improvement and / or increase of the FEF25-75% parameter is an improvement of at least 10%, 25%, 50%, or more compared to baseline. In some embodiments, the methods described herein result in normal FEF25%-75% values ​​in subjects (e.g., values ​​in the range of 50%-60% of the mean and up to 130%).

[0304] Peak morning and evening expiratory flow rates (AM PEF and PM PEF)According to certain implementations, administration of an IL-4R antagonist to a patient results in an increase in morning (AM) and / or evening (PM) peak expiratory flow (AM PEF and / or PM PEF) from baseline. Methods for measuring PEF are known in the art. For example, according to one method of measuring PEF, a patient is given an electronic PEF meter to record morning (AM) and evening (PM) PEF (as well as daily salbutamol use, morning and evening asthma symptom scores, and the number of nighttime awakenings due to asthma symptoms requiring rescue medication). The patient is instructed on the use of the device and given written instructions on the use of the electronic PEF meter. Furthermore, a medical professional may instruct the patient on how to record relevant variables in the electronic PEF meter. AM PEF recording is typically performed within 15 minutes of waking (between 6 and 10 a.m.) before taking any salbutamol. PM PEF recording is typically performed in the evening (between 6 and 10 p.m.) before taking any salbutamol. Subjects should discontinue salbutamol for at least 6 hours prior to their PEF measurement. Three PEF attempts were performed on the patient, and all three values ​​were recorded by an electronic PEF meter. The highest value was typically used for evaluation. Baseline AM PEF can be calculated as the average AM measurement recorded over the 7 days prior to administration of the first dose of the drug composition containing an IL-4R antagonist, and baseline PM PEF can be calculated as the average PM measurement recorded over the 7 days prior to administration of the first dose of the drug composition containing an IL-4R antagonist.

[0305] Such a treatment is provided, which results in an increase of at least 1.0 L / min in AM PEF and / or PM PEF from baseline at week 12 after initiation of treatment with a pharmaceutical composition containing an anti-IL-4R antagonist. For example, according to an exemplary implementation, administration of an IL-4R antagonist to subjects in need results in an increase in PEF from baseline of approximately 0.5 L / min, 1.0 L / min, 1.5 L / min, 2.0 L / min, 2.5 L / min, 3.0 L / min, 3.5 L / min, 4.0 L / min, 4.5 L / min, 5.0 L / min, 5.5 L / min, 6.0 L / min, 6.5 L / min, 7.0 L / min, 7.5 L / min, 8.0 L / min, 8.5 L / min, 9.0 L / min, 9.5 L / min, 10.0 L / min, 10.5 L / min, 11.0 L / min, 12.0 L / min, 15 L / min, 20 L / min or more.

[0306] Use of salbutamol / L-salbutamolAccording to certain implementations, administration of an IL-4R antagonist to a patient results in a reduction in daily salbutamol / levosalbutamol use from baseline. The number of salbutamol / levosalbutamol inhalations can be recorded daily by the patient in a log, PEF meter, or other recording device. During treatment with the pharmaceutical composition described herein, salbutamol / levosalbutamol can typically be used symptomatically and as needed, rather than regularly or prophylactically. The baseline number of salbutamol / levosalbutamol inhalations per day can be calculated based on the mean of the 7 days prior to administration of the first dose of the pharmaceutical composition containing an IL-4R antagonist.

[0307] Such a treatment method is provided, which results in a reduction of at least 0.25 sprays / day from baseline in salbutamol / levosalbutamol usage at week 12 after initiation of treatment with a pharmaceutical composition containing an anti-IL-4R antagonist. For example, administration of an IL-4R antagonist to subjects in need results in a reduction of approximately 0.25 sprays / day, 0.50 sprays / day, 0.75 sprays / day, 1.00 sprays / day, 1.25 sprays / day, 1.5 sprays / day, 1.75 sprays / day, 2.00 sprays / day, 2.25 sprays / day, 2.5 sprays / day, 2.75 sprays / day, 3.00 sprays / day, or more in salbutamol / levosalbutamol usage at week 12 from baseline.

[0308] OCS usage. According to certain implementation schemes, administration of an IL-4R antagonist to a patient may be combined with an OCS (such as oral prednisone). The frequency of OCS administrations may be recorded daily by the patient in a log, PEF meter, or other recording device. During treatment with the pharmaceutical compositions described herein, prednisone may typically be used occasionally for short periods to control acute asthma attacks, for example, where bronchodilators and other anti-inflammatory agents have failed to control symptoms. In other respects, prednisone may be used concomitantly with or as a substitute for ICS. Oral prednisone may be administered at doses of about 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, or 40 mg. Optionally, the OCS may be administered once daily or multiple times daily (e.g., twice daily, three times daily, four times daily, etc.).

[0309] In some exemplary embodiments, methods are provided for reducing or eliminating a subject's dependence on OCS use. Reducing or eliminating steroid dependence is highly advantageous and desirable. In some embodiments, a reduction of 50% or more (e.g., 50%, 60%, 70%, 80%, 90% or more) in the OCS dose is achieved after a certain period of time of administration of IL-4R antibody therapy (e.g., at week 24). In some embodiments, OCS is substantially eliminated 40, 45, 50, 52 weeks or longer after the first dose following the administration of the loading dose. In other embodiments, the level of OCS use is reduced to at least 5 mg / day (e.g., less than 5 mg, 4 mg, 3 mg, 2 mg or less per day). In other embodiments, dependence on OCS use is substantially eliminated 3 months, 6 months, 9 months or 1 year after treatment with the IL4R antibody or a fragment thereof.

[0310] 5-item Asthma Control Questionnaire (ACQ) score Under certain implementation schemes, administration of IL-4R antagonists to patients resulted in a decrease in baseline scores on the five-item Asthma Control Questionnaire (ACQ5). The ACQ5 is a validated questionnaire for assessing asthma control.

[0311] Such treatments are provided that result in a reduction of at least 0.10 points from baseline in the ACQ5 score at week 12 after initiation of treatment with a pharmaceutical composition containing an anti-IL-4R antagonist. For example, administration of an IL-4R antagonist to a subject in need results in a reduction of approximately 0.10, 0.15, 0.20, 0.25, 0.30, 0.35, 0.40, 0.45, 0.50, 0.55, 0.60, 0.65, 0.70, 0.75, 0.80, 0.85, or more in the ACQ score at week 12 from baseline.

[0312] Nighttime awakening According to certain implementation schemes, administration of IL-4R antagonists to patients resulted in a reduction in the average number of nighttime awakenings from baseline.

[0313] In some implementations, the method reduces the average number of nighttime awakenings at week 12 after the start of treatment by at least about 0.10 times per night from baseline. For example, administration of an IL-4R antagonist to subjects in need can reduce the average number of nighttime awakenings at week 12 by about 0.10 times per night, 0.15 times per night, 0.20 times per night, 0.25 times per night, 0.30 times per night, 0.35 times per night, 0.40 times per night, 0.45 times per night, 0.50 times per night, 0.55 times per night, 0.60 times per night, 0.65 times per night, 0.70 times per night, 0.75 times per night, 0.80 times per night, 0.85 times per night, 0.90 times per night, 0.95 times per night, 1.0 times per night, 2.0 times per night, or more from baseline.

[0314] Score of the 22-question Sinus Outcome Test (SNOT-22) According to certain implementation schemes, administration of IL-4R antagonists to patients resulted in a decrease in the number of questions on the 22-question Sinus Outcome Test (SNOT-22) from baseline. SNOT-22 is a validated questionnaire used to assess the impact of chronic sinusitis on quality of life (Hopkins et al. 2009, Clin. Otolaryngol. 34:447-454).

[0315] Such treatments are provided that result in a reduction of at least one point from baseline in the SNOT-22 score at week 12 after initiation of treatment with a pharmaceutical composition containing an anti-IL-4R antagonist. For example, administration of an IL-4R antagonist to subjects in need may result in a reduction of approximately 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13 or more points in the SNOT-22 score at week 12 from baseline.

[0316] biomarkers In some embodiments, subjects experience improvements in lung function as measured by biomarkers, such as those associated with allergic asthma (e.g., severe uncontrolled allergic asthma) and / or those associated with ABPA. For example, biomarkers may be exhaled nitric oxide (FeNO), eosinophil chemokine-3, total IgE, allergen-specific IgE (e.g., Af-associated IgE), periosteal protein, eosinophil (Eos) levels, or thymus and activated regulatory chemokine (TARC). In some embodiments, improvements in lung function are indicated by a decrease or increase at week 4, week 12, or week 24 post-treatment (as applicable).

[0317] Methods for treating asthma and / or ABPA

[0318] In some embodiments, a method is provided for treating asthma in a subject of need, said asthma including, for example, allergic asthma, ABPA-related asthma, moderate to severe uncontrolled asthma, or poorly controlled asthma, and any of these allergic forms, wherein said method comprises administering to the subject a pharmaceutical composition comprising an IL-4R antagonist. In a particular embodiment, the method may be used to treat allergic asthma in a subject, such as moderate to severe uncontrolled allergic asthma. In other particular embodiments, the method may be used to treat ABPA-related asthma in a subject.

[0319] In some embodiments, a method is provided for treating ABPA in a subject in need, wherein the method includes administering a pharmaceutical composition comprising an IL-4R antagonist to the subject. In a particular embodiment, the method may be used to treat ABPA in a subject with comorbid asthma (e.g., moderate to severe uncontrolled asthma).

[0320] As used herein, the term “asthma” may be used interchangeably with “intermittent asthma” or “bronchial asthma.” “Asthma,” “bronchial asthma,” and “intermittent asthma,” as well as any of these allergic forms, means that one or any combination of the following conditions constitutes true asthma: symptoms occur for 2 days or less per week; symptoms do not interfere with normal activities; nocturnal symptoms occur for less than 2 days per month; or one or more pulmonary function tests are normal when the subject is not experiencing an asthma attack (e.g., greater than 80% of forced expiratory volume in one second (FEV1) and / or peak expiratory flow (PEF)).

[0321] As used herein, the term “allergic bronchopulmonary aspergillosis” or “ABPA” refers to an allergic reaction to Aspergillus (usually Aspergillus fumigatus) antigens in the lungs of a subject, which may damage the airways and lead to permanent lung damage. ABPA can be diagnosed by any combination of the following: patient health history (including the presence of asthma and / or cystic fibrosis), X-ray and / or CT scans, allergic skin tests, and blood IgE levels (e.g., total IgE and / or Aspergillus-specific IgE, such as Af-specific IgE). In some embodiments, ABPA is diagnosed by a combination of one or more of the following: (1) total serum IgE levels; (2) eosinophils; (3) Aspergillus-specific IgE, such as Af-specific serum IgE; and (4) Aspergillus-specific IgE, such as Af-specific serum IgG. In a particularly exemplary embodiment, a subject diagnosed with ABPA is a subject exhibiting one or more (e.g., one, two, or all three) of the following biomarkers: (1) a baseline serum IgE level greater than 1000 IU / mL; (2) an Af-specific baseline serum IgE level greater than 0.35 kU / L; and (3) a baseline blood eosinophil level greater than 500 cells / μL.

[0322] In some implementations, ABPA is diagnosed in subjects with an HLA-DR2 serotype (e.g., subtype HLA-DRB1*1501, subtype *HLA-DRB1*1503, or subtype *HLA-DRB1*1601) or an HLA-DR5 serotype (e.g., subtype HLA-DRB1*1101, subtype HLA-DRB1*1104, or subtype HLA-DRB1*1202).

[0323] As used in this article, the term "ABPA-associated asthma" refers to subjects who have comorbid asthma and ABPA.

[0324] “IgE” refers to an antibody isotype containing the ε heavy chain and is a monomer containing all five domains of the immunoglobulin structure. IgE is typically present in plasma at concentrations less than 1 μg / mL and has a half-life of approximately 2 days in serum (Abbas and Lichtman (2004) Basic Immunology functions and disorders of the immune system. 2nd ed. Philadelphia: Saunders). The units kU / L or IU / mL (these units are interchangeable) are commonly used to express IgE levels in peripheral blood, where 1 kU / L equals 2.4 ng / mL (Seagroatt and Anderson (1981) EJ Biol Stand. 9:431).

[0325] IgE (e.g., total serum IgE and / or allergen-specific IgE) can be determined using various methods known in the art. For example, PRIST (radioimmunosorbent assay strip) can be used, in which a serum sample reacts with IgE labeled with radioactive iodine. The bound radioactive iodine is detected, and its amount is proportional to the amount of total IgE in the serum sample. In clinical immunology, the levels of individual classes of immunoglobulins can be measured by turbidimetry (or turbidimetric assay) to characterize the antibody profile of a subject. Other methods for measuring IgE levels include, but are not limited to, ELISA, immunofluorescence, Western blotting, immunodiffusion, immunoelectrophoresis, etc. UniCAP can be used. Serum IgE concentrations were measured using a system (Pharmacia, Uppsala, Sweden) (see GJ Gleich, AKA Verbach and NAS wedlund, Measurement of IgE in normal and allergic serum by radioimmunoassay. J.Lab.Clin.Med.77 (1971), p. 690).

[0326] Allergic asthma refers to asthma triggered by allergens (e.g., inhaled allergens such as dust mites, pet dander, pollen, fungi, etc.). As used herein, the term "allergic asthma" refers to asthma in combination with one or more allergen markers, such as total serum IgE (e.g., ≥30 IU / mL, ≥700 IU / mL, or ≥1000 IU / mL) and / or at least one positive allergen-specific IgE value (e.g., an allergen-specific IgE value ≥0.35 kU / L). In some embodiments, the allergen is an airborne allergen (e.g., an annual or perennial airborne allergen).

[0327] In some exemplary embodiments, subjects with allergic asthma have the following total serum IgE levels: approximately ≥5 IU / mL, approximately ≥10 IU / mL, approximately ≥20 IU / mL, approximately ≥30 IU / mL, approximately ≥40 IU / mL, approximately ≥50 IU / mL, approximately ≥60 IU / mL, approximately ≥70 IU / mL, approximately ≥80 IU / mL, approximately ≥90 IU / mL, approximately ≥100 IU / mL, approximately ≥110 IU / mL, approximately ≥120 IU / mL, approximately ≥130 IU / mL, approximately ≥140 IU / mL, approximately ≥150 IU / mL, approximately ≥160 IU / mL, approximately ≥170 IU / mL, etc. U / mL, approximately ≥180 IU / mL, approximately ≥190 IU / mL, approximately ≥200 IU / mL, approximately ≥250 IU / mL, approximately ≥300 IU / mL, approximately ≥350 IU / mL, approximately ≥400 IU / mL, approximately ≥450 IU / mL, approximately ≥500 IU / mL, approximately ≥550 IU / mL, approximately ≥600 IU / mL, approximately ≥650 IU / mL, approximately ≥700 IU / mL, approximately ≥750 IU / mL, approximately ≥800 IU / mL, approximately ≥850 IU / mL, approximately ≥900 IU / mL, approximately ≥950 IU / mL, approximately ≥1000 IU / mL or greater. In a particularly exemplary embodiment, a subject with allergic asthma has a total serum IgE level greater than approximately 700 IU / mL (e.g., high total serum IgE). In other exemplary embodiments, the subject with allergic asthma has a total serum IgE level greater than about 1000 IU / mL (e.g., very high total serum IgE). In some exemplary embodiments, the subject has a total serum IgE level of at least 700 IU / mL as measured using an ImmunoCAP assay. In some exemplary embodiments, the subject has a total serum IgE level of at least 1000 IU / mL as measured using an ImmunoCAP assay.

[0328] In some exemplary embodiments, a subject suffering from allergic asthma has at least one positive allergen-specific IgE value present in the following amounts: approximately ≥0.05 kU / L, approximately ≥0.10 kU / L, approximately ≥0.15 kU / L, approximately ≥0.20 kU / L, approximately ≥0.21 kU / L, approximately ≥0.22 kU / L, approximately ≥0.23 kU / L, approximately ≥0.24 kU / L, approximately ≥0.25 kU / L, approximately ≥0.26 kU / L, approximately ≥0.27 kU / L, approximately ≥0.28 kU / L, or approximately ≥0.29 kU / L. Approximately ≥0.30 kU / L, approximately ≥0.31 kU / L, approximately ≥0.32 kU / L, approximately ≥0.33 kU / L, approximately ≥0.34 kU / L, approximately ≥0.35 kU / L, approximately ≥0.36 kU / L, approximately ≥0.37 kU / L, approximately ≥0.38 kU / L, approximately ≥0.39 kU / L, approximately ≥0.40 kU / L, approximately ≥0.45 kU / L, approximately ≥0.50 kU / L, approximately ≥0.55 kU / L, approximately ≥0.60 kU / L, approximately ≥0.65 kU / L, approximately ≥0.70 kU / L or greater.

[0329] As used in this article, "perennial airborne allergens" refers to airborne allergens that can exist in the environment year-round, such as dust mites, fungi, and dander. Perennial airborne allergens include, but are not limited to, Alternaria alternifolia, Aspergillus fumigatus, Aureobasidium pullulans, Candida albicans, Cladosporium multiflorum, dust mites, house dust mites, Mucor racemosus, Penicillium chrysogenum, Phona betae, Setomelanomma rostrata, Stemphylium herbarum, cat dander, dog dander, cow dander, chicken feathers, goose feathers, duck feathers, cockroaches (e.g., German cockroach, Oriental cockroach), mouse urine, peanut dust, nut dust, etc.

[0330] As used in this article, "seasonal airborne allergens" refers to airborne allergens present in the environment, such as pollen and spores. Seasonal airborne allergens include, but are not limited to, tree pollen (e.g., birch, alder, cedar, hazel, hornwort, horse chestnut, willow, poplar, linden, pine, maple, oak, olive, etc.), grass pollen (e.g., ryegrass, cat's tail, etc.), weed pollen (e.g., ragweed, plantain, nettle, artemisia, quinoa, oxalis, etc.), and fungal spores (e.g., mold) that increase in certain seasons, temperatures, etc.

[0331] As used herein, the term “persistent asthma” refers to asthma that is more severe than (bronchial) asthma / intermittent (bronchial) asthma. Subjects with persistent asthma or persistent bronchial asthma experience one or more of the following: symptoms lasting more than 2 days / week; symptoms interfering with normal activities; nocturnal symptoms lasting more than 2 days / month; or one or more pulmonary function tests are abnormal when the subject is not experiencing an asthma attack (e.g., less than 80% of forced expiratory volume in one second (FEV1) and / or peak expiratory flow (PEF)); the subject relies on daily asthma control medication; the subject has used systemic steroids more than once in the past year following a severe asthma attack; or uses a short-acting beta-2 agonist for more than two days per week to relieve asthma symptoms.

[0332] Asthma / intermittent asthma, bronchial asthma / intermittent bronchial asthma, and persistent asthma / persistent bronchial asthma, as well as the allergic form of each of these, can be classified as "mild," "moderate," "severe," or "moderate to severe." "Mild intermittent asthma" or "mild intermittent bronchial asthma" is defined as having symptoms less than once a week and ≥80% of the forced expiratory volume in one second (FEV1) or peak expiratory flow (PEF). "Mild persistent asthma" or "mild persistent bronchial asthma" differs in that the frequency of symptoms is greater than once a week but less than once a day, and the variability of FEV1 or PEF is <20%–30%. "Moderate intermittent asthma" or "moderate intermittent bronchial asthma" is defined as having symptoms less than once a week and 60%–80% of the forced expiratory volume in one second (FEV1) or peak expiratory flow (PEF). "Moderate persistent asthma" or "moderate persistent bronchial asthma," or their allergic form, is defined as having daily symptoms, exacerbations that may affect activity and / or sleep, nocturnal symptoms more than once a week, daily use of an inhaled short-acting beta-2 agonist, and 60%-80% of the forced expiratory volume in one second (FEV1) or peak expiratory flow (PEF). "Severe intermittent asthma" or "severe intermittent bronchial asthma," or their allergic form, is defined as having symptoms less than once a week, and 60% of the forced expiratory volume in one second (FEV1) or peak expiratory flow (PEF). "Severe persistent asthma" or "severe persistent bronchial asthma" is defined as having daily symptoms, frequent exacerbations that may affect activity and / or sleep, frequent nocturnal symptoms, limited physical activity, daily use of an inhaled short-acting beta-2 agonist, and 60% of the forced expiratory volume in one second (FEV1) or peak expiratory flow (PEF). "Moderate to severe intermittent asthma" or "moderate to severe intermittent bronchial asthma," or their allergic form, is defined as having symptoms that fall between those of moderate intermittent asthma / moderate intermittent bronchial asthma and severe intermittent asthma / severe intermittent asthma. "Moderate to severe persistent asthma" or "moderate to severe persistent bronchial asthma," or their allergic form, is defined as having symptoms that fall between those of moderate persistent asthma / moderate persistent bronchial asthma and severe persistent asthma / severe persistent asthma.

[0333] As used herein, the term “uncontrolled asthma” or its allergic form refers to a patient whose asthma is “poorly controlled” or “uncontrolled” as defined in “Expert Panel Report 3: Guidelines for the Diagnosis and Management of Asthma,” National Heart, Blood and Lung Institute, NIH, Aug. 28, 2007. “Uncontrolled asthma” or its allergic form is defined as having symptoms more than two days per week, one to three nighttime awakenings per week, some limitation of normal activities, use of a short-acting β2 agonist to control symptoms more than two days per week, FEV1 at 60%–80% of predicted and / or personal best, an ATAQ score of 1–2, an ACQ score of 1.5 or higher, and an ACT score of 16–19. “Poorly controlled asthma” or its allergic form is defined as having symptoms throughout the day, waking up four or more times a week at night, extreme limitation of normal activities, using a short-acting β2 agonist several times a day to control symptoms, FEV1 less than 60% of predicted and / or personal best, ATAQ score of 3-4, ACQ score of N / A, and ACT score less than or equal to 15.

[0334] In some implementations, if a subject receives a diagnosis of moderate to severe uncontrolled asthma from a physician, the subject is identified as having "moderate to severe uncontrolled" asthma (e.g., allergic asthma, ABPA-related asthma, moderate to severe asthma, persistent asthma, etc.), said diagnosis based on the Global Initiative for Asthma (GINA) 2009 guidelines and one or more of the following criteria: i) existing treatment with moderate or high doses of ICS / LABA (fluticasone propionate 250 μg twice daily, or an equivalent daily dose of ICS), wherein the subject has been continuously treated with a stable dose of ICS / LABA for more than 1 month prior to administration of a loading dose of an IL-4R antagonist; ii) in iii) FEV1 was 40% to 80% of the predicted normal value before administration of a loaded dose of IL-4R antagonist; iv) ACQ-5 score was greater than or equal to 1.5 before administration of a loaded dose of IL-4R antagonist; iv) reversibility of at least 12% and 200 mL of FEV1 after 200 μg to 400 μg (2 to 4 inhalations) of salbutamol / terbutaline before administration of a loaded dose of IL-4R antagonist; or v) any of the following events had occurred within 1 year prior to administration of a loaded dose of IL-4R antagonist: (a) treatment with greater than or equal to one systemic (oral or parenteral) steroid pulse due to asthma exacerbation; (b) hospitalization or visit to the emergency department / urgent medical care due to asthma exacerbation.

[0335] “Severe asthma” or “severe allergic asthma” refers to asthma that cannot be adequately controlled by high-dose treatment with inhaled corticosteroids and other controllers (e.g., long-acting inhaled β2 agonists, montelukast, and / or theophylline) or by oral corticosteroid treatment (e.g., for at least six months per year), or that is lost when treatment is reduced. In some embodiments, severe asthma includes asthma treated with high-dose ICS and at least one additional controller (e.g., LABA, montelukast, or theophylline) or oral corticosteroids for >6 months / year, wherein at least one of the following occurs or will occur if treatment is reduced: ACT <20 or ACQ >1.5; at least two exacerbations in the last 12 months; at least one exacerbation requiring hospitalization or mechanical ventilation in the last 12 months; or FEV1 <80% (if FEV1 / FVC is below the lower limit of normal).

[0336] "Steroid-dependent asthma" or "steroid-dependent allergic asthma" refers to asthma that requires one or more of the following treatments: frequent, short-term oral corticosteroid pulse therapy over the past 12 months; regular use of high-dose inhaled corticosteroids over the past 12 months; regular use of injectable long-acting corticosteroids; daily use of oral corticosteroids; every other day oral corticosteroids; or long-term use of oral corticosteroids over the past year.

[0337] "Oral corticosteroid-dependent asthma" or "oral corticosteroid-dependent allergic asthma" refers to a subject who has had ≥3 30-day oral corticosteroid (OCS) fillers within a 12-month period and has been diagnosed with primary asthma within 12 months of the first OCS filler. Subjects with OCS-dependent asthma may also experience one or any combination of the following: having received physician-prescribed LABA and high-dose ICS (total daily dose >500 μg fluticasone propionate dry powder equivalent) for at least 3 months (ICS and LABA may be part of a combination product or administered via a separate inhaler); having received additional maintenance asthma control medications according to standard of care, such as leukotriene receptor antagonists (LTRAs), theophylline, long-acting muscarinic antagonists (LAMAs), secondary ICS, and cromosin. nes; have received OCS (prednisone or prednisone equivalent) at doses between ≥7.5 and ≤30 mg to treat asthma; have received every other day doses of OCS (or different doses every other day); FEV1 <80% of predicted normal before morning bronchodilator (BD); have signs of asthma, such as reversibility of ≥12% and ≥200 mL (15-30 min after 4 doses of salbutamol / terbutaline) after BD via FEV1; or have a history of at least one asthma exacerbation within the past 12 months.

[0338] In one aspect, a method for treating asthma is provided, comprising: (a) selecting a patient exhibiting a blood eosinophil level of at least 300 cells / µL; and (b) administering to the patient a pharmaceutical composition comprising an IL-4R antagonist.

[0339] On the other hand, methods for treating asthma are provided, comprising: (a) selecting patients exhibiting a blood eosinophil level of 200-299 cells / µL; and (b) administering to the patient a pharmaceutical composition comprising an IL-4R antagonist.

[0340] On the other hand, methods for treating asthma are provided, comprising: (a) selecting patients exhibiting blood eosinophil levels of less than 200 cells / µL; and (b) administering to the patients a pharmaceutical composition comprising an IL-4R antagonist.

[0341] In one aspect, a method for treating asthma is provided, comprising: (a) selecting a patient exhibiting a blood eosinophil level of at least 150 cells / µL; and (b) administering to the patient a pharmaceutical composition comprising an IL-4R antagonist.

[0342] In one aspect, a method for treating asthma is provided, comprising: (a) selecting a patient exhibiting a blood eosinophil level of at least 300 cells / µL; and (b) administering to the patient a pharmaceutical composition comprising an IL-4R antagonist.

[0343] In one aspect, a method for treating asthma is provided, comprising: (a) selecting a patient exhibiting a baseline FeNO level of ≥20 ppb; and (b) administering to the patient a pharmaceutical composition comprising an IL-4R antagonist.

[0344] In one aspect, a method for treating asthma is provided, comprising: (a) selecting a patient exhibiting a baseline FeNO level of ≥25 ppb; and (b) administering to the patient a pharmaceutical composition comprising an IL-4R antagonist.

[0345] In one aspect, a method for treating asthma is provided, comprising: (a) selecting a patient exhibiting a baseline FeNO level of ≥50 ppb; and (b) administering to the patient a pharmaceutical composition comprising an IL-4R antagonist.

[0346] In one aspect, a method for treating asthma is provided, comprising: (a) selecting a patient exhibiting a baseline total IgE level of ≥30 IU / mL; and (b) administering to the patient a pharmaceutical composition comprising an IL-4R antagonist.

[0347] In one aspect, a method for treating asthma is provided, comprising: (a) selecting a patient exhibiting a baseline total IgE level of ≥700 IU / mL; and (b) administering to the patient a pharmaceutical composition comprising an IL-4R antagonist.

[0348] In one aspect, a method for treating asthma is provided, comprising: (a) selecting a patient exhibiting a baseline total IgE level of ≥1000 IU / mL; and (b) administering to the patient a pharmaceutical composition comprising an IL-4R antagonist.

[0349] In one aspect, a method for treating asthma is provided, comprising: (a) selecting a patient exhibiting a baseline allergen-specific IgE level of ≥0.15 kU / L; and (b) administering to the patient a pharmaceutical composition comprising an IL-4R antagonist.

[0350] In one aspect, a method for treating asthma is provided, comprising: (a) selecting a patient exhibiting a baseline allergen-specific IgE level of ≥0.35 kU / L; and (b) administering to the patient a pharmaceutical composition comprising an IL-4R antagonist.

[0351] In related aspects, methods for treating asthma are provided that include add-on therapy to background therapy. In some embodiments, an IL-4R antagonist is administered as add-on therapy to an asthma patient receiving background therapy for a period of time (e.g., 1 week, 2 weeks, 3 weeks, 1 month, 2 months, 5 months, 12 months, 18 months, 24 months, or longer) (also referred to as the "stable phase"). In some embodiments, background therapy includes ICS and / or LABA.

[0352] In some implementations, methods are provided for reducing dependence in asthmatic patients on ICS and / or LABA for treating one or more asthma exacerbations, the methods comprising: (a) selecting a patient with moderate to severe asthma that is not controlled by background asthma therapy including ICS, LABA, or combinations thereof; and administering to the patient a pharmaceutical composition comprising an IL-4R antagonist.

[0353] In some implementations, methods are provided for treating or alleviating conditions or complications associated with or having asthma, such as chronic sinusitis, allergic rhinitis, allergic fungal rhinitis, chronic sinusitis, allergic bronchopulmonary aspergillosis (ABPA), uniform airway disease, eosinophilic granulomatosis with polyangiitis (EGPA, formerly known as Churg-Strauss syndrome), gastroesophageal reflux disease (GERD), atopic conjunctivitis, atopic dermatitis, vasculitis, cystic fibrosis (CF), chronic obstructive pulmonary disease (COPD), chronic eosinophilic pneumonia (CEP), and exercise-induced bronchospasm.

[0354] Methods for treating persistent asthma (e.g., persistent allergic asthma) are also provided. As used herein, the term “persistent asthma” means that a subject has symptoms at least once a week during the day and / or at night, with symptoms lasting from several hours to several days. In some alternative implementations, persistent asthma is “mildly persistent” (e.g., more than twice a week but less than once a day, with symptoms severe enough to interfere with daily activities or sleep and / or in which lung function is normal or reversible by inhaled bronchodilators), “moderately persistent” (e.g., symptoms occur daily, interrupting sleep at least once a week and / or with moderately abnormal lung function), or “severely persistent” (e.g., symptoms persist despite proper use of approved medications and / or in which lung function is severely affected).

[0355] Interleukin-4 receptor antagonists

[0356] The methods characterized herein include administering a therapeutic composition comprising an IL-4R antagonist to a subject in need. As used herein, an “IL-4R antagonist” is any agent that binds to or interacts with IL-4R and inhibits the normal biological signaling function of IL-4R when IL-4R is expressed on cells in vitro or in vivo. Non-limiting examples of classes of IL-4R antagonists include small molecule IL-4R antagonists, anti-IL-4R aptamers, peptide-based IL-4R antagonists (e.g., “peptide body” molecules), and antibodies or antigen-binding fragments of antibodies that specifically bind to human IL-4R. According to certain embodiments, IL-4R antagonists comprise anti-IL-4R antibodies that may be used in the context of methods described elsewhere herein. For example, in one embodiment, the IL-4R antagonist is an antibody that specifically binds to IL-4R or an antigen-binding fragment thereof, and comprises heavy chain and light chain (complementarity-determining region) CDR sequences from the heavy chain variable region (HCVR) and light chain variable region (LCVR) of SEQ ID NO: 1 and 2, respectively.

[0357] The term "human IL4R (hIL-4R)" refers to human cytokine receptors, such as IL-4Rα, that specifically bind to interleukin-4 (IL-4).

[0358] The term "antibody" refers to an immunoglobulin molecule comprising four polypeptide chains linked by disulfide bonds—two heavy (H) chains and two light (L) chains—as well as its polymers (e.g., IgM). Each heavy chain contains a heavy chain variable region (abbreviated herein as HCVR or V). H The heavy-chain constant region contains three structural domains, C H 1. C H 2 and C H 3. Each light chain contains a light chain variable region (abbreviated as LCVR or V in this article).L The light chain constant region contains a structural domain (C) and a light chain constant region. L 1). V H and V L The region can be further subdivided into highly variable regions, called complementary determinant regions (CDRs), and more conservative regions, called framing regions (FRs). Each V H and V L It consists of three CDRs and four FRs, arranged in the following order from the amino terminus to the carboxyl terminus: FR1, CDR1, FR2, CDR2, FR3, CDR3, FR4. In different embodiments, the FRs of the anti-IL-4R antibody or its antigen-binding portion may be identical to the human germline sequence, or may be natural or artificially modified. The common amino acid sequence can be defined based on the side-by-side analysis of two or more CDRs.

[0359] The term "antibody" also includes the antigen-binding fragment of the complete antibody molecule. As used herein, the terms "antigen-binding portion" of an antibody, "antigen-binding fragment" of an antibody, etc., include any naturally occurring, enzymatically obtainable, synthetic, or genetically engineered polypeptide or glycoprotein that specifically binds to an antigen to form a complex. The antigen-binding fragment of an antibody can be derived from the complete antibody molecule using any suitable standard technique, such as proteolytic digestion or recombinant genetic engineering techniques involving the manipulation and expression of DNA encoding variable and optional constant domains of the antibody. This DNA is known and / or readily available from, for example, commercial sources, DNA libraries (including, for example, phage-antibody libraries), or can be synthesized. The DNA can be sequenced and manipulated chemically or using molecular biology techniques, for example, to arrange one or more variable and / or constant domains into a suitable conformation, or to introduce codons, generate cysteine ​​residues, modify, add amino acids, or delete them, etc.

[0360] Non-limiting examples of antigen-binding fragments include: (i) Fab fragments; (ii) F(ab')2 fragments; (iii) Fd fragments; (iv) Fv fragments; (v) single-chain Fv (scFv) molecules; (vi) dAb fragments; and (vii) the smallest recognition unit consisting of amino acid residues mimicking the hypervariable region of an antibody (e.g., a separated complementarity-determining region (CDR), such as a CDR3 peptide), or a restricted FR3-CDR3-FR4 peptide. Other engineered molecules, such as domain-specific antibodies, single-domain antibodies, domain-deficient antibodies, chimeric antibodies, CDR-grafted antibodies, biantibodies, triantibodies, tetraantibodies, microantibodies, nanobodies (e.g., monovalent nanobodies, bivalent nanobodies, etc.), small modular immunopharmaceuticals (SMIPs), and shark variable IgNAR domains, are also included in the description “antigen-binding fragments”.

[0361] Antibody antigen-binding fragments typically contain at least one variable domain. Variable domains can have any size or amino acid composition and will generally contain at least one CDR adjacent to or in the same frame as one or more frame sequences. Within this CDR, V... H Domain and V L In antigen-binding fragments associated with structural domains, V H Domain and V L Domains can be positioned relative to each other in any suitable arrangement. For example, variable regions can be dimers and contain V. H -V H V H -V L or V L -V dimer. Alternatively, the antigen-binding fragment of the antibody may contain monomeric V. H or V L Structural domain.

[0362] In some embodiments, the antigen-binding fragment of the antibody may contain at least one variable domain covalently linked to at least one constant domain. Non-limiting exemplary configurations of the variable and constant domains that may be found in the antigen-binding fragment of the antibody described herein include: (i) V H -C H 1; (ii)V H -C H 2; (iii)V H -C H 3; (iv)V H -C H 1-C H 2; (v)V H -C H 1-C H 2-C H 3;(vi)V H -C H 2-C H 3;(vii)V H -C L (viii)V L -C H 1; (ix)V L -C H 2; (x)V L -C H 3;(xi)V L -C H 1-C H 2;(xii)V L -C H 1-C H 2-C H 3; (xiii)V L -CH 2-C H 3; and (xiv)V L -C L In any configuration of the variable and constant domains, including any of the exemplary configurations listed above, the variable and constant domains may be directly connected to each other or may be connected via complete or partial hinge or linker regions. The hinge region may consist of at least two (e.g., 5, 10, 15, 20, 40, 60, or more) amino acids, resulting in a flexible or semi-flexible connection between adjacent variable and / or constant domains in a single polypeptide molecule. Typically, the hinge region may consist of 2 to 60 amino acids, typically 5 to 50, or typically 10 to 40 amino acids. Furthermore, the antigen-binding fragment of the antibody described herein may comprise a homodimer or heterodimer (or other multimer) of any of the variable and constant domain configurations listed above, non-covalently associated with each other and / or with one or more monomers V. H or V L Non-covalent association of structural domains (e.g., via one or more disulfide bonds).

[0363] Just like complete antibody molecules, antigen-binding fragments can be monospecific or multispecific (e.g., bispecific). Multispecific antigen-binding fragments of antibodies will typically contain at least two distinct variable domains, each capable of specifically binding to a single antigen or different epitopes on the same antigen. Using conventional techniques available in the art, any form of multispecific antibody can be applied in the context of the antigen-binding fragments of the antibodies described herein.

[0364] The constant region of an antibody is important in its ability to fix complement and mediate cell-dependent cytotoxicity. Therefore, antibody isotypes can be selected based on whether they are ideal for mediating cytotoxicity.

[0365] The term "human antibody" includes antibodies having variable and constant regions derived from human germline immunoglobulin sequences. Nevertheless, human antibodies described herein may include amino acid residues not encoded by human germline immunoglobulin sequences (e.g., mutations introduced through random or site-specific mutagenesis in vitro or through somatic mutations in vivo), such as in CDRs, and particularly in CDR3. However, the term "human antibody" does not include antibodies in which a germline CDR sequence derived from another mammalian species (such as a mouse) has been grafted onto a human frame sequence.

[0366] The term "recombinant human antibody" includes all human antibodies prepared, expressed, generated, or isolated by recombinant means, such as antibodies expressed using a recombinant expression vector transfected into host cells (described further below), antibodies isolated from a recombinant combined human antibody library (described further below), antibodies isolated from animals (e.g., mice) that are transgenic against human immunoglobulin genes (see, for example, Taylor et al. (1992) Nucl. Acids Res. 20:6287-6295), or antibodies prepared, expressed, generated, or isolated by any other means involving splicing human immunoglobulin gene sequences into other DNA sequences. Such recombinant human antibodies have variable and constant regions derived from human germline immunoglobulin sequences. However, in some embodiments, such recombinant human antibodies are mutagenized in vitro (or, when using animals transgenic against human Ig sequences, in vivo somatic cell mutagenization) and thus the V of the recombinant antibody... H and V L The amino acid sequence of the region is as follows, derived from human lineage V. H and V L When a sequence is associated with a certain sequence, that sequence may not be naturally present in the human antibody germline library.

[0367] Human antibodies can exist in two forms associated with hinge heterogeneity. In one form, the immunoglobulin molecule comprises a stable four-chain construct of approximately 150–160 kDa, where the dimers are held together by interchain heavy-chain disulfide bonds. In the second form, the dimers are not linked by interchain disulfide bonds and form a molecule of approximately 75–80 kDa, consisting of covalently coupled light and heavy chains (half-antibodies). These forms are extremely difficult to separate, even after affinity purification.

[0368] The frequency of the second form in each intact IgG isotype is attributable to, but not limited to, structural differences associated with the hinge region isotype of the antibody. A single amino acid substitution in the hinge region of the human IgG4 hinge can significantly reduce the occurrence rate of the second form (Angal et al. (1993) Molecular Immunology 30:105) to levels typically observed using the human IgG1 hinge. [The remaining text appears to be incomplete and requires further context.] H 2 or C H An antibody with one or more mutations in region 3, said one or more mutations may be desirable, for example, in production, to improve the yield of the desired antibody form.

[0369] "Isolated antibody" means an antibody that has been identified, isolated, and / or recovered from at least one component of its natural environment. For example, an antibody that has been isolated or removed from at least one component of an organism, or from tissues or cells in which antibodies are naturally present or produced, is an "isolated antibody." Isolated antibodies also include in situ antibodies within recombinant cells. An isolated antibody is an antibody that has undergone at least one purification or isolation step. According to certain embodiments, isolated antibodies may be substantially free of other cellular material and / or chemicals.

[0370] The term "specific binding" refers to the formation of a relatively stable complex between an antibody or its antigen-binding fragment and the antigen under physiological conditions. Methods for determining whether an antibody specifically binds to an antigen are well known in the art and include, for example, equilibrium dialysis and surface plasmon resonance. For example, antibodies that "specifically bind" IL-4R include those with the following K... D Antibodies or portions thereof that bind IL-4R (as measured in surface plasmon resonance assays) are less than about 1000 nM, less than about 500 nM, less than about 300 nM, less than about 200 nM, less than about 100 nM, less than about 90 nM, less than about 80 nM, less than about 70 nM, less than about 60 nM, less than about 50 nM, less than about 40 nM, less than about 30 nM, less than about 20 nM, less than about 10 nM, less than about 5 nM, less than about 4 nM, less than about 3 nM, less than about 2 nM, less than about 1 nM, or less than about 0.5 nM. However, isolated antibodies that specifically bind human IL-4R may exhibit cross-reactivity with other antigens, such as IL-4R molecules from other (non-human) species.

[0371] Compared to the corresponding germline sequence of the derived antibody, the anti-IL-4R antibody that can be used in the method may contain one or more amino acid substitutions, insertions, and / or deletions (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 substitutions and / or 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 insertions and / or 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 deletions) in the frame region and / or CDR region of the variable domains of the heavy and light chains. Such mutations can be readily identified by comparing the amino acid sequences disclosed herein with germline sequences available from, for example, public antibody sequence databases. Methods involving the use of antibodies and antigen-binding fragments thereof, said antibodies and antigen-binding fragments derived from any amino acid sequence disclosed herein, wherein one or more frame regions and / or one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 for tetrameric antibodies, and 1, 2, 3, 4, 5, or 6 for HCVR and LCVR of the antibody) CDR regions are mutated to one or more corresponding residues of a germline sequence derived from said antibody, or one or more corresponding residues of another human germline sequence, or conserved amino acid substitutions of said one or more corresponding germline residues (such sequence changes are collectively referred to herein as “germline mutations”). Starting with the heavy chain and light chain variable region sequences disclosed herein, those skilled in the art can readily generate numerous antibody and antigen-binding fragments comprising one or more individual germline mutations or combinations thereof. In some embodiments, V H and / or V LAll frame and / or CDR residues within the domain are mutated back to residues found in the original germline sequence from which the antibody was derived. In other embodiments, only certain residues are mutated back to the original germline sequence, for example, mutated residues found only in the first 8 amino acids of FR1 or the last 8 amino acids of FR4, or mutated residues found only in CDR1, CDR2, or CDR3. In other embodiments, one or more frame and / or CDR residues are mutated to one or more corresponding residues of a different germline sequence (i.e., a germline sequence different from the germline sequence from which the antibody was originally derived). Furthermore, the antibody may contain any combination of two or more germline mutations within the frame and / or CDR region, for example, where certain individual residues are mutated to corresponding residues of a specific germline sequence, while retaining or mutating certain other residues different from the original germline sequence to corresponding residues of a different germline sequence. Once obtained, antibody-antigen binding fragments containing one or more germline mutations can be readily tested for one or more desired properties, such as improved binding specificity, increased binding affinity, improved or enhanced antagonistic or agonistic biological properties (as the case may be), reduced immunogenicity, etc. This invention covers the use of antibody-antigen binding fragments obtained in this general manner.

[0372] The method involves using an anti-IL-4R antibody comprising a variant of any HCVR, LCVR, and / or CDR amino acid sequence disclosed herein with one or more conserved substitutions. For example, the use of an anti-IL-4R antibody having an HCVR, LCVR, and / or CDR amino acid sequence is provided, wherein the antibody has, for example, 10 or fewer, 8 or fewer, 6 or fewer, 4 or fewer conserved amino acid substitutions relative to any HCVR, LCVR, and / or CDR amino acid sequence disclosed herein.

[0373] The term "surface plasmon resonance" refers to an optical phenomenon that allows light to pass through the surface of a surface through a plasmon resonance, for example, using BIAcore. TM The system (Biacore Life Sciences division of GE Healthcare, Piscataway, NJ) analyzes real-time interactions by detecting changes in protein concentrations within a biosensor matrix.

[0374] The term "K" D "" refers to the equilibrium dissociation constant of a specific antibody-antigen interaction.

[0375] The term "epitope" refers to an antigenic determinant that interacts with a specific antigen-binding site called a complementary site in the variable region of an antibody molecule. A single antigen can have more than one epitope. Therefore, different antibodies can bind to different regions on the antigen and can have different biological effects. Epitopes can be conformational or linear. Conformational epitopes are generated by spatially juxtaposed amino acids from different segments of a linear polypeptide chain. Linear epitopes are generated from adjacent amino acid residues in the polypeptide chain. In some cases, an epitope may include portions of a sugar, phosphoryl group, or sulfonyl group on the antigen.

[0376] Preparation of human antibodies

[0377] Methods for generating human antibodies in transgenic mice are known in the art. Any such known method can be used to prepare human antibodies that specifically bind to human IL-4R.

[0378] use The technique (see, for example, US 6,596,541, Regeneron Pharmaceuticals) or any other known method for generating monoclonal antibodies initially isolates a high-affinity chimeric antibody against IL-4R having a human variable region and a mouse constant region. The technology involves generating transgenic mice with a genome containing human heavy and light chain variable regions operatively linked to endogenous mouse constant region loci, such that the mice produce antibodies containing both human variable regions and mouse constant regions in response to antigen stimulation. DNA encoding the antibody heavy and light chain variable regions is isolated and operatively linked to DNA encoding the human heavy and light chain constant regions. The DNA is then expressed in cells capable of expressing fully human antibodies.

[0379] Typically, stimulation is performed using an antigen of interest. Mice are used, and lymphocytes (such as B cells) are recovered from mice expressing antibodies. Lymphocytes can be fused with myeloma cell lines to prepare immortalized hybridoma cell lines, and these hybridoma cell lines can be screened and selected to identify hybridoma cell lines that produce antibodies specific to the antigen of interest. DNA encoding the variable regions of the heavy and light chains can be isolated and linked to desired isotype constant regions of the heavy and light chains. This antibody protein can be produced in cells such as CHO cells. Alternatively, DNA encoding antigen-specific chimeric antibodies or variable domains of the light and heavy chains can be directly isolated from antigen-specific lymphocytes.

[0380] First, a high-affinity chimeric antibody containing a human variable region and a mouse constant region is isolated. Desired characteristics of the antibody, including affinity, selectivity, epitopes, etc., are characterized and selected using standard procedures known to those skilled in the art. The mouse constant region is replaced with the desired human constant region to generate the fully human antibody described herein, such as wild-type or modified IgG1 or IgG4. While the selected constant region may vary depending on the specific application, the variable region possesses characteristics of high-affinity antigen binding and target specificity.

[0381] Typically, antibodies used in the methods described above have high affinity when measured by binding to antigens immobilized on a solid phase or in a solution phase. The mouse constant region is replaced with the desired human constant region to generate the fully human antibody described herein. While the selected constant region may vary depending on the specific application, high-affinity antigen binding and target-specific characteristics exist in the variable region.

[0382] In one embodiment, a human antibody or antigen-binding fragment thereof that specifically binds to IL-4R and can be used in the context of the methods described herein comprises three heavy chain CDRs (HCDR1, HCDR2, and HCDR3) contained within a heavy chain variable region (HCVR) having the amino acid sequence of SEQ ID NO:1. The antibody or antigen-binding fragment may comprise three CDRs (LCVR1, LCVR2, and LCVR3) contained within a light chain variable region (LCVR) having the amino acid sequence of SEQ ID NO:2. Methods and techniques for identifying CDRs within HCVRs and LCVRs are well known in the art and can be used to identify CDRs within the specified HCVR and / or LCVR amino acid sequences disclosed herein. Exemplary rules that can be used to identify CDR boundaries include, for example, the Kabat definition, the Chothia definition, and the AbM definition. Generally, the Kabat definition is based on sequence variability, the Chothia definition is based on the location of structural loop regions, and the AbM definition is a compromise between the Kabat and Chothia methods. See, for example, Kabat, “Sequences of Proteins of Immunological Interest,” National Institutes of Health, Bethesda, Md. (1991); Al-Lazikani et al., J. Mol. Biol. 273:927-948 (1997); and Martin et al., Proc. Natl. Acad. Sci. USA 86:9268-9272 (1989). Public databases are also available for identifying CDR sequences within antibodies.

[0383] In some embodiments, the antibody or its antigen-binding fragment comprises six CDRs (HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3) of the heavy and light chain variable region amino acid sequence pairs (HCVR / LCVR) from SEQ ID NO:1 and 2.

[0384] In some embodiments, the antibody or its antigen-binding fragment comprises six CDRs (HCDR1 / HCDR2 / HCDR3 / LCDR1 / LCDR2 / LCDR3) having the amino acid sequence SEQ ID NO:3 / 4 / 5 / 6 / 7 / 8.

[0385] In some embodiments, the antibody or its antigen-binding fragment comprises the HCVR / LCVR amino acid sequence pair of SEQ ID NO:1 and 2.

[0386] In some implementations, the antibody is dupilumab, which contains the HCVR / LCVR amino acid sequence pair of SEQ ID NO:1 and 2.

[0387] In some embodiments, the antibody sequence is dupilumab, which contains the heavy chain / light chain amino acid sequence pairs of SEQ ID NO:9 and 10.

[0388] Dupilumab HCVR amino acid sequence:

[0389] EVQLVESGGGLEQPGGSLRLSCAGSGFTFRDYAMTWVRQAPGKGLEWVSSISGSGGNTYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAKDRLSITIRPRYYGLDVWGQGTTVTVS (SEQ ID NO: 1).

[0390] Dupilumab LCVR amino acid sequence:

[0391] DIVMTQSPLSLPVTPGEPASISCRSSQSLLYSIGYNYLDWYLQKSGQSPQLLIYLGSNRASGVPDRFSGSGSGTDFTLKISRVEAEDVGFYYCMQALQTPYTFGQGTKLEIK (SEQ ID NO: 2).

[0392] Dupilumab HCDR1 amino acid sequence:

[0393] GFTFRDYA (SEQ ID NO:3).

[0394] Dupilumab HCDR2 amino acid sequence:

[0395] ISGSGGNT (SEQ ID NO:4).

[0396] Dupilumab HCDR3 amino acid sequence:

[0397] AKDRLSITIRPRYYGL (SEQ ID NO:5).

[0398] Dupilumab LCDR1 amino acid sequence:

[0399] QSLLYSIGYNY (SEQ ID NO:6).

[0400] Dupilumab LCDR2 amino acid sequence:

[0401] LGS (SEQ ID NO:7).

[0402] Dupilumab LCDR3 amino acid sequence:

[0403] MQALQTPYT (SEQ ID NO:8).

[0404] Dupilumab HC amino acid sequence:

[0405] EVQLVESGGGLEQPGGSLRLSCAGSGFTFRDYAMTWVRQAPGKGLEWVSSISGSGGNTYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAKDRLSITIRPRYYGLDVWGQGTTVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLG (SEQ ID NO:9) (amino acids 1 - 124 = HCVR; amino acids 125 - 451 = HC constant).

[0406] Dupilumab LC amino acid sequence:

[0407] DIVMTQSPLSLPVTPGEPASISCRSSQSLLYSIGYNYLDWYLQKSGQSPQLLIYLGSNRASGVPDRFSGSGSGTDFTLKISRVEAEDVGFYYCMQALQTPYTFGQGTKLEI KRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC(SEQ ID NO: 10) (Amino acids 1-112 = LCVR; Amino acids 112-219 = LC constant).

[0408] Pharmaceutical Composition

[0409] A method is provided that involves administering an IL-4R antagonist to a patient, wherein the IL-4R antagonist is contained in a pharmaceutical composition. The pharmaceutical compositions described herein are formulated with suitable carriers, excipients, and other agents that provide suitable transfer, delivery, tolerability, etc. Many suitable formulations can be found in formulations known to all medicinal chemists: Remington's Pharmaceutical Sciences, Mack Publishing Company, Easton, PA. These formulations include, for example, powders, pastes, ointments, gels, waxes, oils, lipids, and lipid-containing vesicles (such as LIPOFECTIN). TM DNA conjugates, anhydrous absorbent pastes, oil-in-water and water-in-oil emulsions, carbowax emulsions (polyethylene glycol with different molecular weights), semi-solid gels, and semi-solid mixtures containing carbowax. See also Powell et al., “Compendium of excipients for parenteral formulations”, PDA (1998), JPharm Sci Technol. 52:238-311.

[0410] The dosage of antibodies administered to a patient can vary depending on the patient's age and physique, symptoms, condition, route of administration, etc. Typically, the dosage is calculated based on body weight or body surface area. The frequency and duration of treatment can be adjusted according to the severity of the condition. Effective dosages and schedules for administering pharmaceutical compositions containing anti-IL-4R antibodies can be determined empirically; for example, patient progression can be monitored through regular assessments, and dosages adjusted accordingly. Furthermore, interspecies analogies of dosages can be performed using methods well-known in the art (e.g., Mordenti et al., 1991, Pharmaceut. Res. 8:1351).

[0411] Various delivery systems are known and can be used to administer the pharmaceutical compositions described herein, such as encapsulation in liposomes, microparticles, microcapsules, recombinant cells capable of expressing mutant viruses, and receptor-mediated endocytosis (see, for example, Wu et al., 1987, J. Biol. Chem. 262:4429-4432). Administration methods include, but are not limited to, intradermal, intramuscular, intraperitoneal, intravenous, subcutaneous, intranasal, intratracheal, epidural, and oral routes. The compositions can be administered via any convenient route, such as by infusion or rapid injection, by absorption through the epithelial or mucosal lining of the skin (e.g., oral mucosa, rectal and intestinal mucosa), and can be administered together with other bioactive agents.

[0412] The pharmaceutical compositions described herein can be delivered subcutaneously or intravenously using standard needles and syringes. Alternatively, for subcutaneous delivery, pen-type delivery devices (e.g., auto-injector pens) can be conveniently used to deliver the pharmaceutical compositions described herein. Such pen-type delivery devices can be reusable or disposable. Reusable pen-type delivery devices typically utilize a replaceable cartridge containing the pharmaceutical composition. Once all the pharmaceutical composition in the cartridge has been administered and the cartridge is empty, the empty cartridge can be easily discarded and replaced with a new cartridge containing the pharmaceutical composition. The pen-type delivery device can then be reused. In disposable pen-type delivery devices, there is no replaceable cartridge. Instead, the disposable pen-type delivery device is pre-loaded with the pharmaceutical composition held in a reservoir within the device. Once the reservoir is emptied of the pharmaceutical composition, the entire device is discarded.

[0413] Many reusable pen-based and automated injection delivery devices have been used for the subcutaneous delivery of pharmaceutical compositions. Examples include, but are not limited to, AUTOPEN. TM (Owen Mumford, Inc., Woodstock, UK), DISETRONIC TM Pen (Disetronic Medical Systems, Bodolf, Switzerland), HUMALOG MIX 75 / 25 TM Pen, HUMALOG TM Pen, HUMALIN 70 / 30 TM Pen (Eli Lilly and Co., Indianapolis, Indiana), NOVOPEN TM I, II, and III (Novo Nordisk, Copenhagen, Denmark), NOVOPEN JUNIOR TM (Novo Nordisk, Copenhagen, Denmark), BD TMPen (Becton Dickinson, Franklin Lake, New Jersey), OPTIPEN TM OPTIPEN PRO TM OPTIPEN STARLET TM And OPTICLIK TM (Sanofi-Aventis, Frankfurt, Germany), to name just a few. Examples of disposable pen-type delivery devices for subcutaneous delivery of the pharmaceutical compositions described herein include, but are not limited to, SOLOSTAR. TM Pen (Sanofi-Aventis), FLEXPEN TM (Novo Nordisk) and KWIKPEN TM (Eli Lilly), SURECLICK TM Automatic injectors (Amgen, Thousand Oaks, CA), PENLET TM (Haselmeier, Stuttgart, Germany), EPIPEN (Dey, LP) and HUMIRA TM Pens (Abbott Labs, Abbott Park IL) are just a few examples. Examples of large-volume delivery devices (e.g., large-volume syringes) include, but are not limited to, rapid injectors such as BD Libertas WestSmartDose, Enable Injections, SteadyMed PatchPump, Sensile SenseTrial, YPsomedYpsoDose, Bespak Lapas, etc.

[0414] For direct administration to the sinuses, the pharmaceutical compositions described herein can be administered using, for example, microcatheters (e.g., endoscopes and microcatheters), aerosols, powder dispensers, nebulizers, or inhalers. The method involves administering an IL-4R antagonist to a subject in need in the form of a nebulized formulation. For example, an anti-IL-4R nebulized antibody can be administered to treat asthma (e.g., allergic asthma, ABPA-related asthma, moderate to severe asthma, persistent asthma, etc.) and / or ABPA in a patient. The nebulized antibody can be prepared as described, for example, in US 8,178,098 (which is incorporated herein by reference in its entirety).

[0415] In some cases, the pharmaceutical composition can be delivered using a controlled-release system. In one embodiment, a pump can be used (see Langer, ibid.; Sefton, 1987, CRC Crit. Ref. Biomed. Eng. 14:201). In another embodiment, a polymeric material can be used; see Medical Applications of Controlled Release, Langer and Wise (eds.), 1974, CRC Pres., Pocaraton, Florida. In yet another embodiment, the controlled-release system can be placed near the target of the composition, thus requiring only a fraction of the systemic dose (see, for example, Goodson, 1984, Medical Applications of Controlled Release, ibid., Vol. 2, pp. 115-138). Other controlled-release systems are discussed in a review in Langer, 1990, Science 249:1527-1533.

[0416] Injectable formulations may include dosage forms for intravenous, subcutaneous, intradermal, and intramuscular injection, infusion, etc. These injectable formulations can be prepared by known methods. For example, they can be prepared by dissolving, suspending, or emulsifying, for instance, the antibodies or their salts in a sterile aqueous or oily medium commonly used for injection. As an aqueous medium for injection, examples include physiological saline, an isotonic solution containing glucose and other adjuvants, which can be used in combination with suitable solubilizers such as alcohols (e.g., ethanol), polyols (e.g., propylene glycol, polyethylene glycol), and nonionic surfactants (e.g., polysorbate 80, HCO-50 (a polyoxyethylene (50 mol) adduct of hydrogenated castor oil)). As an oily medium, examples include sesame oil and soybean oil, which can be used in combination with solubilizers such as benzyl benzoate, benzyl alcohol, etc. Injectable formulations prepared in this way are typically filled in suitable ampoules.

[0417] Advantageously, the above-described pharmaceutical compositions for oral or parenteral use are prepared into dosage forms suitable for matching the dosage of the active ingredient. Such dosage forms for unit doses include, for example, tablets, pills, capsules, injections (ampoules), suppositories, etc.

[0418] Exemplary pharmaceutical compositions comprising anti-IL-4R antibodies that can be used as described herein are disclosed, for example, in U.S. Patent Application Publication No. 2012 / 0097565.

[0419] dose

[0420] The amount of IL-4R antagonist (e.g., anti-IL-4R antibody) administered to a subject according to the methods described herein is generally a therapeutically effective amount. As used herein, the phrase “therapeutically effective amount” means an amount of IL-4R antagonist that results in one or more of the following: (a) a reduced incidence of asthma exacerbations; (b) improvement in one or more asthma-related parameters (as defined elsewhere herein); and / or (c) a detectable improvement in one or more symptoms or indicators of upper airway inflammation. “Therapeutically effective amount” also includes an amount of IL-4R antagonist that inhibits, prevents, reduces, or delays the progression of asthma in a subject.

[0421] In the case of anti-IL-4R antibodies, the effective therapeutic dose can be from about 0.05 mg to about 700 mg, for example, about 0.05 mg, about 0.1 mg, about 1.0 mg, about 1.5 mg, about 2.0 mg, about 3.0 mg, about 5.0 mg, about 7.0 mg, about 10 mg, about 20 mg, about 30 mg, about 40 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, about 100 mg, about 110 mg, about 120 mg, about 130 mg, about 140 mg, about 150 mg, about 160 mg, about 170 mg, about 180 mg, about 190 mg, about 200 mg, about 210 mg, about 220 mg, about 230 mg, about 240 mg, about 250 mg, about 260 mg, about 270 mg, about 280 mg, about 290 mg, about 300 mg, about 2 ... 0mg, approximately 310mg, approximately 320mg, approximately 330mg, approximately 340mg, approximately 350mg, approximately 360mg, approximately 370mg, approximately 380mg, approximately 390mg, approximately 400mg, approximately 410mg, approximately 420mg, approximately 430mg, approximately 440mg, approximately 450mg, approximately 460mg, approximately 470mg, approximately 480mg, approximately 490mg, approximately 500mg, approximately 5 Anti-IL-4R antibody in doses of 10 mg, approximately 520 mg, approximately 530 mg, approximately 540 mg, approximately 550 mg, approximately 560 mg, approximately 570 mg, approximately 580 mg, approximately 590 mg, approximately 600 mg, approximately 610 mg, approximately 620 mg, approximately 630 mg, approximately 640 mg, approximately 650 mg, approximately 660 mg, approximately 670 mg, approximately 680 mg, approximately 690 mg, or approximately 700 mg. In some embodiments, 300 mg of anti-IL-4R antibody is administered.

[0422] The amount of IL-4R antagonist contained in a single dose can be expressed as milligrams of antibody per kilogram of patient body weight (i.e., mg / kg). For example, the IL-4R antagonist can be administered to a patient at a dose of about 0.0001 to about 10 mg / kg of patient body weight. For example, the IL-4R antagonist can be administered at doses of 1 mg / kg, 2 mg / kg, 3 mg / kg, 4 mg / kg, 5 mg / kg, or 6 mg / kg.

[0423] In some implementations, the dose of the IL-4R antagonist can be varied based on the eosinophil count. For example, a subject may have a blood eosinophil count of ≥300 cells / μL (i.e., high blood eosinophil count) or 300-499 cells / μL or ≥500 cells / μL (HEo); a blood eosinophil count of 200 to 299 cells / μL (intermediate blood eosinophil count); or a blood eosinophil count of <200 cells / μL (low blood eosinophil count).

[0424] In some implementations, the dose of the IL-4R antagonist can be varied based on the FeNO value. For example, the subject may have a FeNO value ≥50 ppb (e.g., high FeNO); a FeNO value ≥25 ppb; a FeNO value between about 25 ppb and about 50 ppb; a FeNO value <50 ppb; a FeNO value <25 ppb (e.g., low FeNO); or a FeNO value <20 ppb (e.g., low FeNO).

[0425] In some implementations, the dose of the IL-4R antagonist can be varied based on the total serum IgE level. For example, a subject may have a total serum IgE level ≥30 IU / mL; a total serum IgE level ≥700 IU / mL (e.g., high serum IgE); or a total serum IgE level ≥1000 IU / mL (e.g., very high serum IgE).

[0426] In some implementations, the dose of the IL-4R antagonist can be varied based on the allergen-specific IgE level. For example, the subject may have an allergen-specific IgE level ≥0.15 kU / L; or an allergen-specific IgE level ≥0.35 kU / L.

[0427] In some embodiments, the method includes a loading dose of about 400 to about 600 mg of an IL-4R antagonist.

[0428] In some embodiments, the method includes one or more maintenance doses of about 200 to about 300 mg of an IL-4R antagonist.

[0429] In some implementations, ICS and LABA are administered throughout the entire course of the IL-4R antagonist treatment.

[0430] In some embodiments, the loading dose comprises 600 mg of an anti-IL-4R antibody or an antigen-binding fragment thereof, and the one or more maintenance doses comprise 300 mg of the antibody or an antigen-binding fragment thereof administered every other week.

[0431] In some embodiments, the loading dose comprises 400 mg of an anti-IL-4R antibody or an antigen-binding fragment thereof, and the one or more maintenance doses comprise 200 mg of the antibody or an antigen-binding fragment thereof administered every other week.

[0432] In some embodiments, the loading dose comprises 400 mg of anti-IL-4R antibody or its antigen-binding fragment, and the one or more maintenance doses comprise 200 mg of the antibody or its antigen-binding fragment administered every other week, which may be increased to 300 mg of the antibody or its antigen-binding fragment administered every other week.

[0433] In other embodiments, the loading dose comprises 600 mg of an anti-IL-4R antibody or an antigen-binding fragment thereof, and the one or more maintenance doses comprise 300 mg of the antibody or an antigen-binding fragment thereof administered every four weeks.

[0434] In other embodiments, the loading dose comprises 400 mg of an anti-IL-4R antibody or an antigen-binding fragment thereof, and the one or more maintenance doses comprise 200 mg of the antibody or an antigen-binding fragment thereof administered every four weeks.

[0435] In other embodiments, the loading dose comprises 600 mg of an anti-IL-4R antibody or an antigen-binding fragment thereof, and the one or more maintenance doses comprise 300 mg of the antibody or an antigen-binding fragment thereof administered once weekly.

[0436] In other embodiments, the loading dose comprises 400 mg of an anti-IL-4R antibody or an antigen-binding fragment thereof, and the one or more maintenance doses comprise 200 mg of the antibody or an antigen-binding fragment thereof administered once weekly.

[0437] In other embodiments, the loading dose comprises 600 mg of an anti-IL-4R antibody or an antigen-binding fragment thereof, and the one or more maintenance doses comprise 300 mg of the antibody or an antigen-binding fragment thereof administered every three weeks.

[0438] In other embodiments, the loading dose comprises 400 mg of an anti-IL-4R antibody or an antigen-binding fragment thereof, and the one or more maintenance doses comprise 200 mg of the antibody or an antigen-binding fragment thereof administered every three weeks.

[0439] In one implementation, the subject was 6 to <18 years old and was administered IL-4R antibody or its antigen-binding fragment at 2 mg / kg or 4 mg / kg.

[0440] In another implementation, the subject was 12 to <18 years old and was administered IL-4R antibody or its antigen-binding fragment at 2 mg / kg or 4 mg / kg.

[0441] In another implementation, the subjects were 6 to <12 years old and were administered IL-4R antibody or its antigen-binding fragment at 2 mg / kg or 4 mg / kg.

[0442] In another implementation, the subjects were 2 to <6 years old and were administered IL-4R antibody or its antigen-binding fragment at 2 mg / kg or 4 mg / kg.

[0443] In yet another implementation, the subject is <2 years old and is administered IL-4R antibody or its antigen-binding fragment at 2 mg / kg or 4 mg / kg.

[0444] Combination therapy

[0445] Some embodiments of the methods described herein include administering one or more additional therapeutic agents in combination with the IL-4R antagonist to a subject. As used herein, the expression "in combination with" means administering an additional therapeutic agent before, after, or simultaneously with a pharmaceutical composition comprising an IL-4R antagonist. In some embodiments, the term "in combination with" includes administering the IL-4R antagonist sequentially or simultaneously with a second therapeutic agent. Methods for treating asthma (e.g., allergic asthma, ABPA-related asthma, moderate to severe asthma, persistent asthma, etc.) or related conditions or complications, or for reducing at least one exacerbation, are provided, said methods comprising administering an IL-4R antagonist in combination with a second therapeutic agent for adjuvant or synergistic activity.

[0446] For example, when administered "before" a pharmaceutical composition containing an IL-4R antagonist, the additional therapeutic agent may be administered approximately 72 hours, approximately 60 hours, approximately 48 hours, approximately 36 hours, approximately 24 hours, approximately 12 hours, approximately 10 hours, approximately 8 hours, approximately 6 hours, approximately 4 hours, approximately 2 hours, approximately 1 hour, approximately 30 minutes, approximately 15 minutes, or approximately 10 minutes before administration of the pharmaceutical composition containing an IL-4R antagonist. When administered "after" a pharmaceutical composition containing an IL-4R antagonist, the additional therapeutic agent may be administered approximately 10 minutes, approximately 15 minutes, approximately 30 minutes, approximately 1 hour, approximately 2 hours, approximately 4 hours, approximately 6 hours, approximately 8 hours, approximately 10 hours, approximately 12 hours, approximately 24 hours, approximately 36 hours, approximately 48 hours, approximately 60 hours, or approximately 72 hours after administration of the pharmaceutical composition containing an IL-4R antagonist. "Simultaneous" administration with a pharmaceutical composition containing an IL-4R antagonist means that the additional therapeutic agent is administered to the subject in a separate dosage form within 5 minutes (before, after, or simultaneously) of administration of the pharmaceutical composition containing an IL-4R antagonist, or as a single-dose combination of the additional therapeutic agent and the IL-4R antagonist.

[0447] Other therapeutic agents may include, for example, another IL-4R antagonist, IL-1 antagonist (including, for example, the IL-1 antagonist proposed in U.S. Patent No. 6,927,044), IL-6 antagonist, IL-6R antagonist (including, for example, the anti-IL-6R antibody proposed in U.S. Patent No. 7,582,298), TNF antagonist, IL-8 antagonist, IL-9 antagonist, IL-17 antagonist, IL-5 antagonist, IgE antagonist, CD48 antagonist, leukotriene inhibitor, antifungal agent, NSAID, long-acting β2 agonist (e.g., salmeterol or formoterol), inhaled corticosteroids (e.g., fluticasone or budesonide), systemic corticosteroids (e.g., oral or intravenous), methylxanthine, sodium nedocromil, sodium cromoglycate, or combinations thereof. For example, in some embodiments, a pharmaceutical composition comprising an IL-4R antagonist is combined with a long-acting β2 agonist and an inhaled corticosteroid (e.g., fluticasone + salmeterol). (GlaxoSmithKline)); or budesonide + formoterol (e.g., (Astra Zeneca))) is used in combination with other herbs.

[0448] In some embodiments, the additional therapeutic agent administered in combination with the IL-4R antagonist is a vaccine. In some exemplary embodiments, the vaccine is a viral vaccine or a bacterial vaccine. In some exemplary embodiments, the vaccine is a live (e.g., live-attenuated) viral vaccine or a live (e.g., live-attenuated) bacterial vaccine.

[0449] Suitable vaccines include, but are not limited to, adenovirus, anthrax (e.g., AVA vaccine (BioThrax)), cholera (e.g., Vaxchora), diphtheria (e.g., DTaP (Daptacel, Infanrix), Td (Tenivac, Universal), DT (Universal), Tdap (Adacel, Boostrix), DTaP-IPV (Kinrix, Quadracel), DTaP-HepB-IPV (Pediarix), DTaP-IPV / Hib (Pentacel)), hepatitis A (e.g., HepA (Havrix, Vaqta), HepA-HepB (Twinrix)), and hepatitis B (e.g., HepB (Engerix-B, Recombivax)). HB, Heplisav-B), DTaP-HepB-IPV (Pediarix), HepA-HepB (Twinrix)), Haemophilus influenzae type b (Hib) (e.g., Hib (ActHIB, PedvaxHIB, Hiberix), DTaP-IPV / Hib (Pentacel)), Human papillomavirus (HPV) (e.g., HPV9 (Gardasil 9)), Influenza (flu) (e.g., IIV (also known as IIV3, IIV4, RIV3, RIV4 and ccIIV4) (Afluria, Fluad, Flublok, Flucelvax, FluLaval, Fluarix, Fluvirin, Fluzone, Fluzone) High-Dose, Fluzone Intradermal, LAIV (FluMist), Japanese encephalitis (e.g., JE (Ixiaro)), measles (e.g., MMR (MM-RII), MMRV (ProQuad)), meningococcal disease (e.g., MenACWY (Menactra, Menveo), MenB (Bexsero, Trumenba)), mumps (e.g., MMR (MMR II), MMRV (ProQuad)), pertussis (e.g., DTaP (Daptacel, Infanrix), Tdap (Adacel, Boostrix), DTaP-IPV (Kinrix, Quadracel), DTaP-HepB-IPV (Pediarix), DTaP-IPV / Hib (Pentacel)), pneumococcal disease (e.g., PCV13 (Prevnar13), PPSV23 (Pneumovax 23)), poliomyelitis (e.g.,Polio (Ipol), DTaP-IPV (Kinrix, Quadracel), DTaP-HepB-IPV (Pediarix), DTaP-IPV / Hib (Pentacel), rabies (e.g., Rabies (ImovaxRabies, RabAvert)), rotavirus (e.g., RV1 (Rotarix), RV5 (RotaTeq)), rubella (e.g., MMR (MMR) II), MMRV (ProQuad)), herpes zoster (e.g., ZVL (Zostavax), RZV (Shingrix)), smallpox (e.g., cowpox (ACAM2000)), tetanus (e.g., DTaP (Daptacel, Infanrix), Td (Tenivac, generic), DT (generic), Tdap (Adacel, Boostrix), DTaP-IPV (Kinrix, Quadracel), DTaP-HepB-IPV (Pediarix), DTaP-IPV / Hib (Pentacel)), tuberculosis, typhoid fever (e.g., oral typhoid vaccine (Vivotif), typhoid polysaccharide vaccine (Typhim Vi)), varicella (e.g., VAR (varicella vaccine), MMRV (ProQuad)), yellow fever (e.g., YF (YF-Vax)), etc. The U.S. Centers for Disease Control and Prevention's vaccine list (cdc.gov / vaccines / vpd / vaccines-list.html), which is included in this article in its entirety for all purposes, also lists suitable vaccines.

[0450] In some implementations, the vaccine is an inactivated vaccine, a recombinant vaccine, a conjugated vaccine, a subunit vaccine, a polysaccharide vaccine, or a toxoid vaccine. In some implementations, the vaccine is a yellow fever vaccine. In some implementations, subjects treated with the vaccine are simultaneously treated with an IL-4R antagonist for type 2 inflammatory disease. In some implementations, subjects treated with the vaccine are simultaneously treated with an IL-4R antagonist for asthma.

[0451] In some implementations, treatment with the IL-4R antagonist is stopped or terminated prior to vaccine treatment. In some implementations, treatment is initiated approximately 1 to 9 weeks prior to vaccine administration (e.g., approximately 1, approximately 1 week prior to administration). 1 / 2, about 2, about 2 1 / 2, about 3, about 3 1 / 2, about 4, about 4 1 / 2, about 5, about 5 1 / 2, about 6, about 6 1 / 2, about 7, about 7 1 / 2, about 8, about 8 1 / 2. Discontinue treatment with IL-4R antagonists approximately 9 weeks or longer. In some implementations, treatment is discontinued approximately 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, and 31 weeks prior to vaccination. Discontinue treatment with IL-4R antagonists around days 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, or 60.

[0452] In some implementations, treatment with an IL-4R antagonist is resumed after vaccination. In some implementations, this is done approximately 1 to approximately 14 weeks after vaccination (e.g., approximately 1, approximately 1...). 1 / 2, about 2, about 2 1 / 2, about 3, about 3 1 / 2, about 4, about 4 1 / 2, about 5, about 5 1 / 2, about 6, about 6 1 / 2, about 7, about 7 1 / 2, about 8, about 8 1 / 2, about 9, about 9 1 / 2, about 10, about 10 1 / 2, about 11, about 11 1 / 2, about 12, about 12 1 / 2, Approximately 13, Approximately 13 1 / 2, Approximately 14, Approximately 14 1Treatment with an IL-4R antagonist was resumed approximately 1 week or longer after vaccination. In some implementations, treatment was resumed approximately 1 week, 2 week, 3 week, 4 week, 5 week, 6 week, 7 week, 8 week, 9 week, 10 week, 11 week, 12 week, 13 week, 14 week, 15 week, 16 week, 17 week, 18 week, 19 week, 20 week, 21 week, 22 week, 23 week, 24 week, 25 week, 26 week, 27 week, 28 week, 29 week, 30 week, 31 week, 32 week, 33 week, 34 week, 35 week, 36 week, 37 week, 38 week, 39 week, 40 week, 41 week, 42 ​​week, 43 week, 44 week, 45 week, and 46 week after vaccination. Treatment with an IL-4R antagonist resumed approximately 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, or 90 days later.

[0453] In some implementations, the effectiveness of the IL-4R antagonist is not reduced by combination with or subsequent administration of the vaccine. In some implementations, the subject's forced expiratory volume (FEV1) remains stable before and after vaccination.

[0454] In some implementations, the effectiveness of the vaccine is not reduced by administration in combination with an IL-4R antagonist or by administration of an IL-4R antagonist first and / or subsequently. In some implementations, when the vaccine is co-administered with an IL-4R antagonist, subjects exhibit protective neutralizing titers in their serum.

[0455] In some exemplary embodiments, the vaccine described herein is administered to the subject, wherein at least one dose of an IL-4R antagonist is administered to the subject before, during, or after the administration of the vaccine.

[0456] In some implementations, the subject receiving the vaccine has a type 2 inflammatory disease. In some exemplary implementations, the type 2 inflammatory disease is one or any combination of the following: asthma, allergic rhinitis, chronic sinusitis, chronic sinusitis with nasal polyps (CRSsNP), eosinophilic esophagitis (EoE), atopic dermatitis (AD), food and environmental allergies, aspirin-induced respiratory disease (AERD), or respiratory disease exacerbated by nonsteroidal anti-inflammatory drugs (NSAIDs).

[0457] Application plan

[0458] According to certain implementations, multiple doses of an IL-4R antagonist can be administered to a subject over a defined time period. Such methods involve sequentially administering multiple doses of an IL-4R antagonist to a subject. As used herein, “sequentially administering” means administering each dose of the IL-4R antagonist to the subject at different time points, for example, on different dates spaced apart by predetermined intervals (e.g., hours, days, weeks, or months). Methods are provided that involve sequentially administering a single initial dose of an IL-4R antagonist to a patient, followed by one or more secondary doses of the IL-4R antagonist, and optionally subsequently administering one or more tertiary doses of the IL-4R antagonist.

[0459] A method is provided comprising administering a pharmaceutical composition containing an IL-4R antagonist to a subject at the following frequencies: approximately four times a week, twice a week, once a week (q1w), once every two weeks (interchangeable with once every other week, once every two weeks, or q2w), once every three weeks (every three weeks or q3w), once every four weeks (monthly or q4w), once every five weeks (q5w), once every six weeks (q6w), once every eight weeks (q8w), once every twelve weeks (q12w), or lower, as long as a therapeutic response is achieved. In some embodiments involving the administration of a pharmaceutical composition containing an anti-IL-4R antibody, once-weekly administration may be performed in doses of approximately 75 mg, 100 mg, 150 mg, 200 mg, or 300 mg. In other embodiments involving the administration of a pharmaceutical composition comprising an anti-IL-4R antibody, the drug may be administered once every two weeks (every two weeks is interchangeable with every other week, every two weeks, or q2w) in doses of about 75 mg, 100 mg, 150 mg, 200 mg, or 300 mg. In other embodiments involving the administration of a pharmaceutical composition comprising an anti-IL-4R antibody, the drug may be administered once every three weeks in doses of about 75 mg, 100 mg, 150 mg, 200 mg, or 300 mg. In other embodiments involving the administration of a pharmaceutical composition comprising an anti-IL-4R antibody, the drug may be administered once every four weeks in doses of about 75 mg, 100 mg, 150 mg, 200 mg, or 300 mg (monthly). In other embodiments involving the administration of a pharmaceutical composition comprising an anti-IL-4R antibody, the drug may be administered once every five weeks in doses of about 75 mg, 100 mg, 150 mg, 200 mg, or 300 mg. In other embodiments involving the administration of a pharmaceutical composition comprising an anti-IL-4R antibody, the drug may be administered every six weeks in doses of about 75 mg, 100 mg, 150 mg, 200 mg, or 300 mg. In other embodiments involving the administration of a pharmaceutical composition comprising an anti-IL-4R antibody, the drug may be administered every eight weeks in doses of about 75 mg, 100 mg, 150 mg, 200 mg, or 300 mg. In other embodiments involving the administration of a pharmaceutical composition comprising an anti-IL-4R antibody, the drug may be administered every twelve weeks in doses of about 75 mg, 100 mg, 150 mg, 200 mg, or 300 mg. In one embodiment, the route of administration is subcutaneous.

[0460] The term “week” or “weeks” refers to a period of (n x 7 days) ± 2 days, for example (n x 7 days) ± 1 day, or (n x 7 days), where “n” indicates the number of weeks, such as 1, 2, 3, 4, 5, 6, 8, 12 or more.

[0461] The terms “initial dose,” “secondary dose,” and “tertiary dose” refer to the temporal sequence of administration of an IL-4R antagonist. Therefore, the “initial dose” is the dose administered at the start of a treatment regimen (also known as the “baseline dose”); the “secondary dose” is the dose administered after the initial dose; and the “tertiary dose” is the dose administered after the secondary dose. The initial, secondary, and tertiary doses may all contain the same amount of IL-4R antagonist, but they can typically differ from each other in terms of frequency of administration. However, in some embodiments, the amount of IL-4R antagonist contained in the initial, secondary, and / or tertiary doses differs from each other during treatment (e.g., adjusted up or down as appropriate). In some embodiments, two or more (e.g., 2, 3, 4, or 5) doses are administered at the start of a treatment regimen as “loading doses,” followed by subsequent doses administered at a lower frequency (e.g., “maintenance doses”). In one embodiment, the maintenance dose may be lower than the loading dose. For example, one or more loading doses of 600 mg of IL-4R antagonist may be administered, followed by a maintenance dose of approximately 75 mg to approximately 300 mg.

[0462] In some embodiments, the loading dose is about 400 to about 600 mg of an IL-4R antagonist. In one embodiment, the loading dose is 400 mg of an IL-4R antagonist. In another embodiment, the loading dose is 600 mg of an IL-4R antagonist.

[0463] In some embodiments, the maintenance dose is about 200 to about 300 mg of the IL-4R antagonist. In one embodiment, the maintenance dose is 200 mg of the IL-4R antagonist. In another embodiment, the maintenance dose is 300 mg of the IL-4R antagonist.

[0464] In some implementations, the loading dose is twice the maintenance dose.

[0465] In some embodiments, the loading dose comprises 600 mg of the antibody or its antigen-binding fragment, and the one or more maintenance doses comprise 300 mg of the antibody or its antigen-binding fragment administered every other week (every other week is interchangeable with every two weeks, every two weeks once, or q2w).

[0466] In some implementations, the subject has OCS-dependent asthma, and the loading dose includes 600 mg of the antibody or its antigen-binding fragment, and the one or more maintenance doses include 300 mg of the antibody or its antigen-binding fragment administered every other week.

[0467] In some implementations, the subject has comorbid moderate to severe atopic dermatitis, and the loading dose includes 600 mg of the antibody or its antigen-binding fragment, and the one or more maintenance doses include 300 mg of the antibody or its antigen-binding fragment administered every other week.

[0468] In some embodiments, the loading dose comprises 400 mg of the antibody or its antigen-binding fragment, and the one or more maintenance doses comprise 200 mg of the antibody or its antigen-binding fragment administered every other week.

[0469] In some implementations, the subject has OCS-dependent asthma, and the loading dose includes 400 mg of the antibody or its antigen-binding fragment, and the one or more maintenance doses include 200 mg of the antibody or its antigen-binding fragment administered every other week.

[0470] In some implementations, the subject has comorbid moderate to severe atopic dermatitis, and the loading dose includes 400 mg of the antibody or its antigen-binding fragment, and the one or more maintenance doses include 200 mg of the antibody or its antigen-binding fragment administered every other week.

[0471] In some embodiments, the loading dose comprises 600 mg of the antibody or its antigen-binding fragment, and the one or more maintenance doses comprise 300 mg of the antibody or its antigen-binding fragment administered every four weeks.

[0472] In some implementations, the subject has OCS-dependent asthma, and the loading dose includes 600 mg of the antibody or its antigen-binding fragment, and the one or more maintenance doses include 300 mg of the antibody or its antigen-binding fragment administered every four weeks.

[0473] In some implementations, the subject has comorbid moderate to severe atopic dermatitis, and the loading dose comprises 600 mg of the antibody or its antigen-binding fragment, and the one or more maintenance doses comprise 300 mg of the antibody or its antigen-binding fragment administered every four weeks.

[0474] In some embodiments, the loading dose comprises 400 mg of the antibody or its antigen-binding fragment, and the one or more maintenance doses comprise 200 mg of the antibody or its antigen-binding fragment administered every four weeks.

[0475] In some implementations, the subject has OCS-dependent asthma, and the loading dose comprises 400 mg of the antibody or its antigen-binding fragment, and the one or more maintenance doses comprise 200 mg of the antibody or its antigen-binding fragment administered every four weeks.

[0476] In some implementations, the subject has comorbid moderate to severe atopic dermatitis, and the loading dose comprises 400 mg of the antibody or its antigen-binding fragment, and the one or more maintenance doses comprise 200 mg of the antibody or its antigen-binding fragment administered every four weeks.

[0477] In one exemplary embodiment, immediately following the previous dose, 1 to 14 weeks (e.g., 1, 1) 1 / 2、2、2 1 / 2, 3, 3 1 / 2、4、4 1 / 2, 5, 5 1 / 2, 6, 6 1 / 2、7、7 1 / 2、8、8 1 / 2, 9, 9 1 / 2, 10, 10 1 / 2, 11, 11 1 / 2, 12, 12 1 / 2, 13, 13 1 / 2, 14, 14 1 Each secondary and / or tertiary dose is administered (for 2 weeks or longer). The phrase “immediately preceding dose” means, in a sequence of multiple administrations, the dose of the IL-4R antagonist administered to the patient before the dose immediately following the one in the sequence, without any intervening doses.

[0478] The method may include administering any number of secondary and / or tertiary doses of an IL-4R antagonist to a patient. For example, in some embodiments, only a single secondary dose is administered to the patient. In other embodiments, two or more (e.g., 2, 3, 4, 5, 6, 7, 8 or more) secondary doses are administered to the patient. Similarly, in some embodiments, only a single tertiary dose is administered to the patient. In other embodiments, two or more (e.g., 2, 3, 4, 5, 6, 7, 8 or more) tertiary doses are administered to the patient.

[0479] In embodiments involving multiple secondary doses, each secondary dose may be administered at the same frequency as the other secondary doses. For example, each secondary dose may be administered to the patient 1 to 2 weeks after the preceding dose. Similarly, in embodiments involving multiple tertiary doses, each tertiary dose may be administered at the same frequency as the other tertiary doses. For example, each tertiary dose may be administered to the patient 2 to 4 weeks after the preceding dose. Alternatively, the frequency of administration of secondary and / or tertiary doses to the patient may vary throughout the treatment regimen. The frequency may also be adjusted by the physician during treatment based on the individual patient's needs following a clinical examination.

[0480] A method is provided that includes sequentially administering an IL-4R antagonist and a second therapeutic agent to a patient to treat asthma (e.g., allergic asthma, ABPA-related asthma, moderate to severe asthma, persistent asthma, etc.) or related conditions. In some embodiments, the method includes administering one or more doses of an IL-4R antagonist, followed by administering one or more (e.g., 2, 3, 4, 5, 6, 7, 8, or more) doses of a second therapeutic agent. For example, one or more doses of an IL-4R antagonist, from about 75 mg to about 300 mg, may be administered, followed by administering one or more (e.g., 2, 3, 4, 5, 6, 7, 8, or more) doses of a second therapeutic agent (e.g., an inhaled corticosteroid or β2-agonist, or any other therapeutic agent as described elsewhere herein) to treat, alleviate, reduce, or improve one or more asthma symptoms. In some embodiments, administering one or more (e.g., 2, 3, 4, 5, 6, 7, 8, or more) doses of an IL-4R antagonist results in an improvement in one or more asthma-related parameters, followed by administration of a second therapeutic agent to prevent recurrence of at least one asthma symptom. Alternative implementations involve administering an IL-4R antagonist concurrently with a second therapeutic agent. For example, one or more (e.g., 2, 3, 4, 5, 6, 7, 8 or more) doses of the IL-4R antagonist are administered, and the second therapeutic agent is administered at separate doses and at a frequency similar to or different from that of the IL-4R antagonist. In some implementations, the second therapeutic agent is administered before, after, or concurrently with the IL-4R antagonist.

[0481] In some embodiments, the IL-4R antagonist is administered once every week for 12, 14, 16, 18, 20, 22, 24, 26, 28, 30, 32, 34, 36, 38, 40, 42, 44, 46, 48 weeks, or longer. In other embodiments, the IL-4R antagonist is administered once every four weeks for 12, 16, 20, 24, 28, 32, 36, 40, 44, 48 weeks, or longer. In a specific embodiment, the IL-4R antagonist is administered for at least 24 weeks.

[0482] A method is provided for treating a subject with severe uncontrolled asthma (e.g., severe steroid-dependent asthma), the method comprising administering to the subject a loading dose of an antibody or antigen-binding fragment thereof that specifically binds to IL-4R. In some embodiments, the method comprises administering to the subject multiple maintenance doses of the antibody or antigen-binding fragment thereof, wherein the multiple maintenance doses are administered during treatment phases. Treatment phases include an induction phase, an OCS reduction phase, and an OCS maintenance phase.

[0483] In some exemplary embodiments, the induction phase includes a period during which the subject continuously receives one or more doses of OCS. In some exemplary embodiments, the reduction phase includes a period during which the subject receives a lower dose of OCS relative to the dose received during the induction phase. In some exemplary embodiments, the maintenance phase includes a period during which the subject receives a stable amount or one or more doses of OCS. Alternatively, the maintenance phase includes a period during which OCS therapy / administration is reduced or eliminated. In some embodiments, the patient's use of OCS is completely eliminated, and the patient has not used steroids for less than one year after treatment with the IL4R antibody or a fragment thereof (e.g., within one year, six months, three months, or one month of initial treatment).

[0484] In another aspect, a method for treating a subject with severe steroid-dependent asthma and / or severe uncontrolled asthma includes administering to the subject a loading dose of about 600 mg of an antibody or antigen-binding fragment thereof that specifically binds to an interleukin-4 receptor (IL-4R), and administering to the subject multiple maintenance doses of the antibody or antigen-binding fragment thereof. Each maintenance dose is about 300 mg of the antibody or antigen-binding fragment thereof, wherein multiple maintenance doses are administered during a treatment phase including an induction phase, an oral corticosteroid (OCS) reduction phase, and a maintenance phase, and wherein said antibody or antigen-binding fragment thereof comprises heavy chain and light chain CDR sequences from HCVR / LCVR containing SEQ ID NO: 1 and 2.

[0485] Treatment group

[0486] The methods described herein involve administering a therapeutic composition containing an IL-4R antagonist to a subject in need. The term "subject in need" means a human or nonhuman animal exhibiting one or more symptoms or indicators of asthma (e.g., allergic asthma, such as moderate to severe uncontrolled allergic asthma or ABPA-associated asthma) and / or ABPA, or who has been diagnosed with asthma (e.g., allergic asthma, ABPA-associated asthma, moderate to severe asthma, persistent asthma, etc.) and / or ABPA. For example, "subject in need" may include subjects who, prior to treatment, exhibit (or have exhibited) one or more asthma-related (e.g., allergic asthma-related) parameters, such as impaired FEV1 (e.g., less than 2.0 L), impaired FEF 25-75%, impaired AM PEF (e.g., less than 400 L / min), impaired PM PEF (e.g., less than 400 L / min), an ACQ5 score of at least 2.5, at least one nocturnal awakening per night, and / or an SNOT-22 score of at least 20. In various embodiments, the method can be used to treat mild, moderate to severe, and severe asthma (e.g., allergic asthma, ABPA-associated asthma, moderate to severe asthma, persistent asthma, etc.) and / or ABPA in patients in need. In some embodiments, the method can be used to treat mild, moderate to severe, and severe asthma (e.g., allergic asthma, ABPA-associated asthma, moderate to severe asthma, persistent asthma, etc.) and / or ABPA in patients in need, wherein the patients also exhibit comorbid moderate to severe atopic dermatitis.

[0487] In some embodiments, "subject in need" means a human or non-human animal exhibiting a total serum IgE level of at least about 1000 IU / mL, an Aspergillus fumigatus-specific IgE level greater than 0.35 kU / L, or a baseline blood eosinophil count of at least about 500 cells / μl. In some embodiments, "subject in need" means a human or non-human animal exhibiting at least two of the following: a total serum IgE level of at least about 1000 IU / mL, an Aspergillus fumigatus-specific IgE level greater than 0.35 kU / L, and a baseline blood eosinophil count of at least about 500 cells / μl. In some embodiments, "subject in need" means a human or non-human animal exhibiting a total serum IgE level of at least about 1000 IU / mL, an Aspergillus fumigatus-specific IgE level greater than 0.35 kU / L, and a baseline blood eosinophil count of at least about 500 cells / μl.

[0488] In relevant implementations, a “subject in need” can be a subject who has been prescribed or is currently taking an ICS / LABA combination prior to receiving an IL-4R antagonist. Examples of ICS include mometasone furoate, budesonide, and fluticasone propionate. Examples of LABA include formoterol and salmeterol. Examples of ICS / LABA therapies include fluticasone / salmeterol combination therapy and budesonide / formoterol combination therapy. For example, a method is provided that includes administering an IL-4R antagonist to a patient who has been receiving a regular ICS / LABA course for two weeks or more immediately prior to administering the IL-4R antagonist (such prior treatment is referred to herein as “background treatment”). A treatment method is provided in which background treatment continues in conjunction with the administration of the IL-4R antagonist. In yet other implementations, the amount of the ICS component, LABA component, or both is gradually reduced before or after the initiation of IL-4R antagonist administration. In some implementations, a method is provided for treating patients with persistent asthma for at least ≥12 months. In one implementation, a patient with persistent asthma may be resistant to treatment with agents such as corticosteroids and may be given an IL-4R antagonist according to the method of the present invention.

[0489] In some embodiments, a “subject in need” may be a subject with elevated levels of asthma-related biomarkers. Examples of asthma-related and / or ABPA-related biomarkers include, but are not limited to, IgE (e.g., total IgE and / or Aspergillus fumigatus-specific IgE), thymus and activated regulatory chemokine (TARC), blood eosinophils, eosinophil chemokine-3, CEA, YKL-40, and periosteal protein. In some embodiments, a “subject in need” may be a subject with blood eosinophil counts of ≥300 cells / μL, 200-299 cells / μL, or <200 cells / μL. In one embodiment, a “subject in need” may be a subject with elevated levels of bronchial or airway inflammation (e.g., as measured by exhaled nitric oxide fraction (FeNO)). In another embodiment, a “subject in need” may be a subject with elevated eosinophil chemokine levels. In yet another embodiment, a “subject in need” may be a subject with elevated TARC levels. In another implementation, "subjects in need" may be subjects with elevated IgE levels (e.g., total IgE and / or Aspergillus fumigatus-specific IgE levels).

[0490] In some implementations, "subjects in need" are selected from: subjects aged 18 years and older, subjects aged 12 years and older, subjects aged 12 to 17 years (12 to <18 years), subjects aged 6 to 11 years (6 to <12 years), and subjects aged 2 to 5 years (2 to <6 years). In some implementations, "subjects in need" are selected from: adults, adolescents, and children. In some implementations, "subjects in need" are selected from: adults aged 18 years and older, adolescents aged 12 to 17 years (12 to <18 years), children aged 6 to 11 years (6 to <12 years), and children aged 2 to 5 years (2 to <6 years). Subjects may be younger than 2 years, for example, 12 to 23 months, or 6 to 11 months.

[0491] In some implementations, the “subject in need” is a current smoker. In some implementations, the subject is a current smoker who smokes, for example, cigarettes, cigars, pipes, hookahs, and / or vaporizers (i.e., “vapes”). In some implementations, the subject is a current smoker with a smoking history of 10 or more packs of cigarettes per year. In some implementations, the subject is a current smoker with a smoking history of less than 10 packs of cigarettes per year. In some implementations, the subject is a current smoker with a smoking history of more than 1, 5, 10, 15, 20, 25, 30, 35, 40, 45, or 50 packs of cigarettes per year. In some implementations, the subject is a current smoker with a smoking history of 6 months, 1 year, 2 years, 3 years, 5 years, 10 years, or longer.

[0492] In some implementations, "subjects in need" are former smokers. In some implementations, subjects are former smokers with a history of smoking cigarettes, cigars, pipes, hookahs, and / or e-cigarettes. In some implementations, subjects are former smokers with a history of smoking 10 or more packs of cigarettes per year. In some implementations, subjects are former smokers with a history of smoking less than 10 packs per year. In some implementations, subjects are former smokers with a history of smoking more than 1, 5, 10, 15, 20, 25, 30, 35, 40, 45, or 50 packs of cigarettes per year. In some implementations, subjects are former smokers with a smoking history of 6 months, 1 year, 2 years, 3 years, 5 years, 10 years, or longer. In some implementations, subjects are former smokers who have stopped smoking for at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 months. In some implementations, subjects are former smokers who have stopped smoking for at least 6 months. In some implementations, the subjects are former smokers who intend to quit smoking permanently.

[0493] In some implementations, "subjects in need" are non-smokers. In some implementations, subjects are non-smokers without a history of smoking cigarettes, cigars, pipes, hookahs, and / or e-cigarettes. In some implementations, subjects are non-smokers without a history of smoking tobacco.

[0494] In some implementations, "subjects in need" are subjects treated with a vaccine (e.g., a viral vaccine or a bacterial vaccine). In some implementations, the vaccine is a live vaccine, such as a live (e.g., a live-attenuated) viral vaccine or a live (e.g., a live-attenuated) bacterial vaccine.

[0495] Suitable vaccines include, but are not limited to, adenovirus, anthrax (e.g., AVA vaccine (BioThrax)), cholera (e.g., Vaxchora), diphtheria (e.g., DTaP (Daptacel, Infanrix), Td (Tenivac, Universal), DT (Universal), Tdap (Adacel, Boostrix), DTaP-IPV (Kinrix, Quadracel), DTaP-HepB-IPV (Pediarix), DTaP-IPV / Hib (Pentacel)), hepatitis A (e.g., HepA (Havrix, Vaqta), HepA-HepB (Twinrix)), and hepatitis B (e.g., HepB (Engerix-B, Recombivax)). HB, Heplisav-B), DTaP-HepB-IPV (Pediarix), HepA-HepB (Twinrix)), Haemophilus influenzae type b (Hib) (e.g., Hib (ActHIB, PedvaxHIB, Hiberix), DTaP-IPV / Hib (Pentacel)), Human papillomavirus (HPV) (e.g., HPV9 (Gardasil 9)), Influenza (flu) (e.g., IIV (also known as IIV3, IIV4, RIV3, RIV4 and ccIIV4) (Afluria, Fluad, Flublok, Flucelvax, FluLaval, Fluarix, Fluvirin, Fluzone, Fluzone) High-Dose, Fluzone Intradermal, LAIV (FluMist), Japanese encephalitis (e.g., JE (Ixiaro)), measles (e.g., MMR (MM-RII), MMRV (ProQuad)), meningococcal disease (e.g., MenACWY (Menactra, Menveo), MenB (Bexsero, Trumenba)), mumps (e.g., MMR (MMR II), MMRV (ProQuad)), pertussis (e.g., DTaP (Daptacel, Infanrix), Tdap (Adacel, Boostrix), DTaP-IPV (Kinrix, Quadracel), DTaP-HepB-IPV (Pediarix), DTaP-IPV / Hib (Pentacel)), pneumococcal disease (e.g., PCV13 (Prevnar13), PPSV23 (Pneumovax 23)), poliomyelitis (e.g.,Polio (Ipol), DTaP-IPV (Kinrix, Quadracel), DTaP-HepB-IPV (Pediarix), DTaP-IPV / Hib (Pentacel), rabies (e.g., Rabies (ImovaxRabies, RabAvert)), rotavirus (e.g., RV1 (Rotarix), RV5 (RotaTeq)), rubella (e.g., MMR (MMR) II), MMRV (ProQuad)), herpes zoster (e.g., ZVL (Zostavax), RZV (Shingrix)), smallpox (e.g., cowpox (ACAM2000)), tetanus (e.g., DTaP (Daptacel, Infanrix), Td (Tenivac, generic), DT (generic), Tdap (Adacel, Boostrix), DTaP-IPV (Kinrix, Quadracel), DTaP-HepB-IPV (Pediarix), DTaP-IPV / Hib (Pentacel)), tuberculosis, typhoid fever (e.g., oral typhoid vaccine (Vivotif), typhoid polysaccharide vaccine (Typhim Vi)), varicella (e.g., VAR (varicella vaccine), MMRV (ProQuad)), yellow fever (e.g., YF (YF-Vax)), etc. The U.S. Centers for Disease Control and Prevention's vaccine list (cdc.gov / vaccines / vpd / vaccines-list.html), which is included in this article in its entirety for all purposes, also lists suitable vaccines.

[0496] In some implementations, the vaccine is an inactivated vaccine, a recombinant vaccine, a conjugated vaccine, a subunit vaccine, a polysaccharide vaccine, or a toxoid vaccine. In some implementations, the vaccine is a yellow fever vaccine. In some implementations, subjects treated with the vaccine are concurrently treated with an IL-4R antagonist for type 2 inflammatory disease. In some implementations, subjects treated with the vaccine are concurrently treated with an IL-4R antagonist for asthma. In some implementations, subjects discontinue treatment with an IL-4R antagonist before vaccination.

[0497] In some implementations, the vaccine is administered approximately 1 to 9 weeks prior to administration (e.g., approximately 1, approximately 1 week prior to administration). 1 / 2, about 2, about 2 1 / 2, about 3, about 3 1 / 2, about 4, about 4 1 / 2, about 5, about 5 1 / 2, about 6, about 6 1 / 2, about 7, about 7 1 / 2, about 8, about 8 1 / 2. Subjects discontinued treatment with the IL-4R antagonist approximately 9 weeks or longer. In some implementations, approximately 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, and so on, prior to vaccine administration. Subjects discontinued treatment with the IL-4R antagonist at approximately 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, or 60 days.

[0498] In some implementations, subjects resume treatment with an IL-4R antagonist after vaccine treatment. In some implementations, treatment is resumed 1 to 14 weeks after vaccine administration (e.g., approximately 1, approximately 1 week). 1 / 2, about 2, about 2 1 / 2, about 3, about 3 1 / 2, about 4, about 4 1 / 2, about 5, about 5 1 / 2, about 6, about 6 1 / 2, about 7, about 7 1 / 2, about 8, about 8 1 / 2, about 9, about 9 1 / 2, about 10, about 10 1 / 2, about 11, about 11 1 / 2, about 12, about 12 1 / 2, Approximately 13, Approximately 13 1 / 2, Approximately 14, Approximately 14 1Subjects resumed treatment with an IL-4R antagonist approximately 2 weeks or longer after vaccination. In some implementations, approximately 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, and 4... 7. Subjects resumed treatment with an IL-4R antagonist at approximately 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, or 90 days.

[0499] Normal IgE levels in healthy subjects are typically below approximately 100 IU / mL (e.g., as used with...). (Measured by Phadia, Inc. Portitch, Michigan). Therefore, a method is provided comprising selecting a subject exhibiting elevated serum IgE levels and administering to the subject a pharmaceutical composition comprising a therapeutically effective amount of an IL-4R antagonist, said elevated serum IgE levels being greater than about 100 IU / mL, greater than about 150 IU / mL, greater than about 500 IU / mL, greater than about 700 IU / mL, greater than about 1000 IU / mL, greater than about 1500 IU / mL, greater than about 2000 IU / mL, greater than about 2500 IU / mL, greater than about 3000 IU / mL, greater than about 3500 IU / mL, greater than about 4000 IU / mL, greater than about 4500 IU / mL, or greater than about 5000 IU / mL.

[0500] Normal Aspergillus fumigatus (Af)-specific IgE levels in healthy subjects are typically below approximately 0.10 kU / L (e.g., as used with...). (Measured by Phadia, Inc. Portage, MI). Therefore, a method is provided comprising selecting a subject exhibiting elevated serum IgE levels and administering to the subject a pharmaceutical composition comprising a therapeutically effective amount of an IL-4R antagonist, said elevated serum IgE level being greater than or equal to about 0.1 kU / L, greater than about 0.35 kU / L, greater than about 0.70 kU / L, greater than about 3.50 kU / L, greater than about 17.50 kU / L, greater than about 50.00 kU / L, or greater than about 100.00 kU / L.

[0501] In some embodiments, IgE levels (e.g., total IgE levels and / or Aspergillus fumigatus-specific IgE levels) are improved relative to baseline, for example, by about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, about 100% or more from baseline.

[0502] TARC levels in healthy subjects range from 106 ng / L to 431 ng / L, with a mean of approximately 239 ng / L. (An exemplary assay system for measuring TARC levels is the TARC Quantitative ELISA Kit provided by R&D Systems, Minneapolis, MN, under catalog number DDN00.) Therefore, a method is provided comprising selecting subjects exhibiting elevated TARC levels and administering to said subjects a pharmaceutical composition comprising a therapeutically effective amount of an IL-4R antagonist, said elevated TARC levels being greater than approximately 431 ng / L, greater than approximately 500 ng / L, greater than approximately 1000 ng / L, greater than approximately 1500 ng / L, greater than approximately 2000 ng / L, greater than approximately 2500 ng / L, greater than approximately 3000 ng / L, greater than approximately 3500 ng / L, greater than approximately 4000 ng / L, greater than approximately 4500 ng / L, or greater than approximately 5000 ng / L. In some implementations, the TARC level is improved relative to the baseline, for example, by about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, about 100% or more from the baseline.

[0503] Eosinophil chemokine-3 belongs to a group of chemokines released by airway epithelial cells and is upregulated by Th2 cytokines IL-4 and IL-13 (Lilly et al. 1999, J. Allergy Clin. Immunol. 104:786-790). Methods have been provided that involve administering an IL-4R antagonist to treat patients with elevated eosinophil chemokine-3 levels (e.g., more than about 100 pg / ml, more than about 150 pg / ml, more than about 200 pg / ml, more than about 300 pg / ml, or more than about 350 pg / ml). Serum eosinophil chemokine-3 levels can be measured, for example, by ELISA. In some embodiments, serum eosinophil chemokine-3 levels are improved relative to baseline, for example, by about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, about 100% or more from baseline.

[0504] Periostrin is an extracellular matrix protein involved in Th2-mediated inflammatory processes. Periostrin levels have been found to be upregulated in patients with asthma (Jia et al. 2012 J Allergy Clin Immunol. 130:647-654.e10.doi:10.1016 / j.jaci.2012.06.025.Epub 1 August 2012). Approaches involving the administration of IL-4R antagonists to treat patients with elevated periostrin levels have been provided.

[0505] Exhaled NO (FeNO) is a biomarker of bronchial or airway inflammation. FeNO is produced by airway epithelial cells in response to inflammatory cytokines including IL-4 and IL-13 (Alwing et al. 1993, Eur. Respir. J. 6: 1368-1370). FeNO levels in healthy adults range from 2 to 30 parts per billion (ppb). An exemplary assay for measuring FeNO is the NIOX instrument using the Aerocrine AB instrument from Solna, Sweden. Assessment can be performed before spirometry and after fasting for at least 1 hour. A method is provided that involves administering an IL-4R antagonist to a patient with elevated exhaled NO (FeNO) levels (e.g., more than about 30 ppb, more than about 31 ppb, more than about 32 ppb, more than about 33 ppb, more than about 34 ppb, or more than about 35 ppb).

[0506] Carcinoembryonic antigen (CEA) (also known as CEA cell adhesion molecule 5 [CEACAM5]) is a tumor marker that has been found to be associated with non-neoplastic diseases of the lung (Marechal et al. 1988, Anticancer Res. 8:677-680). Serum CEA levels can be measured by ELISA. Methods have been provided that involve administering an IL-4R antagonist to patients with elevated CEA levels (e.g., more than about 1.0 ng / ml, more than about 1.5 ng / ml, more than about 2.0 ng / ml, more than about 2.5 ng / ml, more than about 3.0 ng / ml, more than about 4.0 ng / ml, or more than about 5.0 ng / ml).

[0507] YKL-40 [named after its N-terminal amino acids tyrosine (Y), lysine (K), and leucine (L) and its molecular weight of 40 kDa] is a chitosanase-like protein that has been found to be upregulated and associated with asthma exacerbations, IgE, and eosinophilia (Tang et al. 2010 Eur. Respir. J. 35:757-760). Serum YKL-40 levels are measured by, for example, ELISA. Methods have been provided that involve administering an IL-4R antagonist to patients with elevated YKL-40 levels (e.g., more than about 40 ng / ml, more than about 50 ng / ml, more than about 100 ng / ml, more than about 150 ng / ml, more than about 200 ng / ml, or more than about 250 ng / ml).

[0508] Periostrin is a secretory stromal cell protein associated with fibrosis, and its expression in cultured bronchial epithelial cells and bronchial fibroblasts is upregulated by recombinant IL-4 and IL-13 (Jia et al. (2012) J. Allergy Clin. Immunol. 130:647). In human asthma patients, periostrin expression levels are associated with reticular basement membrane thickness (an indicator of subepithelial fibrosis). Ibid. A method is provided that involves administering an IL-4R antagonist to patients with elevated periostrin levels.

[0509] Induced sputum eosinophils and neutrophils are well-established direct markers of airway inflammation (Djukanovic et al. 2002, Eur. Respire. J. 37: 1S-2S). Sputum was induced by inhalation of hypertonic saline solution and processed for cell counting according to methods known in the art, such as guidelines from the European Respiratory Society.

[0510] In some implementations, subjects are stratified into the following groups: blood eosinophil counts of ≥300 cells / μL or 300-499 cells / μL or ≥500 cells / μL (high blood eosinophils) (HEos), blood eosinophil counts of 200 to 299 cells / μL (intermediate blood eosinophils), or blood eosinophil counts of <200 cells / μL (low blood eosinophils), and anti-IL-4R antibody or its antigen-binding fragment is administered at a dose or dosing regimen based on eosinophil levels.

[0511] In some implementations, subjects are stratified into the following groups: blood eosinophil counts of ≥300 cells / μL, 300-499 cells / μL or ≥500 cells / μL (high blood eosinophils), blood eosinophil counts of ≥150 cells / μL (medium blood eosinophils), or blood eosinophil counts of <150 cells / μL (low blood eosinophils), and anti-IL-4R antibody or its antigen-binding fragment is administered at a dose or dosing regimen based on eosinophil levels.

[0512] In some implementations, the subject has “eosinophilic phenotype” asthma as defined by a blood eosinophil count of ≥150 cells / μL, ≥300 cells / μL, 300-499 cells / μL, or ≥500 cells / μL, and is administered an anti-IL-4R antibody or its antigen-binding fragment.

[0513] In some implementations, subjects are stratified into the following groups: total baseline serum IgE concentration ≥30 IU / mL; total baseline serum IgE concentration ≥100 IU / mL; total baseline serum IgE concentration ≥200 IU / mL; total baseline serum IgE concentration ≥300 IU / mL; total baseline serum IgE concentration ≥400 IU / mL; total baseline serum IgE concentration ≥500 IU / mL; total baseline serum IgE concentration ≥600 IU / mL; total baseline serum IgE concentration ≥700 IU / mL (e.g., high serum IgE); total baseline serum IgE concentration ≥800 IU / mL; total baseline serum IgE concentration ≥900 IU / mL; or total baseline serum IgE concentration ≥1000 IU / mL (e.g., very high IgE), and anti-IL-4R antibody or its antigen-binding fragment is administered at an IgG concentration-based dose or dosing regimen.

[0514] In some implementations, subjects are stratified into the following groups: ≥0.05 kU / L allergen-specific IgE (e.g., Aspergillus fumigatus-specific) concentration; ≥0.10 kU / L allergen-specific (e.g., Aspergillus fumigatus-specific) IgE concentration; ≥0.15 kU / L allergen-specific (e.g., Aspergillus fumigatus-specific) IgE concentration; ≥0.20 kU / L allergen-specific (e.g., Aspergillus fumigatus-specific) IgE concentration; ≥0.25 kU / L allergen-specific (e.g., Aspergillus fumigatus-specific) IgE concentration; ≥0.30 kU / L allergen-specific (e.g., Aspergillus fumigatus-specific) IgE concentration; ≥0.05 kU / L allergen-specific (e.g., Aspergillus fumigatus-specific) IgE concentration; ≥0.25 kU / L allergen-specific (e.g., Aspergillus fumigatus-specific) IgE concentration; ≥0.30 kU / L allergen-specific (e.g., Aspergillus fumigatus-specific) IgE concentration; ≥0.10 kU / L allergen-specific (e.g., Aspergillus fumigatus-specific) IgE concentration; ≥0.25 kU / L allergen-specific (e.g., Aspergillus fumigatus-specific) IgE concentration; ≥0.30 kU / L allergen-specific (e.g., Aspergillus fumigatus-specific) IgE concentration; ≥0.20 kU / L allergen-specific (e.g., Aspergillus fumigatus-specific) IgE concentration; ≥ For example, an allergen-specific (e.g., Aspergillus fumigatus-specific) IgE concentration of ≥0.35 kU / L; an allergen-specific (e.g., Aspergillus fumigatus-specific) IgE concentration of ≥0.40 kU / L; an allergen-specific (e.g., Aspergillus fumigatus-specific) IgE concentration of ≥0.45 kU / L; or an allergen-specific (e.g., Aspergillus fumigatus-specific) IgE concentration of ≥0.50 kU / L, and administering the anti-IL-4R antibody or its antigen-binding fragment at a dose or administration regimen based on the allergen-specific (e.g., Aspergillus fumigatus-specific) IgE concentration.

[0515] In some implementations, subjects are stratified into the following groups: baseline FeNO values ​​≥20 ppb; baseline FeNO values ​​≥25 ppb; baseline FeNO values ​​≥50 ppb (e.g., high FeNO); baseline FeNO values ​​<25 ppb (e.g., low FeNO); baseline FeNO values ​​<50 ppb; or baseline FeNO values ​​between about 25 ppb and about 50 ppb, and the anti-IL-4R antibody or its antigen-binding fragment is administered at a dose or dosing regimen based on the FeNO value.

[0516] Methods for assessing pharmacodynamic parameters related to asthma and / or ABPA-related parameters

[0517] Methods are provided for assessing one or more pharmacodynamic asthma-related parameters and / or one or more pharmacodynamic ABPA-related parameters in subjects of need due to administration of a pharmaceutical composition comprising an IL-4R antagonist. A reduction in the incidence of asthma exacerbations (as described above) or an improvement in one or more asthma-related parameters (as described above) may be associated with an improvement in one or more pharmacodynamic asthma-related parameters; however, such an association is not necessarily observed in all cases.

[0518] Examples of “pharmacodynamic asthma-related parameters” or “pharmacodynamic ABPA-related parameters” include, for example, the following: (a) biomarker expression levels; (b) serum protein and RNA analysis; (c) induced sputum eosinophil and neutrophil levels; (d) exhaled nitric oxide (FeNO); and (e) blood eosinophil count. “Improvement in pharmacodynamic asthma-related parameters” means, for example, a decrease from baseline in one or more biomarkers (such as TARC, eosinophil chemokine-3, or IgE); a decrease in sputum eosinophils or neutrophils, FeNO, periosteal protein, or blood eosinophil count. As used herein, the term “baseline,” in relation to pharmacodynamic asthma-related parameters, means the value of the pharmacodynamic asthma-related parameter in a patient before or at the time of administration of the pharmaceutical composition described herein.

[0519] To assess pharmacodynamic asthma-related parameters or pharmacodynamic ABPA-related parameters, these parameters are quantified at baseline and at time points following administration of the drug composition. For example, pharmacodynamic asthma-related parameters or pharmacodynamic ABPA-related parameters can be measured approximately on day 1, approximately day 2, approximately day 3, approximately day 4, approximately day 5, approximately day 6, approximately day 7, approximately day 8, approximately day 9, approximately day 10, approximately day 11, approximately day 12, approximately day 14, approximately week 3, approximately week 4, approximately week 5, approximately week 6, approximately week 7, approximately week 8, approximately week 9, approximately week 10, approximately week 11, approximately week 12, approximately week 13, approximately week 14, approximately week 15, approximately week 16, approximately week 17, approximately week 18, approximately week 19, approximately week 20, approximately week 21, approximately week 22, approximately week 23, approximately week 24, or longer after initial treatment with the pharmaceutical composition. The difference between the value of the parameter at a specific time point after the start of treatment and the value of the parameter at baseline is used to determine whether the pharmacodynamic asthma-related parameter has changed, such as "improved" (e.g., increased or decreased, depending on the specific parameter being measured).

[0520] In some implementations, administration of an IL-4R antagonist to a patient results in a change in the expression of specific biomarkers, such as a decrease or increase. Asthma-related biomarkers and / or ABPA-related biomarkers include, but are not limited to, the following: (a) total IgE; (b) Af-specific IgE; (c) thymus and activated regulatory chemokine (TARC); (d) YKL-40; (e) serum carcinoembryonic antigen; (f) plasma eosinophil chemokine-3; (g) serum periosteal protein; and (f) serum eosinophil levels. For example, administration of an IL-4R antagonist to asthma patients and / or ABPA patients can cause a decrease in TARC or eosinophil chemokine-3 levels, or a decrease in serum total IgE levels, or more thereof. The decrease can be detected approximately at week 1, approximately week 2, approximately week 3, approximately week 4, approximately week 5, or longer after administration of the IL-4R antagonist. Biomarker expression can be determined using methods known in the art. For example, protein levels can be measured using ELISA (enzyme-linked immunosorbent assay). RNA levels can be measured using reverse transcription-coupled polymerase chain reaction (RT-PCR).

[0521] Biomarker expression (as discussed above) can be measured by detecting proteins or RNA in serum. Serum samples can also be used to monitor additional protein or RNA biomarkers associated with response to IL-4R antagonist therapy, IL-4 / IL-13 signaling, asthma, atopic or eosinophilic diseases (e.g., by measuring soluble IL-4Rα, IL-4, IL-13, and periosteal protein). In some embodiments, RNA samples are used to determine RNA levels (non-genetic analysis), such as the RNA levels of biomarkers; and in other embodiments, RNA samples are used for transcriptome sequencing (e.g., genetic analysis).

[0522] Preparations

[0523] In some embodiments, the antibody or its antigen-binding fragment is formulated in a composition comprising: i) about 150 mg / mL of an antibody or its antigen-binding fragment specifically binding to IL-4R, ii) about 20 mM histidine, iii) about 12.5 mM acetate, iv) about 5% (w / v) sucrose, v) about 25 mM arginine hydrochloride, vi) about 0.2% (w / v) polysorbate 80, wherein the pH of the formulation is about 5.9, and wherein the viscosity of the formulation is about 8.5 cPoise.

[0524] In an alternative embodiment, the antibody or its antigen-binding fragment is formulated in a composition comprising: i) about 175 mg / mL of an antibody or its antigen-binding fragment specifically binding to IL-4R, ii) about 20 mM histidine, iii) about 12.5 mM acetate, iv) about 5% (w / v) sucrose, v) about 50 mM arginine hydrochloride, and vi) about 0.2% (w / v) polysorbate 80, wherein the pH of the formulation is about 5.9, and wherein the viscosity of the formulation is about 8.5 cPoise.

[0525] In a specific embodiment, the antibody or its antigen-binding fragment comprises HCVR having the amino acid sequence of SEQ ID NO:1 and LCVR having the amino acid sequence of SEQ ID NO:2.

[0526] Suitable stabilizing formulations are also set forth in US 8,945,559, which is incorporated herein by reference in its entirety for all purposes.

[0527] The invention is further illustrated by the following embodiments, which should not be construed as further limitations. The accompanying drawings and all references, patents, and published patent applications cited in this application are expressly incorporated herein by reference for all purposes.

[0528] Furthermore, according to the present invention, conventional molecular biology, microbiology, and recombinant DNA techniques within the scope of the art can be employed. Such techniques are well described in the literature. See, for example, Green and Sambrook, Molecular Cloning: A Laboratory Manual, 4th ed. (2012), Cold Spring Harbor Laboratory Press, Cold Spring Harbor, New York; DNA Cloning: A Practical Approach, Volumes I and II (edited by DN Glover, 1985); Oligonucleotide Synthesis (edited by MJ Gait, 1984); Nucleic Acid Hybridization (edited by BD Hames and SJ Higgins, 1985); Transcription and Translation (edited by BD Hames and SJ Higgins, 1984); Animal Cell Culture (edited by RI Freshney, 1986); Immobilized Cells and Enzymes (IRL Press, 1986); B. Perbal, A Practical Guide to Molecular Cloning (1984); FMAusubel et al. (editors), Current Protocols in Molecular Biology, John Wiley & Sons, Inc. (1994).

[0529] Example

[0530] The following examples are provided to provide those skilled in the art with a complete disclosure and description of how to prepare and use the methods and compositions characterized in this invention, and are not intended to limit the scope of what the inventors consider to be their invention. Efforts have been made to ensure the accuracy of the figures used (e.g., amounts, temperatures, etc.), but some experimental errors and biases should be taken into account. Unless otherwise indicated, parts are parts by weight, molecular weights are average molecular weights, temperatures are in degrees Celsius, and pressures are at or near atmospheric pressure.

[0531] An exemplary IL-4R antagonist used in the following examples is a human anti-IL-4R antibody named dupilumab (also referred to herein as “mAb1”).

[0532] Example 1: Method - Allergic Asthma

[0533] Research Design

[0534] QUEST was a phase 3, randomized, double-blind, placebo-controlled study evaluating the efficacy and safety of dupilumab in patients with uncontrolled moderate to severe asthma. A total of 1902 patients aged ≥12 years were randomized in a 2:2:1:1 ratio to receive subcutaneous dupilumab 200 mg (loading dose 400 mg) or 300 mg (loading dose 600 mg) or a matched volume of placebo every 2 weeks (q2w) for 52 weeks. The study was conducted in accordance with the International Conference on Harmonization Good Clinical Practice guidelines and applicable regulatory requirements. An independent data and safety monitoring committee monitored the blinding of patient safety data. Trial conduct and documentation were overseen by the local institutional review committee or ethics committee at each research center. Written informed consent was obtained from all patients prior to participation in the trial.

[0535] The QUEST study compared the effects of dupilumab on key asthma outcome measures in subgroups of patients with and without signs of allergic asthma at baseline. Allergic asthma was defined using the most common criteria used in US clinical practice to determine eligibility for omalizumab biologic therapy (i.e., total serum IgE ≥30 IU / mL and ≥1 perennial airborne allergen-specific IgE ≥0.35 kU / L at baseline) (US Food and Drug Administration, available at: accessdata.fda.gov / drugsatfda_docs / label / 2003 / omalgen062003LB.pdf). Because dupilumab treatment is not limited by body weight or serum total IgE levels, an upper threshold for serum total IgE was specified.

[0536] The study included adults and adolescents (aged ≥12 years) with physician-diagnosed asthma for at least 12 months (based on the Global Initiative for Asthma (GINA) 2014 guidelines) who were receiving treatment with moderate to high doses of inhaled corticosteroids and up to two additional controllers. Eligible patients met the following criteria: a forced expiratory volume in one second (FEV1) ≤80% of the predicted normal value for adults and ≤90% of the predicted normal value for adolescents prior to bronchodilator use; FEV1 reversibility ≥12% and 200 mL; a score ≥1.5 on the 5-item Asthma Control Questionnaire-5; and an asthma exacerbation in the previous year that resulted in hospitalization, emergency medical care, or treatment with systemic corticosteroids for 3 days or longer. Full inclusion and exclusion criteria are available at ClinicalTrials.gov (LIBERTY ASTHMA QUEST (NCT02414854)), and this study is incorporated herein by reference in its entirety.

[0537] patient

[0538] Patients were categorized based on whether they met the criteria for allergic asthma: total serum IgE ≥30 IU / mL at baseline and ≥1 positive perennial airborne allergen-specific IgE value (≥0.35 kU / L). The perennial allergens used were house dust mites, garden dust mites, Alternaria alternifolia, Cladosporium multiflorum, cat and dog dander, German cockroaches, Oriental cockroaches, and Aspergillus fumigatus. No transdermal skin allergy testing was performed. The baseline demographics of the study are summarized in Table 1.

[0539] A total of 1083 patients (57% of the ITT population in the QUEST study) met the criteria for defining allergic asthma: total serum IgE ≥30 IU / mL at baseline and ≥1 positive perennial airborne allergen-specific IgE ≥0.35 kU / L. The remaining patients (n=819; 43% of the ITT population) did not meet the criteria for allergic asthma. Of these 819 patients, 7% (n=55) had ≥1 positive perennial airborne allergen-specific IgE at baseline but total serum IgE <30 IU / mL, 14% (n=114) had ≥1 positive seasonal allergen but were negative for all perennial allergens, 38% (n=314) had a history of allergic rhinitis but were negative for both perennial and seasonal allergens, and 41% (n=336) had no history of allergic rhinitis and were negative for both perennial and seasonal allergens.

[0540] Compared to the subgroup that did not meet the criteria for allergic asthma, patients who met the criteria were generally younger (mean 44.5 years vs. 52.5 years), had asthma attacks at an earlier age (mean 21.6 years vs. 34.2 years), and had a higher proportion of comorbidity-specific conditions (96% vs. 64%) (Table 1). Furthermore, the allergic asthma subgroup had fewer mean severe exacerbations in the previous year (1.94 vs. 2.30) and a higher mean pre-bronchodilator FEV1 (1.85 L vs. 1.67 L). Compared to patients who did not meet the criteria for allergic asthma, these patients also had higher serum TARC concentrations (median 327 pg / mL vs. 277 pg / mL) and similar FeNO levels (median 26 ppb vs. 23 ppb) and blood eosinophil counts (median 250 cells / μL vs. 260 cells / μL).

[0541] end

[0542] The endpoints of the analysis were the annualized rate of severe exacerbations, changes in pre-bronchodilator FEV1(L) from baseline, and changes in ACQ-5 scores from baseline during the 52-week treatment period in subgroups of patients who met and did not meet the criteria for allergic asthma. Within each subgroup, the changes in severe exacerbations during the 52-week treatment period and pre-bronchodilator FEV1(L) from baseline at week 12 were also analyzed in patients with baseline serum eosinophil counts ≥150 cells / μL, ≥300 cells / μL, and baseline exhaled nitric oxide (FeNO) ≥25 ppb. Additional analyses were performed on a subset of allergic asthma patients with baseline serum total IgE >700 IU / mL who were not prescribed omalizumab therapy in the United States.

[0543] In both allergic and non-allergic asthma subgroups, the effects of dupilumab treatment on biomarkers of the following type 2 inflammations were also evaluated: serum total IgE levels; FeNO levels; and serum thymus and activated regulatory chemokine (TARC) levels. In patients who tested positive at baseline (≥0.35 kU / L), the effects of dupilumab treatment on serum specific IgE levels for each perennial airborne allergen tested during the 52-week treatment period were also examined.

[0544] Table 1. Baseline Demographic and Disease Characteristics

[0545]

[0546] Statistical analysis

[0547] Efficacy analyses were performed in an intention-to-treat (ITT) cohort defined as all patients randomly assigned to a subgroup (i.e., those with or without a total serum IgE ≥30 IU / mL and ≥1 positive perennial airborne allergen-specific IgE value (≥0.35 kU / L) at baseline). Data for each subgroup were analyzed according to the four assigned treatment groups (dupixumab vs. placebo), regardless of intervention status (Castro et al. (2018) New Engl. J. Med. 378: 2486-96). The annualized rate of severe exacerbations during the 52-week treatment period was analyzed using a negative binomial regression model, which included the assigned intervention group, age, geographic region, baseline eosinophil count, baseline inhaled corticosteroid dose, and the number of severe exacerbations in the previous year as covariates. All severe exacerbations occurring during the 52-week treatment period were included, regardless of whether patients maintained treatment.

[0548] A mixed-effects model with repeatable measures was used to analyze changes from baseline in pre-bronchodilator FEV1(L) and ACQ-5 scores during the 52-week treatment period. Covariates included four assigned intervention groups, age, geographic region, baseline eosinophil level, baseline inhaled corticosteroid dose, visits, visits via intervention interaction, corresponding baseline values, and baseline values ​​obtained via visit interaction. Additionally, sex and baseline height were included as covariates in the FEV1 analysis. Any measurements recorded after treatment cessation during the entire 52-week treatment period were included if treatment was discontinued.

[0549] Biomarker analyses were performed in the exposed population, defined as all patients exposed to the study drug. For two patient subgroups, rank analysis of a covariance model was used to analyze the differences in changes from baseline in eosinophil and FeNO levels (considered key biomarkers of type 2 inflammation) between dupilumab and matched placebo. The covariance model included four assigned intervention groups, age, sex, geographic region, baseline eosinophil level, baseline inhaled corticosteroid dose, and corresponding baseline values ​​as covariates. For the analysis of specific IgE, the analysis was limited to patients who were positive for specific IgE (≥0.35 kU / L) at baseline.

[0550] A nominal p-value <0.05 for comparisons between each dupilumab dose and matched placebo (within each subgroup) was considered statistically significant.

[0551] The residuals of the linear mixture model from the allergic subgroup with baseline serum IgE > 700 IU / mL were examined to ensure a normally distributed population. Histograms of the residuals and qq plots are shown in Figure 6.

[0552] Example 2: Annualized Severe Asthma Exacerbation Rate - Allergic Asthma

[0553] In the allergic asthma subgroup, dupilumab reduced the modulated annualized rate of severe exacerbations by 36.9% at 200 mg q2w (95% confidence interval (CI) 13.4%–54.0%; nominal P = .004) and by 45.5% at 300 mg q2w (95% CI 26.0%–59.9%; nominal P < .001; Figure 1A) compared to matched placebo. In patients who did not meet the criteria for allergic asthma, compared with placebo, the adjusted annualized rate of severe exacerbations was significantly reduced by 60.0% (95% CI 42.7% to 72.1%; nominal P < .001) with dupilumab 200 mg q2w and by 44.6% (95% CI 21.5% to 60.9%; nominal P < .001) with 300 mg q2w (Figure 1A). In both the allergic asthma and ineligible subgroups, dupilumab 200 mg and 300 mg q2w significantly reduced the rate of severe exacerbations in patients with baseline blood eosinophil counts ≥150 cells / μL and ≥300 cells / μL, and in patients with baseline FeNO ≥25 ppb (all nominal P < .01). The magnitude of the effect was numerically larger compared to the corresponding overall subgroups (Figures 1B–1D). In the allergic asthma subgroup, patients with baseline serum total IgE >700 IU / mL, both dupilumab doses significantly (nominal P < .001) reduced the rate of severe exacerbations over a 52-week treatment period compared with matched placebo, and the magnitude of the effect was numerically larger than that in the overall allergic asthma subgroup (Figure 1E).

[0554] Example 3: Pre-bronchodilator FEV1-allergic asthma

[0555] At week 12, dupilumab 200 mg and 300 mg q2w treatment significantly improved pre-bronchodilator FEV1 compared to placebo, with improvements of 0.13 L (95% CI 0.05 to 0.20; nominal P < .001) and 0.16 L (95% CI 0.09 to 0.23; nominal P < .001) respectively in the allergic asthma subgroup, and improvements of 0.14 L (95% CI 0.07 to 0.22; nominal P < .001) and 0.09 L (95% CI 0.01 to 0.16; nominal P = .02) respectively compared to placebo in those patients who did not meet the criteria described above (Figure 2A). As observed for severe exacerbations, the magnitude of improvement in prebronchodilator FEV1 at week 12 compared to placebo was equal to or greater than the magnitude of improvement described in the corresponding overall subgroups in patients with baseline blood eosinophil counts ≥150 cells / μL and ≥300 cells / μL, and in those with baseline FeNO ≥25 ppb (all nominal P < .05; Figure 2B). In the allergic asthma subgroup, patients with baseline serum total IgE >700 IU / mL showed a similar dose order of action for pre-bronchodilator FEV1 at week 12 compared to the overall subgroup (mean difference in mean LS compared to placebo was 0.12L (95% CI -0.03 to 0.26; nominal P = .11)), while a larger dose order of action was observed in patients treated with dupilumab 200 mg q2w (mean difference in mean LS compared to placebo was 0.27L (95% CI 0.13 to 0.42); nominal P < .001)).

[0556] In both the allergic and non-allergic subgroups, improvements in pre-bronchodilator FEV1 were observed as early as the first evaluation in week 2 and continued until week 52 (Figure 2A).

[0557] Example 4: Asthma Control - Allergic Asthma

[0558] In the allergic asthma subgroup, patients treated with dupilumab 200 mg q2w showed an improvement of -1.39 (standard error [SE] 0.05) in the mean change of ACQ-5 score from baseline compared to placebo (95% CI -0.46 to -0.11; nominal P < .01), and patients treated with dupilumab 300 mg q2w showed an improvement of -1.42 (SE 0.05) in the mean change of ACQ-5 score from baseline at week 24 compared to placebo (95% CI -0.44 to -0.08; nominal P < .01) (Figure 3). In the subgroup that did not meet the criteria for allergic asthma, patients treated with dupilumab 200 mg q2w showed an improvement of -1.51 from baseline in ACQ-5 score at week 24 (SE 0.06) and a difference of -0.44 compared to placebo (95% CI -0.65 to -0.22; nominal P < .0001), and patients treated with dupilumab 300 mg q2w showed an improvement of -1.35 from baseline in ACQ-5 score at week 24 (SE 0.06) and a difference of -0.08 compared to placebo (95% CI -0.29 to 0.12; nominal P = .43) (Figure 3).

[0559] Example 5: Serum total IgE and airborne allergen-specific IgE - allergic asthma

[0560] In both the allergic asthma subgroup and the subgroup that did not meet the criteria for allergic asthma, dupilumab 200 mg and 300 mg q2w dose regimens significantly reduced total serum IgE at week 12 compared with matched placebo (earliest assessment time point; nominal P < .001; Figure 4A). The reduction in total serum IgE was gradual throughout the treatment period (nominal P < .001 at all time points compared with placebo).

[0561] In patients with allergic asthma who tested positive at baseline for the corresponding perennial airborne allergen (≥0.35 kU / L), a significant percentage decrease in antigen-specific serum IgE levels from baseline was observed over time for each of the eight perennial airborne allergens assessed (Figures 5A–5H). These reductions were statistically significant at week 12 (the earliest assessment time point) compared to matched placebo (nominal P < .05) and continued throughout the 52-week treatment period. Too few patients tested positive for the Oriental cockroach allergen to allow for meaningful analysis.

[0562] Example 6: FeNO and serum TARC-allergic asthma

[0563] In both the allergic asthma subgroup and the subgroup that did not meet the criteria for allergic asthma, dupilumab 200 mg and 300 mg q2w dosing regimens were associated with a significant reduction in FeNO at the first evaluation after 2 weeks of treatment compared to placebo. FeNO remained low throughout the 52-week treatment period (nominal P < .001 at all time points) (Figure 4B). By week 52, the median FeNO values ​​for dupilumab 200 mg and 300 mg q2w doses in both subgroups were similar to the published median (16 ppb) in healthy volunteers.

[0564] In both the allergic asthma subgroup and the subgroup that did not meet the criteria for allergic asthma, serum TARC concentrations were significantly lower at week 12 (the earliest assessment time point) in patients treated with dupilumab 200 mg or 300 mg q2w compared to matched placebo. These reductions persisted throughout the 52-week treatment period (nominal P < .001 at all time points) (Figure 4C).

[0565] Example 7: Discussion - Allergic Asthma

[0566] Dupilumab significantly reduced the rate of severe exacerbations and improved FEV1 and asthma control (as measured by ACQ-5) in patients with allergic asthma. Improvements in FEV1 and asthma control were visible at the first evaluation at week 2 and persisted throughout the 52-week treatment period. Some variability in the magnitude of exacerbation rate and asthma control was observed between two dupilumab doses and their corresponding placebos. This is not intended to be construed as scientifically sound and may be related to the need to use two different matched volumes of placebo. The reduction in the rate of severe exacerbations and the improvement in FEV1 were more pronounced in patients with higher baseline levels of type 2 inflammatory biomarkers. The proportion of patients meeting the criteria for allergic asthma in this study (57%) was significantly lower than that of patients in the overall QUEST cohort who reported a history of ≥1 specific condition (Castro et al. (2018) New Engl. J. Med. 378: 2486-96). This difference is primarily due to the exclusion of patients with a history of allergic rhinitis but no signs of hypersensitivity to airborne allergens, patients with hypersensitivity to seasonal allergens only (to a lesser extent), and patients with perennial allergen sensitivity but whose total serum IgE is <30 IU / mL. It should be acknowledged that the timing of specific IgE measurements in this global study was not designed to coincide with peak seasonal allergen exposure in each country.

[0567] Dupilumab has shown efficacy in patients with allergic asthma, as well as in those who do not meet the criteria for allergic asthma. These findings support the key roles of IL-4 and IL-13 in IgE-mediated and non-IgE-mediated type 2 inflammation driving asthma. The clinical benefit observed in this study extends to patients with allergic asthma whose serum total IgE at baseline exceeds 700 IU / mL. This is a clinically relevant subset of patients with allergic asthma who are not prescribed omalizumab as anti-IgE therapy in the United States. (See USDA website: accessdata.fda.gov / drugsatfda_docs / label / 2003 / omalgen062003LB.pdf, accessed April 2, 2019). This subgroup was included in the analysis because, unlike omalizumab, dosing of dupilumab is not limited by weight and serum total IgE in adolescents and adults with uncontrolled moderate to severe asthma.

[0568] Consistent with the mechanism of action of dupilumab in inhibiting IgE production, dupilumab significantly reduced serum total IgE and airborne allergen-specific IgE in patients with allergic asthma, and also reduced serum total IgE in patients who did not meet the criteria for allergic asthma.

[0569] Similarly, dupilumab significantly reduced the levels of other type 2 inflammatory biomarkers, including FeNO and serum TARC, in both patient subgroups. The decrease in total IgE and specific IgE was slower compared to other biomarkers (such as FeNO). The decrease in IgE concentrations did not plateau during the 52-week treatment period.

[0570] In summary, this is the first confirmed clinical and pharmacodynamic effect of dupilumab's dual IL-4 and IL-13 inhibition in patients with allergic asthma defined by total serum IgE ≥30 IU / mL and ≥1 perennial airborne allergen-specific IgE ≥0.35 kU / L at baseline. Dupilumab significantly reduced the rate of severe exacerbations, improved FEV1, and demonstrated clinically meaningful improvements in asthma control (ACQ-5) over a 52-week treatment period, regardless of subgroup, and the treatment was generally well tolerated in the overall study population. Dupilumab treatment in both subgroups also significantly reduced markers of type 2 inflammation, including FeNO, total IgE, and TARC. The findings from this study support the role of IL-4 and IL-13 in IgE and non-IgE-mediated inflammatory pathways in asthma. IL-4 / IL-13 inhibition induced by dupilumab therapy is beneficial for both allergic and non-allergic asthma phenotypes.

[0571] Example 8: Efficacy of dupilumab in patients with uncontrolled moderate to severe asthma and serological signs of allergic bronchopulmonary aspergillosis (ABPA).

[0572] Allergic bronchopulmonary aspergillosis (ABPA) is a severe allergic lung disease caused by a hypersensitivity reaction to the Aspergillus fumigatus (Af) antigen. Not all patients with asthma will develop ABPA upon exposure to the fungus. However, individuals with a genetic predisposition (HLA-DR2 (HLA-DRB1*1501 and *HLA-DRB1*1503) and HLA-DR5) are more susceptible to ABPA upon exposure to the Af antigen. SNPs of IL-4Rα and IL-13 are also involved in genetic susceptibility, and these individuals exhibit a significantly increased type 2 immune response with very high IgE, eosinophil counts, elevated FeNO, etc.

[0573] The primary treatment for ABPA is systemic steroids. However, not all patients respond to systemic steroids, and the disease can progress to bronchiectasis and fibrosis. Therefore, there is a high unmet need for treatment of subjects with ABPA.

[0574] Research

[0575] The Phase 3 LIBERTY ASTHMA QUEST study (NCT02414854) evaluated patients with serological signs of ABPA (baseline total serum IgE >1000 IU / mL, positive serum IgE-Af >0.35 IU / mL, and blood eosinophils >500 cells / μL) who received adjunctive dupilumab (200 mg or 300 mg) and placebo every 2 weeks.

[0576] group

[0577] Of the 1,902 patients with moderate to severe asthma who participated in QUEST, 30 patients (1.6%) were identified with serological signs of ABPA (ABPA-S). Baseline characteristics of these patients and the remaining intention-to-treat (ITT) cohort of QUEST (n = 1,872) are shown in Table 2. At baseline, no significant differences were observed in mean age, FEV1, ACQ-5, or Asthma Quality of Life Questionnaire (AQLQ) between patients with and without ABPA-S, but patients with ABPA-S had higher baseline levels of type 2 biomarkers, namely eosinophils, IgE, and FeNO, compared to asthma patients without ABPA-S.

[0578] End point / visit

[0579] The annualized rate of severe exacerbations (defined as worsening of asthma symptoms requiring ≥3 days of systemic corticosteroid treatment or hospitalization or emergency room visit requiring systemic corticosteroid treatment) and changes in pre-bronchodilator FEV1(L) from baseline and patient-reported five-item Asthma Control Questionnaire-5 (ACQ-5) scores were assessed at regular intervals at baseline at baseline and throughout the 52-week treatment period (Figure 7). The mean change in pre-bronchodilator FEV1(L) from baseline was measured in the ITT population at weeks 24 and 52 (Figure 8). Total (absolute) serum IgE was measured in the exposed population at week 52 (Figure 9). Total (absolute) Af-specific serum IgE was measured in the exposed population at week 52 (Figure 10). Total (absolute) FeNO levels were measured in the exposed population at week 52 (Figure 11).

[0580] Treatment group

[0581] The regimen included dupilumab 200 mg q2w, dupilumab 300 mg q2w, and a matched placebo.

[0582] result

[0583] The annualized rate of severe exacerbations during the 52-week treatment period was analyzed using a negative binomial regression model. The change in the mean LS of FEV1 from baseline to week 24 and week 52 was determined using a mixed-effects model with repeatability. Total IgE, IgE-Af, and FeNO at week 52 were assessed using the Wilcoxon rank-sum test.

[0584] In patients with ABPA-S, dupilumab significantly reduced the annualized rate of severe exacerbations by 81.1% compared with placebo (95% confidence interval [CI] 0.052–0.693; P = .01) (Figure 12).

[0585] Prebronchodilator FEV1

[0586] Improvements in prebronchodilator FEV1 were observed in dupilumab-treated patients with ABPA-S compared to those treated with placebo. These improvements were observed as early as week 2 (the first time point for patient evaluation) and persisted throughout the 52-week treatment period (Figure 13). Dupilumab improved prebronchodilator FEV1 in patients with ABPA-S compared to placebo, with a mean least-squares (LS) difference of 0.21 L (95% CI -0.18 to 0.60; P = .28) at week 12 and 0.33 L (-0.02 to 0.68; P = .07) at week 52.

[0587] Asthma control

[0588] In patients with ABPA-S, dupilumab improved ACQ-5 scores compared to placebo as early as 2 weeks after treatment initiation, with a mean LS difference of -0.56 (95% CI –1.09 to –0.02; P < .05). This continued throughout the 52-week treatment period, with numerical improvements in ACQ-5 scores at every time point except weeks 12 and 16. At week 52, dupilumab improved ACQ-5 scores compared to placebo, with a mean LS difference of -0.20 (-0.86 to 0.46; P = .54) (Figure 4).

[0589] Serum total IgE and Aspergillus fumigatus-specific IgE

[0590] Baseline serum total IgE was significantly elevated in ABPA-S patients compared to asthma patients without ABPA-S (median: 2148–3383 IU / mL vs. 159–165 IU / mL). During treatment, starting at the earliest assessment point at week 12, a significant decrease in serum total IgE was observed in ABPA-S patients treated with dupilumab compared to those treated with placebo (Figure 15A). These decreases continued to gradually decline throughout the treatment period, and by week 52, the median serum total IgE concentration was 691.5 IU / mL (95% CI 323.0–2617.0), representing a median percentage change from baseline of -75.6% (-81.6 to -44.6). In patients treated with placebo, the concentration at week 52 was 1714.0 IU / mL (95% CI 727.0–3048.0), with a median percentage change from baseline of -19.6% (95% CI -56.3 to 102.6; P < .01) (Figure 15A). This is similar to the median percentage change from baseline observed in the overall ITT population of the QUEST study (dupixumab -69.5% [95% CI -79.0 to -56.9] vs. placebo -3.6% [95% CI -22.7 to 20.8]), suggesting that the median percentage change from baseline in total serum IgE is similar with dupilumab and independent of baseline IgE levels.

[0591] In patients with ABPA-S, dupilumab treatment also suppressed Aspergillus fumigatus-specific IgE levels from a median baseline of 2.4 IU / mL (95% CI 0.6–11.2) (median baseline 3.0 IU / mL [95% CI 0.5–28.8] in the placebo group). These reductions became apparent by week 12. After further gradual reductions, the median Aspergillus fumigatus-specific IgE concentration in dupilumab-treated patients was 0.8 IU / mL (95% CI 0.1–2.6) at week 52, representing a median percentage change from baseline of -74.8% (95% CI -83.5 to -56.2). The corresponding values ​​in placebo-treated patients were 4.6 IU / mL (95% CI 0.6–21.5) and -40.4% (95% CI -71.2 to 208.9; P < .05) (Figure 15B).

[0592] Other type 2 biomarkers

[0593] In patients with ABPA-S, the median baseline FeNO concentrations were 49.0 ppb (95% CI 24.0–68.0) in the dupilumab group and 31.0 ppb (95% CI 19.0–63.0) in the placebo group. Dupilumab reduced FeNO concentrations from baseline as early as week 2 of treatment, with a median concentration of 18.0 ppb (95% CI 12.0–26.0) and a median percentage change of -50.8% (95% CI –62.5 to –41.9) in the dupilumab group, compared to a median concentration of 38.0 ppb (95% CI 23.0–50.0) and a percentage change of -5.0% (95% CI –25.4 to 50.0) in the placebo group (P<.01). The reduction in FeNO persisted until week 52, with a median of 18.0 ppb (95% CI 12.0–26.0) and a median percentage change of -60.0% (95% CI –75.0 to –32.7) in patients treated with dupilumab, compared to a median of 25.0 ppb (95% CI 10.0–56.0) and a median percentage change of -24.3% (95% CI –52.2 to 57.1) in patients treated with placebo (P<.05) (Figure 16A). Dupilumab treatment reduced FeNO to a level similar to the median of 16 ppb reported for healthy volunteers.

[0594] In patients with ABPA-S, dupilumab treatment also reduced serum TARC concentrations. The median baseline serum TARC concentrations in the dupilumab and placebo groups were 553.0 pg / mL (95% CI 442.0–1510.0) and 646.0 pg / mL (385.0–894.0), respectively. At week 12, dupilumab reduced serum TARC concentrations to a median of 257.0 pg / mL (193.0–438.0) and a median percentage change from baseline of -62.0% (-76.0 to -35.3), compared to a median of 674.0 pg / mL (462.0–900.0) and a median percentage change of -10.1% (-17.9 to 15.1) in patients treated with placebo (P<.01). These significant reductions persisted throughout the 52-week treatment period, with a median reduction of 234.0 pg / mL (182.0–336.0) at week 52 in patients treated with dupilumab and a median percentage change from baseline of -66.1% (-79.6 to -51.0), compared to a median reduction of 580.0 pg / mL (451.0–1020.0) in the placebo group and a median percentage change from baseline of -17.4% (-35.7 to 25.8) (P<.01) (Figure 16B).

[0595] In patients with ABPA-S, dupilumab treatment also reduced serum eosinophil chemokine-3 concentrations. The reduction was observed starting at week 12, with a median value of 24.5 pg / mL (95% CI 18.0–41.7) and a median percentage change from baseline of -64.9% (-83.3 to -44.7) in dupilumab-treated patients, compared to a median value of 53.1 pg / mL (23.0–125.0) and a median percentage change from baseline of -5.4% (-40.6 to 34.8) in the placebo group (P < .01). These reductions persisted until week 52, with a median of 23.2 pg / mL (16.1–32.1) and a percentage change of -73.1% (-85.0 to -48.6) in the dupilumab group, compared to a median of 35.7 pg / mL (19.3–78.7) and a percentage change of -29.3% (-80.2 to 27.2) in the placebo group (P<.05) (Figure 16C).

[0596] In ABPA-S patients, the median blood eosinophil count at baseline was elevated (825–1075 eosinophils / μL). At week 52, the median blood eosinophil count in patients treated with dupilumab was 595.0 cells / μL (95% CI 360.0–1160.0) with a median percentage change from baseline of -31.3% (-55.2 to 0), compared to 590.0 cells / μL (340.0–1080.0) in patients treated with placebo with a median percentage change from baseline of -45.5% (-55.5 to 0) (P = .69) (Figure 16D).

[0597] Safety in patients with ABPA-S

[0598] The incidence of treatment-induced adverse events (TEAEs) during treatment was similar in patients with ABPA-S and was independent of the treatment received (94.4% in the dupilumab combination versus 100% in the placebo combination) (Table 3). The most common TEAE occurring at a higher rate in patients receiving dupilumab than in those receiving placebo (27.8% in dupilumab versus 25.0% in placebo) was upper respiratory tract infection. Injection site reactions (high-level term in the International Dictionary of Medical Terms) occurred in 16.7% of patients treated with dupilumab versus 0% of patients treated with placebo. All cases of eosinophil count >3000 / mm3 within the 52-week intervention period were reported as adverse events, according to the trial protocol. One ABPA-S patient (5.6%) treated with dupilumab 200 mg every 2 weeks (q2w) reported moderate eosinophilia. This was a laboratory finding without related symptoms, and the patient completed the 52-week treatment period. No eosinophilia was reported in patients treated with dupilumab 300 mg or placebo. Serious TEAEs were reported in 1 patient (5.6%) treated with dupilumab and 2 patients (16.7%) treated with placebo. No TEAEs resulting in death were reported in this cohort.

[0599] discuss

[0600] In the LIBERTY ASTHMA QUEST study, dupilumab demonstrated a beneficial effect in a subgroup of patients subsequently identified as meeting the diagnostic criteria for ABPA-S. Treatment with dupilumab significantly reduced the rate of severe exacerbations and showed a trend toward improved lung function. Although the improvement in FEV1 may not have been statistically significant due to the small sample size, the change in mean FEV1 from baseline of 510 mL at week 52 was clinically significant in patients treated with dupilumab. Improvements in FEV1 occurred rapidly as early as 2 weeks after treatment initiation and persisted throughout the 52-week treatment period. Dupilumab treatment also improved asthma control (ACQ-5 score) in this subgroup of patients whose symptoms are typically difficult to control.

[0601] Consistent with the pathophysiology of ABPA, this subgroup of patients exhibits robust signs of type 2 inflammation, with significantly elevated baseline levels of type 2 biomarkers (including FeNO, blood eosinophils, TARC, serum total IgE, and Aspergillus fumigatus-specific IgE) compared to asthma patients with serological signs of ABPA. Without being bound by scientific theory, the increased FeNO in ABPA patients may indicate accompanying airway inflammation rather than being driven by an allergic reaction, further highlighting the utility of FeNO as a marker of type 2 inflammation. Two defining diagnostic features of ABPA are very high serum concentrations of total IgE and Aspergillus fumigatus-specific IgE. Studies have shown that B cells from patients with ABPA are more sensitive to IL-4 and spontaneously produce large amounts of IgE, IgG, and IgA antibodies against Aspergillus fumigatus antigens. In practice, monitoring serum total IgE concentrations is routinely monitored in the management of ABPA to assess disease activity, with a decrease to near-normal levels considered a marker of disease remission. Dupilumab treatment significantly suppressed both total and specific IgE, consistent with its mechanism of action, which inhibits B-cell isotype switching by blocking IL-4 and IL-13 signaling, thereby suppressing IgE production. Furthermore, biomarkers of type 2 inflammation in the blood (TARC and eosinophil chemokine-3) and local airways (FeNO) were rapidly suppressed in ABPA-S patients treated with dupilumab, indicating that dupilumab can rapidly control the underlying pathogenic type 2 inflammation common to ABPA patients through its dual blockade of IL-4 and IL-13.

[0602] Dupilumab is generally well tolerated in ABPA patients, with similar rates of TEAEs in both dupilumab-treated and placebo-treated patients. The most common TEAE observed in dupilumab-treated patients was upper respiratory tract infection. Unlike transient eosinophilia observed in patients with asthma, only one (5.6%) ABPA patient treated with dupilumab reported intra-treatment eosinophilia in this analysis, although these patients had high eosinophil counts at baseline (median concentration 925.0 cells / μL). Furthermore, unlike asthma studies where eosinophil counts remained unchanged at week 52, ABPA-S patients in this analysis showed an overall decrease in median blood eosinophil count during the 52-week treatment period.

[0603] Clinically, asthma patients with ABPA have poorer symptom control and more frequent exacerbations compared to patients without ABPA. Unlike asthma, ABPA progresses to decreased lung function and fibrotic end-stage lung disease if diagnosis is delayed or treatment is inadequate. These data suggest the efficacy of dupilumab as a novel treatment for patients with ABPA, improving symptoms and lung function by controlling the underlying pathogenic type 2 inflammation.

[0604] Table 2. Baseline demographics and clinical characteristics of the overall ITT patient population with and without ABPA serological signs.

[0605]

[0606]

[0607] ABPA, Allergic Bronchopulmonary Aspergillosis; ACQ-5, 5-item Asthma Control Questionnaire; AQLQ, Asthma Quality of Life Questionnaire; BMI, Body Mass Index; ECP, Eosinophilic Cationic Protein; ICS, Inhaled Corticosteroids; IQR, Interquartile Range; ITT, Intention to Treat; FeNO, Exhaled Nitric Oxide; FEV1, Forced Expiratory Volume in One Second; LABA, Long-Acting Beta-2 Agonist; ppb, Parts Per Billion; q2w, Every 2 Weeks; SD, Standard Deviation; TARC, Thymus and Activator of Chemokine.

[0608] Table 3. Adverse events during treatment in patients with serological signs of ABPA present during intervention – safety population

[0609]

[0610]

[0611] ABPA, Allergic Bronchopulmonary Aspergillosis; MedDRA, International Medical Dictionary; PT, Preferred Terminology; q2w, Every 2 Weeks; TEAE, Adverse Events During Treatment. One patient with ABPA-S in the dupilumab treatment group reported eosinophilia, compared to none in the placebo group. Serious TEAEs include gastroenteritis and asthma in patients treated with placebo, and musculoskeletal chest pain and osteoarthritis in patients treated with dupilumab. Unless otherwise stated, adverse events in this category are reported by PT in MedDRA version 20.0. § Injection site reaction is a high-level term in MedDRA.

[0612] Example 9: Post-hoc analysis of yellow fever vaccine: An open-label extension study evaluating the long-term safety and tolerability of dupilumab in asthmatic patients who participated in previous dupilumab asthma clinical trials.

[0613] Research Design

[0614] The LTS12551 (TRAVERSE) study is a multinational, multicenter, single-arm, open-label, extended study evaluating the long-term safety and tolerability of dupilumab 300 mg q2w in patients with asthma. Patients in this study completed treatment and follow-up in study DRI12544 or in studies EFC13579, EFC13691, or PDY14192. DRI12544 (N=776) is a phase 2b, randomized, double-blind, placebo-controlled, dose-variable, parallel-group study comparing different doses and regimens of subcutaneous (SC) dupilumab for 24 weeks in adult patients with moderate to severe uncontrolled asthma. PDY14192 (N=42) is a phase 2a, exploratory, randomized, double-blind, placebo-controlled study of the effects of dupilumab 300 mg q2w SC for 12 weeks on airway inflammation in adults with uncontrolled persistent asthma. EFC13579 (N=1902) is a phase 3, randomized, double-blind, placebo-controlled, parallel-group study evaluating the efficacy and safety of dupilumab 200 mg and 300 mg q2w SC for 52 weeks in adult and adolescent patients with uncontrolled persistent asthma. EFC13691 (N=210) is a phase 3, randomized, double-blind, placebo-controlled study evaluating the efficacy and safety of dupilumab 300 mg q2w SC for 24 weeks in adult and adolescent patients with severe OCS-dependent asthma.

[0615] While the LTS12551 study was underway, a yellow fever outbreak in Brazil necessitated the administration of yellow fever vaccine (YFV) to all unvaccinated individuals located in at-risk areas. The sponsor implemented Amendment 5 to the regional agreement, which allowed the administration of YFV (live attenuated vaccine) to all patients in need of YFV within the outbreak-affected areas. All affected patients were instructed to discontinue dupilumab and were eligible for vaccination after discontinuation. Patients were allowed to reactivate dupilumab at the investigator's discretion after demonstrating sufficient yellow fever neutralizing titers (i.e., plaque reduction neutralizing titers; PRNT). Once the outbreak subsided, unvaccinated patients were eligible to restart study treatment.

[0616] All patients continued to be followed up until the end of the study, regardless of whether dupilumab treatment was re-established. For those patients scheduled for yellow fever vaccination, samples for pharmacokinetic (PK) and immunogenicity assessments, as well as pre- and post-vaccination antibody titers, were collected 4–6 weeks before and after vaccination, and possibly extended to 8 weeks, with patient consent. Overall, thirty-seven patients discontinued dupilumab treatment and subsequently received the YFV vaccine. Although patients were allowed to resume dupilumab treatment at the discretion of their treating physicians after demonstrating neutralizing titers, none of them resumed dupilumab treatment due to delays in results.

[0617] A post-hoc YFV analysis was performed to evaluate humoral immune response and safety / tolerability of YFV in this subset of 37 patients who participated in the LTS12551 study and received YFV.

[0618] Research Objectives

[0619] The goal of this study was to evaluate the humoral immune response, safety, and tolerability of YFV (a live attenuated vaccine) in patients with moderate to severe asthma who participated in the LTS12551 study and were treated with dupilumab.

[0620] patient

[0621] This analysis included a total of 37 patients who participated in the LTS12551 study (an open-label asthma study) and received YFV. Of these, 33 were from the EFC13579 study and four were from the EFC13691 study. Among the patients enrolled in EFC13579, 11 had previously received placebo in the parent study and then received dupilumab in the LTS12551 study (placebo / dupilumab class), and 22 had previously received dupilumab in the parent study and continued dupilumab treatment in the LTS12551 study (dupilumab / dupilumab class). Among the patients enrolled from EFC13691, three patients had previously been treated with placebo in the parental study and then received dupilumab (placebo / dupilumab class) in the LTS12551 study, and one patient had previously been treated with dupilumab in the parental study and continued dupilumab treatment in the LTS12551 study (dupilumab / dupilumab class).

[0622] Demographic and other baseline characteristics

[0623] The baseline demographics and patient characteristics of the 37 patients receiving YFV were generally similar to those of patients who had previously received placebo or dupilumab in their respective parental studies (see Table 4 below). The mean age of the population was 46.5 years, ranging from 24 to 68 years, with 5 patients (13.5%) being ≥65 years old and 12 patients (32.4%) being male. The mean (SD) BMI (body mass index) was 30.1 (5.7) kg / m². 2 .

[0624] Table 4. Demographic and patient characteristics since yellow fever vaccination - Exposed population - Patients vaccinated with yellow fever in the LTS12551 study

[0625]

[0626]

[0627] Note: Age, weight, height, and BMI were summarized prior to yellow fever vaccination based on the last available assessment; and other demographics were baselines from parental studies.

[0628] The percentage is calculated using the number of patients assessed as the denominator.

[0629] a Asia: Japan, South Korea, and Taiwan; Latin America: Argentina, Brazil, Colombia, Chile, and Mexico; Eastern Europe: Hungary, Poland, Russia, Turkey, and Ukraine.

[0630] Western countries: Australia, Canada, France, Germany, Italy, South Africa, Spain, the United Kingdom, and the United States

[0631] b South America: Canada and the United States; European Union: France, Germany, Hungary, Italy, Poland, Spain, and the United Kingdom; the rest of the world: Argentina, Australia, Brazil, Colombia, Chile, Japan, Mexico, Russia, South Africa, South Korea, Taiwan, Turkey, and Ukraine.

[0632] Medical history

[0633] Patients' comorbidities are shown in Table 5. The majority of patients (91.9%) had a history of comorbidities, with allergic rhinitis being the most common (86.5%).

[0634] Table 5. Comorbidity history of parental studies - exposed populations - patients vaccinated against yellow fever in the LTS12551 study

[0635]

[0636]

[0637] Note: The history of comorbid diseases is the baseline from parental studies.

[0638] a If a patient has a history of or currently has one of the following conditions: atopic dermatitis, allergic conjunctivitis, allergic rhinitis, chronic sinusitis, nasal polyposis, food allergies, or urticaria, the patient will be considered to have a history of comorbidity or a persistent comorbidity.

[0639] b Both allergic conjunctivitis and allergic rhinitis are persistent.

[0640] Safety assessment

[0641] Exposure level

[0642] Table 6 summarizes the extent of exposure to the study drug in the LTS12551 group prior to yellow fever vaccination. The mean (SD) duration of dupilumab treatment in the LTS12551 study was 242.2 (34.4) days, and was similar across all patients receiving YFV. In patients from the EFC13579 study, the mean treatment duration was similar between placebo / duppilumab and dupilumab / duppilumab class (255.0 and 230.1 days, respectively). In patients from the EFC13691 study, the mean treatment duration was similar between placebo / duppilumab and dupilumab / duppilumab class (274.7 and 268.0 days, respectively).

[0643] Table 6. Exposure to the study product prior to yellow fever vaccination – Exposed population – Patients vaccinated against yellow fever in the LTS12551 study

[0644]

[0645] As shown in Table 7, the time between the last dose of dupilumab and the yellow fever vaccination varied from 7 to 51 days, with a mean (SD) of 22.3 (±11.9) days.

[0646] Table 7. Summary of the duration between the last IMP injection and yellow fever vaccination - Exposed population - Population vaccinated with yellow fever in the LTS12551 study

[0647]

[0648] Note: The duration is the time between the last IMP injection date prior to yellow fever vaccination and the date of yellow fever vaccination.

[0649] As shown in Table 8, the mean (SD) follow-up period for all patients after yellow fever vaccination was 186.6 (±72.3) days and ranged from 98 to 553 days.

[0650] Table 8. Summary of follow-up duration after yellow fever vaccination - Exposed population - Patients vaccinated with yellow fever in the LTS12551 study

[0651] Table 5 - Summary of follow-up duration after yellow fever vaccination - Exodus population - Patients vaccinated with yellow fever in the LTS12551 study

[0652]

[0653] Adverse events

[0654] A total of 37 patients received YFV. The vaccine was administered 7 to 51 days after the last dose of dupilumab. One of the 37 patients experienced a non-serious adverse event of bodily pain, feeling unwell and dizzy, reported as a “vaccination complication”. This occurred in a 45-year-old female patient with a history of atopic dermatitis (AD), allergic conjunctivitis, and chronic sinusitis. The event occurred 7 days after yellow fever vaccination and subsided within 2 weeks. The remaining 36 patients tolerated the vaccine and no adverse events possibly related to yellow fever vaccination were reported. No hypersensitivity reactions to the vaccine were reported. No patients resumed dupilumab due to delays in results. Among the 37 patients who received yellow fever vaccination in the LTS12551 study, no deaths, SAEs (serious adverse events) or other significant AEs (adverse events) occurring during treatment were reported.

[0655] Safety conclusions

[0656] YFV administered 7 to 51 days after dupilumab discontinuation was well tolerated in a group of 37 patients with asthma. Of these 37 patients, 36 reported no adverse reactions to YFV. One patient reported a completely regressed, transient, non-serious adverse event, which was a common response to yellow fever vaccination (Monath TP, Nichols R, Archabault WT, Moore L, Marchesani R, Tian J et al. Comparative safety and immunogenicity of two yellow fever 17D vaccines (ARILVAX and YF-VAX) in a phase III multicenter, double-blind clinical trial. Am J Trop Med Hyg. 2002; 66(5):533-541.). Therefore, patients with therapeutic or sub-therapeutic levels of dupilumab in this trial tolerated YFV.

[0657] Pharmacokinetics, immune response and immunogenicity evaluation

[0658] Humoral immune response to vaccines

[0659] Humoral immune response to YFV was determined using a standard plaque reduction neutralizing titer (PRNT) assay (Q Squared solution, LLC), where the reciprocal of the dilution that neutralizes 50% of the virus (PRNT50) was calculated. Post-vaccination neutralizing titers were obtained for all 37 patients, and pre- and post-vaccination PRNT titers were obtained for 23 of the 37 patients (Table 9). The patients' existing history of yellow fever vaccination and / or infection was unknown. As shown in Figures 17A and 17B, of the 23 patients who provided pre-vaccination serum, 13 had PRNT < 1:10 (defined as “seronegative”), while the other 10 patients had titers ranging from 1:10 to 1:160 (defined as “seropositive”).

[0660] All 37 patients exhibited a protective serum titer post-vaccination, defined as a PRNT titer >1:10, with a mean post-vaccination titer of 1:7699 (±10951 SD; median 2560, range 80 to 40960). As shown in Figures 17A and 17B, two of the 23 patients did not have a booster effect on their pre-vaccination titer after vaccination, and two patients already had a protective serum titer prior to YFV. Therefore, all 37 vaccinated patients had a protective yellow fever neutralizing serum titer post-vaccination, including the 13 patients who showed seroconversion with both pre- and post-vaccination titers.

[0661] Table 9. PK Sample Collection and Vaccinated Patients with PRNT Titers

[0662]

[0663] *13 Serum negative at baseline

[0664] Pharmacokinetic and Immunogenicity Evaluation

[0665] PK and ADA (anti-drug antibody) samples were collected before and after vaccination. Serum concentrations of functional dupilumab were measured before and after vaccination. Pre-vaccination PK and ADA samples were collected from 35 and 34 of the 37 patients, respectively. Post-vaccination PK and ADA samples were collected from all 37 patients. PK samples were obtained on the day of vaccination for nineteen patients. Pre-vaccination PK samples were obtained before YFV administration for sixteen patients (Table 9).

[0666] The duration between the last dupilumab dose and yellow fever vaccination, the duration between pre-vaccination PK sampling and yellow fever vaccination, and the duration between yellow fever vaccination and post-vaccination PK sampling are summarized in Table 10.

[0667] Dupilumab concentrations before and after yellow fever vaccination

[0668] During yellow fever vaccination, patients were exposed to dupilumab 300 mg q2w in LTS12551 for at least 24 weeks, reaching a steady-state mean trough concentration of 73.3 mg / L at week 24. On average, the duration between the last dupilumab dose and YFV administration was approximately 3 weeks (median duration 18 days, Table 7). Pre-vaccination PK samples were collected from 35 / 37 patients. The mean concentration of all pre-vaccination PK samples was 59.5 mg / L, with the limitation that not all PK samples were collected on the same day as yellow fever vaccination administration (Table 11). In 19 patients, pre-vaccination PK samples were collected on the same day as YFV administration. The mean dupilumab concentration in serum in those patients was 72.5 mg / L, similar to the mean steady-state dupilumab trough concentration observed in patients treated with dupilumab 300 mg q2w in clinical studies of dupilumab in asthma and AD. For 16 patients, pre-vaccination PK samples were collected 1 to 25 days before YFV administration, and the mean concentration for these patients was 44.0 mg / L.

[0669] Post-vaccination PK samples were collected approximately 5 weeks (range 28–54 days) after YFV administration and approximately 8 weeks (39–79 days) after the last dupilumab dose (Table 10). The mean concentration of the observed post-vaccination PK samples was 13.7 mg / L (N = 37), which was within the expected dupilumab concentration range, and had a washout period of approximately 8 weeks after the last steady-state dose of 300 mg q2w (Table 11).

[0670] Table 10. Summary of PK serum sampling time before and after yellow fever vaccination - PK population - patients vaccinated with yellow fever in the LTS12551 study

[0671]

[0672] Note: PK sampling time during visits before or after yellow fever vaccination refers to unplanned serum samples specifically collected for yellow fever vaccination.

[0673] When the concentration value is below the lower limit of quantification (LLOQ) of 78 ng / mL, half of the LLOQ (39 ng / mL) is used in the statistical summary.

[0674] Table 11. Summary of serum dupilumab concentrations before and after yellow fever vaccination - PK population - patients vaccinated against yellow fever in the LTS12551 study

[0675]

[0676] SEM: Standard error of the mean; CV: Coefficient of variation

[0677] Note: Serum samples were collected prior to the administration of IMP.

[0678] The PK concentrations at visits before or after yellow fever vaccination are from unplanned serum samples specifically collected for yellow fever vaccination.

[0679] When the concentration value is below the lower limit of quantification (LLOQ) of 78 ng / mL, half of the LLOQ (39 ng / mL) is used in the statistical summary.

[0680] Of the 23 patients, PK samples were collected pre-vaccination from 15 patients on the same day as YFV administration. The mean dupilumab concentration in these 15 patients was 76.4 mg / L. Thirteen of these 15 patients had dupilumab concentrations above the mean trough of 37.4 mg / L. It is assumed that serum concentrations above this level are therapeutic, and since 37.4 mg / L is the steady-state mean trough concentration observed in asthmatic patients at 200 mg q2w in the parental phase 3 study (EFC13579), it is consistent with saturation levels of IL-4Rα blockade.

[0681] All 13 patients with serum dupilumab concentrations >37.4 mg / L had protective serum PRNT titers after YFV. Twelve of these patients showed an increase in titer after vaccination, while one of the 13 patients did not show an increase but remained within the protective threshold at baseline. The fold change in PRNT titer levels in these patients is shown in Figure 18. The neutralizing titers in all 13 patients after vaccination ranged from 1:80 to 1:40960, which were comparable to those in patients with dupilumab concentrations <37.4 mg / L (1:160 to 1:40960).

[0682] In summary, this subset of 23 patients with pre- and post-vaccination PK and PRNT titers showed no relationship between serum dupilumab levels and PRNT titers.

[0683] Incidence and titer of ADA before and after yellow fever vaccination

[0684] Table 12 summarizes the incidence and titer categories of ADA observed in patients before and after YFV administration. Positive ADA test responses were observed in three patients before and after yellow fever vaccination. Among the patients with positive ADA test responses, one patient had a low ADA titer (<1000) and two patients had high ADA titers (>10000). The number of patients in each ADA titer category did not change before and after yellow fever vaccination, indicating that yellow fever vaccination had no significant effect on ADA responses. At the end of the study, positive ADA test responses were observed in one or more patients during follow-up, in addition to the three patients who tested positive before and after yellow fever vaccination. Therefore, during follow-up, two of the four patients with positive ADA test responses had low ADA titers (<1000) and two patients had high ADA titers (>10000).

[0685] Table 12. Summary of ADA titers before and after yellow fever vaccination - ADA population - patients vaccinated against yellow fever in LTS12551

[0686]

[0687]

[0688] Note: The percentages are calculated using the number of patients in the ADA population who had reportable ADA status at the time of visit and were vaccinated against yellow fever in the LTS12551 study as the denominator.

[0689] The ADA titers at visits before or after yellow fever vaccination were from unplanned ADA samples specifically collected for yellow fever vaccination.

[0690] Conclusions based on immune response and dupilumab PK

[0691] Immune response and dupilumab p-p-value data indicated that therapeutic serum levels of dupilumab did not suppress the protective immune response to yellow fever vaccination (a live attenuated vaccine). Serum levels continued to decline until post-vaccination titer assessment due to the re-administration of dupilumab after vaccination.

[0692] The effect of immune response to vaccine on the efficacy of dupilumab

[0693] The potential impact of yellow fever vaccination on dupilumab efficacy was evaluated by examining changes in FEV1 before and after vaccination. All patients who discontinued dupilumab treatment due to yellow fever vaccination had been exposed to dupilumab in LTS12551 for a mean duration of 0.7 years and achieved stable improvement in lung function before dupilumab discontinuation (Table 6). FEV1 was stable between visits prior to YFV administration and the first visit after YFV administration (Figures 19 and 20). The mean (SD) FEV1 was 2.08 (0.83) L and 1.98 (0.79) L (Table 13). Generally, based on data observed in EFC13579 and DRI12544, FEV1 levels can be expected to decline approximately 12 weeks after dupilumab discontinuation.

[0694] Table 13. Analysis of changes in FEV1(L) from baseline before and after yellow fever vaccination - Exposed population - Patients vaccinated with yellow fever in the LTS12551 study

[0695]

[0696]

[0697] in conclusion

[0698] In response to a regional yellow fever outbreak, 37 patients were enrolled in LTS12551 who discontinued dupilumab treatment and subsequently received YFV. Dupilumab did not reduce the efficacy of the attenuated yellow fever virus vaccine. All 37 patients who received the YFV vaccine showed post-vaccination yellow fever virus antibody titers consistent with serological protection. Neutralizing titers before and after vaccination were obtained for 23 patients, 15 of whom had pre-vaccination serum available on the day of YFV administration. Of these 23 patients, 10 had pre-vaccination PRNT titers >1:10, indicating potential prior exposure to the virus or previous vaccination. The remaining 13 patients had PRNT titers <1:10 (i.e., “seronegic”), indicating no prior exposure or antibody response attenuating over time. The mean post-vaccination titer level obtained between 28 and 42 days post-vaccination was 1:7699 (±10951 SD; median 2560, range 80 to 40960), with all but two patients showing increased titers post-vaccination, and all 23 patients showing neutralizing titers at levels consistent with serological protection against yellow fever.

[0699] Treatment levels of dupilumab did not suppress the seroprotective immune response to dupilumab. PK measurements were also obtained on the same day of vaccination in 15 patients with pre- and post-vaccination yellow fever titers. At vaccination, 13 of the 15 patients had serum dupilumab concentrations above the mean of 37.4 mg / L, which was considered sufficient to saturate IL-4Rα in asthma (based on the indicated 200 mg q2w regimen). All 13 patients showed a seroprotective immune response. While 12 of the 13 patients showed an increase in neutralizing titers after vaccination, one patient's serum sample had the same neutralizing titer pre- and post-vaccination. These data support that therapeutic dupilumab concentrations in serum at vaccination do not suppress the seroprotective immune response, and that all but one of the 13 patients showed an enhancement of neutralizing antibody titers against yellow fever.

[0700] YFV was well tolerated by all patients exposed. Of the 37 patients who received YFV, one reported a non-serious adverse event, described as “vaccination complications” (i.e., body aches, malaise, and dizziness), a common response to YFV and reported in up to 30% of patients (Monath TP, Nichols R, Archabault WT, Moore L, Marchesani R, Tian J et al. Comparative safety and immunogenicity of two yellow fever 17D vaccines (ARILVAX and YF-VAX) in a phase III multicenter, double-blind clinical trial. Am J Trop Med Hyg. 2002; 66(5):533-541.). The patient’s symptoms were reported as non-serious, and the patient recovered completely within 2 weeks.

[0701] Yellow fever virus vaccination did not affect the efficacy of dupilumab. All vaccinated patients achieved stable improvements in their lung function, as measured by FEV1. FEV1 remained stable before and after yellow fever virus vaccination.

[0702] As a whole, these data support the overall safety and tolerability of yellow fever vaccination in asthmatic patients who recently discontinued dupilumab. Not intended to be constrained by scientific theory, the similar increase in neutralizing antibody titers after vaccination between asthmatic patients with therapeutic serum dupilumab levels and those with sub-therapeutic serum levels suggests that, in the context of dupilumab, the humoral aspect of the adaptive immune system maintains immunity against attenuated YFV. sequence list <110> Sanofi Biotechnology Regeneron Pharmaceuticals <120> Methods of treating or preventing asthma by administering IL-4R antagonists <130> SA9-273PC <140> TBD <141> 2020-07-15 <150> EP 20315237.6 <151> 2020-05-07 <150> 63 / 004,084 <151> 2020-04-02 <150> 62 / 877,031 <151> 2019-07-22 <150> 62 / 874,747 <151> 2019-07-16 <160> 10 <170> PatentIn version 3.5 <210> 1 <211> 124 <212> PRT <213> Artificial sequence <220> <223> Description of artificial sequences: Synthesis HCVR peptide <400> 1 Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Glu Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Gly Ser Gly Phe Thr Phe Arg Asp Tyr 20 25 30 Ala Met Thr Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Ser Ile Ser Gly Ser Gly Gly Asn Thr Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Lys Asp Arg Leu Ser Ile Thr Ile Arg Pro Arg Tyr Tyr Gly Leu 100 105 110 Asp Val Trp Gly Gln Gly Thr Thr Val Thr Val Ser 115 120 <210> 2 <211> 112 <212> PRT <213> Artificial sequence <220> <223> Description of artificial sequences: Synthesis LCVR peptide <400> 2 Asp Ile Val Met Thr Gln Ser Pro Leu Ser Leu Pro Val Thr Pro Gly 1 5 10 15 Glu Pro Ala Ser Ile Ser Cys Arg Ser Ser Gln Ser Leu Leu Tyr Ser 20 25 30 Ile Gly Tyr Asn Tyr Leu Asp Trp Tyr Leu Gln Lys Ser Gly Gln Ser 35 40 45 Pro Gln Leu Leu Ile Tyr Leu Gly Ser Asn Arg Ala Ser Gly Val Pro 50 55 60 Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile 65 70 75 80 Ser Arg Val Glu Ala Glu Asp Val Gly Phe Tyr Tyr Cys Met Gln Ala 85 90 95 Leu Gln Thr Pro Tyr Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys 100 105 110 <210> 3 <211> 8 <212> PRT <213> Artificial sequence <220> <223> Description of artificial sequences: Synthesis HCDR1 peptide <400> 3 Gly Phe Thr Phe Arg Asp Tyr Ala 1 5 <210> 4 <211> 8 <212> PRT <213> Artificial sequence <220> <223> Description of artificial sequences: Synthesis HCDR2 peptide <400> 4 Ile Ser Gly Ser Gly Gly Asn Thr 1 5 <210> 5 <211> 18 <212> PRT <213> Artificial sequence <220> <223> Description of artificial sequences: Synthesis HCDR3 peptide <400> 5 Ala Lys Asp Arg Leu Ser Ile Thr Ile Arg Pro Arg Tyr Tyr Gly Leu 1 5 10 15 Asp Val <210> 6 <211> 11 <212> PRT <213> Artificial sequence <220> <223> Description of artificial sequences: Synthesis LCDR1 peptide <400> 6 Gln Ser Leu Leu Tyr Ser Ile Gly Tyr Asn Tyr 1 5 10 <210> 7 <211> 3 <212> PRT <213> Artificial sequence <220> <223> Description of artificial sequences: Synthesis LCDR2 peptide <400> 7 Leu Gly Ser 1 <210> 8 <211> 9 <212> PRT <213> Artificial sequence <220> <223> Description of artificial sequences: Synthesis LCDR3 peptide <400> 8 Met Gln Ala Leu Gln Thr Pro Tyr Thr 1 5 <210> 9 <211> 451 <212> PRT <213> Artificial sequence <220> <223> Description of artificial sequences: Synthesis polypeptide <220> <223> HC aa 1-124: HCVR aa 125-451: HC constant <400> 9 Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Glu Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Gly Ser Gly Phe Thr Phe Arg Asp Tyr 20 25 30 Ala Met Thr Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Ser Ile Ser Gly Ser Gly Gly Asn Thr Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Lys Asp Arg Leu Ser Ile Thr Ile Arg Pro Arg Tyr Tyr Gly Leu 100 105 110 Asp Val Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser Ala Ser Thr 115 120 125 Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Cys Ser Arg Ser Thr Ser 130 135 140 Glu Ser Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu 145 150 155 160 Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His 165 170 175 Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser 180 185 190 Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Lys Thr Tyr Thr Cys 195 200 205 Asn Val Asp His Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu 210 215 220 Ser Lys Tyr Gly Pro Pro Cys Pro Pro Cys Pro Ala Pro Glu Phe Leu 225 230 235 240 Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu 245 250 255 Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser 260 265 270 Gln Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu 275 280 285 Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr 290 295 300 Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn 305 310 315 320 Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro Ser Ser 325 330 335 Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln 340 345 350 Val Tyr Thr Leu Pro Pro Ser Gln Glu Glu Met Thr Lys Asn Gln Val 355 360 365 Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val 370 375 380 Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro 385 390 395 400 Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Arg Leu Thr 405 410 415 Val Asp Lys Ser Arg Trp Gln Glu Gly Asn Val Phe Ser Cys Ser Val 420 425 430 Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu 435 440 445 Ser Leu Gly 450 <210> 10 <211> 219 <212> PRT <213> Artificial sequence <220> <223> Description of artificial sequences: Synthesis polypeptide <220> <223> LC aa 1-112: LCVR aa 112-219: LC constant <400> 10 Asp Ile Val Met Thr Gln Ser Pro Leu Ser Leu Pro Val Thr Pro Gly 1 5 10 15 Glu Pro Ala Ser Ile Ser Cys Arg Ser Ser Gln Ser Leu Leu Tyr Ser 20 25 30 Ile Gly Tyr Asn Tyr Leu Asp Trp Tyr Leu Gln Lys Ser Gly Gln Ser 35 40 45 Pro Gln Leu Leu Ile Tyr Leu Gly Ser Asn Arg Ala Ser Gly Val Pro 50 55 60 Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile 65 70 75 80 Ser Arg Val Glu Ala Glu Asp Val Gly Phe Tyr Tyr Cys Met Gln Ala 85 90 95 Leu Gln Thr Pro Tyr Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys 100 105 110 Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu 115 120 125 Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe 130 135 140 Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln 145 150 155 160 Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser 165 170 175 Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu 180 185 190 Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser 195 200 205 Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys 210 215

Claims

1. The use of antibody preparation for the treatment of allergic bronchopulmonary aspergillosis in subjects. The antibody specifically binds to the interleukin-4 receptor. The antibody comprises heavy chain CDR1 as shown in SEQ ID NO: 3, heavy chain CDR2 as shown in SEQ ID NO: 4, and heavy chain CDR3 as shown in SEQ ID NO: 5, as well as light chain CDR1 as shown in SEQ ID NO: 6, light chain CDR2 as shown in SEQ ID NO: 7, and light chain CDR3 as shown in SEQ ID NO:

8. The subjects were defined as having a total serum IgE level of at least 1000 IU / mL, an Aspergillus fumigatus-specific IgE level greater than 0.35 kU / L, or a baseline blood eosinophil count of at least 500 cells / µl. The treatment resulted in a decrease in the level of Aspergillus fumigatus-specific IgE.

2. The use according to claim 1, wherein the subject has at least two of the following: a total serum IgE level of at least 1000 IU / mL, an Aspergillus fumigatus-specific IgE level of greater than 0.35 kU / L, and a baseline blood eosinophil count of at least 500 cells / µl.

3. The use according to claim 1, wherein the subject has a total serum IgE level of at least 1000 IU / mL, an Aspergillus fumigatus-specific IgE level of greater than 0.35 kU / L, and a baseline blood eosinophil count of at least 500 cells / µl.

4. The use according to claim 1, wherein the antibody is administered to the subject as a loading dose, followed by the administration of multiple maintenance doses.

5. The use according to claim 4, wherein the antibody is administered using an auto-injector.

6. The use according to claim 4, wherein the antibody is administered using a needle and syringe.

7. The use according to claim 4, wherein the antibody is applied using a pen.

8. The use according to claim 4, wherein the maintenance dose of the antibody is administered once every week.

9. The use according to claim 4, wherein the loading dose is 600 mg of the antibody.

10. The use according to claim 4, wherein each maintenance dose is 300 mg of the antibody.

11. The use according to claim 4, wherein the loading dose is 400 mg of the antibody.

12. The use according to claim 4, wherein each maintenance dose is 200 mg of the antibody.

13. The use according to claim 4, wherein the maintenance dose is administered for at least 24 weeks.

14. The use according to claim 4, wherein the first maintenance dose is administered two weeks after the loading dose.

15. The use according to claim 1, wherein the treatment results in an improvement in lung function, as measured by forced expiratory volume or forced expiratory flow rate at 25%-75% of lung volume.

16. The use according to claim 1, wherein the treatment results in a decrease in total serum IgE levels.

17. The use according to claim 1, wherein the treatment results in a decrease in one or more of the following: TARC level, eosinophil chemokine-3 level, and peripheral blood eosinophil level.

18. The use according to claim 1, wherein the treatment results in a decrease in FeNO.

19. The use according to claim 1, wherein the antibody comprises a heavy chain variable region as shown in SEQ ID NO: 1 and a light chain variable region as shown in SEQ ID NO:

2.

20. The use according to claim 1, wherein the antibody is dupilumab.

21. The use according to claim 1, wherein the subject suffers from comorbid moderate to severe uncontrolled asthma.

22. The use according to claim 21, wherein the treatment results in a reduction of annualized severe asthma exacerbations.

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