Methods for treating or preventing asthma by administering il-4r antagonist

Abstract

To provide methods for treating or preventing asthma (e.g., allergic asthma, asthma associated with allergic bronchopulmonary aspergillosis (ABPA), moderate-to-severe asthma, persistent asthma or the like) and associated conditions (e.g., ABPA, ABPA comorbid with asthma, ABPA comorbid with cystic fibrosis (CF), ABPA comorbid with asthma and CF) in a subject.SOLUTION: The present invention provides methods comprising the step of administering to a subject in need thereof a therapeutic composition comprising an interleukin-4 receptor (IL-4R) antagonist, such as an anti-IL-4R antibody or antigen-binding fragment thereof.SELECTED DRAWING: None

Description

[Technical field]

[0001] Related Applications This application claims the benefit of 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 Patent Application No. 20315237.6, filed May 7, 2020, the contents of which are incorporated by reference in their entireties for all purposes.

[0002] FIELD OF THEINVENTION The present invention relates to the treatment and / or prevention of asthma, such as allergic asthma, and related conditions, such as allergic bronchopulmonary aspergillosis (ABPA).The present invention relates to the administration of an interleukin-4 receptor (IL-4R) antagonist to treat or prevent asthma, such as allergic asthma, asthma associated with ABPA, in a patient in need thereof.The present invention also relates to the administration of an interleukin-4 receptor (IL-4R) antagonist to treat or prevent ABPA, such as ABPA coexisting with asthma, ABPA coexisting with cystic fibrosis, and / or ABPA coexisting with both asthma and cystic fibrosis, in a patient in need thereof. [Background technology]

[0003] Asthma is a chronic inflammatory disease of the airways characterized by airway hyperresponsiveness, acute and chronic bronchoconstriction, airway edema, and mucus plugging. The inflammatory component of asthma is thought to involve many cell types, including mast cells, eosinophils, T lymphocytes, neutrophils, epithelial cells, and their biological products. Patients with asthma often present with symptoms of wheezing, shortness of breath, cough, and chest tightness. For most asthma patients, a regimen of controller and bronchodilator therapy provides adequate long-term control. Inhaled corticosteroids (ICS) are considered the "gold standard" in controlling asthma symptoms, and inhaled β2-agonists are the most effective bronchodilators currently available. Studies have shown that combination therapy of ICS with inhaled long-acting β2-agonists (LABAs) provides better asthma control than high-dose ICS alone. As a result, combination therapy is the recommended treatment for subjects not controlled with low-dose ICS alone.

[0004] Nevertheless, despite maximum recommended treatment with combined anti-inflammatory and bronchodilator drugs, it is estimated that 5%-10% of the population with asthma have symptomatic disease. Furthermore, this severe asthma population accounts for up to 50% of all healthcare costs due to hospitalizations, emergency service use, and unscheduled visits. There is an unmet need for new therapies in this severe asthma population, as many of these patients respond poorly to ICS due to a number of cellular and molecular mechanisms. Furthermore, the long-term adverse effects of systemic and inhaled corticosteroids on bone metabolism, adrenal function, and childhood growth motivate attempts to minimize the amount of corticosteroid use. While the majority of asthma patients are managed to some extent with current therapies, patients with severe uncontrolled asthma (e.g., severe corticosteroid-refractory or steroid-intolerant asthma) have few therapeutic treatment options that can adequately control their disease. The result of non-responsiveness to therapy or lack of compliance with therapy leads to loss of asthma control and ultimately exacerbation of asthma.

[0005] An estimated 45% of patients with severe asthma require treatment to control their disease as well as to improve lung tissue health. Systemic glucocorticoids are required to prevent life-threatening exacerbations associated with increased risk of permanent damage to the asthma wall, progressive fixed airway obstruction, and accelerated decline in lung function. However, systemic glucocorticoids act nonselectively and are associated with significant multiorgan toxicity and widespread immunosuppression. Safer and more effective targeted therapies that prevent exacerbations and lung function impairment, improve asthma symptoms and control, and reduce or eliminate the need for oral glucocorticoids are needed.

[0006] Approximately 20% of patients with asthma have poorly controlled, moderate to severe disease with recurrent exacerbations and persistent symptoms despite maximal standard of care controller therapy. This population is at increased risk for morbidity, particularly exacerbations, and occupies significant healthcare resources. These patients experience substantial declines in lung function despite maximal treatment, and are inexorably destined for further loss of lung function. No currently approved treatments have been shown to slow this inexorable decline or consistently and meaningfully increase lung function in these patients.

[0007] Type 2 high-value asthma is the most common type of persistent, poorly controlled asthma (Non-Patent Document 1). Type 2 high-value asthma includes overlapping phenotypes of allergic asthma (characterized by increased expression of specific immunoglobulin E (IgE) to aeroallergens) and eosinophilic asthma (characterized by eosinophilia in blood and / or airways / tissues) (Non-Patent Document 1, supra; Non-Patent Document 2; Non-Patent Document 3).

[0008] Allergic sensitization is a strong risk factor for the onset and severity of asthma in children and adults (Non-Patent Document 4). Current allergic asthma therapies that address the symptoms and ongoing inflammatory processes of the disease are extremely limited in controlling the progression of allergic asthma because they do not affect the underlying dysregulated immune response (Non-Patent Document 5).

[0009] ABPA is an allergic lung disorder caused by hypersensitivity to Aspergillus species (e.g., A. fumigatus) that colonize the airways. ABPA occurs most often in subjects with asthma or cystic fibrosis.

[0010] ABPA is clinically characterized by wheezing, dyspnea, respiratory deterioration, bronchial hyperresponsiveness, hemoptysis or productive cough (production of brownish-black mucus plugs in 31–69% of patients), central bronchiectasis with formation of mucus plugs, and markedly elevated IgE and blood and tissue eosinophilia.

[0011] There are currently no approved drugs specific for ABPA. The current mainstay of treatment is systemic corticosteroids, with antifungals used as adjuvant therapy. However, more than 50% of patients with ABPA are undertreated or ineffectively treated due to either limited therapeutic efficacy or significant side effects of corticosteroids. Thus, patients with ABPA represent a high unmet medical need.

[0012] Cystic fibrosis (CF), also known as pancreatic fibrosis, is a genetic disorder that affects mostly the lungs, but also the pancreas, liver, kidneys, and intestines. Long-term problems include difficulty breathing and coughing up mucus as a result of frequent lung infections. Other signs and symptoms include sinus infections, poor growth, fatty stools, clubbing of fingers and toes, and male infertility, among others. Subjects may have symptoms of varying severity.

[0013] CF is inherited in an autosomal recessive manner. It is caused by the cystic fibrosis transmembrane conductance regulator. It is caused by the presence of mutations in both copies of the gene for the factor (CFTR) protein. Those with a single working copy are carriers, while the majority of those who do not are normal. CFTR is involved in the production of sweat, digestive juices, and mucus. When CFTR is not functional, secretions, which are normally thin, become thick instead. The condition is diagnosed by sweat tests and genetic testing. In some parts of the world, infants are screened at birth.

[0014] There is no cure for cystic fibrosis. Lung infections are treated with antibiotics that can be given intravenously, inhaled, or orally. Sometimes the antibiotic azithromycin is used long term. Hypertonic saline and inhaled salbutamol may also be helpful. Lung transplantation may be an option if lung function continues to deteriorate. Pancreatic enzyme replacement and fat-soluble vitamin supplementation are important, especially in younger people. Life expectancy is 42-50 years in the developed world. While CF is a multisystem disease, pulmonary problems are the leading cause of morbidity and mortality. Other CF symptoms include pancreatic insufficiency, intestinal obstruction, elevated electrolyte levels in sweat (based on the most common diagnostic test), and male infertility. CF is most common in people of Northern European ancestry, affecting approximately 1 in 2,500-4,000 newborns. Approximately 1 in 25 people are carriers. Treatments for CF are available, but more effective therapies are needed. [Prior art documents] [Non-patent literature]

[0015] [Non-Patent Document 1] Fahy (2015) Nat. Rev. Immunol. 15:57~65 [Non-Patent Document 2] Campo et al. (2013) J.Investig.Allergol.Clin.Immunol.23:76~88 [Non-Patent Document 3] Wenzel(2012)Clin Exp Allergy 42:650~8 [Non-Patent Document 4] Gough et al. (2015) Pediatr. Allergy Immunol. 26:431~437 [Non-Patent Document 5] Dhami et al. (2017) Eur.J.Allergy Clin.Immunol.72(12):1825~1848 Summary of the Invention [Problem to be solved by the invention]

[0016] There is a need for novel targeted therapies for the treatment and / or prevention of asthma, such as allergic asthma, asthma associated with ABPA, and disorders such as ABPA, such as ABPA comorbid with CF, ABPA comorbid with asthma, and ABPA comorbid with both asthma and CF. [Means for solving the problem]

[0017] According to one embodiment, a method for treating a subject with allergic asthma is provided, comprising administering to the subject an antibody or antigen-binding fragment thereof that specifically binds to the interleukin-4 receptor (IL-4R), the antibody or antigen-binding fragment thereof comprising three heavy chain CDR sequences comprising SEQ ID NOs: 3, 4, and 5, respectively, and three light chain CDR sequences comprising SEQ ID NOs: 6, 7, and 8, respectively, and the subject having a total serum IgE level of at least about 700 IU / mL.

[0018] In certain 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 certain 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 certain exemplary embodiments, the subject has an allergen-specific IgE level of at least about 0.35 kU / L.

[0021] In certain exemplary embodiments, the allergen is selected from the group consisting of 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 certain exemplary embodiments, the allergen is selected from the group consisting of cat dander, dog dander, German cockroach, and Asian cockroach.

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

[0024] In certain exemplary embodiments, the antibody or antigen-binding fragment thereof is administered using an autoinjector, a needle and syringe, or a pen.

[0025] In certain exemplary embodiments, the maintenance dose of the antibody or antigen-binding fragment thereof is administered every two weeks (q2w).

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

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

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

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

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

[0031] In certain exemplary embodiments, treatment results in a reduction in annual severe asthma exacerbations.

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

[0033] In certain exemplary embodiments, the antibody or antigen-binding fragment thereof is selected from the group consisting of SEQ ID NO: The present invention comprises a heavy chain variable region (HCVR) sequence of SEQ ID NO:1 and a light chain variable region (LCVR) sequence of SEQ ID NO:2.

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

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

[0036] In certain exemplary embodiments, the subject has moderate to severe uncontrolled allergic asthma.

[0037] In certain exemplary embodiments, the subject exhibits co-morbid cystic fibrosis. In certain exemplary embodiments, the subject exhibits co-morbid allergic asthma and co-morbid cystic fibrosis.

[0038] In certain exemplary embodiments, the subject is an adult. In certain exemplary embodiments, the subject is an adolescent. In certain exemplary embodiments, the subject is a child.

[0039] According to another aspect, there is provided a method for treating a subject having allergic asthma, comprising administering to the subject an antibody or antigen-binding fragment thereof that specifically binds to the interleukin-4 receptor (IL-4R), wherein the antibody or antigen-binding fragment thereof comprises three heavy chain CDR sequences comprising SEQ ID NOs: 3, 4, and 5, respectively, and three light chain CDR sequences comprising SEQ ID NOs: 6, 7, and 8, respectively, and wherein the subject has a baseline blood eosinophil level of at least about 300 cells / μl.

[0040] In certain 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 certain exemplary embodiments, the subject has a total serum IgE level of at least about 700 IU / mL.

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

[0043] In certain exemplary embodiments, the allergen is selected from the group consisting of dust mites, cockroaches, cat dander, dog dander, Dermatophagoides farinae, Dermatophagoides pteronyssinus, Alternaria alternata, Cladosporium herbarum, Aspergillus fumigatus, Blattella germanica, and Blattella orientalis.

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

[0045] In certain exemplary embodiments, the antibody or antigen-binding fragment thereof is administered using an autoinjector, a needle and syringe, or a pen.

[0046] In certain exemplary embodiments, the maintenance dose of the antibody or antigen-binding fragment thereof is administered every two weeks (q2w).

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

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

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

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

[0051] In certain exemplary embodiments, treatment results in a reduction in annual severe asthma exacerbations.

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

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

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

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

[0056] In certain exemplary embodiments, the subject has moderate to severe uncontrolled allergic asthma.

[0057] In certain exemplary embodiments, the subject exhibits co-morbid cystic fibrosis. In certain exemplary embodiments, the subject exhibits co-morbid allergic asthma and co-morbid cystic fibrosis.

[0058] In certain exemplary embodiments, the subject is an adult. In certain exemplary embodiments, the subject is a juvenile. In certain exemplary embodiments, the subject is a child.

[0059] According to another aspect, there is provided a method for treating a subject having allergic asthma, comprising administering to the subject an antibody or antigen-binding fragment thereof that specifically binds to interleukin-4 receptor (IL-4R), wherein the antibody or antigen-binding fragment thereof comprises three heavy chain CDR sequences comprising SEQ ID NOs: 3, 4, and 5, respectively, and three light chain CDR sequences comprising SEQ ID NOs: 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 certain exemplary embodiments, the subject has a baseline FeNO level of at least 25 ppb.

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

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

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

[0064] In certain exemplary embodiments, the allergen is selected from the group consisting of dust mites, cockroaches, cat dander, dog dander, Dermatophagoides farinae, Dermatophagoides pteronyssinus, Alternaria alternata, Cladosporium herbarum, Aspergillus fumigatus, Blattella germanica, and Blattella orientalis.

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

[0066] In certain exemplary embodiments, the antibody or antigen-binding fragment thereof is administered using an autoinjector, a needle and syringe, or a pen.

[0067] In certain exemplary embodiments, the maintenance dose of the antibody or antigen-binding fragment thereof is administered every two weeks (q2w).

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

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

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

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

[0072] In certain exemplary embodiments, treatment results in a reduction in annual severe asthma exacerbations.

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

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

[0075] In certain exemplary embodiments, the antibody or antigen-binding fragment thereof is selected from the group consisting of SEQ ID NO: 9 and the light chain sequence of SEQ ID NO:10.

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

[0077] In certain exemplary embodiments, the subject exhibits co-morbid cystic fibrosis. In certain exemplary embodiments, the subject exhibits co-morbid allergic asthma and co-morbid cystic fibrosis.

[0078] In certain exemplary embodiments, the subject is an adult. In certain exemplary embodiments, the subject is an adolescent. In certain exemplary embodiments, the subject is a child.

[0079] In another aspect, a method is provided for improving lung function as measured by forced expiratory volume (FEV1) or by forced expiratory rate at 25-75% lung capacity (FEF25-75%) in a subject with allergic asthma, comprising administering to the subject an antibody or antigen-binding fragment thereof that specifically binds to interleukin-4 receptor (IL-4R), wherein the antibody or antigen-binding fragment thereof comprises three heavy chain CDR sequences comprising SEQ ID NOs: 3, 4, and 5, respectively, and three light chain CDR sequences comprising SEQ ID NOs: 6, 7, and 8, respectively, and wherein the subject has a total serum IgE level of at least about 700 IU / mL.

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

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

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

[0083] In certain exemplary embodiments, the subject has moderate to severe uncontrolled allergic asthma.

[0084] In certain exemplary embodiments, the subject exhibits co-morbid cystic fibrosis. In certain exemplary embodiments, the subject exhibits co-morbid allergic asthma and co-morbid cystic fibrosis.

[0085] In certain exemplary embodiments, the subject is an adult. In certain exemplary embodiments, the subject is an adolescent. In certain exemplary embodiments, the subject is a child.

[0086] In another aspect, a method is provided for reducing annual severe asthma exacerbations in a subject with allergic asthma, comprising administering to the subject an antibody or antigen-binding fragment thereof that specifically binds to the interleukin-4 receptor (IL-4R), wherein the antibody or antigen-binding fragment thereof comprises three heavy chain CDR sequences comprising SEQ ID NOs: 3, 4, and 5, respectively, and three light chain CDR sequences comprising SEQ ID NOs: 6, 7, and 8, respectively, and wherein the subject has a total serum IgE level of at least about 700 IU / mL.

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

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

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

[0090] In certain exemplary embodiments, the subject has moderate to severe uncontrolled allergic asthma.

[0091] In certain exemplary embodiments, the subject exhibits co-morbid cystic fibrosis. In certain exemplary embodiments, the subject exhibits co-morbid allergic asthma and co-morbid cystic fibrosis.

[0092] In certain exemplary embodiments, the subject is an adult. In certain exemplary embodiments, the subject is an adolescent. In certain exemplary embodiments, the subject is a child.

[0093] In another aspect, a method of improving Asthma Control Questionnaire (ACQ-5) score in a subject with allergic asthma is provided, comprising administering to the subject an antibody or antigen-binding fragment thereof that specifically binds to the interleukin-4 receptor (IL-4R), wherein the antibody or antigen-binding fragment thereof comprises three heavy chain CDR sequences comprising SEQ ID NOs: 3, 4, and 5, respectively, and three light chain CDR sequences comprising SEQ ID NOs: 6, 7, and 8, respectively, and wherein the subject has a total serum IgE level of at least about 700 IU / mL.

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

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

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

[0097] In certain exemplary embodiments, the subject has moderate to severe uncontrolled allergic asthma.

[0098] In certain exemplary embodiments, the subject exhibits co-morbid cystic fibrosis. In certain exemplary embodiments, the subject exhibits co-morbid allergic asthma and co-morbid cystic fibrosis.

[0099] In certain exemplary embodiments, the subject is an adult. In certain exemplary embodiments, the subject is an adolescent. In certain exemplary embodiments, the subject is a child.

[0100] In another aspect, a method is provided for treating a subject having allergic bronchopulmonary aspergillosis (ABPA), comprising administering to the subject an antibody or antigen-binding fragment thereof that specifically binds to interleukin-4 receptor (IL-4R), wherein the antibody or antigen-binding fragment thereof comprises three heavy chain CDR sequences comprising SEQ ID NOs: 3, 4, and 5, respectively, and three light chain CDR sequences comprising SEQ ID NOs: 6, 7, and 8, respectively, and wherein the subject has a total serum IgE level of at least about 1000 IU / mL.

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

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

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

[0104] In certain exemplary embodiments, the antibody or antigen-binding fragment thereof is administered using an autoinjector, a needle and syringe, or a pen.

[0105] In certain exemplary embodiments, the maintenance dose of the antibody or antigen-binding fragment thereof is administered every two weeks (q2w).

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

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

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

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

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

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

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

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

[0114] In certain exemplary embodiments, the subject has moderate to severe uncontrolled asthma. In certain exemplary embodiments, the subject has co-morbid cystic fibrosis. In certain exemplary embodiments, the subject has co-morbid asthma and co-morbid cystic fibrosis.

[0115] In certain exemplary embodiments, the subject is an adult. In certain exemplary embodiments, the subject is an adolescent. In certain exemplary embodiments, the subject is a child.

[0116] In another aspect, a method is provided for treating a subject having allergic bronchopulmonary aspergillosis (ABPA), comprising administering to the subject an antibody or antigen-binding fragment thereof that specifically binds to interleukin-4 receptor (IL-4R), wherein the antibody or antigen-binding fragment thereof comprises three heavy chain CDR sequences comprising SEQ ID NOs: 3, 4, and 5, respectively, and three light chain CDR sequences comprising SEQ ID NOs: 6, 7, and 8, respectively, and wherein the subject has an Aspergillus fumigatus-specific IgE level greater than 0.35 kU / L.

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

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

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

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

[0121] In certain exemplary embodiments, the antibody or antigen-binding fragment thereof is administered using an autoinjector, a needle and syringe, or a pen.

[0122] In certain exemplary embodiments, the maintenance dose of the antibody or antigen-binding fragment thereof is administered every two weeks (q2w).

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

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

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

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

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

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

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

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

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

[0132] In certain exemplary embodiments, the subject has moderate to severe uncontrolled asthma. In certain exemplary embodiments, the subject has co-morbid cystic fibrosis. In certain exemplary embodiments, the subject has co-morbid asthma and co-morbid cystic fibrosis.

[0133] In certain exemplary embodiments, the subject is an adult. In certain exemplary embodiments, the subject is an adolescent. In certain exemplary embodiments, the subject is a child.

[0134] In another aspect, a method is provided for treating a subject having allergic bronchopulmonary aspergillosis (ABPA), comprising administering to the subject an antibody or antigen-binding fragment thereof that specifically binds to interleukin-4 receptor (IL-4R), wherein the antibody or antigen-binding fragment thereof comprises three heavy chain CDR sequences comprising SEQ ID NOs: 3, 4, and 5, respectively, and three light chain CDR sequences comprising SEQ ID NOs: 6, 7, and 8, respectively, and wherein the subject has a baseline blood eosinophil count of at least about 500 cells / μl.

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

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

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

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

[0139] In certain exemplary embodiments, the antibody or antigen-binding fragment thereof is administered using an autoinjector, a needle and syringe, or a pen.

[0140] In certain exemplary embodiments, the maintenance dose of the antibody or antigen-binding fragment thereof is administered every two weeks (q2w).

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

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

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

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

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

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

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

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

[0149] In certain exemplary embodiments, the subject has moderate to severe uncontrolled asthma. In certain exemplary embodiments, the subject has co-morbid cystic fibrosis. In certain exemplary embodiments, the subject has co-morbid asthma and co-morbid cystic fibrosis.

[0150] In certain exemplary embodiments, the subject is an adult. In certain exemplary embodiments, the subject is an adolescent. In certain exemplary embodiments, the subject is a child.

[0151] In another aspect, a method of improving pulmonary function as measured by forced expiratory volume (FEV1) or by forced expiratory rate at 25-75% lung capacity (FEF25-75%) in a subject with asthma associated with allergic bronchopulmonary aspergillosis (ABPA) is provided, the method comprising administering to the subject an antibody or antigen-binding fragment thereof that specifically binds to interleukin-4 receptor (IL-4R), The subject comprises three heavy chain CDR sequences comprising SEQ ID NOs: 3, 4, and 5, respectively, and three light chain CDR sequences comprising SEQ ID NOs: 6, 7, and 8, respectively, and the subject has a total serum IgE level of at least about 1000 IU / mL.

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

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

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

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

[0156] In certain exemplary embodiments, the subject is an adult. In certain exemplary embodiments, the subject is an adolescent. In certain exemplary embodiments, the subject is a child.

[0157] In another aspect, a method is provided for reducing annual severe asthma exacerbations in a subject with asthma associated with allergic bronchopulmonary aspergillosis (ABPA), comprising administering to the subject an antibody or antigen-binding fragment thereof that specifically binds to the interleukin-4 receptor (IL-4R), wherein the antibody or antigen-binding fragment thereof comprises three heavy chain CDR sequences comprising SEQ ID NOs: 3, 4, and 5, respectively, and three light chain CDR sequences comprising SEQ ID NOs: 6, 7, and 8, respectively, and wherein the subject has a total serum IgE level of at least about 1000 IU / mL.

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

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

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

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

[0162] In certain exemplary embodiments, the subject is an adult. In certain exemplary embodiments, the subject is an adolescent. In certain exemplary embodiments, the subject is a child.

[0163] In another aspect, a method of improving Asthma Control Questionnaire (ACQ-5) score in a subject having asthma associated with Allergic Bronchopulmonary Aspergillosis (ABPA) comprising administering to the subject an antibody or antigen-binding fragment thereof that specifically binds to interleukin-4 receptor (IL-4R), wherein the antibody or antigen-binding fragment thereof is , three heavy chain CDR sequences comprising SEQ ID NOs: 3, 4, and 5, respectively, and three light chain CDR sequences comprising SEQ ID NOs: 6, 7, and 8, respectively, and the subject has a total serum IgE level of at least about 1000 IU / mL.

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

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

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

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

[0168] In certain exemplary embodiments, the subject is an adult. In certain exemplary embodiments, the subject is an adolescent. In certain exemplary embodiments, the subject is a child.

[0169] In another aspect, a method is provided for treating a subject with coexisting allergic bronchopulmonary aspergillosis (ABPA) and cystic fibrosis (CF), comprising administering to the subject an antibody or antigen-binding fragment thereof that specifically binds to interleukin-4 receptor (IL-4R), wherein the antibody or antigen-binding fragment thereof comprises three heavy chain CDR sequences comprising SEQ ID NOs: 3, 4, and 5, respectively, and three light chain CDR sequences comprising SEQ ID NOs: 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 certain exemplary embodiments, the subject has a baseline blood eosinophil count of at least about 500 cells / μl.

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

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

[0173] In certain exemplary embodiments, the antibody or antigen-binding fragment thereof is administered using an autoinjector, a needle and syringe, or a pen.

[0174] In certain exemplary embodiments, the maintenance dose of the antibody or antigen-binding fragment thereof is administered every two weeks (q2w).

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

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

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

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

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

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

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

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

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

[0184] In certain exemplary embodiments, the subject has asthma, hi certain exemplary embodiments, the treatment results in a reduction in annual asthma exacerbations.

[0185] In certain exemplary embodiments, the subject is an adult. In certain exemplary embodiments, the subject is an adolescent. In certain exemplary embodiments, the subject is a child.

[0186] In another aspect, a method is provided for treating a subject with coexisting allergic bronchopulmonary aspergillosis (ABPA) and cystic fibrosis (CF), comprising administering to the subject an antibody or antigen-binding fragment thereof that specifically binds to interleukin-4 receptor (IL-4R), wherein the antibody or antigen-binding fragment thereof comprises three heavy chain CDR sequences comprising SEQ ID NOs: 3, 4, and 5, respectively, and three light chain CDR sequences comprising SEQ ID NOs: 6, 7, and 8, respectively, and wherein the subject has an Aspergillus fumigatus-specific IgE level of greater than 0.35 kU / L.

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

[0188] In certain exemplary embodiments, the antibody or antigen-binding fragment thereof is administered by loading dose. The subject is administered one dose at a time, followed by multiple maintenance doses.

[0189] In certain exemplary embodiments, the antibody or antigen-binding fragment thereof is administered using an autoinjector, a needle and syringe, or a pen.

[0190] In certain exemplary embodiments, the maintenance dose of the antibody or antigen-binding fragment thereof is administered every two weeks (q2w).

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

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

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

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

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

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

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

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

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

[0200] In certain exemplary embodiments, the subject has asthma, hi certain exemplary embodiments, the treatment results in a reduction in annual asthma exacerbations.

[0201] In certain exemplary embodiments, the subject is an adult. In certain exemplary embodiments, the subject is an adolescent. In certain exemplary embodiments, the subject is a child.

[0202] In another embodiment, the patient is diagnosed with coexisting allergic bronchopulmonary aspergillosis (ABPA) and sacculus. A method is provided for treating a subject having cystic fibrosis (CF), comprising administering to the subject an antibody or antigen-binding fragment thereof that specifically binds to interleukin-4 receptor (IL-4R), wherein the antibody or antigen-binding fragment thereof comprises three heavy chain CDR sequences comprising SEQ ID NOs: 3, 4, and 5, respectively, and three light chain CDR sequences comprising SEQ ID NOs: 6, 7, and 8, respectively, and wherein the subject has a baseline blood eosinophil count of at least about 500 cells / μl.

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

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

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

[0206] In certain exemplary embodiments, the antibody or antigen-binding fragment thereof is administered using an autoinjector, a needle and syringe, or a pen.

[0207] In certain exemplary embodiments, the maintenance dose of the antibody or antigen-binding fragment thereof is administered every two weeks (q2w).

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

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

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

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

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

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

[0214] In certain exemplary embodiments, the antibody or antigen-binding fragment thereof is selected from the group consisting of SEQ ID NO: The present invention comprises a heavy chain variable region (HCVR) sequence of SEQ ID NO:1 and a light chain variable region (LCVR) sequence of SEQ ID NO:2.

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

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

[0217] In certain exemplary embodiments, the subject has asthma, hi certain exemplary embodiments, the treatment results in a reduction in annual asthma exacerbations.

[0218] In certain exemplary embodiments, the subject is an adult. In certain exemplary embodiments, the subject is an adolescent. In certain exemplary embodiments, the subject is a child.

[0219] In another aspect, a method is provided for treating a subject having allergic bronchopulmonary aspergillosis (ABPA), comprising administering to the subject an antibody or antigen-binding fragment thereof that specifically binds to interleukin-4 receptor (IL-4R), wherein the antibody or antigen-binding fragment thereof comprises three heavy chain CDR sequences comprising SEQ ID NOs: 3, 4, and 5, respectively, and three light chain CDR sequences comprising SEQ ID NOs: 6, 7, and 8, respectively, and wherein the subject has a total serum IgE level of at least about 1000 IU / mL, an Aspergillus fumigatus specific IgE level of greater than 0.35 kU / L, or a baseline blood eosinophil count of at least about 500 cells / μl.

[0220] In certain exemplary embodiments, the subject has at least two of a total serum IgE level of at least about 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 about 500 cells / μl. In certain exemplary embodiments, the subject has a total serum IgE level of at least about 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 about 500 cells / μl.

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

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

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

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

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

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

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

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

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

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

[0231] In certain exemplary embodiments, the subject has moderate to severe uncontrolled asthma, hi certain exemplary embodiments, the treatment results in a reduction in annual severe asthma exacerbations.

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

[0233] In certain exemplary embodiments, the subject is an adult. In certain exemplary embodiments, the subject is an adolescent. In certain exemplary embodiments, the subject is a child.

[0234] In another aspect, a method is provided for treating a subject having asthma, comprising administering to the subject two or more doses of an antibody or antigen-binding fragment thereof that specifically binds to the interleukin-4 receptor (IL-4R), wherein the antibody or antigen-binding fragment thereof comprises three heavy chain CDR sequences comprising SEQ ID NOs: 3, 4, and 5, respectively, and three light chain CDR sequences comprising SEQ ID NOs: 6, 7, and 8, respectively, and wherein the subject is further administered a vaccine.

[0235] In certain exemplary embodiments, administration of the antibody or antigen-binding fragment thereof is temporarily discontinued prior to administering the vaccine.

[0236] In certain exemplary embodiments, the vaccine is administered at least 7 days after the antibody or antigen-binding fragment thereof was last administered to the subject, hi certain exemplary embodiments, the vaccine is administered about 7 days to about 60 days after the antibody or antigen-binding fragment thereof was last administered to the subject.

[0237] In certain exemplary embodiments, administration of the antibody or antigen-binding fragment thereof is resumed following administration of the vaccine.

[0238] In certain exemplary embodiments, the antibody or antigen-binding fragment thereof is administered about 1 day to about 90 days after administration of the vaccine. In certain exemplary embodiments, the antibody or antigen-binding fragment thereof is administered about 7 days after administration of the vaccine. In certain exemplary embodiments, the antibody or antigen-binding fragment thereof is administered about 14 days after administration of the vaccine.

[0239] In certain exemplary embodiments, the antibody or antigen-binding fragment thereof is administered about 21 days after administration of the vaccine.

[0240] In certain exemplary embodiments, the efficacy of the antibody or antigen-binding fragment thereof is not diminished by administration of the vaccine.

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

[0242] In certain exemplary embodiments, the efficacy of the vaccine in a subject is not diminished by administration of the antibody or antigen-binding fragment thereof.

[0243] In certain exemplary embodiments, the subject develops seroprotective neutralizing titers following administration of the vaccine.

[0244] In certain exemplary embodiments, the vaccine is a live vaccine. In certain exemplary embodiments, the vaccine comprises a live attenuated yellow fever virus. In certain exemplary embodiments, the vaccine is specific for the yellow fever virus.

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

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

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

[0248] In certain exemplary embodiments, the subject exhibits co-morbid cystic fibrosis. In certain exemplary embodiments, the subject exhibits co-morbid asthma and co-morbid cystic fibrosis.

[0249] In certain exemplary embodiments, the subject is an adult. In certain exemplary embodiments, the subject is an adolescent. In certain exemplary embodiments, the subject is a child.

[0250] In another aspect, a method is provided for administering a vaccine to a subject, wherein before, during, or after administration of the vaccine, the subject is administered at least one dose of an antibody or antigen-binding fragment thereof that specifically binds to interleukin-4 receptor (IL-4R), wherein the antibody or antigen-binding fragment thereof comprises three heavy chain CDR sequences comprising SEQ ID NOs: 3, 4, and 5, respectively, and three light chain CDR sequences comprising SEQ ID NOs: 6, 7, and 8, respectively.

[0251] In certain exemplary embodiments, the subject has a type 2 inflammatory disease. In certain exemplary embodiments, the type 2 inflammatory disease is asthma, allergic rhinitis, chronic nasal and sinusitis with nasal polyps. In one embodiment, the present invention relates to a respiratory tract infection (ROI) that is caused by a respiratory tract infection (ROI), a respiratory tract infection (RAI), a respiratory tract infection with a pulmonary stenosis (PSS), a respiratory tract infection with a pulmonary stenosis (PSS), a respiratory tract infection with a pulmonary stenosis (PSS ...

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

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

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

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

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

[0257] In certain exemplary embodiments, the subject is an adult. In certain exemplary embodiments, the subject is an adolescent. In certain exemplary embodiments, the subject is a child.

[0258] Other embodiments will become apparent from review of the following detailed description, drawings, tables, and appended claims.

[0259] The foregoing and other features and advantages of the present invention will be more fully understood from the following detailed description of illustrative embodiments taken in conjunction with the accompanying drawings. The file of the invention contains at least one drawing / photograph executed in color. Copies of the invention with color drawing / photograph will be provided by the Office upon request and payment of the necessary fee. [Brief description of the drawings]

[0260] [Figure 1-1]1A-1E show the effect of dupilumab on annualized severe exacerbation rate. FIG. 1A shows that dupilumab reduced the overall annualized severe exacerbation rate in the overall allergic asthma subgroup as well as in the overall asthma subgroup that did not meet the criteria for allergic asthma. FIG. 1B shows the effect of dupilumab in the allergic asthma subgroup as well as in the asthma subgroup that did not meet the criteria for allergic asthma, where the subjects had blood eosinophil levels of 150 cells / μL or more. FIG. 1C shows the effect of dupilumab in the allergic asthma subgroup as well as in the asthma subgroup that did not meet the criteria for allergic asthma, where the subjects had blood eosinophil levels of 300 cells / μL or more. FIG. 1D shows the effect of dupilumab in the allergic asthma subgroup as well as in the asthma subgroup that did not meet the criteria for allergic asthma, where the subjects had baseline blood FeNO of ≧25 ppb. Figure IE shows the effect of dupilumab in the allergic asthma subgroup, as well as in the asthma subgroup that did not meet criteria for allergic asthma and subjects had serum total IgE >700 IU / mL. CI, confidence interval; FeNO, exhaled nitric oxide; ITT, intention to treat; q2w, every 2 weeks. [Figure 1-2] Continued from Figure 1-1. [Figure 1-3] Continued from Figure 1-2. [Figure 2A] FIG. 2 shows the effect of dupilumab on FEV1(L) in the overall allergic asthma subgroup and in the overall asthma subgroup that did not meet criteria for allergic asthma. FIG. 2A shows the change in baseline FEV1 over the 52-week treatment period in the overall allergic asthma subgroup, and indicates the magnitude of effect in subgroups further defined by baseline blood eosinophil levels, FeNO levels, or baseline serum total IgE levels at week 12. [Figure 2B]FIG. 2B shows the effect of dupilumab on FEV1(L) in the overall allergic asthma subgroup and in the overall asthma subgroup that did not meet criteria for allergic asthma. FIG. 2B shows the change in baseline FEV1 over the 52-week treatment period in the overall asthma subgroup that did not meet criteria for allergic asthma, and indicates the magnitude of effect in subgroups further defined by baseline blood eosinophil levels, FeNO levels, or baseline serum total IgE levels at week 12. [Diagram 3] FIG. 1 shows the effect of dupilumab on asthma control (as measured by ACQ-5) during the 52-week treatment period in the overall allergic asthma subgroup and in the overall asthma subgroup that did not meet criteria for allergic asthma. ACQ-5, 5-item Asthma Control Questionnaire; LS, least squares; q2w, every 2 weeks; SE, standard error. [Figure 4A] Figure 4 shows the effect of dupilumab on various biomarkers. Figure 4A shows the effect of dupilumab on serum total IgE levels. CI, confidence interval; FeNO, exhaled nitric oxide; q2w, every 2 weeks; TARC, thymus and activation-regulated chemokine. [Figure 4B] FIG. 4B shows the effect of dupilumab on various biomarkers. FIG. 4B shows the effect of dupilumab on FeNO levels. CI, confidence interval; FeNO, exhaled nitric oxide; q2w, every 2 weeks; TARC, thymus and activation-regulated chemokine. [Figure 4C] Figure 4C shows the effect of dupilumab on various biomarkers. Figure 4C shows the effect of dupilumab on serum TARC levels during the 52-week treatment period in the total allergic asthma subgroup and in the total asthma subgroup that did not meet the criteria for allergic asthma (exposed population). CI, confidence interval; FeNO, exhaled nitric oxide; q2w, every 2 weeks; TARC, thymus and activation-regulated chemokine. [Figure 5-1]5A-5H show the effect of dupilumab on antigen-specific serum IgE levels during the 52-week treatment period in allergic asthma subgroups. FIG. 5A shows the effect of dupilumab on antigen-specific serum IgE levels of ≧0.35 kU / mL (exposed population) in the allergic asthma subgroup exposed to A. fumigatus. FIG. 5B shows the effect of dupilumab on antigen-specific serum IgE levels in the allergic asthma subgroup exposed to cat dander. FIG. 5C shows the effect of dupilumab on antigen-specific serum IgE levels in the allergic asthma subgroup exposed to D. farinae. FIG. 5D shows the effect of dupilumab on antigen-specific serum IgE levels in the allergic asthma subgroup exposed to D. pteronyssinus. Figure 5E shows the effect of dupilumab on antigen-specific serum IgE levels in the allergic asthma subgroup exposed to dog dander. Figure 5F shows the effect of dupilumab on antigen-specific serum IgE levels in the allergic asthma subgroup exposed to German cockroach. Figure 5G shows the effect of dupilumab on antigen-specific serum IgE levels in the allergic asthma subgroup exposed to A. tenuis / alternata. Figure 5H shows the effect of dupilumab on antigen-specific serum IgE levels in the allergic asthma subgroup exposed to C. herbarum / hormodendrum. CI, confidence interval; q2w, every 2 weeks. [Figure 5-2] Continued from Figure 5-1. [Figure 5-3] Continued from Figure 5-2. [Figure 5-4] Continued from Figure 5-3. [Figure 6] Figures 6A-6B show statistical analysis of patients with IgE >= 700 IU / ml. Figure 6A shows a histogram of residuals to confirm normal distribution. Figure 6B shows a qq plot showing normal distribution. [Figure 7] FIG. 1 shows annualized severe exacerbation rates during the 52-week treatment period in patients with allergic bronchopulmonary aspergillosis (ABPA) in the intention-to-treat (ITT) population. [Figure 8] FIG. 1 shows least squares (LS) mean change from baseline in pre-bronchodilator forced expiratory volume in one second (FEV1) at weeks 24 and 52 in the ITT population. [Figure 9] FIG. 1 shows total serum IgE levels at week 52 in a patient population exposed to Aspergillus fumigatus (Af). [Figure 10] FIG. 1 shows total serum Af-specific IgE levels at week 52 in an Af-exposed patient population. [Figure 11] FIG. 1 shows absolute FeNO (ppb) levels at week 52 in a patient population exposed to Af. [Figure 12] FIG. 1 shows the effect of dupilumab q2w on annualized severe exacerbation rate during 52 weeks of treatment in the ITT patient population with serologic evidence of ABPA. [Figure 13] FIG. 1 shows the effect of dupilumab q2w on pre-bronchodilator FEV1(L) during 52 weeks of treatment in the ITT patient population with serologic evidence of ABPA. [Figure 14] FIG. 1 shows the effect of dupilumab q2w on ACQ-5 scores during 52 weeks of treatment in the ITT patient population with serologic evidence of ABPA. [Figure 15] 15A-15B show the effect of dupilumab q2w on serum total IgE (IU / mL) (FIG. 15A) and A. fumigatus-specific serum IgE (IU / mL) (FIG. 15B) during the 52-week treatment period in exposed patients with serologic evidence of ABPA. [Figure 16-1] 16A-D show the effect of dupilumab q2w on type 2 biomarkers during the 52-week treatment period in exposed patients with serologic evidence of ABPA: FeNO (ppb) (FIG. 16A), TARC (pg / mL) (FIG. 16B), eotaxin-3 (pg / mL) (FIG. 16C), and peripheral blood eosinophils (cells / μL) (FIG. 16D). [Figure 16-2] Continued from Figure 16-1. [Figure 17]Figures 17A-B show plaque reduction neutralization titers (PRNT50) of neutralizing YFV-17D antibodies pre- and post-vaccination. Figure 17A shows the concordant neutralization titers of the 23 patients for whom pre-vaccination titers were obtained. Figure 17B shows the pre- and post-vaccination data for all patients. In Figure 17B, patients with dupilumab concentrations below the mean Ctrough concentration of 37.4 mg / L are shown as filled circles, whereas patients with serum concentrations above 37.4 mg / L are shown as open circles. Titers <1:10 were defined as seronegative, and such values ​​were designated "1". Figures 17A-B show that all 37 vaccinated patients had seroprotective yellow fever neutralization titers after vaccination. [Figure 18] Figure 18 shows the increase in (log) PRNT titers (post-vaccination vs. pre-vaccination titers) versus pre-vaccination dupilumab concentrations. In 15 of 23 patients, pre-vaccination PK samples were collected on the same day of YFV administration. All 13 patients with serum dupilumab concentrations greater than 37.4 mg / L had seroprotective PRNT titers after YFV. Twelve of these patients demonstrated an increase in post-vaccination titers, while one of these 13 patients did not demonstrate an increase in titers but was already within the seroprotective threshold at baseline. The fold change in PRNT titer levels for these patients is demonstrated in Figure 18. Pre-vaccination titers were <1:10, and 10 was used to calculate the fold increase in titers. [Figure 19] 19 shows the mean absolute FEV1(L) before and after yellow fever vaccination in patients who received the yellow fever vaccine in the LTS12551 study. FIG. 19 shows that FEV1 was stable from the visit before YFV administration to the first visit after YFV administration. BL: baseline of the parent study; Pre-YF: last visit before yellow fever vaccination; Post-YF: first visit after yellow fever vaccination; FU: visit during follow-up period. [Figure 20]Figure 20 shows the mean change from baseline in FEV1(L) before and after yellow fever vaccination in patients who received the yellow fever vaccine in the LTS12551 study. Figure 20 shows that FEV1 was stable from the visit before YFV administration to the first visit after YFV administration. BL: baseline of the parent study; Pre-YF: last visit before yellow fever vaccination; Post-YF: first visit after yellow fever vaccination; FU: visit during follow-up period. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0261] Before describing the invention, it is to be understood that this invention is not limited to the particular methods and experimental conditions described, since such methods and conditions may vary. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only, and is not intended to be limiting, since the scope of the present invention will be limited only by the appended claims.

[0262] 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 belongs.

[0263] As used herein, the term "about" when used in reference to a particular recited numerical value means that the value may vary from the recited value by up to 1%. For example, as used herein, the expression "about 100" includes 99 and 101 and all values ​​therebetween (e.g., 99.1, 99.2, 99.3, 99.4, etc.).

[0264] As used herein, the terms "treat," "treating," and the like mean to alleviate a symptom, temporarily or permanently remove the causal effect of a symptom, or prevent or slow the onset of a symptom of a specified disorder or condition.

[0265] Although any methods and materials similar or equivalent to those described herein can be used in the practice of the present invention, exemplary methods and materials are now described. All publications mentioned herein are incorporated by reference in their entirety.

[0266] Methods for reducing the incidence of asthma and / or ABPA exacerbations Methods are provided for reducing the incidence of asthma (e.g., allergic asthma, asthma associated with ABPA, moderate to severe asthma, persistent asthma, etc.) and / or exacerbations of ABPA (ABPA, ABPA associated with asthma, ABPA associated with CF, ABPA associated with asthma and CF, etc.) in a subject in need thereof, comprising administering to the subject a pharmaceutical composition comprising an IL-4R antagonist. According to certain embodiments, the IL-4R antagonist is an antibody or antigen-binding fragment thereof that specifically binds to IL-4R. Exemplary anti-IL-4R antibodies that can be used in the context of the methods characterized herein are described elsewhere herein.

[0267] 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 signs of asthma (e.g., allergic asthma, asthma associated with ABPA, moderate to severe asthma, persistent asthma, etc.). "Asthma exacerbation" also includes any worsening of a subject's respiratory health that requires and / or is treatable by therapeutic intervention for asthma (e.g., steroid therapy, inhaled corticosteroid therapy, hospitalization, etc.). Two types of asthma exacerbations These are events, namely loss of asthma control (LOAC) events and severe exacerbation events.

[0268] As used herein, the phrase "exacerbation of allergic bronchopulmonary aspergillosis" or "exacerbation of ABPA" means an increase in the severity and / or frequency and / or duration of one or more symptoms or signs of ABPA, including, but not limited to, wheezing, dyspnea, respiratory exacerbation, bronchial hyperresponsiveness, hemoptysis, productive cough (expectoration of brownish-black mucus plugs), central bronchiectasis with formation of mucus plugs, significantly elevated total IgE, significantly elevated Af-specific IgE and tissue eosinophilia.

[0269] According to certain embodiments, the exacerbation of ABPA is associated with HLA-DR2 serotype (e.g., subtype HLA-DRB1 * 1501, subtype * HLA-DRB1 * 1503 or subtype * HLA-DRB1 * 1601) or HLA-DR5 serotype (e.g., subtype HLA-DRB1 * 1101, subtype HLA-DRB1 * 1104, or subtype HLA-DRB1 * 1202), which optionally increases the susceptibility of the subject to developing ABPA when exposed to Af antigen, compared to subjects who do not have one of these serotypes and / or subtypes.

[0270] According to certain embodiments, a loss of asthma control (LOAC) event is defined as one or more of the following: (a) 6 or more additional reliever puffs of salbutamol / albuterol or levosalbutamol / levalbuterol in a 24-hour period (compared to baseline) on 2 consecutive days; (b) an increase in ICS by 4-fold or more in the dose at Visit 2; and (c) systemic corticosteroid use for 3 or more days; or (d) hospitalization or emergency room visit requiring systemic corticosteroids for asthma.

[0271] In certain instances, an exacerbation of asthma (e.g., allergic asthma, asthma associated with ABPA, moderate to severe asthma, persistent asthma, etc.) can be classified as a "severe asthma exacerbation event". A severe asthma (e.g., severe allergic asthma) exacerbation event refers to an incident that requires immediate intervention in the form of treatment with either systemic or inhaled corticosteroids at 4 times or more the dose taken before the incident. According to certain embodiments, a severe asthma (e.g., severe allergic asthma) exacerbation event is defined as an exacerbation of asthma (e.g., allergic asthma, asthma associated with ABPA, moderate to severe asthma, persistent asthma, etc.) that requires systemic corticosteroid use for 3 days or more; or requires hospitalization or emergency room visit for asthma. Thus, the general expression "asthma exacerbation" includes and encompasses the more detailed subcategories of "severe asthma exacerbation". Thus, methods for reducing the incidence of severe asthma exacerbations in patients in need thereof are included.

[0272] A "reduced incidence" of asthma (e.g., allergic asthma, asthma associated with ABPA, moderate to severe asthma, persistent asthma, etc.) and / or ABPA exacerbations means that a subject receiving a pharmaceutical composition comprising an IL-4R antagonist experiences fewer asthma or ABPA exacerbations (i.e., at least one less exacerbation) after treatment than before treatment, or does not experience an asthma exacerbation at least 4 weeks (e.g., 4, 6, 8, 12, 14 weeks or more) after the start of treatment with the pharmaceutical composition. Alternatively, a "reduced incidence" of asthma and / or ABPA exacerbations means that the likelihood of a subject experiencing an asthma exacerbation after administration of the pharmaceutical composition is reduced by at least 10% (e.g., 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50% or more) compared to a subject not receiving the pharmaceutical composition.

[0273] Methods are provided for reducing the incidence of asthma (e.g., allergic asthma, asthma associated with ABPA, moderate to severe asthma, persistent asthma, etc.) and / or exacerbations of ABPA in a subject in need thereof, comprising administering to the subject a pharmaceutical composition comprising an IL-4R antagonist, and administering to the subject one or more maintenance doses of an inhaled corticosteroid (ICS) and / or one or more maintenance doses of a second controller, e.g., a long-acting beta-agonist (LABA) or a leukotriene receptor antagonist (LTA). Suitable ICS include, but are not limited to, fluticasone (e.g., fluticasone propionate, e.g., Flovent™), budesonide, mometasone (e.g., mometasone furoate, e.g., Asmanex™), flunisolide (e.g., Aerobid™), dexamethasone acetate / phenobarbital / theophylline (e.g., Azmacort™), beclomethasone dipropionate HFA (Qvar™), and the like. Suitable LABA include, but are not limited to, salmeterol (e.g., Serevent™), formoterol (e.g., Foradil™), and the like. Suitable LTA include, but are not limited to, montelukast (e.g., Singulaire™), zafirlukast (e.g., Accolate™), and the like.

[0274] Provided is a method for reducing the incidence of asthma (e.g., allergic asthma, asthma associated with ABPA, moderate to severe asthma, persistent asthma, etc.) and / or ABPA exacerbation in a subject in need thereof, comprising administering to the subject a pharmaceutical composition comprising an IL-4R antagonist, and administering to the subject one or more reliever drugs to eliminate or reduce one or more asthma-related symptoms. Suitable reliever drugs include, but are not limited to, fast-acting β2-adrenergic receptor agonists, such as albuterol (i.e., salbutamol, e.g., Proventil™, Ventolin™, Xopenex™, etc.), pirbuterol (e.g., Maxair™), metaproterenol (e.g., Alupent™), etc.

[0275] Methods for improving asthma-related and / or ABPA-related parameters Also provided is a method for improving one or more asthma-related and / or ABPA-related parameters in a subject in need thereof, comprising administering to the subject a pharmaceutical composition comprising an IL-4R antagonist. (As discussed above) a reduction in the incidence of asthma exacerbations and / or ABPA exacerbations may correlate with an improvement in one or more asthma-related and / or ABPA-related parameters; however, such a correlation is not necessarily observed in all cases.

[0276] Examples of "asthma-related parameters," "ABPA-related asthma parameters," and "allergic asthma-related parameters" include: (1) the percent relative change from baseline (e.g., at week 12) in forced expiratory flow in one second (FEV1); (2) the percent relative change from baseline (e.g., at week 12) as measured by forced expiratory flow at 25-75% lung capacity (FEF25-75%); (3) the annualized rate of events of loss of asthma control during the treatment period; (4) the annualized rate of severe exacerbation events during the treatment period; (5) the time to events of loss of asthma control during the treatment period. (6) time to severe exacerbation during the treatment period; (7) time to loss of asthma control during the entire study period; (8) time to severe exacerbation during the entire study period; (9) health care resource utilization; (10) i) morning and evening asthma symptom score, ii) ACQ-5 score, iii) AQLQ score, iv) morning and evening PEF, v) number of inhalations of salbutamol / albuterol or levosalbutamol / levalbuterol for symptom relief / day, vi) change from baseline (e.g., at week 12) in nighttime awakenings; or (11) i) the 22-item Sinus and Rhinitis Scale (SN OT-22), ii) Hospital Anxiety and Depression Score (HADS), iii) change from baseline (e.g., at week 12 or week 24) in EuroQual questionnaire (EQ-5D-3L or EQ-5D-5L). "Improvement of asthma-related parameters" means an increase from baseline in one or more of FEV1, AM PEF or PM PEF, and / or a decrease from baseline in one or more of daily albuterol / levalbuterol use, ACQ5 score, mean nighttime wakefulness or SNOT-22 score. As used herein, with respect to asthma-related parameters, the term "baseline" refers to the value of the asthma-related parameter for the patient before or at the time of administration of a pharmaceutical composition comprising an IL-4R antagonist.

[0277] To determine whether asthma-related (e.g., allergic asthma-related) parameters or ABPA-related asthma parameters are "improved", the parameters are quantified at baseline and at a time point after administration of the pharmaceutical composition described herein.For example, asthma-related parameters can be measured on the first day, second day, third day, fourth day, fifth day, sixth day, seventh day, eighth day, ninth day, tenth day, eleventh day, twelfth day, or on the third week, fourth week, fifth week, sixth week, seventh week, eighth week, ninth week, tenth week, eleventh week, twelfth week, thirteenth week, fourteenth week, fifteenth week, sixteenth week, seventeenth week, eighteenth week, nineteenth week, twentieth week, twenty-first week, twenty-second week, twenty-third week, twenty-fourth week, or more. The difference between the value of the parameter at a particular time point after initiation of treatment and the value of the parameter at baseline is used to establish whether there has been an "improvement" (e.g., an increase or decrease, as the case may be, depending on the particular parameter being measured) of the asthma-related parameter.

[0278] As used herein, the term "obtain" or "obtaining" refers to taking possession of a physical entity or value, e.g., a numerical value, by "directly obtaining" or "indirectly obtaining" the physical entity or value, e.g., an asthma-related parameter. "Directly obtaining" refers to performing a method (e.g., performing a synthetic or analytical method) to obtain the physical entity or value. "Indirectly obtaining" refers to receiving a physical entity or value from another party or source (e.g., a third-party laboratory where the physical entity or value is obtained directly). Directly obtaining a physical entity includes performing a method that involves a physical change of a material entity, e.g., a starting material. Exemplary changes include making a physical entity from two or more starting materials, shearing or fragmenting a material, separating or purifying a material, combining two or more separate entities in a mixture, and performing a chemical reaction that involves breaking or forming a covalent or non-covalent bond. Obtaining a value directly includes performing a method that involves a physical change of a sample or another substance, such as performing an analytical method that involves a physical change of a substance, such as a sample, analyte, or reagent (sometimes referred to herein as a "physical analysis").

[0279] Indirectly obtained information can be provided in the form of a report, for example, provided in written or electronic form, such as an online database or application ("App"), etc. The report or information can be provided, for example, by a medical institution, such as a hospital or clinic; or a medical provider, such as a doctor or nurse.

[0280] Forced expiratory volume in one second (FEV1). According to certain embodiments, 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, FEV1 can be measured in a patient using a spirometer that meets the 2005 American Thoracic Society (ATS) / European Respiratory Society (ERS) recommendations. ATS / ERS Standardization o f Spirometry can be used as a guideline. Spirometry is typically performed between 6 and 10 AM after at least 6 hours of albuterol withholding. Pulmonary function tests are typically performed in the seated position, and the peak reading is recorded for FEV1 (in liters).

[0281] Methods of treatment are provided that increase FEV1 from baseline by at least 0.05 L at week 12 following initiation of treatment with a pharmaceutical composition comprising an anti-IL-4R antagonist. For example, administration of an IL-4R antagonist to a subject in need thereof increases FEV1 from baseline by about 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.

[0282] FEF 25-75%. According to certain embodiments, administration of an IL-4R antagonist to a patient results in an increase from baseline of FEF 25-75%. Methods for measuring FEF are known in the art. For example, FEV1 can be measured in a patient using a spirometer that meets the 2005 American Thoracic Society (ATS) / European Respiratory Society (ERS) recommendations. FEF 25-75% (between 25% and 75% forced expiratory rate) is the rate (in liters per second) that a person can empty the middle half of their air (i.e., forced vital capacity or FVC) during maximum expiration. The parameter relates to the average flow from the point at which 25 percent of the FVC is exhaled to the point at which 75 percent of the FVC is exhaled. A subject's FEF 25-75% provides information regarding small airway function, such as the degree of small airway disease and / or inflammation. A change in FEF25-75% is an early indicator of obstructive pulmonary disease. In certain embodiments, the improvement and / or increase in FEF25-75% parameters is at least a 10%, 25%, 50% or more improvement when compared to baseline. In certain embodiments, the methods described herein result in a normal FEF25-75% value in a subject (e.g., a value ranging from an average of 50-60% to 130%).

[0283] Morning and evening peak expiratory flow (AM PEF and PM PEF). According to certain embodiments, administration of an IL-4R antagonist to a patient results in an increase from baseline in morning (AM) and / or evening (PM) peak expiratory flow (AM PEF and / or PM PEF). Methods for measuring PEF are known in the art. For example, according to one method of measuring PEF, a patient is provided with an electronic PEF meter to record morning (AM) and evening (PM) PEF (as well as daily albuterol 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 written instructions for use of the electronic PEF meter are provided to the patient. Additionally, a medical professional can instruct the patient on how to record the appropriate variables in the electronic PEF meter. AM PEF is typically performed within 15 minutes of waking up (between 6am and 10am) before administering any albuterol. PM PEF is generally performed in the evening (between 6 pm and 10 pm) prior to administering any albuterol. Subjects should attempt to withhold albuterol for at least 6 hours prior to measuring their PEF. Three PEF efforts are performed by the patient and all three values ​​are recorded by an electronic PEF meter. Usually, the highest value is used for evaluation. The baseline AM PEF can be calculated as the average AM measurement recorded 7 days prior to administration of the first dose of the pharmaceutical composition comprising an IL-4R antagonist, and the baseline PM PEF can be calculated as the average PM measurement recorded 7 days prior to administration of the first dose of the pharmaceutical composition comprising an IL-4R antagonist.

[0284] At least 12 weeks after the start of treatment with a pharmaceutical composition comprising an anti-IL-4R antagonist Methods of treatment are provided that result in an increase in AM PEF and / or PM PEF from a baseline of 1.0 L / min for both. For example, according to exemplary embodiments, administration of an IL-4R antagonist to a subject in need thereof results in an increase in PEF from baseline of about 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 at week 12.

[0285] Use of albuterol / lev albuterol. According to certain embodiments, administration of IL-4R antagonist to a patient results in a reduction in daily albuterol or lev albuterol use from baseline. The number of inhalations of albuterol / lev albuterol can be recorded daily by the patient in a diary, PEF meter, or other recording device. During treatment with the pharmaceutical composition described herein, albuterol / lev albuterol can generally be used non-regularly or prophylactically when necessary for symptoms. The baseline number of inhalations / day of albuterol / lev albuterol can be calculated based on the average of the 7 days before administration of the first dose of the pharmaceutical composition comprising an IL-4R antagonist.

[0286] The method of treatment is provided that results in a reduction in the use of albuterol / lev albuterol from baseline by at least 0.25 puffs per day at 12 weeks after the start of treatment with a pharmaceutical composition comprising an anti-IL-4R antagonist.For example, administering an IL-4R antagonist to a subject in need thereof results in a reduction in the use of albuterol / lev albuterol from baseline by about 0.25 puffs per day, 0.50 puffs per day, 0.75 puffs per day, 1.00 puffs per day, 1.25 puffs per day, 1.5 puffs per day, 1.75 puffs per day, 2.00 puffs per day, 2.25 puffs per day, 2.5 puffs per day, 2.75 puffs per day, 3.00 puffs per day or more at 12 weeks.

[0287] Use of OCS. According to certain embodiments, administration of IL-4R antagonist to a patient can be used in conjunction with OCS, for example, oral prednisone. The number of doses of OCS can be recorded daily by the patient in a diary, PEF meter, or other recording device. During treatment with the pharmaceutical compositions described herein, occasional short-term use of prednisone can generally be used to control acute asthma episodes, for example, episodes where bronchodilators and other anti-inflammatory agents fail to control symptoms. In other aspects, prednisone is used simultaneously with or as a replacement for ICS. Oral prednisone can be administered at a dosage of about 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, or 40 mg. OCS can be administered once a day or multiple times a day (e.g., twice a day, three times a day, four times a day, etc.), depending on the case.

[0288] In certain exemplary embodiments, a method is provided for reducing or eliminating a subject's dependency on the use of OCS. Reducing or eliminating steroid dependency is highly advantageous and desirable. In certain embodiments, a 50% or greater (e.g., 50%, 60%, 70%, 80%, 90% or greater) reduction in OCS dose is achieved after administration of IL-4R antibody therapy at a certain time period (e.g., at week 24). In certain embodiments, OCS is substantially eliminated 40 weeks, 45 weeks, 50 weeks, 52 weeks or greater after administration of the first dose after administration of the loading dose. In other embodiments, the level of OCS usage is reduced to less than 5 mg per day (e.g., less than 5 mg, 4 mg, 3 mg, 2 mg or less per day). In other embodiments, the dependency on OCS usage is reduced to less than 5 mg per day after administration of IL4R antibody or or fragments thereof are substantially eliminated after 3 months, 6 months, 9 months or 1 year of treatment.

[0289] Five-item Asthma Control Questionnaire (ACQ) Score. According to certain embodiments, administration of an IL-4R antagonist to a patient results in a decrease from baseline in the five-item Asthma Control Questionnaire (ACQ5) score. The ACQ5 is a validated questionnaire for assessing asthma control.

[0290] Methods of treatment are provided that result in a decrease in ACQ5 score from baseline of at least 0.10 points at week 12 after initiation of treatment with a pharmaceutical composition comprising an anti-IL-4R antagonist. For example, administration of an IL-4R antagonist to a subject in need thereof results in a decrease in ACQ score from baseline of about 0.10 points, 0.15 points, 0.20 points, 0.25 points, 0.30 points, 0.35 points, 0.40 points, 0.45 points, 0.50 points, 0.55 points, 0.60 points, 0.65 points, 0.70 points, 0.75 points, 0.80 points, 0.85 points or more at week 12.

[0291] Nocturnal Wakes According to certain embodiments, administration of an IL-4R antagonist to a patient results in a decrease from baseline in the average number of nocturnal wakes.

[0292] In certain embodiments, the method reduces the average number of nocturnal awakenings from baseline by at least about 0.10-fold per night 12 weeks after initiation of treatment. For example, administration of an IL-4R antagonist to a subject in need thereof may result in a decrease from baseline in the average number of nighttime wakefulness at 12 weeks of 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.

[0293] 22-item Nasal Sinus and Osteoarthritis Scale (SNOT-22) score. According to certain embodiments, administration of an IL-4R antagonist to a patient results in a reduction from baseline in the 22-item Nasal Sinus and Osteoarthritis Scale (SNOT-22). The SNOT-22 is a validated questionnaire that assesses the impact of chronic rhinosinusitis on quality of life (Hopkins et al., 2009, Clin. Otolaryngol. 34:447-454).

[0294] A method of treatment is provided that results in a decrease in SNOT-22 score from baseline of at least 1 point at 12 weeks after initiation of treatment with a pharmaceutical composition comprising an anti-IL-4R antagonist. For example, administration of an IL-4R antagonist to a subject in need thereof can result in a decrease in SNOT-22 score from baseline of about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13 or more points at 12 weeks.

[0295] Biomarkers. In certain embodiments, the subject experiences improved lung function as measured by a biomarker, for example, a biomarker associated with allergic asthma (e.g., severe uncontrolled allergic asthma) and / or a biomarker associated with ABPA. For example, the biomarker can be exhaled nitric oxide (FeNO), eotaxin-3, total IgE, allergen-specific IgE (e.g., Af-associated IgE), periostin, eosinophil (Eos) levels, or thymus and activation-regulated chemokine (TARC). In certain embodiments, the improvement in lung function is measured at the fourth week after treatment (if necessary), This is indicated by a decrease or increase at 12 or 24 weeks.

[0296] Methods for Treating Asthma and / or ABPA In some embodiments, a method is provided for treating asthma, such as allergic asthma, ABPA-associated asthma, moderate to severe uncontrolled or poorly controlled asthma, and any of these allergic forms, in a subject in need thereof, comprising administering to the subject a pharmaceutical composition comprising an IL-4R antagonist.In certain embodiments, the method is useful for treating allergic asthma, such as moderate to severe uncontrolled allergic asthma, in a subject.In other specific embodiments, the method is useful for treating ABPA-associated asthma in a subject.

[0297] In some embodiments, there is provided a method for treating ABPA in a subject in need thereof, comprising administering to the subject a pharmaceutical composition comprising IL-4R antagonist.In certain embodiments, this method is useful for treating ABPA in the subject with comorbid asthma, for example, moderate to severe uncontrolled asthma.

[0298] As used herein, the term "asthma" can be used synonymously with "intermittent asthma" or "bronchial asthma". "Asthma", "bronchial asthma" and "intermittent asthma" and their respective allergic forms refer to asthma that has one or any combination of the following: symptoms occur 2 or several days per week; symptoms do not interfere with daily activities; nighttime symptoms occur less than 2 days per month; or one or more pulmonary function tests (e.g., forced expiratory volume in one second (FEV1) and / or peak expiratory flow (PEF) greater than 80%) are normal when the subject does not suffer from asthma attacks.

[0299] As used herein, the term "allergic bronchopulmonary aspergillosis" or "ABPA" refers to a hypersensitivity reaction to Aspergillus antigens, typically Aspergillus fumigatus, in the lungs of a subject that can damage the airways and cause permanent lung damage. ABPA can be diagnosed by any combination of the patient's health history (including the presence of asthma and / or cystic fibrosis), X-ray and / or CT scan, allergy skin tests, and blood IgE levels (e.g., total IgE and / or Aspergillus-specific IgE, e.g., Af-specific IgE). In certain embodiments, ABPA is diagnosed by a combination of one or more of: (1) total serum IgE levels; (2) eosinophilia; (3) Aspergillus-specific IgE, e.g., Af-specific serum IgE; and (4) Aspergillus-specific IgE, e.g., Af-specific serum IgG. In certain exemplary embodiments, a subject is diagnosed with ABPA if the subject exhibits 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.

[0300] In certain embodiments, ABPA is associated with HLA-DR2 serotype (e.g., subtype HLA-DRB1 * 1501, subtype *HLA-DRB1 * 1503 or subtype * HLA-DRB1 * 1601) or HLA-DR5 serotype (e.g., subtype HLA-DRB1 * 1101, subtype HLA-DRB1 * 1104, or subtype HLA-DRB1 * 1202).

[0301] As used herein, the term "asthma associated with ABPA" refers to a subject with comorbid asthma and ABPA.

[0302] "IgE" refers to an antibody isotype that is monomeric, containing an epsilon heavy chain and has five domains in its immunoglobulin structure. IgE is typically present in plasma at concentrations of less than 1 μg / mL and has a half-life of about 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 (which can be used interchangeably) are often used to express the level of IgE in peripheral blood, with 1 kU / L being equal to 2.4 ng / mL (Seagroatt and Anderson (1981) EJBiol Stand. 9:431).

[0303] IgE (e.g., total serum IgE and / or allergen-specific IgE) can be determined using various methods known in the art. For example, PRIST (Paper Radioimmunosorbent Test) can be used, in which serum samples react with IgE tagged with radioactive iodine. Bound radioactive iodine is detected, which 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 nephelometry (or turbidimetry) to characterize the antibody profile of a subject. Other methods of measuring IgE levels include, but are not limited to, ELISA, immunofluorescence, Western blot, immunodiffusion, immunoelectrophoresis, etc. Measurement of serum IgE concentrations can be performed using the UniCAP 250® system (Pharmacia, Uppsala, Sweden) (see GJ Gleich, AK Averbach and NA Swedlund, Measurement of IgE in normal and allergic serum by radioimmunoassay. J. Lab. Clin. Med. 77 (1971), p. 690).

[0304] Allergic asthma refers to asthma triggered by allergens, such as inhaled allergens, such as dust mites, pet dander, pollen, fungi, etc. As used herein, the term "allergic asthma" refers to asthma combined with one or more allergy markers, such as total serum IgE (e.g., ≧30 IU / mL total serum IgE, ≧700 IU / mL total serum IgE, or ≧1000 IU / mL total serum IgE), and / or at least one positive allergen-specific IgE value (e.g., ≧0.35 kU / L allergen-specific IgE value). In certain embodiments, the allergen is an airborne aeroallergen (e.g., annual aeroallergen or perennial aeroallergen).

[0305] In certain exemplary embodiments, a subject with allergic asthma is administered about ≧5 IU / mL, about ≧10 IU / mL, about ≧20 IU / mL, about ≧30 IU / mL, about ≧40 IU / mL, about ≧50 IU / mL, about ≧60 IU / mL, about ≧70 IU / mL, about ≧80 IU / mL, about ≧90 IU / mL, about ≧100 IU / mL, about ≧110 IU / mL, about ≧120 IU / mL, about ≧130 IU / mL, about ≧140 IU / mL, about ≧150 IU / mL, about ≧160 IU / mL, about ≧170 IU / mL, about ≧180 IU / mL, about ≧190 IU / mL, about ≧200 IU / mL, about ≧210 IU / mL, about ≧220 IU / mL, about ≧230 IU / mL, about ≧240 IU / mL, about ≧250 IU / mL, about ≧260 IU / mL, about ≧270 IU / mL, about ≧280 IU / mL, about ≧29 ...90 IU / mL, about ≧290 IU / mL, about ≧290 IU / mL, about ≧290 IU / mL, about ≧290 IU / mL, about ≧290 IU / mL, about ≧290 IU / mL, about The subject has a total serum IgE level of 80 IU / mL, about > 190 IU / mL, about > 200 IU / mL, about > 250 IU / mL, about > 300 IU / mL, about > 350 IU / mL, about > 400 IU / mL, about > 450 IU / mL, about > 500 IU / mL, about > 550 IU / mL, about > 600 IU / mL, about > 650 IU / mL, about > 700 IU / mL, about > 750 IU / mL, about > 800 IU / mL, about > 850 IU / mL, about > 900 IU / mL, about > 950 IU / mL, about > 1000 IU / mL or greater. In certain exemplary embodiments, the subject with allergic asthma has a total serum IgE greater than about 700 IU / mL (e.g., high total serum IgE). In certain other exemplary embodiments, the subject with allergic asthma has an inflammatory response of greater than about 1000 IU / mL. In certain exemplary embodiments, the subject has a total serum IgE level of at least 700 IU / mL as measured using an ImmunoCAP assay. In certain exemplary embodiments, the subject has a total serum IgE level of at least 1000 IU / mL as measured using an ImmunoCAP assay.

[0306] In certain exemplary embodiments, a subject with allergic asthma is at least about ≧0.05 kU / L, about ≧0.10 kU / L, about ≧0.15 kU / L, about ≧0.20 kU / L, about ≧0.21 kU / L, about ≧0.22 kU / L, about ≧0.23 kU / L, about ≧0.24 kU / L, about ≧0.25 kU / L, about ≧0.26 kU / L, about ≧0.27 kU / L, about ≧0.28 kU / L, about ≧0.29 kU / L, about ≧0.30 kU / L, about ≧0.31 kU / L, about ≧0.32 kU / L, about ≧0.33 kU / L, about ≧0.34 kU / L, about ≧0.35 kU / L, about ≧0.36 kU / L, about ≧0.37 kU / L, about ≧0.38 kU / L, about ≧0.39 kU / L, about ≧0.40 kU / L, about ≧0.41 kU / L, about ≧0.42 kU / L, about ≧0.43 kU / L, about ≧0.44 kU / L, about ≧0.45 kU / L, about ≧0.46 kU / L, 0.35kU / L, about ≧0.36kU / L, about ≧0.37kU / L, about ≧0.38kU / L, about ≧0.39kU / L, about ≧0.40kU / L, about ≧0.45kU / L, about ≧0.50kU / L, about ≧0.55kU / L, about ≧0.60kU / L, about ≧0.65kU / L, about ≧0.70kU / L, or more.

[0307] As used herein, "perennial aeroallergen" refers to airborne allergens that can be present in the environment all year round, such as dust mites, fungi, dander, etc. Perennial aeroallergens include, but are not limited to, Alternaria alternata, Aspergillus fumigatus, Aureobasidium pullulans, Candida albicans, Cladosporium herbarum, Dermatofagoides farinae, Dermatofagoides pteronyssinus, Mucor racemosus, Penicillium chrysogenum, Phoma betae, Setomelanomma rostrata, Stemphylium herbarum, and others. herbarum), cat dander, dog dander, cow dander, chicken feathers, goose feathers, duck feathers, cockroaches (e.g., Blattella germanica, Blattella orientalis), mouse urine, peanut powder, and nut powder.

[0308] As used herein, "seasonal air allergen" refers to the airborne allergens that exist seasonally in the environment, such as pollen and spores.Seasonal air allergens include, but are not limited to, tree pollen (e.g., birch, alder, cedar, hazel, hornbeam, 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, mugwort, lamb's pear, wood sorrel, etc.), fungal spores (e.g., mold fungus) that increase during certain seasons, temperatures, etc.

[0309] As used herein, the term "persistent asthma" or "persistent bronchial asthma" refers to asthma that is more severe than asthma / intermittent asthma. A subject suffering from persistent asthma or persistent bronchial asthma experiences one or more of the following: symptoms more than 2 days per week; symptoms that interfere with daily activities; nighttime symptoms occurring more than 2 days per month; or one or more pulmonary function tests that are not normal when the subject is not suffering from an asthma attack (e.g., forced expiratory volume in one second (FEV1) and / or peak expiratory flow (PEF) less than 80%); the subject is dependent on daily asthma control medication; the subject has taken systemic steroids more than once since the last year of a severe asthma exacerbation; or or use of short-acting beta-2 agonists more than 2 days per week for the relief of asthma symptoms.

[0310] Asthma / intermittent asthma, asthma / intermittent asthma, and persistent asthma / persistent asthma, as well as their respective allergic forms, can be classified as "mild," "moderate," "severe," or "moderate to severe." "Mild intermittent asthma" or "mild intermittent asthma" is defined as having symptoms less than once a week, and a forced expiratory volume in one second (FEV1) or peak expiratory flow (PEF) of ≥ 80%. "Mild persistent asthma" or "mild persistent asthma" differs in that the frequency of symptoms is more than once a week but less than once a day, and the variability of FEV1 or PEF is < 20% to 30%. "Moderate intermittent asthma" or "moderate intermittent asthma" is defined as having symptoms less than once a week and a forced expiratory volume in one second (FEV1) or peak expiratory flow (PEF) between 60% and 80%. "Moderate persistent asthma" or "moderate persistent asthma" or its allergic forms is defined as having daily symptoms, exacerbations that may affect activity and / or sleep, nocturnal symptoms more than once a week, daily use of inhaled short-acting beta-2 agonists, and a forced expiratory volume in one second (FEV1) or peak expiratory flow (PEF) between 60% and 80%. "Severe intermittent asthma" or "severe intermittent asthma" or its allergic forms is defined as having symptoms less than once a week and a forced expiratory volume in one second (FEV1) or peak expiratory flow (PEF) between 60% and 80%. "Severe persistent asthma" or "severe persistent asthma" is defined as having frequent exacerbations that may affect daily symptoms, activity and / or sleep, frequent nocturnal symptoms, limited physical activity, daily use of inhaled short-acting beta-2 agonists, and a forced expiratory volume in one second (FEV1) or peak expiratory flow (PEF) of 60%. "Moderate to severe intermittent asthma" or "moderate to severe intermittent asthma" or its allergic forms are defined as having symptoms between those of moderate intermittent asthma / moderate intermittent asthma and those of severe intermittent asthma / severe intermittent asthma. "Moderate to severe persistent asthma" or "moderate to severe persistent asthma" or its allergic forms are defined as having symptoms between those of moderate persistent asthma / moderate persistent asthma and those of severe persistent asthma / severe persistent asthma.

[0311] As used herein, the term "inadequately controlled asthma" or its allergic forms refers to patients whose asthma is "inadequately controlled" or "very poorly controlled" as defined by "Expert Panel Report 3: Guidelines for the Diagnosis and Management of Asthma", National Heart, Blood and Lung Institute, NIH, August 28, 2007. "Inadequately controlled asthma" or its allergic forms is defined as symptoms more than 2 days per week, 1-3 nighttime awakenings per week, some limitation in normal activity, use of short-acting β2-agonists for symptom control more than 2 days per week, FEV1 predicted and / or personal best of 60-80%, ATAQ score of 1-2, ACQ score of 1.5 or greater, and ACT score of 16-19. "Very poorly controlled asthma or its allergic form" is defined as symptoms throughout the day, four or more nighttime awakenings per week, severe limitation of normal activities, use of short-acting beta2-agonists several times per day to control symptoms, FEV1 less than 60% predicted and / or personal best, ATAQ score 3-4, ACQ score N / A, and ACT score ≤ 15.

[0312] In some embodiments, the subject meets the Global Initiative for Asthma (GINA) 2009 guidelines and one or more of the following criteria: i) moderate or high dose of ICS / LABA with a stable dose for at least one month prior to administration of a loading dose of an IL-4R antagonist. Existing treatment with S / LABA (250 μg fluticasone propionate twice daily or equipotent daily dose of ICS); ii) FEV1 between 40 and 80% of normal predicted before administration of a loading dose of an IL-4R antagonist; iii) ACQ-5 score of 1.5 or greater before administration of a loading dose of an IL-4R antagonist; iv) FEV1 of at least 12% and 200 mL reversible vasodilator resistance after salbutamol / albuterol 200 μg to 400 μg (2 to 4 inhalations) before administration of a loading dose of an IL-4R antagonist. or v) a subject is identified as having "moderate to severe uncontrolled" asthma (e.g., allergic asthma, asthma associated with ABPA, moderate to severe asthma, persistent asthma, etc.) if such a diagnosis is made by a physician based on experiencing any of the following events within a year prior to administration of a loading dose of an IL-4R antagonist: (a) treatment with one or more systemic (oral or parenteral) steroid bursts for an asthma exacerbation, (b) hospitalization or emergency / urgent medical visit for an asthma exacerbation.

[0313] "Severe asthma" or "severe allergic asthma" refers to asthma in which adequate control cannot be achieved by high-dose treatment with inhaled corticosteroids and additional controllers (e.g., long-acting inhaled β2 agonists, montelukast, and / or theophylline) or by oral corticosteroid treatment (e.g., at least 6 months per year), or is lost when treatment is reduced. In certain 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 >6 months / year, and at least one of the following occurs or should occur when treatment is reduced: ACT<20 or ACQ>1.5; at least two exacerbations in the past 12 months; at least one exacerbation in the past 12 months that is treated in hospital or requires mechanical ventilation; or (if FEV1 / FVC is below the lower limit of normal) FEV1<80% occurs or should occur when treatment is reduced.

[0314] "Steroid-dependent asthma or "steroid-dependent allergic asthma" refers to asthma that requires one or more of the following treatments: frequent, short-term bursts of oral corticosteroid treatment in the past 12 months; regular use of high-dose inhaled corticosteroids in the past 12 months; regular use of injected long-acting corticosteroids; daily use of oral corticosteroids; alternate-day oral corticosteroids; or prolonged use of oral corticosteroids within the past year.

[0315] "Oral corticosteroid-dependent asthma" or "oral corticosteroid-dependent allergic asthma" refers to subjects who have had ≥3 30-day oral corticosteroid (OCS) fills over a 12-month period and a primary asthma diagnosis within 12 months of the first OCS fill. Subjects with OCS-dependent asthma are those who have been receiving a physician-prescribed LABA and high-dose ICS (total daily dose >500 μg fluticasone propionate dry powder combination equivalent) for at least 3 months (ICS and LABA can be part of a combination product or can be administered by separate inhalers); are receiving additional maintenance asthma controller medications per standard medical practice, e.g., leukotriene receptor antagonists (LTRAs), theophylline, long-acting muscarinic antagonists (LAMAs), second-line ICS, and chromones; are receiving treatment for asthma at doses between ≥7.5 and ≤30 mg (prednisone or prednisolone equivalents); are receiving a LABA or ICS (total daily dose >500 μg fluticasone propionate dry powder combination equivalent) for at least 3 months (ICS and LABA can be part of a combination product or can be administered by separate inhalers); are receiving an ICS ... patients may also experience one or any combination of the following: receiving an OCS dose administered every other day (or a different dose administered every other day); having evidence of asthma as documented by a morning pre-bronchodilator (BD) FEV1 < 80% of predicted normal; a post-BD (albuterol / salbutamol) reversible FEV1 ≥ 12% and ≥ 200 mL (15-30 minutes after 4 puffs of albuterol / salbutamol); or a history of at least one asthma exacerbation event within 12 months.

[0316] In one aspect, a method is provided for treating asthma, comprising: (a) selecting a patient having a blood eosinophil level exhibiting at least 300 cells per microliter; and (b) administering to the patient a pharmaceutical composition comprising an IL-4R antagonist.

[0317] In another aspect, a method for treating asthma is provided, comprising: (a) selecting a patient having a blood eosinophil level exhibiting between 200 and 299 cells per microliter; and (b) administering to the patient a pharmaceutical composition comprising an IL-4R antagonist.

[0318] In another aspect, a method is provided for treating asthma, comprising: (a) selecting a patient exhibiting a blood eosinophil level of less than 200 cells per microliter; and (b) administering to the patient a pharmaceutical composition comprising an IL-4R antagonist.

[0319] In one aspect, a method is provided for treating asthma, comprising: (a) selecting a patient exhibiting a blood eosinophil level of at least 150 cells per microliter; and (b) administering to the patient a pharmaceutical composition comprising an IL-4R antagonist.

[0320] In one aspect, a method is provided for treating asthma, comprising: (a) selecting a patient exhibiting a blood eosinophil level of at least 300 cells per microliter; and (b) administering to the patient a pharmaceutical composition comprising an IL-4R antagonist.

[0321] 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.

[0322] 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.

[0323] 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.

[0324] In one aspect, a method is provided for treating asthma, 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.

[0325] 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.

[0326] 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.

[0327] In one aspect, a method for treating asthma is provided, comprising: (a) selecting a patient exhibiting a baseline allergen-specific IgE of ≧0.15 kU / L; and (b) administering to the patient a pharmaceutical composition comprising an IL-4R antagonist.

[0328] In one embodiment, (a) exhibits a baseline allergen-specific IgE of > 0.35 kU / L. A method for treating asthma is provided that includes the steps of: (a) selecting a patient; and (b) administering to the patient a pharmaceutical composition that includes an IL-4R antagonist.

[0329] In a related aspect, a method for treating asthma is provided, comprising adding an add-on therapy to a basic therapy. In certain embodiments, an IL-4R antagonist is administered as an add-on therapy to an asthma patient who is undergoing a basic 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 more) (also called "stable phase"). In some embodiments, the basic therapy comprises an ICS and / or a LABA.

[0330] In some embodiments, a method is provided for reducing an asthma patient's dependency on ICS and / or LABA for the treatment of one or more asthma exacerbations, comprising: (a) selecting a patient with moderate to severe asthma uncontrolled on background asthma therapy comprising an ICS, a LABA, or a combination thereof; and administering to the patient a pharmaceutical composition comprising an IL-4R antagonist.

[0331] In some embodiments, methods are provided for treating or alleviating conditions or complications associated with or coexisting with asthma, such as chronic rhinosinusitis, allergic rhinitis, allergic fungal rhinosinusitis, chronic sinusitis, allergic bronchopulmonary aspergillosis (ABPA), unified 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.

[0332] Also provided is a method for treating persistent asthma (e.g., persistent allergic asthma). As used herein, the term "persistent asthma" means that the subject has symptoms at least once a week during the day and / or at night, and the symptoms last from a few hours to several days. In certain alternative embodiments, persistent asthma is "mild persistent" (e.g., symptoms that are severe enough to interfere with daily activities or sleep occur more than twice a week, but less than every day, and / or lung function is normal or reversible by inhaling bronchodilators), "moderate persistent" (e.g., symptoms that interfere with sleep at least once a week and / or lung function is moderately abnormal occur every day), or "severe persistent" (e.g., symptoms persist and / or lung function is seriously affected despite correct use of approved medication).

[0333] Interleukin-4 receptor antagonist The methods featured herein include administering to a subject in need thereof a therapeutic composition comprising an IL-4R antagonist. As used herein, an "IL-4R antagonist" is any agent that binds to or interacts with IL-4R when expressed on a cell in vitro or in vivo, and inhibits the normal biological signaling function of IL-4R. Non-limiting examples of categories of IL-4R antagonists include small molecule IL-4R antagonists, anti-IL-4R aptamers, peptide-based IL-4R antagonists (e.g., "peptibody" molecules), and antibodies or antigen-binding fragments of antibodies that specifically bind to human IL-4R. According to certain embodiments, the IL-4R antagonist includes anti-IL-4R antibodies that can be used in the context of the methods described elsewhere herein. For example, in one embodiment, the IL-4R antagonist is an antibody or antigen-binding fragment thereof that specifically binds to IL-4R and comprises heavy and light chain (complementarity determining region) CDs from the heavy chain variable region (HCVR) and light chain variable region (LCVR) of SEQ ID NOs: 1 and 2, respectively. Contains the R sequence.

[0334] The term "human IL-4R" (hIL-4R) refers to a human cytokine receptor that specifically binds interleukin-4 (IL-4), e.g., IL-4Rα.

[0335] The term "antibody" refers to an immunoglobulin molecule comprising four polypeptide chains, two heavy (H) chains and two light (L) chains interconnected by disulfide bonds, and multimers thereof (e.g., IgM). Each heavy chain comprises a heavy chain variable region (referred to herein as HCVR or V H The heavy chain constant region is made up of three domains: H 1. C H 2, and C H Each light chain comprises a light chain variable region (herein LCVR or V L The light chain constant region comprises one domain (C L 1) is included. H and V L The regions can be further subdivided into regions of hypervariability called complementarity determining regions (CDRs), and can be interspersed with more conserved regions called framework regions (FRs). H and V L is composed of three CDRs and four FRs arranged from amino terminus to carboxy terminus in the following order: FR1, CDR1, FR2, CDR2, FR3, CDR3, FR4. In different embodiments, the FRs of an anti-IL-4R antibody (or antigen-binding portion thereof) may be identical to human germline sequences or may be naturally or artificially modified. An amino acid consensus sequence may be defined based on side-by-side analysis of two or more CDRs.

[0336] The term "antibody" also includes antigen-binding fragments of complete antibody molecules. As used herein, the terms "antigen-binding portion" of an antibody, "antigen-binding fragment" of an antibody, etc., include any naturally occurring, enzymatically derived, synthetic, or genetically modified polypeptide or glycoprotein that specifically binds to an antigen to form a complex. Antigen-binding fragments of antibodies can be derived, for example, from complete antibody molecules using any suitable standard technique, for example, proteolytic digestion or recombinant genetic engineering techniques using DNA-encoded antibody variable and, optionally, constant domain manipulation and expression. Such DNA is known and / or readily available, for example, from commercial sources, DNA libraries (including, for example, phage antibody libraries), or can be synthesized. The DNA can be sequenced and engineered, for example, by using chemical or molecular biology techniques to arrange one or more variable and / or constant domains in the appropriate configuration, or to introduce codons, create cysteine ​​residues, modify, add, or delete amino acids.

[0337] 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) minimal recognition units consisting of amino acid residues that mimic the hypervariable regions of an antibody (e.g., isolated complementarity determining regions (CDRs), such as CDR3 peptides, or constrained FR3-CDR3-FR4 peptides). Other engineered molecules, such as domain-specific antibodies, single domain antibodies, domain deleted antibodies, chimeric antibodies, CDR-grafted antibodies, bispecific antibodies, trispecific antibodies, tetraspecific antibodies, minibodies, nanobodies (e.g., monovalent nanobodies, bivalent nanobodies, etc.), small modular immunopharmaceuticals (SMIPs), and shark variable IgNAR domains, are also encompassed within the scope of the term "antigen-binding fragment".

[0338] An antigen-binding fragment of an antibody generally comprises at least one variable domain, which may be of any size or amino acid composition and which comprises at least one CDR adjacent to or in-frame with one or more framework sequences. Generally includes. V L V related to domain H In an antigen-binding fragment having a domain, H and V L The domains can be positioned relative to each other in any suitable arrangement. For example, the variable region can be a dimer, with the V H -V H , V H -V L or V L -V L Alternatively, the antigen-binding fragment of the antibody contains a monomeric V dimer. H or V L It may include a domain.

[0339] In certain embodiments, an antigen-binding fragment of an antibody can comprise at least one variable domain covalently linked to at least one constant domain. Non-limiting exemplary arrangements of variable and constant domains that can be found within the antigen-binding fragments of an antibody described herein include: (i) a 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)VL -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 -C H 2-C H 3; and (xiv) V L -C L In any arrangement of variable and constant domains, including any of the exemplary arrangements listed above, the variable and constant domains may be directly linked to each other or may be linked by a complete or partial hinge or linker region. The hinge region may consist of at least two (e.g., 5, 10, 15, 20, 40, 60 or more) amino acids that provide a flexible or semi-flexible linkage between adjacent variable and / or constant domains in a single polypeptide molecule, and typically the hinge region may consist of between 2 and 60 amino acids, typically between 5 and 50, or typically between 10 and 40 amino acids. Additionally, antigen-binding fragments of antibodies described herein may be linked to each other and / or to one or more monomeric V H Or V L The domains may comprise homodimers or heterodimers (or other multimers) of any of the variable and constant domain arrangements listed above in non-covalent association (eg, via disulfide bonds).

[0340] As with intact antibody molecules, antigen-binding fragments can be monospecific or multispecific (e.g., bispecific). Multispecific antigen-binding fragments of antibodies generally contain at least two different variable domains, each capable of specifically binding to a separate antigen or to a different epitope on the same antigen. Any multispecific antibody format can be adapted for use in conjunction with the antigen-binding fragments of antibodies described herein, using routine techniques available in the art.

[0341] The constant region of an antibody is important in the ability of the antibody to fix complement and mediate cell-dependent cytotoxicity. Thus, the isotype of the antibody can be selected based on whether it is desirable for the antibody to mediate cytotoxicity.

[0342] The term "human antibody" includes antibodies having variable and constant regions derived from human germline immunoglobulin sequences. Nevertheless, the human antibodies described herein may contain amino acid residues (e.g., mutations introduced by random or site-specific mutagenesis in vitro or by somatic mutation in vivo) that are not encoded by human germline immunoglobulin sequences, for example, in the CDRs, particularly CDR3. However, the term "human antibody" does not include antibodies in which CDR sequences derived from the germline of another mammalian species, such as a mouse, are grafted onto human framework sequences.

[0343] The term "recombinant human antibody" includes all human antibodies that are produced, expressed, created or isolated by recombinant means, e.g., antibodies expressed using a recombinant expression vector transfected into a host cell (described further below), recombinant, combinatorial, Included are antibodies isolated from a nucleic acid human antibody library (described further below), antibodies isolated from animals (e.g., mice) that are transgenic for human immunoglobulin genes (see, e.g., Taylor et al. (1992) Nucl. Acids Res. 20:6287-6295), or antibodies produced, expressed, created or isolated by any other means involving splicing of 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 certain embodiments, such recombinant human antibodies are subjected to in vitro mutagenesis (or, when animals transgenic for human Ig sequences are used, in vivo somatic mutagenesis) to thereby modify the V and V regions of the recombinant antibodies. H and VL The amino acid sequence of the region is H and V L When derived from and related to the sequences, they are sequences that cannot naturally occur within the human antibody germline repertoire in vivo.

[0344] Human antibodies can exist in two forms related to hinge heterogeneity. In one form, the immunoglobulin molecule comprises a suitable four-chain construct of approximately 150-160 kDa in which dimers are linked by inter-chain heavy chain disulfide bonds. In the second form, dimers are not linked by inter-chain disulfide bonds and molecules of approximately 75-80 kDa composed of covalently linked light and heavy chains (half-antibodies) are formed. These forms are extremely difficult to separate, even after affinity purification.

[0345] The frequency of occurrence of the second form in various intact IgG isotypes is due to, but not limited to, structural differences associated with the antibody hinge region isotype. Single amino acid substitutions in the hinge region of human IgG4 hinges can significantly reduce the occurrence of the second form (Angal et al. (1993) Molecular Immunology 30:105) to levels commonly observed with human IgG1 hinges. For example, in manufacturing, it may be desirable to improve the yield of a desired antibody form, such as by substituting the hinge, C. H 2, or C H Antibodies with one or more mutations in three regions are provided.

[0346] By "isolated antibody" is meant an antibody that has been identified and separated and / or recovered from at least one component of its natural environment. For example, an antibody that has been separated or removed from at least one component of an organism, or an antibody that has been separated or removed from a tissue or cell in which it naturally occurs or is naturally produced, is an "isolated antibody". An isolated antibody also includes an antibody in situ in a recombinant cell. An isolated antibody is an antibody that has been subjected to at least one purification or isolation step. According to certain embodiments, an isolated antibody may be substantially free of other cellular material and / or chemicals.

[0347] The term "specifically binds" and the like means that an antibody or antigen-binding fragment thereof forms a complex with an antigen that is relatively stable 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, surface plasmon resonance, and the like. For example, an antibody that "specifically binds" IL-4R as characterized in the present invention includes an antibody, or a portion thereof, that binds to IL-4R, and is capable of binding to the IL-4R. D is 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, as measured in a surface plasmon resonance assay. However, an isolated antibody that specifically binds human IL-4R may be capable of binding to other antigens, e.g., other antigens, e.g., The IL-4R molecules may have cross-reactivity to IL-4R molecules obtained from other (non-human) species.

[0348] Anti-IL-4R antibodies useful for the present methods 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 framework and / or CDR regions of the heavy and light chain variable domains compared to the corresponding germline sequences from which the antibodies were derived. Such mutations can be readily ascertained by comparing the amino acid sequences disclosed herein to germline sequences available, for example, from public antibody sequence databases. Methods are provided involving the use of antibodies, and antigen-binding fragments thereof, derived from any of the amino acid sequences disclosed herein, in which one or more amino acids (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 for a tetrameric antibody or 1, 2, 3, 4, 5, or 6 for the HCVR and LCVR of the antibody) within one or more framework and / or CDR regions (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acids) are mutated to the corresponding residue in the germline sequence from which the antibody is derived, or to the corresponding residue in another human germline sequence, or to a conservative amino acid substitution of the corresponding germline residue (such sequence changes are collectively referred to herein as "germline mutations"). Starting with the heavy and light chain variable region sequences disclosed herein, one of skill in the art can readily produce a large number of antibodies and antigen-binding fragments containing one or more individual germline mutations or combinations thereof. In certain embodiments, the V H and / or V LAll of the framework and / or CDR residues in the domain are mutated back to the residues found in the original germline sequence from which the antibody is derived. In other embodiments, only certain residues are mutated back to the original germline sequence, for example, only the mutated residues found in the first 8 amino acids of FR1 or the last 8 amino acids of FR4, or only the mutated residues found in CDR1, CDR2 or CDR3. In other embodiments, one or more of the framework and / or CDR residues are mutated to the corresponding residues in a different germline sequence (i.e., a different germline sequence from the germline sequence from which the antibody is originally derived). Furthermore, the antibody may contain any combination of two or more germline mutations in the framework and / or CDR regions, for example, certain individual residues are mutated to the corresponding residues in a particular germline sequence, and certain other residues that differ from the original germline sequence are maintained or mutated to the corresponding residues in a different germline sequence. Once obtained, antibodies and antigen-binding fragments containing one or more germline mutations can be readily tested for one or more desired properties, e.g., improved binding specificity, increased binding affinity, improved or enhanced antagonistic or agonistic biological properties (as the case may be), reduced immunogenicity, etc. Use of antibodies and antigen-binding fragments obtained in this general manner is encompassed within the present invention.

[0349] Methods involving the use of anti-IL-4R antibodies that include variants of any of the HCVR, LCVR, and / or CDR amino acid sequences disclosed herein with one or more conservative substitutions, e.g., no more than 10, no more than 8, no more than 6, no more than 4, etc., conservative amino acid substitutions relative to any of the HCVR, LCVR, and / or CDR amino acid sequences disclosed herein are provided.

[0350] The term "surface plasmon resonance" refers to the measurement of surface plasmon activity in a biosensor matrix using, for example, a BIAcore™ system (Biacore Life Sciences division of GE Healthcare, Piscataway, NJ). It refers to an optical phenomenon that allows for the analysis of real-time interactions by detecting changes in protein concentration.

[0351] The term “K D " refers to the equilibrium dissociation constant of a particular antibody-antigen interaction.

[0352] The term "epitope" refers to an antigenic determinant that interacts with a specific antigen-binding site in the variable region of an antibody molecule known as the paratope. A single antigen may have more than one epitope. Thus, different antibodies may bind to different regions in an antigen and have different biological effects. Epitopes may be conformational or linear. Conformational epitopes are generated by spatially juxtaposed amino acids from different segments of a linear polypeptide chain. Linear epitopes are those generated by adjacent amino acid residues in a polypeptide chain. In certain circumstances, epitopes may include carbohydrate, phosphoryl, or sulfonyl moieties in an antigen.

[0353] Human antibody production Methods for generating human antibodies in transgenic mice are known in the art. Any such known method can be used to generate human antibodies that specifically bind human IL-4R.

[0354] Using VELOCIMMUNE® technology (see, for example, U.S. Patent No. 6,596,541, Regeneron Pharmaceuticals) or any other known method for generating monoclonal antibodies, a high affinity chimeric antibody to IL-4R with a human variable region and a mouse constant region is first isolated. VELOCIMMUNE® technology involves the generation of a transgenic mouse with a genome that includes human heavy and light chain variable regions operably linked to endogenous mouse constant region loci such that the mouse produces an antibody that includes a human variable region and a mouse constant region in response to antigenic stimulation. DNA encoding the variable regions of the antibody's heavy and light chains is isolated and operably linked to DNA encoding the human heavy and light chain constant regions. The DNA is then expressed in a cell capable of expressing a fully human antibody.

[0355] Generally, VELOCIMMUNE® mice are exposed to an antigen of interest, and lymphoid cells (e.g., B cells) are harvested from the mice that express the antibody. The lymphoid cells can be fused with a myeloma cell line to produce an immortal hybridoma cell line, which is 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 the desired isotype constant regions of the heavy and light chains. Such antibody proteins can be produced in cells, e.g., CHO cells. Alternatively, DNA encoding antigen-specific chimeric antibodies or variable domains of the light and heavy chains can be isolated directly from antigen-specific lymphocytes.

[0356] First, a high affinity chimeric antibody having a human variable region and a mouse constant region is isolated. The antibody is characterized and selected for the desired characteristics, including affinity, selectivity, epitope, etc., using standard procedures known to those skilled in the art. The mouse constant region is replaced with the desired human constant region to produce a fully human antibody, such as wild-type or modified IgG1 or IgG4, as described herein. The constant region selected may vary depending on the particular use, and the characteristics of high affinity antigen binding and target specificity reside in the variable region.

[0357] Generally, antibodies that can be used in the present methods have high affinity, as described above, as measured by binding to antigen immobilized in the solid phase or in solution. The mouse constant regions are replaced with the desired human constant regions to produce the fully human antibodies described herein. The constant region selected may vary depending on the particular use, with high affinity antigen binding and target specificity characteristics residing in the variable regions.

[0358] In one embodiment, a human antibody or antigen-binding fragment thereof that specifically binds to IL-4R that 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 can comprise three light chain CDRs (LCVR1, LCVR2, 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 HCVR and LCVR amino acid sequences are well known in the art and can be used to identify CDRs within the designated HCVR and / or LCVR amino acid sequences disclosed herein. Exemplary conventions that can be used to identify the boundaries of CDRs include, for example, the Kabat definition, the Chothia definition, and the AbM definition. In general terms, the Kabat definition is based on sequence diversity, the Chothia definition is based on the location of structural loop regions, and the AbM definition is a compromise between the Kabat and Chothia approaches. See, e.g., 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.

[0359] In certain embodiments, the antibody or antigen-binding fragment thereof comprises six CDRs (HCDR1, HCDR2, HCDR3, LCDR1, LCDR2 and LCDR3) derived from the heavy and light chain variable region amino acid sequence pair (HCVR / LCVR) of SEQ ID NOs: 1 and 2.

[0360] In certain embodiments, the antibody or antigen-binding fragment thereof comprises six CDRs (HCDR1 / HCDR2 / HCDR3 / LCDR1 / LCDR2 / LCDR3) having the amino acid sequences of SEQ ID NOs: 3 / 4 / 5 / 6 / 7 / 8.

[0361] In certain embodiments, the antibody or antigen-binding fragment thereof comprises the HCVR / LCVR amino acid sequence pair of SEQ ID NOs:1 and 2.

[0362] In certain embodiments, the antibody is dupilumab, which comprises the HCVR / LCVR amino acid sequence pair of SEQ ID NOs:1 and 2.

[0363] In one particular embodiment, the antibody sequence is dupilumab and comprises the heavy / light chain amino acid sequence pair of SEQ ID NOs:9 and 10.

[0364] Dupilumab HCVR amino acid sequence: EVQLVESGGGLEQPGGSLRLSCAGSGFTFRDYAMTWVRQAPGKGLEWVSSISGSGGNTYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAKDRLSITIRPRYYGLDVWGQGTTVTVS (SEQ ID NO: 1).

[0365] Dupilumab LCVR amino acid sequence: DIVMTQSPLSLPVTPGEPASISCRSSQSLLYSIGYNYLD WYLQKSGQSPQLLIYLGSNRASGVPDRFSGSGSGTDFTLKISRVEAEDVGFYYCMQALQTPYTFGQGTKLEIK (sequence number 2).

[0366] Dupilumab HCDR1 amino acid sequence: GFTFRDYA (sequence number 3).

[0367] Dupilumab HCDR2 amino acid sequence: ISGSGGNT (sequence number 4).

[0368] Dupilumab HCDR3 amino acid sequence: AKDRLSITIRPRYYGL (sequence number 5).

[0369] Dupilumab LCDR1 amino acid sequence: QSLLYSIGYNY (sequence number 6).

[0370] Dupilumab LCDR2 amino acid sequence: LGS (sequence number 7).

[0371] Dupilumab LCDR3 amino acid sequence: MQALQTPYT (sequence number 8).

[0372] Dupilumab HC amino acid sequence: EVQLVESGGGLEQPGGSLRLSCAGSGFTFRDYAMTWVRQAPGKGLEWVSSISGSGGNTYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAKDRLSITIRPRYYGLDVWGQGTTVTV SSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPEFLGGPSVF LFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLG (SEQ ID NO: 9) (amino acids 1-124 = HCVR; amino acids 125-451 = HC constant).

[0373] Dupilumab LC amino acid sequence: DIVMTQSPLSLPVTPGEPASISCRSSQSLLYSIGYNYLDWYLQKSGQSPQLLIYLGSNRASGVPDRFSGSGSGTDFTLKISRVEAEDVGFYYCMQALQTPYTFGQGTKLEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO: 10) (amino acids 1-112 = LCVR; amino acids 112-219 = LC constant).

[0374] Pharmaceutical Compositions Methods are provided that include administering to a patient an IL-4R antagonist, wherein the IL-4R antagonist is contained within a pharmaceutical composition. The pharmaceutical compositions described herein may be administered with suitable carriers, excipients, and other pharmaceutical agents that provide suitable transport, delivery, tolerance, etc. The excipients are formulated with the agent. Many suitable formulations can be found in the formulary known to all pharmacists: Remington's Pharmaceutical Sciences, Mack Publishing Company, Easton, PA. These formulations include, for example, powders, pastes, ointments, jellies, waxes, oils, lipids, lipid (cationic or anionic)-containing vesicles (e.g., LIPOFECTIN™), DNA conjugates, anhydrous absorbent pastes, oil-in-water and water-in-oil emulsions, emulsions of carbowax (polyethylene glycols of various molecular weights), semi-solid gels, and semi-solid mixtures containing carbowax. See also Powell et al., "Compendium of excipients for parenteral formulations," PDA (1998) J. Pharm. Sci. Technol. 52:238-311.

[0375] The dose of the antibody administered to the patient may vary depending on the age and size of the patient, symptoms, condition, route of administration, etc. The dose is generally calculated according to body weight or body surface area. Depending on the severity of the condition, the frequency and duration of treatment can be adjusted. Effective dosages and schedules for administering pharmaceutical compositions containing anti-IL-4R antibodies can be empirically determined, e.g., the progress of the patient can be monitored by periodic evaluation and dosage adjusted accordingly. Furthermore, inter-species scaling of dosages can be performed using methods well known in the art (e.g., Mordenti et al., 1991, Pharmaceut. Res. 8:1351).

[0376] 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, receptor-mediated endocytosis (see, e.g., Wu et al., 1987, J. Biol. Chem. 262:4429-4432). Methods of administration include, but are not limited to, intradermal, intramuscular, intraperitoneal, intravenous, subcutaneous, intranasal, intratracheal, epidural, and oral routes. The compositions may be administered by any convenient route, such as by infusion or bolus injection, by absorption through epithelial or mucocutaneous linings (e.g., oral mucosa, rectal and intestinal mucosa, etc.), and may be administered together with other bioactive agents.

[0377] The pharmaceutical compositions described herein can be delivered subcutaneously or intravenously with a standard needle and syringe. Furthermore, for subcutaneous delivery, a pen delivery device (e.g., a pen autoinjector) is easily applied in delivering the pharmaceutical compositions described herein. Such pen delivery devices can be reusable or disposable. Reusable pen delivery devices generally 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 delivery device can then be reused. In a disposable pen delivery device, there is no replaceable cartridge. Rather, a disposable pen delivery device is pre-filled with the pharmaceutical composition that is held in a reservoir within the device. Once the reservoir is empty of the pharmaceutical composition, the entire device is discarded.

[0378] A number of reusable pen and autoinjector delivery devices find use in the subcutaneous delivery of pharmaceutical compositions. Examples include, but are not limited to, the AUTOPEN™ (Owen Mumford, Inc., Woodstock, UK), the DISETRONIC™ pen (Disetronic Medical Systems, Bergdorf, Switzerland), the HUMALOG MIX 75 / 25™ pen, the HUMALOG™ pen, the HUMALIN 70 / 30™ pen, to name just a few. 0™ pen (Eli Lilly and Co., Indianapolis, IN), NOVOPEN™ I, II and III (Novo Nordisk, Copenhagen, Denmark), NOVOPEN JUNIOR™ (Novo Nordisk, Copenhagen, Denmark), BD™ pen (Becton Dickinson, Franklin Lakes, NJ), OPTIPEN™, OPTIPEN PRO™, OPTIPEN STARLET™, and OPTICLIK™ (Sanofi-Aventis, Frankfurt, Germany). Examples of disposable pen delivery devices that find use in the subcutaneous delivery of the pharmaceutical compositions described herein include, but are not limited to, the SOLOSTAR™ pen (Sanofi-Aventis), FLEXPEN™ (Novo Nordisk), and KWIKPEN™ (Eli Lilly), the SURECLICK™ autoinjector (Amgen, Thousand Oaks, CA), PENLET™ (Haselmeier, Stuttgart, Germany), EPIPEN (Dey, LP), and the HUMIRA™ pen (Abbott Labs, Abbott Park IL), to name just a few. Examples of large-volume delivery devices (e.g., large-volume injectors) include, but are not limited to, bolus injectors, e.g., BD Libertas West SmartDose, Enable Injections, SteadyMed PatchPump, Sensile SenseTrial, YPsomed YpsoDose, Bespak These include Lapas.

[0379] For direct administration to the sinuses, the pharmaceutical compositions described herein may be administered, for example, using a microcatheter (e.g., endoscope and microcatheter), an aerosolizer, a powder dispenser, a nebulizer, or an inhaler. The method includes administering an IL-4R antagonist in the form of an aerosolized formulation to a subject in need thereof. For example, an aerosolized antibody against IL-4R may be administered to treat asthma (e.g., allergic asthma, asthma associated with ABPA, moderate to severe asthma, persistent asthma, etc.) and / or ABPA in a patient. Aerosolized antibodies may be produced, for example, as described in U.S. Pat. No. 8,178,098, the entirety of which is incorporated herein by reference.

[0380] In certain circumstances, the pharmaceutical composition can be delivered in a controlled release system. In one embodiment, a pump can be used (see Langer, supra; see Sefton, 1987, CRC Crit. Ref. Biomed. Eng. vol. 14:201). In another embodiment, a polymeric material can be used; see Medical Applications of Controlled Release, Langer and Wise (eds.), 1974, CRC Pres., Boca Raton, Florida. In yet other embodiments, the controlled release system can be placed close to the target of the composition, thus requiring only a fraction of the systemic dose (see, e.g., Goodson, 1984, in Medical Applications of Controlled Release, supra, vol. 2:115-138). Other controlled release systems are discussed in the review by Langer, 1990, Science vol. 249:1527-1533.

[0381] The injectable preparations may include dosage forms for intravenous, subcutaneous, intradermal and intramuscular injections, intravenous drip infusions, and the like. These injectable preparations can be produced by known methods. For example, the injectable preparations can be produced by dissolving, suspending or emulsifying, for example, the antibody or the above-mentioned salt thereof in a sterile aqueous medium or oily medium commonly used for injections. Aqueous media for injection include, for example, physiological saline, isotonic solutions containing glucose, and other auxiliary agents, which can be dissolved in a suitable solubilizing agent, for example, alcohol (e.g., For example, ethanol), polyhydric alcohols (e.g., propylene glycol, polyethylene glycol), nonionic surfactants (e.g., polysorbate 80, HCO-50 (polyoxyethylene (50 mol) adduct of hydrogenated castor oil)) can be used in combination. For example, sesame oil, soybean oil, etc. can be used as the oil medium, which may be used in combination with a solubilizer, for example, benzyl benzoate, benzyl alcohol, etc. Therefore, the injections produced are generally filled into suitable ampoules.

[0382] Advantageously, the pharmaceutical compositions for oral or parenteral use described above are prepared in dosage forms with unit doses suitable for the dosage of the active ingredient. Such dosage forms in unit doses include, for example, tablets, pills, capsules, injections (ampoules), suppositories, etc.

[0383] 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.

[0384] Dosage 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" refers to an amount of IL-4R antagonist that causes one or more of the following: (a) a reduction in the incidence of asthma exacerbations; (b) an improvement in one or more asthma-related parameters (as defined elsewhere herein); and / or (c) a detectable improvement in one or more symptoms or signs of an upper airway inflammatory condition. "Therapeutically effective amount" also includes an amount of IL-4R antagonist that inhibits, prevents, reduces, or delays the progression of asthma in a subject.

[0385] In the case of an anti-IL-4R antibody, a therapeutically effective amount is about 0.05 mg to about 700 mg of an anti-IL-4R antibody, 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 80mg, about 90mg, about 100mg, about 110mg, about 120mg, about 130mg, about 140mg, about 150mg, about 160mg, about 170mg, about 180mg, Approximately 190mg, approximately 200mg, approximately 210mg, approximately 220mg, approximately 230mg, approximately 240mg, approximately 250mg, approximately 260mg, approximately 270mg, approximately 280mg, approximately 290m g, about 300mg, about 310mg, about 320mg, about 330mg, about 340mg, about 350mg, about 360mg, about 370mg, about 380mg, about 390mg, about 4 00mg, about 410mg, about 420mg, about 430mg, about 440mg, about 450mg, about 460mg, about 470mg, about 480mg, about 490mg, about 500mg , about 510 mg, about 520 mg, about 530 mg, about 540 mg, about 550 mg, about 560 mg, about 570 mg, about 580 mg, about 590 mg, about 600 mg, about 610 mg, about 620 mg, about 630 mg, about 640 mg, about 650 mg, about 660 mg, about 670 mg, about 680 mg, about 690 mg, or about 700 mg. In certain embodiments, 300 mg of an anti-IL-4R antibody is administered.

[0386] The amount of IL-4R antagonist contained within an individual dose range can be expressed in terms of milligrams of antibody per kilogram of patient body weight (i.e., mg / kg). For example, the IL-4R antagonist may be administered to the patient at a dose of about 0.0001 to about 10 mg per kg of patient body weight. For example, the IL-4R antagonist can be administered at a dose of 1 mg / kg, 2 mg / kg, 3 mg / kg, 4 mg / kg, 5 mg / kg, or 6 mg / kg.

[0387] In some embodiments, the dose of the IL-4R antagonist may vary depending on the eosinophil count. For example, a subject may have a blood eosinophil count (i.e., high blood eosinophil count) of ≧300 cells / mL. blood eosinophil count can be 200-299 cells / μL (moderate blood eosinophils); or blood eosinophil count can be <200 cells / μL (low blood eosinophils).

[0388] In some embodiments, the dose of the IL-4R antagonist may vary depending on the FeNO level. For example, the subject may have an FeNO level of ≧50 ppb (e.g., high FeNO); an FeNO level of ≧25 ppb; an FeNO level of about 25 ppb to about 50 ppb; an FeNO level of <50 ppb; an FeNO level of <25 ppb (e.g., low FeNO); or an FeNO level of <20 ppb (e.g., low FeNO).

[0389] In some embodiments, the dose of the IL-4R antagonist may vary depending on the total serum IgE level. For example, the subject may have a total serum IgE level of ≧30 IU / mL; a total serum IgE level of ≧700 IU / mL (e.g., high serum IgE); or a total serum IgE level of ≧1000 IU / mL (e.g., very high serum IgE).

[0390] In some embodiments, the dose of the IL-4R antagonist may vary according to the allergen-specific IgE level. In some embodiments, the dose of the IL-4R antagonist may vary according to the Af-specific IgE level. For example, the subject may have an allergen-specific IgE level of ≧0.15 kU / L; or an allergen-specific IgE level of ≧0.35 kU / L.

[0391] In certain embodiments, the methods include one or more maintenance doses of about 200 to about 300 mg of an IL-4R antagonist.

[0392] In certain embodiments, the ICS and LABA are administered for the duration of the administration of the IL-4R antagonist.

[0393] In certain embodiments, the loading dose comprises 600 mg of the anti-IL-4R antibody or antigen-binding fragment thereof, and one or more maintenance doses comprise 300 mg of the antibody or antigen-binding fragment thereof administered every other week.

[0394] In certain embodiments, the loading dose comprises 400 mg of the anti-IL-4R antibody or antigen-binding fragment thereof, and one or more maintenance doses comprise 200 mg of the antibody or antigen-binding fragment thereof administered every other week.

[0395] In certain embodiments, the loading dose comprises 400 mg of the anti-IL-4R antibody or antigen-binding fragment thereof, and one or more maintenance doses comprise 200 mg of the antibody or antigen-binding fragment thereof administered every other week, which can be increased to 300 mg of the antibody or antigen-binding fragment thereof administered every other week.

[0396] In other embodiments, the loading dose comprises 600 mg of the anti-IL-4R antibody or antigen-binding fragment thereof, and one or more maintenance doses comprise 300 mg of the antibody or antigen-binding fragment thereof administered every four weeks.

[0397] In other embodiments, the loading dose comprises 400 mg of the anti-IL-4R antibody or antigen-binding fragment thereof, and one or more maintenance doses comprise 200 mg of the antibody or antigen-binding fragment thereof administered every four weeks.

[0398] In another embodiment, the loading dose comprises 600 mg of the anti-IL-4R antibody or antigen-binding fragment thereof and one or more maintenance doses of the antibody or antigen-binding fragment thereof administered once weekly. Contains 300 mg of original binding fragment.

[0399] In other embodiments, the loading dose comprises 400 mg of the anti-IL-4R antibody or antigen-binding fragment thereof, and one or more maintenance doses comprise 200 mg of the antibody or antigen-binding fragment thereof administered once weekly.

[0400] In other embodiments, the loading dose comprises 600 mg of the anti-IL-4R antibody or antigen-binding fragment thereof, and one or more maintenance doses comprise 300 mg of the antibody or antigen-binding fragment thereof administered every three weeks.

[0401] In other embodiments, the loading dose comprises 400 mg of the anti-IL-4R antibody or antigen-binding fragment thereof, and one or more maintenance doses comprise 200 mg of the antibody or antigen-binding fragment thereof administered every three weeks.

[0402] In one embodiment, the subject is 6 to <18 years old and the IL-4R antibody or antigen-binding fragment thereof is administered at 2 mg / kg or 4 mg / kg.

[0403] In another embodiment, the subject is 12 to <18 years of age and the IL-4R antibody or antigen-binding fragment thereof is administered at 2 mg / kg or 4 mg / kg.

[0404] In another embodiment, the subject is 6 to <12 years old and the IL-4R antibody or antigen-binding fragment thereof is administered at 2 mg / kg or 4 mg / kg.

[0405] In another embodiment, the subject is 2 to <6 years old and the IL-4R antibody or antigen-binding fragment thereof is administered at 2 mg / kg or 4 mg / kg.

[0406] In yet other embodiments, the subject is <2 years old and the IL-4R antibody or antigen-binding fragment thereof is administered at 2 mg / kg or 4 mg / kg.

[0407] Combination therapy Certain embodiments of the methods described herein include administering to a subject one or more additional therapeutic agents in combination with an IL-4R antagonist. As used herein, the term "in combination with" means that the additional therapeutic agent is administered before, after, or simultaneously with a pharmaceutical composition comprising an IL-4R antagonist. In some embodiments, the term "in combination with" includes sequential or simultaneous administration of an IL-4R antagonist and a second therapeutic agent. Methods for treating asthma (e.g., allergic asthma, asthma associated with ABPA, moderate to severe asthma, persistent asthma, etc.) or related conditions or complications, or reducing at least one exacerbation, are provided, comprising administering an IL-4R antagonist in combination with a second therapeutic agent for additive or synergistic activity.

[0408] For example, when administered "before" a pharmaceutical composition comprising an IL-4R antagonist, the additional therapeutic agent may be administered about 72 hours, about 60 hours, about 48 hours, about 36 hours, about 24 hours, about 12 hours, about 10 hours, about 8 hours, about 6 hours, about 4 hours, about 2 hours, about 1 hour, about 30 minutes, about 15 minutes, or about 10 minutes before administration of the pharmaceutical composition comprising an IL-4R antagonist. When administered "after" a pharmaceutical composition comprising an IL-4R antagonist, the additional therapeutic agent may be administered about 10 minutes, about 15 minutes, about 30 minutes, about 1 hour, about 2 hours, about 4 hours, about 6 hours, about 8 hours, about 10 hours, about 12 hours, about 24 hours, about 36 hours, about 48 hours, about 60 hours, or about 72 hours after administration of the pharmaceutical composition comprising an IL-4R antagonist. "Concurrent" administration of a pharmaceutical composition comprising an IL-4R antagonist means that the additional therapeutic agent is This means that the additional therapeutic agent is administered to the subject in a separate dosage form within less than 5 minutes of (before, after, or simultaneously with) administration of a pharmaceutical composition containing an IL-4R antagonist, or that the additional therapeutic agent is administered to the subject as a combined single-dose formulation containing an IL-4R antagonist and an additional therapeutic agent.

[0409] The additional therapeutic agent may be, for example, another IL-4R antagonist, an IL-1 antagonist (including, for example, the IL-1 antagonists described in U.S. Pat. No. 6,927,044), an IL-6 antagonist, an IL-6R antagonist (including, for example, the anti-IL-6R antibodies described in U.S. Pat. No. 7,582,298), a TNF antagonist, an IL-8 antagonist, an IL-9 antagonist, an IL-17 antagonist, an IL-20 antagonist, an IL-22 antagonist, an IL-23 antagonist, an IL-24 antagonist, an IL-25 antagonist, an IL-26 antagonist, an IL-27 antagonist, an IL-28 antagonist, an IL-29 antagonist, an IL-30 antagonist, an IL-31 antagonist, an IL-32 antagonist, an IL-33 antagonist, an IL-34 antagonist, an IL-35 antagonist, an IL-36 antagonist, an IL-37 antagonist, an IL-38 antagonist, an IL-39 antagonist, an IL-39 antagonist, an IL-40 antagonist, an IL-41 antagonist, an IL-42 antagonist, an IL-43 antagonist, an IL-44 antagonist, an IL-45 antagonist, an IL-46 antagonist, an IL-47 antagonist, an IL-48 antagonist, an IL-4 ...1 antagonist, an IL-42 antagonist, an IL-43 antagonist, an IL-44 antagonist, an IL-45 antagonist, an IL-46 antagonist, an IL-47 antagonist, an The therapeutic agent may be an IL-5 antagonist, an IgE antagonist, a CD48 antagonist, a leukotriene inhibitor, an antifungal agent, an NSAID, a long-acting beta2 agonist (e.g., salmeterol or formoterol), an inhaled corticosteroid (e.g., fluticasone or budesonide), a systemic corticosteroid (e.g., oral or intravenous), a methylxanthine, nedocromil sodium, cromolyn sodium, or a combination thereof. For example, in certain embodiments, a pharmaceutical composition comprising an IL-4R antagonist is administered in combination with a combination comprising a long-acting beta2 agonist and an inhaled corticosteroid (e.g., fluticasone + salmeterol (e.g., Advair® (GlaxoSmithKline)); or budesonide + formoterol (e.g., SYMBICORT® (Astra Zeneca)).

[0410] In some embodiments, the additional therapeutic agent administered in combination with IL-4R antagonist is a vaccine.In certain exemplary embodiments, the vaccine is a viral vaccine or a bacterial vaccine.In certain exemplary embodiments, the vaccine is a live (e.g., live attenuated) viral vaccine or a live (e.g., live attenuated) bacterial vaccine.

[0411] 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, generic), DT (generic), 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)), 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 called 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 (MMR II), MMRV (ProQuad)), meningococcal (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, Q uadracel), DTaP-HepB-IPV (Pediarix), DTaP-IPV / Hib (Pentacel)), Pneumococcus (e.g., PCV13 (Prevnar13), PPSV23 (Pneumovax23)), Polio (e.g., Polio (Ipol), DTaP-IPV (Kinrix, Quadracel), DTaP-HepB-IPV (Pediarix), DTaP-IPV / Hib (Pentacel)), Rabies (e.g., Rabies (Imovax Rabies, 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., Vaccinia (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., Typhoid Oral (Vivotif), Typhoid Polysaccharide (Typhim Vi), Chickenpox (e.g., VAR (Varivax), MMRV (ProQuad)), Yellow Fever (e.g., YF (YF-Vax)), etc. Suitable vaccines are also listed in the US Centers for Disease Control's Vaccine List (cdc.gov / vaccines / vpd / vaccines-list.html), which is incorporated herein in its entirety for all purposes.

[0412] In some embodiments, the vaccine is an inactivated vaccine, a recombinant vaccine, a conjugate vaccine, a subunit vaccine, a polysaccharide vaccine, or a toxoid vaccine. In some embodiments, the vaccine is a yellow fever vaccine. In some embodiments, the subject treated with the vaccine is simultaneously treated with an IL-4R antagonist for a type 2 inflammatory disease. In some embodiments, the subject treated with the vaccine is simultaneously treated with an IL-4R antagonist for asthma.

[0413] In certain embodiments, treatment with the IL-4R antagonist is discontinued or terminated prior to treatment with the vaccine. In certain embodiments, treatment with the IL-4R antagonist is discontinued for about 1 to about 9 (e.g., about 1, about 1½, about 2, about 2½, about 3, about 3½, about 4, about 4½, about 5, about 5½, about 6, about 6½, about 7, about 7½, about 8, about 8½, about 9 or more) weeks prior to administration of the vaccine. In some embodiments, treatment with an IL-4R antagonist is administered for about 1, about 2, about 3, about 4, about 5, about 6, about 7, about 8, about 9, about 10, about 11, about 12, about 13, about 14, about 15, about 16, about 17, about 18, about 19, about 20, about 21, about 22, about 23, about 24, about 25, about 26, about 27, about 28, about 29, about 30, about 31, about 32, about 33, about 34, about 35, about 36, about 37, about 38, about 39, about 40, about 41, about 42, about 43, about 44, about 45, about 46, about 47, about 48, about 49, about 50, about 51, about 52, about 53, about 54, about 55, about 56, about 57, about 58, about 59, about 60, about 61, about 62, about 63, about 64, about 65, about 66, about 67, about 68, about 69, about 70, about 71, about 72, about 73, about 74, about 75, about 76, about 77, about 78, about 79, about 80, about 81, about 82, about 83, about 84, about 85, about 86, about 87, about 88, about 89, about 90, about 91, about 92, about 93, about 94, about 95, about 96, about 97, about 98, about 99, about 100, about 1 about 28, about 29, about 30, about 31, about 32, about 33, about 34, about 35, about 36, about 37, about 38, about 39, about 40, about 41, about 42, about 43, about 44, about 45, about 46, about 47, about 48, about 49, about 50, about 51, about 52, about 53, about 54, about 55, about 56, about 57, about 58, about 59, or about 60 days.

[0414] In certain embodiments, treatment with the IL-4R antagonist is resumed after treatment with the vaccine. In certain embodiments, treatment with the IL-4R antagonist is resumed about 1 to about 14 (e.g., about 1, about 1½, about 2, about 2½, about 3, about 3½, about 4, about 4½, about 5, about 5½, about 6, about 6½, about 7, about 7½, about 8, about 8½, about 9, about 9½, about 10, about 10½, about 11, about 11½, about 12, about 12½, about 13, about 13½, about 14, about 14½, or more) weeks after administration of the vaccine. In some embodiments, , about 1, about 2, about 3, about 4, about 5, about 6, about 7, about 8, about 9, about 10, about 11, about 12, about 13, about 14, about 15, about 16, about 17, about 18, about 19, about 20, about 21, about 22, about 23, about 24, about 25, about 26, about 27, about 28, about 29, about 30, about 31, about 32, about 33, about 34, about 35, about 36, about 37, about 38, about 39, about 40, about 41, about 42, about 43, about 44, about 45, about 46, about 47, about 48, about 49, about 50, about 51, about 52, about 53, about 54, about 55, about 56, about 57, about 58, about 59, about 60, about 61, about 62, about 63, about 64, about 65, about 66, about 67, about 68, about 69, about 70, about 71, about 72, about 73, about 74, about 75, about 76, about 77, about 78, about 79, about 80, about 81, about 82, about 83, about 84, about 85, about 86, about 87, about 88, about 89, about 90, about 91, about 92, about 93, about 94, about 95, about 96, about 97, about 98, about 99, about 100, about 101, about 102, about 103 or about 90 days.

[0415] In certain embodiments, the efficacy of the IL-4R antagonist is not reduced by administration in combination with or subsequent to the administration of the vaccine. In some embodiments, the forced expiratory volume (FEV1) of the subject is stable before and after administration of the vaccine.

[0416] In some embodiments, the efficacy of the vaccine is not diminished by administration in combination with an IL-4R antagonist, or by prior and / or subsequent administration of an IL-4R antagonist, in some embodiments, subjects develop seroprotective neutralizing titers to the vaccine when the vaccine is co-administered with an IL-4R antagonist.

[0417] In certain exemplary embodiments, a subject is administered a vaccine described herein, where the subject is administered at least one dose of an IL-4R antagonist prior to, during, or after administration of the vaccine.

[0418] In some embodiments, the subject to whom the vaccine is administered has a type 2 inflammatory disease. In certain exemplary embodiments, the type 2 inflammatory disease is one or any combination of asthma, allergic rhinitis, chronic rhinosinusitis, chronic rhinosinusitis with nasal polyps (CRSsNP), eosinophilic esophagitis (EoE), atopic dermatitis (AD), food and environmental allergies, aspirin-exacerbated respiratory disease (AERD), or nonsteroidal anti-inflammatory drug (NSAID)-exacerbated respiratory disease.

[0419] Dosing regimen According to certain embodiments, multiple doses of an IL-4R antagonist may be administered to a subject over a defined time course. Such methods include sequentially administering multiple doses of an IL-4R antagonist to a subject. As used herein, "sequentially administering" means that each dose of an IL-4R antagonist is administered to a subject at different times, e.g., on different days separated by a predefined interval (e.g., hours, days, weeks, or months). Methods are provided that include sequentially administering to a patient a single initial dose of an IL-4R antagonist, followed by one or more second doses of the IL-4R antagonist, optionally followed by one or more third doses of the IL-4R antagonist.

[0420] Methods are provided which include administering to a subject a pharmaceutical composition comprising an IL-4R antagonist at a dosing frequency of about 4 times per week, twice per week, once per week (q1w), once every 2 weeks (every 2 weeks is used synonymously with every other week, once every 2 weeks or q2w), once every 3 weeks (once per 3 weeks or q3w), once every 4 weeks (monthly or q4w), once every 5 weeks (q5w), once every 6 weeks (q6w), once every 8 weeks (q8w), once every 12 weeks (q12w), or less frequently as long as a therapeutic response is achieved. In certain embodiments, weekly dosing in an amount of about 75 mg, 100 mg, 150 mg, 200 mg, or 300 mg can be used. In other embodiments involving administration of a pharmaceutical composition comprising an anti-IL-4R antibody, biweekly dosing (biweekly is used synonymously with biweekly, biweekly, or q2w) in an amount of about 75 mg, 100 mg, 150 mg, 200 mg, or 300 mg can be employed. In other embodiments involving administration of a pharmaceutical composition comprising an anti-IL-4R antibody, triweekly dosing in an amount of about 75 mg, 100 mg, 150 mg, 200 mg, or 300 mg can be used. In other embodiments involving administration of a pharmaceutical composition comprising an anti-IL-4R antibody, quadruple-weekly dosing (monthly dosing) in an amount of about 75 mg, 100 mg, 150 mg, 200 mg, or 300 mg can be used. In other embodiments involving administration of a pharmaceutical composition comprising an anti-IL-4R antibody, a dose of about 75 mg, 100 mg, 150 mg, 200 mg, or 300 mg may be used once every 5 weeks. In other embodiments involving administration of a pharmaceutical composition comprising an anti-IL-4R antibody, a dose of about 75 mg, 100 mg, 150 mg, 200 mg, or 300 mg may be used once every 6 weeks. In other embodiments involving administration of a pharmaceutical composition comprising an anti-IL-4R antibody, a dose of about 75 mg, 100 mg, 150 mg, 200 mg, or 300 mg may be used once every 8 weeks. In other embodiments involving administration of a pharmaceutical composition comprising an anti-IL-4R antibody, a dose of about 75 mg, 100 mg, 150 mg, 200 mg, or 300 mg may be used once every 12 weeks. In one embodiment, the route of administration is subcutaneous.

[0421] The term "week" refers to a period of (n x 7 days) ± 2 days, e.g., (n x 7 days) ± 1 day, or (n x 7 days), where "n" indicates the number of weeks, e.g., 1, 2, 3, 4, 5, 6, 8, 12 weeks or more.

[0422] The terms "initial dose", "second dose" and "third dose" refer to the time sequence of administration of IL-4R antagonist. Thus, "initial dose" is the dose administered at the beginning of a treatment regimen (also referred to as "baseline dose"); "second dose" is the dose administered after the initial dose; and "third dose" is the dose administered after the second dose. The initial dose, second dose and third dose can all contain the same amount of IL-4R antagonist, but generally can differ from each other in terms of the number of administrations. However, in certain embodiments, the amount of IL-4R antagonist contained in the initial dose, second dose and / or third dose varies from each other during treatment (e.g., adjusted up or down as necessary). In certain embodiments, two or more (e.g., 2, 3, 4, or 5) doses are administered at the beginning of the treatment regimen as a "loading dose," followed by subsequent doses (e.g., "maintenance doses") administered less frequently. In one embodiment, the maintenance dose may be less than the loading dose. For example, one or more loading doses of 600 mg of the IL-4R antagonist may be administered followed by a maintenance dose of about 75 mg to about 300 mg.

[0423] In certain embodiments, the loading dose is about 400 to about 600 mg of the IL-4R antagonist. In one embodiment, the loading dose is 400 mg of the IL-4R antagonist. In another embodiment, the loading dose is 600 mg of the IL-4R antagonist.

[0424] In certain 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.

[0425] In certain embodiments, the loading dose is twice the maintenance dose.

[0426] In some embodiments, the loading dose comprises an antibody or antigen-binding fragment thereof 600 mg, with one or more maintenance doses including 300 mg of the antibody or antigen-binding fragment thereof administered every other week (every other week is used synonymously with every 2 weeks, once every 2 weeks or q2w).

[0427] In some embodiments, the subject has OCS-dependent asthma, and the loading dose comprises 600 mg of the antibody or antigen-binding fragment thereof and one or more maintenance doses comprise 300 mg of the antibody or antigen-binding fragment thereof administered every other week.

[0428] In some embodiments, the subject has concomitant moderate to severe atopic dermatitis, and the loading dose comprises 600 mg of the antibody or antigen-binding fragment thereof, and one or more maintenance doses comprise 300 mg of the antibody or antigen-binding fragment thereof administered every other week.

[0429] In some embodiments, the loading dose comprises 400 mg of the antibody or antigen-binding fragment thereof, and one or more maintenance doses comprise 200 mg of the antibody or antigen-binding fragment thereof administered every other week.

[0430] In some embodiments, the subject has OCS-dependent asthma, and the loading dose comprises 400 mg of the antibody or antigen-binding fragment thereof and one or more maintenance doses comprise 200 mg of the antibody or antigen-binding fragment thereof administered every other week.

[0431] In some embodiments, the subject has concomitant moderate to severe atopic dermatitis, and the loading dose comprises 400 mg of the antibody or antigen-binding fragment thereof, and one or more maintenance doses comprise 200 mg of the antibody or antigen-binding fragment thereof administered every other week.

[0432] In some embodiments, the loading dose comprises 600 mg of the antibody or antigen-binding fragment thereof and one or more maintenance doses comprise 300 mg of the antibody or antigen-binding fragment thereof administered every four weeks.

[0433] In some embodiments, the subject has OCS-dependent asthma, and the loading dose comprises 600 mg of the antibody or antigen-binding fragment thereof and one or more maintenance doses comprise 300 mg of the antibody or antigen-binding fragment thereof administered every 4 weeks.

[0434] In some embodiments, the subject has concomitant moderate to severe atopic dermatitis, and the loading dose comprises 600 mg of the antibody or antigen-binding fragment thereof, and one or more maintenance doses comprise 300 mg of the antibody or antigen-binding fragment thereof administered every 4 weeks.

[0435] In some embodiments, the loading dose comprises 400 mg of the antibody or antigen-binding fragment thereof and one or more maintenance doses comprise 200 mg of the antibody or antigen-binding fragment thereof administered every fourth week.

[0436] In some embodiments, the subject has OCS-dependent asthma, and the loading dose comprises 400 mg of the antibody or antigen-binding fragment thereof and one or more maintenance doses comprise 200 mg of the antibody or antigen-binding fragment thereof administered every 4 weeks.

[0437] In some embodiments, the subject has concomitant moderate to severe atopic dermatitis and the loading dose comprises 400 mg of the antibody or antigen-binding fragment thereof and one or more maintenance doses comprise 200 mg of the antibody or antigen-binding fragment thereof administered every 4 weeks. Contains g.

[0438] In an exemplary embodiment, each second and / or third dose is administered 1 to 14 (e.g., 1, 1½, 2, 2½, 3, 3½, 4, 4½, 5, 5½, 6, 6½, 7, 7½, 8, 8½, 9, 9½, 10, 10½, 11, 11½, 12, 12½, 13, 13½, 14, 14½ or more) weeks after the immediately preceding dose. The phrase "immediately preceding dose" refers to a dose of an IL-4R antagonist administered to a patient prior to administration of the next dose in a series of multiple doses in a sequence that does not interrupt that dose.

[0439] The method can include administering multiple second and / or third doses of IL-4R antagonist to the patient. For example, in certain embodiments, only a single second dose is administered to the patient. In other embodiments, two or more (e.g., 2, 3, 4, 5, 6, 7, 8 or more) second doses are administered to the patient. For example, in certain embodiments, only a single third dose is administered to the patient. In other embodiments, two or more (e.g., 2, 3, 4, 5, 6, 7, 8 or more) third doses are administered to the patient.

[0440] In embodiments that include multiple second doses, each second dose may be administered at the same times as the other second doses. For example, each second dose may be administered to the patient 1-2 weeks after the immediately preceding dose. Similarly, in embodiments that include multiple third doses, each third dose may be administered at the same times as the other third doses. For example, each third dose may be administered to the patient 2-4 weeks after the immediately preceding dose. Alternatively, the number of times that the second and / or third doses are administered to the patient may vary during the treatment regimen. The number of administrations may also be adjusted during treatment by the physician according to the needs of the individual patient after clinical testing.

[0441] Methods are provided that involve sequential administration of an IL-4R antagonist and a second therapeutic agent to a patient for treating asthma (e.g., allergic asthma, asthma associated with ABPA, moderate to severe asthma, persistent asthma, etc.) or related conditions. In some embodiments, the methods involve administering one or more doses of an IL-4R antagonist, followed by one or more (e.g., 2, 3, 4, 5, 6, 7, 8 or more) doses of the second therapeutic agent. For example, one or more doses of about 75 mg to about 300 mg of an IL-4R antagonist can be administered, followed by one or more (e.g., 2, 3, 4, 5, 6, 7, 8 or more) doses of the second therapeutic agent (e.g., an inhaled corticosteroid or a β2-agonist or any other therapeutic agent as described elsewhere herein) to treat, alleviate, relieve, or ameliorate one or more symptoms of asthma. In some embodiments, the IL-4R antagonist is administered in one or more (e.g., 2, 3, 4, 5, 6, 7, 8 or more) doses that result in the improvement of one or more asthma-related parameters, and then a second therapeutic agent is administered to prevent the recurrence of at least one symptom of asthma. Alternative embodiments involve the simultaneous administration of an IL-4R antagonist and a second therapeutic agent. For example, one or more (e.g., 2, 3, 4, 5, 6, 7, 8 or more) doses of an IL-4R antagonist are administered, and the second therapeutic agent is administered in a separate dosage at similar or different times relative to the IL-4R antagonist. In some embodiments, the second therapeutic agent is administered before, after, or simultaneously with the IL-4R antagonist.

[0442] In certain embodiments, the IL-4R antagonist is administered every other week for 12 weeks, 14 weeks, 16 weeks, 18 weeks, 20 weeks, 22 weeks, 24 weeks, 26 weeks, 28 weeks, 30 weeks, 32 weeks, 34 weeks, 36 weeks, 38 weeks, 40 weeks, 42 weeks, 44 weeks, 46 weeks, In other embodiments, the IL-4R antagonist is administered once every 4 weeks for 12, 16, 20, 24, 28, 32, 36, 40, 44, 48 or more weeks. In particular embodiments, the IL-4R antagonist is administered for at least 24 weeks.

[0443] Provided is a method for treating a subject with severe uncontrolled asthma (e.g., severe steroid-dependent asthma), comprising administering to the subject a loading dose of an antibody or antigen-binding fragment thereof that specifically binds to IL-4R. In certain embodiments, the method comprises administering to the subject a maintenance dose of one or more antibodies or antigen-binding fragments thereof, the maintenance doses being administered during a treatment phase. The treatment phase includes an induction phase, an OCS tapering phase, and an OCS maintenance phase.

[0444] In certain exemplary embodiments, the induction phase includes a period during which the subject is continuously administered their OCS dose. In certain exemplary embodiments, the reduction phase includes a period during which the subject is administered a lower OCS dose relative to the dose administered during the induction phase. In certain exemplary embodiments, the maintenance phase includes a period during which the subject is administered a certain appropriate amount or dose of OCS. Alternatively, the maintenance phase includes a period during which OCS therapy / administration is reduced or eliminated. In certain embodiments, the use of OCS by the patient is completely eliminated, and the patient does not use steroids within less than one year of treatment with the IL4R antibody or fragment thereof (e.g., within one year, six months, three months, or one month of the first treatment).

[0445] In another embodiment, 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 interleukin-4 receptor (IL-4R), and administering to the subject multiple maintenance doses of the antibody or antigen-binding fragment thereof, each maintenance dose being about 300 mg of the antibody or antigen-binding fragment thereof, and the multiple maintenance doses being administered during a treatment period that includes an induction phase, an oral corticosteroid (OCS) tapering phase, and a maintenance phase, wherein the antibody or antigen-binding fragment thereof comprises heavy and light chain CDR sequences from the HCVR / LCVR sequence pair comprising SEQ ID NOs: 1 and 2.

[0446] Treatment population The method provided herein comprises administering a therapeutic composition comprising an IL-4R antagonist to a subject in need thereof.The term "subject in need thereof" refers to a human or non-human animal that shows one or more symptoms or signs of asthma (e.g., allergic asthma, e.g., moderate to severe uncontrolled allergic asthma or ABPA-associated asthma) and / or ABPA, or is diagnosed with asthma (e.g., allergic asthma, ABPA-associated asthma, moderate to severe asthma, persistent asthma, etc.) and / or ABPA. For example, a "subject in need thereof" may include a subject who, e.g., exhibits (or has exhibited), prior to treatment, one or more asthma-related (e.g., allergic asthma-related) parameters, such as, for example, an impaired FEV1 (e.g., less than 2.0 L), an impaired FEF 25-75%; an impaired AM PEF (e.g., less than 400 L / min), an 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 a SNOT-22 score of at least 20, etc. In various embodiments, the methods can be used to treat mild, moderate-to-severe, and severe asthma (e.g., allergic asthma, asthma associated with ABPA, moderate-to-severe asthma, persistent asthma, etc.) and / or ABPA in a patient in need thereof. In certain embodiments, the methods can be used to treat mild, moderate to severe, and severe asthma, e.g., allergic asthma, asthma associated with ABPA, moderate to severe asthma, persistent asthma, and / or ABPA, in a patient in need thereof, and the patient may further be suffering from a comorbid condition. This patient has moderate to severe atopic dermatitis.

[0447] In certain embodiments, a "subject in need thereof" refers to a human or non-human animal that exhibits a total serum IgE level of at least about 1000 IU / mL, an Aspergillus fumigatus specific IgE level of greater than 0.35 kU / L, or a baseline blood eosinophil count of at least about 500 cells / μl. In certain embodiments, a "subject in need thereof" refers to a human or non-human animal that exhibits at least two of a total serum IgE level of at least about 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 about 500 cells / μl. In certain embodiments, a "subject in need thereof" refers to a human or non-human animal that exhibits a total serum IgE level of at least about 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 about 500 cells / μl.

[0448] In a related embodiment, the "patient in need thereof" may be a subject who has been prescribed an ICS / LABA combination prior to receiving the IL-4R antagonist or is currently receiving an ICS / LABA combination. Examples of ICS include mometasone furoate, budesonide, and fluticasone propionate. Examples of LABA include formoterol and salmeterol. Examples of ICS / LABA therapy 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 received a regular course of ICS / LABA for 2 weeks or more immediately prior to administration of the IL-4R antagonist (such prior treatment is referred to herein as "basal treatment"). Methods of treatment are provided in which the basal treatment is continued in combination with administration of the IL-4R antagonist. In yet another embodiment, the amount of the ICS component, the LABA component, or both is tapered before or after the administration of the IL-4R antagonist is started.In some embodiments, a method is provided for treating a patient with persistent asthma for at least ≧12 months.In one embodiment, a patient with persistent asthma may be resistant to treatment with a therapeutic agent, such as a corticosteroid, and according to the method, an IL-4R antagonist can be administered.

[0449] In some embodiments, the "subject in need thereof" may be a subject with elevated levels of an asthma-associated biomarker. Examples of asthma-associated and / or ABPA-associated biomarkers include, but are not limited to, IgE (e.g., total IgE and / or A. fumigatus specific IgE), thymus and activation-regulated chemokine (TARC), blood eosinophils, eotaxin-3, CEA, YKL-40, and periostin. In some embodiments, the "subject in need thereof" may be a subject with blood eosinophils ≧300 cells / μL, 200-299 cells / μL, or <200 cells / μL. In one embodiment, the "patient in need thereof" may be a subject with elevated levels of bronchial or airway inflammation as measured by exhaled nitric oxide (FeNO). In another embodiment, the "subject in need thereof" may be a subject with elevated eotaxin levels. In another embodiment, the "subject in need thereof" may be a subject with elevated TARC levels. In another embodiment, a "subject in need thereof" can be a subject with elevated IgE levels (eg, total IgE and / or A. fumigatus-specific IgE levels).

[0450] In some embodiments, the "patient in need thereof" is selected from the group consisting of subjects age 18 years or older, subjects age 12 years or older, subjects age 12-17 years (12-<18 years), subjects age 6-11 years (6-<12 years), and subjects age 2-5 years (2-<6 years). In some embodiments, the "patient in need thereof" is selected from the group consisting of adults, adolescents, and children. In some embodiments, the "patient in need thereof" is selected from the group consisting of adults age 1 Selected from the group consisting of 8 years and older, adolescent age 12-17 years (12-<18 years), pediatric age 6-11 years (6-<12 years), and pediatric age 2-5 years (2-<6 years). The subject may be under 2 years of age, e.g., 12-23 months, or 6-11 months.

[0451] In some embodiments, a "patient in need thereof" is a subject who is a habitual smoker. In some embodiments, the subject is a habitual smoker who smokes, for example, cigarettes, cigars, pipes, hookahs, and / or vaporizers (i.e., "vapes"). In some embodiments, the subject is a habitual smoker who has a smoking history of 10 or more packs of cigarettes per year. In some embodiments, the subject is a habitual smoker who has a smoking history of less than 10 packs of cigarettes per year. In some embodiments, the subject is a habitual smoker who has a smoking history of more than 1, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50 or more packs of cigarettes per year. In some embodiments, the subject is a habitual smoker who has a smoking history of more than 6 months, 1 year, 2 years, 3 years, 5 years, 10 years or more.

[0452] In some embodiments, the "patient in need thereof" is a subject who is a former smoker. In some embodiments, the subject is a former smoker with a history of smoking cigarettes, cigars, pipes, hookahs, and / or vapes. In some embodiments, the subject is a former smoker with a history of smoking 10 or more packs of cigarettes per year. In some embodiments, the subject is a former smoker with a history of smoking less than 10 packs per year. In some embodiments, the subject is a former smoker with a history of smoking more than 1, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50 or more packs of cigarettes per year. In some embodiments, the subject is a former smoker with a history of smoking 6 months, 1 year, 2 years, 3 years, 5 years, 10 years or more. In some embodiments, the subject is a former smoker who has stopped smoking for at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 months. In some embodiments, the subject is a former smoker who has quit smoking for at least six months. In some embodiments, the subject is a former smoker who intends to quit smoking permanently.

[0453] In some embodiments, a "patient in need thereof" is a subject who is a non-smoker. In some embodiments, the subject is a non-smoker who has no history of smoking cigarettes, cigars, pipes, hookahs and / or vapes. In some embodiments, the subject is a non-smoker who has no history of smoking tobacco.

[0454] In some embodiments, a "subject in need thereof" is a subject to be treated with a vaccine, e.g., a viral or bacterial vaccine. In some embodiments, the vaccine is a live vaccine, e.g., a live (e.g., live attenuated) viral vaccine or a live (e.g., live attenuated) bacterial vaccine.

[0455] 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, generic), DT (generic), 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)), 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 called 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 (MMR II), MMRV (ProQuad)), meningococcal (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)), pneumococcus (e.g., PCV13 (Prevnar13), PPSV23 (Pneumovax23)), polio (e.g., Polio (Ipol), DTaP-IPV (Kinrix, Quadracel), DTaP-HepB-IPV (Pediarix), DTaP-IPV / Hib (Pentacel)), rabies (e.g., Rabies (Imovax Rabies, 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., Vaccinia (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 (e.g., Typhoid Oral (Vivotif), Typhoid Polysaccharide (Typhim Vi), Chickenpox (e.g., VAR (Varivax), MMRV (ProQuad)), Yellow Fever (e.g., YF (YF-Vax)), etc.Suitable vaccines are also listed in the US Centers for Disease Control's Vaccine List (cdc.gov / vaccines / vpd / vaccines-list.html), which is incorporated herein in its entirety for all purposes.

[0456] In some embodiments, the vaccine is an inactivated vaccine, a recombinant vaccine, a conjugate vaccine, a subunit vaccine, a polysaccharide vaccine, or a toxoid vaccine. In some embodiments, the vaccine is a yellow fever vaccine. In some embodiments, the subject treated with the vaccine is simultaneously treated with an IL-4R antagonist for a type 2 inflammatory disease. In some embodiments, the subject treated with the vaccine is simultaneously treated with an IL-4R antagonist for asthma. In some embodiments, the subject discontinues treatment with an IL-4R antagonist prior to administration of the vaccine.

[0457] In certain embodiments, the subject discontinues treatment with the IL-4R antagonist for about 1 to about 9 (e.g., about 1, about 1½, about 2, about 2½, about 3, about 3½, about 4, about 4½, about 5, about 5½, about 6, about 6½, about 7, about 7½, about 8, about 8½, about 9, or more) weeks prior to administration of the vaccine. In certain embodiments, the subject is administered treatment with an IL-4R antagonist for about 1, about 2, about 3, about 4, about 5, about 6, about 7, about 8, about 9, about 10, about 11, about 12, about 13, about 14, about 15, about 16, about 17, about 18, about 19, about 20, about 21, about 22, about 23, about 24, about 25, about 26, about 27, about 28, about 29, about 30, about 31, about 32, about 33, about 34, about 35, about 36, about 37, about 38, about 39, about 40, about 41, about 42, about 43, about 44, about 45, about 46, about 47, about 48, about 49, about 50, about 51, about 52, about 53, about 54, about 55, about 56, about 57, about 58, about 59, about 60, about 61, about 62, about 63, about 64, about 65, about 66, about 67, about 68, about 69, about 70, about 71, about 72, about 73, about 74, about 75, about 76, about 77, about 78, about 79, about 80, about 81, about 82, about 83, about 84, about 85, about 86, about 87, about 88, about 89, about 90, about 91, about 92, about 93, about 94, about 95, about 96, about 97, about 98, about 99, about 100, about Discontinue for about 2, about 43, about 44, about 45, about 46, about 47, about 48, about 49, about 50, about 51, about 52, about 53, about 54, about 55, about 56, about 57, about 58, about 59, or about 60 days.

[0458] In certain embodiments, the subject resumes treatment with the IL-4R antagonist after treatment with the vaccine. In certain embodiments, the subject resumes treatment with the IL-4R antagonist 1 to 14 (e.g., about 1, about 1½, about 2, about 2½, about 3, about 3½, about 4, about 4½, about 5, about 5½, about 6, about 6½, about 7, about 7½, about 8, about 8½, about 9, about 9½, about 10, about 10½, about 11, about 11½, about 12, about 12½, about 13, about 13½, about 14, about 14½, or more) weeks after administration of the vaccine. In certain embodiments, the subject receives treatment with an IL-4R antagonist for about 1, about 2, about 3, about 4, about 5, about 6, about 7, about 8, about 9, about 10, about 11, about 12, about 13, about 14, about 15, about 16, about 17, about 18, about 19, about 20, about 21, about 22, about 23, about 24, about 25, about 26, about 27, about 28, about 29, about 30, about 31, about 32, about 33, about 34, about 35, about 36, about 37, about 38, about 39, about 40, about 41, about 42, about 43, about 44, about 45, about 46, about 47, about 48, about 49, about 50, about 51, about 52, about 53, about 54, about 55, about 56, about 57, about 58, about 59, about 60, about 61, about 62, about 63, about 64, about 65, about 66, about 67, about 68, about 69, about 70, about 71, about 72, about 73, about 74, about 75, about 76, about 77, about 78, about 79, about 80, about 81, about 82, about 83, about 84, about 85, about 86, about 87, about 88, about 89, about 90, about 91, about 92, about 93, about 94, about 95, about 96, about 97, about 98, about 99, about 100, about 2, about 43, about 44, about 45, about 46, about 47, about 48, about 49, about 50, about 51, about 52, about 53, about 54, about 55, about 56, about 57, about 58, about 59, about 60, about 61, about 62, about 63, about 64, about 65, about 66, about 67, about 68, about 69, about 70, about 71, about 72, about 73, about 74, about 75, about 76, about 77, about 78, about 79, about 80, about 81, about 82, about 83, about 84, about 85, about 86, about 87, about 88, about 89, or about 90 days.

[0459] Normal IgE levels in healthy subjects are typically less than about 100 IU / mL (e.g., as measured using the IMMUNOCAP® assay (Phadia, Inc. Portage, Mich.)). Thus, provided is a method that includes selecting a subject exhibiting elevated serum IgE levels, where the serum IgE levels are 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, and administering to the subject a pharmaceutical composition comprising a therapeutically effective amount of an IL-4R antagonist.

[0460] Normal Aspergillus fumigatus (Af)-specific IgE levels in healthy subjects are typically less than about 0.10 kU / L (e.g., as measured using the IMMUNOCAP® assay (Phadia, Inc. Portage, MI)). Thus, provided are methods that include selecting a subject exhibiting elevated serum IgE levels, where the serum IgE level is greater than 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, and administering to the subject a pharmaceutical composition comprising a therapeutically effective amount of an IL-4R antagonist.

[0461] In certain embodiments, IgE levels (e.g., total IgE levels and / or A. fumigatus-specific IgE levels) are improved compared to baseline, e.g., improved 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.

[0462] TARC levels in healthy subjects range from 106 ng / L to 431 ng / L, with a mean of about 239 ng / L. (The system is a TARC quantitative ELISA kit provided by R&D Systems, Minneapolis, MN under catalog number DDN00.) Thus, methods are provided that include selecting a subject exhibiting elevated TARC levels, where the serum TARC level is greater than about 431 ng / L, greater than about 500 ng / L, greater than about 1000 ng / L, greater than about 1500 ng / L, greater than about 2000 ng / L, greater than about 2500 ng / L, greater than about 3000 ng / L, greater than about 3500 ng / L, greater than about 4000 ng / L, greater than about 4500 ng / L, or greater than about 5000 ng / L, and administering to the subject a pharmaceutical composition comprising a therapeutically effective amount of an IL-4R antagonist. In certain embodiments, TARC levels are improved compared to baseline, e.g., improved 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.

[0463] Eotaxin-3 belongs to a group of chemokines released by airway epithelial cells that are upregulated by the Th2 cytokines IL-4 and IL-13 (Lilly et al., 1999, J. Allergy Clin. Immunol. vol. 104:786-790). Methods are provided that include administering an IL-4R antagonist to treat a patient with elevated eotaxin-3 levels, for example, greater than about 100 pg / ml, greater than about 150 pg / ml, greater than about 200 pg / ml, greater than about 300 pg / ml, or greater than about 350 pg / ml. Serum eotaxin-3 levels can be measured, for example, by ELISA. In certain embodiments, serum eotaxin-3 levels are improved compared to baseline, for example, improved 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.

[0464] Periostin is an extracellular matrix protein involved in Th2-mediated inflammatory processes. Periostin 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 Aug. 2012). A method is provided that includes administering an IL-4R antagonist to treat a patient with elevated levels of periostin.

[0465] Exhaled nitric oxide (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 Aerocrine By using a NIOX device by AB, Solna, Sweden. The evaluation is performed before spirometry and after at least 1 hour of fasting. For example, a method is provided that includes administering an IL-4R antagonist to a patient with elevated levels of exhaled NO (FeNO), such as greater than about 30 ppb, greater than about 31 ppb, greater than about 32 ppb, greater than about 33 ppb, greater than about 34 ppb, or greater than about 35 ppb.

[0466] Carcinoembryonic antigen (CEA) (also known as CEA cell adhesion molecule 5 [CEACAM5]) is a tumor marker found in association with non-neoplastic diseases of the lung (Marechal et al., 1988, Anticancer Res. 8:677-680). Serum CEA levels can be measured by ELISA. For example, greater than about 1.0 ng / ml, greater than about 1.5 ng / ml, greater than about 2.0 ng / ml, greater than about 2.5 ng / ml, greater than about 3.0 ng / ml, greater than about 4.0 ng / ml, greater than about 5.0 ng / ml, greater than about 6.0 ng / ml, greater than about 7.0 ng / ml, greater than about 8.0 ng / ml, greater than about 9.0 ng / ml, greater than about 10.0 ng / ml, greater than about 11.0 ng / ml, greater than about 12.0 ng / ml, greater than about 13.0 ng / ml, greater than about 14.0 ng / ml, greater than about 15.0 ng / ml, greater than about 16.0 ng / ml, greater than about 17.0 ng / ml, greater than about 18.0 ng / ml, greater than about 19.0 ng / ml, greater than about 20.0 ng / ml, greater than about 21.0 ng / ml, greater than about 22.0 ng / ml, greater than about 23.0 ng / ml, greater than about 24.0 ng / ml, greater than about 25.0 ng / ml, greater than about 26.0 ng / ml, greater than about 27.0 ng / ml, greater than about 28.0 ng / ml, greater than about 29.0 ng / ml, greater than about 30.0 ng / ml, greater than about 31.0 ng / ml, The methods include administering an IL-4R antagonist to a patient with elevated levels of CEA greater than about 1.0 ng / ml, greater than about 3.0 ng / ml, greater than about 4.0 ng / ml, or greater than about 5.0 ng / ml.

[0467] YKL-40 (derived from its N-terminal amino acids tyrosine (Y), lysine (K) and leucine (L) and with a molecular weight of 40 kD) is a chitinase-like protein that has been found to be upregulated and associated with asthma exacerbations, IgE, and eosinophils (Tang et al., 2010 Eur. Respir. J. 35:757-760). Serum YKL-40 levels are measured, for example, by ELISA. Methods are provided that include administering an IL-4R antagonist to a patient with elevated levels of YKL-40, for example, greater than about 40 ng / ml, greater than about 50 ng / ml, greater than about 100 ng / ml, greater than about 150 ng / ml, greater than about 200 ng / ml, or greater than about 250 ng / ml.

[0468] Periostin is a secreted matricellular protein associated with fibrosis, and its expression is upregulated by recombinant IL-4 and IL-13 in cultured bronchial epithelial cells and bronchial fibroblasts (Jia et al. (2012) J. Allergy Clin. Immunol. 130:647). In human asthma patients, periostin expression levels correlate with reticular basement membrane thickness, an indicator of subepithelial fibrosis. Id. Methods are provided that include administering an IL-4R antagonist to a patient with elevated levels of periostin.

[0469] Eosinophils and neutrophils in induced sputum are well-established direct markers of airway inflammation (Djukanovic et al., 2002, Eur. Respire. J. vol. 37:1S-2S). Sputum is induced by inhalation of hypertonic saline and processed for cell counts according to methods known in the art, e.g., according to the European Respiratory Society guidelines.

[0470] In some embodiments, subjects are stratified into the following groups: blood eosinophil count > 300 cells / μL (HEos) or 300-499 cells / μL or > 500 cells / μL, blood eosinophil count 200-299 cells / μL (moderate blood eosinophils), or blood eosinophil count < 200 cells / μL (low blood eosinophils) and are administered an anti-IL-4R antibody or antigen-binding fragment thereof at a dose or dosing regimen based on eosinophil levels.

[0471] In some embodiments, subjects are stratified into the following groups: blood eosinophil count >= 300 cells / μL, 300-499 cells / μL, or >= 500 cells / μL (high blood eosinophils); blood eosinophil count >= 150 cells / μL (moderate blood eosinophils); or blood eosinophil count < 150 cells / μL (low blood eosinophils) and are administered an anti-IL-4R antibody or antigen-binding fragment thereof at a dose or dosing regimen based on eosinophil levels.

[0472] In some embodiments, the subject has "eosinophilic phenotype" asthma defined by a blood eosinophil count >= 150 cells / μL, a blood eosinophil count >= 300 cells / μL, a blood eosinophil count between 300-499 cells / μL, or a blood eosinophil count >= 500 cells / μL, and is administered an anti-IL-4R antibody or antigen-binding fragment thereof.

[0473] In some embodiments, subjects are classified into the following groups: total baseline serum IgE concentration of ≧30 IU / mL; total baseline serum IgE concentration of ≧100 IU / mL; total baseline serum IgE concentration of ≧200 IU / mL; total baseline serum IgE concentration of ≧300 IU / mL; total baseline serum IgE concentration of ≧400 IU / mL; total baseline serum IgE concentration of ≧500 IU / mL; total baseline serum IgE concentration of ≧600 IU / mL; total baseline serum IgE concentration of ≧700 IU / mL (e.g., high serum IgE); total baseline serum IgE concentration of ≧80 or a total baseline serum IgE concentration of ≥ 1000 IU / mL (e.g., very high IgE) and receive an anti-IL-4R antibody or antigen-binding fragment thereof at a dose or dose regimen based on IgG concentration.

[0474] In some embodiments, the subject is classified into the following groups: an allergen-specific IgE (e.g., A. fumigatus specific) concentration of ≧0.05 kU / L; an allergen-specific (e.g., A. fumigatus specific) IgE concentration of ≧0.10 kU / L; an allergen-specific (e.g., A. fumigatus specific) IgE concentration of ≧0.15 kU / L; an allergen-specific (e.g., A. fumigatus specific) IgE concentration of ≧0.20 kU / L; an allergen-specific (e.g., A. fumigatus specific) IgE concentration of ≧0.25 kU / L; an allergen-specific (e.g., A. fumigatus specific) IgE concentration of ≧0.30 kU / L. an allergen-specific (e.g., A. fumigatus specific) IgE concentration of ≥ 0.35 kU / L; an allergen-specific (e.g., A. fumigatus specific) IgE concentration of ≥ 0.40 kU / L; an allergen-specific (e.g., A. fumigatus specific) IgE concentration of ≥ 0.45 kU / L; or an allergen-specific (e.g., A. fumigatus specific) IgE concentration of ≥ 0.50 kU / L and are administered an anti-IL-4R antibody or antigen-binding fragment thereof at a dose or dose regimen based on the allergen-specific (e.g., A. fumigatus specific) IgE concentration.

[0475] In some embodiments, subjects are stratified into the following groups: baseline FeNO values ​​of ≧20 ppb; baseline FeNO values ​​of ≧25 ppb; baseline FeNO values ​​of ≧50 ppb (e.g., high FeNO); baseline FeNO values ​​of <25 ppb (e.g., low FeNO); baseline FeNO values ​​of <50 ppb; or baseline FeNO values ​​between about 25 ppb and about 50 ppb and are administered an anti-IL-4R antibody or antigen-binding fragment thereof at a dose or dose regimen based on the FeNO value.

[0476] Methods for assessing pharmacodynamic asthma-related and / or ABPA-related parameters Methods are provided for evaluating one or more pharmacodynamic asthma-related parameters and / or one or more pharmacodynamic ABPA-related parameters in a subject in need thereof, which are caused by administering a pharmaceutical composition comprising an IL-4R antagonist.The reduction in the incidence of asthma exacerbations (as described above) or the improvement in one or more asthma-related parameters (as described above) may be correlated with the improvement in one or more pharmacodynamic asthma-related parameters; however, such correlation is not necessarily observed in all cases.

[0477] Examples of "pharmacodynamic asthma-related parameters" or "pharmacodynamic ABPA-related parameters" include, for example: (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 of pharmacodynamic asthma-related parameters" refers, for example, to a reduction from baseline in one or more biomarkers, such as TARC, eotaxin-3, or IgE, a reduction in sputum eosinophils or neutrophils, FeNO, periostin, or blood eosinophil count. As used herein, the term "baseline" with respect to pharmacodynamic asthma-related parameters refers to the value of the pharmacodynamic asthma-related parameter for a patient before or at the time of administration of a pharmaceutical composition described herein.

[0478] To assess a pharmacodynamic asthma-related parameter or a pharmacodynamic ABPA-related parameter, the parameter is quantified at baseline and at time points after administration of the pharmaceutical composition. For example, a pharmacodynamic asthma-related parameter or a pharmacodynamic ABPA-related parameter is The rate may be measured at about 1 day, about 2 day, about 3 day, about 4 day, about 5 day, about 6 day, about 7 day, about 8 day, about 9 day, about 10 day, about 11 day, about 12 day, about 14 day, or about 3 weeks, about 4 weeks, about 5 weeks, about 6 weeks, about 7 weeks, about 8 weeks, about 9 weeks, about 10 weeks, about 11 weeks, about 12 weeks, about 13 weeks, about 14 weeks, about 15 weeks, about 16 weeks, about 17 weeks, about 18 weeks, about 19 weeks, about 20 weeks, about 21 weeks, about 22 weeks, about 23 weeks, about 24 weeks, or more after the first treatment with the pharmaceutical composition. The difference between the parameter value at a particular time point after initiation of treatment and the parameter value at baseline is used to establish whether there is a change, e.g., "improvement" (e.g., an increase or decrease, as the case may be, depending on the particular parameter being measured), in the pharmacodynamic asthma-related parameter.

[0479] In certain embodiments, administration of IL-4R antagonists to patients results in changes in the expression of certain biomarkers, for example, decreases or increases. Asthma- and / or ABPA-related biomarkers include, but are not limited to: (a) total IgE; (b) Af-specific IgE; (c) thymus and activation-regulated chemokine (TARC); (d) YKL-40; (e) serum carcinoembryonic antigen; (f) plasma eotaxin-3; (g) serum periostin; and (h) serum eosinophil levels. For example, administration of IL-4R antagonists to asthma and / or ABPA patients can cause one or more of a decrease in TARC or eotaxin-3 levels, or a decrease in total serum IgE levels. The decrease can be detected about 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 5 weeks, or more after administration of IL-4R antagonists. The expression of biomarkers can be assayed by methods known in the art. For example, protein levels can be measured by ELISA (enzyme-linked immunosorbent assay). RNA levels can be measured by, for example, reverse transcription coupled to polymerase chain reaction (RT-PCR).

[0480] As discussed above, expression of biomarkers can be assayed by detection of protein or RNA in serum. Serum samples can also be used to monitor additional protein or RNA biomarkers associated with response to treatment with IL-4R antagonists, IL-4 / IL-13 signaling, asthma, atopy, or eosinophilic disease (e.g., by measuring soluble IL-4Rα, IL-4, IL-13, periostin). In some embodiments, RNA samples are used to determine RNA levels (non-genetic analysis), e.g., RNA levels of biomarkers, and in other embodiments, RNA samples are used for transcriptome sequencing (e.g., genetic analysis).

[0481] compound In some embodiments, the antibody or antigen-binding fragment thereof is formulated in a composition comprising i) about 150 mg / mL of an antibody or antigen-binding fragment thereof that specifically binds 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 the viscosity of the formulation is about 8.5 centipoise.

[0482] In an alternative embodiment, the antibody or antigen-binding fragment thereof is formulated in a composition comprising: i) about 175 mg / mL of an antibody or antigen-binding fragment thereof that specifically binds 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 the viscosity of the formulation is about 8.5 centipoise.

[0483] In a specific embodiment, the antibody or antigen-binding fragment thereof comprises a HCVR comprising the amino acid sequence of SEQ ID NO:1 and a LCVR comprising the amino acid sequence of SEQ ID NO:2.

[0484] Suitable stabilized formulations are also described in US Pat. No. 8,945,559, which is incorporated herein by reference in its entirety for all purposes.

[0485] The present invention is further illustrated by the following examples, which should not be construed as further limiting. The contents of the figures and all references, patents and published patent applications cited throughout this application are expressly incorporated herein by reference for all purposes.

[0486] Furthermore, in accordance with the present invention, conventional molecular biology, microbiology, and recombinant DNA techniques within the skill of the art can be employed. Such techniques are described in detail in the literature. For example, see Green and Sambrook, Molecular Cloning: A Laboratory Manual, 4th Edition (2012) Cold Spring Harbor Laboratory Press, Cold Spring Harbor, New York; DNA Cloning: A Practical Approach, Volumes I and II (D.N. Glover, ed., 1985); Oligonucleotide Synthesis (M.J. Gait, ed., 1984); Nucleic Acid Hybridization [B.D. Hames and S.J. Higgins, ed. (1985)]; Transcription And Translation [B.D. Hames and S.J. Higgins, ed. (1984)]; Animal Cell Culture [R.I. Freshney, ed. (1986)]; Immobilized Cells And Enzymes [IRL Press, (1986)]; B. Perbal, A Practical Guide To Molecular Cloning (1984); FMAusubel et al. (eds.), Current Protocols in Molecular Biology, John Wiley & Sons, Inc. (1994). EXAMPLES

[0487] The following examples are presented to provide those skilled in the art with a complete disclosure and description of how to make and use the methods and compositions featured 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 accuracy with respect to numbers used (e.g., amounts, temperatures, etc.), but some experimental error and deviation should be accounted for. Unless otherwise indicated, parts are parts by weight, molecular weight is average molecular weight, temperature is in degrees Celsius, and pressure is at or near atmospheric pressure.

[0488] The exemplary IL-4R antagonist used in the following examples is a human anti-IL-4R antibody named dupilumab (also referred to herein as "mAb1"). EXAMPLES

[0489] Methods - Allergic Asthma Study design QUEST was a phase 3, randomized, double-blind, placebo-controlled trial evaluating the efficacy and safety of dupilumab in patients with uncontrolled moderate-to-severe asthma. A total of 1902 patients aged 12 years or older were randomized in a 2:2:1:1 ratio to receive add-on subcutaneous dupilumab 200 mg (400 mg loading dose) or 300 mg (600 mg loading dose) every 2 weeks (q2w) or volume-matched placebo for 52 weeks. The trial was conducted in accordance with the Declaration of Helsinki, the International Conference on Asthma and Clinical Trials (ICC), and the International Conference on Asthma and Clinical Trials (ICC). The study was performed in accordance with Harmonization Good Clinical Practice guidelines and applicable regulatory requirements. An independent Data and Safety Monitoring Committee performed blinded monitoring of patient safety data. Local Institutional Review Boards or Ethics Committees at each study center oversaw trial conduct and documentation. All patients provided written informed consent prior to study participation.

[0490] The effect of dupilumab on the primary asthma outcome measure in subgroups of patients with and without evidence of allergic asthma at baseline in the QUEST trial was compared. Allergic asthma was defined using the most common criteria in US clinical practice for determining eligibility for biologic therapy with omalizumab (i.e., total serum IgE ≥ 30 IU / mL and ≥ 1 perennial aeroallergen-specific IgE ≥ 0.35 kU / L at baseline) (US Food and Drug Administration, available on the website: accessdata.fda.gov / drugsatfda_docs / label / 2003 / omalgen062003LB.pdf). An upper limit for serum total IgE was not specified because dupilumab treatment is not limited by weight or serum levels of total IgE.

[0491] Adults and adolescents (≥12 years) with physician-diagnosed asthma for at least 12 months (based on the 2014 Global Initiative for Asthma (GINA) guidelines) who were receiving treatment with medium-to-high doses of inhaled glucocorticoids and up to two additional controllers were enrolled in the study. Eligible patients met the following criteria: pre-bronchodilator forced expiratory volume in 1 second (FEV1) ≤80% of predicted normal for adults and ≤90% of predicted normal for adolescents; FEV1 reversibility of ≥12% and ≥200 mL; score of ≥1.5 on the 5-item Asthma Control Questionnaire (ACQ-5); and asthma exacerbations in the previous year leading to hospitalization, emergency department visits, or treatment with systemic glucocorticoids for 3 or more days. Complete inclusion and exclusion criteria are published on Clinical Trials.gov (LIBERTY ASTHMA QUEST (NCT02414854)), which is incorporated herein by reference in its entirety.

[0492] patient Patients were classified according to whether they met criteria for allergic asthma based on: total serum IgE ≥ 30 IU / mL and ≥ 1 positive perennial aeroallergen-specific IgE value (≥ 0.35 kU / L) at baseline. The perennial allergens used were Dermatophagoides farinae, Dermatophagoides pteronyssinus, Alternaria alternata, Cladosporium herbarum, cat and dog dander, Blattella germanica, Blattella orientalis, and Aspergillus fumigatus. No percutaneous allergy skin tests were performed. Table 1 summarizes the baseline demographics for this study.

[0493] A total of 1083 patients (57% of the QUEST ITT population) met the criteria used to define allergic asthma: total serum IgE ≥ 30 IU / mL and ≥ 1 positive perennial aeroallergen-specific IgE ≥ 0.35 kU / L at baseline. 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 aeroallergen-specific IgE at baseline but < 30 IU / mL total serum IgE, 14% (n = 114) had ≥ 1 positive seasonal allergen but tested negative to all perennial allergens, 38% (n = 314) had a history of allergic rhinitis but tested negative to all perennial and seasonal allergens, and 41% (n = 336) did not have a history of allergic rhinitis and also tested negative to all perennial and seasonal allergens.

[0494] Patients who met criteria for allergic asthma were generally younger (mean 44.5 years vs. 52.5 years), had asthma onset at an earlier age (mean 21.6 years vs. 34.2 years), and a higher proportion had a comorbid atopic condition (96% vs. 64%) compared with the subgroup who did not meet criteria for allergic asthma (Table 1). In addition, 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 vs. 1.67 L). These patients also had higher serum TARC concentrations (median 327 pg / mL vs. 277 pg / mL) and similar levels of FeNO (median 26 ppb vs. 23 ppb) and blood eosinophil counts (median 250 cells / μL vs. 260 cells / μL) compared with patients who did not meet criteria for allergic asthma.

[0495] Endpoints The endpoints analyzed were annualized rate of severe exacerbations over the 52-week treatment period in subgroups of patients who did and did not meet allergic asthma criteria, change from baseline in pre-bronchodilator FEV1(L), and change from baseline in ACQ-5 score. Within each subgroup, severe exacerbations over the 52-week treatment period and change from baseline in pre-bronchodilator FEV1(L) at week 12 were also analyzed in the populations of patients with baseline blood eosinophils ≥ 150 cells / μL, ≥ 300 cells / μL, and baseline exhaled nitric oxide (FeNO) ≥ 25 ppb. Additional analyses were performed in the subset of allergic asthma patients with baseline serum total IgE > 700 IU / mL, patients for whom omalizumab therapy is not designated in the United States.

[0496] The effect of dupilumab treatment on the following biomarkers of type 2 inflammation: serum total IgE levels; FeNO levels; and serum thymus- and activation-regulated chemokine (TARC) levels were also evaluated in the allergic versus nonallergic asthma subgroups. The effect of dupilumab treatment on serum specific IgE levels to each of the perennial aeroallergens tested during the 52-week treatment period was also examined in patients who tested positive (≥0.35 kU / L) at baseline.

[0497] [Table 1-1] [Table 1-2]

[0498] statistical analysis Efficacy analyses were performed on the intention-to-treat (ITT) population, defined as all randomized patients divided into subgroups (i.e., with or without total serum IgE ≥ 30 IU / mL and ≥ 1 positive perennial aeroallergen-specific IgE value (≥ 0.35 kU / L) at baseline). For each subgroup, data were analyzed according to the four assigned treatment arms (dupilumab vs. placebo) regardless of whether they received the intervention (Castro et al. (2018) New Engl. J. Med. 378: 2486-96). Annualized rates of severe exacerbations over the 52-week treatment period were analyzed using negative binomial regression models that included assigned intervention arm, age, geographic region, baseline eosinophil layer, baseline dose of inhaled glucocorticoids, and number of severe exacerbations in the previous year as covariates. All severe exacerbations that occurred during the 52-week treatment period were included regardless of whether the patient was on treatment or not.

[0499] Changes from baseline in pre-bronchodilator FEV1(L) and ACQ-5 scores during the 52-week treatment period were analyzed using mixed-effects models with repeated measures including the four assigned intervention groups, age, geographic region, baseline eosinophil strata, baseline dose of inhaled glucocorticoids, visits, visit-by-intervention interactions, corresponding baseline values, and baseline-by-visit interactions as covariates. In addition, sex and baseline height were included as covariates in the FEV1 analysis. If treatment was interrupted, all measurements recorded after interruption over the 52-week treatment period were included.

[0500] Biomarker analysis was performed in the exposed population, defined as all patients exposed to study drug therapy. For both patient subgroups, the difference between dupilumab and combined placebo in the change from baseline in levels of eosinophils and FeNO, considered the main biomarkers of type 2 inflammation, was analyzed using a rank analysis of covariance model that included the four assigned intervention groups, age, sex, geographic region, baseline eosinophil strata, baseline dose of inhaled glucocorticoids, and the corresponding baseline values ​​as covariates. For the analysis of specific IgE, the analysis was restricted to patients who were positive for specific IgE (≥0.35 kU / L) at baseline.

[0501] A nominal P value of <0.05 (within each subgroup) for the comparison of each dupilumab dose versus placebo was considered statistically significant.

[0502] Residuals from the linear mixed model for the allergic subgroup with baseline serum IgE >700 IU / mL were examined to confirm normally distributed populations. Figure 6 shows the qq plots in addition to the histograms of the residuals. EXAMPLES

[0503] Annual rate of severe asthma exacerbations - allergic asthma In the allergic asthma subgroup, dupilumab reduced the adjusted annualized severe exacerbation rate by 36.9% (95% confidence interval (CI) 13.4% to 54.0%; nominal P = .004) with 200 mg q2w and 45.5% (95% CI 26.0% to 59.9%; nominal P < .001; Figure 1A) with 300 mg q2w compared with matched placebo. In patients who did not meet criteria for allergic asthma, the adjusted annualized severe exacerbation event rate was also reduced by 60.0% (95% CI 0.02% to 0.51%; nominal P < .001; Figure 1A). Dupilumab 200 mg and 300 mg q2w significantly (all nominal P < 0.01) reduced severe exacerbation rates in patients with baseline blood eosinophils ≥ 150 cells / μL and ≥ 300 cells / μL, as well as in patients with baseline FeNO ≥ 25 ppb, in both allergic asthma subgroups and in subgroups that did not meet criteria for allergic asthma. The magnitude of effects was numerically larger compared with the respective overall subgroups (Figures 1B–1D). Among patients in the allergic asthma subgroup with baseline serum total IgE >700 IU / mL, both dupilumab doses significantly (nominal P < 0.001) reduced the severe exacerbation rate compared with combined placebo over the 52-week treatment period, with the magnitude of effect being numerically greater for the combined allergic asthma subgroup ( Fig. 1E ). EXAMPLES

[0504] Pre-bronchodilator FEV1-Allergic asthma At week 12, dupilumab 200 mg and 300 mg q2w treatment significantly improved pre-bronchodilator FEV1 versus placebo by least squares (LS) means of 0.13 L (95% CI, 0.05 to 0.20; nominal P < 0.001) and 0.16 L (95% CI, 0.09 to 0.23; nominal P < 0.001), respectively, in the allergic asthma subgroup, and by 0.14 L (95% CI, 0.07 to 0.22; nominal P < 0.001) and 0.09 L (95% CI, 0.01 to 0.16; nominal P = 0.02), respectively, in patients who did not meet the criteria (Figure 2A). As observed for severe exacerbations, the magnitude of improvement versus placebo in pre-bronchodilator FEV1 at week 12 was equal to or greater in patients with baseline blood eosinophils ≥150 cells / μL and ≥300 cells / μL and in patients with baseline FeNO ≥25 ppb compared with the respective overall subgroups (all nominal P < 0.05; Figure 2B). Among patients in the allergic asthma subgroup with baseline serum total IgE >700 IU / mL, dupilumab 300 mg q2w showed a similar magnitude of effect on pre-bronchodilator FEV1 at week 12 compared with the overall subgroup (LS mean difference vs placebo 0.12 L (95% CI -0.03 to 0.26; nominal P = 0.11)), whereas a larger magnitude of effect was observed in patients treated with dupilumab 200 mg q2w (LS mean difference vs placebo 0.27 L (95% CI 0.13 to 0.42); nominal P < 0.001).

[0505] In both allergic and non-allergic subgroups, improvements in pre-bronchodilator FEV1 were observed as early as the first assessment at week 2 and persisted through week 52 (Figure 2A). EXAMPLES

[0506] Asthma Control - Allergic Asthma In the allergic asthma subgroup, the LS mean change from baseline in ACQ-5 score was -1.39 (standard error [SE] 0.05) for a difference vs. placebo of -0.28 (95% CI -0.46 to -0.11; nominal P < 0.01) in dupilumab 200 mg q2w-treated patients at week 24; In patients treated with q2w, improvements were observed in ACQ-5 scores from baseline at week 24 of -1.42 (SE 0.05) with a difference vs. placebo of -0.26 (95% CI -0.44 to -0.08; nominal P < 0.01) (Figure 3). In the subgroup who did not meet allergic asthma criteria, improvements in ACQ-5 scores from baseline at week 24 were observed in patients treated with dupilumab 200 mg q2w with a difference vs. placebo of -1.51 (SE 0.06) with a difference vs. placebo of -0.44 (95% CI -0.65 to -0.22; nominal P < 0.0001) and in patients treated with dupilumab 300 mg q2w with a difference vs. placebo of -1.35 (SE 0.06) with a difference vs. placebo of -0.08 (95% CI -0.29 to 0.12; nominal P = 0.43) (Figure 3). EXAMPLES

[0507] Serum total IgE and aeroallergen-specific IgE - Allergic asthma In the allergic asthma subgroup and in the subgroup that did not meet criteria for allergic asthma, both dupilumab 200 mg and 300 mg q2w dose regimens significantly reduced total serum IgE compared with matched placebo at week 12 (earliest assessed time point; nominal P<0.001; Figure 4A). Reductions in total serum IgE occurred gradually over the treatment period (nominal P<0.001 vs placebo at all time points).

[0508] In patients with allergic asthma who tested positive (≥0.35 kU / L) to each perennial aeroallergen at baseline, significant reductions from baseline in percentage antigen-specific serum IgE levels were observed over time for each of the eight perennial aeroallergens evaluated (Figure 5A-H). These reductions were statistically significant (nominal P < 0.05) compared with the combined placebo at week 12 (earliest assessed time point) and continued over the 52-week treatment period. There were too few patients who tested positive to Asian cockroach allergen at baseline to allow for meaningful analyses. EXAMPLES

[0509] FeNO and Serum TARC-Allergic Asthma In both the allergic asthma subgroup and the subgroup that did not meet criteria for allergic asthma, dupilumab 200 mg and 300 mg q2w dose regimens versus placebo were associated with significant reductions in FeNO at the first assessment after 2 weeks of treatment. FeNO reductions were sustained over the 52-week treatment period (nominal P < 0.001 at all time points) (Figure 4B). By week 52, median FeNO values ​​for dupilumab 200 mg and 300 mg q2w doses in both subgroups were similar to published medians in healthy subjects (16 ppb).

[0510] Allergic asthma subgroups and subgroups that did not meet the criteria for allergic asthma In both loops, serum TARC concentrations were significantly higher at 200 mg or 300 mg dupilumab. There were significant reductions in patients treated q2w compared with matched placebo at week 12 (earliest assessed time point), and these reductions were sustained over the 52-week treatment period (nominal P < 0.001 at all time points) (Figure 4C). EXAMPLES

[0511] Discussion - Allergic Asthma Dupilumab significantly reduced the severe exacerbation rate and improved FEV1 and asthma control (as measured by ACQ-5) in patients with allergic asthma. Improvements in FEV1 and asthma control were evident by the first assessment at week 2 and sustained over the 52-week treatment period. Some variation was observed between the two dupilumab doses in their respective exacerbation rates and magnitude of asthma control relative to placebo. Without intending to be bound by scientific theory, this could be related to the need to use two different volumes of combined placebo. The reduction in severe exacerbation rate and improvement in FEV1 were greater in patients with higher baseline levels of type 2 inflammatory biomarkers. The proportion of patients who met criteria for allergic asthma in this study (57%) was significantly lower than those who reported a history of ≥1 atopic condition in the total QUEST population (Castro et al. (2018) New Engl. J. Med. 378:2486-96). This difference is primarily due to the exclusion of patients who had a history of allergic rhinitis but no evidence of hypersensitivity to aeroallergens, the exclusion of patients who had hypersensitivity (albeit to a lower degree) only to seasonal allergens, and the exclusion of patients with perennial allergen sensitivity but whose total serum IgE was <30 IU / mL.It should be recognized that the timing of specific IgE measurements in this global study was not designed to coincide with peak seasonal allergen exposure in each country / region.

[0512] Dupilumab was shown to be effective in patients with allergic asthma as well as in patients who did not meet criteria for allergic asthma. These findings support the important role of IL-4 and IL-13 in promoting IgE- and non-IgE-mediated type 2 inflammation in asthma. The clinical benefit observed in this study extended to patients with allergic asthma who had serum total IgE >700 IU / mL at baseline. This is a clinically relevant subset of patients with allergic asthma for whom anti-IgE therapy with omalizumab is not designated 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 dosing of dupilumab, unlike omalizumab, is not limited by weight and serum total serum IgE in adolescent and adult patients with poorly controlled moderate-to-severe asthma.

[0513] Consistent with dupilumab's mechanism of action in suppressing IgE production, dupilumab significantly reduced serum total IgE and aeroallergen-specific IgE in patients with allergic asthma and reduced serum total IgE in patients who did not meet criteria for allergic asthma.

[0514] Similarly, dupilumab significantly reduced levels of other type 2 inflammatory biomarkers, including FeNO and serum TARC, in both patient subgroups. The decline in total and specific IgE was slower than other biomarkers, such as FeNO. The decline in IgE concentrations did not reach a plateau over the 52-week treatment period.

[0515] In summary, this was consistent with baseline total serum IgE ≥ 30 IU / mL and This is the first demonstration of clinical and pharmacodynamic effects of dual IL-4 and IL-13 inhibition with dupilumab in patients with allergic asthma defined by the presence of one perennial aeroallergen-specific IgE ≥ 0.35 kU / L. Dupilumab significantly reduced severe exacerbation rates and improved FEV1 during the 52-week treatment period regardless of subgroup, demonstrating clinically meaningful improvements in asthma control (ACQ-5), and treatment was generally well tolerated in the entire study population. Markers of type 2 inflammation, including FeNO, total IgE, and TARC, were also significantly reduced with dupilumab treatment in both subgroups. 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 with dupilumab therapy is beneficial for both allergic and non-allergic asthma phenotypes. EXAMPLES

[0516] Efficacy of dupilumab in patients with uncontrolled moderate-to-severe asthma and serological evidence of allergic bronchopulmonary aspergillosis (ABPA) Allergic bronchopulmonary aspergillosis (ABPA) is a severe allergic lung disease caused by hypersensitivity to Aspergillus fumigatus (Af) antigens. Not all patients with asthma develop ABPA when exposed to the fungus. However, genetic predisposition (HLA-DR2 (HLA-DRB1 * 1501 and * HLA-DRB1 * Individuals with HLA-DR5 and HLA-1503 are susceptible to developing ABPA when exposed to Af antigens. SNPs in IL-4Rα and IL-13 also contribute to genetic susceptibility, and these individuals develop a severe type 2 immune response with very high IgE, eosinophilia, and elevated FeNO.

[0517] The mainstay of ABPA treatment is systemic steroids. However, not all patients respond to systemic steroids, and the disease may progress to bronchiectasis and fibrosis. Therefore, there is a high unmet need to treat subjects with ABPA.

[0518] test Phase 3 LIBERTY ASTHMA QUEST trial (NCT02414854), which evaluated patients with serologic evidence of ABPA (baseline serum total IgE >1000 IU / mL, positive serum IgE-Af >0.35 IU / mL, blood eosinophils >500 cells / μL) receiving add-on dupilumab (200 mg or 300 mg) every 2 weeks versus placebo.

[0519] Group Among 1902 patients with moderate-to-severe asthma enrolled in QUEST, 30 patients with serologic evidence of ABPA (ABPA-S) were identified (1.6%). Baseline characteristics of these and the remaining intention-to-treat (ITT) population of QUEST (n=1872) are shown in Table 2. No significant differences were observed in mean age, FEV1, ACQ-5, or Asthma Quality of Life Questionnaire (AQLQ) at baseline between patients with and without ABPA-S, but patients with ABPA-S had higher baseline levels of the type 2 biomarkers eosinophils, IgE, and FeNO compared to asthma patients without ABPA-S.

[0520] Endpoints / Visits The annualized severe exacerbation event rate (defined as a worsening of asthma symptoms requiring 3 or more days of treatment with systemic corticosteroids, or hospitalization or emergency room visit requiring systemic corticosteroids) and the change from baseline in pre-bronchodilator FEV1(L) Changes in these parameters, and patient-reported 5-item Asthma Control Questionnaire (ACQ-5) scores were assessed at baseline and periodically over the 52-week treatment period (Figure 7). In the ITT population, LS mean changes from baseline in pre-bronchodilator FEV1(L) were determined at weeks 24 and 52 (Figure 8). In the exposed population, total (absolute) serum IgE was determined at week 52 (Figure 9). In the exposed population, total (absolute) Af-specific serum IgE was determined at week 52 (Figure 10). In the exposed population, total (absolute) FeNO levels were determined at week 52 (Figure 11).

[0521] Treatment Arm Pooled dupilumab 200 mg q2w, dupilumab 300 mg q2w, and matched placebo.

[0522] result Annualized rates of severe exacerbations during the 52-week treatment period were analyzed using negative binomial regression models. LS mean changes in FEV1 from baseline to weeks 24 and 52 were determined using mixed-effects models with repeated measures. Total IgE, IgE-Af, and FeNO at week 52 were assessed using the Wilcoxon rank-sum test.

[0523] In patients with ABPA-S, dupilumab significantly reduced the adjusted annual rate of severe exacerbations by 81.1% compared with placebo (95% confidence interval [CI] 0.052 to 0.693; P = 0.01) (Figure 12).

[0524] FEV1 before bronchodilator administration Numerical improvements in pre-bronchodilator FEV1 were observed in patients with ABPA-S treated with dupilumab compared with patients with ABPA-S treated with placebo. Improvements were observed as early as week 2, the first time point that patients were evaluated, and were maintained over the 52-week treatment period (Figure 13). Versus placebo, dupilumab improved pre-bronchodilator FEV1 in patients with ABPA-S by a least-squares (LS) mean difference of 0.21 L at week 12 (95% CI -0.18 to 0.60; P = 0.28) and 0.33 L at week 52 (-0.02 to 0.68; P = 0.07).

[0525] Asthma control In patients with ABPA-S, dupilumab improved ACQ-5 scores as early as 2 weeks after treatment initiation, with an LS mean difference vs. placebo of -0.56 (95% CI -1.09 to -0.02; P < 0.05). This continued over the 52-week treatment period, with ACQ-5 scores at each time point numerically improving except at weeks 12 and 16. At week 52, dupilumab improved ACQ-5 scores with an LS mean difference vs. placebo of -0.20 (-0.86 to 0.46; P = 0.54) (Figure 14).

[0526] Serum total IgE and A. fumigatus-specific IgE Baseline serum total IgE was significantly elevated in ABPA-S patients compared to asthma patients without ABPA-S (median values: 2148-3383 IU / mL vs. 159-165 IU / mL). During treatment, substantial reductions in serum total IgE from the earliest assessed time point at week 12 were observed in dupilumab-treated ABPA-S patients compared to placebo-treated ABPA-S patients (Figure 15A). These reductions continued to gradually decline over the treatment period, with the median serum total IgE concentration at week 52 being 691.5 IU / mL (95% CI 323.0-2617.0), a median percentage change from baseline of -75.6% (-81.6 to -44.6). In placebo-treated patients, concentrations at week 52 were 1714.0 IU / mL (95% CI 727.0 to 3048.0), a median percentage change from baseline of -1 The median percentage change from baseline in serum total IgE was 9.6% (95% CI, -56.3 to 102.6; P < 0.01) (Figure 15A). This was similar to the median percentage change from baseline in serum total IgE observed in the full ITT population of the QUEST trial (dupilumab -69.5% [95% CI, -79.0 to -56.9] vs placebo -3.6% [95% CI, -22.7 to 20.8]), demonstrating that the median percentage change from baseline in serum total IgE with dupilumab was similar regardless of baseline IgE level.

[0527] Dupilumab treatment in patients with ABPA-S also suppressed A. fumigatus-specific IgE levels from a median baseline value of 2.4 IU / mL (95% CI 0.6 to 11.2) (placebo group baseline median value 3.0 IU / mL [95% CI 0.5 to 28.8]). These reductions were evident by week 12. After further gradual reductions, in dupilumab-treated patients, the median A. fumigatus-specific IgE concentration at week 52 was 0.8 IU / mL (95% CI 0.1 to 2.6), 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 to 21.5) and -40.4% (95% CI -71.2 to 208.9; P < 0.05) (Figure 15B).

[0528] Other type 2 biomarkers In patients with ABPA-S, the median baseline FeNO concentrations were 49.0 ppb (95% CI 24.0 to 68.0) and 31.0 ppb (95% CI 19.0 to 63.0) in the dupilumab and placebo groups, respectively. Dupilumab reduced FeNO concentrations from baseline as early as the second week of treatment, with a median concentration of 18.0 ppb (95% CI 12.0 to 26.0) and a median percentage change of -50.8% (95% CI -62.5 to -41.9) in the dupilumab group compared with 38.0 ppb (95% CI 23.0 to 50.0) and a percentage change of -5.0% (95% CI -25.4 to 50.0) in the placebo group (P<0.01). Reductions in FeNO persisted through week 52 with a median of 18.0 ppb (95% CI 12.0 to 26.0) and a median percentage change of -60.0% (95% CI -75.0 to -32.7) in dupilumab-treated patients compared with a median of 25.0 ppb (95% CI 10.0 to 56.0) and a median percentage change of -24.3% (95% CI -52.2 to 57.1) in placebo-treated patients (P<0.05) (Figure 16A). Dupilumab treatment reduced FeNO to levels similar to the published median value of 16 ppb in healthy subjects.

[0529] Serum concentrations of TARC were also reduced by dupilumab treatment in patients with ABPA-S: median baseline serum TARC concentrations were 553.0 pg / mL (95% CI 442.0 to 1510.0) and 646.0 pg / mL (385.0 to 894.0) in the dupilumab and placebo groups, respectively. At week 12, dupilumab reduced serum TARC concentrations to a median of 257.0 pg / mL (193.0 to 438.0), with a median percentage change from baseline of -62.0% (-76.0 to -35.3), compared with a median value of 674.0 pg / mL (462.0 to 900.0) and a median percentage change of -10.1% (-17.9 to 15.1) in placebo-treated patients (P<0.01). These significant reductions persisted over the 52-week treatment period, with dupilumab-treated patients having a median value of 234.0 pg / mL (182.0 to 336.0) and a median percentage change from baseline of -66.1% (-79.6 to -51.0) at week 52 compared with 580.0 pg / mL (451.0 to 1020.0) and -17.4% (-35.7 to 25.8) in placebo (P<0.01) (Figure 16B).

[0530] Treatment with dupilumab also reduced serum concentrations of eotaxin-3 in patients with ABPA-S. Reductions were observed from week 12, with median values ​​of 24.5 pg / mL (95% CI 18.0 to 41.7) and a median percentage change from baseline of -64.9% (-83.3 to -44.7) in dupilumab-treated patients compared with 53.1 pg / mL (23.0 to 125.0) and -5.4% (-40.6 to 34.8) in the placebo-treated group (P<0.01). These reductions persisted through week 52 with a median value of 23.2 pg / mL (16.1 to 32.1) and a percentage change of -73.1% (-85.0 to -48.6) in the dupilumab group compared with 35.7 pg / mL (19.3 to 78.7) and -29.3% (-80.2 to 27.2) in the placebo group (P<0.05) (Figure 16C).

[0531] In patients with ABPA-S, median blood eosinophil counts at baseline were elevated (825-1075 eosinophils / μL). At week 52, patients treated with dupilumab had a median blood eosinophil count of 595.0 cells / μL (95% CI 360.0-1160.0) and a median percentage change from baseline of -31.3% (-55.2-0) compared with 590.0 cells / μL (340.0-1080.0) and -45.5% (-55.5-0) in placebo-treated patients (P=0.69) (Figure 16D).

[0532] Safety in Patients with ABPA-S The incidence of treatment-emergent adverse events (TEAEs) in patients with ABPA-S was similar regardless of the treatment received (94.4% in the dupilumab combination and 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, was upper respiratory tract infection (27.8% of patients receiving dupilumab vs. 25.0% of patients receiving placebo). Injection site reactions (Medical Dictionary for Regulatory Activities High Level Term) occurred in 16.7% of dupilumab-treated patients vs. 0% of placebo-treated patients. Per the study protocol, all cases of eosinophil counts >3000 / mm3 during the 52-week intervention period were reported as adverse events. One ABPA-S patient (5.6%) treated with dupilumab 200 mg every 2 weeks (q2w) reported moderate eosinophilia. This was a laboratory finding, there were no associated symptoms, and the patient completed the 52-week treatment period. No patients treated with dupilumab 300 mg or placebo reported eosinophilia. Serious TEAEs were reported in one (5.6%) dupilumab-treated patient and two (16.7%) placebo-treated patients. No TEAEs resulting in death were reported in this population.

[0533] Discussion In the LIBERTY ASTHMA QUEST trial, dupilumab demonstrated beneficial effects in a subgroup of patients identified post hoc as meeting diagnostic criteria for ABPA-S. Treatment with dupilumab significantly reduced the rate of severe exacerbations and demonstrated a trend toward improved lung function. Although improvements in FEV1 did not meet statistical significance, likely due to the small sample size, the mean change from baseline of 510 mL at week 52 in dupilumab-treated patients was clinically meaningful. FEV1 improvements occurred rapidly, as early as 2 weeks after initiation of treatment, and were sustained over 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.

[0534] Consistent with the pathophysiology of ABPA, this subgroup of patients had evidence of robust type 2 inflammation and showed significantly higher levels of FeNO, plasma creatinine, and erythropoietin, compared with asthmatics without serological evidence of ABPA. Baseline levels of type 2 biomarkers, including eosinophils, TARC, serum total IgE, and A. fumigatus-specific IgE, were significantly elevated. Without intending to be bound by scientific theory, increased FeNO concentrations in ABPA patients may represent comorbid airway inflammation not driven by an allergic response, further highlighting the utility of FeNO as a marker for type 2 inflammation. Two of the diagnostic features of unequivocal ABPA are very high serum concentrations of total IgE and A. fumigatus-specific IgE. Studies have shown that B cells from patients with ABPA have a higher sensitivity to IL-4 and spontaneously produce large amounts of IgE, IgG, and IgA antibodies against A. fumigatus antigens. Indeed, serum total IgE concentrations are routinely monitored in the management of ABPA to assess disease activity, and reduction to near-normal levels is considered a marker of disease remission. Treatment with dupilumab significantly suppressed both total and specific IgE, consistent with dupilumab's mechanism of action of inhibiting B cell isotype switching and therefore IgE production by blocking IL-4 and IL-13 signaling. In addition, biomarkers of type 2 inflammation were also rapidly suppressed in both blood (TARC and eotaxin-3) and local airway (FeNO) in ABPA-S patients treated with dupilumab, indicating that through its dual blockade of IL-4 and IL-13, dupilumab was able to rapidly control the underlying pathogenic type 2 inflammation common to ABPA patients.

[0535] Dupilumab was generally well tolerated in ABPA patients, and the occurrence of TEAEs was similar in dupilumab- and placebo-treated patients. The most frequent TEAE observed in dupilumab-treated patients was upper respiratory tract infection. Unlike the transient eosinophilia observed in patients with asthma, in this analysis only one dupilumab-treated ABPA patient (5.6%) reported eosinophilia during the treatment period, despite these patients being hypereosinophilic at baseline (median concentration of 925.0 cells / μL). Furthermore, unlike in the asthma study, where eosinophil counts remained unchanged at week 52, in this analysis ABPA-S patients showed an overall reduction in median blood eosinophil counts during the 52-week treatment period.

[0536] Clinically, asthma patients with ABPA have poorer symptom control and more frequent exacerbations compared with patients without ABPA. Unlike asthma, if ABPA is diagnosed late or the disease is inadequately treated, it progresses to decline in lung function and end-stage fibrotic lung disease. These data demonstrate the utility of dupilumab as a novel treatment for patients with ABPA, improving symptoms and lung function by controlling the underlying pathogenic type 2 inflammation.

[0537] [Table 2-1] [Table 2-2]

[0538] [Table 3] EXAMPLES

[0539] Yellow Fever Vaccine Post-Hot Analysis: An Open-Label Extension Study to Evaluate the Long-Term Safety and Tolerability of Dupilumab in Patients with Asthma Who Participated in a Previous Dupilumab Asthma Clinical Trial Study design The LTS12551 (TRAVERSE) trial is evaluating dupilumab 300 mg in patients with asthma who have completed the treatment and follow-up period in Study DRI12544, or who have completed the treatment period in Studies EFC13579, EFC13691, or PDY14192. DRI12544 (N=776) was a phase 2b, randomized, double-blind, placebo-controlled, dose-ranging, parallel-group, multicenter, multicenter, multicenter, open-label ... PDY14192 (N=42) was a phase 2a exploratory randomized, double-blind, placebo-controlled study of the effect of 12 weeks of SC dupilumab 300 mg q2w on airway inflammation in adults with uncontrolled persistent asthma. EFC13579 (N=1902) was a phase 3 randomized, double-blind, placebo-controlled, parallel-group study to evaluate 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) was a phase 3 randomized, double-blind, placebo-controlled study to evaluate the efficacy and safety of dupilumab 300 mg q2w SC for 24 weeks in adult and adolescent patients with severe OCS-dependent asthma.

[0540] While Study LTS12551 was ongoing, a yellow fever outbreak in Brazil necessitated administration of yellow fever vaccine (YFV) to all unvaccinated individuals in at-risk areas. The sponsor implemented local protocol amendment 5, which allows administration of YFV (live attenuated vaccine) to all patients who require YFV in the affected areas of the outbreak. All affected patients were required to interrupt dupilumab, and vaccination could be administered after dupilumab interruption. Patients could reinitiate dupilumab at the investigator's discretion after demonstration of sufficient yellow fever neutralizing titers (i.e., plaque reduction neutralizing titers; PRNT). Unvaccinated patients were eligible to reinitiate study treatment after the outbreak subsided.

[0541] All patients were followed continuously until the end of the study, regardless of whether dupilumab treatment was re-established. For patients in whom yellow fever vaccination was planned, samples to assess drug pharmacokinetics (PK) and immunogenicity along with pre- and post-vaccination antibody titers were collected both before and 4-6 weeks and, with patient consent, could be extended up to 8 weeks after vaccination. In summary, 37 patients discontinued treatment with dupilumab and were subsequently vaccinated with YFV. No patient resumed dupilumab due to delayed results, even though patients were allowed to resume dupilumab treatment after demonstration of neutralizing titers at the discretion of the treating physician.

[0542] A post-hoc analysis of YFV was performed to evaluate the humoral immune response and safety / tolerability of YFV in this subset of 37 patients who participated in the LTS12551 trial and received YFV.

[0543] Purpose of the test The objective of this study was to evaluate the humoral immune response, safety, and tolerability of the live attenuated YFV vaccine in patients with moderate-to-severe asthma treated with dupilumab in study LTS12551.

[0544] patient A total of 37 patients who participated in the LTS12551 trial (an open-label asthma trial) and received YFV were included in this analysis. Of these, 33 were carryovers from the EFC13579 trial and 4 were carryovers from the EFC13691 trial. Eleven of the patients enrolled from EFC13579 were pretreated with placebo in the parent trial and then received dupilumab in the LTS12551 trial (placebo / dupilumab category), and 22 were pretreated with dupilumab in the parent trial and continued on dupilumab in the LTS12551 trial (dupilumab / dupilumab category). Of the patients enrolled from the EFC13691 trial, 3 patients were pretreated with placebo in the parent trial and then received dupilumab in the LTS12551 trial (placebo / dupilumab category), and 1 patient was pretreated with dupilumab in the parent trial and continued on dupilumab in the LTS12551 trial (dupilumab / dupilumab category).

[0545] Demographics and other baseline characteristics Baseline demographics and patient characteristics of the 37 patients who received YFV were generally similar between patients who had previously received placebo or dupilumab in each parent study (see Table 4 below). The mean age of the population was 46.5 years with a range of 24-68 years, 5 (13.5%) patients were ≥65 years, and 12 (32.4%) patients were male. The mean (SD) BMI (body mass index) was 30.1 (5.7) kg / m 2 It was.

[0546] [Table 4-1] [Table 4-2]

[0547] Medical history The medical history of the patients' comorbidities is presented in Table 5. The majority of patients (91.9%) had a history of comorbid diseases, with allergic rhinitis being the most frequent (86.5%).

[0548] [Table 5-1] [Table 5-2]

[0549] Safety assessment Extent of exposure Table 6 summarizes the extent of exposure to the investigational drug in the exposed population in LTS12551 prior to yellow fever vaccination. The mean (SD) duration of treatment with dupilumab in study LTS12551 was 242.2 (34.4) days, similar across all patients who received YFV. In patients who were carryovers from the EFC13579 study, the mean treatment duration was similar between the placebo / dupilumab and dupilumab / dupilumab categories (255.0 and 230.1 days, respectively). In patients who were carryovers from the EFC13691 study, the mean treatment duration was similar between the placebo / dupilumab and dupilumab / dupilumab categories (274.7 and 268.0 days, respectively).

[0550] [Table 6]

[0551] As shown in Table 7 , the time between the last dose of dupilumab and yellow fever vaccination varied from 7 to 51 days, with a mean (SD) of 22.3 (±11.9) days.

[0552] [Table 7]

[0553] 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.

[0554] [Table 8]

[0555] Adverse events 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 body aches, fatigue, and dizziness after receiving the vaccine, which was 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 rhinosinusitis. The event occurred 7 days after yellow fever vaccination and resolved within 2 weeks. The remaining 36 patients tolerated the vaccine and did not report any adverse events that could be related to yellow fever vaccination. There were no reports of hypersensitivity reactions to the vaccine. No patients restarted dupilumab due to delayed results. No deaths, treatment-emergent SAEs, or other significant AEs were reported among the 37 patients who received the yellow fever vaccine in the LTS12551 study.

[0556] Safety Conclusion YFV administered 7 to 51 days after discontinuation of dupilumab was well tolerated in a group of 37 patients with asthma. Thirty-six of these 37 patients did not report any adverse reactions to YFV. One patient reported a transient non-serious adverse event that fully resolved, a common reaction to yellow fever vaccination (Monath TP, Nichols R, Archambault 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 t (Rial. Am J Trop Med Hyg. 2002;66(5):533-541.) Therefore, patients with therapeutic or subtherapeutic levels of dupilumab in this trial tolerated YFV.

[0557] Pharmacokinetics, immune response, and immunogenicity assessment Humoral immune responses to vaccines Humoral immune responses to YFV were determined using a standard plaque reduction neutralization titer (PRNT) assay (Q Squared solutions, LLC), where the reciprocal dilution at which 50% of the virus was neutralized (PRNT50) was calculated. Post-vaccine neutralization titers were obtained for all 37 patients, and pre- and post-vaccine PRNT titers were obtained for 23 of the 37 patients (Table 9). Patients' prior 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 a PRNT < 1:10 (defined as "seronegative"), while the other 10 patients had titers in the range of 1:10 to 1:160 (defined as "seropositive").

[0558] All 37 patients demonstrated seroprotective titers after vaccination, defined as PRNT titers >1:10, with a mean post-vaccination titer of 1:7699 (±10,951 SD; median 2,560, range 80-40,960). As shown in Figures 17A and 17B, two of the 23 patients had pre-vaccination titers that were not boosted after vaccination, but both patients already had seroprotective titers prior to YFV. Thus, all 37 vaccinated patients, including the 13 patients who demonstrated seroconversion with pre- and post-vaccination titers, had seroprotective yellow fever neutralizing titers after vaccination.

[0559] [Table 9]

[0560] Pharmacokinetic and immunogenicity evaluation Pre- and post-vaccination PK and ADA (anti-drug antibody) samples were collected. Functional dupilumab concentrations in serum were measured pre- and post-vaccination. Of the 37 patients, 35 and 34 patients had pre-vaccination PK and pre-vaccination ADA samples collected, respectively. All 37 patients had post-vaccination PK and ADA samples collected. 19 patients had PK samples obtained on the day of vaccination. 16 patients had pre-vaccination PK obtained prior to YFV administration (Table 9).

[0561] Table 10 summarizes the interval from the last dupilumab dose to administration of the yellow fever vaccination, the interval from pre-vaccination PK sampling to administration of the yellow fever vaccination, and the interval from administration of the yellow fever vaccination to post-vaccination PK sampling.

[0562] Dupilumab concentrations before and after yellow fever vaccination At the time of yellow fever vaccination, patients received dupilumab 300 mg in LTS12551. mg q2w for at least 24 weeks, reaching steady state at week 24 with a mean trough concentration of 73.3 mg / L. On average, the time from the last dupilumab dose to administration of YFV was approximately 3 weeks (median time of 18 days, Table 7). In 35 of 37 patients, a pre-vaccination PK sample was collected. The mean concentration of all pre-vaccination PK samples was 59.5 mg / L, although not all PK samples were collected on the same day of yellow fever vaccination administration (Table 11). In 19 patients, a pre-vaccination PK sample was collected on the same day as YFV administration. The mean dupilumab concentration in serum of these patients was 72.5 mg / L, which was similar to the mean steady-state trough concentration of dupilumab observed in patients treated with dupilumab 300 mg q2w in clinical trials of dupilumab in asthma and AD. For 16 patients, pre-vaccination PK samples were collected 1 to 25 days prior to YFV administration; for these patients, the mean concentration was 44.0 mg / L.

[0563] 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 observed mean concentration of post-vaccination PK samples was 13.7 mg / L (N=37), within the range of expected dupilumab concentrations at the approximately 8-week washout period after the last steady-state dose of 300 mg q2w (Table 11).

[0564] [Table 10]

[0565] [Table 11]

[0566] In 15 of 23 patients, pre-vaccination PK samples were collected on the same day of YFV administration. The mean dupilumab concentration in these 15 patients was 76.4 mg / L. Thirteen of 15 patients had dupilumab concentrations higher than the mean trough concentration of 37.4 mg / L. Because the mean steady-state trough concentration observed in asthma patients at 200 mg q2w in the parent Phase 3 study (EFC13579) was 37.4 mg / L, serum concentrations above this level were assumed to be therapeutic and consistent with a saturation level of IL-4Rα blockade.

[0567] All 13 patients with serum dupilumab concentrations greater than 37.4 mg / L had seroprotective PRNT titers after YFV. Twelve of these patients demonstrated an increase in titer after vaccination, while one of these 13 patients did not demonstrate an increase in titer but was already within the seroprotective threshold at baseline. The fold change in PRNT titer levels of these patients is demonstrated in Figure 18. Neutralizing titers of all 13 patients after vaccination were greater than 37.4 mg / L. The post-vaccination titers ranged from 1:80 to 1:40960, comparable to the post-vaccination titers in patients who received the vaccine (1:160 to 1:40960).

[0568] Taken together, in this subset of 23 patients with pre- and post-vaccine PK and PRNT titers, there was no apparent relationship between serum dupilumab levels and PRNT titers.

[0569] ADA incidence and titers before and after yellow fever vaccination Table 12 summarizes the ADA incidence rates and ADA titer categories observed in patients before and after YFV administration. In three patients, positive ADA assay responses were observed both before and after yellow fever vaccination. Among patients with positive ADA assay responses, one patient had a low ADA titer (<1000) and two had high ADA titers (>10000). The number of patients in each ADA titer category did not change before and after yellow fever vaccination, suggesting that there was no clear effect of yellow fever vaccination on ADA responses. In addition to the three patients who were positive before and after yellow fever vaccination at the end of the study, a positive ADA assay response was observed in one further patient at the follow-up visit. Thus, among a total of four patients with positive ADA assay responses at the follow-up visit, two patients had low ADA titers (<1000) and two patients had high ADA titers (>10000).

[0570] [Table 12-1] [Table 12-2]

[0571] Conclusions based on immune response and dupilumab PK Immune response and dupilumab PK data suggest that therapeutic serum levels of dupilumab do not inhibit protective immune responses to live-attenuated yellow fever vaccination. Because dupilumab was not reinitiated after vaccination, serum levels continued to decline until post-vaccination titer assessment.

[0572] Impact of immune response to vaccine on dupilumab efficacy The possible impact of yellow fever vaccination on dupilumab efficacy was evaluated by examining changes in FEV1 before and after vaccination. All patients who discontinued treatment with dupilumab for yellow fever vaccination had been exposed to dupilumab for an average of 0.7 years in LTS12551 and achieved stable improvement in lung function before dupilumab discontinuation (Table 6). FEV1 was stable between the visit before YFV administration and the first visit after YFV (Figure 19, Figure 20). Mean (SD) FEV1 was 2.08 (0.83) L and 1.98 (0.79) L, respectively (Table 13). In general, based on the data observed in EFC13579 and DRI12544, FEV1 levels can be expected to fall approximately 12 weeks after dupilumab discontinuation.

[0573] [Table 13-1] [Table 13-2]

[0574] conclusion In response to a local yellow fever outbreak, 37 patients enrolled in LTS12551 discontinued dupilumab treatment and subsequently received YFV. Dupilumab did not reduce the efficacy of the live attenuated yellow fever virus vaccine. All 37 patients who received YFV demonstrated postvaccination yellow fever virus antibody titers consistent with seroprevalence. Pre- and postvaccination neutralization titers were obtained for 23 patients, and 15 of these patients had prevaccination sera obtained on the day of YFV administration. Ten of these 23 patients had prevaccination PRNT titers >1:10, indicating possible prior exposure to the virus or prior vaccination. The remaining 13 patients had PRNT titers <1:10 (i.e., "seronegative"), suggesting no prior exposure or waning of antibody response over time. The mean postvaccination titer level obtained 28 to 42 days after vaccination was 1:7699 (±10,951 SD; median 2,560, range 80 to 40,960), with all but two patients showing increased postvaccination titers and all 23 patients showing neutralizing titers at levels consistent with seroprevalence to yellow fever.

[0575] Therapeutic levels of dupilumab did not appear to inhibit seroprotective immune responses to dupilumab. In 15 patients who had both pre- and post-vaccination yellow fever titers, PK measurements were also obtained on the same day as vaccination. At the time of vaccination, 13 of the 15 patients had serum dupilumab concentrations higher than a mean concentration of 37.4 mg / L, a serum level considered sufficient to saturate IL-4Rα in asthma (based on the 200 mg q2w regimen shown). All 13 patients demonstrated seroprotective immune responses. Twelve of the 13 patients demonstrated increased neutralizing titers after vaccination, while one patient's serum sample had the same neutralizing titer pre- and post-vaccination. These data support that therapeutic serum dupilumab concentrations at the time of vaccination do not inhibit seroprotective immune responses, and all but one of these 13 patients demonstrated a boost in neutralizing antibody titers to yellow fever.

[0576] YFV was well tolerated by all exposed patients. Among patients, one patient reported a non-serious adverse event reported as a "vaccination complication" (i.e., body aches, fatigue, and dizziness), which is a common reaction to YFV and was reported in up to 30% of patients (Monath TP, Nichols R, Archambault 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-severe, and the patient recovered satisfactorily within 2 weeks.

[0577] Yellow fever virus vaccination did not appear to affect dupilumab efficacy. All vaccinated patients achieved a stable improvement in their lung function as measured by FEV1. FEV1 remained stable both before and after yellow fever virus vaccination.

[0578] Overall, these data support the overall safety and tolerability of yellow fever vaccination in asthmatics who have recently discontinued dupilumab. Without intending to be bound by scientific theory, similar increases in neutralizing antibody titers following vaccination were observed between asthmatics who had therapeutic and subtherapeutic serum levels of dupilumab, indicating that in the case of dupilumab, the immunity generating capacity of the humoral arm of the adaptive immune system against live attenuated YFV is maintained.

Claims

1. A pharmaceutical composition comprising an antibody for use in treating allergic asthma in a subject in need thereof, wherein the antibody comprises three heavy chain CDR sequences, each comprising SEQ ID NO: 3, 4, and 5, and three light chain CDR sequences, each comprising SEQ ID NO: 6, 7, and 8, and the subject has a baseline total serum IgE level of at least about 30 IU / mL and at least one allergen-specific IgE level greater than 0.35 kU / L at baseline, said pharmaceutical composition.

2. The pharmaceutical composition comprising the antibody for use according to claim 1, wherein the subject has a baseline blood eosinophil count of at least about 150 cells / μl.

3. The pharmaceutical composition comprising the antibody for use according to claim 1 or 2, wherein the subject has a total serum IgE greater than 700 IU / mL at baseline.

4. The pharmaceutical composition comprising the antibody for use according to any one of claims 1 to 3, wherein the subject has a total serum FeNO of 25 ppb or more at baseline.

5. The pharmaceutical composition comprising the antibody for use according to any one of claims 1 to 4, wherein the antibody is administered to the subject as a loading dose followed by a plurality of maintenance doses.

6. The pharmaceutical composition comprising the antibody for use according to claim 1, wherein the antibody is administered using an autoinjector, needle and syringe, or pen.

7. The loading dose is about 600 mg of the antibody and each maintenance dose is about 300 mg of the antibody, and each maintenance dose is administered once every two weeks, said pharmaceutical composition comprising the antibody for use according to claim 5.

8. The loading dose is about 400 mg of the antibody and each maintenance dose is about 200 mg of the antibody, and each maintenance dose is administered once every two weeks, said pharmaceutical composition comprising the antibody for use according to claim 5.

9. The pharmaceutical composition comprising the antibody for use according to claim 5, 7, or 8, wherein the maintenance dose of the antibody is administered for at least 24 weeks.

10. The treatment results in an improvement in lung function as measured by bronchodilator forced expiratory volume in 1 second (FEV1); or The treatment results in a reduction in annual severe asthma exacerbations, said pharmaceutical composition comprising the antibody for use according to any one of claims 1 to 9.

11. The treatment is a pharmaceutical composition comprising the antibody for use according to any one of claims 1 to 9, which brings about a decrease in one or both of the total serum IgE level and the allergen-specific IgE level.

12. The treatment is a pharmaceutical composition comprising the antibody for use according to any one of claims 1 to 9, which brings about a decrease in one or more of the serum thymus and activation-regulated chemokine (TARC) level, the serum eotaxin-3 level, and the peripheral blood eosinophil level.

13. The treatment is a pharmaceutical composition comprising the antibody for use according to any one of claims 1 to 9, which brings about an improvement in the asthma control questionnaire (ACQ-5) score.

14. The antibody is a pharmaceutical composition comprising the antibody for use according to any one of claims 1 to 9, which comprises a heavy chain variable region sequence containing SEQ ID NO: 1 and a light chain variable region sequence containing SEQ ID NO:

2.

15. The antibody is dupilumab, and the pharmaceutical composition comprises the antibody for use according to any one of claims 1 to 9.

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