RU2832774C2 - Methods of treating or preventing asthma by administering il-4r antagonist - Google Patents

Abstract

FIELD: chemistry.

SUBSTANCE: invention relates to biochemistry, particularly to use of an antibody or its antigen-binding fragment, which specifically binds to an interleukin-4 receptor.

EFFECT: invention provides effective treatment of allergic bronchopulmonary aspergillosis.

12 cl, 20 dwg, 13 tbl, 9 ex

Description

RELATED APPLICATIONS

[0001] This application claims the benefit of U.S. Provisional Patent Application No. 63/004,084, filed April 2, 2020; U.S. Provisional Patent Application No. 62/877,031, filed July 22, 2019; U.S. Provisional Patent 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 entirety for all purposes.

FIELD OF TECHNOLOGY TO WHICH THE INVENTION RELATES

[0002] 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 for the treatment or prevention of asthma, such as allergic asthma, ABPA-associated asthma, and the like, to a patient in need thereof. The present invention also relates to the administration of an interleukin-4 receptor (IL-4R) antagonist for the treatment or prevention of ABPA in a patient in need thereof, such as ABPA associated with asthma, ABPA associated with cystic fibrosis, and/or ABPA associated with both asthma and cystic fibrosis.

PREREQUISITES FOR THE CREATION OF THE INVENTION

[0003]Asthma is a chronic inflammatory disease of the airways characterized by airway hyperresponsiveness, acute and chronic bronchospasm, edema, and mucus plugging of the airways. The inflammatory component of asthma is thought to involve many cell types, including mast cells. cells, eosinophils, T-lymphocytes, neutrophils, epithelial cells, and their biological products. Patients with asthma most often exhibit symptoms of wheezing, shortness of breath, coughing and chest tightness. For most patients with asthma, a regimen of controller medications and bronchodilator therapy provides adequate long-term control. Inhaled corticosteroids (ICS) are considered the "gold standard" for asthma symptom control, with inhaled beta-2 agonists being the most effective bronchodilators currently available. Studies have shown that combination therapy with an ICS and an inhaled long-acting beta-2 agonist (LABA) provides better asthma control than high doses of ICS alone. Therefore, combination therapy was the recommended treatment for subjects who failed to achieve control with low doses ICS separately.

[0004]However, it is estimated that 5% to 10% of the population has clinical asthma, despite the maximum recommended treatment with combinations of anti-inflammatory drugs and bronchodilators. In addition, this population with severe asthma accounts for up to 50% of all costs of maintaining health during hospitalization, use of emergency services and unscheduled physician visits. There is an unmet need for a new therapeutic agent in this severe asthma population because Many of these patients respond poorly to ICS due to a number of cellular and molecular factors mechanisms. In addition, the long-term side effects of systemic and inhaled corticosteroids in relation to bone metabolism, adrenal function and growth in children lead to attempts to minimize amount of corticosteroid consumption. Despite the fact that the condition of most patients with asthma is adequately controlled with existing treatments, in patients with severe uncontrolled asthma (e.g., severe (corticosteroid-resistant or steroid-intolerant asthma) there are few therapeutic options that can control the disease at the proper level. The consequence of resistance to therapy or lack of compliance treatment regimen is loss of asthma control and ultimately exacerbation of asthma.

[0005] An estimated 45% of patients with severe asthma require systemic glucocorticoids to control their disease and prevent life-threatening exacerbations associated with increased risk of irreversible lung tissue damage, progressive persistent airflow obstruction, and accelerated decline in lung function. However, systemic glucocorticoids act non-selectively and are associated with significant multi-organ toxicity and widespread immunosuppression. There is a need for safer and more effective targeted therapies that prevent exacerbations and lung function decline, improve asthma symptoms and control, and reduce or eliminate the need for oral glucocorticoids.

[0006] Approximately 20% of patients with asthma have uncontrolled moderate to severe disease with recurrent exacerbations and persistent symptoms despite maximal standard treatment with controller medications. This population is at increased risk of morbidity (especially exacerbations) and represents a significant drain on healthcare resources. These patients have significantly reduced lung function despite maximal treatment and are destined to inevitably lose lung function in the future. No currently approved treatment has been shown to slow this inevitable decline in these patients or to consistently and significantly improve lung function.

[0007] Type 2 asthma with high TH2 content is the most common type of persistent uncontrolled asthma (Fahy (2015) Nat. Rev. Immunol. 15:57-65). It includes overlapping phenotypes of allergic asthma (characterized by increased expression of aeroallergen-specific immunoglobulin E (IgE)) and eosinophilic asthma (characterized by blood and/or airway/tissue eosinophilia) (Fahy, Supra ; Campo et al. (2013) J. Investig. Allergol. Clin. Immunol. 23:76-88; Wenzel (2012) Clin Exp Allergy 42:650-8).

[0008] Allergic sensitization is a strong risk factor for asthma inception and severity in children and in adults (Gough et al. (2015) Pediatr. Allergy Immunol. 26:431–437). Current therapies for allergic asthma, which focus on relieving symptoms and the ongoing inflammatory process of the disease, do not affect the underlying impaired immune response and are therefore very limited in controlling the progression of allergic asthma (Dhami et al. (2017) Eur. J. Allergy Clin. Immunol. 72(12):1825–1848).

[0009] ABPA is an allergic lung disease caused by hypersensitivity to Aspergillus species (eg, A. fumigatus ) that colonize the respiratory tract. ABPA most often occurs in patients with asthma or cystic fibrosis.

[0010] ABPA is clinically characterized by wheezing, dyspnea, respiratory exacerbations, bronchial hyperreactivity, hemoptysis or productive cough (coughing up brownish-black mucus in 31-69% of patients), central bronchiectasis with mucus plugging and markedly elevated IgE levels, and blood and tissue eosinophilia.

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

[0012] Cystic fibrosis (CF), also known as mucoviscidosis, is a genetic disorder that primarily affects the lungs, but also the pancreas, liver, kidneys, and intestines. Long-term problems include difficulty breathing and coughing up mucus due to frequent lung infections. Other signs and symptoms include sinusitis, poor growth, fatty stools, clubbing of the fingers and toes, and infertility in men, among others. Individuals may have varying degrees of symptoms.

[0013] CF is inherited in an autosomal recessive pattern. It is caused by mutations in both copies of the gene for the protein cystic fibrosis transmembrane conductance regulator (CFTR). Individuals who have one working copy of the gene are carriers and are otherwise generally healthy. CFTR is involved in the production of sweat, digestive juices, and mucus. When CFTR is not functioning, secretions that are normally thin become thick. The condition is diagnosed by sweat testing and genetic testing. In some parts of the world, babies are screened at birth.

[0014] Cystic fibrosis is an incurable disease. Lung infections are treated with antibiotics, which may be given intravenously, inhaled, or orally. Sometimes the antibiotic azithromycin is used long-term. Inhaled hypertonic saline and salbutamol may also be helpful. Lung transplantation may be an option if lung function continues to deteriorate. Pancreatic enzyme replacement therapy and fat-soluble vitamin supplements are important, especially in younger patients. Average life expectancy in developed countries is 42 to 50 years. Although cystic fibrosis is a multiorgan disease, lung problems are the dominant cause of morbidity and mortality. Other symptoms of cystic fibrosis include pancreatic insufficiency, intestinal obstruction, elevated sweat electrolytes (the basis of the most common diagnostic test), and male infertility. CF is most common among people of Northern European descent and affects approximately one in every 2,500 to 4,000 newborns. About one in 25 people is a carrier. Although treatments for CF exist, more effective therapies are needed.

[0015] There is a need for new types of targeted therapies for the treatment and/or prevention of asthma, such as allergic asthma, ABPA-associated asthma, etc., as well as disorders such as ABPA, including ABPA associated with CF, ABPA associated with asthma, and ABPA associated with both asthma and cystic fibrosis.

BRIEF DESCRIPTION OF THE INVENTION

[0016] According to one aspect, a method of treating a subject having allergic asthma is provided. The method comprises administering to the subject an antibody or antigen-binding fragment thereof that specifically binds to an interleukin-4 receptor (IL-4R), wherein the antibody or antigen-binding fragment thereof comprises three heavy chain CDR sequences 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.

[0017] 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.

[0018] In certain exemplary embodiments, the subject has a baseline fractional exhaled nitric oxide (FeNO) level of at least about 25 ppb or at least about 20 ppb.

[0019] In certain exemplary embodiments, the subject has an allergen-specific IgE level of at least about 0.35 kU/L.

[0020] In certain exemplary embodiments, the allergen is selected from the group consisting of animal (e.g., dust mite (e.g., Dermatophagoides farinae or Dermatophagoides pteronyssinus ), cockroach, cat, or dog), fungus (e.g., Alternaria alternata , Cladosporium herbarum , or Aspergillus fumigatus ), and plant allergens.

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

[0022] In certain exemplary embodiments, the antibody or antigen-binding fragment thereof is administered to a subject as a loading dose followed by a plurality of maintenance doses.

[0023] In certain exemplary embodiments, the antibody or antigen-binding fragment thereof is administered using an autoinjector, a needle and syringe, or a pen.

[0024] In certain exemplary embodiments, the maintenance dose of the antibody or antigen-binding fragment thereof is administered once every two weeks (q2w).

[0025] 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.

[0026] 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 approximately 200 mg of the antibody or antigen-binding fragment thereof.

[0027] In certain exemplary embodiments, maintenance doses of the antibody or antigen-binding fragment thereof are administered for at least 24 weeks.

[0028] 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.

[0029] In certain exemplary embodiments, treatment results in a reduction in severe asthma exacerbations on an annualized basis.

[0030] In certain exemplary embodiments, the treatment results in an improvement in lung function as measured by forced expiratory volume (FEV ₁ ) or forced expiratory flow at 25-75% of lung volume (FEF25-75%).

[0031] In certain exemplary embodiments, the antibody or antigen-binding fragment thereof comprises the heavy chain variable region (HCVR) sequence of SEQ ID NO: 1 and the light chain variable region (LCVR) sequence of SEQ ID NO: 2.

[0032] 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.

[0033] In certain exemplary embodiments, the antibody is dupilumab.

[0034] In certain exemplary embodiments, the subject has uncontrolled allergic asthma with a severity ranging from moderate to severe.

[0035] In certain exemplary embodiments, the subject has comorbid cystic fibrosis. In certain exemplary embodiments, the subject has comorbid allergic asthma and comorbid cystic fibrosis.

[0036] 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.

[0037] According to another aspect, a method of treating a subject with allergic asthma is provided, comprising administering to the subject an antibody or antigen-binding fragment thereof that specifically binds to an interleukin-4 receptor (IL-4R), wherein the antibody or antigen-binding fragment thereof comprises three heavy chain CDR sequences 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 300 cells/μL.

[0038] In certain exemplary embodiments, the subject has a baseline fractional exhaled nitric oxide (FeNO) level of at least about 25 ppb or at least about 20 ppb.

[0039] In certain exemplary embodiments, the subject has a total serum IgE level of at least about 700 IU/mL.

[0040] In certain exemplary embodiments, the subject has an allergen-specific IgE level of at least about 0.35 kU/L.

[0041] In certain exemplary embodiments, the allergen is selected from the group consisting of dust mite, cockroach, cat dander, dog dander, Dermatophagoides farinae , Dermatophagoides pteronyssinus , Alternaria alternata , Cladosporium herbarum , Aspergillus fumigatus , German cockroach, and black cockroach allergens.

[0042] In certain exemplary embodiments, the antibody or antigen-binding fragment thereof is administered to a subject as a loading dose followed by a plurality of maintenance doses.

[0043] In certain exemplary embodiments, the antibody or antigen-binding fragment thereof is administered using an autoinjector, a needle and syringe, or a pen.

[0044] In certain exemplary embodiments, the maintenance dose of the antibody or antigen-binding fragment thereof is administered once every two weeks (q2w).

[0045] 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.

[0046] 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.

[0047] In certain exemplary embodiments, maintenance doses of the antibody or antigen-binding fragment thereof are administered for at least 24 weeks.

[0048] 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.

[0049] In certain exemplary embodiments, treatment results in a reduction in severe asthma exacerbations on an annualized basis.

[0050] In certain exemplary embodiments, the treatment results in an improvement in lung function as measured by forced expiratory volume (FEV ₁ ) or forced expiratory flow at 25-75% of lung volume (FEF25-75%).

[0051] In certain exemplary embodiments, the antibody or antigen-binding fragment thereof comprises the heavy chain variable region (HCVR) sequence of SEQ ID NO: 1 and the light chain variable region (LCVR) sequence of SEQ ID NO: 2.

[0052] 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.

[0053] In certain exemplary embodiments, the antibody is dupilumab.

[0054] In certain exemplary embodiments, the subject has uncontrolled allergic asthma with a severity ranging from moderate to severe.

[0055] In certain exemplary embodiments, the subject has comorbid cystic fibrosis. In certain exemplary embodiments, the subject has comorbid allergic asthma and comorbid cystic fibrosis.

[0056] 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.

[0057] According to another aspect, a method of treating a subject with allergic asthma is provided, comprising administering to the subject an antibody or antigen-binding fragment thereof that specifically binds to an interleukin-4 receptor (IL-4R), wherein the antibody or antigen-binding fragment thereof comprises three heavy chain CDR sequences 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 level of fractional exhaled nitric oxide (FeNO) of at least about 20 ppb.

[0058] In certain exemplary embodiments, the subject has a baseline FeNO level of at least 25 ppb.

[0059] In certain exemplary embodiments, the subject has a baseline blood eosinophil count 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.

[0060] In certain exemplary embodiments, the subject has a total serum IgE level of at least about 700 IU/mL.

[0061] In certain exemplary embodiments, the subject has an allergen-specific IgE level of at least about 0.35 kU/L.

[0062] In certain exemplary embodiments, the allergen is selected from the group consisting of dust mite, cockroach, cat dander, dog dander, Dermatophagoides farinae , Dermatophagoides pteronyssinus , Alternaria alternata , Cladosporium herbarum , Aspergillus fumigatus , German cockroach, and black cockroach allergens.

[0063] In certain exemplary embodiments, the antibody or antigen-binding fragment thereof is administered to a subject as a loading dose followed by a plurality of maintenance doses.

[0064] In certain exemplary embodiments, the antibody or antigen-binding fragment thereof is administered using an autoinjector, a needle and syringe, or a pen.

[0065] In certain exemplary embodiments, the maintenance dose of the antibody or antigen-binding fragment thereof is administered once every two weeks (q2w).

[0066] 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.

[0067] 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.

[0068] In certain exemplary embodiments, maintenance doses of the antibody or antigen-binding fragment thereof are administered for at least 24 weeks.

[0069] 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.

[0070] In certain exemplary embodiments, treatment results in a reduction in severe asthma exacerbations on an annualized basis.

[0071] In certain exemplary embodiments, treatment results in an improvement in lung function as measured by forced expiratory volume (FEV ₁ ) or forced expiratory flow at 25-75% of lung volume (FEF25-75%).

[0072] In certain exemplary embodiments, the antibody or antigen-binding fragment thereof comprises the heavy chain variable region (HCVR) sequence of SEQ ID NO: 1 and the light chain variable region (LCVR) sequence of SEQ ID NO: 2.

[0073] 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.

[0074] In certain exemplary embodiments, the antibody is dupilumab.

[0075] In certain exemplary embodiments, the subject has comorbid cystic fibrosis. In certain exemplary embodiments, the subject has comorbid allergic asthma and comorbid cystic fibrosis.

[0076] 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.

[0077] In another aspect, there is provided a method for improving pulmonary function, as measured by forced expiratory volume (FEV ₁ ) or forced expiratory flow at 25-75% of lung volume (FEF25-75%), in a subject having allergic asthma, comprising administering to the subject an antibody or antigen-binding fragment thereof that specifically binds to an interleukin-4 receptor (IL-4R), wherein the antibody or antigen-binding fragment thereof comprises three heavy chain CDR sequences 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 characterized by a total serum IgE level of at least about 700 IU/mL.

[0078] In certain exemplary embodiments, the antibody or antigen-binding fragment thereof comprises the heavy chain variable region (HCVR) sequence of SEQ ID NO: 1 and the light chain variable region (LCVR) sequence of SEQ ID NO: 2.

[0079] 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.

[0080] In certain exemplary embodiments, the antibody is dupilumab.

[0081] In certain exemplary embodiments, the subject has uncontrolled allergic asthma with a severity ranging from moderate to severe.

[0082] In certain exemplary embodiments, the subject has comorbid cystic fibrosis. In certain exemplary embodiments, the subject has comorbid allergic asthma and comorbid cystic fibrosis.

[0083] 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.

[0084] In another aspect, a method is provided for reducing severe asthma exacerbations per year in a subject with allergic asthma, comprising administering to the subject an antibody or antigen-binding fragment thereof that specifically binds to an interleukin-4 receptor (IL-4R), wherein the antibody or antigen-binding fragment thereof comprises three heavy chain CDR sequences 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.

[0085] In certain exemplary embodiments, the antibody or antigen-binding fragment thereof comprises the heavy chain variable region (HCVR) sequence of SEQ ID NO: 1 and the light chain variable region (LCVR) sequence of SEQ ID NO: 2.

[0086] 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.

[0087] In certain exemplary embodiments, the antibody is dupilumab.

[0088] In certain exemplary embodiments, the subject has uncontrolled allergic asthma with a severity ranging from moderate to severe.

[0089] In certain exemplary embodiments, the subject has comorbid cystic fibrosis. In certain exemplary embodiments, the subject has comorbid allergic asthma and comorbid cystic fibrosis.

[0090] 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.

[0091] In another aspect, a method is provided for improving the Asthma Control Questionnaire (ACQ-5) score in a subject with allergic asthma, comprising administering to the subject an antibody or antigen-binding fragment thereof that specifically binds to an interleukin-4 receptor (IL-4R), wherein the antibody or antigen-binding fragment thereof comprises three heavy chain CDR sequences 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.

[0092] In certain exemplary embodiments, the antibody or antigen-binding fragment thereof comprises the heavy chain variable region (HCVR) sequence of SEQ ID NO: 1 and the light chain variable region (LCVR) sequence of SEQ ID NO: 2.

[0093] 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.

[0094] In certain exemplary embodiments, the antibody is dupilumab.

[0095] In certain exemplary embodiments, the subject has uncontrolled allergic asthma with a severity ranging from moderate to severe.

[0096] In certain exemplary embodiments, the subject has comorbid cystic fibrosis. In certain exemplary embodiments, the subject has comorbid allergic asthma and comorbid cystic fibrosis.

[0097] 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.

[0098] In another aspect, a method of treating a subject with allergic bronchopulmonary aspergillosis (ABPA) is provided, comprising administering to the subject an antibody or antigen-binding fragment thereof that specifically binds to an interleukin-4 receptor (IL-4R), wherein the antibody or antigen-binding fragment thereof comprises three heavy chain CDR sequences comprising SEQ ID NOs: 3, 4, and 5, respectively, and three light chain CDR sequences comprising SEQ ID NOs: 6, 7, and 8, respectively, wherein the subject has a total serum IgE level of at least about 1000 IU/mL.

[0099] In certain exemplary embodiments, the subject has a baseline blood eosinophil count of at least about 500 cells/μL.

[00100] In certain exemplary embodiments, the subject has an allergen-specific IgE level in the blood serum of at least about 0.35 kU/L. In certain exemplary embodiments, the allergen is Aspergillus fumigatus .

[00101] In certain exemplary embodiments, the antibody or antigen-binding fragment thereof is administered to a subject as a loading dose followed by a plurality of maintenance doses.

[00102] In certain exemplary embodiments, the antibody or antigen-binding fragment thereof is administered using an autoinjector, a needle and syringe, or a pen.

[00103] In certain exemplary embodiments, the maintenance dose of the antibody or antigen-binding fragment thereof is administered once every two weeks (q2w).

[00104] 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.

[00105] 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.

[00106] In certain exemplary embodiments, maintenance doses of the antibody or antigen-binding fragment thereof are administered for at least 24 weeks.

[00107] 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.

[00108] In certain exemplary embodiments, the treatment results in a reduction in severe asthma exacerbations on an annualized basis. In certain exemplary embodiments, the treatment results in an improvement in lung function as measured by forced expiratory volume (FEV ₁ ) or forced expiratory flow at 25-75% of lung volume (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 levels in serum. In certain exemplary embodiments, the treatment results in a decrease in one or more of TARC levels, eotaxin-3 levels, and eosinophil levels in peripheral blood. In certain exemplary embodiments, FeNO (ppb) is reduced.

[00109] In certain exemplary embodiments, the antibody or antigen-binding fragment thereof comprises the heavy chain variable region (HCVR) sequence of SEQ ID NO: 1 and the light chain variable region (LCVR) sequence of SEQ ID NO: 2.

[00110] 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.

[00111] In certain exemplary embodiments, the antibody is dupilumab.

[00112] In certain exemplary embodiments, the subject has uncontrolled asthma of moderate to severe severity. In certain exemplary embodiments, the subject has comorbid cystic fibrosis. In certain exemplary embodiments, the subject has comorbid asthma and comorbid cystic fibrosis.

[00113] 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.

[00114] In another aspect, a method of treating a subject with allergic bronchopulmonary aspergillosis (ABPA) is provided, comprising administering to the subject an antibody or antigen-binding fragment thereof that specifically binds to an interleukin-4 receptor (IL-4R), wherein the antibody or antigen-binding fragment thereof comprises three heavy chain CDR sequences 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.

[00115] In certain exemplary embodiments, the subject has a baseline blood eosinophil count of at least about 300 cells/μL.

[00116] In certain exemplary embodiments, the subject has a total serum IgE level of at least about 1000 IU/mL.

[00117] In certain exemplary embodiments, the subject has a baseline blood eosinophil count of at least about 500 cells/μL.

[00118] In certain exemplary embodiments, the antibody or antigen-binding fragment thereof is administered to the subject as a loading dose followed by a plurality of maintenance doses.

[00119] In certain exemplary embodiments, the antibody or antigen-binding fragment thereof is administered using an autoinjector, a needle and syringe, or a pen.

[00120] In certain exemplary embodiments, the maintenance dose of the antibody or antigen-binding fragment thereof is administered once every two weeks (q2w).

[00121] 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.

[00122] 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.

[00123] 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.

[00124] In certain exemplary embodiments, maintenance doses of the antibody or antigen-binding fragment thereof are administered for at least 24 weeks.

[00125] 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.

[00126] In certain exemplary embodiments, the treatment results in a reduction in severe asthma exacerbations on an annualized basis. In certain exemplary embodiments, the treatment results in an improvement in lung function as measured by forced expiratory volume (FEV ₁ ) or forced expiratory flow at 25-75% of lung volume (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 levels in serum. In certain exemplary embodiments, the treatment results in a decrease in one or more of TARC levels, eotaxin-3 levels, and eosinophil levels in peripheral blood. In certain exemplary embodiments, FeNO (ppb) is reduced.

[00127] In certain exemplary embodiments, the antibody or antigen-binding fragment thereof comprises the heavy chain variable region (HCVR) sequence of SEQ ID NO: 1 and the light chain variable region (LCVR) sequence of SEQ ID NO: 2.

[00128] 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.

[00129] In certain exemplary embodiments, the antibody is dupilumab.

[00130] In certain exemplary embodiments, the subject has uncontrolled asthma of moderate to severe severity. In certain exemplary embodiments, the subject has comorbid cystic fibrosis. In certain exemplary embodiments, the subject has comorbid asthma and comorbid cystic fibrosis.

[00131] 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.

[00132] In another aspect, a method of treating a subject with allergic bronchopulmonary aspergillosis (ABPA) is provided, comprising administering to the subject an antibody or antigen-binding fragment thereof that specifically binds to an interleukin-4 receptor (IL-4R), wherein the antibody or antigen-binding fragment thereof comprises three heavy chain CDR sequences 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.

[00133] In certain exemplary embodiments, the subject has a serum allergen-specific IgE level of at least about 0.35 kU/L.

[00134] In certain exemplary embodiments, the allergen is Aspergillus fumigatus .

[00135] In certain exemplary embodiments, the subject has a total serum IgE level of at least about 1000 IU/mL.

[00136] In certain exemplary embodiments, the antibody or antigen-binding fragment thereof is administered to a subject as a loading dose followed by a plurality of maintenance doses.

[00137] In certain exemplary embodiments, the antibody or antigen-binding fragment thereof is administered using an autoinjector, a needle and syringe, or a pen.

[00138] In certain exemplary embodiments, the maintenance dose of the antibody or antigen-binding fragment thereof is administered once every two weeks (q2w).

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.

[00139] 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.

[00140] In certain exemplary embodiments, maintenance doses of the antibody or antigen-binding fragment thereof are administered for at least 24 weeks.

[00141] 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.

[00142] In certain exemplary embodiments, the treatment results in a reduction in severe asthma exacerbations on an annualized basis. In certain exemplary embodiments, the treatment results in an improvement in lung function as measured by forced expiratory volume (FEV ₁ ) or forced expiratory flow at 25-75% of lung volume (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 levels in serum. In certain exemplary embodiments, the treatment results in a decrease in one or more of TARC levels, eotaxin-3 levels, and eosinophil levels in peripheral blood. In certain exemplary embodiments, FeNO (ppb) is reduced.

[00143] In certain exemplary embodiments, the antibody or antigen-binding fragment thereof comprises the heavy chain variable region (HCVR) sequence of SEQ ID NO: 1 and the light chain variable region (LCVR) sequence of SEQ ID NO: 2.

[00144] 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.

[00145] In certain exemplary embodiments, the antibody is dupilumab.

[00146] In certain exemplary embodiments, the subject has uncontrolled asthma of moderate to severe severity. In certain exemplary embodiments, the subject has comorbid cystic fibrosis. In certain exemplary embodiments, the subject has comorbid asthma and comorbid cystic fibrosis.

[00147] 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.

[00148] In another aspect, there is provided a method for improving pulmonary function, as measured by forced expiratory volume (FEV ₁ ) or forced expiratory flow at 25-75% of lung volume (FEF25-75%), 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 an 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 characterized by a total serum IgE level of at least about 1000 IU/mL.

[00149] In certain exemplary embodiments, the antibody or antigen-binding fragment thereof comprises the heavy chain variable region (HCVR) sequence of SEQ ID NO: 1 and the light chain variable region (LCVR) sequence of SEQ ID NO: 2.

[00150] 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.

[00151] In certain exemplary embodiments, the antibody is dupilumab.

[00152] In certain exemplary embodiments, the subject has uncontrolled allergic asthma of moderate to severe severity. In certain exemplary embodiments, the subject has comorbid cystic fibrosis. In certain exemplary embodiments, the subject has comorbid asthma and comorbid cystic fibrosis.

[00153] 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.

[00154] In another aspect, a method is provided for reducing severe asthma exacerbations per year in a subject with allergic bronchopulmonary aspergillosis-associated asthma (ABPA), comprising administering to the subject an antibody or antigen-binding fragment thereof that specifically binds to an interleukin-4 receptor (IL-4R), wherein the antibody or antigen-binding fragment thereof comprises three heavy chain CDR sequences 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.

[00155] In certain exemplary embodiments, the antibody or antigen-binding fragment thereof comprises the heavy chain variable region (HCVR) sequence of SEQ ID NO: 1 and the light chain variable region (LCVR) sequence of SEQ ID NO: 2.

[00156] 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.

[00157] In certain exemplary embodiments, the antibody is dupilumab.

[00158] In certain exemplary embodiments, the subject has uncontrolled allergic asthma of moderate to severe severity. In certain exemplary embodiments, the subject has comorbid cystic fibrosis. In certain exemplary embodiments, the subject has comorbid asthma and comorbid cystic fibrosis.

[00159] 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.

[00160] In another aspect, a method is provided for improving the Asthma Control Questionnaire (ACQ-5) score in a subject with allergic bronchopulmonary aspergillosis-associated asthma (ABPA), comprising administering to the subject an antibody or antigen-binding fragment thereof that specifically binds to an interleukin-4 receptor (IL-4R), wherein the antibody or antigen-binding fragment thereof comprises three heavy chain CDR sequences 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.

[00161] In certain exemplary embodiments, the antibody or antigen-binding fragment thereof comprises the heavy chain variable region (HCVR) sequence of SEQ ID NO: 1 and the light chain variable region (LCVR) sequence of SEQ ID NO: 2.

[00162] 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.

[00163] In certain exemplary embodiments, the antibody is dupilumab.

[00164] In certain exemplary embodiments, the subject has uncontrolled allergic asthma of moderate to severe severity. In certain exemplary embodiments, the subject has comorbid cystic fibrosis. In certain exemplary embodiments, the subject has comorbid asthma and comorbid cystic fibrosis.

[00165] 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.

[00166] In another aspect, a method of treating a subject with concomitant allergic bronchopulmonary aspergillosis (ABPA) and cystic fibrosis (CF) is provided, comprising administering to the subject an antibody or antigen-binding fragment thereof that specifically binds to an interleukin-4 receptor (IL-4R), wherein the antibody or antigen-binding fragment thereof comprises three heavy chain CDR sequences 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.

[00167] In certain exemplary embodiments, the subject has a baseline blood eosinophil count of at least about 500 cells/μL.

[00168] In certain exemplary embodiments, the subject has an allergen-specific IgE level in the blood serum of at least about 0.35 kU/L. In certain exemplary embodiments, the allergen is Aspergillus fumigatus .

[00169] In certain exemplary embodiments, the antibody or antigen-binding fragment thereof is administered to a subject as a loading dose followed by a plurality of maintenance doses.

[00170] In certain exemplary embodiments, the antibody or antigen-binding fragment thereof is administered using an autoinjector, a needle and syringe, or a pen.

[00171] In certain exemplary embodiments, the maintenance dose of the antibody or antigen-binding fragment thereof is administered once every two weeks (q2w).

[00172] 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.

[00173] 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.

[00174] In certain exemplary embodiments, maintenance doses of the antibody or antigen-binding fragment thereof are administered for at least 24 weeks.

[00175] 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.

[00176] In certain exemplary embodiments, treatment results in an improvement in lung function as measured by forced expiratory volume (FEV ₁ ) or forced expiratory flow at 25-75% of lung volume (FEF25-75%).

[00177] 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 the serum. In certain exemplary embodiments, the treatment results in a decrease in one or more of TARC levels, eotaxin-3 levels, and eosinophil levels in the peripheral blood. In certain exemplary embodiments, FeNO (ppb) is decreased.

[00178] In certain exemplary embodiments, the antibody or antigen-binding fragment thereof comprises the heavy chain variable region (HCVR) sequence of SEQ ID NO: 1 and the light chain variable region (LCVR) sequence of SEQ ID NO: 2.

[00179] 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.

[00180] In certain exemplary embodiments, the antibody is dupilumab.

[00181] In certain exemplary embodiments, the subject has asthma. In certain exemplary embodiments, the treatment results in a reduction in asthma exacerbations on an annualized basis.

[00182] 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.

[00183] In another aspect, a method of treating a subject with concomitant allergic bronchopulmonary aspergillosis (ABPA) and cystic fibrosis (CF) is provided, comprising administering to the subject an antibody or antigen-binding fragment thereof that specifically binds to an interleukin-4 receptor (IL-4R), wherein the antibody or antigen-binding fragment thereof comprises three heavy chain CDR sequences 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.

[00184] 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 serum total 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.

[00185] In certain exemplary embodiments, the antibody or antigen-binding fragment thereof is administered to a subject as a loading dose followed by a plurality of maintenance doses.

[00186] In certain exemplary embodiments, the antibody or antigen-binding fragment thereof is administered using an autoinjector, a needle and syringe, or a pen.

[00187] In certain exemplary embodiments, the maintenance dose of the antibody or antigen-binding fragment thereof is administered once every two weeks (q2w).

[00188] 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.

[00189] 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.

[00190] In certain exemplary embodiments, maintenance doses of the antibody or antigen-binding fragment thereof are administered for at least 24 weeks.

[00191] 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.

[00192] In certain exemplary embodiments, treatment results in an improvement in lung function as measured by forced expiratory volume (FEV ₁ ) or forced expiratory flow at 25-75% of lung volume (FEF25-75%).

[00193] In certain exemplary embodiments, the treatment results in a decrease in one or both of total serum IgE levels and Aspergillus fumigatus -specific serum IgE levels. In certain exemplary embodiments, the treatment results in a decrease in one or more of TARC levels, eotaxin-3 levels, and eosinophil levels in peripheral blood. In certain exemplary embodiments, FeNO (ppb) is decreased.

[00194] In certain exemplary embodiments, the antibody or antigen-binding fragment thereof comprises the heavy chain variable region (HCVR) sequence of SEQ ID NO: 1 and the light chain variable region (LCVR) sequence of SEQ ID NO: 2.

[00195] 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.

[00196] In certain exemplary embodiments, the antibody is dupilumab.

[00197] In certain exemplary embodiments, the subject has asthma. In certain exemplary embodiments, the treatment results in a reduction in asthma exacerbations on an annualized basis.

[00198] 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.

[00199] In another aspect, a method of treating a subject with concomitant allergic bronchopulmonary aspergillosis (ABPA) and cystic fibrosis (CF) is provided, comprising administering to the subject an antibody or antigen-binding fragment thereof that specifically binds to an interleukin-4 receptor (IL-4R), wherein the antibody or antigen-binding fragment thereof comprises three heavy chain CDR sequences 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 characterized by a blood eosinophil count at baseline of at least about 500 cells/μL.

[00200] In certain exemplary embodiments, the subject has an allergen-specific IgE level in the blood serum of at least about 0.35 kU/L. In certain exemplary embodiments, the allergen is Aspergillus fumigatus .

[00201] In certain exemplary embodiments, the subject has a total serum IgE level of at least about 1000 IU/mL.

[00202] In certain exemplary embodiments, the antibody or antigen-binding fragment thereof is administered to a subject as a loading dose followed by a plurality of maintenance doses.

[00203] In certain exemplary embodiments, the antibody or antigen-binding fragment thereof is administered using an autoinjector, a needle and syringe, or a pen.

[00204] In certain exemplary embodiments, the maintenance dose of the antibody or antigen-binding fragment thereof is administered once every two weeks (q2w).

[00205] 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.

[00206] 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.

[00207] In certain exemplary embodiments, maintenance doses of the antibody or antigen-binding fragment thereof are administered for at least 24 weeks.

[00208] 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.

[00209] In certain exemplary embodiments, treatment results in an improvement in lung function as measured by forced expiratory volume (FEV ₁ ) or forced expiratory flow at 25-75% of lung volume (FEF25-75%).

[00210] In certain exemplary embodiments, the treatment results in a decrease in one or both of total serum IgE levels and Aspergillus fumigatus -specific serum IgE levels. In certain exemplary embodiments, the treatment results in a decrease in one or more of TARC levels, eotaxin-3 levels, and eosinophil levels in peripheral blood. In certain exemplary embodiments, FeNO (ppb) is decreased.

[00211] In certain exemplary embodiments, the antibody or antigen-binding fragment thereof comprises the heavy chain variable region (HCVR) sequence of SEQ ID NO: 1 and the light chain variable region (LCVR) sequence of SEQ ID NO: 2.

[00212] 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.

[00213] In certain exemplary embodiments, the antibody is dupilumab.

[00214] In certain exemplary embodiments, the subject has asthma. In certain exemplary embodiments, the treatment results in a reduction in asthma exacerbations on an annualized basis.

[00215] 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.

[00216] In another aspect, a method of treating a subject with allergic bronchopulmonary aspergillosis (ABPA) is provided, comprising administering to the subject an antibody or antigen-binding fragment thereof that specifically binds to an interleukin-4 receptor (IL-4R), wherein the antibody or antigen-binding fragment thereof comprises three heavy chain CDR sequences comprising SEQ ID NOs: 3, 4, and 5, respectively, and three light chain CDR sequences comprising SEQ ID NOs: 6, 7, and 8, respectively, wherein the subject has a serum total 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.

[00217] 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, or 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.

[00218] In certain exemplary embodiments, the antibody or antigen-binding fragment thereof is administered to the subject as a loading dose followed by a plurality of maintenance doses. In certain exemplary embodiments, the antibody or antigen-binding fragment thereof is administered using an autoinjector, a needle and syringe, or a pen. In certain exemplary embodiments, the maintenance dose of the antibody or antigen-binding fragment thereof is administered once every two weeks (q2w).

[00219] 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.

[00220] 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.

[00221] In certain exemplary embodiments, maintenance doses of the antibody or antigen-binding fragment thereof are administered for at least 24 weeks.

[00222] 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.

[00223] In certain exemplary embodiments, treatment results in an improvement in lung function as measured by forced expiratory volume (FEV ₁ ) or forced expiratory flow at 25-75% of lung volume (FEF25-75%).

[00224] 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 the serum. In certain exemplary embodiments, the treatment results in a decrease in one or more of TARC levels, eotaxin-3 levels, and eosinophil levels in the peripheral blood. In certain exemplary embodiments, FeNO (ppb) is decreased.

[00225] In certain exemplary embodiments, the antibody or antigen-binding fragment thereof comprises the heavy chain variable region (HCVR) sequence of SEQ ID NO: 1 and the light chain variable region (LCVR) sequence of SEQ ID NO: 2.

[00226] 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.

[00227] In certain exemplary embodiments, the antibody is dupilumab.

[00228] In certain exemplary embodiments, the subject has uncontrolled asthma with a severity ranging from moderate to severe. In certain exemplary embodiments, the treatment results in a reduction in severe asthma exacerbations on an annualized basis.

[00229] In certain exemplary embodiments, the subject has comorbid asthma. In certain exemplary embodiments, the subject has comorbid cystic fibrosis. In certain exemplary embodiments, the subject has comorbid asthma and comorbid cystic fibrosis.

[00230] 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.

[00231] In another aspect, a method of treating a subject with asthma is provided, comprising administering to the subject two or more doses of an antibody or antigen-binding fragment thereof that specifically binds to an interleukin-4 receptor (IL-4R), wherein the antibody or antigen-binding fragment thereof comprises three heavy chain CDR sequences 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.

[00232] In certain exemplary embodiments, administration of the antibody or antigen-binding fragment thereof is temporarily suspended prior to administration of the vaccine.

[00233] In certain exemplary embodiments, the vaccine is administered at least 7 days after the last administration of the antibody or antigen-binding fragment thereof to the subject. In certain exemplary embodiments, the vaccine is administered between about 7 days and about 60 days after the last administration of the antibody or antigen-binding fragment thereof to the subject.

[00234] In certain exemplary embodiments, administration of the antibody or antigen-binding fragment thereof is resumed after administration of the vaccine.

[00235] In certain exemplary embodiments, the antibody or antigen-binding fragment thereof is administered between about 1 day and 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.

[00236] In certain exemplary embodiments, the antibody or antigen-binding fragment thereof is administered approximately 21 days after administration of the vaccine.

[00237] In certain exemplary embodiments, the efficacy of the antibody or antigen-binding fragment thereof is not reduced upon administration of the vaccine.

[00238] In certain exemplary embodiments, the forced expiratory volume (FEV ₁ ) of the subject is approximately the same before and after administration of the vaccine.

[00239] In certain exemplary embodiments, the efficacy of the vaccine in a subject is not reduced by administration of the antibody or antigen-binding fragment thereof.

[00240] In certain exemplary embodiments, the subject develops a seroprotective neutralizing antibody titer following administration of the vaccine.

[00241] 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 yellow fever virus.

[00242] In certain exemplary embodiments, the antibody or antigen-binding fragment thereof comprises the heavy chain variable region (HCVR) sequence of SEQ ID NO: 1 and the light chain variable region (LCVR) sequence of SEQ ID NO: 2.

[00243] 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.

[00244] In certain exemplary embodiments, the antibody is dupilumab.

[00245] In certain exemplary embodiments, the subject has comorbid cystic fibrosis. In certain exemplary embodiments, the subject has comorbid asthma and comorbid cystic fibrosis.

[00246] 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.

[00247] In another aspect, a method of administering a vaccine to a subject is provided, wherein before, during, or after administering the vaccine, the subject is administered at least one dose of an antibody or antigen-binding fragment thereof that specifically binds to an interleukin-4 receptor (IL-4R), wherein the antibody or antigen-binding fragment thereof comprises three heavy chain CDR sequences comprising SEQ ID NOs: 3, 4, and 5, respectively, and three light chain CDR sequences comprising SEQ ID NOs: 6, 7, and 8, respectively.

[00248] In certain exemplary embodiments, the subject has a type 2 inflammatory disease. In certain exemplary embodiments, the type 2 inflammatory disease is selected from the group consisting of one or any combination of the following diseases: asthma, allergic rhinitis, chronic rhinosinusitis with nasal polyps (CRSsNP), eosinophilic esophagitis (EoE), atopic dermatitis (AD), food and environmental allergy, aspirin-induced respiratory disease (AERD), and other nonsteroidal anti-inflammatory drug (NSAID)-induced respiratory disease.

[00249] In certain exemplary embodiments, the vaccine is administered to the subject within about 1 day to about 90 days after the last dose of the antibody or antigen-binding fragment thereof.

[00250] In certain exemplary embodiments, the antibody or antigen-binding fragment thereof comprises the heavy chain variable region (HCVR) sequence of SEQ ID NO: 1 and the light chain variable region (LCVR) sequence of SEQ ID NO: 2.

[00251] 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.

[00252] In certain exemplary embodiments, the antibody is dupilumab.

[00253] In certain exemplary embodiments, the subject has asthma. In certain exemplary embodiments, the subject has cystic fibrosis. In certain exemplary embodiments, the subject has comorbid asthma and comorbid cystic fibrosis.

[00254] 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.

[00255] Other embodiments will be apparent from a review of the following detailed description, drawings, tables, and the appended claims.

BRIEF DESCRIPTION OF GRAPHIC MATERIALS

[00256] The above and other features and advantages of the present invention will be more clearly understood from the following detailed description of illustrative embodiments in conjunction with the accompanying drawings. The file of the present patent contains at least one drawing/photograph made in color. Copies of the present patent with the color drawing(s)/photograph(s) will be provided by the patent office upon request and payment of the required fee.

[00257] Fig. 1A - Fig. 1E show the effect of dupilumab on the annualized rate of severe exacerbations. Fig. 1A shows that dupilumab reduced the overall annualized rate of severe exacerbations in the overall allergic asthma subgroup as well as in the overall asthma subgroup who did not meet criteria for allergic asthma. Fig. 1B shows the effect of dupilumab in the allergic asthma subgroup as well as in the asthma subgroup who did not meet criteria for allergic asthma, where subjects had blood eosinophils ≥150 cells/μL. Fig. 1C shows the effect of dupilumab in the subgroup with allergic asthma and in the subgroup with asthma that did not meet the criteria for allergic asthma, where subjects had blood eosinophils ≥300 cells/μL. Fig. 1D shows the effect of dupilumab in the subgroup with allergic asthma and in the subgroup with asthma that did not meet the criteria for allergic asthma, where subjects had baseline blood FeNO ≥25 ppb. Fig. 1E shows the effect of dupilumab in the subgroup with allergic asthma and in the subgroup with asthma that did not meet the criteria for allergic asthma, where subjects had serum total IgE >700 IU/mL. CI, confidence interval; FeNO, fractional exhaled nitric oxide; ITT, intent-to-treat population; q2w, once every 2 weeks.

[00258] Figure 2 shows the effect of dupilumab on FEV ₁ (L) in the overall allergic asthma subgroup and in the overall asthma subgroup who did not meet criteria for allergic asthma. Figure 2A shows the change in baseline FEV ₁ over the 52-week treatment period in the overall allergic asthma subgroup, and shows the magnitude of the subgroup effects additionally determined by baseline blood eosinophils, FeNO, or baseline serum total IgE at Week 12. Figure 2B shows the change in baseline FEV ₁ over the 52-week treatment period in the overall asthma subgroup who did not meet criteria for allergic asthma, and shows the magnitude of the subgroup effects additionally determined by baseline blood eosinophils, FeNO, or baseline serum total IgE at Week 12.

[00259] Figure 3 shows the effect of dupilumab on asthma control (measured by the ACQ-5) over the 52-week treatment period in the overall subgroup with allergic asthma and in the overall subgroup with asthma that did not meet criteria for allergic asthma. ACQ-5, 5-item asthma control questionnaire; LS, least squares; q2w, once every 2 weeks; SE, standard error.

[00260] Figures 4A through 4C show the effect of dupilumab on various biomarkers. Figure 4A shows the effect of dupilumab on total serum IgE levels. Figure 4B shows the effect of dupilumab on FeNO levels. Figure 4C shows the effect of dupilumab on serum TARC levels over the 52-week treatment period in the overall allergic asthma subgroup and in the overall asthma subgroup who did not meet criteria for allergic asthma (exposed population). CI, confidence interval; FeNO, fractionated exhaled nitric oxide; q2w, once every 2 weeks; TARC, thymus- and activation-regulated chemokine.

[00261] Figures 5A through 5H show the effect of dupilumab on serum antigen-specific IgE levels over the 52-week treatment period in the allergic asthma subgroup. Figure 5A shows the effect of dupilumab on serum antigen-specific IgE levels ≥0.35 kU/mL (exposed population) in the A. fumigatus -exposed allergic asthma subgroup. Figure 5B shows the effect of dupilumab on serum antigen-specific IgE levels in the cat dander-exposed allergic asthma subgroup. Figure 5C shows the effect of dupilumab on serum antigen-specific IgE levels in the D. farinae -exposed allergic asthma subgroup. Figure Figure 5D shows the effect of dupilumab on serum antigen-specific IgE levels in the D. pteronyssinus- exposed allergic asthma subgroup. Figure 5E shows the effect of dupilumab on serum antigen-specific IgE levels in the dog dander-exposed allergic asthma subgroup. Figure 5F shows the effect of dupilumab on serum antigen-specific IgE levels in the German cockroach-exposed allergic asthma subgroup. Figure 5G shows the effect of dupilumab on serum antigen-specific IgE levels in the A. tenuis/alternata -exposed allergic asthma subgroup. Figure 5H shows the effect of dupilumab on serum antigen-specific IgE levels in the C. herbarum/hormodendrum- exposed allergic asthma subgroup. CI, confidence interval; q2w, once every 2 weeks.

[00262] Fig. 6A - Fig. 6B show a statistical analysis of patients with IgE ≥700 IU/mL. Fig. 6A shows a histogram of residuals to ensure normal distribution. Fig. 6B shows a qq plot demonstrating normal distribution.

[00263] Fig. 7 shows the annualized rate of severe exacerbations during the 52-week treatment period in patients with allergic bronchopulmonary aspergillosis (ABPA) in an intent-to-treat (ITT) population.

[00264] Figure 8 shows the change in least squares (LS) mean values from baseline in forced expiratory volume in one second (FEV1) before bronchodilator use at weeks 24 and 52 in the ITT population.

[00265] Fig. 9 shows total serum IgE levels at week 52 in a patient population exposed to Aspergillus fumigatus (Af).

[00266] Fig. 10 shows Af-specific IgE levels in serum at week 52 in the Af-exposed patient population.

[00267] Fig. 11 graphically shows absolute FeNO levels (ppb) at week 52 in the Af-exposed patient population.

[00268] Figure 12 graphically shows the effect of dupilumab q2w on the annualized rate of severe exacerbations over the 52-week treatment period in the ITT population of patients with serologic evidence of ABPA.

[00269] Figure 13 graphically shows the effect of dupilumab q2w on pre-bronchodilator FEV1 (L) over a 52-week treatment period in the ITT population of patients with serologic evidence of ABPA.

[00270] Fig. 14 graphically shows the effect of dupilumab q2w on ACQ-5 score over a 52-week treatment period in the ITT population of patients with serologic evidence of ABPA.

[00271] Fig. 15A - Fig. 15B graphically show the effect of dupilumab q2w on total serum IgE (IU/mL) ( Fig. 15A ) and A. fumigatus -specific serum IgE (IU/mL) ( Fig. 15B ) over a 52-week treatment period in exposed patients with serologic evidence of ABPA.

[00272] Figures 16A-16D graphically show the effect of dupilumab q2w on type 2 biomarkers over the 52-week treatment period in exposed patients with ABPA serology. FeNO (ppb) ( Figure 16A ), TARC (pg/mL) ( Figure 16B ), eotaxin-3 (pg/mL) ( Figure 16C ), and peripheral blood eosinophils (cells/μL) ( Figure 16D ).

[00273] Fig. 17A-Fig. 17B are graphs of plaque neutralization titers (PRNT ₅₀ ) of YFV-17D neutralizing antibody before and after vaccination. Fig. 17A shows matched neutralization titers for 23 patients who had pre-vaccination titers. Fig. 17B shows pre- and post-vaccination data for all patients. In Fig. 17B, patients with dupilumab concentrations below the median _Ctrough of 37.4 mg/L are indicated by filled circles, while patients with serum concentrations greater than 37.4 mg/L are indicated by open circles. A titer <1:10 is defined as seronegative, and these values are designated as "1". In Fig. 17A-Fig. 17B showed that all 37 vaccinated patients had seroprotective neutralizing titers against yellow fever after vaccination.

[00274] Figure 18 graphically shows the log increase in PRNT titer (post vs. pre titer) as a function of pre-vaccination dupilumab concentration. Pre-vaccination PK samples were collected on the day of YFV administration in 15 of 23 patients. All 13 patients with serum dupilumab concentrations >37.4 mg/L had seroprotective PRNT titers post-YFV. Twelve of these patients demonstrated an increase in titer post-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 in these patients is shown in Figure 18 . Pre titer <1:10, 10 was used to calculate the fold increase in titer.

[00275] Figure 19 graphically shows the mean absolute FEV ₁ (L) before and after yellow fever vaccination in yellow fever vaccinated patients in study LTS12551. Figure 19 shows that the FEV ₁ was stable from the pre-YFV visit to the first post-YFV visit. BL: initial study baseline; Pre-YF: last visit before yellow fever vaccination; Post-YF: first visit after yellow fever vaccination; FU: follow-up visit.

[00276] Figure 20 graphically shows the change in mean FEV1 (L) from baseline before and after yellow fever vaccination in yellow fever vaccinated patients in study LTS12551. Figure 20 shows that FEV1 was stable from the pre-YFV visit to the first post-YFV visit. BL: initial study baseline; Pre-YF: last visit before yellow fever vaccination; Post-YF: first visit after yellow fever vaccination; FU: follow-up visit.

DETAILED DESCRIPTION

[00277] Before describing the present invention, it should be understood that the present invention is not limited to the particular methods and experimental conditions described, since such methods and conditions may vary. It should also 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.

[00278] Unless defined otherwise, 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.

[00279]As used herein, the term "approximately," when used in reference to a specific numerical value being described, means that the value may vary from the value being described by no more than 1%. For example, as used herein, the expression "approximately 100" includes 99 and 101 and all values in between (e.g., 99.1, 99.2, 99.3, 99.4, etc.).

[00280] As used herein, the terms "treat,""treatment," or the like mean to alleviate symptoms, remove the cause of symptoms, either temporarily or permanently, or prevent or slow down the onset of symptoms of the said disorder or condition.

[00281] Although any methods and materials similar or equivalent to those described herein can be used in the practice of the present invention, representative methods and materials are described below. All publications mentioned herein are herein incorporated by reference in their entirety.

Ways to reduce the frequency of asthma and/or ABPA exacerbations

[00282] Methods are provided for reducing the incidence of exacerbations of asthma (e.g., allergic asthma, ABPA-associated asthma, moderate to severe asthma, persistent asthma, etc.) and/or 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. In certain embodiments, the IL-4R antagonist is an antibody or antigen-binding fragment thereof that specifically binds to IL-4R. Exemplary IL-4R antibodies that may be used in the context of the methods provided herein are described elsewhere herein.

[00283] As used herein, the term "asthma exacerbation" means an increase in the severity and/or frequency of occurrence and/or duration of one or more symptoms or manifestations of asthma (e.g., allergic asthma, ABPA-associated asthma, moderate to severe asthma, persistent asthma, etc.). The term "asthma exacerbation" also includes any worsening of a subject's respiratory condition that requires or is treatable with a therapeutic intervention for asthma (such as, for example, steroid treatment, inhaled corticosteroid treatment, hospitalization, etc.). There are two types of asthma exacerbation events: a loss of asthma control event (LOAC) and a severe exacerbation event.

[00284] 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 manifestations of ABPA, including, but not limited to, wheezing, dyspnea, respiratory exacerbations, bronchial hyperreactivity, hemoptysis, productive cough (coughing up brownish-black mucus), central bronchiectasis with mucosal plugging, markedly elevated total IgE levels, markedly elevated Af-specific IgE levels, and tissue eosinophilia.

[00285] According to certain embodiments, the ABPA exacerbation occurs in a subject that has an HLA-DR2 serotype (e.g., an HLA-DRB1*1501 subtype, an *HLA-DRB1*1503 subtype, or an *HLA-DRB1*1601 subtype) or an HLA-DR5 serotype (e.g., an HLA-DRB1*1101 subtype, an HLA-DRB1*1104 subtype, or an HLA-DRB1*1202 subtype), wherein optionally the subject has an increased susceptibility to developing ABPA upon exposure to an Af antigen compared to a subject that does not have any of these serotypes and/or subtypes.

[00286] In certain embodiments, a loss of asthma control event (LOAC) is defined as one or more of the following: (a) 6 or more additional breath-relieving puffs of salbutamol/albuterol or levosalbutamol/levalbuterol in a 24-hour period (compared to baseline) for 2 consecutive days; (b) an increase in ICS dose by 4 times or more relative to the dose at Visit 2, and (c) the use of systemic corticosteroids for 3 or more days, or (d) a hospitalization or emergency department visit due to asthma requiring systemic corticosteroids.

[00287] In certain cases, an exacerbation of asthma (e.g., allergic asthma, ABPA-associated asthma, moderate to severe asthma, persistent asthma, etc.) may be classified as a "severe asthma exacerbation event." A severe asthma exacerbation event (e.g., severe allergic asthma exacerbation) is one that requires immediate intervention in the form of treatment with either systemic corticosteroids or inhaled corticosteroids at a dose four or more times the dose taken prior to the event. In certain embodiments, a severe asthma exacerbation event (e.g., a severe exacerbation of allergic asthma) is defined as a worsening of asthma (e.g., allergic asthma, ABPA-associated asthma, moderate to severe asthma, persistent asthma, etc.) requiring the following: use of systemic corticosteroids for 3 days or more, or hospitalization or emergency department visit due to asthma requiring systemic corticosteroids. Thus, the general term "asthma exacerbation" includes and encompasses the more specific subcategory of "severe asthma exacerbations." Accordingly, methods for reducing the incidence of severe asthma exacerbations in a patient in need thereof are included.

[00288] "Reducing the frequency" of exacerbations of asthma (e.g., allergic asthma, ABPA-associated asthma, moderate to severe asthma, persistent asthma, etc.) and/or ABPA means that a subject who has received a pharmaceutical composition comprising an IL-4R antagonist experiences fewer asthma or ABPA exacerbations (i.e., an amount that is less than at least one asthma exacerbation) after treatment than before treatment, or does not experience asthma exacerbations for at least 4 weeks (e.g., 4, 6, 8, 12, 14, or more weeks) after starting treatment with the pharmaceutical composition. "Reducing the incidence" of asthma exacerbation and/or ABPA alternatively means that after administration of the pharmaceutical composition, the likelihood that a subject will experience an asthma exacerbation is reduced by at least 10% (e.g., 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50% or more) compared to a subject who did not receive the pharmaceutical composition.

[00289] Methods are provided for reducing the incidence of asthma exacerbations (e.g., allergic asthma, ABPA-associated asthma, moderate to severe asthma, persistent asthma, etc.) and/or ABPA exacerbations 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 drug, such as 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™), etc. Suitable LABAs include, but are not limited to, salmeterol (e.g., Serevent™), formoterol (e.g., Foradil™), etc. Suitable LTAs include, but are not limited to, montelukast (e.g., Singulaire™), zafirlukast (e.g., Accolate™), etc.

[00290] Methods are provided for reducing the incidence of asthma exacerbations (e.g., allergic asthma, ABPA-associated asthma, moderate to severe asthma, persistent asthma, etc.) and/or ABPA exacerbations 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 breathing-facilitating drugs to eliminate or reduce one or more symptoms associated with asthma. Suitable respiratory facilitating drugs include, but are not limited to, long-acting beta ₂ -adrenergic receptor agonists such as, for example, albuterol (e.g., salbutamol, e.g., Proventil™, Ventolin™, Xopenex™, etc.), pirbuterol (e.g., Maxair™), metaproterenol (e.g., Alupent™), etc.

Ways to improve asthma-associated and/or ABPA-associated parameters

[00291] Also provided are methods for improving one or more asthma-associated and/or ABPA-associated parameters in a subject in need thereof, wherein the methods comprise administering to the subject a pharmaceutical composition comprising an IL-4R antagonist. A reduction in the incidence of asthma exacerbations and/or ABPA exacerbations (as described above) may be associated with an improvement in one or more asthma-associated parameters and/or ABPA-associated parameters; however, such an association is not necessarily observed in all cases.

[00292] Examples of "asthma-associated parameters,""asthma and ABPA-associated parameters," and "allergic asthma-associated parameters" include: (1) the relative percentage change from baseline (e.g., at Week 12) in forced expiratory volume in 1 second ( _FEV1 ); (2) the relative percentage change from baseline (e.g., at Week 12) measured by forced expiratory flow at 25-75% of lung volume (FEF25-75%); (3) the annualized rate of loss of asthma control events during the treatment period; (4) the annualized rate of severe exacerbation events during the treatment period; (5) the time to loss of asthma control events during the treatment period; (6) the time to severe exacerbation events during the treatment period; (7) the time to loss of asthma control events during the entire study period; (8) time to onset of severe exacerbation events throughout the study period; (9) healthcare use; (10) change from baseline (e.g., Week 12) in i) morning and evening asthma symptom scores, ii) ACQ-5 score, iii) AQLQ score, iv) morning and evening PEF, v) number of inhalations/day of salbutamol/albuterol or levosalbutamol/levalbuterol for relief, vi) night awakenings; or (11) change from baseline (e.g., Week 12 or Week 24) in i) 22-item Nasal and Sinus Outcome Test (SNOT-22) score, ii) Hospital Anxiety and Depression Scale (HADS) score, iii) EuroQual questionnaire (EQ-5D-3L or EQ-5D-5L) score. "Improvement in an asthma-associated parameter" 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, average number of nighttime awakenings, or SNOT-22 score. As used herein, the term "baseline" with respect to an asthma-associated parameter means a numerical value of an asthma-associated parameter for a patient prior to or throughout the period of administration of a pharmaceutical composition comprising an IL-4R antagonist.

[00293]To determine whether an asthma-associated (e.g., allergic asthma-associated) parameter or an asthma and ABPA-associated parameter has "improved," the parameter is measured quantitatively at baseline and at a time point following administration of the pharmaceutical composition described herein. For example, an asthma-associated parameter may be measured at day 1, day 2, day 3, day 4, day 5, day 6, day 7, day 8, day 9, day 10, day 11, day 12, day 14, or at week 3, week 4, week 5, week 6, week 7, week 8, week 9, week 10, week 11, week 12, week 13, week 14, week 15, week 16, week 17, week 18, week 19, week 20, week 21, week 22, week 23, week 24, or longer after initial treatment with the pharmaceutical composition. The difference between the value of the parameter at a particular time point after the start of treatment and the value of the parameter at baseline is used to determine whether an "improvement" in the asthma-associated parameter has occurred (e.g., increase or decrease, depending on the situation, depending on the specific parameter being measured).

[00294] The terms "acquire" or "acquisition" as used herein refer to obtaining possession of a physical object or quantity, such as a numerical quantity, by "direct acquisition" or "indirect acquisition" of a physical object or quantity, such as an asthma-associated parameter. "Direct acquisition" means performing a method (e.g., performing a synthetic or analytical method) to obtain a physical object or quantity. "Indirect acquisition" refers to obtaining a physical object or quantity from another party or source (e.g., a third party laboratory that directly acquired the physical object or quantity). Direct acquisition of a physical object includes performing a method that involves physically changing a physical substance, such as a starting material. Exemplary changes include obtaining a physical object from two or more starting materials, cutting or fragmenting a substance, separating or purifying a substance, combining two or more separate objects into a mixture, performing a chemical reaction that involves breaking or forming a covalent or non-covalent bond. Direct acquisition of a quantity involves performing a process that involves a physical change in a sample or other substance, such as performing an analytical process that involves a physical change in a substance, such as a sample, analyte, or reagent (sometimes referred to in this document as "physical analysis").

[00295] The information that is acquired directly may be in the form of a report, such as one provided in paper or electronic form, such as from a database or an online application ("App"). The report or information may be provided, for example, by a healthcare institution, such as a hospital or clinic; or by a healthcare professional, such as a physician or nurse.

[00296] Forced expiratory volume in 1 second (FEV ₁ ) . In certain embodiments, administering an IL-4R antagonist to a patient results in an increase from a baseline in forced expiratory volume in 1 second (FEV ₁ ). Methods for measuring FEV ₁ are known in the art. For example, a spirometer that complies with the 2005 American Thoracic Society (ATS)/European Respiratory Society (ERS) guidelines can be used to measure FEV ₁ in a patient. The ATS/ERS standardization of spirometry can be used as a guide. Spirometry is typically performed between 6 a.m. and 10 a.m. after abstinence from albuterol for at least 6 hours. Pulmonary function tests are typically performed in a sitting position, and the highest value is recorded as FEV ₁ (in liters).

[00297] Therapeutic methods are provided that result in an increase in FEV ₁ from baseline of at least 0.05 L at week 12 after initiation of treatment with a pharmaceutical composition comprising an IL-4R antagonist. For example, administration of an IL-4R antagonist to a subject in need thereof causes an increase in _FEV1 from baseline of approximately 0.05 L, 0.10 L, 0.12 L, 0.14 L, 0.16 L, 0.18 L, 0.20 L, 0.22 L, 0.24 L, 0.26 L, 0.28 L, 0.30 L, 0.32 L, 0.34 L, 0.36 L, 0.38 L, 0.40 L, 0.42 L, 0.44 L, 0.46 L, 0.48 L, 0.50 L, or greater at week 12.

[00298] FEF25-75%. According to certain embodiments, administering an IL-4R antagonist to a patient results in an increase in FEF25-75% from a baseline. Methods for measuring FEF are known in the art. For example, a spirometer that complies with the 2005 American Thoracic Society (ATS)/European Respiratory Society (ERS) guidelines can be used to measure FEV ₁ in a patient. FEF25-75 %; (forced expiratory flow between 25% and 75 % of lung volume) is the rate (in liters per second) at which a person can expel the middle half of their air during maximal exhalation (i.e., forced vital capacity or FVC). The parameter refers to the average flow from the point at which 25 percent of the FVC has been exhaled to the point at which 75 percent of the FVC has been exhaled. The FEF25-75 %% of a subject provides information about 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 lung disease. In certain embodiments, an improvement and/or increase in the FEF25-75% parameter is an improvement of at least 10%, 25%, 50%, or more compared to the baseline. In certain embodiments, the methods described herein achieve normal FEF25-75% values in a subject (e.g., values in the range of 50-60% and up to 130% of the mean).

[00299] Morning and evening peak expiratory flow (AM PEF and PM PEF) . In certain embodiments, administering an IL-4R antagonist to a patient results in an increase from a baseline in morning and/or evening (PM) peak expiratory flow (AM PEF and/or PM PEF). Methods for measuring PEF are known in the art. For example, in one method for measuring PEF, patients are 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 that require emergency medication use). Patients are instructed in the use of the device and written instructions for the use of the electronic PEF meter are provided to the patient. Additionally, the health care professional may instruct patients on how to record the appropriate variables on the electronic PEF meter. AM PEF is typically measured within 15 minutes of rising (6 a.m. to 10 a.m.) before any dose of albuterol. PM PEF is typically measured in the evening (6 a.m. to 10 p.m.) before any dose of albuterol. Subjects should try to avoid albuterol for at least 6 hours before measuring their PEF. The patient attempts three PEF measurements, and all 3 values are recorded on the electronic PEF meter. The highest value is typically used for the assessment. The baseline AM PEF may be calculated as the average of the AM measurements recorded during the 7 days prior to the administration of the first dose of the IL-4R antagonist-containing pharmaceutical composition, and the baseline PM PEF may be calculated as the average of the PM measurements recorded during the 7 days prior to the administration of the first dose of the IL-4R antagonist-containing pharmaceutical composition.

[00300] Therapeutic methods are provided that result in an increase in am PEF and/or pm PEF from baseline by at least 1.0 L/min at week 12 after initiation of treatment with a pharmaceutical composition comprising an IL-4R antagonist. For example, in exemplary embodiments, administration of an IL-4R antagonist to a subject in need thereof causes an increase in PEF from baseline of approximately 0.5 L/min, 1.0 L/min, 1.5 L/min, 2.0 L/min, 2.5 L/min, 3.0 L/min, 3.5 L/min, 4.0 L/min, 4.5 l/min., 5.0 l/min., 5.5 l/min., 6.0 l/min., 6.5 l/min., 7.0 l/min., 7.5 l/min., 8.0 l/min., 8.5 l/min., 9.0 l/min., 9.5 l/min., 10.0 l/min., 10.5 l/min., 11.0 l/min., 12.0 L/min, 15 L/min, 20 L/min or more at week 12.

[00301] Albuterol/levalbuterol administration . In certain embodiments, administration of an IL-4R antagonist to a patient results in a reduction from a baseline in the daily use of albuterol or levalbuterol. The number of albuterol/levalbuterol inhalations may be recorded by patients daily in a diary, PEF meter, or other recording device. During treatment with the pharmaceutical composition described herein, albuterol/levalbuterol administration may generally be on an as-needed basis depending on symptoms, rather than on a continuous or prophylactic basis. The baseline number of albuterol/levalbuterol inhalations per day may be calculated based on an average over the 7 days prior to administration of the first dose of the pharmaceutical composition comprising the IL-4R antagonist.

[00302] Therapeutic methods are provided that result in a reduction in albuterol/levalbuterol use from baseline by at least 0.25 puffs per day at week 12 after initiation of treatment with a pharmaceutical composition comprising an IL-4R antagonist. For example, administration of an IL-4R antagonist to a subject in need thereof causes a decrease in albuterol/levalbuterol use from baseline of approximately 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 Week 12.

[00303] Use of an OCS. In certain embodiments, administration of an IL-4R antagonist to a patient may be used in combination with an OCS, such as oral prednisone. The number of OCS administrations may be recorded daily by patients in a diary, PEF meter, or other recording device. During treatment with the pharmaceutical composition described herein, intermittent short-term administration of prednisone may typically be used to control acute asthma episodes, such as episodes in which bronchodilators and other anti-inflammatory agents fail to control symptoms. In other aspects, prednisone is used concurrently with another ICS or as a replacement for another ICS. Oral prednisone may be administered at doses of about 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, or 40 mg. OCS may optionally be administered once daily or several times a day (e.g. twice daily, three times daily, four times daily, etc.)

[00304] In certain exemplary embodiments, methods are provided for reducing or eliminating a subject's dependence on the use of OCS. Reducing or eliminating steroid dependence is highly advantageous and desirable. In certain embodiments, a 50% or greater (e.g., 50%, 60%, 70%, 80%, 90%, or greater) reduction in the OCS dose is achieved after administration of the anti-IL-4R antibody therapy for a certain period of time (e.g., at week 24. In certain embodiments, OCS is substantially eliminated at 40 weeks, 45 weeks, 50 weeks, 52 weeks, or more after the first dose following administration of a loading dose. In other embodiments, the level of OCS use 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, dependence on OCS use is substantially eliminated at 3 months, 6 months, 9 months, or 1 year after treatment with the anti-IL4R antibody or fragment thereof.

[00305] Asthma Control Questionnaire 5-Item (ACQ) Score . In certain embodiments, administration of an IL-4R antagonist to a patient results in a reduction from baseline in an Asthma Control Questionnaire 5-Item (ACQ5) score. The ACQ5 is a validated questionnaire for assessing asthma control.

[00306] Therapeutic methods 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 IL-4R antagonist. For example, administration of an IL-4R antagonist to a subject in need thereof causes 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.

[00307] Nighttime awakenings . In certain embodiments, administration of an IL-4R antagonist to a patient results in a decrease from baseline in the average number of nighttime awakenings.

[00308] In certain embodiments, the methods provide a reduction in the mean number of nighttime awakenings from baseline by at least about 0.10 times per night at week 12 after initiation of treatment. For example, administration of an IL-4R antagonist to a subject in need thereof may cause a reduction in the mean number of nighttime awakenings from baseline of approximately 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 at Week 12.

[00309] 22-Item Nasal and Sinus Outcome Test (SNOT-22) score . In certain embodiments, administering an IL-4R antagonist to a patient results in a decrease from baseline in the 22-Item Nasal and Sinus Outcome Test (SNOT-22) score. The SNOT-22 is a validated questionnaire for determining the impact of chronic rhinosinusitis on quality of life (Hopkins et al. 2009, Clin. Otolaryngol. 34: 447-454).

[00310] Therapeutic methods are provided that result in a decrease in SNOT-22 score from baseline by at least 1 point at week 12 after initiation of treatment with a pharmaceutical composition comprising an IL-4R antagonist. For example, administration of an IL-4R antagonist to a subject in need thereof may result in a decrease in SNOT-22 score from baseline by about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13 points or more at week 12.

[00311] Biomarkers . In certain embodiments, the subject exhibits an improvement in lung function as measured by a biomarker, such as 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 fractional exhaled nitric oxide (FeNO), eotaxin-3, total IgE, allergen-specific IgE (e.g., Af-associated IgE), periostin, eosinophil (Eos), or thymus-regulated activation chemokine (TARC). In certain embodiments, an improvement in lung function is indicated by a decrease or increase (as appropriate) at week 4, week 12, or week 24 after treatment.

Treatment options for asthma and/or ABPA

[00312] In some embodiments, methods are provided for treating asthma, including, for example, allergic asthma, ABPA-associated asthma, moderate to severe uncontrolled asthma, or poorly controlled asthma, and allergic forms of any of the foregoing asthma in a subject in need thereof, wherein the methods comprise administering to the subject a pharmaceutical composition comprising an IL-4R antagonist. In particular embodiments, the methods are useful for treating allergic asthma, such as moderate to severe uncontrolled allergic asthma, in a subject. In other particular embodiments, the methods are useful for treating ABPA-associated asthma in a subject.

[00313] In some embodiments, methods are provided for treating ABPA in a subject in need thereof, wherein the methods comprise administering to the subject a pharmaceutical composition comprising an IL-4R antagonist. In particular embodiments, the methods are useful for treating ABPA in a subject with comorbid asthma, such as moderate to severe uncontrolled asthma.

[00314] As used herein, the term "asthma" may be used interchangeably with "recurrent asthma" or "bronchial asthma.""Asthma,""bronchialasthma," and "recurrent asthma," and allergic forms of each of the foregoing asthma, refer to asthma in which one or any combination of the following is true: symptoms occur on or less than 2 days per week; symptoms do not interfere with daily activities; night-time symptoms occur less than 2 days per month; or one or more pulmonary function test results (e.g., forced expiratory volume in one second ( _FEV1 ) and/or peak expiratory flow (PEF) greater than 80%) are within normal limits when the subject is not experiencing an asthma attack.

[00315] As used herein, the term "allergic bronchopulmonary aspergillosis" or "ABPA" refers to a hypersensitivity reaction to an Aspergillus antigen, typically Aspergillus fumigatus , in the lungs of a subject that can damage the airways and lead to irreversible lung damage. ABPA can be diagnosed based on any combination of the following: a patient's medical history (including the presence of asthma and/or cystic fibrosis), radiography and/or CT scanning, skin testing, and blood IgE levels (e.g., total IgE and/or Aspergillus -specific IgE, such as Af-specific IgE). In certain embodiments, ABPA is diagnosed using a combination of one or more of the following: (1) serum total IgE levels; (2) eosinophilia; (3) Aspergillus -specific IgE, such as Af-specific IgE in serum; and (4) Aspergillus -specific IgE, such as Af-specific IgG in serum. In certain exemplary embodiments, a subject is diagnosed with ABPA if the subject has 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) a baseline serum Af-specific IgE level greater than 0.35 kU/L; and (3) a baseline blood eosinophil level greater than 500 cells/μL.

[00316] In certain embodiments, ABPA is diagnosed in a subject having an HLA-DR2 serotype (e.g., an HLA-DRB1*1501 subtype, an *HLA-DRB1*1503 subtype, or an *HLA-DRB1*1601 subtype) or an HLA-DR5 serotype (e.g., an HLA-DRB1*1101 subtype, an HLA-DRB1*1104 subtype, or an HLA-DRB1*1202 subtype).

[00317] As used herein, the term "ABPA-associated asthma" refers to a subject who has concomitant asthma and ABPA.

[00318] "IgE" refers to an antibody isotype that contains the ε heavy chain and is a monomer having five domains in the immunoglobulin structure. IgE is normally present in plasma at a concentration of less than 1 μg/mL and has a half-life in serum of approximately 2 days (Abbas and Lichtman (2004) Basic Immunology functions and disorders of the immune system. 2nd ed. Philadelphia: Saunders). The units kU/L or IU/mL (these units can be used interchangeably) are often used to express the level of IgE in peripheral blood, with one kU/L equal to 2.4 ng/mL (Seagroatt and Anderson (1981) EJ Biol Stand. 9:431).

[00319] 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 assay) can be used, in which serum samples are reacted with IgE labeled with radioactive iodine. The bound radioactive iodine is detected and is proportional to the amount of total IgE in the serum sample. In clinical immunology, levels of individual immunoglobulin classes can be measured using nephelometry (or turbidimetry) to characterize a subject's antibody profile. Other methods for measuring IgE levels include, but are not limited to, ELISA, immunofluorescence, Western blotting, immunodiffusion, immunoelectrophoresis, etc. Measurement of IgE concentration in serum can be accomplished 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.)

[00320] Allergic asthma refers to asthma that is 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 in combination with one or more allergic markers, such as total serum IgE (e.g., total serum IgE ≥30 IU/mL, total serum IgE ≥700 IU/mL, or total serum IgE ≥1000 IU/mL) and/or at least one positive allergen-specific IgE value (e.g., allergen-specific IgE value ≥0.35 kU/L). In certain embodiments, the allergen is an airborne aeroallergen (e.g., an annual aeroallergen or year-round aeroallergen)

[00321] In certain exemplary embodiments, a subject with allergic asthma is characterized by a total serum IgE level of 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, approximately ≥160 IU/mL, approximately ≥170 IU/mL, approximately ≥180 IU/mL, approximately ≥190 IU/mL, approximately ≥200 IU/mL, approximately ≥250 IU/mL, approximately ≥300 IU/mL, approximately ≥350 IU/mL, approximately ≥400 IU/mL, approximately ≥450 IU/mL, approximately ≥500 IU/mL, approximately ≥550 IU/mL, approximately ≥600 IU/mL, approximately ≥650 IU/mL, approximately ≥700 IU/mL, approximately ≥750 IU/mL, approximately ≥800 IU/mL, about ≥850 IU/mL, about ≥900 IU/mL, about ≥950 IU/mL, about ≥1000 IU/mL, or greater In specific exemplary embodiments, the subject with allergic asthma has a total serum IgE level of greater than about 700 IU/mL (e.g., has high total serum IgE). In other specific exemplary embodiments, the subject with allergic asthma has a total serum IgE level of greater than about 1000 IU/mL (e.g., has very high total serum IgE). In certain exemplary embodiments, the subject has a total serum IgE level of at least 700 IU/mL, as measured by an ImmunoCAP assay. In certain exemplary embodiments, the subject has a total serum IgE level of at least 1000 IU/mL as measured by an ImmunoCAP assay.

[00322] In certain exemplary embodiments, a subject with allergic asthma is characterized by at least one positive allergen-specific IgE value in an amount of 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, approximately ≥0.31 kU/L, approximately ≥0.32 kU/L, approximately ≥0.33 kU/L, approximately ≥0.34 kU/L, approximately ≥0.35 kU/L, approximately ≥0.36 kU/L, approximately ≥0.37 kU/L, approximately ≥0.38 kU/L, approximately ≥0.39 kU/L, approximately ≥0.40 kU/L, approximately ≥0.45 kU/L, approximately ≥0.50 kU/L, approximately ≥0.55 kU/L, approximately ≥0.60 kU/L, approximately ≥0.65 kU/L, approximately ≥0.70 kU/L or more.

[00323] As used herein, the term "perennial aeroallergen" refers to airborne allergens that may be present in the environment 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 , cat dander, dog dander, cow dander, chicken feathers, goose feathers, duck feathers, cockroach (e.g., German cockroach, black cockroach), mouse urine, peanut dust, tree nut dust, etc.

[00324] As used herein, the term "seasonal aeroallergen" refers to airborne allergens that are present in the environment seasonally, such as pollen and spores. Seasonal aeroallergens 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, cattail, etc.), weed pollen (e.g., ragweed, plantain, nettle, mugwort, white goosefoot, sorrel, etc.), fungal spores that increase in number during certain seasons, at certain temperatures, etc. (e.g., mold fungi), etc.

[00325] As used herein, the term "persistent asthma" or "persistent asthma" refers to asthma that is more severe than asthma/recurrent asthma. A subject with persistent asthma or persistent asthma has one or more of the following: symptoms more than 2 days per week; symptoms that do not interfere with daily activities; night-time symptoms that occur more than 2 days per month; or one or more pulmonary function tests (e.g., forced expiratory volume in one second (FEV ₁ ) and/or peak expiratory flow (PEF) less than 80%) that are abnormal when the subject is not experiencing asthma attacks; the subject is dependent on daily use of a medication to control asthma; the subject has taken a systemic steroid more than once in the past year after a severe asthma attack or used a short-acting beta-2 agonist more than two days per week to relieve asthma symptoms.

[00326] Asthma/recurrent asthma, bronchial asthma/recurrent asthma, and persistent asthma/persistent asthma and allergic forms of each of the above asthmas may be classified as "mild,""moderate,""severe," or "moderate to severe.""Mild recurrent asthma" or "mild recurrent asthma" is defined as the presence of symptoms less than once a week and a forced expiratory volume in one second (FEV ₁ ) or peak expiratory flow (PEF) ≥ 80%. "Mild persistent asthma" or "mild persistent asthma" is defined by the frequency of symptoms being more than once per week but less than once per day and the variability of FEV ₁ or PEF being < 20% to 30%. "Moderate recurrent asthma" or "moderate recurrent asthma" is defined by the presence of symptoms less than once per week and a forced expiratory volume in one second (FEV ₁ ) or peak expiratory flow (PEF) of 60% to 80%. "Moderate persistent asthma" or "moderate persistent asthma" or their allergic forms is defined by the occurrence of daily symptoms, exacerbations that may affect activity and/or sleep, nocturnal symptoms more than once a week, daily use of an inhaled short-acting beta-2 agonist, and a forced expiratory volume in one second (FEV ₁ ) or peak expiratory flow (PEF) of 60-80%. "Severe recurrent asthma" or "severe recurrent asthma" or their allergic forms is defined by the occurrence of symptoms less than once a week and a forced expiratory volume in one second (FEV ₁ ) or peak expiratory flow (PEF) of 60%. "Severe persistent asthma" or "severe persistent asthma" is defined by the presence of daily symptoms, frequent exacerbations that may interfere with activity and/or sleep, frequent night-time symptoms, limitation of physical activity, daily use of an inhaled short-acting beta-2 agonist, and a forced expiratory volume in one second (FEV ₁ ) or peak expiratory flow (PEF) of 60%. "Moderate to severe recurrent asthma" or "moderate to severe recurrent asthma" or their allergic forms are defined by the presence of symptoms between those of moderate recurrent asthma/moderate recurrent asthma and severe recurrent asthma/severe recurrent asthma. "Moderate to severe persistent asthma" or "moderate to severe persistent asthma" or their allergic forms are defined by the presence of symptoms between those of moderate persistent asthma/moderate persistent asthma and severe persistent asthma/severe persistent asthma.

[00327] As used herein, the term "poorly controlled asthma" or allergic asthma refers to patients whose asthma is either "not adequately controlled" or "very poorly controlled" as defined in "Expert Panel Report 3: Guidelines for the Diagnosis and Management of Asthma," National Heart, Blood and Lung Institute, NIH, Aug. 28, 2007. "Uncontrolled asthma" or its allergic form is defined by the presence of symptoms more than two days per week, awakenings at night one to three times per week, some limitations in daily activities, use of a short-acting beta ₂ -agonist to control symptoms more than twice per week, FEV ₁ of 60-80% of predicted and/or personal best, ATAQ score of 1-2, ACQ score of 1.5 or greater, and ACT score of 16-19. "Very poorly controlled asthma" or allergic asthma is defined by the presence of symptoms during the day, awakenings at night four or more times per week, significant limitations in daily activities, use of a short-acting beta ₂ -agonist to control symptoms several times per day, FEV ₁ less than 60% of predicted and/or personal best, an ATAQ score of 3-4, no ACQ data, and an ACT score of 15 or less.

[00328] In some embodiments, a subject is defined as having "uncontrolled moderate to severe asthma" (e.g., allergic asthma, ABPA-associated asthma, moderate to severe asthma, persistent asthma, etc.) if the subject receives such a diagnosis from a physician based on the 2009 Global Initiative for Asthma (GINA) guidelines and one or more of the following criteria: i) current treatment with moderate or high doses of an ICS/LABA (2 administrations of 250 mcg fluticasone propionate twice daily or an equipotent daily dose of ICS) with a stable dose of ICS/LABA for a period of 1 month or greater prior to administration of a loading dose of an IL-4R antagonist; ii) an _FEV1 that is 40-80% of predicted normal before the IL-4R antagonist loading dose; iii) an ACQ-5 score of 1.5 or greater before the IL-4R antagonist loading dose; iv) at least 12% reversibility and 200 mL of _FEV1 after 200-400 mcg (2-4 puffs) of salbutamol/albuterol before the IL-4R antagonist loading dose; or v) any of the following events within 1 year before the IL-4R antagonist loading dose: (a) treatment with 1 or more systemic pulse steroids (oral or parenteral) due to asthma exacerbation, or (b) hospitalization or emergency department/urgent care visit due to asthma exacerbation.

[00329] The term "severe asthma" or "severe allergic asthma" refers to asthma in which adequate control cannot be achieved with treatment with high-dose inhaled corticosteroids and additional controller medications (e.g., inhaled long-acting beta 2-agonists, montelukast and/or theophylline) or with oral corticosteroid therapy (e.g., for at least six months per year), or is lost when treatment is tapered. In certain embodiments, severe asthma includes asthma treated with high-dose ICS and at least one additional controller medication (e.g., LABA, montelukast, or theophylline) or oral corticosteroids > 6 months/year, wherein at least one of the following occurs or is likely to occur if treatment is tapered: ACT < 20 or ACQ >1.5; at least 2 exacerbations in the past 12 months; at least 1 exacerbation treated in hospital or requiring mechanical ventilation in the past 12 months; or _FEV1 <80% (if _FEV1 /FVC is below the lower limit of normal).

[00330] The term "steroid-responsive asthma""steroid-responsive allergic asthma" refers to asthma that requires one or more of the following treatments: treatment with frequent courses of short-term pulsed oral corticosteroids within the past 12 months; regular use of high-dose inhaled corticosteroids within the past 12 months; regular use of long-acting injectable corticosteroids; daily use of oral corticosteroids; use of alternate-day oral corticosteroids; or long-term use of oral corticosteroids within the past year.

[00331] The term "oral corticosteroid-dependent asthma""oral corticosteroid-dependent allergic asthma" refers to a subject with a history of ≥ 3 30-day courses of oral corticosteroid (OCS) within a 12-month period and a primary diagnosis of asthma within 12 months of the first course of OCS. Subjects with OCS-dependent asthma may also have one or any combination of the following: have received a physician-prescribed LABA and a high dose of ICS (total daily dose > 500 mcg fluticasone propionate dry powder equivalent) for at least 3 months (ICS and LABA may be part of a combination product or provided in separate inhalers); received additional maintenance asthma controller medications according to standard of care, such as leukotriene receptor antagonists (LTRAs), theophylline, long-acting muscarinic antagonists (LAMAs), secondary ICS, and cromones; received OCS for asthma at a dose of ≥ 7.5 to ≤ 30 mg (prednisone or prednisolone equivalent); received an alternate-day dose of OCS (or different doses every other day); _FEV1 in the morning before bronchodilator (BD) administration was < 80% of predicted normal; the presence of asthma evidenced by reversibility of _FEV1 ≥ 12% and ≥ 200 mL after BD (albuterol/salbutamol) (15-30 min after 4 puffs of albuterol/salbutamol); or they have a history of at least one asthma exacerbation within 12 months.

[00332] In one aspect, methods of treating asthma are provided, comprising: (a) selecting a patient that has a blood eosinophil count of at least 300 cells per microliter; and (b) administering to the patient a pharmaceutical composition comprising an IL-4R antagonist.

[00333] In another aspect, methods of treating asthma are provided, comprising: (a) selecting a patient who has a blood eosinophil count of 200-299 cells per microliter; and (b) administering to the patient a pharmaceutical composition comprising an IL-4R antagonist.

[00334] In another aspect, methods of treating asthma are provided, comprising: (a) selecting a patient that has a blood eosinophil count of less than 200 cells per microliter; and (b) administering to the patient a pharmaceutical composition comprising an IL-4R antagonist.

[00335] In one aspect, methods of treating asthma are provided, comprising: (a) selecting a patient that has a blood eosinophil count of at least 150 cells per microliter; and (b) administering to the patient a pharmaceutical composition comprising an IL-4R antagonist.

[00336] In one aspect, methods of treating asthma are provided, comprising: (a) selecting a patient that has a blood eosinophil count of at least 300 cells per microliter; and (b) administering to the patient a pharmaceutical composition comprising an IL-4R antagonist.

[00337] In one aspect, methods of treating asthma are provided, comprising: (a) selecting a patient that has a baseline FeNO level of ≥20 ppb; and (b) administering to the patient a pharmaceutical composition comprising an IL-4R antagonist.

[00338] In one aspect, methods of treating asthma are provided, comprising: (a) selecting a patient that has a baseline FeNO level of ≥25 ppb; and (b) administering to the patient a pharmaceutical composition comprising an IL-4R antagonist.

[00339] In one aspect, methods of treating asthma are provided, comprising: (a) selecting a patient that has a baseline FeNO level of ≥50 ppb; and (b) administering to the patient a pharmaceutical composition comprising an IL-4R antagonist.

[00340] In one aspect, methods of treating asthma are provided, comprising: (a) selecting a patient that has a baseline total IgE level of ≥30 IU/mL; and (b) administering to the patient a pharmaceutical composition comprising an IL-4R antagonist.

[00341] In one aspect, methods of treating asthma are provided, comprising: (a) selecting a patient that has a baseline total IgE level of ≥700 IU/mL; and (b) administering to the patient a pharmaceutical composition comprising an IL-4R antagonist.

[00342] In one aspect, methods of treating asthma are provided, comprising: (a) selecting a patient that has a baseline total IgE level of ≥1000 IU/mL; and (b) administering to the patient a pharmaceutical composition comprising an IL-4R antagonist.

[00343] In one aspect, methods of treating asthma are provided, comprising: (a) selecting a patient that has a baseline allergen-specific IgE level of ≥0.15 kU/L; and (b) administering to the patient a pharmaceutical composition comprising an IL-4R antagonist.

[00344] In one aspect, methods of treating asthma are provided, comprising: (a) selecting a patient that has a baseline allergen-specific IgE level of ≥0.35 kU/L; and (b) administering to the patient a pharmaceutical composition comprising an IL-4R antagonist.

[00345] In a related aspect, methods of treating asthma are provided that comprise an add-on therapy to background therapy. In certain embodiments, an IL-4R antagonist is administered as an add-on therapy to a patient with asthma who has been receiving background therapy for a certain period of time (e.g., 1 week, 2 weeks, 3 weeks, 1 month, 2 months, 5 months, 12 months, 18 months, 24 months, or longer) (also referred to as a "stable phase"). In some embodiments, the background therapy comprises an ICS and/or a LABA.

[00346] In some embodiments, a method is provided for reducing a patient with asthma's dependence on an ICS and/or a LABA intended for treating one or more asthma exacerbations, comprising: (a) selecting a patient with moderate to severe asthma that is not controlled by 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.

[00347] In some embodiments, methods are provided for treating or ameliorating conditions or complications associated with asthma or accompanying asthma, such as chronic rhinosinusitis, allergic rhinitis, allergic fungal rhinosinusitis, chronic sinusitis, allergic bronchopulmonary aspergillosis (ABPA), combined 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.

[00348] Also provided are methods for treating persistent asthma (e.g., persistent allergic asthma). As used herein, the term "persistent asthma" means that the subject experiences symptoms at least once a week during the day and/or night, with symptoms lasting from several hours to several days. In certain alternative embodiments, persistent asthma is "mildly persistent" (e.g., more than twice a week but less than once a day with symptoms that are severe enough to interfere with daily activities or sleep, and/or if respiratory function is normal or reversible with inhalation of a bronchodilator), "moderately persistent" (e.g., symptoms occur daily, with sleep interrupted at least once a week, and/or if respiratory function is moderately impaired), or "severely persistent" (e.g., continuous symptoms despite correct use of approved medications, and/or if respiratory function is severely impaired).

Interleukin-4 receptor antagonists

[00349] The methods provided herein comprise administering to a subject in need thereof a therapeutic composition comprising an IL-4R antagonist. As used herein, the term "IL-4R antagonist" means any agent that binds or interacts with human IL-4R and inhibits the normal biological signaling function of IL-4R when IL-4R is expressed on a cell in vitro or in vivo . Non-limiting examples of categories of IL-4R antagonists include small molecule IL-4R antagonists, aptamers to IL-4R, peptide antagonists of IL-4R (e.g., "peptide-associated antibody" molecules), and antibodies or antigen-binding fragments of antibodies that specifically bind human IL-4R. In certain embodiments, an IL-4R antagonist provides an antibody to IL-4R 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 the heavy chain and light chain CDR (complementarity determining region) sequences of the heavy chain variable region (HCVR) and the light chain variable region (LCVR) of SEQ ID NO: 1 and 2, respectively.

[00350] The term "human IL4R" (hIL-4R) refers to a human cytokine receptor that specifically binds to interleukin-4 (IL-4), such as IL-4Rα.

[00351]The term "antibody" refers to immunoglobulin molecules containing four polypeptide chains, two heavy (H) chains and two light (L) chains, linked together by disulfide bonds, as well as their multimers (e.g., IgM). Each heavy chain contains a heavy chain variable region (abbreviated herein as HCVR or V_H) and the constant region of the heavy chain. The constant region of the heavy chain contains three domains: C_H1, C_H2 and C_H3. Each light chain contains a light chain variable region (abbreviated herein as LCVR or V_L) and the constant region of the light chain. The constant region of the light chain contains one domain (C_L1). Plots V_Hand V_Lcan be further subdivided into regions of hypervariability, called complementarity determining regions (CDRs), interspersed with more conserved regions, called framework regions (FRs). Each V_Hand V_Lconsists of three CDRs and four FRs arranged from amino terminus to carboxyl terminus in the following order: FR1, CDR1, FR2, CDR2, FR3, CDR3, FR4. In various embodiments, the FRs of the anti-IL-4R antibody (or antigen-binding portion thereof) may be identical to human germline immunoglobulin sequences or may be naturally or artificially modified. The amino acid consensus sequence may be determined based on a side-by-side analysis of two or more CDRs.

[00352]The term "antibody" also includes antigen-binding fragments of whole antibody molecules. The terms "antigen-binding portion" of an antibody, "antigen-binding fragment" of an antibody, etc., as used herein include any naturally occurring, enzymatically produced, synthetic, or genetically engineered polypeptide or glycoprotein that specifically binds to an antigen to form a complex. Antigen-binding fragments of an antibody can be produced, for example, from whole antibody molecules by any suitable standard techniques, such as proteolytic cleavage or recombinant genetic engineering techniques involving manipulation and expression of DNA encoding the variable and optionally constant domains of the antibody. Such DNA is known and/or readily available, such as from commercial sources, DNA libraries (including, for example, phage-antibody libraries), or may be synthesized. The DNA may be sequenced and manipulated chemically or by molecular biology techniques, such as to arrange one or more variable and/or constant domains in a suitable configuration or to introduce codons, create cysteine residues, modify, add or delete amino acids, etc.

[00353]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 molecules (scFv); (vi) dAb fragments, and (vii) minimal recognition units consisting of amino acid residues that mimic a hypervariable region of an antibody (e.g., an isolated complementarity determining region (CDR) such as a CDR3 peptide) or a FR3-CDR3-FR4 peptide. Other engineered molecules, such as domain-specific antibodies, single-domain antibodies, domain-deleted antibodies, chimeric antibodies, CDR-grafted antibodies, diabodies, triabodies, tetrabodies, minibodies, nanobodies (e.g., monovalent antibodies, bivalent antibodies, etc.), small sized modular protein (SMIP)-based immunopharmaceuticals and shark IgNAR variable domains are also included in the expression "antigen-binding fragment".

[00354] An antigen-binding fragment of an antibody will typically comprise at least one variable domain. The variable domain may be of any size or amino acid composition, and will typically comprise at least one CDR that is adjacent to or in frame with one or more framework sequences. In antigen-binding fragments having a V _H domain linked to a V _L domain, the V _H and V _L domains may be arranged relative to one another in any suitable order. For example, the variable region may be dimeric and comprise V _H -V _H , V _H -V _L , or V _L -V _L dimers. Alternatively, the antigen-binding fragment of an antibody may comprise a monomeric V _H or V _L domain.

[00355] In certain embodiments, an antigen-binding fragment of an antibody may comprise at least one variable domain covalently linked to at least one constant domain. Non-limiting exemplary configurations of variable and constant domains that may be found in an antigen-binding fragment of an antibody described herein include: (i) V _H -C _H 1; (ii) V _H -C _H 2; (iii) V _H -C _H 3; (iv) V _H -C _H 1-C _H 2; (v) V _H -C _H 1-C _H 2-C _H 3; (vi) V _H -C _H 2-C _H 3; (vii) V _H -C _L ; (viii) V _L -C _H 1; (ix) V _L -C _H 2; (x) V _L -C _H 3; (xi) V _L -C _H 1-C _H 2; (xii) V _{L -CH1} - _CH2 - _CH3 ; (xiii) V _{L -CH2} - _CH3 ; and (xiv) V _{L -CH} . In any configuration of the variable and constant domains, including any of the exemplary configurations listed above, the variable and constant domains may be either directly linked to each other or may be linked via all or part of a hinge or linker region. The hinge region may be at least 2 (e.g., 5, 10, 15, 20, 40, 60, or more) amino acids that result in a flexible or semi-flexible linkage between adjacent variable and/or constant domains in a single polypeptide molecule, typically a hinge region may be 2-60 amino acids, typically 5-50, or typically 10-40 amino acids. In addition, an antigen-binding fragment of an antibody described herein may comprise a homodimer or heterodimer (or other multimer) of any of the variable and constant domain configurations described above in non-covalent association with each other and/or with one or more monomeric V _H or V _L domains (e.g., via disulfide bond(s)).

[00356]As with whole antibody molecules, antigen-binding fragments can be monospecific or multispecific (e.g., bispecific). A multispecific antigen-binding antibody fragment will typically comprise at least two different variable domains, where each variable domain is capable of specifically binding to a separate antigen or to a different epitope of the same antigen. Any multispecific antibody format can be adapted for use in the context of the antigen-binding antibody fragment described herein using standard techniques available in the art.

[00357] The constant region of an antibody is important in terms of the ability of the antibody to bind complement and mediate cell-dependent cytotoxicity. Thus, the isotype of an antibody can be selected based on whether the antibody is required to mediate cytotoxicity.

[00358] The term "human antibody" includes antibodies having variable and constant regions derived from human germline immunoglobulin sequences. The human antibodies described herein may include amino acid residues not encoded by human germline immunoglobulin sequences (e.g., mutations introduced by random or site-directed mutagenesis in vitro or somatic mutation in vivo ), such as in the CDRs, and in particular 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.

[00359] The term "recombinant human antibody" includes all human antibodies produced, expressed, created, or isolated by recombinant techniques, such as antibodies expressed by a recombinant expression vector transfected into a host cell (described further below), antibodies isolated from a combinatorial library of recombinant human antibodies (described further below), antibodies isolated from an animal (e.g., a mouse) that is 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 that involves splicing of human immunoglobulin gene sequences with 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, in the case of an animal transgenic for human Ig sequences, in vivo somatic mutagenesis) and, thus, the amino acid sequences of the V _H and V _L regions of the recombinant antibodies are sequences that, while derived from and related to human germline V _H and V _L sequences, may not naturally occur in the human germline antibody repertoire in vivo .

[00360] Human antibodies can occur in two forms, due to the heterogeneity of the hinge regions. In one form, the immunoglobulin molecule comprises a stable four-chain structure of approximately 150-160 kDa, in which the dimers are held together by an interchain disulfide bond that links the heavy chains. In the second form, the dimers are not linked by interchain disulfide bonds, and a molecule of approximately 75-80 kDa is formed, consisting of covalently linked light and heavy chains (a half-antibody). These forms are extremely difficult to separate, even after affinity purification.

[00361] The frequency of occurrence of the second form in different intact IgG isotypes is due, without limitation, to structural differences associated with the isotype of the hinge region of the antibody. A single amino acid substitution in the hinge region of human IgG4 hinge can significantly reduce the occurrence of the second form (Angal et al. (1993) Molecular Immunology 30:105) to levels normally observed with the human IgG1 hinge. Antibodies with one or more mutations in the hinge, C _H 2 or C _H 3 region are provided, which may be advantageous, for example, under production conditions, to increase the yield of the preferred form of the antibody.

[00362] The term "isolated antibody" means 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 from a tissue or cell in which the antibody is originally present or naturally produced, is an "isolated antibody." An isolated antibody also includes an antibody in situ in a recombinant cell. Isolated antibodies are antibodies that have undergone at least one purification or isolation step. In certain embodiments, an isolated antibody may be substantially free of other cellular material and/or other chemical compounds.

[00363] The term "specifically binds," etc., means that the antibody or antigen-binding fragment thereof forms a complex with the antigen that is relatively stable under physiological conditions. Methods for determining the presence of specific binding of an antibody 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 includes antibodies that bind IL-4R or a portion thereof with a K _D of 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 by surface plasmon resonance analysis. However, an isolated antibody that specifically binds to human IL-4R is characterized by cross-reactivity with other antigens, such as IL-4R molecules from other (non-human) species.

[00364] Anti-IL-4R antibodies useful for the methods can comprise 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 regions 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 identified by comparing the amino acid sequences disclosed herein to germline sequences available, for example, from public antibody sequence databases. Methods are provided comprising the use of antibodies and antigen-binding fragments thereof that are derived from any of the amino acid sequences disclosed herein, wherein one or more amino acids (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acids) in one or more framework regions and/or one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 with respect to a tetrameric antibody or 1, 2, 3, 4, 5, or 6 with respect to the HCVR and LCVR of an antibody) CDR regions are mutated to the corresponding residue(s) of the germline sequence from which the antibody is derived, or to the corresponding residue(s) of another human germline sequence, or to a conservative amino acid substitution corresponding germline residue(s) (such sequence changes are referred to herein collectively as "germline mutations"). One of skill in the art, starting from the heavy and light chain variable region sequences disclosed herein, can readily generate a variety of antibodies and antigen-binding fragments that comprise one or more individual germline mutations, or combinations thereof. In certain embodiments, all framework and/or CDR residues in the V _H and/or V _L domains are backmutated to residues found in the original germline sequence from which the antibody was derived. In other embodiments, only certain residues are backmutated to the original germline sequence, such as only mutated residues found in the first 8 amino acids of FR1 or the last 8 amino acids of FR4, or only mutated residues found in CDR1, CDR2, or CDR3. In other embodiments, one or more framework and/or CDR residues are mutated to the corresponding residue(s) of a different germline sequence (i.e., a germline sequence that is different from the germline sequence from which the antibody was originally derived). Additionally, antibodies can comprise any combination of two or more germline mutations in framework and/or CDR regions, such as where certain individual residues are mutated to the corresponding residue of a certain germline sequence, while certain other residues that are different from the original germline sequence are retained or mutated to the corresponding residue of a different germline sequence. Once obtained, antibodies and antigen-binding fragments that contain one or more germline mutations can be readily assayed for one or more preferred properties, such as improved binding specificity, increased binding affinity, improved or enhanced biological antagonist or agonist properties (as appropriate), reduced immunogenicity, etc. The use of antibodies and antigen-binding fragments obtained by this general method is encompassed by the present invention.

[00365]The methods include using IL-4R antibodies comprising variants of any of the HCVR, LCVR and/or CDR amino acid sequences disclosed herein with one or more conservative substitutions. For example, using IL-4R antibodies with HCVR, LCVR and/or CDR amino acid sequences is provided, such as, with 10 or less, 8 or less, 6 or less, 4 or less, etc., conservative amino acid substitutions relative to any of the HCVR, LCVR and/or CDR amino acid sequences disclosed herein.

[00366] The term "surface plasmon resonance" refers to an optical phenomenon that enables real-time analysis of interactions by detecting changes in protein concentrations in a biosensor array, such as those provided by the BIAcore™ system (Biacore Life Sciences Division of GE Healthcare, Piscataway, NJ).

[00367] The term "K _D " refers to the equilibrium dissociation constant of the interaction of a particular antibody and antigen.

[00368] 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 a paratope. A single antigen may have more than one epitope. Thus, different antibodies may bind to different regions on the antigen and may exert different biological effects. Epitopes may be conformational or linear. A conformational epitope is formed by spatially juxtaposed amino acids from different segments of a linear polypeptide chain. A linear epitope is formed by contiguous amino acid residues in a polypeptide chain. Under certain conditions, an epitope may include fragments of saccharides, phosphoryl groups, or sulfonyl groups of the antigen.

Obtaining human antibodies

[00369] Methods for producing human antibodies in transgenic mice are known in the art. Any such known methods can be used to create human antibodies that specifically bind to human IL-4R.

[00370] Using VELOCIMMUNE® technology (see, for example, US 6,596,541, Regeneron Pharmaceuticals) or any other known method for producing monoclonal antibodies, high-affinity chimeric antibodies to IL-4R with a human variable region and a mouse constant region are initially isolated. VELOCIMMUNE® technology involves generating a transgenic mouse with a genome comprising human heavy and light chain variable regions operably linked to endogenous mouse constant region loci such that the mouse produces an antibody comprising a human variable region and a mouse constant region in response to antigen stimulation. DNA encoding the heavy and light chain variable regions of the antibody 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.

[00371] Typically, a VELOCIMMUNE® mouse is exposed to an antigen of interest, and lymphatic cells (such as B cells) are recovered from mice that express the antibodies. The lymphatic cells can be fused with a myeloma cell line to produce immortalized hybridoma cell lines, and such hybridoma cell lines are screened and selected to identify hybridoma cell lines that produce antibodies specific for the antigen of interest. DNA encoding the variable regions of the heavy chain and light chain can be isolated and linked to the constant regions of the desired heavy chain and light chain isotypes. Such an antibody protein can be produced in a cell, such as a CHO cell. Alternatively, DNA encoding antigen-specific chimeric antibodies or the variable domains of the light and heavy chains can be isolated directly from antigen-specific lymphocytes.

[00372] Initially, high-affinity chimeric antibodies with a human variable region and a mouse constant region are isolated. The antibodies are characterized and selected for preferred characteristics, including affinity, selectivity, epitope, etc., using standard procedures known to those skilled in the art. The mouse constant regions are replaced with the desired human constant region to produce a fully human antibody described herein, such as a wild-type or modified IgG1 or IgG4. While the constant region selected may vary depending on the particular application, the variable region retains the characteristics of high-affinity antigen binding and target specificity.

[00373] Typically, antibodies that can be used in the methods are characterized by high affinity, as described above, when measuring binding to an antigen in both solid-phase and liquid-phase immobilization. The mouse constant regions are replaced with the desired human constant regions to produce the fully human antibodies described herein. While the constant region selected may vary depending on the particular application, the variable region retains the characteristics of high-affinity antigen binding and target specificity.

[00374]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) with 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) with the amino acid sequence of SEQ ID NO: 2. Methods and techniques for identifying CDRs in HCVR and LCVR amino acid sequences are well known in the art and can be used to identify CDRs in certain HCVR and/or LCVR amino acid sequences disclosed herein. Illustrative, commonly used methods that can be used to identify CDR boundaries include, for example, the Kabat definition, the Chothia definition, and the AbM definition. In general, the Kabat definition is based on sequence variability, the Chothia definition is based on the position of structural loop regions, and the AbM definition is a compromise between the Kabat and Chothia approaches. See, for example, "Kabat, Sequences of Proteins of Immunological Interest", National Institutes of Health, Bethesda, Md. (1991); Al-Lazikani et al.,J. Mol. Biol. 273:927-948 (1997); and Martinet al.,Proc. Natl. Acad. Sci. USA 86:9268–9272 (1989). Publicly available databases are also available for identifying CDR sequences in an antibody.

[00375] In certain embodiments, the antibody or antigen-binding fragment thereof comprises six CDRs (HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3) of the heavy and light chain variable region amino acid sequence pairs (HCVR/LCVR) of SEQ ID NOs: 1 and 2.

[00376] In certain embodiments, the antibody or antigen-binding fragment thereof comprises six CDRs (HCDR1/HCDR2/HCDR3/LCDR1/LCDR2/LCDR3) with amino acid sequences of SEQ ID NO: 3/4/5/6/7/8.

[00377] 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.

[00378] In certain embodiments, the antibody is dupilumab, which comprises the HCVR/LCVR amino acid sequence pairs of SEQ ID NOs: 1 and 2.

[00379] In certain embodiments, the antibody sequence is dupilumab, which comprises the heavy chain/light chain amino acid sequence pair of SEQ ID NOs: 9 and 10.

The amino acid sequence of HCVR of dupilumab is:

[00380] EVQLVESGGGLEQPGGSLRLSCAGSGFTFRDYAMTWVRQAPGKGLEWVSSISGSGGNTYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAKDRLSITIRPRYYGLDVWGQGTTVTVS (SEQ ID NO: 1).

The amino acid sequence of LCVR of dupilumab is:

[00381] DIVMTQSPLSLPVTPGEPASISCRSSQSLLYSIGYNYLDWYLQKSGQSPQLLIYLGSNRASGVPDRFSGSGSGTDFTLKISRVEAEDVGFYYCMQALQTPYTFGQGTKLEIK (SEQ ID NO: 2).

Amino acid sequence of HCDR1 of dupilumab:

[00382] GFTFRDYA (SEQ ID NO: 3).

Amino acid sequence of HCDR2 of dupilumab:

[00383] ISGSGGNT (SEQ ID NO: 4).

The amino acid sequence of HCDR3 of dupilumab is:

[00384] AKDRLSITIRPRYYGL (SEQ ID NO: 5).

Amino acid sequence of dupilumab LCDR1.

[00385] QSLLYSIGYNY (SEQ ID NO: 6).

Amino acid sequence of LCDR2 of dupilumab.

[00386] LGS (SEQ ID NO: 7).

Amino acid sequence of LCDR3 of dupilumab.

[00387] MQALQTPYT (SEQ ID NO: 8).

Amino acid sequence of HC dupilumab.

[00388] EVQLVESGGGLEQPGGSLRLSCAGSGFTFRDYAMTWVRQAPGKGLEWVSSISGSGGNTYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAKDRLSITIRPRYYGL DVWGQGTTVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVES KYGPPCPPCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLG (SEQ ID NO: 9) (amino acids 1-124=HCVR; amino acids 125-451=HC constant region).

Amino acid sequence of LC of dupilumab.

[00389] DIVMTQSPLSLPVTPGEPASISCRSSQSLLYSIGYNYLDWYLQKSGQSPQLLIYLGSNRASGVPDRFSGSGSGTDFTLKISRVEAEDVGFYYCMQALQTPYTFGQGTKLEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO: 10) (amino acids 1-112=LCVR; amino acids 112-219=LC constant region).

Pharmaceutical compositions

[00390] Methods are provided that comprise administering to a patient an IL-4R antagonist, wherein the IL-4R antagonist is contained in a pharmaceutical composition. The pharmaceutical compositions described herein are formulated with suitable carriers, excipients, and other means that provide suitable transport, delivery, tolerability, etc. Many suitable formulations can be found in a reference book familiar to all pharmaceutical chemists: Remington's Pharmaceutical Sciences, Mack Publishing Company, Easton, Pa. These formulations include, for example, powders, pastes, ointments, jellies, waxes, oils, lipids, vesicles containing (cationic or anionic) lipids (such as LIPOFECTIN™), DNA conjugates, anhydrous absorption pastes, oil-in-water and water-in-oil emulsions, carbowax emulsions (polyethylene glycols of various molecular weights), semi-liquid gels, and semi-liquid mixtures containing carbowax. See also Powell et al. "Compendium of excipients for parenteral formulations" PDA (1998) J Pharm Sci Technol. 52:238-311.

[00391] The dose of the antibody administered to the patient may vary depending on the age and size characteristics of the patient, symptoms, conditions, route of administration, etc. The dose is usually 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 doses and administration schedules of pharmaceutical compositions containing antibodies to IL-4R can be determined empirically; for example, the dynamics of the patient's condition can be monitored by periodic assessment and the dose adjusted accordingly. In addition, interspecies dosage calculation can be performed using methods well known in the art (e.g., Mordenti et al. , 1991, Pharmaceut. Res. 8 :1351).

[00392] 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). Routes of administration include, but are not limited to, intradermal, intramuscular, intraperitoneal, intravenous, subcutaneous, intranasal, intratracheal, epidural, and oral routes. The composition can be administered by any convenient route, such as by infusion or bolus injection, absorption through epithelial or mucocutaneous tissues (e.g., oral mucosa, rectal and intestinal mucosa, etc.), and can be co-administered with other biologically active agents.

[00393] The pharmaceutical composition described herein can be delivered subcutaneously or intravenously using a standard needle and syringe. In addition, with respect to subcutaneous delivery, a pen-type delivery device (e.g., an autoinjector pen) is widely used to deliver the pharmaceutical composition described herein. Such a pen-type delivery device can be reusable or disposable. A reusable pen-type delivery device typically uses a replaceable cartridge that contains the pharmaceutical composition. After all of the pharmaceutical composition has been administered from the cartridge and after the cartridge has been emptied, the empty cartridge can be easily disposed of and replaced with a new cartridge that contains the pharmaceutical composition. The pen-type delivery device can then be reused. A disposable pen-type delivery device does not have a replaceable cartridge. Instead, the disposable pen-style delivery device is supplied pre-filled with the pharmaceutical composition contained in the device's reservoir. Once the reservoir is emptied of the pharmaceutical composition, the device is completely disposed of.

[00394] Numerous reusable delivery devices in the form of a pen and autoinjector are used in the subcutaneous delivery of a pharmaceutical composition. Examples include, but are not limited to, AUTOPEN™ (Owen Mumford, Inc., Woodstock, UK), DISETRONIC™ pen (Disetronic Medical Systems, Burgdorf, Switzerland), HUMALOG MIX 75/25™ pen, HUMALOG™ pen, HUMALIN 70/30™ 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), to name a few. Examples of reusable pen delivery devices used in the subcutaneous administration of the pharmaceutical composition 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, U.S.A.), the PENLET™ (Haselmeier, Stuttgart, Germany), EPIPEN (Dey, LP), and the HUMIRA™ pen (Abbott Labs, Abbott Park, IL, U.S.A.), to name a few. Examples of high volume delivery devices (e.g., high volume injectors) include, but are not limited to, bolus injectors such as, for example, BD Libertas West SmartDose, Enable Injections, SteadyMed PatchPump, Sensile SenseTrial, YPsomed YpsoDose, Bespak Lapas, etc.

[00395] For direct administration to the sinuses, the pharmaceutical compositions described herein can be administered using, for example, a microcatheter (e.g., an endoscope and a microcatheter), an aerosol nebulizer, a powder dispenser, a nebulizer, or an inhaler. The methods involve administering an IL-4R antagonist to a subject in need thereof in an aerosol formulation. For example, aerosolized IL-4R antibodies can be administered to treat asthma (e.g., allergic asthma, ABPA-associated asthma, moderate to severe asthma, persistent asthma, etc.) and/or ABPA in a patient. Aerosolized antibodies can be prepared as described, for example, in U.S. Patent No. 8,178,098, which is incorporated herein by reference in its entirety.

[00396] In certain situations, the pharmaceutical composition can be delivered in a controlled release system. In one embodiment, a pump can be used (see Langer, supra; Sefton, 1987, CRC Crit. Ref. Biomed. Eng. 14:201). In another embodiment, polymeric materials can be used; see Medical Applications of Controlled Release, Langer and Wise (eds.), 1974, CRC Pres., Boca Raton, Florida. In yet another embodiment, the controlled release system can be placed near the target of the composition, requiring only a fraction of the systemic dose (see, e.g., Goodson, 1984, in Medical Applications of Controlled Release, supra, vol. 2, pp. 115-138). Other controlled release systems are reviewed by Langer, 1990, Science 249:1527-1533.

[00397]Injectable preparations may include dosage forms for intravenous, subcutaneous, intradermal and intramuscular injections, drip infusions, etc. These injectable preparations can be obtained using known methods. For example, injectable preparations can be obtained, for example, by dissolving, suspending or emulsifying the antibody or its salt described above in a sterile aqueous medium or oil medium commonly used for injection. The aqueous injection medium is, for example, physiological saline solution, isotonic solution containing glucose and other auxiliary agents, etc., which can be used in combination with a suitable solubilizing agent such as alcohol (e.g. ethanol), polyhydric alcohol (e.g. propylene glycol, polyethylene glycol), nonionic surfactant (e.g. polysorbate 80, HCO-50 (polyoxyethylene (50 mol) adduct of hydrogenated castor oil)) etc. As an oil medium, for example, sesame oil, soybean oil, etc. are used, which can be used in combination with a solubilizing agent such as benzyl benzoate, benzyl alcohol, etc. The injection form thus obtained is usually filled into a suitable ampoule.

[00398] Advantageously, the pharmaceutical compositions for oral or parenteral use described above are prepared in unit dose dosage forms suitable for adjusting the dose of the active ingredients. Such unit dose dosage forms include, for example, tablets, pills, capsules, injection forms (ampoules), suppositories, etc.

[00399] Illustrative pharmaceutical compositions comprising an IL-4R antibody that can be used as described herein are disclosed, for example, in U.S. Patent Application Publication No. 2012/0097565.

Dose

[00400] The amount of an IL-4R antagonist (e.g., an anti-IL-4R antibody) administered to a subject according to the methods described herein is typically a therapeutically effective amount. As used herein, the term "therapeutically effective amount" means an amount of an IL-4R antagonist that results in one or more of the following: (a) a reduction in the frequency of asthma exacerbations; (b) an improvement in one or more asthma-associated parameters (as defined elsewhere herein); and/or (c) a detectable improvement in one or more symptoms or manifestations of an upper airway inflammatory condition. The term "therapeutically effective amount" also includes an amount of an IL-4R antagonist that inhibits, prevents, reduces, or delays the progression of asthma in a subject.

[00401]In the case of an antibody to IL-4R, a therapeutically effective amount may be from about 0.05 mg to about 700 mg, for example, about 0.05 mg, about 0.1 mg, about 1.0 mg, about 1.5 mg, about 2.0 mg, about 3.0 mg, about 5.0 mg, about 7.0 mg, about 10 mg, about 20 mg, about 30 mg, about 40 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, about 100 mg, about 110 mg, about 120 mg, about 130 mg, about 140 mg, about 150 mg, about 160 mg, about 170 mg, about 180 mg, about 190 mg, about 200 mg, about 210 mg, about 220 mg, about 230 mg, about 240 mg, about 250 mg, about 260 mg, about 270 mg, about 280 mg, about 290 mg, about 300 mg, about 310 mg, about 320 mg, about 330 mg, about 340 mg, about 350 mg, about 360 mg, about 370 mg, about 380 mg, about 390 mg, about 400 mg, about 410 mg, about 420 mg, about 430 mg, about 440 mg, about 450 mg, about 460 mg, about 470 mg, about 480 mg, about 490 mg, about 500 mg, 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 of an anti-IL-4R antibody. In certain embodiments, 300 mg of an anti-IL-4R antibody is administered.

[00402] The amount of IL-4R antagonist contained in individual doses can be expressed as milligrams of antibody per kilogram of patient body weight (i.e., mg/kg). For example, the IL-4R antagonist can be administered to a patient at a dose of from about 0.0001 to about 10 mg/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.

[00403] In some embodiments, the dose of the IL-4R antagonist may vary based on the eosinophil count. For example, the subject may have a blood eosinophil count (i.e., high blood eosinophil count) of ≥ 300 cells/μL, or 300-499 cells/μL, or ≥ 500 cells/μL (high blood eosinophil count); a blood eosinophil count of 200-299 cells/μL (moderate blood eosinophil count); or a blood eosinophil count of < 200 cells/μL (low blood eosinophil count).

[00404] In some embodiments, the dose of the IL-4R antagonist may vary based on the FeNO score. For example, the subject may have a FeNO score of ≥50 ppb (e.g., high FeNO score); a FeNO score of ≥25 ppb; a FeNO score of between about 25 ppb and about 50 ppb; a FeNO score of <50 ppb; a FeNO score of <25 ppb (e.g., low FeNO score); or a FeNO score of <20 ppb (e.g., low FeNO score).

[00405] In some embodiments, the dose of the IL-4R antagonist may vary based 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 level); or a total serum IgE level of ≥1000 IU/mL (e.g., very high serum IgE level).

[00406] In some embodiments, the dose of the IL-4R antagonist may vary based on the allergen-specific IgE level. In some embodiments, the dose of the IL-4R antagonist may vary based on 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.

[00407] In certain embodiments, the methods comprise a loading dose of about 400 to about 600 mg of the IL-4R antagonist.

[00408] In certain embodiments, the methods comprise one or more maintenance doses of about 200 to about 300 mg of the IL-4R antagonist.

[00409] In certain embodiments, ICS and LABA are administered throughout the period of administration of the IL-4R antagonist.

[00410] In certain embodiments, the loading dose comprises 600 mg of the 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 two weeks.

[00411] In certain embodiments, the loading dose comprises 400 mg of the 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 every two weeks.

[00412] In certain embodiments, the loading dose comprises 400 mg of the 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 two weeks, which can be increased to 300 mg of the antibody or antigen-binding fragment thereof, administered every two weeks.

[00413] In other embodiments, the loading dose comprises 600 mg of the 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 once every four weeks.

[00414] In other embodiments, the loading dose comprises 400 mg of the 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 every four weeks.

[00415] In other embodiments, the loading dose comprises 600 mg of the 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 once weekly.

[00416] In other embodiments, the loading dose comprises 400 mg of the 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.

[00417] In other embodiments, the loading dose comprises 600 mg of the 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 once every three weeks.

[00418] In other embodiments, the loading dose comprises 400 mg of the 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 every three weeks.

[00419] In one embodiment, the subject is between 6 and < 18 years of age and the IL-4R antibody or antigen-binding fragment thereof is administered at a dose of 2 mg/kg or 4 mg/kg.

[00420] In another embodiment, the subject is between 12 and < 18 years of age and the IL-4R antibody or antigen-binding fragment thereof is administered at a dose of 2 mg/kg or 4 mg/kg.

[00421] In another embodiment, the subject is 6 to < 12 years of age and the IL-4R antibody or antigen-binding fragment thereof is administered at a dose of 2 mg/kg or 4 mg/kg.

[00422] In another embodiment, the subject is 2 to <6 years of age and the IL-4R antibody or antigen-binding fragment thereof is administered at a dose of 2 mg/kg or 4 mg/kg.

[00423] In yet another embodiment, the subject is < 2 years of age and the IL-4R antibody or antigen-binding fragment thereof is administered at a dose of 2 mg/kg or 4 mg/kg.

Combination therapy agents

[00424] Certain embodiments of the methods described herein comprise administering to a subject one or more therapeutic agents in combination with an IL-4R antagonist. As used herein, the term "in combination with" means that the additional therapeutic agents are administered before, after, or concurrently with a pharmaceutical composition comprising an IL-4R antagonist. In some embodiments, the term "in combination with" includes sequential or concomitant administration of an IL-4R antagonist and a second therapeutic agent. Provided are methods of treating asthma (e.g., allergic asthma, ABPA-associated asthma, moderate to severe asthma, persistent asthma, etc.) or an associated condition or complication to reduce the incidence of at least one exacerbation, comprising administering an IL-4R antagonist in combination with a second therapeutic agent for additive or synergistic activity.

[00425] For example, when administered "prior to" the pharmaceutical composition comprising the IL-4R antagonist, the additional therapeutic agent can 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 prior to administration of the pharmaceutical composition comprising the IL-4R antagonist. When administered "after" the pharmaceutical composition comprising the 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 the IL-4R antagonist. Administering "in conjunction with" the pharmaceutical composition comprising the IL-4R antagonist means that the additional therapeutic agent is administered to the subject in a separate dosage form within less than 5 minutes (before, after, or at the same time) of administration of the pharmaceutical composition comprising the IL-4R antagonist, or is administered to the subject in a single combination dosage formulation containing both the additional therapeutic agent and the IL-4R antagonist.

[00426] The additional therapeutic agent can be, for example, another IL-4R antagonist, an IL-1 antagonist (including, for example, an IL-1 antagonist as described in U.S. Patent No. 6,927,044), an IL-6 antagonist, an IL-6R antagonist (including, for example, an IL-6R antibody as described in U.S. Patent No. 7,582,298), a TNF antagonist, an IL-8 antagonist, an IL-9 antagonist, an IL-17 antagonist, an IL-5 antagonist, an IgE antagonist, a CD48 antagonist, a leukotriene inhibitor, an antifungal, an NSAID, a long-acting beta ₂ -agonist (e.g., salmeterol or formoterol), an inhaled corticosteroid (e.g., fluticasone or budesonide), a systemic corticosteroid (e.g., oral or intravenous), methylxanthine, nedocromil sodium, cromolyn sodium, or combinations 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 beta ₂ -agonist and an inhaled corticosteroid (e.g., fluticasone + salmeterol (e.g., Advair® (GlaxoSmithKline)) or budesonide + formoterol (e.g., SYMBICORT® (Astra Zeneca))).

[00427] In some embodiments, the additional therapeutic agent administered in combination with the 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.

[00428] Suitable vaccines include, but are not limited to, vaccines against 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 (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), Men B (Bexsero, Trumenba)), mumps (e.g., MMR (MMR II), MMRV (ProQuad)), pertussis (e.g., DTaP (Daptacel, Infanrix), Tdap (Adacel, Boostrix), DTaP-IPV (Kinrix, Quadracel), DTaP-HepB-IPV (Pediarix), DTaP-IPV/Hib (Pentacel)), pneumococcal (e.g., PCV13 (Prevnar13), PPSV23 (Pneumovax 23)), 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)), shingles (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 CDC Vaccine List, which is incorporated in its entirety for all purposes (cdc.gov/vaccines/vpd/vaccines-list.html).

[00429] 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 concurrently receiving treatment for a type 2 inflammatory disease with an IL-4R antagonist. In some embodiments, the subject treated with the vaccine is concurrently receiving treatment for asthma with an IL-4R antagonist.

[00430] In certain embodiments, treatment with an IL-4R antagonist is paused or discontinued prior to administration of the vaccine. In certain embodiments, treatment with an IL-4R antagonist is paused for a period of 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 suspended 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, approximately 47, approximately 48, approximately 49, approximately 50, approximately 51, approximately 52, approximately 53, approximately 54, approximately 55, approximately 56, approximately 57, approximately 58, approximately 59, or approximately 60 days prior to administration of the vaccine.

[00431] In certain embodiments, treatment with an IL-4R antagonist is resumed after administration of the vaccine. In certain embodiments, treatment with an IL-4R antagonist is resumed at a time period of from 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, treatment with an IL-4R antagonist is resumed at 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, approximately 48, approximately 49, approximately 50, approximately 51, approximately 52, approximately 53, approximately 54, approximately 55, approximately 56, approximately 57, approximately 58, approximately 59, approximately 60, approximately 61, approximately 62, approximately 63, approximately 64, approximately 65, approximately 66, approximately 67, approximately 68, approximately 69, approximately 70, approximately 71, approximately 72, approximately 73, approximately 74, approximately 75, approximately 76, approximately 77, approximately 78, approximately 79, approximately 80, approximately 81, approximately 82, approximately 83, approximately 84, approximately 85, approximately 86, approximately 87, approximately 88, approximately 89, or approximately 90 days after administration of the vaccine.

[00432] In certain embodiments, the efficacy of the IL-4R antagonist is not reduced when administered in combination with a vaccine or when administered subsequent to a vaccine. In some embodiments, the forced expiratory volume (FEV ₁ ) of the subject is stable before and after administration of the vaccine.

[00433] In some embodiments, the efficacy of the vaccine is not reduced when administered in combination with an IL-4R antagonist or when administered prior and/or subsequent to an IL-4R antagonist. In some embodiments, the subject develops seroprotective neutralizing titers in response to the vaccine when the vaccine is co-administered with an IL-4R antagonist.

[00434] In certain exemplary embodiments, a subject is administered a vaccine described herein, wherein prior to, during, or following administration of the vaccine, the subject is administered at least one dose of an IL-4R antagonist.

[00435] In some embodiments, the subject to which 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 the following diseases: asthma, allergic rhinitis, chronic rhinosinusitis, chronic rhinosinusitis with nasal polyps (CRSsNP), eosinophilic esophagitis (EoE), atopic dermatitis (AD), food and environmental allergy, aspirin-induced respiratory disease (AERD), or nonsteroidal anti-inflammatory drug-induced respiratory disease (NSAID).

Administration schemes

[00436] According to certain embodiments, multiple doses of an IL-4R antagonist can be administered to a subject over a period of time. These methods involve sequentially administering multiple doses of an IL-4R antagonist to a subject. As used herein, the term "sequential administration" means that each dose of an IL-4R antagonist is administered to the subject at a different time, such as on different days separated by a predetermined interval (e.g., hours, days, weeks, or months). Methods are provided that include sequentially administering to a patient one initial dose of an IL-4R antagonist, then one or more secondary doses of an IL-4R antagonist, and then optionally one or more tertiary doses of an IL-4R antagonist.

[00437] Methods are provided comprising administering to a subject a pharmaceutical composition comprising an IL-4R antagonist at a dosing frequency of about four times per week, twice per week, once per week (q1w), once every two weeks (the term once every two weeks is used interchangeably with the term every other week, every two weeks or q2w), once every three weeks (q3w or q3w), once every four weeks (monthly or q4w), once every five weeks (q5w), once every six weeks (q6w), once every eight weeks (q8w), once every twelve weeks (q12w), or a lesser frequency until a therapeutic response is achieved. In certain embodiments comprising administering a pharmaceutical composition comprising an anti-IL-4R antibody, dosing at about 75 mg, 100 mg, 150 mg, 200 mg, or 300 mg once per week can be used. In other embodiments involving administration of a pharmaceutical composition comprising an antibody to IL-4R, administration of a dose of about 75 mg, 100 mg, 150 mg, 200 mg, or 300 mg once every two weeks can be used (the term once every two weeks is used interchangeably with the term every other week, every two weeks, or q2w). In other embodiments involving administration of a pharmaceutical composition comprising an antibody to IL-4R, administration of a dose of about 75 mg, 100 mg, 150 mg, 200 mg, or 300 mg once every three weeks can be used. In other embodiments involving administration of a pharmaceutical composition comprising an antibody to IL-4R, administration of a dose of about 75 mg, 100 mg, 150 mg, 200 mg, or 300 mg once every four weeks (monthly dosing) can be used. In other embodiments involving administration of a pharmaceutical composition comprising an antibody to IL-4R, administration of a dose of about 75 mg, 100 mg, 150 mg, 200 mg or 300 mg once every five weeks can be used. In other embodiments involving administration of a pharmaceutical composition comprising an antibody to IL-4R, administration of a dose of about 75 mg, 100 mg, 150 mg, 200 mg or 300 mg once every six weeks can be used. In other embodiments involving administration of a pharmaceutical composition comprising an antibody to IL-4R, administration of a dose of about 75 mg, 100 mg, 150 mg, 200 mg or 300 mg once every eight weeks can be used. In other embodiments involving administration of a pharmaceutical composition comprising an antibody to IL-4R, administration of a dose of about 75 mg, 100 mg, 150 mg, 200 mg or 300 mg once every twelve weeks may be used. In other embodiments, the route of administration may be subcutaneous.

[00438] The term "week" or "weeks" refers to a period of (n x 7 days) ± 2 days, such as (n x 7 days) ± 1 day or (n x 7 days), where "n" is a number of weeks, such as 1, 2, 3, 4, 5, 6, 8, 12 or more.

[00439] The terms "initial dose,""secondarydoses," and "tertiary doses" refer to the temporal sequence of administration of the IL-4R antagonist. Thus, an "initial dose" is a dose that is administered at the beginning of a treatment regimen (also referred to as an "initial dose");"secondarydoses" are doses that are administered after the initial dose; and "tertiary doses" are doses that are administered after the secondary doses. The initial, secondary, and tertiary doses may all contain the same amount of IL-4R antagonist, but may generally differ from one another in the frequency of administration. However, in certain embodiments, the amount of IL-4R antagonist contained in the initial, secondary, and/or tertiary doses differs from one another (e.g., adjusted upward or downward as needed) over the course of treatment. In certain embodiments, two or more (e.g., 2, 3, 4, or 5) doses are administered at the beginning of the treatment regimen as "loading doses," then subsequent doses are administered at less frequent intervals (e.g., "maintenance doses"). In one embodiment, the maintenance dose may be lower than the loading dose. For example, one or more loading doses of 600 mg of the IL-4R antagonist may be administered followed by maintenance doses of about 75 mg to about 300 mg.

[00440] In certain embodiments, the loading dose of the IL-4R antagonist is from about 400 to about 600 mg. In one embodiment, the loading dose of the IL-4R antagonist is 400 mg. In another embodiment, the loading dose of the IL-4R antagonist is 600 mg.

[00441] In certain embodiments, the maintenance dose of the IL-4R antagonist is from about 200 to about 300 mg. In one embodiment, the maintenance dose of the IL-4R antagonist is 200 mg. In another embodiment, the maintenance dose of the IL-4R antagonist is 300 mg.

[00442] In certain embodiments, the loading dose is twice the maintenance dose.

[00443] 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 other week (the term every other week is used interchangeably with the term once every two weeks, every two weeks, or q2w).

[00444] 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 two weeks.

[00445] 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 two weeks.

[00446] 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 once every two weeks.

[00447] 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 two weeks.

[00448] 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 two weeks.

[00449] 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 once every four weeks.

[00450] 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 once every four weeks.

[00451] 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 once every four weeks.

[00452] 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 once every four weeks.

[00453] 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 once every four weeks.

[00454] 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 once every four weeks.

[00455]According to one exemplary embodiment, each secondary and/or tertiary dose is administered 1-14 (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 term "immediately preceding dose" means, in a sequence of multiple administrations, the dose of IL-4R antagonist that is administered to a patient before the next subsequent dose in the sequence with no intermediate doses.

[00456] The methods may include administering to the patient any number of secondary and/or tertiary doses of the IL-4R antagonist. For example, in certain embodiments, the patient is administered only one secondary dose. In other embodiments, the patient is administered two or more (e.g., 2, 3, 4, 5, 6, 7, 8, or more) secondary doses. Similarly, in certain embodiments, the patient is administered only one tertiary dose. In other embodiments, the patient is administered two or more (e.g., 2, 3, 4, 5, 6, 7, 8, or more) tertiary doses.

[00457] In embodiments comprising multiple secondary doses, each secondary dose can be administered at the same frequency as the other secondary doses. For example, each secondary dose can be administered to the patient 1-2 weeks after the immediately preceding dose. Similarly, in embodiments comprising multiple tertiary doses, each tertiary dose can be administered at the same frequency as the other tertiary doses. For example, each tertiary dose can be administered to the patient 2-4 weeks after the immediately preceding dose. Alternatively, the frequency with which secondary and/or tertiary doses are administered to the patient can vary throughout the treatment regimen. The frequency of administration can be adjusted by the physician throughout the course of treatment based on the needs of the individual patient following clinical evaluation.

[00458] Methods are provided comprising sequentially administering an IL-4R antagonist and a second therapeutic agent to a patient to treat asthma (e.g., allergic asthma, ABPA-associated asthma, moderate to severe asthma, persistent asthma, etc.) or an associated condition. In some embodiments, the methods comprise administering one or more doses of an IL-4R antagonist, then administering one or more doses (e.g., 2, 3, 4, 5, 6, 7, 8, or more) of the second therapeutic agent. For example, one or more doses of an IL-4R antagonist of about 75 mg to about 300 mg can be administered, followed by one or more doses (e.g., 2, 3, 4, 5, 6, 7, 8 or more) of a second therapeutic agent (e.g., an inhaled corticosteroid or any beta2-agonist or any other therapeutic agent described elsewhere herein) to treat, alleviate, reduce or lessen the severity of one or more symptoms of asthma. In some embodiments, the IL-4R antagonist is administered in one or more doses (e.g., 2, 3, 4, 5, 6, 7, 8 or more) that result in an improvement in one or more asthma-associated parameters after administration of the secondary therapeutic agent, to prevent recurrence of at least one symptom of asthma. Alternative embodiments relate to concomitant administration of the IL-4R antagonist and the second therapeutic agent. For example, one or more doses (e.g., 2, 3, 4, 5, 6, 7, 8, or more) of an IL-4R antagonist are administered and a second therapeutic agent is administered in a separate dose at the same or different frequency relative to the IL-4R antagonist. In some embodiments, the second therapeutic agent is administered before, after, or together with the IL-4R antagonist.

[00459] In certain embodiments, the IL-4R antagonist is administered once every two weeks 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, 48 weeks, or more. In other embodiments, the IL-4R antagonist is administered once every four weeks for 12 weeks, 16 weeks, 20 weeks, 24 weeks, 28 weeks, 32 weeks, 36 weeks, 40 weeks, 44 weeks, 48 weeks, or more. In particular embodiments, the IL-4R antagonist is administered for at least 24 weeks.

[00460] Methods are provided 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 methods comprise administering to the subject a plurality of maintenance doses of the antibody or antigen-binding fragment thereof, wherein the plurality of maintenance doses are administered during a treatment phase. The treatment phase includes an induction phase, an OCS reduction phase, and an OCS maintenance phase.

[00461] In certain exemplary embodiments, the induction phase includes a period during which the subjects continuously receive their dose(s) of OCS. In certain exemplary embodiments, the taper phase includes a period during which the subjects receive a lower dose of OCS than the dose received during the induction phase. In certain exemplary embodiments, the maintenance phase includes a period during which the subject receives a certain stable amount or dose(s) of OCS. Alternatively, the maintenance phase includes a period during which OCS therapy/administration is reduced or eliminated. In certain embodiments, the patient's use of OCS is completely discontinued and the patient does not receive steroids for less than 1 year of treatment with the anti-IL4R antibody or fragment thereof (e.g., for 1 year, 6 months, 3 months, or 1 month after the initial treatment).

[00462] In another aspect, a method of treating a subject suffering from severe steroid-dependent asthma and/or severe uncontrolled asthma comprises administering to the subject a loading dose of about 600 mg of an antibody or antigen-binding fragment thereof that specifically binds to an interleukin-4 receptor (IL-4R), and administering to the subject a plurality of maintenance doses of the antibody or antigen-binding fragment thereof. Each maintenance dose is about 300 mg of the antibody or antigen-binding fragment thereof, wherein the plurality of maintenance doses are administered during a treatment phase comprising an induction phase, an oral corticosteroid tapering (OCS) phase, and a maintenance phase, wherein the antibody or antigen-binding fragment thereof comprises heavy and light chain CDR sequences of the HCVR/LCVR sequence pair comprising SEQ ID NOs: 1 and 2.

Treatment populations

[00463] The methods provided herein include administering to a subject in need thereof a therapeutic composition comprising an IL-4R antagonist. The term "subject in need thereof" means a human or animal, other than a human, who exhibits one or more symptoms or manifestations of asthma (e.g., allergic asthma, such as moderate to severe uncontrolled allergic asthma or ABPA-associated asthma) and/or ABPA, or who has been diagnosed with asthma (e.g., allergic asthma, ABPA-associated asthma, moderate to severe asthma, persistent asthma, etc.) and/or ABPA. For example, a "subject in need thereof" may include, for example, subjects who, prior to treatment, are (or were) characterized by one or more parameters associated with asthma (e.g., associated with allergic asthma), such as, for example, an abnormal _FEV1 (e.g., less than 2.0 L), an abnormal FEF25-75%; impaired PEF before midday (e.g., less than 400 L/min), impaired PEF after midday (e.g., less than 400 L/min), an ACQ5 score of at least 2.5, at least 1 nighttime awakening, and/or a SNOT-22 score of at least 20. In various embodiments, the methods can be used to treat mild, moderate to severe, and severe asthma (e.g., allergic asthma, ABPA-associated asthma, moderate to severe asthma, persistent asthma, etc.) and/or ABPA in patients in need thereof. In certain embodiments, the methods can be used to treat mild, moderate to severe, and severe asthma (e.g., allergic asthma, ABPA-associated asthma, moderate to severe asthma, persistent asthma, etc.) and/or ABPA in patients in need thereof, wherein the patients additionally exhibit concomitant moderate to severe atopic dermatitis.

[00464] In certain embodiments, a "subject in need thereof" means a human or non-human animal that 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. In certain embodiments, a "subject in need thereof" means a human or non-human animal that 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, or a baseline blood eosinophil count of at least about 500 cells/μL. In certain embodiments, a "subject in need thereof" means a human or non-human animal that 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.

[00465] In a related embodiment, a "subject in need thereof" may be a subject who has been administered or is currently receiving an ICS/LABA combination prior to receiving the IL-4R antagonist. Examples of ICS include mometasone furoate, budesonide, and fluticasone propionate. Examples of LABAs include formoterol and salmeterol. Examples of ICS/LABA therapies include fluticasone/salmeterol combination therapy and budesonide/formoterol combination therapy. For example, methods are provided that comprise administering an IL-4R antagonist to a patient who has been receiving a regular course of ICS/LABA for two or more weeks immediately prior to administration of the IL-4R antagonist (such prior therapies are referred to herein as "background therapies"). Therapeutic methods are provided in which background therapies are continued in combination with administration of the IL-4R antagonist. In yet other embodiments, the amount of the ICS component, the LABA component, or both is gradually reduced before or after the start of administration of the IL-4R antagonist. In some embodiments, methods are provided for treating patients 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 can be administered an IL-4R antagonist according to the methods of the present invention.

[00466] In some embodiments, a "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-regulated activation chemokine (TARC), blood eosinophils, eotaxin-3, CEA, YKL-40, and periostin. In some embodiments, a "subject in need thereof" may be a subject with a blood eosinophil count of ≥ 300 cells/μL, 200-299 cells/μL, or < 200 cells/μL. In one embodiment, a "subject in need thereof" may be a subject with elevated levels of inflammation in the bronchi or airways as measured by fractional exhaled nitric oxide (FeNO). In another embodiment, a "subject in need thereof" may be a subject with elevated levels of eotaxin. In another embodiment, a "subject in need thereof" may be a subject with elevated levels of TARC. In another embodiment, a "subject in need thereof" may be a subject with elevated levels of IgE (e.g., total IgE and/or A. fumigatus -specific IgE).

[00467] In some embodiments, the "subject in need thereof" is selected from the group consisting of a subject 18 years of age or older, a subject 12 years of age or older, a subject 12 to 17 years of age (12 to < 18 years), a subject 6 to 11 years of age (6 to < 12 years), and a subject 2 to 5 years of age (2 to < 6 years). In some embodiments, the "subject in need thereof" is selected from the group consisting of an adult, an adolescent, and a child. In some embodiments, the "subject in need thereof" is selected from the group consisting of an adult 18 years of age or older, an adolescent 12 to 17 years of age (12 to < 18 years), a child 6 to 11 years of age (6 to < 12 years), and a child 2 to 5 years of age (2 to < 6 years). The subject's age may be less than 2 years, such as 12 to 23 months or 6 to 11 months.

[00468] In some embodiments, a "subject in need thereof" is a subject who is an active smoker. In some embodiments, the subject is an active smoker who smokes, for example, cigarettes, cigars, pipes, hookahs, and/or vaporizers (i.e., "vapes"). In some embodiments, the subject is an active smoker who has a smoking history of 10 or more packs of cigarettes per year. In some embodiments, the subject is an active smoker and has a smoking history of smoking less than 10 packs of cigarettes per year. In some embodiments, the subject is an active smoker and has a smoking 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 an active smoker with a smoking history of 6 months, 1 year, 2 years, 3 years, 5 years, 10 years, or longer.

[00469] In some embodiments, a "subject in need thereof" is a subject who is a former smoker. In some embodiments, the subject is a former smoker who has a smoking history of smoking cigarettes, cigars, pipes, hookahs, and/or vapes. In some embodiments, the subject is a former smoker who has a smoking history of smoking 10 or more packs of cigarettes per year. In some embodiments, the subject is a former smoker who has a smoking history of smoking less than 10 packs per year. In some embodiments, the subject is a former smoker who has a smoking 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 smoking history of 6 months, 1 year, 2 years, 3 years, 5 years, 10 years, or longer. In some embodiments, the subject is a former smoker who quit smoking at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 months ago. In some embodiments, the subject is a former smoker who quit smoking at least 6 months ago. In some embodiments, the subject is a former smoker who no longer intends to start smoking.

[00470] In some embodiments, a "subject in need thereof" is a subject who is a non-smoker. In some embodiments, the subject is a non-smoker who does not have a history of smoking cigarettes, cigars, pipes, hookahs, and/or vapes. In some embodiments, the subject is a non-smoker who does not have a history of smoking tobacco.

[00471] In some embodiments, the "subject in need thereof" is a subject that is being treated with a vaccine, such as a viral vaccine or a bacterial vaccine. In some embodiments, the vaccine is a live vaccine, such as a live (e.g., live attenuated) viral vaccine or a live (e.g., live attenuated) bacterial vaccine.

[00472] Suitable vaccines include, but are not limited to, vaccines against 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 (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), Men B (Bexsero, Trumenba)), mumps (e.g., MMR (MMR II), MMRV (ProQuad)), pertussis (e.g., DTaP (Daptacel, Infanrix), Tdap (Adacel, Boostrix), DTaP-IPV (Kinrix, Quadracel), DTaP-HepB-IPV (Pediarix), DTaP-IPV/Hib (Pentacel)), pneumococcal (e.g., PCV13 (Prevnar13), PPSV23 (Pneumovax 23)), 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)), shingles (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 CDC Vaccine List, which is incorporated in its entirety for all purposes (cdc.gov/vaccines/vpd/vaccines-list.html).

[00473] 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 concurrently receiving treatment for a type 2 inflammatory disease with an IL-4R antagonist. In some embodiments, the subject treated with the vaccine is concurrently receiving treatment for asthma with an IL-4R antagonist. In some embodiments, the subject pauses treatment with the IL-4R antagonist prior to administration of the vaccine.

[00474] In certain embodiments, the subject pauses treatment with the IL-4R antagonist for a period of 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 pauses treatment with the 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, approximately 47, approximately 48, approximately 49, approximately 50, approximately 51, approximately 52, approximately 53, approximately 54, approximately 55, approximately 56, approximately 57, approximately 58, approximately 59, or approximately 60 days prior to administration of the vaccine.

[00475] In certain embodiments, the subject resumes treatment with the IL-4R antagonist after administration of the vaccine. In certain embodiments, the subject resumes treatment with the IL-4R antagonist at a time between 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 certain embodiments, the subject resumes treatment with the IL-4R antagonist at 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, approximately 48, approximately 49, approximately 50, approximately 51, approximately 52, approximately 53, approximately 54, approximately 55, approximately 56, approximately 57, approximately 58, approximately 59, approximately 60, approximately 61, approximately 62, approximately 63, approximately 64, approximately 65, approximately 66, approximately 67, approximately 68, approximately 69, approximately 70, approximately 71, approximately 72, approximately 73, approximately 74, approximately 75, approximately 76, approximately 77, approximately 78, approximately 79, approximately 80, approximately 81, approximately 82, approximately 83, approximately 84, approximately 85, approximately 86, approximately 87, approximately 88, approximately 89, or approximately 90 days after administration of the vaccine.

[00476] Normal IgE levels in healthy subjects are typically less than approximately 100 IU/mL (e.g., as measured using the IMMUNOCAP® assay (Phadia, Inc. Portage, MI, USA)). Thus, methods are provided comprising selecting a subject that has an elevated level of IgE in the blood serum, wherein the level of IgE in the blood serum is 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.

[00477] A normal Aspergillus fumigatus (Af)-specific IgE level in healthy subjects is typically less than about 0.10 kU/L (e.g., as measured using the IMMUNOCAP® assay (Phadia, Inc. Portage, MI, USA)). Accordingly, methods are provided comprising selecting a subject that has an elevated serum IgE level, wherein the serum IgE level is greater than or equal to about 0.1 kU/L, greater than about 0.35 kU/L, greater than about 0.70 kU/L, greater than about 3.50 kU/L, greater than about 17.50 kU/L, greater than about 50.00 kU/L, or greater than about 100.00 kU/L, and administering to the subject a pharmaceutical composition comprising a therapeutically effective amount of an IL-4R antagonist.

[00478] In certain embodiments, IgE levels (e.g., total IgE levels and/or A. fumigatus -specific IgE levels) are improved compared to a baseline, such as 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 compared to a baseline.

[00479] TARC levels in healthy subjects range from 106 ng/L to 431 ng/L, with a mean of approximately 239 ng/L. (An exemplary assay system for measuring TARC levels is the TARC Assay ELISA Kit available as Cat. No. DDN00 from R&D Systems, Minneapolis, Minn.) Thus, methods are provided comprising selecting a subject who has an elevated serum TARC level, wherein 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 IL-4R antagonist. In certain embodiments, TARC levels are improved compared to baseline, such as 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 compared to baseline.

[00480] Eotaxin-3 belongs to a group of chemokines released by airway epithelial cells that is upregulated by the Th2 cytokines IL-4 and IL-13 (Lilly et al 1999, J. Allergy Clin. Immunol. 104: 786-790). Methods are provided comprising administering an IL-4R antagonist for treating patients with elevated eotaxin-3 levels, such as 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, eotaxin-3 levels are improved compared to baseline, such as 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 compared to baseline.

[00481] Periostin is an extracellular matrix protein involved in Th2-mediated inflammatory processes. Periostin levels have been found to be elevated in patients with asthma (Jia et al 2012 J Allergy Clin Immunol. 130:647-654.e10. doi: 10.1016/j.jaci.2012.06.025. electronic publication August 1, 2012). Methods comprising administering an IL-4R antagonist for treating patients with elevated periostin levels are provided.

[00482] Fractional exhaled NO (FeNO) is a biomarker of bronchial or airway inflammation. FeNO is produced by airway epithelial cells in response to inflammatory cytokines, including IL-4 and IL-13 (Alwing et al 1993, Eur. Respir. J. 6: 1368-1370). FeNO levels in healthy adults range from 2 to 30 parts per billion (ppb). An illustrative assay for measuring FeNO is the NIOX Aerocrine AB, Solna, Sweden device. Assessment can be performed prior to spirometry or after fasting for at least an hour. Methods are provided comprising administering an IL-4R antagonist to patients with elevated exhaled NO (FeNO) levels, 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.

[00483] Carcinoembryonic antigen (CEA) (also known as CEA cell adhesion molecule 5 [CEACAM5]) is a tumor marker that has been found to be associated with non-neoplastic lung diseases (Marechal et al. 1988, Anticancer Res. 8: 677-680). Serum CEA levels can be measured by ELISA. Methods are provided comprising administering an IL-4R antagonist to patients with elevated CEA levels, such as 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, or greater than about 5.0 ng/mL.

[00484] YKL-40 (named for its N-terminal amino acids tyrosine (Y), lysine (K), and leucine (L) and its molecular weight of 40 kDa) is a chitinase-like protein that has been found to be upregulated and associated with asthma exacerbation, IgE, and eosinophils (Tang et al 2010 Eur. Respir. J. 35: 757-760). Serum levels of YKL-40 are measured, for example, by ELISA. Methods are provided comprising administering an IL-4R antagonist to patients with elevated YKL-40 levels, such as 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.

[00485] Periostin is a secreted extracellular matrix 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 patients with asthma, periostin expression levels are associated with reticular basement membrane thickness, an indicator of subepithelial fibrosis. Ibid. Methods are provided comprising administering an IL-4R antagonist to patients with elevated periostin levels.

[00486] Eosinophils and neutrophils in induced sputum are well-established direct markers of airway inflammation (Djukanovic et al. 2002, Eur. Respire. J. 37: 1S-2S). Sputum production is induced by inhalation of hypertonic saline and the number of cells is counted according to methods known in the art, for example according to the guidelines of the European Respiratory Society.

[00487] In some embodiments, subjects are classified into the following groups: a blood eosinophil count (high blood eosinophil count) of ≥ 300 cells/μL (HEo), or 300-499 cells/μL, or ≥ 500 cells/μL, a blood eosinophil count of 200-299 cells/μL (moderate eosinophil count), or a blood eosinophil count of < 200 cells/μL (low eosinophil count), and the administration of the IL-4R antibody or antigen-binding fragment thereof is carried out at a dose or according to a schedule of administration based on the eosinophil level.

[00488] In some embodiments, subjects are classified into the following groups: a blood eosinophil count of ≥ 300 cells/μL, 300-499 cells/μL, or ≥ 500 cells/μL (high blood eosinophil count); a blood eosinophil count of ≥ 150 cells/μL (moderate blood eosinophil count); or a blood eosinophil count of < 150 cells/μL (low blood eosinophil count), and the anti-IL-4R antibody or antigen-binding fragment thereof is administered at a dose or according to a dosing schedule based on the eosinophil level.

[00489] In some embodiments, the subject has asthma of the "eosinophilic phenotype" as defined by a blood eosinophil count of ≥ 150 cells/μL, a blood eosinophil count of ≥ 300 cells/μL, a blood eosinophil count of 300-499 cells/μL, or a blood eosinophil count of ≥ 500 cells/μL, and is administered an anti-IL-4R antibody or antigen-binding fragment thereof.

[00490] In some embodiments, subjects are classified into the following groups: a baseline total serum IgE concentration of ≥30 IU/mL; a baseline total serum IgE concentration of ≥100 IU/mL; a baseline total serum IgE concentration of ≥200 IU/mL; a baseline total serum IgE concentration of ≥300 IU/mL; a baseline total serum IgE concentration of ≥400 IU/mL; a baseline total serum IgE concentration of ≥500 IU/mL; a baseline total serum IgE concentration of ≥600 IU/mL; a baseline total serum IgE concentration of ≥700 IU/mL (e.g., high serum IgE); a baseline total serum IgE concentration of ≥800 IU/mL; a baseline total serum IgE concentration of ≥900 IU/mL; or a baseline total serum IgE concentration of ≥1000 IU/mL (e.g., very high IgE concentration), and the anti-IL-4R antibody or antigen-binding fragment thereof is administered at a dose or according to a dosing schedule based on the IgG concentration.

[00491] In some embodiments, the subjects are classified into the following groups: an allergen-specific (e.g., A. fumigatus -specific) IgE 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; allergen-specific (e.g. A. fumigatus -specific) IgE concentration ≥0.30 kU/L; allergen-specific (e.g. A. fumigatus -specific) IgE concentration ≥0.35 kU/L; allergen-specific (e.g. A. fumigatus -specific) IgE concentration ≥0.40 kU/L; allergen-specific (e.g. A. fumigatus -specific) IgE concentration ≥0.45 kU/L; or an allergen-specific (e.g., A. fumigatus -specific) IgE concentration of ≥0.50 kU/L, and the IL-4R antibody or antigen-binding fragment thereof is administered at a dose or according to a dosing schedule based on the allergen-specific (e.g., A. fumigatus -specific) IgE concentration.

[00492] In some embodiments, subjects are classified into the following groups: a baseline FeNO of ≥20 ppb; a baseline FeNO of ≥25 ppb; a baseline FeNO of ≥50 ppb (e.g., high FeNO); a baseline FeNO of <25 ppb (e.g., low FeNO); a baseline FeNO of <50 ppb; or a baseline FeNO of between about 25 ppb and about 50 ppb, and an anti-IL-4R antibody or antigen-binding fragment thereof is administered at a dose or dosing schedule based on the FeNO.

Methods for assessing asthma-associated pharmacodynamic parameters and/or ABPA-associated parameters

[00493] Methods are provided for assessing one or more pharmacodynamic parameters associated with asthma and/or one or more pharmacodynamic parameters associated with ABPA in a subject in need thereof, which are the results of administering a pharmaceutical composition comprising an IL-4R antagonist. A reduction in the frequency of asthma exacerbations (as described above) or an improvement in one or more asthma-associated parameters (as described above) may be associated with an improvement in one or more pharmacodynamic parameters associated with asthma; however, such an association is not necessarily observed in all cases.

[00494] Examples of "asthma-associated pharmacodynamic parameters" or "ABPA-associated pharmacodynamic parameters" include, for example, the following: (a) biomarker expression levels; (b) serum protein and RNA analysis; (c) induced sputum eosinophil and neutrophil levels; (d) exhaled nitric oxide (FeNO); and (e) blood eosinophil count. "Improvement in an asthma-associated pharmacodynamic parameter" means, for example, a decrease from baseline in one or more biomarkers such as TARC, eotaxin-3, or IgE, a decrease in sputum eosinophil or neutrophil count, FeNO, periostin, or blood eosinophil count. As used herein, the term "baseline" with respect to an asthma-associated pharmacodynamic parameter means the numerical value of the asthma-associated pharmacodynamic parameter for a patient prior to or throughout the period of administration of the pharmaceutical composition described herein.

[00495]To assess an asthma-associated pharmacodynamic parameter or an ABPA-associated pharmacodynamic parameter, the parameter is measured quantitatively at baseline and at a time point following administration of the pharmaceutical composition. For example, a pharmacodynamic parameter associated with asthma or a pharmacodynamic parameter associated with ABPA can be measured at approximately day 1, day 2, day 3, day 4, day 5, day 6, day 7, day 8, day 9, day 10, day 11, day 12, day 14, or at week 3, week 4, week 5, week 6, week 7, week 8, week 9, week 10, week 11, week 12, week 13, week 14, week 15, week 16, week 17, week 18, week 19, week 20, week 21, week 22, week 23, week 24, or later after initial treatment with the pharmaceutical composition. The difference between the value of a parameter at a given time point after the start of treatment and the value of the parameter at baseline is used to establish whether a change, such as an "improvement," in an asthma-related pharmacodynamic parameter has occurred (e.g. increase or decrease, depending on the situation, depending on the specific parameter being measured).

[00496] In certain embodiments, administration of an IL-4R antagonist to a patient causes a change, such as a decrease or increase in the expression of a particular biomarker. Biomarkers associated with asthma and/or biomarkers associated with ABPA include, but are not limited to, the following: (a) total IgE; (b) Af-specific IgE; (c) thymus-regulated activation chemokine (TARC); (d) YKL-40; (e) carcinoembryonic antigen in serum; (f) eotaxin-3 in blood plasma; (g) periostin in serum; and (h) serum eosinophil levels. For example, administration of an IL-4R antagonist to a patient with asthma and/or a patient with ABPA can cause one or more of a decrease in TARC or eotaxin-3 levels or a decrease in total IgE levels in serum. The reduction can be detected at about week 1, about week 2, about week 3, about week 4, about week 5 or later after administration of the IL-4R antagonist. Expression of biomarkers can be determined by methods known in the art. For example, protein levels can be measured by ELISA (enzyme-linked immunosorbent assay). RNA levels can be measured, for example, by reverse transcription coupled to polymerase chain reaction (RT-PCR).

[00497] Expression of the biomarkers described above can be determined by detecting protein or RNA in serum. Serum samples can also be used to monitor additional protein or RNA biomarkers associated with response to IL-4R antagonist treatment, IL-4/IL-13 signaling, asthma, atopy, or eosinophilic diseases (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), such as RNA levels of biomarkers; and in other embodiments, RNA samples are used for transcriptome sequencing (e.g., genetic analysis).

Compositions

[00498] 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 wherein the viscosity of the formulation is about 8.5 centipoise.

[00499] In alternative embodiments, 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 wherein the viscosity of the formulation is about 8.5 centipoise.

[00500] In specific embodiments, the antibody or antigen-binding fragment thereof comprises an HCVR comprising the amino acid sequence of SEQ ID NO: 1 and an LCVR comprising the amino acid sequence of SEQ ID NO: 2.

[00501] Suitable stabilized compositions are also disclosed in U.S. Patent 8,945,559, which is incorporated herein by reference in its entirety for all purposes.

[00502] The present invention is further illustrated by the following examples, which should not be construed as further limiting. The contents of the drawings and all references, patents and published patent applications cited in this application are incorporated herein by reference in their entirety for all purposes.

[00503]In addition, conventional molecular biology, microbiology and recombinant DNA techniques within the skill of the art can be used in the present invention. Such techniques are fully explained in the literature. See, for example, Green & Sambrook,Molecular Cloning: A Laboratory Manual, Fourth 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 & S.J. Higgins eds. (1985)]; Transcription and Translation [B.D. Hames & S.J. Higgins, eds. (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); F.M. Ausubel et al. (eds.), Current Protocols in Molecular Biology, John Wiley & Sons, Inc. (1994).

EXAMPLES

[00504] The following examples are set forth to provide those skilled in the art with a complete disclosure and description of the preparation and use of the methods and compositions described in the present invention, and are not intended to limit the scope of what the present inventors consider to be their invention. Efforts have been made to ensure accuracy with respect to the numbers used (e.g., amounts, temperatures, etc.), however, some experimental errors and variations must be taken into account. Unless otherwise indicated, parts are parts by weight, molecular weight is average molecular weight, temperature is in degrees Celsius, and pressure is atmospheric or near atmospheric.

[00505] An exemplary IL-4R antagonist used in the following examples is a human anti-IL-4R antibody called dupilumab (also referred to herein as "mAb1").

EXAMPLE 1. Methods - Allergic asthma

Research plan

[00506] QUEST was a randomized, double-blind, placebo-controlled phase 3 study evaluating the efficacy and safety of dupilumab in patients with uncontrolled moderate to severe asthma. A total of 1902 patients aged ≥12 years were randomized in a 2:2:1:1 ratio to receive additional subcutaneous dupilumab 200 mg (400 mg loading dose) or 300 mg (600 mg loading dose) once every 2 weeks (q2w) or matched placebo for 52 weeks. The study was conducted in accordance with the Declaration of Helsinki, International Conference on Harmonization guidelines, and applicable regulatory requirements. An independent Data and Safety Monitoring Committee performed blinded patient safety data monitoring. The local institutional review board or ethics committee at each study site monitored trial conduct and documentation. All patients provided written informed consent before participating in the trial.

[00507] The QUEST study compared the effects of dupilumab on key asthma outcome measures in subgroups of patients with and without evidence of allergic asthma at baseline. Allergic asthma was defined using the most commonly used criteria in clinical practice in the United States 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) (U.S. Food and Drug Administration, available at: accessdata.fda.gov/drugsatfda_docs/label/2003/omalgen062003LB.pdf). Because dupilumab treatment is not limited by body weight or serum total IgE levels, an upper threshold for serum total IgE was not specified.

[00508] The study included adults and adolescents (aged ≥12 years) with physician-diagnosed asthma for at least 12 months (according to the 2014 Global Initiative for Asthma (GINA) guidelines) who were treated with a moderate to high dose of inhaled glucocorticoids and no more than two additional controller medications. Eligible patients met the following criteria: pre-bronchodilator forced expiratory volume in 1 second (FEV ₁ ) ≤80% of predicted normal value for adults and ≤90% of predicted normal value for adolescents; FEV ₁ reversibility ≥12% and 200 mL; Asthma Control Questionnaire-5 (ACQ-5) score ≥1.5; and an asthma exacerbation in the previous year that resulted in hospitalization, emergency medical care, or treatment with systemic glucocorticoids for 3 or more days. Full inclusion and exclusion criteria are published on the Clinical Trials.gov website (LIBERTY ASTHMA QUEST (NCT02414854)), and the study is incorporated herein by reference in its entirety.

Patients

[00509] Patients were classified based on whether they met criteria for allergic asthma based on the following: total serum IgE ≥30 IU/mL and ≥1 positive perennial aeroallergen-specific IgE (≥0.35 kU/L) at baseline. Perennial allergens included Dermatophagoides farinae , Dermatophagoides pteronyssinus , Alternaria alternata , Cladosporium herbarum , cat and dog dander, German cockroach, black cockroach, and Aspergillus fumigatus . Percutaneous skin testing was not performed. Baseline demographic data for the study are provided in Table 1.

[00510] A total of 1083 patients (57% of the ITT population of the QUEST study) 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 total serum IgE <30 IU/mL, 14% (n=114) had ≥1 positive seasonal allergen but were negative for all perennial allergens, 38% (n=314) had a history of allergic rhinitis but were negative for all perennial and seasonal allergens, and 41% (n=336) had no history of allergic rhinitis but were negative for all perennial and seasonal allergens.

[00511] Patients who met criteria for allergic asthma tended to be younger (mean 44.5 years versus 52.5 years), had asthma onset at an earlier age (mean 21.6 years versus 34.2 years), and had a higher proportion of comorbid atopic conditions (96% versus 64%) compared with the subgroup who did not meet criteria for allergic asthma (Table 1). In addition, the subgroup with allergic asthma had a lower mean number of severe exacerbations in the previous year (1.94 versus 2.30) and a higher mean _FEV1 before bronchodilator use (1.85 L versus 1.67 L). These patients, compared with patients who did not meet criteria for allergic asthma, also had higher serum TARC concentrations (median 327 pg/mL versus 277 pg/mL) and similar FeNO levels (median 26 ppb versus 23 ppb) and blood eosinophil counts (median 250 cells/μL versus 260 cells/μL).

End points

[00512] The endpoints analyzed were the annualized rate of severe exacerbations, change from baseline in pre-bronchodilator FEV ₁ (L), and change from baseline in ACQ-5 score during the 52-week treatment period in the subgroups of patients who met and did not meet criteria for allergic asthma. Within each subgroup, severe exacerbations during the 52-week treatment period and changes from baseline in pre-bronchodilator FEV ₁ (L) at Week 12 were also analyzed in the populations of patients with baseline blood eosinophils ≥150 cells/μL, ≥300 cells/μL, and baseline fractional exhaled nitric oxide (FeNO) ≥25 ppb. An additional analysis was performed in a subgroup of patients with allergic asthma with baseline serum total IgE >700 IU/mL, patients for whom omalizumab therapy is not indicated in the United States.

[00513] The effect of dupilumab treatment on the following biomarkers of type 2 inflammation was also assessed in the allergic asthma subgroups compared with the non-allergic asthma subgroups: serum total IgE levels; FeNO levels; and serum thymus- and activation-regulated chemokine (TARC) levels. The effect of dupilumab treatment on serum specific IgE levels for each of the year-round aeroallergens tested over the 52-week treatment period was also examined in patients who tested positive (≥0.35 kU/L) at baseline.

Table 1. Demographic data and disease characteristics of patients at baseline Allergic asthma
(n=1083) Did not meet criteria for allergic asthma
(n=819) 1.14 ml/200 mg q2w 2 ml/300 mg q2w 1.14 ml/200 mg q2w 2 ml/300 mg q2w Placebo
(n=183) Dupilumab
(n=360) Placebo
(n=179) Dupilumab
(n=361) Placebo
(n=134) Dupilumab
(n=271) Placebo
(n=142) Dupilumab
(n=272) Age, mean (SD), years 44.0 (16.8) 45.5 (16.0) 44.1 (14.9) 43.9 (15.8) 54.0 (11.8) 51.0 (13.7) 53.2 (12.8) 52.7 (13.6) Women, n (%) 101 (55.2) 196 (54.4) 114 (63.7) 216 (59.8) 97 (72.4) 191 (70.5) 104 (73.2) 178 (65.4) BMI, mean (SD), kg/ ^m2 29.3 (7.35) 28.47 (6.35) 28.78 (6.88) 28.91 (6.91) 30.39 (7.09) 29.82 (6.67) 29.76 (7.02) 29.27 (6.37) Age at asthma onset, mean (SD), years 20.9 (17.9) 23.0 (19.5) 20.9 (16.9) 20.8 (17.8) 35.9 (17.3) 32.5 (17.3) 35.7 (17.4) 34.2 (18.8) With persistent atopic pathological condition,* n (%) 176 (96.2) 337 (93.6) 173 (96.6) 354 (98.1) 90 (67.2) 172 (63.5) 93 (65.5) 170 (62.5) Atopic dermatitis 21 (11.5) 48 (13.3) 32 (17.9) 42 (11.6) 14 (10.4) 13 (4.8) 6 (4.2) 20 (7.4) Allergic rhinitis 142 (77.6) 265 (73.6) 140 (78.2) 284 (78.7) 79 (59) 156 (57.6) 85 (59.9) 154 (56.6) Food allergy 21 (11.5) 35 (9.7) 25 (14.0) 32 (8.9) 7 (5.2) 13 (4.8) 11 (7.7) 15 (5.5) Hives 13 (7.1) 16 (4.4) 9 (5.0) 22 (6.1) 6 (4.5) 14 (5.2) 6 (4.2) 8 (2.9) Past smokers, n (%) 27 (14.8) 75 (20.8) 38 (21.2) 67 (18.6) 32 (23.9) 51 (18.8) 29 (20.4) 49 (18.0) Severe asthma exacerbations in the past year, mean (SD), n 1.89 (1.48) 1.98 (2.99) 2.22 (1.99) 1.79 (1.33) 2.32 (1.68) 2.18 (2.16) 2.43 (2.17) 2.33 (2.35) FEV ₁ before bronchodilator use, mean (SD), L 1.84 (0.64) 1.85 (0.64) 1.84 (0.61) 1.88 (0.58) 1.66 (0.55) 1.70 (0.58) 1.64 (0.49) 1.66 (0.61) ACQ-5 score, ^† mean (SD) 2.69 (0.69) 2.73 (0.82) 2.73 (0.76) 2.74 (0.78) 2.75 (0.77) 2.80 (0.77) 2.81 (0.79) 2.80 (0.74) Total IgE in serum, median value (IQR), IU/ml; n 337.0 (147.0-629.0); 183 304.0 (137.0-835.5); 360 315.0 (142.0-763.0); 179 326.0 (152.0-762.0); 361 60.0 (24.0-147.0); 131 63.0 (24.0-135.0); 264 67.0 (24.0-154.0); 139 64.0 (24.0-150.0); 265 FeNO, median (IQR), ppb; n 27.0 (15.0-50.0); 180 25.0 (16.0-45.0); 358 30.0 (17.5-53.0); 176 24.0 (14.0-42.0); 358 24.0 (14.0-42.0); 131 22.0 (13.0-36.0); 266 22.5 (13.5-39.5); 140 24.0 (14.0-43.0); 269 Serum TARC, median (IQR), pg/mL; n 307.0 (218.0-508.0); 179 351.0 (224.5-478.5); 360 313.0 (206.0-525.0); 179 317.0 (198.0-456.0); 357 284.0 (196.0-421.0); 130 265.0 (187.5-402.5); 264 281.5 (186.0-449.0); 140 276.0 (178.0-386.0); 265 Blood eosinophil count, median (IQR), cells/µl; n 290.0 (150.0-490.0); 183 240.0 (120.0-470.0); 359 260.0 (160.0-440.0); 179 240.0 (140.0-430.0); 361 250.0 (130.0-470.0); 134 250.0 (120.00-460.0); 271 270.0 (120.0-470.0); 141 270.0 (130.0-510.0); 272

Statistical analyses

[00514] Efficacy analyses were performed in the intent-to-treat (ITT) population, which was defined as all randomized patients stratified into subgroups (i.e., with or without total serum IgE ≥ 30 IU/mL and ≥ 1 positive perennial aeroallergen-specific IgE (≥ 0.35 kU/L) at baseline). Data were analyzed for each subgroup according to the four intention-to-treat arms (dupilumab versus placebo), regardless of whether the intervention was received (Castro et al. (2018) New Engl. J. Med. 378:2486–96). The annualized rate of severe exacerbations over the 52-week treatment period was analyzed using a negative binomial regression model that included as covariates intervention assignment, age, geographic region, baseline eosinophil count strata, baseline inhaled glucocorticoid dose, and number of severe exacerbations in the previous year. All severe exacerbations that occurred during the 52-week treatment period were included regardless of whether the patient continued treatment.

[00515] Change from baseline in pre-bronchodilator FEV ₁ (L) and ACQ-5 scores over the 52-week treatment period were analyzed using repeated-measures mixed-effects models that included as covariates the four intervention groups assigned, age, geographic region, baseline eosinophil count strata, baseline inhaled glucocorticoid dose, visit, interaction with the effect of the intervention factor by visit, corresponding baseline value, and interaction with the effect of the baseline factor by visit. In addition, sex and height at baseline were also included as covariates for the FEV ₁ analysis. If treatment was discontinued, all measurements recorded after discontinuation were included during the 52-week treatment period.

[00516] Biomarker analyses were performed in the exposed population, defined as all patients exposed to study drug. For both patient subgroups, differences between dupilumab and matching placebo in change from baseline in eosinophils and FeNO, considered key biomarkers of type 2 inflammation, were analyzed using an analysis of covariance rank model including the 4 intervention assignments, age, sex, geographic region, baseline eosinophil count strata, baseline inhaled glucocorticoid dose, and corresponding baseline value as covariates. For specific IgE analyses, analyses were restricted to patients who were positive (≥0.35 kU/L) for specific IgE at baseline.

[00517] A nominal P-value <0.05 for the comparison between each dupilumab dose and the corresponding placebo (in each subgroup) was considered statistically significant.

[00518] The residuals from the linear mixed model for the allergic asthma subgroup with baseline serum IgE >700 IU/mL were examined to ensure a normally distributed population. A histogram of the residuals as well as a qq plot are shown in Fig. 6 .

EXAMPLE 2. Frequency of severe asthma exacerbations per year - allergic asthma

[00519] In the subgroup of patients with allergic asthma, dupilumab reduced the adjusted annualized rate of severe exacerbations compared with placebo by 36.9% at 200 mg q2w (95% confidence interval (CI) 13.4%-54.0%; nominal P-value = 0.004) and by 45.5% at 300 mg q2w (95% CI 26.0%-59.9%; nominal P-value <0.001; Fig. 1A ). In patients who did not meet criteria for allergic asthma, the adjusted annualized rate of severe exacerbations was also significantly reduced by 60.0% with dupilumab 200 mg q2w (95% CI 42.7%-72.1%; nominal P-value <0.001) and by 44.6% with dupilumab 300 mg q2w (95% CI 21.5%-60.9%; nominal P-value <0.001) compared with placebo ( Fig. 1A ). In both the allergic asthma subgroup and the subgroup that did not meet criteria for allergic asthma, dupilumab 200 mg and 300 mg q2w significantly (all nominal P-values <0.01) reduced the incidence of severe exacerbations in patients with baseline blood eosinophils ≥150 cells/μL and ≥300 cells/μL and in patients with baseline FeNO ≥25 ppb. The effect size was numerically larger compared with the corresponding overall subgroup ( Fig. 1B–1D ). Among patients in the allergic asthma subgroup with baseline serum total IgE >700 IU/mL, both doses of dupilumab significantly (nominal P-value <0.001) reduced the incidence of severe exacerbations over the 52-week treatment period compared with corresponding placebo, and the effect size was numerically larger compared with the overall allergic asthma subgroup ( Fig. 1E ).

EXAMPLE 3. FEV ₁ before using a bronchodilator - Allergic asthma

[00520] At week 12, treatment with dupilumab 200 mg and 300 mg q2w significantly improved pre-bronchodilator mean _FEV1 compared with placebo, as determined by least squares (LS), by 0.13 L (95% CI 0.05-0.20; nominal P-value <0.001) and 0.16 L (95% CI 0.09-0.23; nominal P-value <0.001), respectively, in the allergic asthma subgroup and by 0.14 L (95% CI 0.07-0.22; nominal P-value <0.001) and 0.09 L (95% CI 0.01-0.16; nominal P-value =0.02), respectively, in those patients who did not met the criteria ( Fig. 2A ). As observed in severe exacerbations, the magnitude of improvement compared with placebo in pre-bronchodilator _FEV1 at week 12 was equal to or greater than that in patients with baseline blood eosinophils ≥150 cells/μL and ≥300 cells/μL and in patients with baseline FeNO ≥25 ppb, compared with their respective overall subgroups (all nominal P-values <0.05; Fig. 2B ). Among patients in the allergic asthma subgroup with baseline serum total IgE >700 IU/mL, dupilumab 300 mg q2w demonstrated a similar magnitude of effect on pre-bronchodilator _FEV1 at week 12 compared with the overall subgroup (least squares mean difference vs. placebo 0.12 L (95% CI -0.03 to 0.26; nominal P-value = 0.11)), while a larger effect was observed in patients receiving dupilumab 200 mg q2w (least squares mean difference vs. placebo 0.27 L (95% CI 0.13 to 0.42); nominal P-value < 0.001).

[00521] In both the allergic asthma and non-allergic asthma subgroups, improvements in pre-bronchodilator FEV ₁ were observed as early as the first assessment at week 2 and were maintained through week 52 ( Figure 2A ).

EXAMPLE 4. Control asthma - Allergic asthma

[00522] In the allergic asthma subgroup, the change from baseline in least squares means for the ACQ-5 score improved by -1.39 (standard error [SE] 0.05) with a difference compared to placebo of -0.28 (95% CI -0.46 to -0.11; nominal P-value <0.01) in patients receiving dupilumab 200 mg q2w and by -1.42 (SE 0.05) with a difference compared to placebo of -0.26 (95% CI -0.44 to -0.08; nominal P-value <0.01) at week 24 ( Figure 3 ) in patients receiving dupilumab 300 mg q2w. In the subgroup that did not meet criteria for allergic asthma, the improvement in ACQ-5 score from baseline at week 24 was -1.51 (SE 0.06), with a difference compared with placebo of -0.44 (95% CI -0.65 to -0.22; nominal P-value < 0.0001), in patients receiving dupilumab 200 mg q2w, and -1.35 (SE 0.06), with a difference compared with placebo of -0.08 (95% CI -0.29 to 0.12; nominal P-value = 0.43), observed in patients receiving dupilumab 300 mg q2w ( Fig. 3 ).

EXAMPLE 5. Total IgE in serum and aeroallergen-specific IgE - Allergic asthma

[00523] In the allergic asthma subgroup and the subgroup that did not meet criteria for allergic asthma, the dupilumab 200 mg and 300 mg q2w dose regimens significantly reduced total serum IgE compared with placebo at week 12 (earliest time point evaluable; nominal P-value <0.001; Fig. 4A ). The reduction in total serum IgE occurred gradually throughout the treatment period (nominal P-value <0.001 compared with placebo at all time points).

[00524] In patients with allergic asthma who tested positive at baseline (≥0.35 kU/L) for the relevant perennial aeroallergen, significant reductions from baseline in the percentage of serum antigen-specific IgE were observed over time for each of the 8 perennial aeroallergens assessed ( Fig. 5A-H ). This reduction was statistically significant at week 12 (the earliest time point assessed) compared with the corresponding placebo (nominal P-value <0.05) and was maintained throughout the 52-week treatment period. Too few patients tested positive for black cockroach allergens at baseline to allow meaningful analysis.

EXAMPLE 6. FeNO and TARC in blood serum - Allergic asthma

[00525] In both the allergic asthma subgroup and the subgroup that did not meet criteria for allergic asthma, the dupilumab 200 mg and 300 mg q2w dose regimens were associated with significant reductions in FeNO at the first assessment after 2 weeks of treatment compared with placebo. The reduction in FeNO was maintained over the 52-week treatment period (nominal P-value < 0.001 at all time points) ( Fig. 4B ). By week 52, median FeNO values for the dupilumab 200 mg and 300 mg q2w doses in both subgroups were similar to the published median values in healthy volunteers (16 ppb).

[00526] In both the allergic asthma subgroup and the subgroup that did not meet criteria for allergic asthma, serum TARC concentrations were significantly reduced compared with placebo at week 12 (the earliest evaluable time point) in patients receiving dupilumab 200 mg or 300 mg q2w. This reduction was maintained over the 52-week treatment period (nominal P -value <0.001 at all time points) ( Fig. 4C ).

EXAMPLE 7. Discussion - Allergic asthma

[00527] Dupilumab significantly reduced the rate of severe exacerbations and improved FEV ₁ and asthma control (as measured by the ACQ-5) in patients with allergic asthma. Improvements in FEV ₁ and asthma control were evident at the first assessment at week 2 and were maintained over the 52-week treatment period. Some variability in exacerbation rates and asthma control was observed between the two doses of dupilumab and the corresponding placebo. Without wishing to be bound by a specific scientific theory, this was likely due to the need to use two different placebos of comparable size. The reduction in severe exacerbations and improvement in FEV ₁ were greater in patients with higher levels of type 2 inflammation biomarkers at baseline. The proportion of patients who met criteria for allergic asthma (57%) in this study was significantly lower than patients who reported a history of ≥1 atopic condition in the overall QUEST population (Castro et al. (2018) New Engl. J. Med. 378:2486–96). This difference is primarily due to the exclusion of patients with a history of allergic rhinitis but no evidence of hypersensitivity to aeroallergens, the exclusion of patients who were hypersensitized only to seasonal allergens (to a lesser extent), and the exclusion of patients with sensitivity to year-round allergens but whose total serum IgE was <30 IU/mL. It should be acknowledged that the timing of specific IgE measurements in this global study was not timed to coincide with peak seasonal allergen exposure in each country/region.

[00528] Dupilumab was shown to be effective in patients with allergic asthma as well as in those who did not meet criteria for allergic asthma. These data support the critical role of IL-4 and IL-13 in the development of IgE-mediated and non-IgE-mediated type 2 inflammation in asthma. The clinical benefits observed in this study were generalizable to patients with allergic asthma who had baseline serum total IgE levels greater than 700 IU/mL. This is a clinically important subgroup of patients with allergic asthma for whom anti-IgE therapy with omalizumab is not indicated 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 dupilumab dosing, unlike omalizumab, is not limited by body weight and total serum IgE levels in adolescent and adult patients with uncontrolled moderate to severe asthma.

[00529] Consistent with dupilumab's mechanism of action to suppress IgE production, dupilumab significantly reduced total serum IgE and aeroallergen-specific IgE levels in patients with allergic asthma, and reduced total serum IgE levels in those who did not meet criteria for allergic asthma.

[00530] Similarly, dupilumab significantly reduced levels of other type 2 inflammation biomarkers, including FeNO and serum TARC, in both patient subgroups. The reduction in total and specific IgE levels was slower compared to other biomarkers, such as FeNO. The reduction in IgE concentrations did not stabilize over the 52-week treatment period.

[00531] In summary, this is the first demonstration of the clinical and pharmacodynamic effects of dual IL-4 and IL-13 inhibition with dupilumab in patients with allergic asthma, defined as serum total IgE ≥30 IU/mL and ≥1 perennial aeroallergen-specific IgE ≥0.35 kU/L at baseline. Dupilumab significantly reduced the incidence of severe exacerbations, improved _FEV1 , and demonstrated clinically meaningful improvements in asthma control (ACQ-5) over the 52-week treatment period regardless of subgroup, and treatment was generally well tolerated in the study population. Markers of type 2 inflammation, including FeNO, total IgE, and TARC, were also significantly reduced with dupilumab treatment in both subgroups. The results of this study support the role of IL-4 and IL-13 in IgE-mediated and non-IgE-mediated inflammatory pathways in asthma. Inhibition of IL-4/IL-13 by dupilumab therapy is beneficial in both allergic and non-allergic asthma phenotypes.

EXAMPLE 8. Efficacy of dupilumab in patients with uncontrolled moderate to severe asthma and serologic evidence of allergic bronchopulmonary aspergillosis (ABPA)

[00532] Allergic bronchopulmonary aspergillosis (ABPA) is a severe allergic lung disease caused by hypersensitivity to Aspergillus fumigatus (Af) antigen. Not all patients with asthma develop ABPA upon exposure to the fungus. However, individuals with a genetic predisposition (HLA-DR2 (HLA-DRB1*1501 and *HLA-DRB1*1503) and HLA-DR5) are susceptible to developing ABPA upon exposure to Af antigen. IL-4Rα and IL-13 SNPs are also involved in the genetic predisposition, and these individuals develop a pronounced type 2 immune response with very high IgE levels, eosinophilia, elevated FeNO, etc.

[00533] The mainstay of treatment for ABPA is systemic steroids. However, not all patients respond to systemic steroids, and the disease may progress to bronchiectasis and fibrosis. Accordingly, there is a large unmet need for treatment in subjects with ABPA.

Study

[00534] The Phase 3 LIBERTY ASTHMA QUEST study (NCT02414854) evaluated patients with serologic evidence of ABPA (baseline total serum IgE >1000 IU/mL, positive serum IgE-Af >0.35 IU/mL, blood eosinophils >500 cells/μL) receiving additional dupilumab (200 mg or 300 mg) once every 2 weeks versus placebo.

Population

[00535] Of the 1902 patients with moderate to severe asthma enrolled in the QUEST study, 30 patients with serologic evidence of ABPA (ABPA-S) (1.6%) were identified. Baseline characteristics of these patients and the remaining QUEST intent-to-treat (ITT) population (n=1872) are shown in Table 2. At baseline, no significant differences were observed in mean age, _FEV1 , ACQ-5, or Asthma Quality of Life Questionnaire (AQLQ) scores between patients with and without ABPA-S, although patients with ABPA-S had higher baseline levels of type 2 biomarkers, eosinophils, IgE, and FeNO compared with patients with asthma without ABPA-S.

Endpoints/Visit

[00536] Annualized incidence of severe exacerbations (defined as worsening asthma symptoms requiring treatment with systemic corticosteroids for ≥3 days, or hospitalization or emergency department visit requiring systemic corticosteroids) and change from baseline in pre-bronchodilator FEV1 (L) and the patient-reported 5-item Asthma Control Questionnaire (ACQ-5) score assessed at baseline and at regular intervals during the 52-week treatment period ( Fig. 7 ). Change in least squares means from pre-bronchodilator FEV1 (L) at baseline were determined at weeks 24 and 52 in the ITT population ( Fig. 8 ). Total (absolute) serum IgE was determined at week 52 in the exposed population ( Fig. 9 ). Total (absolute) Af-specific IgE levels in serum were determined at week 52 in the exposed population ( Fig. 10 ). Total (absolute) FeNO levels were determined at week 52 in the exposed population ( Fig. 11 ).

Treatment groups

[00537] 200 mg dupilumab q2w and 300 mg dupilumab q2w and matched placebo, pooled.

Results

[00538] The annualized rate of severe exacerbations during the 52-week treatment period was analyzed using negative binomial regression models. Changes in mean least squares _FEV1 values from baseline to weeks 24 and 52 were determined using repeated-measures mixed-effects models. Total IgE, IgE-Af, and FeNO at week 52 were assessed using the Wilcoxon rank-sum test.

[00539] In patients with ABPA-S, dupilumab significantly reduced the adjusted annualized rate of severe exacerbations compared with placebo by 81.1% (95% confidence interval [CI] 0.052-0.693; P=0.01) ( Fig. 12 ).

FEV ₁ before administration of a bronchodilator

[00540] Patients receiving dupilumab experienced numerical improvements in pre-bronchodilator FEV1 compared with placebo in patients with ABPA-S. Improvements were observed as early as week 2, the first time point at which patients were assessed, and were maintained over the 52-week treatment period ( Figure 13 ). Dupilumab, compared with placebo, improved pre-bronchodilator _FEV1 in patients with ABPA-S by a least squares (LS) mean difference of 0.21 L (95% CI -0.18 to 0.60; P=0.28) at week 12 and by 0.33 L (-0.02 to 0.68; P=0.07) at week 52.

Asthma control

[00541] In patients with ABPA-S, dupilumab improved ACQ-5 score as early as 2 weeks after treatment initiation, with a least squares (LS) mean difference of -0.56 (95% CI -1.09 to -0.02; P < .05) compared with placebo. This was maintained throughout the 52-week treatment period, with numerical improvements in ACQ-5 score at every time point except weeks 12 and 16. At week 52, dupilumab improved ACQ-5 score by a least squares (LS) mean difference of -0.20 (-0.86 to 0.46; P = .54) compared with placebo ( Figure 14 ).

Total IgE and A. fumigatus-specific IgE levels in serum

[00542] Total serum IgE at baseline was significantly increased in patients with ABPA-S compared to patients with asthma without ABPA-S (median values: 2148-3383 IU/mL compared to 159-165 IU/mL). During treatment, significant reductions in total serum IgE were observed in patients with ABPA-S receiving dupilumab compared to patients with ABPA-S receiving placebo, beginning at the earliest evaluable time point of week 12 ( Fig. 15A ). This decrease continued to gradually diminish throughout the treatment period, and by week 52, the median serum total IgE concentration was 691.5 IU/mL (95% CI, 323.0 to 2617.0), with a median percent change from baseline of -75.6% (-81.6 to -44.6). In patients receiving placebo, the concentration at week 52 was 1714.0 IU/mL (95% CI, 727.0 to 3048.0), with a median percent change from baseline of -19.6% (95% CI, -56.3 to 102.6; P < 0.01) ( Fig. 15A ). This was similar to the median percentage change from baseline in total serum IgE observed in the overall ITT population of the QUEST study (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 total serum IgE with dupilumab was similar regardless of baseline IgE values.

[00543] Dupilumab treatment in patients with ABPA-S also suppressed A. fumigatus -specific IgE levels from a median baseline of 2.4 IU/mL (95% CI 0.6, 11.2) (placebo group median baseline of 3.0 IU/mL [95% CI 0.5, 28.8]). These reductions were evident by week 12. After further gradual reduction, the median A. fumigatus -specific IgE concentration at week 52 was 0.8 IU/mL (95% CI 0.1, 2.6), with a median percent change from baseline of -74.8% (95% CI -83.5, -56.2) in dupilumab-treated patients. 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) ( Fig. 15B ).

Other type 2 biomarkers

[00544] In patients with ABPA-S, median baseline FeNO concentrations were 49.0 ppb (95% CI 24.0-68.0) and 31.0 ppb (95% CI 19.0-63.0) in the dupilumab and placebo groups, respectively. Dupilumab reduced FeNO concentrations from baseline as early as week 2 of treatment, with a median concentration of 18.0 ppb (95% CI 12.0 to 26.0) and a median percent change of -50.8% (95% CI -62.5 to -41.9) in the dupilumab group compared with a median concentration of 38.0 ppb (95% CI 23.0 to 50.0) and a median percent change of -5.0% (95% CI -25.4 to 50.0) in the placebo group (P < 0.01). FeNO reduction was maintained through week 52 with a median of 18.0 ppb (95% CI 12.0 to 26.0) and median percent 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 median percent change of -24.3% (95% CI -52.2 to 57.1) in placebo-treated patients (P < 0.05) ( Fig. 16A ). Dupilumab treatment reduced FeNO to levels similar to the published median of 16 ppb in healthy volunteers.

[00545] Serum TARC concentrations were also reduced by dupilumab treatment in patients with ABPA-S. Median serum TARC concentrations at baseline were 553.0 pg/mL (95% CI 442.0-1510.0) and 646.0 pg/mL (385.0-894.0) 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 percent change from baseline of -62.0% (-76.0 to -35.3) compared with a median of 674.0 pg/mL (462.0 to 900.0) and a median percent change of -10.1% (-17.9 to 15.1) in placebo-treated patients (P < 0.01). This significant reduction was maintained over the 52-week treatment period with a median of 234.0 pg/mL (182.0 to 336.0) and a median percent change from baseline of -66.1% (-79.6 to -51.0) at week 52 in patients receiving dupilumab compared with 580.0 pg/mL (451.0 to 1020.0) and -17.4% (-35.7 to 25.8) in patients receiving placebo (P < 0.01) ( Fig. 16B ).

[00546] Dupilumab treatment also reduced serum eotaxin-3 concentrations in patients with ABPA-S. Reductions were observed beginning at week 12 with a median of 24.5 pg/mL (95% CI 18.0 to 41.7) and a median percent change from baseline of -64.9% (-83.3 to -44.7) in patients receiving dupilumab compared with 53.1 pg/mL (23.0 to 125.0) and -5.4% (-40.6 to 34.8) in the placebo group (P < 0.01). This reduction was maintained through week 52 with a median 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) ( Fig. 16C ).

[00547] The median blood eosinophil count at baseline was increased (825 to 1075 eosinophils/μL) in patients with ABPA-S. At week 52, patients receiving dupilumab had a median blood eosinophil count of 595.0 cells/μL (95% CI 360.0 to 1160.0) and a median percent change from baseline of -31.3% (-55.2 to 0) compared with 590.0 cells/μL (340.0 to 1080.0) and -45.5% (-55.5 to 0) in patients receiving placebo (P=0.69) ( Fig. 16D ).

Safety in patients with ABPA-S

[00548] The incidence of treatment-emergent adverse events (TEAEs) in patients with ABPA-S was similar regardless of treatment (94.4% in the dupilumab combination group and 100% in the placebo combination group) (Table 3). The most common TEAE, occurring more frequently in patients receiving dupilumab than in patients receiving placebo, was upper respiratory tract infection (27.8% of patients receiving dupilumab compared with 25.0% of patients receiving placebo). Injection site reactions (Medical Dictionary for Regulatory Activities, high-level term) occurred in 16.7% of patients receiving dupilumab compared with 0% of patients receiving placebo. According to the study protocol, all cases of eosinophil count >3000/mm3 during the 52-week intervention period were recorded as adverse events. One patient with ABPA-S (5.6%) receiving dupilumab 200 mg q2w experienced moderate eosinophilia. This was a laboratory finding without associated symptoms, and the patient completed the 52-week treatment period. No patients receiving dupilumab 300 mg or placebo experienced eosinophilia. Serious TEAEs occurred in one patient (5.6%) receiving dupilumab and two patients (16.7%) receiving placebo. No TEAEs resulting in death were reported in this population.

Discussion

[00549] In the LIBERTY ASTHMA QUEST study, dupilumab demonstrated beneficial effects in a subgroup of patients defined post hoc as meeting ABPA-S diagnostic criteria. Treatment with dupilumab significantly reduced the incidence of severe exacerbations and showed a trend toward improvement in lung function. Although the improvement in FEV ₁ was not statistically significant, likely due to the small sample size, the mean change from baseline of 510 mL at week 52 in patients receiving dupilumab was clinically meaningful. Improvement in FEV ₁ occurred rapidly, as early as 2 weeks after treatment initiation, and was maintained over the 52-week treatment period. Treatment with dupilumab also improved asthma control (ACQ-5 score) in this subgroup of patients with typically difficult-to-control symptoms.

[00550] Consistent with the pathophysiology of ABPA, this subset of patients exhibited evidence of persistent type 2 inflammation with markedly elevated baseline levels of type 2 biomarkers including FeNO, blood eosinophils, TARC, total serum IgE, and A. fumigatus -specific IgE compared to asthma patients without serologic evidence of ABPA. Without wishing to be tied to a specific scientific theory, the elevated FeNO concentrations in patients with ABPA likely represent concomitant airway inflammation not caused by an allergic reaction, further emphasizing the utility of FeNO as a marker of type 2 inflammation. Two defining diagnostic features of ABPA are very high serum concentrations of total IgE and 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 to A. fumigatus antigens. Indeed, total serum IgE concentrations are routinely monitored during ABPA treatment to assess disease activity, with a decrease to near-normal levels considered a marker of disease remission. Dupilumab treatment markedly suppressed both total and specific IgE, consistent with the mechanism of action of dupilumab, which by blocking IL-4 and IL-13 signaling inhibits B cell isotype switching and hence IgE production. Furthermore, type 2 inflammation biomarkers in both blood (TARC and eotaxin-3) and local airways (FeNO) were also rapidly suppressed in ABPA-S patients treated with dupilumab, indicating that through dual blockade of IL-4 and IL-13, dupilumab was able to rapidly control the underlying pathogenic type 2 inflammation characteristic of ABPA patients.

[00551] Dupilumab was generally well tolerated in patients with ABPA, with a similar TEAE incidence profile in patients receiving dupilumab compared with placebo. The most common TEAE observed in patients receiving dupilumab was upper respiratory tract infection. In contrast to the transient eosinophilia observed in patients with asthma, only 1 (5.6%) patient with ABPA receiving dupilumab in this analysis reported eosinophilia during the treatment period, despite these patients having hypereosinophilia at baseline (median 925.0 cells/μL). Additionally, unlike the asthma studies where eosinophil counts were unchanged at week 52, in this analysis, ABPA-S patients showed an overall decrease in median blood eosinophil counts over the 52-week treatment period.

[00552] Clinically, patients with asthma who have ABPA are characterized by poor symptom control and more frequent exacerbations compared to those without ABPA. Unlike asthma, if ABPA diagnosis is delayed or the disease is left untreated, it progresses to decreased lung function and end-stage pulmonary fibrosis. These data suggest the utility of dupilumab as a new treatment for patients with ABPA that improves symptoms and lung function by controlling the underlying pathogenic type 2 inflammation.

Table 2. Demographics and clinical characteristics of the overall ITT patient population with and without serologic evidence of ABPA at baseline With ABPA Without ABPA Placebo q2w data taken together
(n=12) Dupilumab 200/300 mg q2w data taken together
(n=18) Placebo q2w data taken together
(n=626) Dupilumab 200/300 mg q2w data pooled (n=1246) Age, mean (SD), years 48.5 (19.4) 40.0 (19.7) 48.2 (15.1) 47.9 (15.3) Women, n (%) 8 (66.7) 7 (38.9) 408 (65.2) 774 (62.1) BMI, mean (SD), kg/ ^m2 30.66 (6.61) 24.04 (4.70) 29.46 (7.11) 29.13 (6.59) FEV ₁ before bronchodilator use, mean (SD), L 1.59 (0.49) 2.00 (0.68) 1.76 (0.59) 1.78 (0.61) FEV ₁ before bronchodilator administration, mean (SD), % of predicted 58.33 (13.98) 60.94 (15.30) 58.39 (13.54) 58.41 (13.49) FEV ₁ reversibility, mean (SD), % 13.64 (8.44) 23.43 (12.73) 25.99 (18.27) 26.60 (23.42) Exacerbations in the last year, mean (SD), n 2.50 (1.68) 2.28 (1.53) 2.19 (1.85) 2.04 (2.30) High-dose ICS/LABA use, n (%) 10 (83.3) 9 (50.0) 329 (52.6) 631 (50.6) ACQ-5 score, mean (SD) 2.82 (0.83) 2.70 (0.67) 2.74 (0.75) 2.76 (0.78) Total score according to AQLQ, mean (SD) 4.36 (0.73) 4.53 (1.05) 4.28 (1.03) 4.29 (1.07) Blood eosinophil content, cells/µl
Median value (IQR, Q1-Q3) 1075,00
(645.00-1365.00) 825,00
(670.00-1100.00) 260,00
(140.00-450.00) 250,00
(130.00-440.00) Mean (SD) 1075.00 (438.96) 936.11 (379.60) 367.52 (367.49) 341.61 (350.04) ECP, ng/ml
Median value (IQR, Q1-Q3) 37,00
(21.00-54.00) 38.50
(23.00-59.00) 17.00
(9.00-31.00) 16.00
(8.00-32.00) Mean (SD) 40.36 (24.27) 56.22 (57.12) 26.33 (29.44) 24.79 (27.76) FeNO, ppb
Median value (IQR, Q1-Q3) 31,00
(19.50-53.00) 49,00
(24.00-68.00) 26.00
(15.00-47.00) 24.00
(14.00-42.00) Mean (SD) 39.08 (27.17) 50.33 (30.06) 36.39 (33.81) 33.99 (32.40) Total IgE, IU/ml
Median value (IQR, Q1-Q3) 2148,00
(1445.50-2734.00) 3383,00
(1480.00-5000.00) 165,00
(59.00-423.00) 159,00
(61.00-432.50) Mean (SD) 2128.58 (878.16) 3335.67 (1687.73) 388.31 (672.17) 395.65 (651.79) A. fumigatus-specific IgE, IU/ml
Median value (IQR, Q1-Q3) 2.96
(0.52-28.80) 2.44
(0.64-11.20) 0.05
(0.05-0.05) 0.05
(0.05-0.05) Mean (SD) 11.58 (17.03) 7.27 (10.34) 0.50 (2.66) 0.36 (1.66) Periostin, ng/ml
Median value (IQR, Q1-Q3) 88.10
(58.10-115.35) 108.30
(84.70-151.60) 71,00
(54.10-94.30) 69,70
(54.30-92.70) Mean (SD) 86.72 (33.51) 136.78 (78.09) 80.16 (38.81) 78.34 (37.06) Eotaxin-3, pg/ml
Median value (IQR, Q1-Q3) 46.50
(29.40-165.00) 66.95
(51.50-153.00) 36.70
(22.80-62.20) 38.50
(25.10-59.20) Mean (SD) 95.30 (96.82) 123.33 (136.33) 50.72 (72.68) 73.17 (419.78) TARC, pg/ml
Median value (IQR, Q1-Q3) 646,00
(470.50-891.50) 553,00
(442.00-1510.00) 296,00
(202.00-460.50) 301,00
(197.00-443.00) Mean (SD) 670.00 (321.41) 1387.35 (2065.80) 382.61 (315.47) 365.31 (284.44)

ABPA , allergic bronchopulmonary aspergillosis; ACQ-5 , 5-item asthma control questionnaire; AQLQ , Asthma Quality of Life Questionnaire; BMI , body mass index; ECP , eosinophil cationic protein; ICS , inhaled corticosteroids; IQR , interquartile range; ITT , intention-to-treat population; FeNO , fractional nitric oxide in expired air; FEV1 , forced expiratory volume in 1 second; LABA , long-acting β2-agonist; ppb , parts per billion; q2w , once every 2 weeks; SD , standard deviation; TARC , thymus- and activation-regulated chemokine.

Table 3. Treatment-emergent adverse events in patients with ABPA serology that occurred during the intervention period - safety population Phenomenon, n (%) Comparable q2w placebo taken together
(n=12) Dupilumab 200/300 mg q2w taken together
(n=18) Any TEAE 12 (100) 17 (94.4) Any serious TEAE ^† 2 (16.7) 1 (5.6) Any TEAE resulting in death 0 0 TEAEs occurring in ≥ 10% of patients (MedDRA PT) ^‡ Upper respiratory tract infection 3 (25.0) 5 (27.8) Viral upper respiratory tract infection 6 (50.0) 3 (16.7) Allergic conjunctivitis 0 2 (11.1) Arthralgia 2 (16.7) 3 (16.7) Musculoskeletal chest pain 0 2 (11.1) Accidental overdose 0 2 (11.1) Injection site reactions ^§ 0 3 (16.7)

ABPA , allergic bronchopulmonary aspergillosis; MedDRA , Medical Dictionary for Regulatory Activities; PT , preferred term; q2w , once every 2 weeks; TEAE , treatment-emergent adverse event. One patient with ABPA-S in the dupilumab group reported eosinophilia, compared with no eosinophilia in the placebo group. ^† Serious TEAEs included gastroenteritis and asthma in patients receiving placebo and musculoskeletal chest pain and osteoarthritis in patients receiving dupilumab. ^‡ Adverse events in this category were reported according to PT in MedDRA version 20.0 unless otherwise noted. ^§ Injection site reaction is a high-level term in MedDRA.

EXAMPLE 9. Post-hoc analysis of yellow fever vaccine: an open-label extension study to evaluate the long-term safety and tolerability of dupilumab in patients with asthma who participated in a previous clinical trial of dupilumab in asthma

Research plan

[00553] Study LTS12551 (TRAVERSE) was a multinational, multicenter, single-arm, open-label extension study to evaluate the long-term safety and tolerability of dupilumab 300 mg q2w in patients with asthma who completed the treatment and follow-up periods of study DRI12544 or completed the treatment periods of studies EFC13579, EFC13691, or PDY14192. DRI12544 (N=776) was a randomized, double-blind, placebo-controlled, parallel-group, phase 2b dose-ranging study of varying doses and schedules of subcutaneous (SC) dupilumab for 24 weeks in adult patients with moderate to severe asthma. PDY14192 (N=42) was an exploratory, randomized, double-blind, placebo-controlled, phase 2a study investigating the effect of dupilumab 300 mg q2w SC for 12 weeks on airway inflammation in adults with uncontrolled persistent asthma. EFC13579 (N=1902) was a randomized, double-blind, parallel-group, placebo-controlled, phase 3 study evaluating the efficacy and safety of dupilumab 200 mg and 300 mg q2w SC for 52 weeks in adults and adolescents with uncontrolled persistent asthma. EFC13691 (N=210) was a randomized, double-blind, placebo-controlled phase 3 study to evaluate the efficacy and safety of dupilumab 300 mg q2w SC for 24 weeks in adults and adolescents with severe OCS-dependent asthma.

[00554] While the LTS12551 study was ongoing, a yellow fever outbreak in Brazil required administration of yellow fever vaccine (YFV) to all unvaccinated individuals residing in at-risk areas. The sponsor implemented Amendment 5 to the regional protocol, which allowed administration of YFV (live attenuated vaccine) to all patients requiring YFV in the outbreak-affected area. All affected patients were required to discontinue dupilumab, and vaccination could be administered after discontinuation of dupilumab. Patients were allowed to restart dupilumab at the discretion of the investigator after demonstrating sufficient yellow fever neutralization titers (i.e., plaque neutralization titers; PRNT). Patients who were not vaccinated were eligible to restart study treatment after the outbreak had subsided.

[00555] All patients continued to be followed until the end of the study, regardless of whether dupilumab treatment was restarted. For those patients scheduled for yellow fever vaccination, samples to assess drug pharmacokinetic (PK) and immunogenicity, as well as pre- and post-vaccination antibody titers, were to be collected both before and 4-6 weeks post-vaccination, with the possibility of extending to 8 weeks, with patient consent. A total of thirty-seven patients discontinued dupilumab treatment and were subsequently vaccinated with YFV. Although patients were allowed to restart dupilumab treatment upon demonstration of neutralizing titers at the discretion of the treating physician, no patients restarted dupilumab treatment due to delayed results.

[00556] A post hoc analysis of YFV was performed to assess the humoral immune response and safety/tolerability of YFV in this subgroup of 37 patients who participated in the LTS12551 study and received YFV.

Objectives of the study

[00557] The objective of this study was to evaluate the humoral immune response, safety and tolerability of YFV, a live attenuated vaccine, in patients with moderate to severe asthma who participated in the LTS12551 study and received dupilumab.

Patients

[00558] A total of 37 patients who entered study LTS12551 (an open-label asthma study) and received YFV were included in this analysis. Of these, 33 crossed over from study EFC13579 and four crossed over from study EFC13691. Of the patients who entered from study EFC13579, 11 had previously received placebo in the parent study and then received dupilumab in study LTS12551 (placebo/dupilumab category), and 22 had previously received dupilumab in the parent study and continued dupilumab treatment in study LTS12551 (dupilumab/dupilumab category). Of the patients included from study EFC13691, three patients had previously received placebo in the parent study and then received dupilumab in study LTS12551 (placebo/dupilumab category), and one patient had previously received dupilumab in the parent study and continued dupilumab treatment in study LTS12551 (dupilumab/dupilumab category).

Demographic data and other characteristics at baseline

[00559] Baseline patient demographics and characteristics for the 37 patients receiving YFV were generally similar among patients previously treated with placebo or dupilumab in each parent study (see Table 4 below). The median age in the population was 46.5 years, with a range of 24 to 68 years, 5 (13.5%) patients were ≥ 65 years of age, and 12 (32.4%) patients were male. The mean (SD) BMI was 30.1 (5.7) kg/ ^m2 .

Table 4. Demographics and patient characteristics at the time of yellow fever vaccination - Exposed population - Patients vaccinated against yellow fever in study LTS12551

Medical history

[00560] The history of concomitant diseases of the patients is presented in Table 5. The majority of patients (91.9%) had a history of concomitant disease, the most common of which was allergic rhinitis (86.5%).

Table 5. History of comorbidities from the parent study - Exposed population - Patients vaccinated against yellow fever in study LTS12551

Safety assessment

Degree of impact

[00561] The extent of study drug exposure in the exposed population in study LTS12551 prior to yellow fever vaccination is summarized in Table 6. The mean (SD) duration of dupilumab treatment in study LTS12551 was 242.2 (34.4) days and was similar for all patients receiving YFV. In patients crossing over from study EFC13579, the mean duration of treatment was similar in the placebo/dupilumab and dupilumab/dupilumab groups (255.0 and 230.1 days, respectively). In patients crossing over from study EFC13691, the mean duration of treatment was similar in the placebo/dupilumab and dupilumab/dupilumab groups (274.7 and 268.0 days, respectively).

Table 6. Exposure to study drug prior to yellow fever vaccination - Exposed population - Patients vaccinated against yellow fever in study LTS12551.

[00562] As shown in Table 7, the time between the last dose of dupilumab and yellow fever vaccination ranged from 7 to 51 days with a mean (SD) of 22.3 (±11.9) days.

Table 7. Summary of time between last IMP injection and yellow fever vaccination - Exposed population - Patients vaccinated against yellow fever in study LTS12551

[00563] 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.

Table 8. Summary of duration of follow-up after yellow fever vaccination - Exposed population - Patients vaccinated against yellow fever in study LTS12551

Adverse events

[00564] A total of 37 patients received YFV. Vaccine was administered 7-51 days after the last dose of dupilumab. One of the 37 patients experienced a non-serious adverse event of body pain, malaise, and dizziness after receiving the vaccine, which was reported as a "vaccine 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 well 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. None of the patients resumed dupilumab due to delayed results. Among 37 patients who received yellow fever vaccine in the LTS12551 study, there were no treatment-emergent deaths, SAEs (serious adverse events), or other significant AEs (adverse events).

Safety Conclusions

[00565]YFV given 7-51 days after stopping 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 resolved completely and is a common reaction to yellow fever vaccination. fevers (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 TropMedHyg. 2002; 66(5):533–541.). Thus, patients with therapeutic or subtherapeutic levels of dupilumab in this study tolerated YFV administration.

Pharmacokinetics, immune response and immunogenicity assessment

Humoral immune response to vaccine

[00566] The humoral immune response to YFV was determined using a standard plaque neutralization titer (PRNT) assay (Q Squared Solutions, LLC), which calculated the dilution factor that neutralizes 50% of the virus (PRNT50). Post-vaccination neutralization titers were obtained for all 37 patients, and pre- and post-vaccination PRNT titers were obtained for 23 of the 37 patients (Table 9). The patients' history of yellow fever vaccination and/or infection was unknown. As shown in Figs. 17A and 17B, of the 23 patients from whom pre-vaccination sera were obtained, 13 had PRNT <1:10 (defined as "seronegative"), while the remaining 10 patients had titers ranging from 1:10 to 1:160 (defined as "seropositive").

[00567] All 37 patients had seroprotective titers, defined as a PRNT titer >1:10, post-vaccination, with a mean post-vaccination titer of 1:7699 (±10951 SD; median 2560, range 80 to 40960). As shown in Figs. 17A and 17B, although two of the 23 patients had no increase in pre-vaccination titers post-vaccination, both patients already had seroprotective titers to YFV. Thus, all 37 vaccinated patients had seroprotective yellow fever neutralizing titers post-vaccination, including 13 patients with pre- and post-vaccination titers who seroconverted.

Table 9. Sample collection for PK assessment and vaccinated patients with PRNT titers

Evaluation of pharmacokinetics and immunogenicity

[00568] PK and ADA (anti-drug antibody) samples were collected before and after vaccination. Serum functional dupilumab concentrations were measured before and after vaccination. Among the 37 patients, 35 and 34 patients had pre-vaccination PK samples and pre-vaccination ADA samples, respectively. All 37 patients had post-vaccination PK and ADA samples. Nineteen patients had PK samples collected on the day of vaccination. Sixteen patients had PK samples collected before YFV administration (Table 9).

[00569] The time between the last dose of dupilumab and yellow fever vaccine administration, the time between pre-vaccination PK sample collection and yellow fever vaccine administration, and the time between yellow fever vaccine administration and post-vaccination PK sample collection are provided in Table 10.

Dupilumab concentrations before and after yellow fever vaccination

[00570] At the time of yellow fever vaccination, patients had been receiving dupilumab 300 mg q2w in study LTS12551 for at least 24 weeks and had reached steady state with a mean trough concentration of 73.3 mg/L at week 24. The mean time between the last dupilumab dose and YFV administration was approximately 3 weeks (median time 18 days, Table 7). Pre-vaccination PK samples were collected from 35/37 patients. The mean concentration of all pre-vaccination PK samples was 59.5 mg/L with the caveat that not all PK samples were collected on the day of yellow fever vaccine administration (Table 11). Pre-vaccination PK samples were collected on the day of YFV administration in 19 patients. The mean serum concentration in these patients was 72.5 mg/L, which was similar to the mean steady-state dupilumab trough concentration observed in patients receiving dupilumab 300 mg q2w in the dupilumab asthma and AD clinical studies. In 16 patients, pre-vaccination PK samples were collected 1-25 days before YFV administration, and for these patients, the mean concentration was 44.0 mg/L.

[00571] Post-vaccination PK samples were collected approximately 5 weeks (range 28 to 54 days) after YFV administration and approximately 8 weeks (range 39 to 79 days) after the last dose of dupilumab (Table 10). The observed mean post-vaccination PK sample concentration was 13.7 mg/L (N=37), within the range of expected dupilumab concentrations, with an approximately 8-week washout period after the last 300 mg q2w steady-state dose (Table 11).

Table 10. Summary of timing of serum sampling for PK assessment before and after yellow fever vaccination - PK assessment population - Yellow fever vaccinated patients in study LTS12551

Table 11. Summary of dupilumab serum concentrations before and after yellow fever vaccination - PK population - Yellow fever vaccinated patients in study LTS12551

[00572] Pre-vaccination PK samples were collected on the day of YFV administration in 15 of 23 patients. The mean dupilumab concentration in these 15 patients was 76.4 mg/L. Thirteen of the 15 patients had dupilumab concentrations above the mean trough concentration of 37.4 mg/L. Serum concentrations above this level were considered therapeutic and consistent with saturation levels of IL-4Rα blockade, as 37.4 mg/L was the mean steady-state trough concentration observed in asthma patients at the 200 mg q2w dose in the original Phase 3 study (EFC13579).

[00573] All 13 patients with serum dupilumab concentrations >37.4 mg/L had seroprotective PRNT titers following YFV. Twelve of these patients demonstrated an increase in titers following 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 in these patients is shown in Figure 18. Neutralization titers in all 13 patients following vaccination ranged from 1:80 to 1:40960, which is comparable to post-vaccination titers in patients with dupilumab concentrations <37.4 mg/L (1:160 to 1:40960).

[00574] Thus, in this subgroup of 23 patients with pre- and post-vaccination PK and PRNT titers, no association was observed between serum dupilumab levels and PRNT titer.

Incidence of ADA formation and titer before and after yellow fever vaccination

[00575] The incidence of ADA formation before and after YFV administration and the ADA titer category observed in patients are summarized in Table 12. Positive ADA assay responses were observed in three patients both before and after yellow fever vaccination. Among the patients with a positive ADA assay response, one patient had low ADA titers (<1,000) and two patients had high ADA titers (>10,000). The number of patients in each ADA titer category did not change before and after yellow fever vaccination, indicating no apparent effect of yellow fever vaccination on ADA responses. At the end of the study, in addition to the three patients who had a positive response before and after yellow fever vaccination, a positive ADA assay response was observed in one additional patient during the follow-up visit. Thus, among the four patients with a positive ADA assay, two patients had low ADA titers (<1000) and two patients had high ADA titers (>10,000) at the follow-up visit.

Table 12. Summary of ADA titers before and after yellow fever vaccination - ADA evaluation population - Yellow fever vaccinated patients in study LTS12551

Inferences based on the immune response and pharmacokinetics of dupilumab.

[00576] Immune response and pharmacokinetic data for dupilumab indicate that therapeutic serum levels of dupilumab do not inhibit protective immune responses to yellow fever vaccination with a live attenuated vaccine. Because dupilumab was not resumed following vaccination, serum levels continued to decline until post-vaccination titer assessment.

Impact of Vaccine Immune Response on Dupilumab Efficacy

[00577] The potential impact of yellow fever vaccination on the efficacy of dupilumab was assessed by examining the change in FEV ₁ before and after vaccination. All patients who discontinued dupilumab due to yellow fever vaccination were exposed to dupilumab in study LTS12551 for a median of 0.7 years and achieved stable improvement in lung function before discontinuing dupilumab (Table 6). FEV ₁ was stable from the pre-YFV visit to the first post-YFV visit (Fig. 19, Fig. 20). The mean (SD) FEV ₁ was 2.08 (0.83) L and 1.98 (0.79) L, respectively (Table 13). Overall, based on the observed data in the EFC13579 and DRI12544 studies, FEV ₁ levels would be expected to decline approximately 12 weeks after discontinuing dupilumab.

Table 13. Analysis of FEV change ₁ (l) compared with baseline before and after yellow fever vaccination - Exposed population - Patients vaccinated against yellow fever in study LTS12551.

Conclusions

[00578] In response to a regional outbreak of yellow fever, 37 patients enrolled in the LTS12551 study discontinued dupilumab and subsequently received YFV. Dupilumab did not reduce the efficacy of the live attenuated yellow fever vaccine. All 37 patients who received YFV demonstrated post-vaccination yellow fever virus antibody titers consistent with seroprotection. Pre- and post-vaccination neutralizing titers were obtained in 23 patients, 15 of whom had pre-vaccination sera obtained on the day of YFV administration. Of these 23 patients, 10 had pre-vaccination 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., were "seronegative"), indicating no prior exposure or a waning antibody response over time. The mean post-vaccination titer levels obtained 28-42 days after vaccination were 1:7699 (±10951 SD; median 2560, range 80-40960), with all but 2 patients having elevated neutralizing titers after vaccination and all 23 patients having titers at levels consistent with seroprotection against yellow fever.

[00579] Therapeutic levels of dupilumab do not appear to inhibit the seroprotective immune response to dupilumab. In 15 patients who had titers both before and after yellow fever vaccination, PK measurements were also obtained on the day of vaccination. At the time of vaccination, 13 of 15 patients had dupilumab serum concentrations above the median concentration of 37.4 mg/L, which is considered the serum level sufficient to saturate IL-4Rα in asthma (based on the specified 200 mg q2w dosing regimen). All 13 patients had seroprotective immune responses. While 12 of 13 patients had increases in neutralization titers after vaccination, one patient's serum sample had similar neutralization titers before and after vaccination. These data confirm that therapeutic serum concentrations of dupilumab at the time of vaccination did not inhibit seroprotective immune responses, and all but one of these 13 patients experienced increases in yellow fever virus neutralizing antibody titers.

[00580]The YFV vaccine was well tolerated by all exposed patients. Of the 37 patients who received YFV, one patient reported a non-serious adverse event, reported as a "vaccination complication" (i.e., body pain, malaise, and dizziness), which is a common reaction to YFV and has been reported in up to 30% sick (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 TropMedHyg. 2002; 66(5):533-541.). The patient's symptoms were reported as non-serious and the patient fully recovered within 2 weeks.

[00581] Yellow fever vaccination did not appear to affect the efficacy of dupilumab. All vaccinated patients achieved stable improvement in lung function as measured by FEV ₁ . FEV ₁ remained stable both before and after yellow fever vaccination.

[00582] Overall, these data support the overall safety and tolerability of yellow fever vaccination in patients with asthma who have recently discontinued dupilumab treatment. Without wishing to be bound by a particular scientific theory, the similar increases in neutralizing antibody titers following vaccination in patients with asthma who had therapeutic serum levels of dupilumab compared to those who had subtherapeutic serum levels indicate that humoral immune competence against live attenuated YFV is maintained in the dupilumab-treated setting.

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SEQUENCE LIST

<110> SANOFI BIOTECHNOLOGY

REGENERON PHARMACEUTICALS, INC.

<120> METHOD OF TREATMENT OR PREVENTION OF ASTHMA BY ADMINISTRATION OF IL-4R ANTAGONIST

<130> SA9-273PC

<140> TBD

<141> 2020-07-15

<150>EP 20315237.6

<151> 2020-05-07

<150> 63/004,084

<151> 2020-04-02

<150> 62/877,031

<151> 2019-07-22

<150> 62/874,747

<151> 2019-07-16

<160> 10

<170> PatentIn version 3.5

<210> 1

<211> 124

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Description of the artificial sequence: Synthetic polypeptide HCVR

<400> 1

Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Glu Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Gly Ser Gly Phe Thr Phe Arg Asp Tyr

20 25 30

Ala Met Thr Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Ser Ser Ile Ser Gly Ser Gly Gly Asn Thr Tyr Tyr Ala Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Lys Asp Arg Leu Ser Ile Thr Ile Arg Pro Arg Tyr Tyr Gly Leu

100 105 110

Asp Val Trp Gly Gln Gly Thr Thr Val Thr Val Ser

115 120

<210> 2

<211> 112

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Description of the artificial sequence: Synthetic polypeptide LCVR

<400> 2

Asp Ile Val Met Thr Gln Ser Pro Leu Ser Leu Pro Val Thr Pro Gly

1 5 10 15

Glu Pro Ala Ser Ile Ser Cys Arg Ser Ser Gln Ser Leu Leu Tyr Ser

20 25 30

Ile Gly Tyr Asn Tyr Leu Asp Trp Tyr Leu Gln Lys Ser Gly Gln Ser

35 40 45

Pro Gln Leu Leu Ile Tyr Leu Gly Ser Asn Arg Ala Ser Gly Val Pro

50 55 60

Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile

65 70 75 80

Ser Arg Val Glu Ala Glu Asp Val Gly Phe Tyr Tyr Cys Met Gln Ala

85 90 95

Leu Gln Thr Pro Tyr Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys

100 105 110

<210> 3

<211> 8

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Description of the artificial sequence: Synthetic peptide HCDR1

<400> 3

Gly Phe Thr Phe Arg Asp Tyr Ala

1 5

<210> 4

<211> 8

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Description of the artificial sequence: Synthetic peptide HCDR2

<400> 4

Ile Ser Gly Ser Gly Gly Asn Thr

1 5

<210> 5

<211> 18

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Description of the artificial sequence: Synthetic peptide HCDR3

<400> 5

Ala Lys Asp Arg Leu Ser Ile Thr Ile Arg Pro Arg Tyr Tyr Gly Leu

1 5 10 15

Asp Val

<210> 6

<211> 11

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Description of the synthetic sequence: Synthetic peptide LCDR1

<400> 6

Gln Ser Leu Leu Tyr Ser Ile Gly Tyr Asn Tyr

1 5 10

<210> 7

<211> 3

<212> PROTEIN

<213> Artificial sequence

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<223> Description of the synthetic sequence: Synthetic peptide LCDR2

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Leu Gly Ser

1

<210> 8

<211> 9

<212> PROTEIN

<213> Artificial sequence

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<223> Description of the synthetic sequence: Synthetic peptide LCDR3

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Met Gln Ala Leu Gln Thr Pro Tyr Thr

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<210> 9

<211> 451

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Description of the artificial sequence: Synthetic polypeptide

<220>

<223> HC aa 1-124: HCVR aa 125-451: HC constant region

<400> 9

Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Glu Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Gly Ser Gly Phe Thr Phe Arg Asp Tyr

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Ala Met Thr Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

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Ser Ser Ile Ser Gly Ser Gly Gly Asn Thr Tyr Tyr Ala Asp Ser Val

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Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Cys Ser Arg Ser Thr Ser

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Glu Ser Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu

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Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His

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Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser

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Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Lys Thr Tyr Thr Cys

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Asn Val Asp His Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu

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Ser Lys Tyr Gly Pro Pro Cys Pro Pro Cys Pro Ala Pro Glu Phe Leu

225 230 235 240

Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu

245 250 255

Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser

260 265 270

Gln Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu

275 280 285

Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr

290 295 300

Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn

305 310 315 320

Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro Ser Ser

325 330 335

Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln

340 345 350

Val Tyr Thr Leu Pro Pro Ser Gln Glu Glu Met Thr Lys Asn Gln Val

355 360 365

Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val

370 375 380

Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro

385 390 395 400

Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Arg Leu Thr

405 410 415

Val Asp Lys Ser Arg Trp Gln Glu Gly Asn Val Phe Ser Cys Ser Val

420 425 430

Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu

435 440 445

Ser Leu Gly

450

<210> 10

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<212> PROTEIN

<213> Artificial sequence

<220>

<223> Description of the artificial sequence: Synthetic polypeptide

<220>

<223> LC aa 1-112: LCVR aa 112-219: LC constant region

<400> 10

Asp Ile Val Met Thr Gln Ser Pro Leu Ser Leu Pro Val Thr Pro Gly

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Glu Pro Ala Ser Ile Ser Cys Arg Ser Ser Gln Ser Leu Leu Tyr Ser

20 25 30

Ile Gly Tyr Asn Tyr Leu Asp Trp Tyr Leu Gln Lys Ser Gly Gln Ser

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Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile

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Leu Gln Thr Pro Tyr Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys

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Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu

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Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe

130 135 140

Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln

145 150 155 160

Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser

165 170 175

Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu

180 185 190

Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser

195 200 205

Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys

210 215

<---

Claims (15)

1. The use of an antibody or antigen-binding fragment thereof that specifically binds to an interleukin-4 receptor in a method of treating allergic bronchopulmonary aspergillosis in a subject, 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, wherein the antibody or antigen-binding fragment thereof is administered to the subject as a loading dose followed by a plurality of maintenance doses, wherein each maintenance dose is administered once every two weeks, and wherein (i) the loading dose is approximately 600 mg of the antibody or antigen-binding fragment thereof, and each maintenance dose is approximately 300 mg of the antibody or antigen-binding fragment thereof; or (ii) the loading dose is approximately 400 mg of the antibody or antigen-binding fragment thereof, and each maintenance dose is approximately 200 mg of the antibody or antigen-binding fragment thereof, and wherein the subject is characterized by 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. 2. Use of an antibody or antigen-binding fragment thereof according to claim 1, wherein the subject is characterized by at least two of a total IgE level in the blood serum of at least about 1000 IU/mL, an Aspergillus fumigatus -specific IgE level of more than 0.35 kU/L, and a baseline blood eosinophil count of at least about 500 cells/μL. 3. Use of an antibody or antigen-binding fragment thereof according to claim 1, wherein the subject is characterized by a total IgE level in the blood serum of at least about 1000 IU/ml, an Aspergillus fumigatus -specific IgE level of more than 0.35 kU/l, and a baseline blood eosinophil count of at least about 500 cells/μl. 4. Use of an antibody or antigen-binding fragment thereof according to any one of claims 1-3, wherein the antibody or antigen-binding fragment thereof is administered using an autoinjector, a needle and syringe, or a syringe pen. 5. Use of an antibody or antigen-binding fragment thereof according to any one of claims 1-4, wherein maintenance doses of the antibody or antigen-binding fragment thereof are administered for at least 24 weeks. 6. The use of an antibody or antigen-binding fragment thereof according to any one of claims 1 to 5, wherein the treatment results in an improvement in lung function measured by forced expiratory volume or forced expiratory flow rate at 25-75% of lung volume, or wherein the treatment results in a reduction in severe asthma exacerbations on an annualized basis. 7. Use of an antibody or antigen-binding fragment thereof according to any one of claims 1-5, wherein the treatment results in a decrease in one or both of total IgE levels in the blood serum and Aspergillus fumigatus -specific IgE levels in the blood serum. 8. The use of an antibody or antigen-binding fragment thereof according to any one of claims 1-5, wherein the treatment results in a decrease in one or more of TARC levels, eotaxin-3 levels, and eosinophil levels in peripheral blood. 9. Use of an antibody or antigen-binding fragment thereof according to any one of claims 1-5, wherein the FeNO index is reduced. 10. The use of an antibody or antigen-binding fragment thereof according to any of the preceding claims, wherein the antibody or antigen-binding fragment thereof comprises the heavy chain variable region sequence of SEQ ID NO: 1 and the light chain variable region sequence of SEQ ID NO: 2. 11. The use of an antibody or antigen-binding fragment thereof according to any of the preceding paragraphs, wherein the antibody is dupilumab. 12. The use of an antibody or antigen-binding fragment thereof according to any of the preceding paragraphs, wherein the subject has uncontrolled asthma of moderate to severe severity or has concomitant asthma and/or concomitant cystic fibrosis.