Biopharmaceutical compositions and methods for pediatric patients

Abstract

The present invention provides compositions and related methods for treating interleukin-5 (IL-5) mediated diseases in children. [Solution] A method for treating a disease in a child, comprising the steps of: a) identifying a child weighing less than 40 kg who has a disease selected from the group consisting of asthma, mild asthma, moderate asthma, severe asthma, mild eosinophilic asthma, moderate eosinophilic asthma, severe eosinophilic asthma, poorly controlled eosinophilic asthma, etc.; and b) subcutaneously administering a therapeutically effective dose of mepolizumab to the child, wherein the therapeutically effective dose of the antibody results in a maximum plasma concentration (Cmax) of antibody of approximately 10.1960 ± 0.3345 μg / mL and an area under the curve [0-infinity] value of approximately 454.39 ± 15.8876 μg* / mL, thereby treating the disease in the child.

Description

[Technical Field]

[0001] This disclosure relates to compositions and related methods for treating interleukin-5 (IL-5) mediated diseases in pediatric patients. [Background technology]

[0002] IL-5 is a secreted protein. IL-5 plays a role in several different diseases, such as asthma, mild asthma, moderate asthma, severe asthma, mild eosinophilic asthma, moderate eosinophilic asthma, severe eosinophilic asthma, poorly controlled eosinophilic asthma, eosinophilic asthma, sub-eosinophilic asthma, chronic obstructive pulmonary disease, eosinophilic granulomatosis with polyangiitis, eosinophilic syndrome, nasal polyps, bullous pemphigoid, eosinophilic esophagitis, atopic dermatitis, moderate atopic dermatitis, and severe atopic dermatitis. Hundreds of millions of people worldwide, including children, suffer from these severe diseases. [Overview of the Initiative] [Problems that the invention aims to solve]

[0003] This means that there is a need for a suitable composition for treating IL-5-mediated diseases in pediatric patients. Such compositions and related methods are provided by this disclosure. [Means for solving the problem]

[0004] One aspect of the present disclosure is a method for treating a disease in a child, a) a child having a disease selected from the group consisting of asthma, mild asthma, moderate asthma, severe asthma, mild eosinophilic asthma, moderate eosinophilic asthma, severe eosinophilic asthma, poorly controlled eosinophilic asthma, eosinophilic asthma, subtype eosinophilic asthma, chronic obstructive pulmonary disease, eosinophilic granulomatosis with polyangiitis, eosinophilic syndrome, nasal polyps, bullous pemphigoid, eosinophilic esophagitis, atopic dermatitis, moderate atopic dermatitis, and severe atopic dermatitis, weighing 4 A method for treating a disease in a pediatric subject, comprising the steps of: a) identifying a pediatric subject weighing less than 0 kg; and b) subcutaneously administering a therapeutically effective dose of an antibody containing the heavy chain amino acid sequence shown in SEQ ID NO: 1 and the light chain amino acid sequence shown in SEQ ID NO: 2, wherein the therapeutically effective dose of the antibody results in a maximum plasma concentration (Cmax) of approximately 10.1960 ± 0.3345 μg / mL of the antibody and an area under the curve [0-infinity] value of approximately 454.39 ± 15.8876 μg* / mL.

[0005] Another aspect of the present disclosure is a method for treating a disease in a child, a) a child having a disease selected from the group consisting of asthma, mild asthma, moderate asthma, severe asthma, mild eosinophilic asthma, moderate eosinophilic asthma, severe eosinophilic asthma, poorly controlled eosinophilic asthma, eosinophilic asthma, subtype eosinophilic asthma, chronic obstructive pulmonary disease, eosinophilic granulomatosis with polyangiitis, eosinophilic syndrome, nasal polyps, bullous pemphigoid, eosinophilic esophagitis, atopic dermatitis, moderate atopic dermatitis, and severe atopic dermatitis, weighing 4 A method for treating a disease in a pediatric subject, comprising the steps of: a) identifying a pediatric subject weighing 0 kg or more; and b) subcutaneously administering a therapeutically effective dose of an antibody containing the heavy chain amino acid sequence shown in SEQ ID NO: 1 and the light chain amino acid sequence shown in SEQ ID NO: 2, wherein the therapeutically effective dose of the antibody results in a maximum plasma concentration (Cmax) of approximately 16.3412 ± 0.6364 μg / mL of the antibody and an area under the curve [0-infinity] value of approximately 675.20 ± 35.8980 μg* / mL.

[0006] Another aspect of this disclosure relates to a method for reducing the absolute number of eosinophils in the blood of a child subject, wherein the child subject weighing less than 40 kg has a condition selected from the group consisting of asthma, mild asthma, moderate asthma, severe asthma, mild eosinophilic asthma, moderate eosinophilic asthma, severe eosinophilic asthma, poorly controlled eosinophilic asthma, eosinophilic asthma, subtype eosinophilic asthma, chronic obstructive pulmonary disease, eosinophilic granulomatosis with polyangiitis, eosinophilic syndrome, nasal polyps, bullous pemphigoid, eosinophilic esophagitis, and atopic dermatitis. A method comprising the steps of identifying, and a) subcutaneously administering a therapeutically effective dose of an antibody comprising the heavy chain amino acid sequence shown in SEQ ID NO: 1 and the light chain amino acid sequence shown in SEQ ID NO: 2 to a pediatric subject, wherein the therapeutically effective dose of the antibody results in a maximum plasma concentration (Cmax) of approximately 10.1960 ± 0.3345 μg / mL of the antibody and an area under the curve [0-infinity] value of approximately 454.39 ± 15.8876 μg* / mL, thereby reducing the absolute number of eosinophils in the blood of the pediatric subject.

[0007] Another aspect of this disclosure relates to a method for reducing the absolute number of eosinophils in the blood of a child subject, wherein the child subject weighing 40 kg or more has a condition selected from the group consisting of asthma, mild asthma, moderate asthma, severe asthma, mild eosinophilic asthma, moderate eosinophilic asthma, severe eosinophilic asthma, poorly controlled eosinophilic asthma, eosinophilic asthma, subtype eosinophilic asthma, chronic obstructive pulmonary disease, eosinophilic granulomatosis with polyangiitis, eosinophilic syndrome, nasal polyps, bullous pemphigoid, eosinophilic esophagitis, and atopic dermatitis. A method comprising the steps of identifying, and a) subcutaneously administering a therapeutically effective dose of an antibody comprising the heavy chain amino acid sequence shown in SEQ ID NO: 1 and the light chain amino acid sequence shown in SEQ ID NO: 2 to a pediatric subject, wherein the therapeutically effective dose of the antibody results in a maximum plasma concentration (Cmax) of approximately 16.3412 ± 0.6364 μg / mL of the antibody and an area under the curve [0-infinity] value of approximately 675.20 ± 35.8980 μg* / mL, thereby reducing the absolute number of eosinophils in the blood of the pediatric subject.

[0008] Another aspect of this disclosure relates to the treatment of asthma, mild asthma, moderate asthma, severe asthma, mild eosinophilic asthma, moderate eosinophilic asthma, severe eosinophilic asthma, poorly controlled eosinophilic asthma, eosinophilic asthma, subtype eosinophilic asthma, chronic obstructive pulmonary disease, eosinophilic granulomatosis with polyangiitis, eosinophilic syndrome, nasal polyps, bullous pemphigoid, eosinophilic esophagitis, atopic dermatitis, moderate atopic dermatitis, and severe atopic dermatitis in children weighing less than 40 kg. A composition for treating diseases selected from the group consisting of dermatitis, comprising an antibody containing the heavy chain amino acid sequence shown in SEQ ID NO: 1 and the light chain amino acid sequence shown in SEQ ID NO: 2, wherein the therapeutically effective dose of the antibody administered subcutaneously to a child yields a maximum plasma concentration (Cmax) of approximately 10.1960 ± 0.3345 μg / mL of the antibody and an area under the curve [0-infinity] value of approximately 454.39 ± 15.8876 μg* / mL.

[0009] Another aspect of this disclosure relates to the treatment of asthma, mild asthma, moderate asthma, severe asthma, mild eosinophilic asthma, moderate eosinophilic asthma, severe eosinophilic asthma, poorly controlled eosinophilic asthma, eosinophilic asthma, subtype eosinophilic asthma, chronic obstructive pulmonary disease, eosinophilic granulomatosis with polyangiitis, eosinophilic syndrome, nasal polyps, bullous pemphigoid, eosinophilic esophagitis, atopic dermatitis, moderate atopic dermatitis, and severe atopic dermatitis in children weighing 40 kg or more. A composition for treating diseases selected from the group consisting of dermatitis, comprising an antibody containing the heavy chain amino acid sequence shown in SEQ ID NO: 1 and the light chain amino acid sequence shown in SEQ ID NO: 2, wherein the therapeutically effective dose of the antibody administered subcutaneously to a child yields a maximum plasma concentration (Cmax) of approximately 16.3412 ± 0.6364 μg / mL of the antibody, and an area under the curve [0-infinity] value of approximately 675.20 ± 35.8980 μg* / mL.

[0010] Another aspect of the present disclosure is a composition for reducing the absolute number of eosinophils in the blood of children weighing less than 40 kg, wherein the children have asthma, mild asthma, moderate asthma, severe asthma, mild eosinophilic asthma, moderate eosinophilic asthma, severe eosinophilic asthma, poorly controlled eosinophilic asthma, eosinophilic asthma, subtype eosinophilic asthma, chronic obstructive pulmonary disease, eosinophilic granulomatosis with polyangiitis, eosinophilic syndrome, nasal polyps, bullous pemphigoid, eosinophilic esophagitis, atopic dermatitis, and moderate The composition is for a disease selected from the group consisting of moderate atopic dermatitis and severe atopic dermatitis, and comprises an antibody containing the heavy chain amino acid sequence shown in SEQ ID NO: 1 and the light chain amino acid sequence shown in SEQ ID NO: 2, wherein the therapeutically effective dose of the antibody administered subcutaneously to a child yields a maximum plasma concentration (Cmax) of approximately 10.1960 ± 0.3345 μg / mL of the antibody, and an area under the curve [0-infinity] value of approximately 454.39 ± 15.8876 μg* / mL.

[0011] Another aspect of the present disclosure is a composition for reducing the absolute number of eosinophils in the blood of children weighing 40 kg or more, wherein the children have asthma, mild asthma, moderate asthma, severe asthma, mild eosinophilic asthma, moderate eosinophilic asthma, severe eosinophilic asthma, poorly controlled eosinophilic asthma, eosinophilic asthma, subtype eosinophilic asthma, chronic obstructive pulmonary disease, eosinophilic granulomatosis with polyangiitis, eosinophilic syndrome, nasal polyps, bullous pemphigoid, eosinophilic esophagitis, atopic dermatitis The patient has a disease selected from the group consisting of dermatitis, moderate atopic dermatitis, and severe atopic dermatitis, and the composition comprises an antibody containing the heavy chain amino acid sequence shown in SEQ ID NO: 1 and the light chain amino acid sequence shown in SEQ ID NO: 2, and the therapeutically effective dose of the antibody yields a maximum plasma concentration (Cmax) of approximately 16.3412 ± 0.6364 μg / mL of the antibody, and an area under the curve [0-infinity] value of approximately 675.20 ± 35.8980 μg* / mL. [Brief explanation of the drawing]

[0012] [Figure 1] Box 1-1. This is a diagram of a clinical practice - initial symptom diagnosis flowchart. [Figure 2]Box 3-5. It is a diagram of a stepwise approach to control symptoms and minimize future risks. [Figure 3] It is a diagram of the ratio of blood eosinophil count to baseline (geometric mean 95% confidence interval).

Mode for Carrying Out the Invention

[0013] The present disclosure provides compositions and methods for treating interleukin-5 (IL-5)-mediated diseases in pediatric patients, as well as related subjects.

[0014] As used herein, the term "asthma" means an inflammatory disease of the airways characterized by reversible airflow obstruction and bronchospasm. Common symptoms include wheezing, coughing, chest tightness, and shortness of breath. Asthma is usually a heterogeneous disease characterized by chronic airway inflammation. This is defined by a history of respiratory symptoms such as wheezing, shortness of breath, chest tightness, and coughing that vary over time and in intensity, together with variable expiratory airflow limitation.

[0015] In the methods of the present disclosure, the diagnosis of asthma in a subject can be performed according to the guidance provided by the Global Initiative for Asthma (GINA), Global Strategy for Management and Prevention of Asthma (2016 updated version) document. Those skilled in the art will be familiar with the GINA diagnostic flowchart (Figure 1) for clinical practice, as well as the diagnostic criteria for asthma (Table 1) and other aspects of the guidance (e.g., regarding pregnant women, etc.) in adults, adolescents, and children aged 6 - 11 years shown below. See also Tables 2 and 3.

[0016]

Table 1

[0017] [Table 2]

[0018] [Table 3]

[0019] In the methods of this disclosure, “asthma” may be “mild asthma,” “moderate asthma,” or “severe asthma.” In the methods of this disclosure, the severity of asthma can be assessed in accordance with GINA guidelines. In particular, the severity of asthma can be assessed retrospectively from the level of treatment required to control symptoms and exacerbations. For example, a patient may be assessed after several months of controller treatment, and, if appropriate, an attempt may be made to step down treatment to find the minimum effective level of treatment for the patient. The severity of asthma is not a static characteristic and can change over months or years.

[0020] The severity of asthma can be assessed when a patient has been receiving regular control treatment for several months: "Mild asthma" is asthma that is well controlled by Step 1 or Step 2 treatment (see Figure 2, boxes 3-5), i.e., by reliever medication alone as needed, or by low-efficacy controller treatment such as low-dose ICS, leukotriene receptor antagonists, or chromone. "Moderate asthma" is asthma that is well controlled by Step 3 treatment (see Figure 2, boxes 3-5), such as low-dose ICS / LABA. • “Severe asthma” is defined as asthma requiring Step 4 or 5 treatment (see Figure 2, boxes 3-5) to prevent “poor control,” such as high-dose ICS / LABA, or asthma that remains “poorly controlled” despite this treatment. Many patients with poorly controlled asthma may be difficult to manage due to inappropriate or unsuitable treatment, persistent adherence problems, or comorbidities such as chronic sinusitis or obesity. However, the European Respiratory Society / American Thoracic Society Task Force on Severe Asthma believes that the definition of “severe asthma” should be reserved for patients with refractory asthma and asthma patients whose response to treatment of comorbidities is incomplete. Table 4 can also be referenced when assessing the severity of asthma.

[0021] [Table 4]

[0022] In the methods of this disclosure, “asthma” may be “mild eosinophilic asthma,” “moderate eosinophilic asthma,” or “severe eosinophilic asthma.”

[0023] "Mild eosinophilic asthma" is mild asthma with an eosinophilic phenotype. For example, a person with mild eosinophilic asthma may have mild asthma and have blood eosinophil counts of 150 or more eosinophils per μL of blood in the past 12 months, 200 or more eosinophils per μL of blood in the past 12 months, 300 or more eosinophils per μL of blood in the past 12 months, or 350 or more eosinophils per μL of blood in the past 12 months.

[0024] "Moderate eosinophilic asthma" is moderate asthma with an eosinophilic phenotype. For example, a person with moderate eosinophilic asthma may have moderate asthma and have blood eosinophil counts of 150 or more eosinophils per μL of blood in the past 12 months, 200 or more eosinophils per μL of blood in the past 12 months, 300 or more eosinophils per μL of blood in the past 12 months, or 350 or more eosinophils per μL of blood in the past 12 months.

[0025] "Severe eosinophilic asthma" is severe asthma with an eosinophilic phenotype. For example, a person with severe eosinophilic asthma may have severe asthma and have blood eosinophil counts of 150 or more eosinophils per μL of blood in the past 12 months, 200 or more eosinophils per μL of blood in the past 12 months, 300 or more eosinophils per μL of blood in the past 12 months, or 350 or more eosinophils per μL of blood in the past 12 months.

[0026] Subjects with severe eosinophilic asthma may also meet one or more of the criteria listed in Table 5.

[0027] [Table 5] TIFF2026086897000007.tif155143

[0028] Importantly, subjects with severe eosinophilic asthma according to these criteria may have fewer than 150 eosinophils per μL of blood at the start of treatment.

[0029] Mepolizumab is a monoclonal antibody comprising the heavy chain amino acid sequence shown in SEQ ID NO: 1 and the light chain amino acid sequence shown in SEQ ID NO: 2. Patients may be treated according to the methods of this disclosure using antibody molecules comprising mepolizumab and antigen-binding proteins, particularly the heavy chain CDR and light chain CDR of mepolizumab (e.g., SEQ ID NOs. 5-10), or the heavy chain variable region and light chain variable region of mepolizumab (e.g., SEQ ID NOs. 3 and 4). Mepolizumab specifically binds to human IL-5 (SEQ ID NO: 11) and antagonizes the activity of the IL-5R receptor (including SEQ ID NOs. 12 and 13). NUCALA® is an example of a mepolizumab-containing pharmaceutical composition approved by the FDA.

[0030] Mepolizumab, or any composition of the Disclosure comprising mepolizumab, may be indicated as an additional maintenance treatment for severe eosinophilic asthma in pediatric patients characterized by a serum eosinophil count of 300 cells / μL or higher over the past 12 months, and / or a serum eosinophil count of 150 cells / μL or higher at the start of treatment, and / or a serum eosinophil count of less than 150 cells / μL at the start of treatment. Alternatively, mepolizumab, or any composition of the Disclosure comprising mepolizumab, may be indicated as an additional maintenance treatment for severe eosinophilic asthma in pediatric patients characterized by a serum eosinophil count of 300 cells / μL or higher over the past 12 months, and / or a serum eosinophil count of 150 cells / μL or higher at the start of treatment. Mepolizumab or compositions comprising mepolizumab of the Disclosure may be indicated as an additional maintenance treatment for severe eosinophilic asthma in pediatric patients, identified by a serum eosinophil count of 300 cells / μL or higher over the past 12 months and / or a serum eosinophil count of less than 150 cells / μL at the start of treatment. Such pediatric patients may be between 11 years of age and 6 years of age or older. Treatment with mepolizumab or compositions comprising mepolizumab of the Disclosure may reduce asthma exacerbations in pediatric patients (e.g., patients with a history of exacerbations). The method of the Disclosure may be used when treatment with mepolizumab or compositions comprising mepolizumab of the Disclosure is indicated (i.e., such treatment with mepolizumab may be combined with the method of the Disclosure). Treatment with mepolizumab or compositions comprising mepolizumab of the Disclosure may reduce asthma exacerbations in pediatric patients (e.g., patients with a history of exacerbations). a) It can result in a reduction in the frequency of exacerbations. Compared to placebo, treatment with mepolizumab or compositions of the present disclosure containing mepolizumab can reduce the rates of 1) clinically significant exacerbations, 2) exacerbations requiring hospitalization or ED transport, and 3) exacerbations requiring hospitalization. This benefit may result in a reduction in the prevalence of asthma and a reduction in fatal events. b) A reduction in the daily dose of OCS may be achieved. Treatment with mepolizumab or a composition of the disclosure containing mepolizumab may reduce the daily dose of concomitant corticosteroids in subjects without experiencing a loss of asthma control. Subjects treated with mepolizumab or a composition of the disclosure containing mepolizumab may achieve a median percentage reduction from baseline in the daily dose of oral corticosteroids (OCS) compared to subjects treated with placebo. In addition, subjects treated with mepolizumab or a composition of the disclosure containing mepolizumab, or an antigen-binding composition of the disclosure, may achieve a reduction in OCS dose compared to subjects treated with placebo. c) It may result in improved lung function. Clinically relevant changes in FEV1 before and after bronchodilator administration can be demonstrated by treatment with mepolizumab or compositions of the Disclosure comprising mepolizumab compared to placebo. Any improvement in lung function is particularly clinically important, as most of this population are receiving maximum asthma treatment, including high-dose ICS (inhaled corticosteroids) and / or OCS plus controller medication. d) It can result in improved asthma control. Statistically significant and clinically relevant improvements in ACQ-5 or ACQ-7 can be observed with mepolizumab or compositions of the disclosure comprising mepolizumab compared with placebo, demonstrating that subjects can achieve asthma control when mepolizumab or compositions of the disclosure comprising mepolizumab are added to their existing asthma treatment. e) It may result in an improvement in quality of life. Statistically significant and clinically relevant changes in SGRQ scores have been demonstrated with mepolizumab or compositions of the present disclosure containing mepolizumab compared to placebo. Subjects may experience a significant improvement in asthma symptoms and the ability to perform daily activities. f) It can provide sustained efficacy and pharmacodynamic effects. Over the course of treatment (e.g., 4, 8, 9, 12, 16, and 20 weeks), improvements in lung function, asthma control, and quality of life may be observed without asthma exacerbations, sustained reductions in blood eosinophils, or the development of resistance. and g) A reduction in blood eosinophils may occur. Treatment with a composition comprising mepolizumab or a composition of the present disclosure comprising mepolizumab may result in a rapid reduction in blood eosinophils in a subject.

[0031] In the methods of the Disclosure, “asthma” may mean “severe asthma.” In the methods of the Disclosure, “asthma” may also mean “mild asthma,” “moderate asthma,” “severe asthma,” “mild eosinophilic asthma,” “moderate eosinophilic asthma,” or “severe eosinophilic asthma,” as discussed above. These conditions may be treated in accordance with the methods of the Disclosure using a composition comprising mepolizumab or a treatment with a composition comprising mepolizumab of the Disclosure.

[0032] In the method of this disclosure, "asthma" may mean "poorly controlled uncontrolled asthma." Subjects with poorly controlled uncontrolled asthma meet the criteria listed in Table 6.

[0033] [Table 6] TIFF2026086897000009.tif34143

[0034] Poorly controlled poorly controlled saccharinophilic asthma may be treated in accordance with the methods of the disclosure using a composition comprising mepolizumab or a treatment with a composition of the disclosure comprising mepolizumab.

[0035] In the method of this disclosure, "asthma" may refer to "subtype eosinophilic asthma." Subjects having subtype eosinophilic asthma meet the criteria listed in Table 7.

[0036] [Table 7]

[0037] In the method of this disclosure, "asthma" may refer to "subtype eosinophilic asthma." Subjects with subtype eosinophilic asthma meet the criteria listed in Table 8.

[0038] [Table 8]

[0039] Eosinophilic asthma may be treated using a composition comprising mepolizumab or treatment with a composition of the disclosure comprising mepolizumab, and similarly, subtype eosinophilic asthma may be treated according to the methods of the disclosure.

[0040] As used herein, the term “bullous pemphigoid” (BP) refers to an acute or chronic autoimmune skin disease characterized by the formation of blisters, more appropriately known as cutaneous vesicles in the space between the epidermis and dermis of the skin layers. BP is the most common autoimmune vesicular skin disease. It is characteristically prevalent in older adults (>70 years) with an annual incidence of 5–35 per million people. The incidence of BP is increasing dramatically by an average of 17% each year. BP often begins as a highly itchy skin lesion resembling eczema or urticaria, followed by the development of vesicles and blisters. In 10–30% of patients, BP also affects the oral mucosa. The severity of the disease can be determined by the Autoimmune Bullous Skin Injury Severity Score (ABSIS), which assesses the area of ​​the affected area and the activity of the disease. The disease is caused by an autoimmune response to structural elements of junctional adhesion molecular complexes, resulting in damage to the dermal-epidermal junction with subepidermal vesicle formation. Specifically, autoreactive B and T cell responses to hemiadhesion plaque antigens BP180 and BP230 have been identified. Serum levels of autoantibodies against BP180 reflect the severity and activity of the disease. T cells are memory CD4+ cells that produce both Th1 and Th2 cytokines, mainly IL-4, IL-5, and IL-13. IL-5 and eotaxin are abundantly found in blister fluid. IL-5 production is indeed associated with serum eosinophilia and significant eosinophil infiltration in the skin of BP patients. Eosinophils are thought to be critically involved in blister formation by releasing toxic granular proteins (ESP, MBP) and proteolytic enzymes.

[0041] As used herein, the term “eosinophilic esophagitis” (EoE) refers to an allergic inflammatory condition of the esophagus accompanied by eosinophils. Symptoms include dysphagia, food impaction, and heartburn. EoE is characterized by numerous infiltrations of eosinophilic leukocytes into the endothelial layer of the esophagus. EoE is considered an allergic reaction to ingested food, based on the important role that eosinophils play in allergic reactions. EoE can be diagnosed using an EoE diagnostic panel. EoE may also be diagnosed when gastroesophageal reflux does not respond to a 6-week trial of high-dose proton pump inhibitors (PPIs) twice daily, or when gastroesophageal reflux disease (GERD) is ruled out by a negative duodenal pH test. Endoscopically, elevated lesions, longitudinal grooves, or annular grooves may be observed on the esophageal wall. Sometimes, multiple cricoid grooves are present in the esophagus, leading to the term "multiple cricoid stenosis," or "feline esophagus" due to the similarity between the cricoid grooves and the feline esophagus. The presence of white exudate in the esophagus also suggests a diagnosis. Biopsies taken during endoscopy typically show a large number of eosinophils in the surface epithelium. A minimum of 15 eosinophils per high-magnification field is required for diagnosis. Eosinophilic inflammation is not limited to the esophagus but spreads throughout the entire digestive tract. Highly degranulated eosinophils can also be present, as can microabscesses and basal layer enlargement. On X-ray, the term "cricoesophagus" is used to indicate the appearance of eosinophilic esophagitis, in contrast to the transient transverse folds (called "feline esophagus") sometimes seen in cases of esophageal reflux during barium swallowing examinations.

[0042] COPD may be treated in accordance with the methods of the disclosure using a composition comprising mepolizumab or a treatment with a composition of the disclosure comprising mepolizumab.

[0043] Subjects with "Chronic Obstructive Pulmonary Disease" (COPD) may meet one or more of the following criteria: a) Prior COPD diagnosis: Subjects with a clinically confirmed history of COPD for at least one year according to the definition of the American Thoracic Society / European Respiratory Society; b) Severity of COPD: Subjects may exhibit the following: Forced expiratory volume in one second (FEV1 / FVC) ratio <0.70 measured before and after salbutamol to confirm the diagnosis of COPD; FEV1 measured after salbutamol >20 percent and ≤80 percent of the predicted normal value calculated using the National Institute of Health and Nutrition (NHANES) III criteria; c) History of exacerbations: A well-confirmed history (verification of medical records) of at least two moderate COPD exacerbations in a 12-month period. Moderate is defined as the use of systemic corticosteroids (IM, intravenous, or oral) and / or treatment with antibiotics, or at least one severe COPD exacerbation. Severe is defined as requiring hospitalization. Note: The subject must have experienced at least one exacerbation while using inhaled corticosteroids (ICS) plus a long-acting beta-2 agonist (LABA) plus a long-acting muscarinic antagonist (LAMA). Note: Prior use of antibiotics alone is not eligible as a moderate exacerbation unless the use was specifically for the treatment of worsening COPD symptoms, and d) Combination COPD therapy: Including ICS plus two additional COPD medications (i.e., triple therapy) in the preceding 12 months, with a well-established requirement of background therapy of optimized standard care (SoC) that meets the following criteria: immediately before a consultation with a healthcare provider, using an inhaled corticosteroid (dose ≥ 500 micrograms (mcg) / day fluticasone propionate dose equivalent plus), or LABA and LAMA for a minimum of 3 months.

[0044] COPD may be treated in accordance with the methods of the disclosure using a composition comprising mepolizumab or a treatment with a composition of the disclosure comprising mepolizumab.

[0045] As used herein, the term “eosinophilic granulomatosis with polyangiitis” (EGPA) refers to an autoimmune condition that causes inflammation (vasculitis) of small and moderate-sized blood vessels in individuals with a history of allergic hypersensitivity (atopic) of the airways. EGPA may also be called Churg-Strauss syndrome (CSS) or allergic granulomatosis. EGPA typically presents in three stages. The initial (prodromal) stage is characterized by prominent inflammation of the airways, and almost all patients experience asthma and / or allergic rhinitis. The second stage is characterized by an abnormally large number of eosinophils (eosinophilia), which causes damage to tissues, most commonly the lungs and gastrointestinal tract. The third stage consists of vasculitis, which ultimately leads to cell death and can be life-threatening.

[0046] Individuals with EGPA may meet one or more of the following criteria: a) asthma, b) eosinophil levels greater than 10% of white blood cell percentage, c) presence of mononeuropathy or polyneuropathy, d) unspecified pulmonary exudate, e) presence of sinus abnormalities, and e) histological evidence of extravascular eosinophils. For classification purposes, a patient is said to have EGPA if at least four of the above six criteria are positive.

[0047] EGPA may be treated in accordance with the methods of the disclosure using a composition comprising mepolizumab or a treatment with the composition of the disclosure comprising mepolizumab. The composition of the disclosure may be administered to pediatric EGPA patients at a dose of 300 mg once every four weeks.

[0048] As used herein, the term "eosinophilia syndrome" (HES) refers to a condition characterized by a persistently elevated blood eosinophil count (eosinophils ≥ 1500 / mm³) for at least six months, affecting the heart, nervous system, or bone marrow without any known cause. 3 It refers to a disease characterized by ).

[0049] Subjects with eosinophilic syndrome may meet one or more of the following criteria: a) a confirmed history of eosinophilic syndrome, b) a blood eosinophil count greater than 1500 cells for the past six months, c) signs and symptoms of organ system involvement, and d) no evidence of parasitic, allergic, or other causes of eosinophilia after comprehensive evaluation.

[0050] Eosinophilia syndrome may be treated in accordance with the methods of the disclosure using a composition comprising mepolizumab or a treatment with a composition of the disclosure comprising mepolizumab.

[0051] As used herein, the term “nasal polyp” means a condition characterized by the presence of polyps in the nasal cavity. Such polyps may be located in the upper part of the nasal cavity and / or may originate from within the natural opening of the middle meatus.

[0052] Subjects with nasal polyps may meet one or more of the following criteria: a) a history of confirmed nasal polyps, or b) nasal polyps revealed by examination (e.g., endoscopy).

[0053] Nasal polyps may be treated in accordance with the method of the present disclosure using a composition comprising mepolizumab or a treatment with a composition of the present disclosure comprising mepolizumab.

[0054] As used herein, the term "atopic dermatitis" refers to an inflammatory skin condition characterized by chronic itching, lichenification, xerosis, erythematous papules, and plaques.

[0055] In the method of this disclosure, "atopic dermatitis" may mean "moderate to severe atopic dermatitis." Subjects with moderate to severe atopic dermatitis may meet one or more of the criteria listed in Table 9.

[0056] [Table 9] TIFF2026086897000013.tif108142

[0057] Subjects with moderate to severe atopic dermatitis may include children under 18 years of age, adults at least 18 years of age or older, adults aged 18 to 70 years, or children aged 6 to 11 years of age. Subjects may be male or female. Female subjects treated are preferably not pregnant, not breastfeeding, and / or not likely to become pregnant.

[0058] The diagnosis of atopic dermatitis is based on the revised Eichenfield criteria by Hanifin and Rajka. See Table 10 and Eichenfield et al., 70 J Am Acad Dermatol, page 338 (2014).

[0059] [Table 10] TIFF2026086897000015.tif123143

[0060] The Healthcare Professional Assessment (HGA) is a clinical tool for assessing the current state / severity of atopic dermatitis in a patient. See Rehal et al., 6 PLos ONE e17520 (2011) and Table 11. This is a static 5-point morphological assessment of overall disease severity determined by a trained healthcare professional, using clinical features of erythema, infiltration, papulogenesis, exudation, and crusting as guidelines. The HGA is performed without referring to previous scores. Each assessment should be performed as a visual "average" of the severity of all affected areas at the time of assessment.

[0061] [Table 11]

[0062] The Percentage of Body Surface Area (%BSA) assessment is an estimate of the percentage of total affected skin in individuals with atopic dermatitis. See Table 12. The %BSA assessment can be performed by examining the inflammatory areas within each of four distinct body surface regions: head and neck, upper extremities, trunk, and lower extremities, each of which can potentially have up to 100% affected skin. The assessor (e.g., a medical professional) estimates the percentage of affected skin for each region of the %BSA area score and then multiplies it by an appropriate proportional multiplier to obtain the local %BSA affected value (for subjects aged ≥ 8 years, 0.1 for head and neck, 0.2 for upper extremities, 0.3 for trunk, and 0.4 for lower extremities). The local %BSA affected values ​​are summed to generate the total affected %BSA. The local %BSA area score is also used as part of the matrix for calculating the EASI score.

[0063] [Table 12]

[0064] The EASI scoring system is a standardized clinical tool for assessing atopic dermatitis that takes into account the overall extent of affected % body surface area (%BSA) and the severity scores of each clinical sign: erythema, sclerosis / papulogenesis, abrasions, and lichenification. See Hanifin et al., 10 Exp Dermatol 11 (2001); Rullo et al., 36 Allergol et Immunopathol 201 (2008), and Table 13. The %BSA area score from the %BSA assessment is used as part of the matrix for calculating the EASI score. The severity score of each clinical sign (erythema, sclerosis / papulogenesis, abrasions, and lichenification) is graded on a 4-point scale (0-3) for each of the four body regions (head and neck, upper extremities, lower extremities, and trunk). The severity score for each symptom is summed for each region, multiplied by the %BSA area score, and then multiplied by an appropriate proportional multiplier (0.1 for the head and neck, 0.2 for the upper limbs, 0.3 for the trunk, and 0.4 for the lower limbs for subjects aged ≥ 8 years) to generate a local EASI score. Next, the local EASI scores are summed to obtain the final EASI score. The EASI score is a fixed assessment performed without referring to previous scores.

[0065] [Table 13] TIFF2026086897000019.tif57142

[0066] A therapeutically effective dose of mepolizumab or a composition of the present disclosure containing mepolizumab can be used to treat a patient having atopic dermatitis or to reduce the absolute number of eosinophils in the blood of such a patient. Such atopic dermatitis may be moderate or severe.

[0067] Treatment of atopic dermatitis, such as moderate or severe atopic dermatitis, by mepolizumab or a method comprising mepolizumab as described herein may result in at least one outcome selected from the following group: a) HGA score of 0 or 1, and an improvement of at least two grades in HGA (e.g., compared to the initial HGA score), b) Reduction in Eczema Area and Severity Index (EASI) score (e.g., compared to the baseline EASI score), c) A decrease in the percentage of affected total body surface area (%BSA) (e.g., compared to the initial %BSA), and / or d) A medical professional's determination that the subject does not have atopic dermatitis, in accordance with the revised Eichenfield criteria by Hanifin and Rajka (Eichenfield et al., 70 J Am Acad Dermatol, p. 338 (2014)).

[0068] The EASI score after treatment according to the method of this disclosure may be less than 16, for example, about 0 to less than 16. The EASI score after treatment may also be about 0 to about 15, about 0 to about 14, about 0 to about 13, about 0 to about 12, about 0 to about 11, about 0 to about 10, about 0 to about 9, about 0 to about 8, about 0 to about 7, about 0 to about 6, about 0 to about 5, about 0 to about 4, about 0 to about 3, about 0 to about 2, about 0 to about 1, about 1 to less than 16, about 2 to less than 16, about 3 to less than 16, about 4 to less than 16, about 5 to less than 16, about 6 to less than 16, about 7 to less than 16, It may be approximately 8 to less than 16, approximately 9 to less than 16, approximately 10 to less than 16, approximately 11 to less than 16, approximately 12 to less than 16, approximately 13 to less than 16, approximately 14 to less than 16, approximately 15 to less than 16, approximately 2 to approximately 15, approximately 3 to approximately 14, approximately 4 to approximately 13, approximately 5 to approximately 12, approximately 6 to approximately 11, approximately 7 to approximately 10, approximately 8 to approximately 9, approximately 0 to approximately 8, approximately 8 to less than 16, approximately 0 to approximately 4, approximately 4 to approximately 8, approximately 8 to approximately 12, and approximately 12 to less than 16.

[0069] The %BSA after treatment according to the method disclosed herein may be less than approximately 10%, for example, between approximately 0% and less than 10%. Post-treatment %BSA may also be approximately 1% to less than 10%, approximately 2% to less than 10%, approximately 3% to less than 10%, approximately 4% to less than 10%, approximately 5% to less than 10%, approximately 6% to less than 10%, approximately 7% to less than 10%, approximately 8% to less than 10%, approximately 9% to less than 10%, approximately 0% to approximately 9%, approximately 0% to approximately 8%, approximately 0% to approximately 7%, approximately 0% to approximately 6%, approximately 0% to approximately 5%, approximately 0% to approximately 4%, approximately 0% to approximately 3%, approximately 0% to approximately 3%, approximately 0% to approximately 2%, approximately 0% to approximately 1%, approximately 0% to approximately 5%, approximately 5% to less than 10%, approximately 0% to approximately 2.5%, approximately 2.5% to approximately 5%, approximately 5% to approximately 7.5%, and approximately 7.5% to less than 10%.

[0070] As used herein, the term "antigen-binding protein" refers to isolated antibodies, antibody fragments (e.g., Fab, etc.), and other antibody-derived protein constructs, such as protein constructs containing an antibody domain capable of binding to human IL-5 (SEQ ID NO: 11) (e.g., domain antibodies, etc.).

[0071] As used herein, the term “antibody” refers to a molecule having an immunoglobulin-like domain (e.g., IgG, IgM, IgA, IgD, or IgE), and includes monoclonal, recombinant, polyclonal, chimeric, human, and humanized molecules of this type. Monoclonal antibodies can be produced by eukaryotic cell clones that express the antibody. Monoclonal antibodies can also be produced by eukaryotic cell lines in which the heavy and light chains of the antibody can be expressed recombinantly by introducing the nucleic acid sequences encoding them into the cells. Methods for producing antibodies from different eukaryotic cell lines, e.g., Chinese hamster ovary cells, hybridomas, or immortalized cells derived from animals (e.g., humans) are well known.

[0072] The antibodies may be derived from nucleic acids encoding antibody molecules, produced using techniques such as molecular biology, from rats, mice, primates (e.g., cynomolgus macaques, Old World monkeys, or great apes), humans, or other sources.

[0073] Antibodies may also contain a constant region, which may be a region of any isotype or subclass. The constant region may be a region of an IgG isotype, such as IgG1, IgG2, IgG3, IgG4, or a variant thereof. The constant region of an antigen-binding protein may be IgG1.

[0074] Antigen-binding proteins may include one or more modifications selected from mutated constant domains so that the antibody has enhanced effector function / ADCC and / or complement activation.

[0075] Antibodies may be able to bind to target antigens. An example of such a target antigen is human IL-5, which contains the amino acid sequence shown in SEQ ID NO: 11.

[0076] Mepolizumab containing the heavy chain amino acid sequence shown in SEQ ID NO: 1 and the light chain amino acid sequence shown in SEQ ID NO: 2 is an example of such an antibody. Mepolizumab or compositions of the present disclosure containing mepolizumab bind to and antagonize the activity of human IL-5.

[0077] Mepolizumab is a recombinant humanized monoclonal antibody (IgG1, kappa). Mepolizumab has two light chains and two heavy chains.

[0078] The mepolizumab heavy and light chains are covalently linked by a single disulfide bond, and the heavy chain is linked to itself by two disulfide bonds, resulting in a typical IgG molecule.

[0079] Mepolizumab or a composition of the present disclosure comprising mepolizumab may be provided as a lyophilized powder containing an antibody and an excipient, which can be reconstituted with a pharmaceutically acceptable carrier (e.g., sterile water). This reconstituted pharmaceutical composition can then be administered subcutaneously or intravenously (e.g., after further dilution). Mepolizumab or a composition of the present disclosure comprising mepolizumab may also be provided as a liquid formulation containing an antibody, an excipient, and a pharmaceutically acceptable carrier. This liquid pharmaceutical composition can then be administered subcutaneously or intravenously (e.g., after further dilution).

[0080] As used herein, the term “antibody variant” means an antibody that differs from a parent antibody by at least one amino acid modification (e.g., by having a different amino acid side chain), post-translational modification, or other modification in at least one heavy chain, light chain, or combination thereof that results in a structural change compared to the parent antibody (e.g., a different amino acid side chain, a different post-translational modification, or other modification). Mepolizumab is an example of such a parent antibody. Structural changes can be determined directly by various methods well known in the art, such as LC-MS, direct sequencing, or indirectly by methods such as isoelectric focusing. Such methods are well known to those skilled in the art.

[0081] As used herein, the term "IL-5" refers to human IL-5 containing the amino acid sequence shown in Sequence ID No. 11.

[0082] As used herein in connection with an antigen-binding protein, the term "specifically binds" means that the antigen-binding protein binds to a target antigen, as well as to discrete domains or discrete amino acid sequences within the target antigen, without binding, or without significantly binding, to other (e.g., unrelated) proteins. However, this term does not exclude the fact that an antigen-binding protein may also be cross-reactive with related molecules (e.g., molecules having a high degree of sequence identity or molecules from another genus or species). The antigen-binding proteins described herein can bind to human IL-5 or the human IL-5 receptor with an affinity that is at least 2, 5, 10, 50, 100, or 1000 times higher than binding to related molecules.

[0083] The binding affinity (K D ) of an antigen-binding protein-target antigen interaction can be 1 mM or less, 100 nM or less, 10 nM or less, 2 nM or less, or 1 nM or less. Alternatively, K D can be between 5-10 nM, or between 1-2 nM. K D can be between 1 pM-500 pM, or between 500 pM-1 nM. The binding affinity of an antigen-binding protein is determined by the association constant (Ka) and the dissociation constant (Kd) (KD = Kd / Ka). The binding affinity can be measured by BIACORE™, for example, by capturing a test antibody on a protein A-coated sensor surface and flowing a target antigen over this surface. Alternatively, the binding affinity can be measured by FORTEBIO, for example, by capturing a test antibody receptor on a protein A-coated needle and flowing a target antigen over this surface.

[0084] K d can be 1×10 -3 Ms -1 or less, 1×10 -4 Ms -1 or less, or 1×10 -5 Ms -1 or less. K d can be 1×10 -5 Ms -1 ~1×10-4 Ms -1 Between, or 1 × 10 -4 Ms -1 ~1 × 10 -3 Ms -1 It could be between. Slow K d This can lead to slower dissociation of the antigen-binding protein-target antigen complex and improved neutralization of the target antigen.

[0085] As used herein, the term "specific antigen-binding activity" refers to antigen-binding activity measured by surface plasmon resonance (SPR). IL-5 specific binding activity can be determined, for example, by SPR performed in binding mode using a BIACORE® instrument. This is the binding activity divided by the total protein content in the sample.

[0086] As used herein, the term "FcRn binding activity" refers to neonatal Fc(FcRn) receptor binding activity as measured by surface plasmon resonance (SPR). FcRn binding can be determined using a BIACORE® instrument. This is the binding activity to the FcRn receptor divided by the total protein concentration of the sample.

[0087] SPR methods for specific antigen binding and FcRn binding utilize a mepolizumab reference standard. The mepolizumab reference standard is used in the assay to obtain system qualification and sample comparability data, ensuring the method is performed correctly and reliably. A calibration curve can be established using the reference standard, and sample concentrations can be interpolated from the curve.

[0088] "Isolated" means that molecules such as antigen-binding proteins or nucleic acids have been removed from the environment in which they are naturally found. For example, molecules can be purified from substances that normally coexist with them in nature. For example, the mass of molecules in a sample may be 95% of the total mass. Importantly, mepolizumab antibodies and the antigen-binding proteins of this disclosure are typically provided as compositions that may comprise any combination of the nucleic acids, buffers, residual buffers, salts, counterions, water, alcohols, or vectors of this disclosure.

[0089] The term "V" as used in this specification H " and "V L " refers to the heavy chain variable region and light chain variable region of antigen-binding proteins, respectively.

[0090] "CDR" is defined as the complementarity-determining region amino acid sequence of an antigen-binding protein. These are the hypervariable regions of the immunoglobulin heavy and light chains. The variable region of an immunoglobulin contains three heavy chain and three light chain CDRs (or CDR regions). Thus, as used herein, "CDR" refers to all three heavy chain CDRs, all three light chain CDRs, all heavy and light chain CDRs, or at least one CDR, where at least one CDR is CDRH3. A framework region follows each of these CDR regions. Acceptable heavy chain variable regions and light chain variable regions Framework 1, Framework 2, and Framework 3 regions are readily recognizable to those skilled in the art. Acceptable heavy chain constant regions (including the hinge region) and light chain constant regions are also readily recognizable to those skilled in the art. Acceptable antibody isotypes are also readily recognizable to those skilled in the art.

[0091] Throughout this specification, amino acid residues in variable domain sequences and full-length antibody sequences are numbered according to Kabat numbering rules. Similarly, the terms “CDR”, “CDRL1”, “CDRL2”, “CDRL3”, “CDRH1”, “CDRH2”, and “CDRH3” used herein also conform to Kabat numbering rules.

[0092] It is obvious to those skilled in the art that alternative numbering rules exist for amino acid residues in variable domain sequences and full-length antibody sequences. Similarly, there are sequences that are described according to alternative numbering rules for CDR sequences, such as the Chothia numbering rule. The structure and protein folding of the antibody may mean that other residues are considered to be part of the CDR sequence and are understood as such by those skilled in the art.

[0093] Other numbering rules for CDR sequences available to those skilled in the art include the "AbM" (University of Bath) and "contact" (University College London) methods. At least two of the Kabat, Chothia, AbM, and contact methods can be used to determine the minimum overlapping region and provide a "minimum binding unit." The minimum binding unit may be a portion of the CDR.

[0094] Table 14 below shows one definition using each numbering rule for each CDR or binding unit. The Kabat numbering scheme is used in Table 14 to number the variable domain amino acid sequences. It should be noted that some CDR definitions may vary depending on the individual publication used.

[0095] [Table 14]

[0096] The "percent identity" between the query nucleic acid sequence and the target nucleic acid sequence is an "identity" value expressed as a percentage, calculated by the BLASTN algorithm after performing pairwise BLASTN alignment, if the target nucleic acid sequence has 100% query coverage with the query nucleic acid sequence. Such pairwise BLASTN alignment between the query nucleic acid sequence and the target nucleic acid sequence is performed using the default settings of the BLASTN algorithm, available on the National Center for Biotechnology website, with low-complexity region filtering turned off. Importantly, the query sequence may be described by a nucleic acid sequence identified in one or more claims herein.

[0097] Nucleic acid sequences that may be useful and may be included in the compositions and related methods of this disclosure may have about 85% to about 100%, about 90% to about 100%, about 95% to about 100%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, about 99%, and about 100% identity with the nucleic acid sequences identified in this disclosure (e.g., nucleic acids encoding antibody heavy chains or antibody light chains). In this disclosure, the percentage identity between the nucleic acid sequences described may include any distinct subrange of the percentage identity ranges listed above (e.g., any range of integer values ​​within a particular range or distinct subranges within a particular range).

[0098] The "percent identity" between the query amino acid sequence and the target amino acid sequence is a "identical" value expressed as a percentage, calculated by the BLASTP algorithm after performing pairwise BLASTP alignment if the target amino acid sequence has 100% query coverage with the query amino acid sequence. Such pairwise BLASTP alignment between the query amino acid sequence and the target amino acid sequence is performed using the default settings of the BLASTP algorithm available on the National Center for Biotechnology website, with filtering of low complexity regions turned off. Importantly, the query sequence may be described by an amino acid sequence identified in one or more claims herein.

[0099] Amino acid sequences that are useful in and may be included in the compositions and related methods of this disclosure may have about 85% to about 100%, about 90% to about 100%, about 95% to about 100%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, about 99%, and about 100% identity with amino acid sequences identified in this disclosure (e.g., antibody heavy chain or antibody light chain). In this disclosure, the percentage identity between the amino acid sequences described may include any distinct subrange of the percentage identity ranges listed above (e.g., any range of integer values ​​within a particular range or distinct subvalues ​​within a particular range).

[0100] The terms "peptide," "polypeptide," "protein," and "peptide chain" each refer to molecules containing two or more amino acid residues. Peptides can be monomers or polymers.

[0101] It is well recognized in the art that certain amino acid substitutions are considered “conservative.” Amino acids are classified into groups based on their common side-chain properties and whether they maintain all or substantially all of the binding affinity of antigen-binding proteins that are considered conservative substitutions. See Table 15. Antigen-binding proteins disclosed herein may include such “conservative” amino acid substitutions.

[0102] [Table 15]

[0103] As used herein, the term "pharmaceutical composition" means a composition suitable for administration to a patient.

[0104] The pharmaceutical compositions described herein may include purified preparations of antibodies described herein.

[0105] For example, a pharmaceutical preparation may include, in combination with a pharmaceutically acceptable carrier, a purified preparation of an antibody as described herein.

[0106] Typically, such pharmaceutical compositions include pharmaceutically acceptable carriers that are known and required by accepted pharmaceutical practice. Examples of such carriers include sterile carriers, such as saline, Ringer's solution, or dextrose solution buffered to a pH range of 5–8 with an optional buffer.

[0107] The pharmaceutical composition may be administered by injection or infusion (e.g., intravenous, intraperitoneal, intradermal, subcutaneous, intramuscular, or portal vein). Such compositions preferably do not contain visible particulate matter. The pharmaceutical composition may contain 1 mg to 10 g of antigen-binding protein, for example, 5 mg to 1 g of antigen-binding protein. Alternatively, the composition may contain between 5 mg and 500 mg of antigen-binding protein, for example, between 5 mg and 50 mg.

[0108] Methods for preparing such pharmaceutical compositions are well known to those skilled in the art. The pharmaceutical composition may optionally contain 1 mg to 10 g of antigen-binding protein in a unit dosage form, along with instructions for use. The pharmaceutical composition may be freeze-dried and reconstituted before administration according to methods well known or obvious to those skilled in the art. If the antibody has an IgG1 isotype, a copper chelating agent, such as citrate (sodium citrate), EDTA, or histidine, may be added to the pharmaceutical composition to reduce the degree of copper-mediated degradation of this isotype antibody. The pharmaceutical composition may also contain a solvent, such as arginine, a surfactant / anticoagulant, such as polysorbate 80, and an inert gas, such as nitrogen, to replace oxygen in the head gap of the vial.

[0109] As used herein, the term “therapeutic dose” means the amount of a drug (e.g., an antibody or pharmaceutical composition) that provides a therapeutic benefit in the treatment or management of one or more symptoms of the condition being treated (e.g., asthma, mild asthma, moderate asthma, severe asthma, mild eosinophilic asthma, moderate eosinophilic asthma, severe eosinophilic asthma, controlled poor eosinophilic asthma, eosinophilic asthma, subtype eosinophilic asthma, chronic obstructive pulmonary disease, eosinophilic granulomatosis with polyangiitis, eosinophilic syndrome, nasal polyps, bullous pemphigoid, eosinophilic esophagitis, atopic dermatitis, moderate atopic dermatitis, and severe atopic dermatitis). Examples of such treatment or management of one or more symptoms of asthma, including asthma, mild asthma, moderate asthma, severe asthma, mild eosinophilic asthma, moderate eosinophilic asthma, severe eosinophilic asthma, poorly controlled eosinophilic asthma, eosinophilic asthma, and subtype eosinophilic asthma, include: 1) reduction in the frequency of asthma exacerbations; 2) reduction in the time to the first clinically significant exacerbation requiring oral or systemic corticosteroids, hospitalization, and / or transport to the emergency department (ED); 3) reduction in the frequency of exacerbations requiring hospitalization (including tracheal intubation and transport to the intensive care unit) or transport to the ED; 4) reduction in the time to the first exacerbation requiring hospitalization or transport to the ED; 5) change from baseline in FEV1 before clinical administration of bronchodilators; 6) change from baseline in FEV1 after clinical administration of bronchodilators; 7) asthma control 7) Improvements in lung function assessed by spirometry (e.g., vital capacity (VC), forced vital capacity (FVC), forced expiratory vital capacity (FEV1), forced expiratory flow rate (FEF25-75) at 0.5, 1.0 (FEV1), 2.0, and 3.0 second intervals, 25-75% of forced expiratory flow rate (FEF25-75), and maximal tidal volume (MVV), total vital capacity, tidal volume, residual volume, expiratory reserve volume, inspiratory reserve volume, inspiratory volume, inspiratory vital capacity, vital capacity, functional residual volume, residual volume expressed as a percentage of total vital capacity, alveolar volume, actual lung volume including guided airway volume, forced vital capacity, etc.), and 8) reduction in asthma exacerbations requiring steroids for control (e.g., oral steroids or steroids administered via any route, e.g., prednisone, prednisolone, etc.).Such a reduction in asthma exacerbations requiring steroids for control could be approximately a 50% reduction in exacerbations requiring steroids (e.g., oral steroids).

[0110] The effective dosage and treatment regimen are generally determined empirically and may depend on factors such as the patient's age, weight, and health status, as well as the disease or disorder being treated. Such factors are within the scope of the attending physician.

[0111] The dosage of antigen-binding protein administered to a subject is generally between 1 μg / kg and 150 mg / kg, between 0.1 mg / kg and 100 mg / kg, between 0.5 mg / kg and 50 mg / kg, between 1 and 25 mg / kg, between approximately 0.3 mg / kg and approximately 3 mg / kg, or between 1 and 10 mg / kg of the subject's body weight. For example, the dosage may be 10 mg / kg, 30 mg / kg, or 60 mg / kg. The dosage may also be between 10 mg / kg and 110 mg / kg, 15 mg / kg and 25 mg / kg, or between 15 mg / kg and 100 mg / kg. Antigen-binding protein can be administered, for example, parenterally, subcutaneously, intravenously, or intramuscularly. The dosage per subject may be, for example, approximately 20 mg / subject to approximately 750 mg / subject, approximately 75 mg / subject to approximately 750 mg / subject, or approximately 20 mg / subject to approximately 200 mg / subject. The dose may be any separate sub-range within these dose ranges. For example, the dose may also be administered subcutaneously per subject, for example, about 100 mg / subject (e.g., once every four weeks), or 300 mg / subject (or other doses may be administered subcutaneously, as long as a bioavailability comparable to or similar to that of intravenous administration is achieved—e.g., three doses of 100 mg / subject to achieve the total subcutaneous dose of 300 mg / subject).

[0112] For children weighing less than 40 kg, a dose of 40 mg is preferably administered, and for children weighing 40 kg or more, a dose of 100 mg of mepolizumab is preferably administered. Such doses are even more preferably administered subcutaneously.

[0113] Any type of range provided herein includes all values ​​within the specified range and values ​​near the end of the specified range.

[0114] If desired, the effective daily dose of the antibody or antigen-binding protein of this disclosure (e.g., as a pharmaceutical composition) may be administered as a unit dosage form in two, three, four, five, or six or more individual doses at appropriate intervals throughout the day. For example, a 100 mg dose administered to a child weighing 40 kg or more may be administered as two separate 0.5 ml doses (e.g., subcutaneous injections), each containing 50 mg of mepolizumab.

[0115] The dose may be administered as a slow, continuous infusion over a period of 2 to 24 hours, for example, 2 to 12 hours or 2 to 6 hours. Such administration may result in a reduction of side effects.

[0116] The dosage may be repeated one or more times as needed, for example, three times a day, once a day, once every two days, once a week, once every 14 days, once every month, once every three months, once every four months, once every six months, or once every twelve months. Antigen-binding proteins may be administered once a week as maintenance therapy for a period of six months or more. Antigen-binding proteins may also be administered as intermittent therapy, for example, after 3 to 6 months of administration, with no administration for 3 to 6 months, and then again in cycles of 3 to 6 months.

[0117] For example, the dosage may be administered subcutaneously once every 14 or 28 days in the form of multiple doses on each administration day. In one embodiment, the dose of the composition is 100 mg once every 4 weeks (28 days).

[0118] Antigen-binding proteins can be administered to a target to target the treatment to a specific site (e.g., the upper arm or thigh).

[0119] The antigen-binding protein in the method disclosed herein may be used in combination with one or more other therapeutic agents, such as antibodies or small molecule inhibitors.

[0120] As used herein, the term “to treat” and its grammatical variations mean therapeutic treatment. Referring to a particular condition, to treat means (1) improving one or more aspects of the biological manifestation of the condition; (2) a) interfering with one or more points in the biological cascade in which the condition occurs or causes the condition, or b) interfering with one or more aspects of the biological manifestation of the condition; (3) reducing one or more symptoms, effects, or side effects associated with the condition or its treatment; (4) delaying the progression of the condition or one or more aspects of its biological manifestation; or (5) preventing the occurrence of one or more aspects of the biological manifestation of the condition. Preventive treatment is also intended thereby. Those skilled in the art will recognize that “prevention” is not an absolute term. In medicine, “prevention” is understood to mean the prophylactic administration of a drug to substantially reduce the likelihood or severity of a condition or its biological manifestation, or to delay the occurrence of such a condition or its biological manifestation.

[0121] The terms “individual,” “subject,” and “patient” are used interchangeably herein. A subject is typically a human. A subject may also be a mammal, e.g., a mouse, rat, or primate (e.g., a marmoset or monkey). A subject may be a non-human animal. The antigen-binding proteins, compositions, and methods of this disclosure also have veterinary applications. The subject to be treated may be a farm animal, e.g., a cattle or bull, sheep, pig, steer, goat, or horse, or a domestic animal such as a dog or cat. The animal may be of any age or a mature adult.

[0122] Treatment may be therapeutic, preventive, or deterrent. The target is the person who needs it. The person requiring treatment may include individuals who are already suffering from a specific medical condition, in addition to those who may develop the disease in the future.

[0123] Thus, the methods, antigen-binding proteins, and compositions described herein can be used for prophylactic or preventive measures, as specified. In this case, the methods, antigen-binding proteins, and compositions may be used to prevent or delay the onset of one or more embodiments or symptoms of a disease. Subjects may be asymptomatic. Subjects may have a genetic predisposition to the disease. A prophylactic effective dose of the antigen-binding protein is administered to such individuals. A prophylactic effective dose is the amount that prevents or delays the onset of one or more embodiments or symptoms of the disease described herein.

[0124] The methods, antigen-binding proteins, and compositions of this disclosure do not need to affect complete healing or to eradicate all symptoms or manifestations of a disease in order to constitute a viable therapeutic measure. As is recognized in the art, a drug used as a therapeutic agent in a method of treatment may reduce the severity of a given disease condition, but it does not need to eliminate all manifestations of the disease to be considered a useful therapeutic agent. Similarly, a prophylactically administered treatment does not need to be completely effective in preventing the onset of the disease in order to be a viable prophylactic agent. It is sufficient to merely reduce the effects of the disease (e.g., by reducing the frequency or severity of its symptoms, or by increasing the effectiveness of another treatment, or by producing another beneficial effect), or to reduce the likelihood that the disease will occur (e.g., by delaying the onset of the disease) or worsen in a subject.

[0125] As used herein, “Area under the curve,” or “AUC,” is the area under the curve in a plot of the concentration of a substance in plasma against time. AUC can be a measure of the integral of instantaneous concentrations over a time interval and has units of mass*time / volume. AUC is typically calculated by the trapezoidal rule (e.g., linear, linear-logarithmic). AUC is usually given for time intervals from zero to infinity, but other time intervals are also shown (e.g., AUC(t1,t2) where t1 and t2 are the start and end times of the interval). Thus, as used herein, “AUC 0-24'' refers to the AUC over a 24-hour period, while AUC(0-infinity) refers to the AUC over an infinite period.

[0126] As used herein, "Tmax" refers to the time observed until the highest concentration of a substance is reached in the plasma of a mammal after administration of that substance to the mammal.

[0127] As used herein, “maximum plasma concentration” or “Cmax” means the highest concentration of the substance (or antibody) observed in the plasma of a mammal after administration of the substance to the mammal.

[0128] As used herein, "maximum steady-state plasma concentration" or "Cmax SS" refers to the maximum plasma concentration at steady state determined by pharmacokinetic modeling, and is a population estimate of steady-state Cmax obtained by population PK method. Steady state refers to the state in which the total uptake of a drug is in proper dynamic equilibrium with its excretion. Typically, steady state is generally considered to be reached 4 to 5 times the half-life of the drug after the start of regular administration.

[0129] As used herein, “serum or plasma half-life” refers to the time required for half of the amount of a substance administered to a mammal to be metabolized or excreted from the mammal’s serum or plasma by normal biological processes.

[0130] One aspect of the present disclosure is a method for treating a disease in a child, a) a child having a disease selected from the group consisting of asthma, mild asthma, moderate asthma, severe asthma, mild eosinophilic asthma, moderate eosinophilic asthma, severe eosinophilic asthma, controlled poor eosinophilic asthma, eosinophilic asthma, subtype eosinophilic asthma, chronic obstructive pulmonary disease, eosinophilic granulomatosis with polyangiitis, eosinophilic syndrome, nasal polyps, bullous pemphigoid, eosinophilic esophagitis, atopic dermatitis, moderate atopic dermatitis, and severe atopic dermatitis, weighing 40 A method for treating a disease in a pediatric subject, comprising the steps of: a) identifying a pediatric subject weighing less than 1 kg; and b) subcutaneously administering a therapeutically effective dose of an antibody containing the heavy chain amino acid sequence shown in SEQ ID NO: 1 and the light chain amino acid sequence shown in SEQ ID NO: 2, wherein the therapeutically effective dose of the antibody results in a maximum plasma concentration (Cmax) of approximately 10.1960 ± 0.3345 μg / mL of the antibody and an area under the curve [0-infinity] value of approximately 454.39 ± 15.8876 μg* / mL.

[0131] In one embodiment of the method disclosed herein, the therapeutically effective dose of the antibody is approximately 40 mg.

[0132] In another embodiment of the method disclosed herein, the antibody is administered approximately once a month.

[0133] In another embodiment of the method of the present disclosure, the pediatric subject has an absolute number of blood eosinophils selected from the group consisting of 150 cells / μL or more and 300 cells / μL or more.

[0134] In another embodiment of the method of the present disclosure, the pediatric subjects are selected from the group consisting of premature newborns, full-term newborns, children aged 28 days to 11 months, children aged 12 months to 23 months, children aged 2 years to 6 years, children aged 16 years to 12 years, children aged 6 years to under 18 years, and children aged 12 years to 18 years.

[0135] In another embodiment of the method disclosed herein, the child subject is approximately 6 years of age or older and approximately 12 years of age or younger.

[0136] In another embodiment of the method disclosed herein, the pediatric subject has severe eosinophilic asthma.

[0137] In another aspect of the method of the present disclosure, the pediatric subject has treatment outcomes selected from the group consisting of a decrease in the absolute number of blood eosinophils compared to the absolute number of blood eosinophils before antibody administration, a decrease in the score of the seven scales of the asthma control questionnaire compared to the score of the seven scales of the asthma control questionnaire compared to the score of the pediatric asthma control test compared to the score of the pediatric asthma control test compared to the score of the pediatric asthma control test compared to the score of the pediatric asthma control test before antibody administration.

[0138] In another embodiment of the method of this disclosure, the antibody is administered by a syringe with a safety device or by an auto-injector.

[0139] Another aspect of the present disclosure is a method for treating a disease in a child, a) a child having a disease selected from the group consisting of asthma, mild asthma, moderate asthma, severe asthma, mild eosinophilic asthma, moderate eosinophilic asthma, severe eosinophilic asthma, poorly controlled eosinophilic asthma, eosinophilic asthma, subtype eosinophilic asthma, chronic obstructive pulmonary disease, eosinophilic granulomatosis with polyangiitis, eosinophilic syndrome, nasal polyps, bullous pemphigoid, eosinophilic esophagitis, atopic dermatitis, moderate atopic dermatitis, and severe atopic dermatitis, weighing 4 A method for treating a disease in a pediatric subject, comprising the steps of: a) identifying a pediatric subject weighing 0 kg or more; and b) subcutaneously administering a therapeutically effective dose of an antibody containing the heavy chain amino acid sequence shown in SEQ ID NO: 1 and the light chain amino acid sequence shown in SEQ ID NO: 2, wherein the therapeutically effective dose of the antibody results in a maximum plasma concentration (Cmax) of approximately 16.3412 ± 0.6364 μg / mL of the antibody and an area under the curve [0-infinity] value of approximately 675.20 ± 35.8980 μg* / mL.

[0140] In another embodiment of the method disclosed herein, the therapeutically effective dose of the antibody is approximately 100 mg.

[0141] Another aspect of this disclosure relates to a method for reducing the absolute number of eosinophils in the blood of a child subject, wherein the child subject weighing less than 40 kg has a condition selected from the group consisting of asthma, mild asthma, moderate asthma, severe asthma, mild eosinophilic asthma, moderate eosinophilic asthma, severe eosinophilic asthma, poorly controlled eosinophilic asthma, eosinophilic asthma, subtype eosinophilic asthma, chronic obstructive pulmonary disease, eosinophilic granulomatosis with polyangiitis, eosinophilic syndrome, nasal polyps, bullous pemphigoid, eosinophilic esophagitis, and atopic dermatitis. A method comprising the steps of identifying, and a) subcutaneously administering a therapeutically effective dose of an antibody comprising the heavy chain amino acid sequence shown in SEQ ID NO: 1 and the light chain amino acid sequence shown in SEQ ID NO: 2 to a pediatric subject, wherein the therapeutically effective dose of the antibody results in a maximum plasma concentration (Cmax) of approximately 10.1960 ± 0.3345 μg / mL of the antibody and an area under the curve [0-infinity] value of approximately 454.39 ± 15.8876 μg* / mL, thereby reducing the absolute number of eosinophils in the blood of the pediatric subject.

[0142] Another aspect of this disclosure relates to a method for reducing the absolute number of eosinophils in the blood of a child subject, wherein the child subject weighing 40 kg or more has a condition selected from the group consisting of asthma, mild asthma, moderate asthma, severe asthma, mild eosinophilic asthma, moderate eosinophilic asthma, severe eosinophilic asthma, poorly controlled eosinophilic asthma, eosinophilic asthma, subtype eosinophilic asthma, chronic obstructive pulmonary disease, eosinophilic granulomatosis with polyangiitis, eosinophilic syndrome, nasal polyps, bullous pemphigoid, eosinophilic esophagitis, and atopic dermatitis. A method comprising the steps of identifying, and a) subcutaneously administering a therapeutically effective dose of an antibody comprising the heavy chain amino acid sequence shown in SEQ ID NO: 1 and the light chain amino acid sequence shown in SEQ ID NO: 2 to a pediatric subject, wherein the therapeutically effective dose of the antibody results in a maximum plasma concentration (Cmax) of approximately 16.3412 ± 0.6364 μg / mL of the antibody and an area under the curve [0-infinity] value of approximately 675.20 ± 35.8980 μg* / mL, thereby reducing the absolute number of eosinophils in the blood of the pediatric subject.

[0143] Another embodiment of the present disclosure is a composition and / or method of the present disclosure for use in therapeutic purposes.

[0144] Another embodiment of the present disclosure is a composition and / or method of the present disclosure for use in the treatment of asthma, mild asthma, moderate asthma, severe asthma, mild eosinophilic asthma, moderate eosinophilic asthma, severe eosinophilic asthma, controlled poor eosinophilic asthma, eosinophilic asthma, subtype eosinophilic asthma, chronic obstructive pulmonary disease, eosinophilic granulomatosis with polyangiitis, eosinophilic syndrome, nasal polyps, bullous pemphigoid, eosinophilic esophagitis, atopic dermatitis, moderate atopic dermatitis, and severe atopic dermatitis.

[0145] Another aspect of this disclosure relates to the treatment of asthma, mild asthma, moderate asthma, severe asthma, mild eosinophilic asthma, moderate eosinophilic asthma, severe eosinophilic asthma, poorly controlled eosinophilic asthma, eosinophilic asthma, subtype eosinophilic asthma, chronic obstructive pulmonary disease, eosinophilic granulomatosis with polyangiitis, eosinophilic syndrome, nasal polyps, bullous pemphigoid, eosinophilic esophagitis, atopic dermatitis, moderate atopic dermatitis, and severe atopic dermatitis in children weighing less than 40 kg. A composition for treating diseases selected from the group consisting of dermatitis, comprising an antibody containing the heavy chain amino acid sequence shown in SEQ ID NO: 1 and the light chain amino acid sequence shown in SEQ ID NO: 2, wherein the therapeutically effective dose of the antibody administered subcutaneously to a child yields a maximum plasma concentration (Cmax) of approximately 10.1960 ± 0.3345 μg / mL of the antibody and an area under the curve [0-infinity] value of approximately 454.39 ± 15.8876 μg* / mL.

[0146] In another embodiment of the composition of this disclosure, the therapeutically effective dose of the antibody is approximately 40 mg.

[0147] Another aspect of this disclosure relates to the treatment of asthma, mild asthma, moderate asthma, severe asthma, mild eosinophilic asthma, moderate eosinophilic asthma, severe eosinophilic asthma, poorly controlled eosinophilic asthma, eosinophilic asthma, subtype eosinophilic asthma, chronic obstructive pulmonary disease, eosinophilic granulomatosis with polyangiitis, eosinophilic syndrome, nasal polyps, bullous pemphigoid, eosinophilic esophagitis, atopic dermatitis, moderate atopic dermatitis, and severe atopic dermatitis in children weighing 40 kg or more. A composition for treating diseases selected from the group consisting of dermatitis, comprising an antibody containing the heavy chain amino acid sequence shown in SEQ ID NO: 1 and the light chain amino acid sequence shown in SEQ ID NO: 2, wherein the therapeutically effective dose of the antibody administered subcutaneously to a child yields a maximum plasma concentration (Cmax) of approximately 16.3412 ± 0.6364 μg / mL of the antibody, and an area under the curve [0-infinity] value of approximately 675.20 ± 35.8980 μg* / mL.

[0148] In another embodiment of the composition of this disclosure, the therapeutically effective dose of the antibody is about 100 mg.

[0149] Another aspect of the present disclosure is a composition for reducing the absolute number of eosinophils in the blood of children weighing less than 40 kg, wherein the children have asthma, mild asthma, moderate asthma, severe asthma, mild eosinophilic asthma, moderate eosinophilic asthma, severe eosinophilic asthma, poorly controlled eosinophilic asthma, eosinophilic asthma, subtype eosinophilic asthma, chronic obstructive pulmonary disease, eosinophilic granulomatosis with polyangiitis, eosinophilic syndrome, nasal polyps, bullous pemphigoid, eosinophilic esophagitis, atopic dermatitis, and moderate The composition is for a disease selected from the group consisting of moderate atopic dermatitis and severe atopic dermatitis, and comprises an antibody containing the heavy chain amino acid sequence shown in SEQ ID NO: 1 and the light chain amino acid sequence shown in SEQ ID NO: 2, wherein the therapeutically effective dose of the antibody administered subcutaneously to a child yields a maximum plasma concentration (Cmax) of approximately 10.1960 ± 0.3345 μg / mL of the antibody, and an area under the curve [0-infinity] value of approximately 454.39 ± 15.8876 μg* / mL.

[0150] Another aspect of the present disclosure is a composition for reducing the absolute number of eosinophils in the blood of children weighing 40 kg or more, wherein the children have asthma, mild asthma, moderate asthma, severe asthma, mild eosinophilic asthma, moderate eosinophilic asthma, severe eosinophilic asthma, poorly controlled eosinophilic asthma, eosinophilic asthma, subtype eosinophilic asthma, chronic obstructive pulmonary disease, eosinophilic granulomatosis with polyangiitis, eosinophilic syndrome, nasal polyps, bullous pemphigoid, eosinophilic esophagitis, atopic dermatitis The patient has a disease selected from the group consisting of dermatitis, moderate atopic dermatitis, and severe atopic dermatitis, and the composition comprises an antibody containing the heavy chain amino acid sequence shown in SEQ ID NO: 1 and the light chain amino acid sequence shown in SEQ ID NO: 2, and the therapeutically effective dose of the antibody yields a maximum plasma concentration (Cmax) of approximately 16.3412 ± 0.6364 μg / mL of the antibody, and an area under the curve [0-infinity] value of approximately 675.20 ± 35.8980 μg* / mL.

[0151] In one embodiment of the method of this disclosure, the amount of antigen-binding protein is approximately 2 mg to approximately 600 mg. For example, the amount of antigen-binding protein (e.g., antibody) may be 2 mg, 10 mg, 30 mg, 100 mg, 300 mg, or 600 mg.

[0152] In one embodiment of the method of the present disclosure, the antigen-binding protein is administered once every three months or once every six months.

[0153] One embodiment of the present disclosure is a method comprising an aqueous liquid formulation having a pH of approximately 5.5 to 6.0, in which a pharmaceutically effective carrier contains approximately 40 mM histidine, approximately 180 mM trehalose, approximately 100 mM arginine, approximately 8 mM methionine, approximately 0.02 wt / vol% polysorbate 80, and approximately 0.05 mM EDTA.

[0154] The compositions of the present disclosure, and compositions comprising antibodies or antigen-binding proteins of the present disclosure, may further include a buffer selected from the group consisting of dibasic sodium phosphate heptahydrate, phosphates, citric acid, citrates, sodium phosphate, potassium phosphate, sodium citrate, and histidine, resulting in a pH between 6.8 and 7.2, or between 6.2 and 6.6, preferably a pH of 6.3. The buffer in the compositions of the present disclosure may be present in a range of about 10 to 30 mM, about 10 to 20 mM, about 20 mM, or about 15.5 mM. For example, the buffer in the compositions of the present disclosure may be present as about 20 mM or about 15.5 mM dibasic sodium phosphate heptahydrate. These compositions are useful in the methods of the present disclosure.

[0155] The compositions of this disclosure may contain dibasic sodium phosphate heptahydrate and a citrate buffer, providing a pH of 6.2 to 6.6, preferably 6.3. The dibasic sodium phosphate heptahydrate buffer may be present in a range of about 15 to 16.4 mM, and the citrate buffer may be present in a range of about 3.8 to 4.9 mM. For example, the compositions of this disclosure may contain about 15.5 mM dibasic sodium phosphate heptahydrate and about 4.5 mM citrate monohydrate.

[0156] The compositions of the present disclosure may further contain sugars. The compositions of the present disclosure may further contain sucrose. Sucrose may be present in the compositions of the present disclosure in amounts ranging from about 5 to 20%, about 10 to 15%, about 11 to 13%, or about 12% by weight / volume.

[0157] The compositions of this disclosure may further comprise polysorbate 80, which may be present in an amount of about 0.01 to 0.1% by weight / volume. For example, polysorbate 80 may be present in an amount of about 0.02% by weight / volume, or about 0.05% by weight / volume.

[0158] The compositions of this disclosure may further contain EDTA, which may be present in a concentration of about 0.01 to 0.1 mM. For example, EDTA may be present in a concentration of about 0.05 mM.

[0159] In one embodiment, the composition of the present disclosure further comprises 20 mM dibasic sodium phosphate heptahydrate, 12% by weight / volume sucrose, and 0.05% by weight / volume polysorbate 80.

[0160] In another embodiment, the composition of the present disclosure may further comprise 15.5 mM dibasic sodium phosphate, 3.9 mM citric acid monohydrate, 12% by weight / volume sucrose, 0.02% by weight / volume polysorbate 80, and 0.05 mM EDTA.

[0161] The compositions of this disclosure may include aqueous liquid formulations with a pH of 6.2 containing 16.1 mM dibasic sodium phosphate heptahydrate, 3.9 mM citric acid monohydrate, 12% by weight / volume sucrose, 0.02% by weight / volume polysorbate 80, and 0.05 mM EDTA.

[0162] The compositions of this disclosure may include aqueous liquid formulations with a pH of 6.2 containing 15.2 mM dibasic sodium phosphate heptahydrate, 4.8 mM citric acid monohydrate, 12% by weight / volume sucrose, 0.02% by weight / volume polysorbate 80, and 0.05 mM EDTA.

[0163] The compositions of this disclosure may include aqueous liquid formulations with a pH of 6.4 containing 15.8 mM dibasic sodium phosphate heptahydrate, 4.2 mM citric acid monohydrate, 12% by weight / volume sucrose, 0.02% by weight / volume polysorbate 80, and 0.05 mM EDTA.

[0164] The compositions of this disclosure may include aqueous liquid formulations with a pH of 6.6 containing 16.3 mM dibasic sodium phosphate heptahydrate, 3.7 mM citric acid monohydrate, 12% by weight / volume sucrose, 0.02% by weight / volume polysorbate 80, and 0.05 mM EDTA.

[0165] The compositions of the present disclosure may include aqueous liquid formulations with a pH of 6.3 containing 15.5 mM dibasic sodium phosphate heptahydrate, 4.5 mM citrate monohydrate, 12 wt / vol% sucrose, 0.02 wt / vol% polysorbate 80, and 0.05 mM EDTA. Importantly, the tangential flow filtration and ultrafiltration exchange steps of the production process may be modified to produce compositions of the present disclosure, such as the composition of the present disclosure or other such liquid formulations, with a pH of 6.3 containing 15.5 mM dibasic sodium phosphate heptahydrate, 4.5 mM citrate monohydrate, 12 wt / vol% sucrose, 0.02 wt / vol% polysorbate 80, and 0.05 mM EDTA.

[0166] The compositions of this disclosure include purified preparations of monoclonal antibodies and buffers, wherein the pH of the composition is 6.8 to 7.2, and the buffer is histidine, phosphate, citric acid, citrate, or a salt thereof.

[0167] In the compositions of this disclosure, the buffering agent may be at least one selected from the group consisting of dibasic sodium phosphate heptahydrate, phosphates, citric acid, and citrates.

[0168] In the compositions of this disclosure, the buffering agent may be sodium phosphate, potassium phosphate, or sodium citrate.

[0169] The compositions of this disclosure may include sugars, carbohydrates, and / or salts.

[0170] The compositions of this disclosure may also include sucrose or trehalose.

[0171] The compositions of the present disclosure may also include purified preparations of a monoclonal antibody and a buffer, wherein the pH of the composition is 6.8 to 7.2 and the buffer is a phosphate or a salt thereof.

[0172] The compositions of this disclosure may also include formulations selected from a first formulation comprising 20 mM dibasic sodium phosphate heptahydrate, 12 wt / vol% sucrose, and 0.05 wt / vol% polysorbate 80; a second formulation comprising 15.5 mM dibasic sodium phosphate heptahydrate, 3.9 mM citric acid monohydrate, 12 wt / vol% sucrose, 0.02 wt / vol% polysorbate 80, and 0.05 mM EDTA; and a third formulation comprising 26 mM dibasic sodium phosphate heptahydrate, 15 wt / vol% sucrose, and 0.065 wt / vol% polysorbate 80. The pH of the composition may be between about 6.8 and about 7.2, about 6.1 and about 6.5, or about 6 and about 6.6.

[0173] The compositions described herein can be produced by any number of conventional techniques. For example, the compositions can be expressed and purified from recombinant expression systems. In one embodiment, the compositions are produced by culturing host cells under conditions suitable for the expression of polypeptides comprising SEQ ID NOs: 1 and SEQ ID NOs: 2, and the compositions are expressed, optionally purified, and optionally formulated into pharmaceutical compositions.

[0174] The composition can be produced using several different expression systems and purification regimes. Generally, host cells are transformed with a recombinant expression vector encoding an antibody. A wide range of host cells can be used, including mammalian eukaryotic cell lines (e.g., CHO, Perc6, HEK293, HeLa, NS0). Suitable host cells include mammalian cells such as CHO (e.g., CHOK1 and CHODG44).

[0175] A host cell can be an isolated host cell. A host cell is usually not part of a multicellular organism (e.g., a plant or animal). A host cell can be a non-human host cell.

[0176] Suitable cloning and expression vectors for use with eukaryotic or mammalian cell hosts and cloning methods are known to those skilled in the art.

[0177] Cells can be cultured under conditions that promote antibody expression. For example, cells can be cultured using a production bioreactor. The volume of the production bioreactor may be (i) approximately 20,000 liters, approximately 10,000 liters, approximately 5,000 liters, approximately 2,000 liters, approximately 1,000 liters, or approximately 500 liters, or (ii) between 500 and 20,000 liters, between 500 and 10,000 liters, between 500 and 5,000 liters, between 1,000 and 10,000 liters, or between 2,000 and 10,000 liters. For example, cells can be cultured in a production bioreactor with a pH of approximately 6.75 to 7.00. Alternatively, cells can be cultured in a production bioreactor for approximately 12 to 18 days. Alternatively, cells can be cultured in a production bioreactor with a pH of approximately 6.75 to 7.00 for approximately 12 to 18 days. This culture step may be useful for controlling the level of deamidating antibody variants, for example, by reducing the level of deamidating antibody variants.

[0178] The composition can be recovered and purified by conventional protein purification procedures. For example, the composition can be collected directly from the culture medium. Collection of the cell culture medium can be performed via clarification, for example, by centrifugation and / or depth filtration. After the recovery of the composition, purification is performed to ensure adequate purity.

[0179] One or more chromatography steps, for example, one or more chromatography resins, and / or one or more filtration steps may be used for purification. For example, the composition may be purified using affinity chromatography using a resin, for example, protein A, G, or L. Alternatively, the composition may be purified using an ion exchange resin, such as cation exchange resin. Alternatively, the composition may be purified using a hydrophobic interaction chromatography resin. Alternatively, the purification step may include an affinity chromatography resin step, followed by a cation exchange resin step, followed by a hydrophobic interaction chromatography resin step.

[0180] For example, the sample is brought into contact with a protein A resin. The solution containing the composition may be eluted from the protein A resin and treated at pH 3.3-3.7 for 15-240 minutes. This protein A resin step may be useful to control the level of aggregated antibody variants, for example, to reduce the level of aggregated antibody variants.

[0181] Next, the solution containing the composition may be further clarified by depth filtration and / or double-layer filtration.

[0182] Alternatively, an anion exchange resin may be used. The solution containing the composition may be brought into contact with an anion exchange resin (e.g., Q-SEPHAROSE® Fast Flow anion exchange chromatography) at a loading pH of 8.3–8.7. The solution containing the composition may be eluted from the anion exchange resin and held for up to 96 hours. This anion exchange resin step may be useful for controlling the level of deamidated antibody variants, for example, to reduce the level of deamidated antibody variants.

[0183] Optionally, guanidine and / or ammonium sulfate may be added to the solution containing the composition and held for 15 to 240 minutes.

[0184] Alternatively, or in addition, a hydrophobic interaction chromatography resin may be used. The solution containing the composition may be contacted with a hydrophobic interaction chromatography resin (e.g., Phenyl SEPHAROSE® high-performance chromatography) at a load ratio of 12–27 g protein / L resin. For example, the solution containing the composition may be eluted using an elution gradient volume (bed volume; BV) of about 9–11. An elution peak cut stop (%) of about 17–23 (percentage of maximum peak height) may be used during elution from the hydrophobic interaction chromatography resin. This hydrophobic interaction chromatography resin step may be useful to control the level of aggregated antibody variants, for example, to reduce the level of aggregated antibody variants.

[0185] Next, the solution containing the composition may be filtered to remove the virus. Then, the solution containing the composition may be formulated with antibody concentrations ranging from about 76 g protein / L to about 82 g protein / L or about 100 g protein / L. The solution containing the composition may be filled into containers and frozen. Aliquots of the solution containing the composition may be freeze-dried. The freeze-dried material may be reconstituted by adding water to produce a composition with a pH of about 6.8 to about 7.2 containing 75 mg / L of protein, monoclonal anti-IL-5 antibody, and 20 mM dibasic sodium phosphate heptahydrate, 12 wt / vol% sucrose, and 0.05 wt / vol% polysorbate 80.

[0186] The methods and compositions of the present disclosure may also be used to achieve low doses of steroids or other drugs, such as those shown in Figure 2 or Table 4.

[0187] In summary, this disclosure is: In one embodiment, a method for treating a disease in a child, comprising a) a child having a disease selected from the group consisting of asthma, mild asthma, moderate asthma, severe asthma, mild eosinophilic asthma, moderate eosinophilic asthma, severe eosinophilic asthma, poorly controlled eosinophilic asthma, eosinophilic asthma, subtype eosinophilic asthma, chronic obstructive pulmonary disease, eosinophilic granulomatosis with polyangiitis, eosinophilic syndrome, nasal polyps, bullous pemphigoid, eosinophilic esophagitis, atopic dermatitis, moderate atopic dermatitis, and severe atopic dermatitis, weighing 40 A method comprising the steps of: a) identifying a pediatric subject weighing less than 1 kg; and b) subcutaneously administering a therapeutically effective dose of an antibody comprising the heavy chain amino acid sequence shown in SEQ ID NO: 1 and the light chain amino acid sequence shown in SEQ ID NO: 2 to the pediatric subject, wherein the therapeutically effective dose of the antibody results in a maximum plasma concentration (Cmax) of approximately 10.1960 ± 0.3345 μg / mL of the antibody and an area under the curve [0-infinity] value of approximately 454.39 ± 15.8876 μg* / mL, thereby treating a disease in the pediatric subject.

[0188] Another aspect of the present disclosure is a method for treating a disease in a child, a) a child having a disease selected from the group consisting of asthma, mild asthma, moderate asthma, severe asthma, mild eosinophilic asthma, moderate eosinophilic asthma, severe eosinophilic asthma, poorly controlled eosinophilic asthma, eosinophilic asthma, subtype eosinophilic asthma, chronic obstructive pulmonary disease, eosinophilic granulomatosis with polyangiitis, eosinophilic syndrome, nasal polyps, bullous pemphigoid, eosinophilic esophagitis, atopic dermatitis, moderate atopic dermatitis, and severe atopic dermatitis, weighing 4 A method for treating a disease in a pediatric subject, comprising the steps of: a) identifying a pediatric subject weighing 0 kg or more; and b) subcutaneously administering a therapeutically effective dose of an antibody containing the heavy chain amino acid sequence shown in SEQ ID NO: 1 and the light chain amino acid sequence shown in SEQ ID NO: 2, wherein the therapeutically effective dose of the antibody results in a maximum plasma concentration (Cmax) of approximately 16.3412 ± 0.6364 μg / mL of the antibody and an area under the curve [0-infinity] value of approximately 675.20 ± 35.8980 μg* / mL.

[0189] Another aspect of this disclosure relates to a method for reducing the absolute number of eosinophils in the blood of a child subject, wherein the child subject weighing less than 40 kg has a condition selected from the group consisting of asthma, mild asthma, moderate asthma, severe asthma, mild eosinophilic asthma, moderate eosinophilic asthma, severe eosinophilic asthma, poorly controlled eosinophilic asthma, eosinophilic asthma, subtype eosinophilic asthma, chronic obstructive pulmonary disease, eosinophilic granulomatosis with polyangiitis, eosinophilic syndrome, nasal polyps, bullous pemphigoid, eosinophilic esophagitis, and atopic dermatitis. A method comprising the steps of identifying, and a) subcutaneously administering a therapeutically effective dose of an antibody comprising the heavy chain amino acid sequence shown in SEQ ID NO: 1 and the light chain amino acid sequence shown in SEQ ID NO: 2 to a pediatric subject, wherein the therapeutically effective dose of the antibody results in a maximum plasma concentration (Cmax) of approximately 10.1960 ± 0.3345 μg / mL of the antibody and an area under the curve [0-infinity] value of approximately 454.39 ± 15.8876 μg* / mL, thereby reducing the absolute number of eosinophils in the blood of the pediatric subject.

[0190] Another aspect of this disclosure relates to a method for reducing the absolute number of eosinophils in the blood of a child subject, wherein the child subject weighing 40 kg or more has a condition selected from the group consisting of asthma, mild asthma, moderate asthma, severe asthma, mild eosinophilic asthma, moderate eosinophilic asthma, severe eosinophilic asthma, poorly controlled eosinophilic asthma, eosinophilic asthma, subtype eosinophilic asthma, chronic obstructive pulmonary disease, eosinophilic granulomatosis with polyangiitis, eosinophilic syndrome, nasal polyps, bullous pemphigoid, eosinophilic esophagitis, and atopic dermatitis. A method comprising the steps of identifying, and a) subcutaneously administering a therapeutically effective dose of an antibody comprising the heavy chain amino acid sequence shown in SEQ ID NO: 1 and the light chain amino acid sequence shown in SEQ ID NO: 2 to a pediatric subject, wherein the therapeutically effective dose of the antibody results in a maximum plasma concentration (Cmax) of approximately 16.3412 ± 0.6364 μg / mL of the antibody and an area under the curve [0-infinity] value of approximately 675.20 ± 35.8980 μg* / mL, thereby reducing the absolute number of eosinophils in the blood of the pediatric subject.

[0191] In one embodiment of the method disclosed herein, the therapeutically effective dose of the antibody is approximately 40 mg.

[0192] In another embodiment of the method disclosed herein, the antibody is administered approximately once a month.

[0193] In another embodiment of the method of the present disclosure, the pediatric subject has an absolute number of blood eosinophils selected from the group consisting of 150 cells / μL or more and 300 cells / μL or more.

[0194] In another embodiment of the method of the present disclosure, the pediatric subjects are selected from the group consisting of premature newborns, full-term newborns, children aged 28 days to 11 months, children aged 12 months to 23 months, children aged 2 years to 6 years, children aged 16 years to 12 years, children aged 6 years to under 18 years, and children aged 12 years to 18 years.

[0195] In another embodiment of the method disclosed herein, the child subject is approximately 6 years of age or older and approximately 12 years of age or younger.

[0196] In another embodiment of the method of this disclosure, the pediatric subject has severe eosinophilic asthma.

[0197] In another aspect of the method of the present disclosure, the pediatric subject has treatment outcomes selected from the group consisting of a decrease in the absolute number of blood eosinophils compared to the absolute number of blood eosinophils before antibody administration, a decrease in the score of the seven scales of the asthma control questionnaire compared to the score of the seven scales of the asthma control questionnaire compared to the score of the pediatric asthma control test compared to the score of the pediatric asthma control test compared to the score of the pediatric asthma control test compared to the score of the pediatric asthma control test before antibody administration.

[0198] In another embodiment of the method of this disclosure, the antibody is administered by a syringe with a safety device or by an auto-injector.

[0199] In another embodiment of the method disclosed herein, the therapeutically effective dose of the antibody is approximately 100 mg.

[0200] Another embodiment of the present invention is a composition according to any one aspect or embodiment of the method of the present disclosure for use in therapeutic purposes.

[0201] Another embodiment of the present disclosure is a composition according to any one aspect or embodiment of the method of the present disclosure for use in the treatment of asthma, mild asthma, moderate asthma, severe asthma, mild eosinophilic asthma, moderate eosinophilic asthma, severe eosinophilic asthma, controlled poor eosinophilic asthma, eosinophilic asthma, subtype eosinophilic asthma, chronic obstructive pulmonary disease, eosinophilic granulomatosis with polyangiitis, eosinophilic syndrome, nasal polyps, bullous pemphigoid, eosinophilic esophagitis, atopic dermatitis, moderate atopic dermatitis, and severe atopic dermatitis.

[0202] Another aspect of this disclosure relates to the treatment of asthma, mild asthma, moderate asthma, severe asthma, mild eosinophilic asthma, moderate eosinophilic asthma, severe eosinophilic asthma, poorly controlled eosinophilic asthma, eosinophilic asthma, subtype eosinophilic asthma, chronic obstructive pulmonary disease, eosinophilic granulomatosis with polyangiitis, eosinophilic syndrome, nasal polyps, bullous pemphigoid, eosinophilic esophagitis, atopic dermatitis, moderate atopic dermatitis, and severe atopic dermatitis in children weighing less than 40 kg. A composition for treating diseases selected from the group consisting of dermatitis, comprising an antibody containing the heavy chain amino acid sequence shown in SEQ ID NO: 1 and the light chain amino acid sequence shown in SEQ ID NO: 2, wherein the therapeutically effective dose of the antibody administered subcutaneously to a child yields a maximum plasma concentration (Cmax) of approximately 10.1960 ± 0.3345 μg / mL of the antibody and an area under the curve [0-infinity] value of approximately 454.39 ± 15.8876 μg* / mL.

[0203] Another aspect of this disclosure relates to the treatment of asthma, mild asthma, moderate asthma, severe asthma, mild eosinophilic asthma, moderate eosinophilic asthma, severe eosinophilic asthma, poorly controlled eosinophilic asthma, eosinophilic asthma, subtype eosinophilic asthma, chronic obstructive pulmonary disease, eosinophilic granulomatosis with polyangiitis, eosinophilic syndrome, nasal polyps, bullous pemphigoid, eosinophilic esophagitis, atopic dermatitis, moderate atopic dermatitis, and severe atopic dermatitis in children weighing 40 kg or more. A composition for treating a disease selected from the group consisting of dermatitis, comprising an antibody comprising the heavy chain amino acid sequence shown in SEQ ID NO: 1 and the light chain amino acid sequence shown in SEQ ID NO: 2, wherein a therapeutically effective dose of the antibody administered subcutaneously to a pediatric subject results in a maximum plasma concentration (Cmax) of the antibody of approximately 16.3412 ± 0.6364 μg / mL and an area under the curve [0-infinity] value of approximately 675.20 ± 35.8980 μg* / mL. Another embodiment is the composition of the present disclosure in which the therapeutically effective dose of the antibody is approximately 40 mg.

[0204] Another aspect of the present disclosure is a composition for reducing the absolute number of eosinophils in the blood of children weighing less than 40 kg, wherein the children have asthma, mild asthma, moderate asthma, severe asthma, mild eosinophilic asthma, moderate eosinophilic asthma, severe eosinophilic asthma, poorly controlled eosinophilic asthma, eosinophilic asthma, subtype eosinophilic asthma, chronic obstructive pulmonary disease, eosinophilic granulomatosis with polyangiitis, eosinophilic syndrome, nasal polyps, bullous pemphigoid, eosinophilic esophagitis, atopic dermatitis, and moderate The composition is for a disease selected from the group consisting of moderate atopic dermatitis and severe atopic dermatitis, and comprises an antibody containing the heavy chain amino acid sequence shown in SEQ ID NO: 1 and the light chain amino acid sequence shown in SEQ ID NO: 2, wherein the therapeutically effective dose of the antibody administered subcutaneously to a child yields a maximum plasma concentration (Cmax) of approximately 10.1960 ± 0.3345 μg / mL of the antibody, and an area under the curve [0-infinity] value of approximately 454.39 ± 15.8876 μg* / mL.

[0205] A composition for reducing the absolute number of eosinophils in the blood of children weighing 40 kg or more, wherein the children have asthma, mild asthma, moderate asthma, severe asthma, mild eosinophilic asthma, moderate eosinophilic asthma, severe eosinophilic asthma, poorly controlled eosinophilic asthma, eosinophilic asthma, subtype eosinophilic asthma, chronic obstructive pulmonary disease, eosinophilic granulomatosis with polyangiitis, eosinophilic syndrome, nasal polyps, bullous pemphigoid, eosinophilic esophagitis, atopic dermatitis, A composition comprising an antibody having a disease selected from the group consisting of moderate atopic dermatitis and severe atopic dermatitis, wherein the composition comprises an antibody having a heavy chain amino acid sequence shown in SEQ ID NO: 1 and a light chain amino acid sequence shown in SEQ ID NO: 2, and the therapeutically effective dose of the antibody yields a maximum plasma concentration (Cmax) of approximately 16.3412 ± 0.6364 μg / mL and an area under the curve [0-infinity] value of approximately 675.20 ± 35.8980 μg* / mL.

[0206] Another embodiment is the composition of the Disclosure, in which the antibody is administered approximately once a month.

[0207] Another embodiment is the composition of the present disclosure, wherein the pediatric subject has an absolute number of blood eosinophils selected from the group consisting of 150 cells / μL or more and 300 cells / μL or more.

[0208] Another embodiment is a composition of the Disclosure in which the pediatric subject is selected from the group consisting of premature newborns, full-term newborns, children aged 28 days to 11 months, children aged 12 to 23 months, children aged 2 to 6 years, children aged 16 to 12 years, children aged 6 to under 18 years, and children aged 12 to 18 years.

[0209] Another embodiment is the composition of the present disclosure, wherein the target child is approximately 6 years of age or older and approximately 12 years of age or younger.

[0210] Another embodiment is a composition of the present disclosure in which a child subject has severe eosinophilic asthma.

[0211] Another embodiment is a composition of the present disclosure in which a pediatric subject has a treatment outcome selected from the group consisting of a decrease in the absolute number of blood eosinophils compared to the absolute number of blood eosinophils before administration of the antibody, a decrease in the score of the seven scales of the asthma control questionnaire compared to the score of the seven scales of the asthma control questionnaire compared to the score of the pediatric asthma control test compared to the score of the pediatric asthma control test compared to the score of the pediatric asthma control test before administration of the antibody.

[0212] Another embodiment is a composition of the Disclosure in which the antibody is administered by a syringe with a safety device or an auto-injector.

[0213] Another embodiment is the composition of the present disclosure, wherein the therapeutically effective dose of the antibody is approximately 100 mg.

[0214] [Examples] [Example 1] Pharmacokinetics and pharmacodynamics of mepolizumab administered subcutaneously to children. Mepolizumab is a humanized immunoglobulin G (IgG1) monoclonal antibody (mAb) that exhibits dose-dependent and time-independent pharmacokinetics. The pharmacokinetics (PK) and pharmacodynamics (PD) of mepolizumab in children aged 6–11 years with severe eosinophilic asthma were studied as described herein. Part A of the study describes the PK / PD of subcutaneously administered mepolizumab 40 mg or 100 mg, depending on the participant's body weight. Part B of the study is a long-term safety / pharmacodynamic phase offering a further 52-week long-term treatment option for subjects eligible for continued treatment.

[0215] In the trial, mepolizumab 40 mg was administered subcutaneously to the upper arm or thigh of children weighing <40 kg at visit 2 (week 0), and mepolizumab 100 mg was administered subcutaneously to participants weighing ≥40 kg. Approximately 40 male or female participants aged 6 to 11 years were screened, and approximately 28 eligible participants were obtained to enter the treatment phase, ensuring that at least 6 participants were enrolled in the <40 kg group and 20 evaluable participants were available. The total duration of the trial was 22 weeks, including a 1-2 week induction period, a 12-week treatment period, and an 8-week follow-up phase. Participants were considered to have completed the trial when they had completed all phases of the trial, including the follow-up phase (week 20 [visit 8]).

[0216] In the first arm of the study, participants were administered 40 mg of mepolizumab (this arm included patients who had completed Part A of the PK / PD study and were scheduled to complete Part B). In this arm of the study, participants weighing <40 kg received 0.4 ml (mL) of reconstituted mepolizumab subcutaneously into the upper arm or thigh. Mepolizumab in this arm was supplied as a 100 mg lyophilized cake in a sterile vial for subcutaneous administration into the upper arm or thigh. Vials were reconstituted with sterile water for injection immediately before individual use.

[0217] In the second arm of the study, participants were administered 100 mg of mepolizumab (this arm included patients who had completed Part A of the PK / PD trial and were scheduled to complete Part B). In this arm of the study, participants weighing ≥40 kg received 1.0 mL of reconstituted mepolizumab subcutaneously in the upper arm or thigh. The mepolizumab in this second arm was supplied and reconstituted as described above with respect to the first arm of the study.

[0218] The pediatric patients in the study met the following inclusion criteria: • At the time of screening, the child must be between 6 and 11 years old. • A diagnosis of severe asthma as defined by local asthma guidelines (i.e., the National Institutes of Health (NIH), Global Initiative for Asthma (GINA), etc.) for at least 12 months prior to the first visit. If the participant is visiting the study site for the first time, the participant / guardian must self-report the physician's diagnosis of asthma, which the principal investigator must confirm by reviewing the medical history together with the participant / guardian. Eosinophilic airway inflammation associated with asthma, characterized as essentially eosinophilic, as evidenced by a peripheral blood eosinophil count of ≥300 cells / microliter (cells / μL) demonstrated over the past 12 months, or a peripheral blood eosinophil count of ≥150 cells / μL at visit 1. • A well-established requirement of regular treatment with inhaled corticosteroids (>200 μg / day of fluticasone propionate drug powder inhaler [DPI] or equivalent daily) for 12 months prior to the first visit, with or without maintenance oral corticosteroids (OCS). The ICS dose should represent a moderate or high dose in children aged 6–11 years [GINA]. • Confirmed failure of current treatment with additional controller medication for at least 3 months, or with additional controller medication [e.g., long-acting beta-2 agonists (LABAs), leukotriene receptor antagonists (LTRAs), or theophylline] for at least 3 consecutive months within the past 12 months. • Forced expiratory volume in one second (FEV1): Persistent airflow obstruction at either visit 1 or visit 2, indicated by a FEV1 before bronchodilator administration being <110% of the predicted value (Quanjer, 2012), or a forced vital capacity (FVC) ratio of <0.8 (FEV1 measured before the first dose of the study drug). • A previously documented history of two or more exacerbations requiring treatment with systemic corticosteroids (CS) (intramuscular [IM], intravenous, or oral) within the 12 months prior to the first visit, despite the use of high-dose inhaled corticosteroids (ICS). For participants receiving maintenance CS, CS treatment for exacerbations must be at least a doubling of the dose. • No changes in baseline ICS and / or additional controller medication dosages or regimens during the induction period. • Males or females: Women of childbearing age must commit to consistent and accurate use of an approved method of contraception throughout the trial period and for four months after the last dose of the investigational drug. Girls of childbearing age are required to undergo a urine pregnancy test. This test will be performed on the first screening visit (visit 1) and on each planned trial visit before administration of the investigational drug, during early discontinuation, and during follow-up visits. Parents / guardians may submit written informed consent prior to taking the test, including their agreement to the requirements and restrictions outlined in the consent form. Where applicable, participants may and willingly agree to take the test in accordance with local requirements. Regarding Part B: Participants have completed all trial assessments up to Visit 8 and including Visit 8, and have received all three doses of the investigational drug (IP) in Part A. Regarding Part B: The principal investigator (PI) will conduct a benefit / risk assessment, and this assessment will serve as the basis for continuing treatment with mepolizumab. The parent (or guardian) of the person concerned must submit a consent form, and the person concerned must submit a consent form for continued treatment.

[0219] The results for patients treated according to Part A of the study are as follows (Table 16); the areas of outcomes evaluated in Part B of the study are similarly described below:

[0220] [Table 16] TIFF2026086897000023.tif226160TIFF2026086897000024.tif225161TIFF2026086897000025.tif222160TIFF2026086897000026.tif219160TIFF2026086897000027.tif228160TIFF2026086897000028.tif227162TIFF2026086897000029.tif228162TIFF2026086897000030.tif227159TIFF2026086897000031.tif227160TIFF2026086897000032.tif228161TIFF2026086897000033.tif226160TIFF2026086897000034.tif226161TIFF2026086897000035.tif226163TIFF2026086897000036.tif227161TIFF2026086897000037.tif226160TIFF2026086897000038.tif230160TIFF2026086897000039.tif228161TIFF2026086897000040.tif226161TIFF2026086897000041.tif228159TIFF2026086897000042.tif228161TIFF2026086897000043.tif228160TIFF2026086897000044.tif225160TIFF2026086897000045.tif228159TIFF2026086897000046.tif228161TIFF2026086897000047.tif227161TIFF2026086897000048.tif226162TIFF2026086897000049.tif228160TIFF2026086897000050.tif228161TIFF2026086897000051.tif230160TIFF2026086897000052.tif229159TIFF2026086897000053.tif229160TIFF2026086897000054.tif226160TIFF2026086897000055.tif228161TIFF2026086897000056.tif230158TIFF2026086897000057.tif230161TIFF2026086 897000058.tif228161TIFF2026086897000059.tif229159TIFF2026086897000060.tif222160T IFF2026086897000061.tif230158TIFF2026086897000062.tif228161TIFF2026086897000063. tif228158TIFF2026086897000064.tif229160TIFF2026086897000065.tif227160TIFF2026086 897000066.tif227160TIFF2026086897000067.tif230160TIFF2026086897000068.tif226161T IFF2026086897000069.tif228161TIFF2026086897000070.tif228161TIFF2026086897000071. tif229161TIFF2026086897000072.tif228161TIFF2026086897000073.tif228158TIFF2026086 897000074.tif228160TIFF2026086897000075.tif228157TIFF2026086897000076.tif132159.

[0221] For a particular column, the "50kg" group identified above corresponds to pediatric patients weighing 40kg or more, while for a particular column, the "27kg" group identified above corresponds to pediatric patients weighing less than 40kg.

[0222] [Example 2] Pharmacokinetic and pharmacodynamic analysis Pharmacokinetic (PK) and pharmacodynamic (PD) analyses of the study results were performed as partially described here. Plasma PK concentrations of mepolizumab collected in the first part of the study were analyzed using the population PK method with the NLMIXED procedure in SAS software (version 9.2). To minimize the number of blood samplings, a two-compartment PK model parameterized with respect to macro constants (i.e., A, B, alpha, beta) for primary absorption and primary excretion was used, with distribution parameters fixed to adult values. The ratio of serum eosinophil count to baseline was summarized using descriptive statistics. An indirect response PK / PD model was used to estimate the serum concentration that yielded the maximum drug effect (maximum reduction in eosinophil count) and 50% of the maximum drug effect. The exposure (area under the concentration-time curve up to infinite time), normalized to the mean body weight in each of the subcutaneous administration groups, was 454 μg* / day / mL (40 mg [subject < 40 kg]) and 675 μg* / day / mL (100 mg [subject ≥ 40 kg]). Estimated half-life (t 1 / 2 The PK time was approximately 23 days. The PK data is shown in Table 17. In the methods or compositions of this disclosure, Cmax SS values ​​relating to the values ​​listed in Table 17 or including the range of notation shown in Table 17 may be listed instead of the Cmax values.

[0223] [Table 17] TIFF2026086897000078.tif107112

[0224] Significant and similar reductions in serum eosinophils were observed in both treatment groups in this 6–11 year old population, which were evident from week 4 (post-initial administration assessment), maintained throughout the treatment phase, and returned towards baseline after 8 weeks of the treatment phase (Figure 3). At week 12, the reduction from baseline in serum eosinophil count was 89% (40 mg SC), 83% (100 mg SC), and 87% (overall) (Figure 3). The absolute number of serum eosinophils (geometric mean) showed similar reductions and trends. In Figure 3, weeks 0–12 are considered to be during treatment, and weeks 16–20 are considered to be post-treatment; if a result of zero was recorded, a small value (0.005) was added before logarithmic transformation.

[0225] [Example 3] Unofficial Sequence List The following underlined text identifies CDR sequences, or nucleic acid sequences encoding these CDR sequences, according to Kabat's definition of CDRs in the variable heavy and variable light chain portions of antibodies. For example, in Sequence ID No. 1, the frameworks and CDRs are represented as plain text framework1, underlined CDR1, plain text framework2, underlined CDR2, plain text framework3, underlined CDR3, and plain text framework4, in order from the amino-proximal to the carboxy-terminal portion of the displayed sequence. The following italics identify signal sequences. An asterisk to the right of a single-letter amino acid code indicates that the amino acid residue to the left is an N-glycosylation site. This scheme is used, for example, in Sequence IDs No. 1-4, 11, 12, and 19-22. The amino-terminal methionine residues shown in these sequences can be cleaved. Thus, the following sequences showing amino-terminal methionine residues should also be considered to disclose cleavage forms of these proteins lacking such amino-terminal methionine residues. Nucleic acid sequences should be represented as DNA nucleic acid sequences, containing "t" nucleic acid residues, and the corresponding RNA sequences should also be considered to disclose such that the "t" nucleic acid residues may also be considered to disclose "u" nucleic acid residues. In addition, the 5' proximal "atg" start codon and the 3' proximal "taa", "tag", and "tga" stop codons are omitted from the following cDNA nucleic acid sequences. This applies, for example, to sequence numbers 31-34.

[0226] TIFF2026086897000079.tif119142TIFF2026086897000080.tif210147TIFF2026086897000081.tif229146TIFF2026086897000082.tif16147

[0227] Having fully described the present invention, it will be apparent to those skilled in the art that many changes and modifications can be made to the invention without departing from the spirit or scope of the appended claims. The following are embodiments of the present invention. (1) A method for treating diseases in children, a) A step to identify children weighing less than 40 kg who have a disease selected from the group consisting of asthma, mild asthma, moderate asthma, severe asthma, mild eosinophilic asthma, moderate eosinophilic asthma, severe eosinophilic asthma, poorly controlled eosinophilic asthma, eosinophilic asthma, subtype eosinophilic asthma, chronic obstructive pulmonary disease, eosinophilic granulomatosis with polyangiitis, eosinophilic syndrome, nasal polyps, bullous pemphigoid, eosinophilic esophagitis, atopic dermatitis, moderate atopic dermatitis, and severe atopic dermatitis, and b) A step of subcutaneously administering a therapeutically effective dose of an antibody containing the heavy chain amino acid sequence shown in SEQ ID NO: 1 and the light chain amino acid sequence shown in SEQ ID NO: 2 to a child, wherein the therapeutically effective dose of the antibody results in a maximum plasma concentration (Cmax) of approximately 10.1960 ± 0.3345 μg / mL of the antibody and an area under the curve [0-infinity] value of approximately 454.39 ± 15.8876 μg* / day / mL. A method including, thereby for treating a disease in a child. (2) A method for reducing the absolute number of eosinophils in the blood of children, a) A step of identifying children weighing less than 40 kg who have a condition selected from the group consisting of asthma, mild asthma, moderate asthma, severe asthma, mild eosinophilic asthma, moderate eosinophilic asthma, severe eosinophilic asthma, poorly controlled eosinophilic asthma, eosinophilic asthma, subtype eosinophilic asthma, chronic obstructive pulmonary disease, eosinophilic granulomatosis with polyangiitis, eosinophilic syndrome, nasal polyps, bullous pemphigoid, eosinophilic esophagitis, and atopic dermatitis, and b) A step of subcutaneously administering a therapeutically effective dose of an antibody containing the heavy chain amino acid sequence shown in SEQ ID NO: 1 and the light chain amino acid sequence shown in SEQ ID NO: 2 to a child, wherein the therapeutically effective dose of the antibody results in a maximum plasma concentration (Cmax) of approximately 10.1960 ± 0.3345 μg / mL of the antibody and an area under the curve [0-infinity] value of approximately 454.39 ± 15.8876 μg* / day / mL. A method comprising, thereby reducing the absolute number of eosinophils in the blood of a child subject. (3) The method according to (1) or (2), wherein the therapeutically effective dose of the antibody is approximately 40 mg or between 1 μg / kg and 150 mg / kg. (4) A method for treating diseases in children, a) A step to identify children weighing 40 kg or more who have a disease selected from the group consisting of asthma, mild asthma, moderate asthma, severe asthma, mild eosinophilic asthma, moderate eosinophilic asthma, severe eosinophilic asthma, poorly controlled eosinophilic asthma, eosinophilic asthma, subtype eosinophilic asthma, chronic obstructive pulmonary disease, eosinophilic granulomatosis with polyangiitis, eosinophilic syndrome, nasal polyps, bullous pemphigoid, eosinophilic esophagitis, atopic dermatitis, moderate atopic dermatitis, and severe atopic dermatitis, and b) A step of subcutaneously administering a therapeutically effective dose of an antibody containing the heavy chain amino acid sequence shown in SEQ ID NO: 1 and the light chain amino acid sequence shown in SEQ ID NO: 2 to a child, wherein the therapeutically effective dose of the antibody results in a maximum plasma concentration (Cmax) of approximately 16.3412 ± 0.6364 μg / mL of the antibody and an area under the curve [0-infinity] value of approximately 675.20 ± 35.8980 μg* / day / mL. A method including, thereby for treating a disease in a child. (5) A method for reducing the absolute number of eosinophils in the blood in children, a) A step to identify children weighing 40 kg or more who have a condition selected from the group consisting of asthma, mild asthma, moderate asthma, severe asthma, mild eosinophilic asthma, moderate eosinophilic asthma, severe eosinophilic asthma, poorly controlled eosinophilic asthma, eosinophilic asthma, subtype eosinophilic asthma, chronic obstructive pulmonary disease, eosinophilic granulomatosis with polyangiitis, eosinophilic syndrome, nasal polyps, bullous pemphigoid, eosinophilic esophagitis, and atopic dermatitis, and b) A step of subcutaneously administering a therapeutically effective dose of an antibody containing the heavy chain amino acid sequence shown in SEQ ID NO: 1 and the light chain amino acid sequence shown in SEQ ID NO: 2 to a child, wherein the therapeutically effective dose of the antibody results in a maximum plasma concentration (Cmax) of approximately 16.3412 ± 0.6364 μg / mL of the antibody and an area under the curve [0-infinity] value of approximately 675.20 ± 35.8980 μg* / day / mL. A method comprising, thereby reducing the absolute number of eosinophils in the blood of a child subject. (6) The method according to (4) or (5), wherein the therapeutically effective dose of the antibody is approximately 100 mg or between 1 μg / kg and 150 mg / kg. (7) The method according to any one of (1) to (6), wherein the antibody is administered approximately once a month. (8) The method according to any one of (1) to (7), wherein the pediatric subject has an absolute number of blood eosinophils selected from the group consisting of 150 cells / μL or more and 300 cells / μL or more. (9) The method according to any one of (1) to (8), wherein the child subject is selected from the group consisting of premature newborns, full-term newborns, children aged 28 days to 11 months, children aged 12 to 23 months, children aged 2 to 6 years, children aged 16 to 12 years, children aged 6 to under 18 years, and children aged 12 to 18 years. (10) The method according to any one of (1) to (9), wherein the child subject is approximately 6 years of age or older and approximately 12 years of age or younger. (11) The method according to any one of (1) to (10) for a child having severe eosinophilic asthma. (12) The method according to any one of (1) to (11), wherein the pediatric subjects have treatment outcomes selected from groups consisting of a decrease in the absolute number of blood eosinophils compared to the absolute number of blood eosinophils before antibody administration, a decrease in the score of the seven scales of the asthma control questionnaire compared to the score of the seven scales of the asthma control questionnaire compared to the score of the pediatric asthma control test compared to the score of the pediatric asthma control test compared to the score of the pediatric asthma control test before antibody administration. (13) The method according to any one of (1) to (12), wherein the antibody is administered by a syringe with a safety device or an auto-injector. (14) In children weighing less than 40 kg, from asthma, mild asthma, moderate asthma, severe asthma, mild eosinophilic asthma, moderate eosinophilic asthma, severe eosinophilic asthma, poorly controlled eosinophilic asthma, eosinophilic asthma, subtype eosinophilic asthma, chronic obstructive pulmonary disease, eosinophilic granulomatosis with polyangiitis, eosinophilic syndrome, nasal polyps, bullous pemphigoid, eosinophilic esophagitis, atopic dermatitis, moderate atopic dermatitis, and severe atopic dermatitis A composition for treating a disease selected from the group, wherein the composition comprises an antibody comprising the heavy chain amino acid sequence shown in SEQ ID NO: 1 and the light chain amino acid sequence shown in SEQ ID NO: 2, and the therapeutically effective dose of the antibody administered subcutaneously to a child yields a maximum plasma concentration (Cmax) of approximately 10.1960 ± 0.3345 μg / mL of the antibody, and an area under the curve [0-infinity] value of approximately 454.39 ± 15.8876 μg* / mL. (15) A composition for reducing the absolute number of eosinophils in the blood of children weighing less than 40 kg, wherein the children have asthma, mild asthma, moderate asthma, severe asthma, mild eosinophilic asthma, moderate eosinophilic asthma, severe eosinophilic asthma, poorly controlled eosinophilic asthma, eosinophilic asthma, subtype eosinophilic asthma, chronic obstructive pulmonary disease, eosinophilic granulomatosis with polyangiitis, eosinophilic syndrome, nasal polyps, bullous pemphigoid, eosinophilic esophagitis, atopic dermatitis, moderate a A composition comprising an antibody having a disease selected from the group consisting of totopic dermatitis and severe atopic dermatitis, wherein the composition comprises an antibody having a heavy chain amino acid sequence shown in SEQ ID NO: 1 and a light chain amino acid sequence shown in SEQ ID NO: 2, and the therapeutically effective dose of the antibody administered subcutaneously to a child yields a maximum plasma concentration (Cmax) of approximately 10.1960 ± 0.3345 μg / mL of the antibody, and an area under the curve [0-infinity] value of approximately 454.39 ± 15.8876 μg* / mL. (16) The composition according to (14) or (15), wherein the therapeutically effective dose of the antibody is approximately 40 mg or between 1 μg / kg and 150 mg / kg. (17) In children weighing 40 kg or more, the following conditions are present: asthma, mild asthma, moderate asthma, severe asthma, mild eosinophilic asthma, moderate eosinophilic asthma, severe eosinophilic asthma, poorly controlled eosinophilic asthma, eosinophilic asthma, subtype eosinophilic asthma, chronic obstructive pulmonary disease, eosinophilic granulomatosis with polyangiitis, eosinophilic syndrome, nasal polyps, bullous pemphigoid, eosinophilic esophagitis, atopic dermatitis, moderate atopic dermatitis, and severe atopic dermatitis. A composition for treating a disease selected from the group, wherein the composition comprises an antibody comprising the heavy chain amino acid sequence shown in SEQ ID NO: 1 and the light chain amino acid sequence shown in SEQ ID NO: 2, and the therapeutically effective dose of the antibody administered subcutaneously to a child yields a maximum plasma concentration (Cmax) of approximately 16.3412 ± 0.6364 μg / mL of the antibody, and an area under the curve [0-infinity] value of approximately 675.20 ± 35.8980 μg* / mL. (18) A composition for reducing the absolute number of eosinophils in the blood of children weighing 40 kg or more, wherein the children have asthma, mild asthma, moderate asthma, severe asthma, mild eosinophilic asthma, moderate eosinophilic asthma, severe eosinophilic asthma, poorly controlled eosinophilic asthma, eosinophilic asthma, subtype eosinophilic asthma, chronic obstructive pulmonary disease, eosinophilic granulomatosis with polyangiitis, eosinophilic syndrome, nasal polyps, bullous pemphigoid, eosinophilic esophagitis, atopic dermatitis A composition comprising an antibody comprising a heavy chain amino acid sequence shown in SEQ ID NO: 1 and a light chain amino acid sequence shown in SEQ ID NO: 2, wherein the therapeutically effective dose of the antibody yields a maximum plasma concentration (Cmax) of approximately 16.3412 ± 0.6364 μg / mL and an area under the curve [0-infinity] value of approximately 675.20 ± 35.8980 μg* / mL. (19) The composition according to (17) or (18), wherein the therapeutically effective dose of the antibody is approximately 100 mg or between 1 μg / kg and 150 mg / kg. (20) The composition according to any one of (14) to (19), wherein the antibody is administered approximately once a month. (21) The composition according to any one of (14) to (20), wherein the pediatric subject has an absolute number of blood eosinophils selected from the group consisting of 150 cells / μL or more and 300 cells / μL or more. (22) The composition according to any one of (14) to (21), wherein the target child is selected from the group consisting of premature newborns, full-term newborns, children aged 28 days to 11 months, children aged 12 to 23 months, children aged 2 to 6 years, children aged 16 to 12 years, children aged 6 to under 18 years, and children aged 12 to 18 years. (23) The composition according to any one of (14) to (22), wherein the target child is approximately 6 years of age or older and approximately 12 years of age or younger. (24) The composition according to any one of (14) to (23), for which the subject is a child having severe eosinophilic asthma. (25) The composition according to any one of (14) to (24), wherein the pediatric subject has treatment outcomes selected from the group consisting of a decrease in the absolute number of blood eosinophils compared to the absolute number of blood eosinophils before administration of the antibody, a decrease in the score of the seven scales of the asthma control questionnaire compared to the score of the seven scales of the asthma control questionnaire compared to the score of the pediatric asthma control test compared to the score of the pediatric asthma control test before administration of the antibody. (26) The composition according to any one of (14) to (25), wherein the antibody is administered by a syringe with a safety device or an auto-injector. (27) A composition according to any one of (14) to (26) for use in treatment. (28)a) Reduction in the frequency of exacerbations, b) Reduction of OCS daily dose, c) Improvement of lung function, d) Improvement of asthma control, e) Improvement of quality of life, g) Reduction of eosinophils in the blood A method according to any one of (1) to (13) that produces at least one selected from the group consisting of the following. (29)a) Reduction in the frequency of exacerbations, b) Reduction of OCS daily dose, c) Improvement of lung function, d) Improvement of asthma control, e) Improvement of quality of life, and g) Reduction of blood eosinophils The composition according to any one of (14) to (27), which causes at least one selected from the group consisting of:

[0228] [Sequence Listing] SEQUENCE LISTING <110> GLAXOSMITHKLINE LLC <120> BIOPHARMACEUTICAL COMPOSITIONS AND METHODS FOR PEDIATRIC PATIENTS <130> PA26 - 100 <150> US 62 / 515,641 <151> 2017 - 06 - 06 <150> US 62 / 619,206 <151> 2018 - 01 - 19 <160> 13 <170> FastSEQ for Windows Version 4.0 <210> 1 <211> 449 <212> PRT <213> Artificial Sequence <220> <223> Amino acid sequence identified using molecular (This part seems to be incomplete in the original, but translated as is for the remaining text) biology techniques. <400> 1 Gln Val Thr Leu Arg Glu Ser Gly Pro Ala Leu Val Lys Pro Thr Gln 1 5 10 15 Thr Leu Thr Leu Thr Cys Thr Val Ser Gly Phe Ser Leu Thr Ser Tyr 20 25 30 Ser Val His Trp Val Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp Leu 35 40 45 Gly Val Ile Trp Ala Ser Gly Gly Thr Asp Tyr Asn Ser Ala Leu Met 50 55 60 Ser Arg Leu Ser Ile Ser Lys Asp Thr Ser Arg Asn Gln Val Val Leu 65 70 75 80 Thr Met Thr Asn Met Asp Pro Val Asp Thr Ala Thr Tyr Tyr Cys Ala 85 90 95 Arg Asp Pro Pro Ser Ser Leu Leu Arg Leu Asp Tyr Trp Gly Arg Gly 100 105 110 Thr Pro Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe 115 120 125 Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu 130 135 140 Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp 145 150 155 160 Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu 165 170 175 Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser 180 185 190 Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro 195 200 205 Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys Ser Cys Asp Lys 210 215 220 Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro 225 230 235 240 Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser 245 250 255 Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp 260 265 270 Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn 275 280 285 Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val 290 295 300 Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu 305 310 315 320 Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys 325 330 335 Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr 340 345 350 Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr 355 360 365 Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu 370 375 380 Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu 385 390 395 400 Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys 405 410 415 Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu 420 425 430 Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly 435 440 445 Lys <210> 2 <211> 220 <212> PRT <213> Artificial Sequence <220> <223> Amino acid sequence identified using molecular biology techniques. <400> 2 Asp Ile Val Met Thr Gln Ser Pro Asp Ser Leu Ala Val Ser Leu Gly 1 5 10 15 Glu Arg Ala Thr Ile Asn Cys Lys Ser Ser Gln Ser Leu Leu Asn Ser 20 25 30 Gly Asn Gln Lys Asn Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln 35 40 45 Pro Pro Lys Leu Leu Ile Tyr Gly Ala Ser Thr Arg Glu Ser Gly Val 50 55 60 Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr 65 70 75 80 Ile Ser Ser Leu Gln Ala Glu Asp Val Ala Val Tyr Tyr Cys Gln Asn 85 90 95 Val His Ser Phe Pro Phe Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile 100 105 110 Lys Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp 115 120 125 Glu Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn 130 135 140 Phe Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu 145 150 155 160 Gln Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp 165 170 175 Ser Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr 180 185 190 Glu Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser 195 200 205 Ser Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys 210 215 220 <210> 3 <211> 119 <212> PRT <213> Artificial Sequence <220> <223> Amino acid sequence identified using molecular biology techniques. <400> 3 Gln Val Thr Leu Arg Glu Ser Gly Pro Ala Leu Val Lys Pro Thr Gln 1 5 10 15 Thr Leu Thr Leu Thr Cys Thr Val Ser Gly Phe Ser Leu Thr Ser Tyr 20 25 30 Ser Val His Trp Val Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp Leu 35 40 45 Gly Val Ile Trp Ala Ser Gly Gly Thr Asp Tyr Asn Ser Ala Leu Met 50 55 60 Ser Arg Leu Ser Ile Ser Lys Asp Thr Ser Arg Asn Gln Val Val Leu 65 70 75 80 Thr Met Thr Asn Met Asp Pro Val Asp Thr Ala Thr Tyr Tyr Cys Ala 85 90 95 Arg Asp Pro Pro Ser Ser Leu Leu Arg Leu Asp Tyr Trp Gly Arg Gly 100 105 110 Thr Pro Val Thr Val Ser Ser 115 <210> 4 <211> 113 <212> PRT <213> Artificial Sequence <220> <223> Amino acid sequence identified using molecular biology techniques. <400> 4 Asp Ile Val Met Thr Gln Ser Pro Asp Ser Leu Ala Val Ser Leu Gly 1 5 10 15 Glu Arg Ala Thr Ile Asn Cys Lys Ser Ser Gln Ser Leu Leu Asn Ser 20 25 30 Gly Asn Gln Lys Asn Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln 35 40 45 Pro Pro Lys Leu Leu Ile Tyr Gly Ala Ser Thr Arg Glu Ser Gly Val 50 55 60 Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr 65 70 75 80 Ile Ser Ser Leu Gln Ala Glu Asp Val Ala Val Tyr Tyr Cys Gln Asn 85 90 95 Val His Ser Phe Pro Phe Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile 100 105 110 Lys <210> 5 <211> 5 <212> PRT <213> Artificial Sequence <220> <223> Amino acid sequence identified using molecular biology techniques. <400> 5 Ser Tyr Ser Val His 1 5 <210> 6 <211> 16 <212> PRT <213> Artificial Sequence <220> <223> Amino acid sequence identified using molecular biology techniques. <400> 6 Val Ile Trp Ala Ser Gly Gly Thr Asp Tyr Asn Ser Ala Leu Met Ser 1 5 10 15 <210> 7 <211> 11 <212> PRT <213> Artificial Sequence <220> <223> Amino acid sequence identified using molecular biology techniques. <400> 7 Asp Pro Pro Ser Ser Leu Leu Arg Leu Asp Tyr 1 5 10 <210> 8 <211> 17 <212> PRT <213> Artificial Sequence <220> <223> Amino acid sequence identified using molecular biology techniques. <400> 8 Lys Ser Ser Gln Ser Leu Leu Asn Ser Gly Asn Gln Lys Asn Tyr Leu 1 5 10 15 Ala <210> 9 <211> 7 <212> PRT <213> Artificial Sequence <220> <223> Amino acid sequence identified using molecular biology techniques. <400> 9 Gly Ala Ser Thr Arg Glu Ser 1 5 <210> 10 <211> 9 <212> PRT <213> Artificial Sequence <220> <223> Amino acid sequence identified using molecular biology techniques. <400> 10 Gln Asn Val His Ser Phe Pro Phe Thr 1 5 <210> 11 <211> 9 <212> PRT <213> Human <400> 11 Gln Asn Val His Ser Phe Pro Phe Thr 1 5 <210> 12 <211> 400 <212> PRT <213> Human <400> 12 Asp Leu Leu Pro Asp Glu Lys Ile Ser Leu Leu Pro Pro Val Asn Phe 1 5 10 15 Thr Ile Lys Val Thr Gly Leu Ala Gln Val Leu Leu Gln Trp Lys Pro 20 25 30 Asn Pro Asp Gln Glu Gln Arg Asn Val Asn Leu Glu Tyr Gln Val Lys 35 40 45 Ile Asn Ala Pro Lys Glu Asp Asp Tyr Glu Thr Arg Ile Thr Glu Ser 50 55 60 Lys Cys Val Thr Ile Leu His Lys Gly Phe Ser Ala Ser Val Arg Thr 65 70 75 80 Ile Leu Gln Asn Asp His Ser Leu Leu Ala Ser Ser Trp Ala Ser Ala 85 90 95 Glu Leu His Ala Pro Pro Gly Ser Pro Gly Thr Ser Ile Val Asn Leu 100 105 110 Thr Cys Thr Thr Asn Thr Thr Glu Asp Asn Tyr Ser Arg Leu Arg Ser 115 120 125 Tyr Gln Val Ser Leu His Cys Thr Trp Leu Val Gly Thr Asp Ala Pro 130 135 140 Glu Asp Thr Gln Tyr Phe Leu Tyr Tyr Arg Tyr Gly Ser Trp Thr Glu 145 150 155 160 Glu Cys Gln Glu Tyr Ser Lys Asp Thr Leu Gly Arg Asn Ile Ala Cys 165 170 175 Trp Phe Pro Arg Thr Phe Ile Leu Ser Lys Gly Arg Asp Trp Leu Ala 180 185 190 Val Leu Val Asn Gly Ser Ser Lys His Ser Ala Ile Arg Pro Phe Asp 195 200 205 Gln Leu Phe Ala Leu His Ala Ile Asp Gln Ile Asn Pro Pro Leu Asn 210 215 220 Val Thr Ala Glu Ile Glu Gly Thr Arg Leu Ser Ile Gln Trp Glu Lys 225 230 235 240 Pro Val Ser Ala Phe Pro Ile His Cys Phe Asp Tyr Glu Val Lys Ile 245 250 255 His Asn Thr Arg Asn Gly Tyr Leu Gln Ile Glu Lys Leu Met Thr Asn 260 265 270 Ala Phe Ile Ser Ile Ile Asp Asp Leu Ser Lys Tyr Asp Val Gln Val 275 280 285 Arg Ala Ala Val Ser Ser Met Cys Arg Glu Ala Gly Leu Trp Ser Glu 290 295 300 Trp Ser Gln Pro Ile Tyr Val Gly Asn Asp Glu His Lys Pro Leu Arg 305 310 315 320 Glu Trp Phe Val Ile Val Ile Met Ala Thr Ile Cys Phe Ile Leu Leu 325 330 335 Ile Leu Ser Leu Ile Cys Lys Ile Cys His Leu Trp Ile Lys Leu Phe 340 345 350 Pro Pro Ile Pro Ala Pro Lys Ser Asn Ile Lys Asp Leu Phe Val Thr 355 360 365 Thr Asn Tyr Glu Lys Ala Gly Ser Ser Glu Thr Glu Ile Glu Val Ile 370 375 380 Cys Tyr Ile Glu Lys Pro Gly Val Glu Thr Leu Glu Asp Ser Val Phe 385 390 395 400 <210> 13 <211> 881 <212> PRT <213> Human <400> 13 Trp Glu Arg Ser Leu Ala Gly Ala Glu Glu Thr Ile Pro Leu Gln Thr 1 5 10 15 Leu Arg Cys Tyr Asn Asp Tyr Thr Ser His Ile Thr Cys Arg Trp Ala 20 25 30 Asp Thr Gln Asp Ala Gln Arg Leu Val Asn Val Thr Leu Ile Arg Arg 35 40 45 Val Asn Glu Asp Leu Leu Glu Pro Val Ser Cys Asp Leu Ser Asp Asp 50 55 60 Met Pro Trp Ser Ala Cys Pro His Pro Arg Cys Val Pro Arg Arg Cys 65 70 75 80 Val Ile Pro Cys Gln Ser Phe Val Val Thr Asp Val Asp Tyr Phe Ser 85 90 95 Phe Gln Pro Asp Arg Pro Leu Gly Thr Arg Leu Thr Val Thr Leu Thr 100 105 110 Gln His Val Gln Pro Pro Glu Pro Arg Asp Leu Gln Ile Ser Thr Asp 115 120 125 Gln Asp His Phe Leu Leu Thr Trp Ser Val Ala Leu Gly Ser Pro Gln 130 135 140 Ser His Trp Leu Ser Pro Gly Asp Leu Glu Phe Glu Val Val Tyr Lys 145 150 155 160 Arg Leu Gln Asp Ser Trp Glu Asp Ala Ala Ile Leu Leu Ser Asn Thr 165 170 175 Ser Gln Ala Thr Leu Gly Pro Glu His Leu Met Pro Ser Ser Thr Tyr 180 185 190 Val Ala Arg Val Arg Thr Arg Leu Ala Pro Gly Ser Arg Leu Ser Gly 195 200 205 Arg Pro Ser Lys Trp Ser Pro Glu Val Cys Trp Asp Ser Gln Pro Gly 210 215 220 Asp Glu Ala Gln Pro Gln Asn Leu Glu Cys Phe Phe Asp Gly Ala Ala 225 230 235 240 Val Leu Ser Cys Ser Trp Glu Val Arg Lys Glu Val Ala Ser Ser Val 245 250 255 Ser Phe Gly Leu Phe Tyr Lys Pro Ser Pro Asp Ala Gly Glu Glu Glu 260 265 270 Cys Ser Pro Val Leu Arg Glu Gly Leu Gly Ser Leu His Thr Arg His 275 280 285 His Cys Gln Ile Pro Val Pro Asp Pro Ala Thr His Gly Gln Tyr Ile 290 295 300 Val Ser Val Gln Pro Arg Arg Ala Glu Lys His Ile Lys Ser Ser Val 305 310 315 320 Asn Ile Gln Met Ala Pro Pro Ser Leu Asn Val Thr Lys Asp Gly Asp 325 330 335 Ser Tyr Ser Leu Arg Trp Glu Thr Met Lys Met Arg Tyr Glu His Ile 340 345 350 Asp His Thr Phe Glu Ile Gln Tyr Arg Lys Asp Thr Ala Thr Trp Lys 355 360 365 Asp Ser Lys Thr Glu Thr Leu Gln Asn Ala His Ser Met Ala Leu Pro 370 375 380 Ala Leu Glu Pro Ser Thr Arg Tyr Trp Ala Arg Val Arg Val Arg Thr 385 390 395 400 Ser Arg Thr Gly Tyr Asn Gly Ile Trp Ser Glu Trp Ser Glu Ala Arg 405 410 415 Ser Trp Asp Thr Glu Ser Val Leu Pro Met Trp Val Leu Ala Leu Ile 420 425 430 Val Ile Phe Leu Thr Ile Ala Val Leu Leu Ala Leu Arg Phe Cys Gly 435 440 445 Ile Tyr Gly Tyr Arg Leu Arg Arg Lys Trp Glu Glu Lys Ile Pro Asn 450 455 460 Pro Ser Lys Ser His Leu Phe Gln Asn Gly Ser Ala Glu Leu Trp Pro 465 470 475 480 Pro Gly Ser Met Ser Ala Phe Thr Ser Gly Ser Pro Pro His Gln Gly 485 490 495 Pro Trp Gly Ser Arg Phe Pro Glu Leu Glu Gly Val Phe Pro Val Gly 500 505 510 Phe Gly Asp Ser Glu Val Ser Pro Leu Thr Ile Glu Asp Pro Lys His 515 520 525 Val Cys Asp Pro Pro Ser Gly Pro Asp Thr Thr Pro Ala Ala Ser Asp 530 535 540 Leu Pro Thr Glu Gln Pro Pro Ser Pro Gln Pro Gly Pro Pro Ala Ala 545 550 555 560 Ser His Thr Pro Glu Lys Gln Ala Ser Ser Phe Asp Phe Asn Gly Pro 565 570 575 Tyr Leu Gly Pro Pro His Ser Arg Ser Leu Pro Asp Ile Leu Gly Gln 580 585 590 Pro Glu Pro Pro Gln Glu Gly Gly Ser Gln Lys Ser Pro Pro Pro Gly 595 600 605 Ser Leu Glu Tyr Leu Cys Leu Pro Ala Gly Gly Gln Val Gln Leu Val 610 615 620 Pro Leu Ala Gln Ala Met Gly Pro Gly Gln Ala Val Glu Val Glu Arg 625 630 635 640 Arg Pro Ser Gln Gly Ala Ala Gly Ser Pro Ser Leu Glu Ser Gly Gly 645 650 655 Gly Pro Ala Pro Pro Ala Leu Gly Pro Arg Val Gly Gly Gln Asp Gln 660 665 670 Lys Asp Ser Pro Val Ala Ile Pro Met Ser Ser Gly Asp Thr Glu Asp 675 680 685 Pro Gly Val Ala Ser Gly Tyr Val Ser Ser Ala Asp Leu Val Phe Thr 690 695 700 Pro Asn Ser Gly Ala Ser Ser Val Ser Leu Val Pro Ser Leu Gly Leu 705 710 715 720 Pro Ser Asp Gln Thr Pro Ser Leu Cys Pro Gly Leu Ala Ser Gly Pro 725 730 735 Pro Gly Ala Pro Gly Pro Val Lys Ser Gly Phe Glu Gly Tyr Val Glu 740 745 750 Leu Pro Pro Ile Glu Gly Arg Ser Pro Arg Ser Pro Arg Asn Asn Pro 755 760 765 Val Pro Pro Glu Ala Lys Ser Pro Val Leu Asn Pro Gly Glu Arg Pro 770 775 780 Ala Asp Val Ser Pro Thr Ser Pro Gln Pro Glu Gly Leu Leu Val Leu 785 790 795 800 Gln Gln Val Gly Asp Tyr Cys Phe Leu Pro Gly Leu Gly Pro Gly Pro 805 810 815 Leu Ser Leu Arg Ser Lys Pro Ser Ser Pro Gly Pro Gly Pro Glu Ile 820 825 830 Lys Asn Leu Asp Gln Ala Phe Gln Val Lys Lys Pro Pro Gly Gln Ala 835 840 845 Val Pro Gln Val Pro Val Ile Gln Leu Phe Lys Ala Leu Lys Gln Gln 850 855 860 Asp Tyr Leu Ser Leu Pro Pro Trp Glu Val Asn Lys Pro Gly Glu Val 865 870 875 880 Cys

Claims

1. (a) 40 mg of antibody containing the heavy chain amino acid sequence shown in SEQ ID NO: 1 and the light chain amino acid sequence shown in SEQ ID NO: 2 (b) A buffer selected from dibasic sodium phosphate heptahydrate, phosphates, citric acid, citrates, sodium phosphate, potassium phosphate, sodium citrate, histidine, or combinations thereof. (c) pH between pH 6.2 and pH 6.6 (d) sugar, (e) Polysorbate 80, and (f) EDTA A water-based liquid formulation containing [a specific ingredient / method].

2. The aqueous liquid formulation according to claim 1, wherein a sugar is present in an amount in the range of 5 to 20% by weight / volume, and the sugar is sucrose.

3. The aqueous liquid formulation according to claim 1, wherein polysorbate 80 is present in an amount in the range of 0.01 to 0.1 wt / vol%.

4. The aqueous liquid formulation according to claim 3, wherein polysorbate 80 is present in an amount of 0.05% by weight / volume.

5. The aqueous liquid formulation according to claim 1, wherein sucrose is present in an amount of 12% by weight / volume.

6. The aqueous liquid formulation according to claim 1, wherein EDTA is present in an amount in the range of 0.01 to 0.1 mM.

7. The aqueous liquid formulation according to claim 6, wherein EDTA is present in an amount of 0.05 mM.

8. The aqueous liquid formulation according to claim 1, wherein the buffering agent is selected from dibasic sodium phosphate heptahydrate, citric acid monohydrate, or a combination thereof.

9. The aqueous liquid formulation according to claim 8, wherein dibasic sodium phosphate heptahydrate is present in an amount ranging from 10 to 30 mM.

10. The aqueous liquid formulation according to claim 9, wherein dibasic sodium phosphate heptahydrate is present in an amount in the range of 15.5 to 16.4 mM.

11. The aqueous liquid formulation according to claim 8, wherein citric acid monohydrate is present in an amount in the range of 3.8 to 4.9 mM.

12. The aqueous liquid formulation according to claim 8, wherein dibasic sodium phosphate heptahydrate is present in an amount of 15.5 mM and citric acid monohydrate is present in an amount of 4.5 mM.

13. The aqueous liquid formulation according to claim 1, wherein the pH is 6.

3.

14. (a) 40 mg of antibody containing the heavy chain amino acid sequence shown in SEQ ID NO: 1 and the light chain amino acid sequence shown in SEQ ID NO: 2 (b) 15.5 mM dibasic sodium phosphate heptahydrate and 4.5 mM citric acid monohydrate at pH 6.3, (c) 12% by weight / volume of sucrose, (d) 0.02 wt / volt% polysorbate 80, and (e) 0.05 mM EDTA A water-based liquid formulation containing [a specific ingredient / method].

15. A self-injection device comprising the aqueous liquid formulation according to claim 14.

16. A syringe with a safety device containing the aqueous liquid formulation described in claim 14.

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