TR201819492T4 - Methods for treating or preventing asthma by administering a IL-4r antagonist. - Google Patents

Abstract

The present invention provides methods for treating or preventing asthma and related health problems in a patient. The methods of the present invention include administering to a subject in need a therapeutic composition containing an interleukin-4 receptor (IL-4R) antagonist, such as an anti-IL-4R antibody.

Description

DESCRIPTION OF THE INVENTION: METHODS FOR TREATING OR PREVENTING ASTHMA BY APPLYING AN IL-4R ANTAGONIST. The field of the invention relates to the treatment and/or prevention of asthma and related health problems. More specifically, this finding relates to the application of an interleukin-4-receptor (lL-4R) to treat or prevent asthma in a patient in need. INFRASTRUCTURE Asthma is a chronic inflammatory disease of the airways characterized by airway hypersensitivity, acute and chronic bronchoconstriction, airway edema, and mucus obstruction. The inflammatory component of asthma is thought to involve many cell types, including mast cells, eosinophils, T1 lymphocytes, neutrophils, epithelial cells, and their biological products. Patients with asthma frequently experience symptoms such as wheezing, shortness of breath, coughing, and chest tightness. For most asthma patients, a control therapy regimen and bronchodilator therapy provide sufficient long-term control. Inhaled corticosteroids (ICS) are considered the "gold standard" for controlling asthma symptoms, and inhaled beta-Z-agonists are currently the most effective bronchodilators available. Studies have shown that combination therapy consisting of an ICS and an inhaled long-acting beta2-agonist (LABA) provides better asthma control than high doses of ICS alone. In conclusion, combination therapy, despite the maximum recommended treatment with combinations of anti-inflammatory and bronchodilator drugs, is effective against symptomatic disease in 5% to 10% of the asthmatic population. Furthermore, this significant asthma population accounts for up to 50% of total healthcare costs through hospital admissions, emergency room use, and unscheduled physician visits. There is an unmet need for a novel treatment in this severe asthma population, as many of these patients respond poorly to ICS due to a range of cellular and molecular mechanisms. Furthermore, the long-term adverse effects of systemic and inhaled corticosteroids on bone metabolism, adrenal function, and growth in children have paved the way for initiatives aimed at minimizing the amount of corticosteroid use. Although a large proportion of asthma patients are maintained reasonably well with current treatments, patients with severe corticosteroid-refractory asthma have limited therapeutic options that can adequately control their condition. The consequence of not responding to or adhering to therapy is loss of asthma control and consequently, an asthma exacerbation. One reason for the poor response to medication in some patients with severe asthma may be the heterogeneity of the disease. Interest in understanding these different phenotypes is increasing, as targeted therapy is more likely to be successful in patients exhibiting similar underlying pathobiological characteristics. New therapeutic approaches in asthma. The focus has been on attempting to control the T helper cell-2 response. Upregulation of interleukin-4 (IL-4) and interleukin-13 (IL-13) has been shown to be a significant inflammatory component of asthma progression. J. Corren et al. ("A Randomized, Controlled, Phase 2 Study of AMG 317, an IL-4R Antagonist, in Patients with Asthma", AMERICAN JOURNAL OF RESPIRATORY AND 796), describes a phase II study of human monoclonal antibody against IL-4R alpha AMG 317 in the treatment of asthma, where patients receiving 150 mg and 300 mg of AMG 317 subcutaneously once weekly for 12 weeks experienced a reduction in the number of exacerbations and the time to exacerbation. Accordingly, in technology, new targeted therapies are needed for the treatment and/or prevention of asthma. BRIEF DESCRIPTION OF THE INVENTION One aspect of the present invention provides pharmaceutical compounds that can be used to reduce the incidence of asthma exacerbations in a subject in need. In a related direction, pharmaceutical compounds are provided for use in improving one or more asthma-related parameters in a subject in need. Another aspect of the current discovery is the provision of pharmaceutical compounds to treat asthma, such as moderate to severe eosinophilic asthma, in a subject in need. The pharmaceutical formulations proposed in this study contain a therapeutically effective amount of an interleukin-4 receptor (IL-4R) antagonist. It is a coupling fragment and contains the heavy chain and light chain (complementarity determination region) CDR sequences from the heavy chain variable region (HCVR) and light chain variable region (LCVR) of SEQ ID NO: 162 and 164, respectively. Examples of anti-IL-4R antibodies that can be used in the context of this finding are described elsewhere in this document, including Study Sample 1. In one application, a pharmaceutical compound is provided for use in reducing the incidence of one or more asthma exacerbations in a subject suffering from persistent asthma. An asthma exacerbation may be caused by one or more of the following: (a) a 30% or greater decrease in morning peak expiratory flow (PEF) from baseline on two consecutive days; (b) six or more additional puffs of albuterol or levalbuterol in a 24-hour period (compared to baseline) to provide relief on two consecutive days; and (c) a worsening of asthma requiring: (i) systemic (oral and/or parenteral) steroid therapy or (ii) at least a fourfold increase in the last inhaled corticosteroid dose taken before discontinuation of treatment or hospitalization. In another application, a pharmaceutical compound is provided for use in a subject suffering from persistent asthma to achieve improvement in one or more asthma-related parameters, where improvement in an asthma-related parameter is defined as one of the following: an increase in FEV1 from baseline; an increase in AM PEF from baseline; an increase in PM PEF from baseline; a decrease in albuterol/Ievalbuterol use from baseline; a decrease in nocturnal awakenings from baseline; and/or a decrease in SNOT-22 score from baseline. Examples of parameters associated with asthma include: (a) forced expiratory volume in 1 second (FEV1); (b) peak expiratory flow rate (PEF), including morning PEF (AM PEF) and evening PEF (PM PEF); (c) albuterol or ACQ5 score; (d) nocturnal awakenings; and (e) 22-item Sino-Nasal Outcome Test (SNOT-22) score. In this application, improvement in an asthma-related parameter is selected from among the following: at least 0 in FEV1 relative to baseline. A 10L increase; at least 10 in AM PEF relative to baseline. An increase of 0 L/min; at least 1 in PM PEF compared to baseline. An increase of 0 L/min; a decrease of at least 1 puff per day in albuterol/Ievalbuterol use compared to baseline; a decrease of at least 0 in ACQ5 score compared to baseline. A 5-point decrease; at least 0 nightly awakenings compared to baseline. A twofold reduction; and at least a 5-point improvement in the SNOT-22 score compared to baseline. This finding also provides pharmaceutical compounds for use in reducing the incidence of asthma exacerbations or achieving improvement in one or more asthma-related parameters in a subject suffering from persistent asthma, where use involves the sequential administration of a single initial dose of a pharmaceutical compound containing an IL-4R antagonist (an anti-IL-4R antibody or its antigen-binding fragment), followed by one or more secondary doses of the pharmaceutical compound containing the IL-4R antagonist, to a subject in need. The pharmaceutical formulation containing the lL-4R antagonist can be administered subcutaneously, intranasally, or intravenously to the subject in need. According to some applications, the discovery provides pharmaceutical compounds intended for use in a subject in need to reduce the incidence of asthma exacerbations or to achieve improvement in one or more asthma-related parameters, where use involves the administration of approximately 75 to 300 mg of a pharmaceutical compound containing an antibody or antigen-binding fragment that specifically binds to IL-4R to the subject. According to this approach, the pharmaceutical compound can be administered to the subject with a dosing frequency, for example, once a week. The current explanation also describes the selection of a subject exhibiting one or more symptoms or signs of asthma and the administration of a pharmaceutical compound containing an IL-4R antagonist (e.g., an anti-IL-4R antibody or its antigen-binding fragment) to treat asthma (e.g., eosinophilic asthma, moderate to severe eosinophilic asthma, etc.). ) includes methods of treatment where the subject exhibits one or more of the following asthma symptoms or signs: (1) the subject has received fluticasone/salmeterol combination therapy (250/50 µg BID) or budesonide/formoterol combination therapy (16019 µg BID) for at least 3 months prior to screening; (3) the subject has 300 cells/µL or more of blood eosinophils; (4) the subject has 3% or more sputum eosinophils; (5) the subject has IgE. Thymus and activation regulator chemokine (TARC), eotaxin-3, carcinoembryonic antigen (CEA), YKL-40 or periostin levels are increased; (5) fractional exhaled nitric oxide (FeNO) level is increased in the subject; and/or (6) subject has a score. The applications highlighted in this statement relate to pharmaceutical compounds to be used as described above, and the aforementioned use also includes the administration of a second therapeutic agent in combination with an IL-4R antagonist. The second therapeutic agent may be administered to a subject in need before, after, or concurrently with the IL-4R antagonist. A second set of therapeutic agents, while not limited to these, include one or more of the following in combination: IL-1 inhibitors, IL-5 inhibitors, IL-8 inhibitors, IgE inhibitors, tumor necrosis factor (TNF) inhibitors; corticosteroids, long-acting beta2-agonists, and leukotriene inhibitors. The explanation, in another aspect, relates to IL-4R antagonists intended for use in reducing or eliminating dependence on background asthma therapy in an asthmatic patient, and involves selecting a patient with moderate to severe asthma that is not controlled or is only partially controlled by background asthma therapy; administering a defined dose of an IL-4R antagonist to this patient during an initial treatment period while continuing the patient's background therapy; and gradually reducing or eliminating the dosage of one or more components of the background therapy in a subsequent treatment period while continuing to administer the IL-4R antagonist at the defined frequency and dose used during the initial treatment period. In this treatment, background therapy includes an inhaled corticosteroid (ICS), a long-acting beta-agonist (LABA), or a combination of an ICS and a LABA. In some treatments, background therapy is gradually reduced or withdrawn over a period of 2-8 weeks. In one treatment, background therapy is gradually reduced over a subsequent treatment period. Another explanation relates to the selection of a patient with elevated levels of a biomarker such as thymus and activation-regulating chemokine (TARC), IgE, eotaxin-S, periostin, carcinoembryonic antigen (CEA), or YKL-40, or with an elevated fractional exhaled nitric oxide (FeNO) level; and the use of IL-4R antagonists for the treatment of moderate to severe persistent asthma by administering a therapeutically effective amount of the IL-4R antagonist to this patient. Another approach suggests a method for monitoring the effectiveness of treatment for moderate to severe asthma in a subject by, for example, (a) determining the expression level of a biomarker such as TARC or eotaxin-S or both, or the total serum level of IgE in a biological sample taken from the subject before treatment with an IL-4R antagonist; (b) determining the expression level of the biomarker in a biological sample taken from the subject after treatment with an IL-4R antagonist; (c) comparing the expression level obtained in step (a) with the level in step (b); and (d) concluding that the treatment is effective if the level determined in step (b) is lower than the level determined in step (a), or concluding that the treatment is ineffective if the level determined in step (b) is equal to or higher than the level determined in step (a). In one application, the biomarker is FeNO, and if FeNO levels decrease after administration of the antagonist, treatment with the 1L-4R antagonist is determined to be effective. The expression level of the biomarker can be determined after administration of the 1L-4R antagonist, for example, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks or longer, and compared to the expression level before antagonist administration. The dose or dosing regimen of the IL-4R antagonist (e.g., an anti-IL4R antibody) can be adjusted after this determination process. For example, if the expression of the biomarker does not decrease after 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks or longer following the administration of the antagonist, treatment with the antagonist may be stopped or the dose of the antagonist may be increased. If biomarker expression decreases after antagonist administration, the antagonist dosage can be maintained or reduced, for example, to determine a minimally effective dose. In some treatments, therapy is continued at the minimally effective dose. In another direction, the present finding proposes a method for monitoring a subject's response to treatment with an IL-4R antagonist by determining the expression level of a biomarker, such as TARC or eotaxin-S, or the total serum level of IgE in a biological sample taken from the subject after administration of an IL-4R antagonist, and providing an indication that treatment should be continued if the expression level of the biomarker is decreased compared to the level before treatment with the IL-4R antagonist, where the subject has moderate to severe asthma. In one application, the biomarker is FeNO, and if a decrease in FeNO levels is detected following antibody administration, it provides an indication for continued treatment with an IL-4R antagonist. This explanation also applies to asthma as described herein (e.g., eosinophilic asthma, moderate to severe eosinophilic asthma, etc.). It also includes an IL-4R antagonist for use in the manufacture of a drug for the treatment and/or prevention of ) or for the treatment of any of the other indications or health problems described herein. This explanation also applies to asthma as described herein (e.g., eosinophilic asthma, moderate to severe eosinophilic asthma, etc.). It also includes an IL-4R antagonist for use in the treatment and/or prevention of ) or any of the other indications or health problems described herein. This description includes a pharmaceutical compound containing an anti-IL4R antibody antagonist or its antigen-binding fragment, intended for use in the treatment and/or prevention of asthma and related health problems. This description also includes a pharmaceutical compound containing an anti-IL4R antibody antagonist or its antigen-binding fragment, to be used in reducing the incidence of one or more asthma exacerbations in a subject in need. This description also includes a pharmaceutical compound containing an anti-IL4R antibody antagonist or its antigen-binding fragment, intended for use in improving one or more asthma-related parameters in a subject in need. This explanation concerns the thymus and the activation-modulating chemokine (TARC), IgE. Eotaxin-S contains a pharmaceutical compound that includes an anti-IL4R antibody antagonist or its antigen-binding fragment, intended for use in the treatment of asthma and related health problems in a patient with elevated levels of a selected biomarker from a group consisting of periostin, carcinoembryonic antigen (CEA), YKL-40, and fractional exhaled nitric oxide (FeNO). This description also includes a pharmaceutical compound containing an anti-IL4R antibody antagonist or its antigen-binding fragment, intended for use in the treatment of asthma or moderate to severe eosinophilic asthma in a subject in need, whereby the patient is tested for the presence of a blood eosinophil level of at least 300 cells per microliter and/or a sputum eosinophil level of at least 3%, and if these blood eosinophil and/or sputum levels are found, the administration of the pharmaceutical compound is to be initiated/continued. Other applications of the invention will become apparent upon examination of the following detailed description. BRIEF DESCRIPTION OF THE FIGURES Figure 1 shows a Kaplan-Meier plot of the time to asthma exacerbation in patients treated with placebo (open circles) compared to patients treated with the anti-IL-4R antibody mAb1 (star signs). The effect of treatment with an anti-IL-4R antibody, mAb1, persists over time, including up to 8 weeks after steroid withdrawal, when patients are at a higher risk of developing a flare-up. The dashed vertical lines indicate the withdrawal of LABA. Figure 2 shows the mean change from baseline in forced expiratory volume in liters per second (FEV1) in patients treated with the anti-IL-4R antibody mAb1 (closed circles) compared to patients treated with placebo (open triangles). The dashed vertical lines indicate the withdrawal of LABA. Figure 3 is a graph showing the mean change from baseline in morning peak expiratory flow rate in liters per minute (AM PEF) in patients treated with placebo (open triangles) compared to patients treated with the anti-IL-4R antibody mAb1 (closed circles). Figure 4 is a graph showing the mean change from baseline in evening peak expiratory flow rate in liters per minute (PM PEF) in patients treated with placebo (open triangles) compared to patients treated with the anti-IL-4R antibody mAb1 (closed circles). Figure 5 is a graph showing the mean change from baseline in daily albuterol inhalation use in patients treated with placebo (open triangles) compared to patients treated with the anti-IL-4R antibody mAb1 (closed circles). The dashed vertical lines indicate the withdrawal of LABA. Figure 6 shows the mean change from baseline in five-item asthma control questionnaire (ACQ5) scores in patients treated with placebo (open triangles) compared to patients treated with the anti-1L-4R antibody mAb1 (closed circles). The dashed vertical lines indicate the withdrawal of LABA. Figure 7 shows the mean change from baseline in the number of nightly awakenings in patients treated with the anti-IL-4R antibody mAb1 (closed circles) compared to patients treated with placebo (open triangles). The dashed vertical lines indicate the withdrawal of LABA. Figure 8 shows the mlTT population treated with placebo (closed circles) compared to patients treated with the anti-IL-4R antibody mAb1 (closed squares) at 0, 1, 4, 8, and 12. This is a graph showing the average percentage change in TARC from baseline up to the next week's examination. The dashed vertical lines indicate the withdrawal of LABA. Figure 9 shows the mlTT population treated with placebo (closed circles) compared to patients treated with the anti-IL-4R antibody mAb1 (closed squares) at 0, 1, 4, 8, and 12. This is a graph showing the average percentage change in Eotaxin-S from baseline up to the next week's examination. The dashed vertical lines indicate the withdrawal of LABA. Figure 10 shows the mlTT population treated with placebo (closed circles) compared to patients treated with the anti-IL-4R antibody mAb1 (closed squares) at 0, 1, 4, 8, and 12. This is a graph showing the average percentage change in total IgE from baseline until the next weekly examination. The dashed vertical lines indicate the withdrawal of LABA. Figure 11 shows the mlTT population treated with placebo (closed circles) compared to patients treated with the anti-IL-4R antibody mAb1 (closed squares), at 0, 1, 4, 8, and 12. This is a graph showing the average percentage change in periostitis from baseline until the next weekly examination. Figure 12 shows the placebo-treated mITT population (closed circles) compared to patients treated with the anti-IL-4R antibody mAb1 (closed squares), at 0, 1, 4, 8, and 12. This is a graph showing the average percentage change in carcinoembryogenic antigen (CEA) from baseline to the next weekly examination. Figure 13 shows the placebo-treated mITT population (closed circles) compared to patients treated with the anti-IL-4R antibody mAb1 (closed squares) at 0, 1, 4, 8, and 12. until their weekly check-ups. This is a graph showing the average percentage change in YKL-40 relative to the baseline. Figure 14 shows the placebo-treated mITT population (closed circles) compared to patients treated with the anti-IL-4R antibody mAb1 (closed squares), at 0, 1, 2, 4, 6, 8, and 12. This is a graph showing the average percentage change in blood eosinophils from baseline until the next weekly examination. Figure 15 shows the placebo-treated mITT population (closed circles) compared to patients treated with the anti-IL-4R antibody mAb1 (closed squares) at 0, 4, 8, and 12. This is a graph showing the average percentage change in fractional exhaled nitric oxide (NO) levels from baseline until the next weekly examination. The dashed vertical lines indicate the withdrawal of LABA. Figure 16 shows the ratio of fractional exhaled nitric oxide (FeNO) (PPB) at baseline to patients treated with the anti-1L-4R antibody mAb1 (plus sign and dashed line) in the placebo-treated mITT population (open circles and solid line), 12. It is a scatter plot of the change in FEV1 (L) from baseline over the week. Figure 17 shows the baseline levels of FeNO₃ (PPB₂) in the placebo-treated mITT population (open circles and solid line) compared to patients treated with the anti-lL-4R antibody mAb1 (plus sign and dashed line). This is a scatter plot of the change in AM-PEF (L/minute) from baseline over the week. Figure 18 shows the baseline levels of FeNO₃ (PPB₂) in the placebo-treated mITT population (open circles and solid line) compared to patients treated with the anti-lL-4R antibody mAb1 (plus sign and dashed line). This is a scatter plot of the change in PM-PEF (L/minute) from baseline over the week. Figure 19 shows the blood eosinophil count (G1G/L) in the placebo-treated mITT population (open circles and solid line) compared to patients treated with the anti-1L-4R antibody mAb1 (plus sign and dashed line), 12. It is a scatter plot of the change in FEV1 (L) from baseline over the week. Figure 20 shows the blood eosinophil count (GIGA/L) in the placebo-treated mITT population (open circles and solid line) compared to patients treated with the anti-1L-4R antibody mAb1 (plus sign and dashed line), 12. This is a scatter plot of the change in ACQ from baseline over the week. Figure 21 shows the blood eosinophil count (G1G/L) in the placebo-treated mITT population (open circles and solid line) compared to patients treated with the anti-IL-4R antibody mAb1 (plus sign and dashed line), 12. This is a scatter plot showing the change in daily albuterol/Ievalbuterol use from baseline over a week. Figure 22 shows baseline periostin in the placebo-treated mITT population (open circles and solid line) compared to patients treated with the anti-IL-4R antibody mAb1 (plus sign and dashed line), 12. This is a scatter plot of the change in ACQ from baseline over the week. Figure 23 shows the ratio of YKL-40 to the placebo-treated mITT population (open circles and solid line) compared to patients treated with the anti-lL-4R antibody mAb1 (plus sign and dashed line), 12. This is a scatter plot of the change in ACQ from baseline over the week. Figure 24 is a schematic representation of the timing and dosing regimens for the treatment of asthma patients. Figure 25 is a diagram describing the patient distribution of a randomized, placebo-controlled, double-blind, parallel-group study in which patients with moderate to severe persistent eosinophilic asthma, partially controlled/uncontrolled with inhaled corticosteroid (ICS) and long-acting beta2 agonist (LABA) therapy, received either 300 mg mAb1 or placebo subcutaneously once a week for 12 weeks. Figures 26A and 26B are scatter plots of morning (A) and evening (B) asthma symptoms measured over 12 weeks following administration of either placebo (open triangles) or mAb1 (closed circles). Figure 27 is a graph showing serum IgE levels in humanized IL-4/IL-4R mice (IL-4""lhu lL-4R0ihulhu) following house dust mite (HDM) forcing and treatment with anti-IL-4R antibody or an IL-13Ra2-Fc pseudoreceptor molecule or sham treatment. 40. Samples were taken daily (24 hours before the first dose of treatment) and on day 85. Measurements were taken at the end of each day's experiment. Figure 28 is a graph showing serum IgE levels in wild-strain (BaIb/c) mice following house dust mite (HDM) forcing and isotype control, treatment with anti-1L-4R antibody or an IL-13Ra2-Fc pseudoreceptor molecule, or sham treatment. Figure 29 is a graph showing the collagen content (expressed in µg/L) of the lungs of humanized IL-4/IL-4R mice after HDM induction and indicated treatment. Figure 30 is a graph showing the collagen content (expressed in pg/Iob) of the lungs of wild-strain mice after HDM forcing and indicated treatment. Figure 31A is a graph showing the levels of eosinophils and neutrophils in humanized IL-4/IL-4R mice following HDM forcing and indicated treatment, and Figure 31B is a graph showing the levels of resident dendritic cells and inflammatory dendritic cells in mice. DETAILED EXPLANATION Before describing the present invention, it should be understood that this invention is not limited to the specific methods and experimental conditions described, and therefore these methods and conditions are subject to change. It should also be understood that the terminology used here is intended solely to describe specific applications. Unless otherwise defined, all technical and scientific terms used herein shall have the meaning of being commonly understood by a person with ordinary expertise in the field to which this invention relates. As used here, the term "approximately" means that when referring to a specific numerical value, that value may differ from the stated value by no more than 1%. For example, as used here, "approximately 100" is 99. 4 etc. It will include ). As used herein, the terms "to treat," "treating," or similar terms mean to alleviate the symptoms of the disorder or health problem in question, to temporarily or permanently eliminate the occurrence of symptoms, or to stop or slow the appearance of symptoms. Now, the preferred methods and materials will be described. Methods to Reduce the Incidence of Asthma Exacerbations This description outlines methods to reduce the incidence of asthma exacerbations in a subject in need, including the administration of a pharmaceutical compound containing an interleukin-4 receptor (IL-4R) antagonist. As used here, "asthma exacerbation" means an increase in the severity and/or frequency and/or duration of one or more symptoms or signs of asthma. An "asthma exacerbation" can also be defined as a change in a subject's respiratory health following a therapeutic intervention related to asthma (e.g., steroid treatment, inhaled corticosteroid treatment, hospitalization, etc.). This includes any deterioration that requires (such as) intervention and/or can be treated with this intervention. According to some applications of the study, an asthma exacerbation is defined as one or more of the following: (a) a 30% or greater reduction in morning peak expiratory flow (as defined elsewhere in this document, "AM PEF") from baseline on two consecutive days; (b) six or more additional puffs of albuterol or levalbuterol taken over a 24-hour period (compared to baseline) to provide relief on two consecutive days; and (c) a worsening of asthma (as determined, for example, by a physician or other type of doctone) requiring at least one of the following: (i) systemic (oral and/or parenteral) steroid therapy; or (ii) an increase of at least four times the last inhaled corticosteroid dose from baseline; or (iii) hospitalization. In some cases, an asthma flare-up may be categorized as a "severe asthma flare-up". A severe asthma exacerbation means a case requiring urgent intervention, in the form of treatment with systemic corticosteroids or inhaled corticosteroids at four or more times the dose taken before the incident. Therefore, the general term "asthma exacerbation" includes and encompasses a more specific subcategory called "severe asthma exacerbations." Accordingly, the current statement includes methods to reduce the incidence of severe asthma exacerbations in a patient in need. A "reduction in the incidence" of an asthma exacerbation means that a subject receiving a pharmaceutical component of the present discovery experiences fewer asthma exacerbations after treatment (i.e., at least one fewer exacerbation) than before treatment, or does not experience an asthma exacerbation for at least 4 weeks (e.g., 4, 6, 8, 12, 14 or more weeks) after initiation of treatment with a pharmaceutical component of the present discovery. Alternatively, following an asthma exacerbation, a subject has at least a 10% chance of experiencing an asthma exacerbation compared to a subject who has not received a pharmaceutical component of the present discovery (e.g., 10%). Methods for Improving Asthma-Related Parameters This description includes methods for improving one or more asthma-related parameters in a subject in need, where the methods involve the administration of a pharmaceutical compound containing an interleukin-4 receptor (IL-4R) antagonist to the subject. In line with the aims of this finding, a reduction in the incidence of an asthma exacerbation (as described above) may be associated with an improvement in one or more asthma-related parameters; however, such an association is not necessarily observed in all cases. (b) forced expiratory volume (FEV1); (c) peak expiratory flow rate (PEF), including morning PEF (AM PEF) and evening PEF (PM PEF); (d) use of an inhaled bronchodilator such as albuterol or levalbuterol; (e) five-item Asthma Control Questionnaire (ACQ5) score; (d) nocturnal awakenings; and (e) 22-item Sino-Nasal Outcome Test (SNOT-22) score. "Improvement in an asthma-related parameter" means an increase in one or more of the FEV1, AM PEF, or PM PEF and/or a decrease in one or more of the following parameters from baseline: daily albuterol/Ievalbuterol use, ACQÖ score, mean nocturnal awakenings, or SNOT-22 score. As used herein, the term "baseline" for an asthma-related parameter means the numerical value of a patient's asthma-related parameter before or during the administration of a pharmaceutical component of the present invention. To determine whether there has been an "improvement" in an asthma-related parameter, the amount of this parameter is measured at baseline and at a time point after administration of the pharmaceutical formulation of the current discovery. For example, a parameter associated with asthma could be measured some time after initial treatment with a pharmaceutical component of the current finding. The difference between the parameter's value at a specific point in time after the start of treatment and its baseline value is used to determine whether there has been an "improvement" (e.g., an increase or decrease depending on the specific parameter being measured) in the asthma-related parameter. As used here, the terms "to acquire" or "acquiring" refer to the acquisition of ownership of a physical entity or a value, such as a numerical value, either through "direct acquisition" or "indirect acquisition" of that physical entity or value, such as a parameter associated with asthma. "Direct acquisition" means carrying out a process (for example, performing a method of synthesis or analysis) to obtain a physical asset or value. "Indirect acquisition" refers to the transfer of a physical asset or value from another person or source (for example, from a third-party laboratory that has directly acquired the physical asset or value). The direct acquisition of a physical entity involves carrying out a process that includes a physical change in a physical substance, for example, a starting material. Examples of significant changes include the creation of a physical entity from two or more starting materials, the clipping or splitting of a substance, the separation or purification of a substance, the combination of two or more substances into a mixture, and the performance of a chemical reaction involving the breaking or formation of a covalent or non-covalent bond. The direct acquisition of a value involves carrying out an analytical process (sometimes referred to here as "physical analysis") that includes a physical change in a sample or other substance, for example, a physical change in a substance, such as a sample, analyte, or reactant. Information obtained indirectly may be provided in electronic form, for example, in a report form provided on paper or obtained from an online database or application ("an Application"). The report or information may be provided by a healthcare institution, such as a hospital or clinic; or by a healthcare professional, such as a doctor or nurse. Forced Expiratory Volume per Second (FEV1). According to some applications of the study, administration of an 1L-4R antagonist to a patient results in an increase in forced expiratory volume in 1 second (FEV1) compared to baseline. Methods for measuring FEV1 are well-known in the field. For example, a spirometer that meets the recommendations of the European Respiratory Society (ERS) can be used to measure FEV1 in a patient. The ATS/ERS Spirometry Standards can be used as a guide. Spirometry is usually performed between 6 and 10 a.m. after at least 6 hours of albuterol abstinence. Pulmonary function tests are usually measured in a sitting position, and the highest measurement is recorded for FEV1 (in liters). The current statement refers to the 12th day following the initiation of treatment with a pharmaceutical compound containing an anti-1L-4R antagonist. at least 0 per week, relative to baseline. It includes therapeutic methods that provide a 0.5 L increase in FEV1. For example, according to the study, administering an IL-4R antagonist to a subject in need resulted in a 12. This leads to a larger increase than the baseline per week. Morning and Evening Peak Expiratory Flow (AM PEF and PM PEF). According to some applications of the study, administration of an IL-4R antagonist to a patient results in an increase in peak expiratory flow (AM PEF and/or PM PEF) in the morning (AM) and/or evening (PM) compared to baseline. Methods for measuring PEF are well-known in the field. For example, according to a method for measuring PEF, they were given an electronic PEF meter to measure their morning (AM) and evening (PM) PEF (and also daily albuterol use, morning and evening asthma symptom scores, and the number of nighttime awakenings due to asthma symptoms requiring rescue medication). Patients were informed about how to use the device and were given written instructions on how to use the electronic PEF meter. Additionally, a healthcare professional can inform patients about how to record specific variables on an electronic PEF meter. AM PEF is usually performed within 15 minutes of waking up (between 6 AM and 10 AM) and before any albuterol use. PM PEF is usually performed in the evening (between 6 pm and 10 pm) before any albuterol use. Subjects should avoid taking albuterol for at least 6 hours before measuring their PEF (Peak Efficiency Level). The patient performs three PEF (percutaneous ejection fraction) tests, and all three values are recorded by the electronic PEF meter. The highest value is usually used for evaluation. Baseline AM PEF can be calculated as the average AM measurement recorded over the previous 7 days, and baseline PM PEF can be calculated as the average PM measurement recorded over the 7 days prior to administration of the first dose of the pharmaceutical compound containing the 1L-4R antagonist. The current statement refers to the 12th day following the initiation of treatment with a pharmaceutical compound containing an anti-IL-4R antagonist. at least 1 week above baseline. It includes therapeutic methods that provide an AM PEF and/or PM PEF increase of 0 L/min. For example, according to the findings, administering an 1L-4R antagonist to a subject in need resulted in a 12. PEF approximately 0.00% from baseline per week. 5 L/minute, 1. 0 L/minute, 1. It leads to 5 increases. AlbuteroI/Levalbuterol Use. According to some applications of the finding, administering an 1L-4R antagonist to a patient results in a reduction in daily albuterol or levalbuterol use compared to baseline. The number of ibuterol/ievalbuterol inhalations can be recorded daily by patients using a diary, PEF meter, or other recording device. With the pharmaceutical composition of Bulusun, the use of albuteroI/levalbuterol during treatment should typically be as needed for symptoms, not on a regular or prophylactic basis. The baseline albuteroI/evalbuterol inhalation/day can be calculated based on the average of the 7 days preceding the administration of the first dose of the pharmaceutical compound containing the IL-4R antagonist. The current statement refers to the 12th day following the initiation of treatment with a pharmaceutical compound containing an anti-1L-4R antagonist. At least 0.5% daily, compared to baseline, when using albuteroI/evalbuterol per week. It includes therapeutic methods that provide a reduction of 25 puffs. For example, according to the study, administering an IL-4R antagonist to a subject in need resulted in a 12. Approximately 3 daily doses of albuteroI/levalbuterol per week, based on baseline. This leads to a reduction of 00 puffs or more. - Asthma Control Questionnaire (ACQ) Score. According to some applications of the finding, administering an IL-4R antagonist to a patient results in a decrease in their five-item Asthma Control Questionnaire (ACQ5) score compared to baseline. ACQ5 is a validated questionnaire for evaluating asthma control. The current statement refers to the 12th day following the initiation of treatment with a pharmaceutical compound containing an anti-IL-4R antagonist. weekly, at least 0 points above baseline in ACQ5 score. It includes therapeutic methods that provide a 10-point reduction. For example, according to the study, administering an IL-4R antagonist to a subject in need resulted in a 12. This leads to a decrease of one or more base points per week. Nighttime Awakenings. According to some applications of the study, administering an IL-4R antagonist to a patient results in a reduction in the average number of nocturnal awakenings compared to baseline. The current statement refers to the 12th day following the initiation of treatment with a pharmaceutical compound containing an anti-1L-4R antagonist. The average number of nighttime awakenings per week is at least approximately 0 per night, relative to the baseline. It includes therapeutic methods that provide a tenfold reduction. For example, according to the study, administering an IL-4R antagonist to a subject in need resulted in a 12. The average number of nighttime awakenings per week is approximately 0 per night, compared to the baseline. 10 times, 0 per night. 15 times, 0 per night. 20 times, 2 per night. It leads to a decrease of 0 times or more. 22-Item Sinonasal Outcome Test (SNOT-22) Score. According to some applications of the finding, administration of an IL-4R antagonist to a patient leads to a decrease in the baseline score on the 22-item Sinonasal Outcome Test (SNOT-22). SNOT-22 is a validated study to evaluate the impact of chronic rhinosinusitis on quality of life. The current statement describes the 12th week following initiation of treatment with a pharmaceutical compound containing an anti-1L-4R antagonist. It includes therapeutic methods that achieve at least a 1-point reduction in the SNOT-22 score from baseline per week. For example, according to the study, administering an IL-4R antagonist to a subject in need resulted in a 12. This leads to a decrease of one or more points per week. Methods for Treating Asthma This description provides methods for treating asthma, including eosinophilic asthma, in a subject in need, according to some practices, where the methods involve administering a pharmaceutical compound containing an interleukin-4 receptor (IL-4R) antagonist to the subject. In some applications, the methods of current explanation are useful for the treatment of moderate to severe eosinophilic asthma (e.g., moderate to severe persistent eosinophilic asthma) in a subject. According to the study, if a subject shows a blood eosinophil level of at least 300 cells per microliter and/or a sputum eosinophil level of at least 3%, that subject is considered to have moderate to severe eosinophilic asthma. Any known and currently available method in the technique for measuring blood and/or sputum eosinophil levels may be used in the context of this discovery to determine whether a subject has moderate to severe eosinophilic asthma and is therefore a suitable subject for the therapeutic methods of the presented description. According to a relevant aspect of the current statement, methods for treating asthma are provided, including: (a) selection of a patient showing a blood eosinophil level of at least 300 cells per microliter and/or a sputum eosinophil level of at least 3%; and (b) administration of a pharmaceutical compound containing an 1L-4R antagonist to this patient. In another direction, methods are provided to reduce or eliminate the dependence of an asthma patient on inhaled corticosteroids (ICS) and/or long-acting beta agonists (LABA) during the treatment of moderate to severe asthma. In some applications, these methods include: selecting a patient with moderate to severe asthma that is not controlled or is only partially controlled with background therapy; administering a set dose of an IL-4R antagonist, preferably an anti-IL-4R antibody, to the patient for an initial treatment period, during which the patient's background therapy is continued; and gradually reducing the dosage of one or more components of the background therapy in a subsequent treatment period while continuing the IL-4R antagonist. It refers to traditional therapeutic agents. In some applications, background therapy and/or the dosage of LABA is discontinued or completely withdrawn after the initial treatment period. For example, a LABA such as salmeterol or formoterol is administered during an initial treatment period and then completely stopped or withdrawn during subsequent treatment periods. An example of a treatment regimen for a patient with moderate to severe asthma is shown in Figure 24, where an IL-4R antagonist is administered to a patient with moderate to severe asthma. During an initial treatment period (also called the "stable phase"), the patient receives LABA and ICS as background therapy. During a subsequent treatment period (also called the "withdrawal phase"), LABA administration is stopped, meaning LABA is withdrawn or discontinued. During the subsequent treatment period, ICS is gradually reduced and eventually discontinued. In a related direction, asthma treatment methods are provided that include supportive therapy to background therapy along with the withdrawal of systemic background therapy. In some applications, an 1L-4R antagonist is administered as support therapy to an asthma patient receiving background therapy for a specific period of time (e.g., 1 week, 2 weeks, 3 weeks, 1 month, 2 months, 5 months, 12 months, 18 months, 24 months, or longer) (also referred to as the "stable phase"). In some applications, background therapy includes an ICS and/or a LABA. The stabilization phase is followed by a background therapy withdrawal phase, where one or more components of the background therapy are withdrawn, reduced, or discontinued while supportive therapy is continued. In some applications, background therapy may be reduced by approximately 5%, approximately 10%, approximately 20%, approximately 30%, approximately 40%, approximately 50% or more during the withdrawal phase. The withdrawal phase can last from weeks to 12 weeks or even longer. In a preferred approach, background therapy can be reduced by approximately 5% during the withdrawal phase, which can last 1 week, 2 weeks, 3 weeks, or longer. In a preferred approach, background therapy can be reduced by approximately 10% during the withdrawal phase, and the withdrawal phase can last for 1 week, 2 weeks, 3 weeks, or 4 weeks. In a preferred approach, background therapy can be reduced by approximately 20% during the withdrawal phase, and the withdrawal phase can last 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, or longer. In a preferred approach, background therapy can be reduced by approximately 30% during the withdrawal phase, and the withdrawal phase can last 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, or longer. In a preferred approach, background therapy can be reduced by approximately 40% during the withdrawal phase, and the withdrawal phase can last 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, or longer. In a preferred approach, background therapy can be reduced by approximately 50% during the withdrawal phase, and the withdrawal phase can last 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, or longer. In some other applications, the current explanation encompasses methods aimed at treating or alleviating health problems or complications associated with asthma, such as chronic rhinosinusitis, allergic rhinitis, allergic fungal rhinosinusitis, allergic bronchopulmonary aspergillosis, fused airway disease, Churg-Strauss syndrome, vasculitis, chronic obstructive pulmonary disease (COPD), and exercise-induced bronchospasm. The current statement also includes methods for treating persistent asthma. As used herein, the term "persistent asthma" means that the subject experiences symptoms at least once a week, during the day and/or night, and these symptoms may last from a few hours to several days. In some alternative approaches, persistent asthma is classified as "mild persistent" (e.g., more than twice a week but less than every day, with symptoms severe enough to interfere with daily activities or sleep and/or normal lung function or reversible with bronchodilator inhalation), "moderate persistent" (e.g., symptoms occur daily, with sleep interrupted at least weekly and/or moderately abnormal lung function), or "severe persistent" (e.g., symptoms persist despite the correct use of approved medications and/or lung function is severely affected). Interleukin-4 Receptor Antagonists The methods described in the current explanation involve administering a therapeutic compound containing an interleukin-4 receptor (IL-4R) antagonist to a subject in need. As used here, an "IL-4R antagonist" is any agent that binds to or interacts with IL-4R and inhibits the normal biological signaling function of IL-4R when IL-4R is expressed in vitro or in vivo on a cell. Examples of non-limiting categories of IL-4R antagonists include small molecule IL-4R antagonists, anti-IL-4R aptamers, and peptide-based IL-4R antagonists (e.g., antibody-antigen binding fragments). It refers to immunoglobulin molecules that contain a chain and two light (L) chains, as well as their multimers (e.g., IgM). Each heavy chain contains a heavy chain variable region (abbreviated here as HCVR or VH) and a heavy chain stationary region. Heavy chain fixed zone, 0. It contains three domains: 41 GHz and CH3. Each light chain comprises a light chain variable zone (abbreviated here as LCVR or VL) and a light chain fixed zone. The light chain fixed zone includes an area (CL1). The VH and VL regions can also be subdivided into hypervariability regions, which are called complementarity determination regions (CDRs), nested within more protected regions called frame regions (FRs). Each VH and VL consists of three CDRs and four FRs, arranged from amino-terminus to carboxy-terminus in the following order: FR1, CDR1, FR2, CDR2, FR3, CDR3, FR4. FRs of anti-IL-4R antibody (or the portion thereof that binds to the antigen) in different applications. They may be identical to human germline sequences, or they may be naturally or artificially modified. An amino acid consensus sequence can be identified based on the side-by-side analysis of two or more CDRs. includes. Terms such as "antigen-binding portion" of an antibody, "antigen-binding fragment" of an antibody, and so on, as used herein, include any naturally occurring, enzymatically produced, synthetic, or genetically engineered polypeptide or glycoprotein that specifically binds to an antigen to form a complex. Antigen-binding fragments of an antibody can be derived from whole antibody molecules, for example, using any suitable standard technique such as proteolytic digestion or recombinant genetic engineering techniques, which involve the manipulation and expression of DNA encoding the variable and optionally fixed domains of the antibody. Such DNA is known and/or can be readily obtained or synthesized, for example, from commercial sources, DNA libraries (including phage-antibody libraries). DNA can, for example, arrange one or more variable and/or constant regions in a suitable configuration, execute codons, form cysteine residues, modify, add or delete amino acids, etc. They can be sequenced and manipulated chemically or using molecular biological techniques. Non-restrictive examples of antigen-binding fragments include: (i) Fab fragments; (ii) F(ab')2 fragments; (iii) Fd fragments; (iv) Fv fragments; (v) single-stranded Fv (scFv) molecules; (vi) dAb fragments; and (vii) minimal recognition units consisting of amino acid residues mimicking the hypervariable region of an antibody (e.g., an isolated complementarity determination region (CDR) such as a CDR3 peptide) or a restricted FR3-CDR3-FR4 peptide. Domain-specific antibodies, single-domain antibodies, alani-deleted antibodies, chimeric antibodies, CDR-grafted antibodies, diachords, triochres, tetrachords, minichords, nanochords (e.g., monovalent nanochords, bivalent nanochords, etc.) Other engineered molecules, such as small modular immunopharmaceuticals (SMIPs) and shark variable IgNAR domains, also fall within the scope of the term "antigen-binding fragment". An antibody-binding fragment to an antigen typically contains at least one variable domain. The variable domain can be of any size or amino acid composition and typically contains at least one CDR that is adjacent to or frame-bound with one or more frame sequences. In antigen-binding fragments that have a VH domain associated with a VL domain, the VH and VL domains can be associated with each other in any suitable arrangement. For example, the variable region could be dimeric and contain VH-VH, VH-VL, or VL-VL dimers. Alternatively, the antigen-binding fragment of an antibody may contain a monomeric VH or VL alanine. In some applications, an antibody binding fragment to an antigen may contain at least one variable domain covalently bonded to at least one stable domain. The current description includes non-restrictive, exemplary configurations of variable and constant domains that may be found within an antibody-to-antigen binding fragment, such as: (i) VH-CH1; (ii) VH-CH2; (iii) V-CH3; (iv) VH-CH1-CH2; (v) V-CH1-CHZ-CHS; (vi) VH-CH2-CH3; (xiii) VL-CH2-CH3; and (xiv) VL-CL. In any configuration of variable and fixed fields, including any of the example configurations listed above, the variable and fixed fields may be directly connected to each other or connected by a full or partial hinge or connecting zone. Within a single polypeptide molecule, the adjacent variable and/or fixed sites may consist of one or more (flexible or semi-flexible) amino acids, preferably with a hinge region of 2 to 60, preferably 5 to 50, or preferably 10 to 40 amino acids. Furthermore, the current description suggests that an antibody binding fragment to an antigen may contain a homo-dimer or hetero-dimer (or other multimer) of any of the variable and fixed domain configurations listed above, in a non-covalent relationship with each other and/or with one or more monomeric VH or VL domains (e.g., via disulfide bond(s)). As with complete antibody molecules, antigen-binding fragments can be monospecific or multispecific (e.g., bispecific). A fragment of an antibody binding to a multispecific antigen typically contains at least two distinct variable domains, each capable of specifically binding to a separate antigen or to a different epitope on the same antigen. Any form of multispecific antibody can be adapted for use in the context of an antibody's antigen binding fragment, using routine techniques currently available in the field. The stable region of an antibody is important in its ability to repair complement and mediator cell-dependent cytotoxicity. Therefore, the isotope of an antibody can be chosen depending on whether or not it is desired for the antibody to mediate cytotoxicity. and includes antibodies with fixed regions. The human antibodies highlighted in the current statement may nevertheless contain amino acid residues not encoded by human germline immunoglobulin sequences, for example in CDRs and particularly CDR3 (e.g., mutations introduced in vitro by random or site-specific mutagenesis or in vivo somatic mutations). However, the term "human antibody" does not include antibodies in which CDR sequences derived from the germline of other mammalian species, such as mice, are grafted onto human frame sequences. This includes all human antibodies that are produced, generated, or isolated, such as antibodies expressed using a recombinant expression vector transfected into a host cell (described in detail below), antibodies isolated from a recombinant, combinatorial human antibody library (described in detail below), antibodies isolated from an animal (e.g., a mouse) that is transgenic for human immunoglobulin genes, or antibodies prepared, expressed, generated, or isolated by any other means involving the insertion of human immunoglobulin gene sequences into other DNA sequences. These types of recombinant human antibodies have variable and constant regions derived from human germline immunoglobulin sequences. However, in some applications, these recombinant human antibodies are subjected to in vitro mutagenesis (or in vivo somatic mutagenesis when an animal transgenic for human germline sequences is used), so that the amino acid sequences of the VH and VL regions of the recombinant antibodies, although derived from and related to human germline VH and VL sequences, are sequences that may not naturally exist in the human antibody germline repertoire in vivo. Human antibodies may exist in two forms, which are associated with hinge heterogeneity. In one form, an immunoglobulin molecule contains a stable, four-chain structure of approximately 150–160 kDa, where dimers are held together by an interchain heavy-chain disulfide bond. In a second form, the dimers are not linked by interchain disulfide bonds, forming a molecule of approximately 75-80 kDa consisting of a covalently paired light and heavy chain (half antibody). Separating these forms has been extremely difficult, even after affinity purification. The frequency of occurrence of the second form among various intact IgG isotypes is due to structural differences related to, but not limited to, the hinge region isotype of the antibody. A single amino acid substitution in the hinge region of the human IgG4 hinge can significantly reduce the appearance of the second form to levels typically observed when using a human IgG1 hinge (Angal et al.). (1993) Molecular Immunology 30:105). The current description covers antibodies with one or more mutations in the hinge, CH2, or CH3 region, which may be desirable in production, for example, to improve the yield of the desired antibody form. An "isolated antibody" means an antibody that has been identified and isolated and/or recovered from at least one component in its natural environment. For example, an antibody isolated or extracted from at least one component of an organism or from a tissue or cell in which the antibody is naturally present or naturally produced is, for the purposes of the present invention, an "isolated antibody". An isolated antibody also contains an antibody located in situ within a recombinant cell. Isolated antibodies are antibodies that have undergone at least one purification or isolation step. According to some applications, an isolated antibody may not contain much other cellular material and/or chemicals. This means that the binding fragment can form a complex with an antigen that is relatively stable under physiological conditions. Methods for determining whether an antibody specifically binds to an antigen are well-known in the field and include, for example, equilibrium dialysis, surface plasmon resonance, and similar techniques. For example, an antibody that "specifically binds" IL-4R, as used in the context of the present discovery and as measured in a surface plasmon resonance assay, may bind IL-4R or a portion of it at concentrations of less than approximately 1000 nM, less than approximately 500 nM, less than approximately 80 nM, less than approximately 70 nM, less than approximately 60 nM, less than approximately 50 nM, less than approximately 40 nM, less than approximately 30 nM, less than approximately 20 nM, less than approximately 10 nM, less than approximately 5 nM, less than approximately 4 nM, less than approximately 3 nM, less than approximately 2 nM, less than approximately 1 nM, or less than approximately 0. It includes antibodies that bind to a KD less than 5 nM. However, an isolated antibody that specifically binds human IL-4R may show cross-reactivity with other antigens, such as IL-4R molecules from other (non-human) species. The anti-1L-4R antibodies used for the methods described herein exhibit one or more amino acid substitutions in the framework and/or CDR regions of the heavy and light chain variational regions compared to the corresponding germline sequences from which the antibodies are derived. Such mutations can be easily identified by comparing the amino acid sequences described herein with germline sequences available, for example, from publicly available antibody sequence databases. The present description includes methods involving the use of antibodies and their antigen-binding fragments derived from any of the amino acid sequences described herein, where one or more frameworks and/or one or more amino acids (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acids) within one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10) CDR regions (for tetrameric antibodies) are mutated into the corresponding remnant(s) of the germline sequence from which the antibody is derived, or into the corresponding remnant(s) of another human germline sequence, or into a conservative amino acid substitution of the corresponding germline remnant(s) (such sequence changes are collectively derived from the heavy and light chain variable region sequences described herein). By expelling it, it can readily produce various antibodies and their antigen-binding fragments, containing one or more individual germline mutations or combinations thereof. In some applications, all frame and/or CDR remnants within the VH and/or VL domains are mutated back to remnants found in the original germline sequence from which the antibody was derived. In other applications, only certain remnants, for example, mutated remnants located only within the first 8 amino acids of FR1 or the last 8 amino acids of FR4, or mutated remnants located within CDR1, CDR2, or CDR3, are mutated back into the original germline sequence. In other applications, one or more frame and/or CDR residues are mutated into the corresponding residue(s) of a different germline sequence (i.e., a germline sequence different from the one from which the antibody was originally derived). Furthermore, the antibodies in the current description may contain any combination of two or more germline mutations within the frame and/or CDR regions, for example, where some individual residues are replaced by mutation to the corresponding residue of a specific germline sequence, while other residues that are different from the original germline sequence are preserved or replaced by mutation to the corresponding sequence of a different germline sequence. Antibodies or antigen-binding fragments containing one or more germline mutations, once obtained, may exhibit improved binding specificity, increased binding affinity, improved or enhanced antagonistic or agonistic biological properties (depending on the situation), decreased immunogenicity, etc. It can be easily tested in terms of one or more characteristics, such as these. The use of antibodies and antigen-binding fragments obtained in this general manner falls within the scope of the current explanation. The current description also includes methods involving the use of anti-1L-4R antibodies containing variants of any of the HCVR, LCVR, and/or CDR amino acid sequences described herein, with one or more conservative substitutions. For example, the current description may not relate to any of the HCVR, LCVR, and/or CDR amino acid sequences described herein, e.g., 10 or fewer, 8 or fewer, 6 or fewer, 4 or fewer, etc. This involves the use of anti-1L-4R antibodies containing HCVR, LCVR, and/or CDR amino acid sequences with conservative amino acid substitution. It refers to an optical phenomenon (used by Biacore Life Sciences, a division of Healthcare) that allows for the analysis of real-time interactions by detecting changes in protein concentrations within a biosensor matrix. It refers to an antigenic determinant that interacts with a binding site to a specific antigen within it. A single antigen can have more than one epitope. Therefore, different antibodies can bind to different sites on an antigen and have different biological effects. Epitopes can be conformational or linear. A conformational epitope is generated by spatially adjacent amino acids from different segments of a linear polypeptide chain. A linear epitope is an epitope produced by adjacent amino acid residues within a polypeptide chain. In some cases, an epitope may contain saccharide portions, phosphoryl groups, or sulfonyl groups on the antigen. Preparation of Human Antibodies: Methods for producing human antibodies in transgenic mice are known in the field of technology. Any of these known methods, within the context of the current explanation, could be used to produce human antibodies that specifically bind to human IL-4R. Using VELOCIMMUNETM technology (see, for example, US 6,596,541, Regeneron Pharmaceuticals) or any other known method for producing monoclonal antibodies, chimeric antibodies with high affinity for 1L-4R, containing a human variable site and a mouse constant site, are first isolated. VELOCIMMUNE® technology involves the production of a transgenic mouse with a genome containing human heavy and light chain variable regions functionally linked to endogenous mouse stable region locations, whereby the mouse produces an antibody containing a human variable region and a mouse stable region in response to antigenic stimulation. DNA encoding the variable regions of the antibody's heavy and light chains is isolated and binding computed to DNA encoding the constant regions of the human heavy and light chains. The DNA is then fully expressed within a cell capable of expressing human antibodies. Typically, a VELOCIMMUNE® mouse is challenged with the antigen of interest, and lymphatic cells (such as B-cells) are recovered from mice expressing antibodies. Lymphatic cells are combined with a myeloma cell line to create immortal hybridoma cell lines, and these hybridoma cell lines are then screened and selected to identify those that produce antibodies specific to the antigen of interest. DNA encoding the variable regions of the heavy and light strands can be isolated and bound to the desired isotypic constant regions of the heavy and light strands. Such an antibody protein can be produced within a cell, such as a CHO cell. Alternatively, antigen-specific chimeric antibodies or DNA encoding variable domains of the light and heavy chains can be isolated directly from antigen-specific lymphocytes. Initially, high-affinity chimeric antibodies with a human variable region and a mouse constant region are isolated. Antibodies are characterized using standard procedures known to experts in the field, and affinity, selectivity, epitope, etc. are evaluated. They are selected based on desired characteristics such as these. By replacing mouse fixed sites with a desired human fixed site, a fully human antibody, such as a natural strain or modified IgG1 or IgG4, as highlighted in the present description, is produced. Although the chosen fixed region may vary depending on the specific use, the characteristics of high-affinity antigen binding and target specificity are found in the variable region. In general, antibodies that can be used in the methods of current detection have high affinities when measured by binding to the antigen in solid phase or solution phase, as described above. Mouse fixed regions are replaced with desired human fixed regions to produce fully human antibodies, as highlighted in the current description. Although the chosen fixed region may vary depending on the specific use, the characteristics of high-affinity antigen binding and target specificity are found in the variable region. Within the context of the methods of the current explanation, human antibodies or antibody-antigen-binding fragments that specifically bind 1L-4R include any antibody or antigen-binding fragment containing three heavy-chain CDRs (HCDR1, HCDR2, and HCDR3) located within a heavy-chain variable region (HCVR) with an amino acid sequence selected from groups 258 and 262. It may include three light chain CDRs (LCVR1, LCVR2, LCVR3) located within a single light chain variable region (LCVR). Methods and techniques for identifying CDRs within HCVR and LCVR amino acid sequences are well-known in the field and can be used to identify CDRs within the specified HCVR and/or LCVR amino acid sequences described herein. Examples of conventions that can be used to define the boundaries of CDRs include the Kabat definition, the Chothia definition, and the AbM definition. In general, the Kabat definition is based on sequence variability, the Chothia definition is based on the location of structural cycle regions, and the AbM definition is a middle ground between the Kabat and Chothia approaches. See, e.g., Kabat, "Sequences of Proteins of Immunological Interest," National Institutes of Health, Bethesda, Md. There are also publicly available databases for this purpose. In some applications of the current explanation, the antibody or its antigen-binding light chain variable region amino acid sequence pairs (HCVR/LCVR) include six CDRs (HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDRB). In some applications of the current specification, the antibody or its antigen binding amino acid sequences include six CDRs. In some applications of the current specification, the antibody or its antigen binding amino acid sequences include HCVR/LCVR amino acid sequence pairs. Pharmaceutical Compositions The current description includes methods involving the administration of an IL-4R antagonist to a patient, where the IL-4R antagonist is incorporated into a pharmaceutical composition. The pharmaceutical compounds highlighted in the invention are formulated with suitable carriers, excipients, and other agents that ensure appropriate transfer, distribution, tolerance, and the like. Many suitable formulations can be found in the formulary known to all pharmaceutical chemists: Remington's Pharmaceutical Sciences, Mack Publishing Company, Easton, PA. These formulations include, for example, powders, pastes, ointments, gels, waxes, oils, lipids, lipid-containing vesicles (such as LIPOFECTINTM), DNA conjugates, anhydrous absorption pastes, oil-in-water and oil-in-water emulsions, carbowax emulsions (polyethylene glycols of various molecular weights), semi-solid gels, and semi-solid mixtures containing carbowax. See also Powell et al. According to the methods outlined in the "Compendium of excipients for" explanation, the dose of antibody administered to a patient may vary depending on the patient's age and size, symptoms, health problems, route of administration, and similar factors. The preferred dose is typically calculated based on body weight or body surface area. The frequency and duration of treatment can be adjusted depending on the severity of the health problem. Effective dosages and schedules for the administration of pharmaceutical compounds containing anti-IL-4R antibodies can be determined empirically; for example, patient progression can be monitored through periodic assessments, and the dose adjusted accordingly. Furthermore, cross-species scaling of dosages can be achieved using well-known methods in the field (e.g., Mordenti et al.). , 1991, Pharmaceut. Image. &1351). Various delivery systems, such as lysosomes, microparticles, encapsulation into microcapsules, and recombinant cells capable of expressing mutant viruses (4432), are known and can be used for the application of the pharmaceutical compounds highlighted in the discovery. Application methods include, but are not limited to, intradermal, intramuscular, intraperitoneal, intravenous, subcutaneous, intranasal, intratracheal, epidural, and oral routes. The compound can be administered via any suitable route, e.g., by infusion or bolus injection, into the epithelial or mucocutaneous lining (e.g., oral mucosa, rectal and intestinal mucosa, etc.). It can be administered via absorption and in combination with other biologically active agents. Bulusun is a pharmaceutical compound that can be released subcutaneously or intravenously using a standard needle and syringe. Furthermore, with regard to subcutaneous delivery, a pen-shaped dispensing device for releasing a pharmaceutical compound also has considerable application. Such a pen dispenser can be reusable or single-use. A reusable pen dispenser typically uses a replaceable cartridge containing a pharmaceutical compound. After the entire pharmaceutical compound in the cartridge has been applied and the cartridge is empty, the empty cartridge should be discarded immediately and replaced with a new cartridge containing the pharmaceutical compound. The pen dispenser can then be reused. A single-use pen dispenser does not have a replaceable cartridge. Instead, the single-use pen dispenser comes pre-filled with the pharmaceutical compound, which is held in a reservoir inside the device. The entire device is discarded once the pharmaceutical compound in the reservoir is depleted. In the subcutaneous delivery of a pharmaceutical compound, various reusable pens and auto-injector dispensing devices have a field of application. To name a few, examples include, but are not limited to: AUTOPENTM (Owen Mumford, Inc. , Woodstock, UK), DISETRONICT'V' pen (Disetronic Medical Systems, Bergdorf, Switzerland), HUMALOG MIX 75/25T'V' pen, HUMALOGTM pen, HUMALIN , NOVOPENTM l, II and III (Novo Nordisk, Copenhagen, Denmark), NOVOPEN JUNIORTM (Novo Nordisk, Copenhagen, Denmark), BDTM pen (Becton Dickinson, Franklin Lakes, NJ), OPTIPENTM, OPTIPEN PROTM, OPTIPEN STARLETT'VI, and OPTILCLIKTM (sanofi-aventis, Frankfurt, Germany). To name a few, examples of single-use pen dispensing devices with applications in the subcutaneous delivery of a pharmaceutical compound include, but are not limited to, the following: SOLOSTART'Vl pen (sanofi-aventis), FLEXPENT™ (Novo Nordisk) and KWIKPENT'V' (Eli Lilly), SURECLICK™ Autoinjector (Amgen, Thousand Oaks, CA), PENLET™ (Haselmeier, Stuttgart, Germany), EPIPEN (Dey, L. P. ) and HUMIRATM Pen (Abbott Labs, Abbott Park IL). For direct application to the sinuses, the pharmaceutical components of the drug can be administered using, for example, a microcatheter (e.g., an endoscope and microcatheter), an aerosolizer, a powder dispenser, a nebulizer, or an inhaler. The methods involve administering an IL-4R antagonist in an aerosolized formulation to a subject in need. For example, aerosolized IL-4R antibodies can be administered to treat asthma in a patient. Aerosolized antibodies can be prepared as described, for example, in U88178098. In some cases, the pharmaceutical compound may be released within a controlled-release system. A pump may be used in an application (see Langer, above; Sefton, 1987, CRC Crit.). Ref. Biomed. Eng 14:201). In another application, polymeric materials may be used; see Medical Applications of Controlled Release, Langer and Wise (eds. ), 1974, CRC Press. Boca Raton, Florida. In yet another application, a controlled release system can be placed near the target of the compound, thus requiring only a fraction of the systemic dose (see, for example, Goodson, discussed in the review). Injectable preparations include intravenous, subcutaneous, intracutaneous, and intramuscular injections, drip infusions, etc. It may include dosage forms. These injectable preparations can be prepared using known methods. For example, injectable preparations can be prepared by dissolving, suspending, or emulsifying the antibody or its salt, as described above, in a sterile aqueous medium or an oily medium conventionally used for injections. For injections, aqueous media such as glucose and other excipients, etc. containing an alcohol (e.g., ethanol), a polyalcohol (e.g., propylene glycol, polyethylene glycol), a nonionic surfactant [e.g., polysorbate 80, HCO-SO (addition product of hydrogenated castor oil, polyoxyethylene (50 mol))], etc. Physiological saline is an isotonic solution that can be used in combination with a suitable solubilizing agent. Fatty mediums include, for example, benzyl benzoate, benzyl alcohol, etc. Sesame oil, soybean oil, etc., which can be used in combination with a solubilizing agent. It is used. The injection prepared in this way is conveniently packaged in a suitable ampoule. The pharmaceutical compounds described above for oral or parenteral use are prepared in dosage forms with a single unit dose containing the active substances. Such dosage forms within a single dose include, for example, tablets, pills, capsules, injections (ampoules), suppositories, etc. includes. Examples of pharmaceutical compounds containing an anti-IL-4R antibody that could be used in the context of this invention include, for example, US Patent Application Publication No. According to the methods of current explanation, the amount of IL-4R antagonist (e.g., anti-IL-4R antibody) administered to a subject is generally a therapeutically effective amount. As used herein, "a therapeutically effective amount" means an amount of IL-4R antagonist that produces one or more of the following: (a) a reduction in the incidence of asthma exacerbations; (b) an improvement in one or more asthma-related parameters (as defined elsewhere in this document); and/or (c) a detectable improvement in one or more symptoms or signs of an inflammatory problem of the upper respiratory tract. "A therapeutically effective amount" also includes an amount of IL-4R antagonist that inhibits, prevents, reduces, or delays the progression of asthma in a subject. When it comes to an anti-IL-4R antibody, a therapeutically effective amount might be approximately 600 mg of anti-IL-4R antibody. In some treatments, 300 mg of anti-1L-4R antibody is administered. The amount of 1L-4R antagonist contained in individual doses can be expressed in milligrams of antibody per kilogram of the patient's body weight (i.e., mg/kg). For example, an IL-4R antagonist is given to a patient at a dose approximately 0 times the patient's body weight. It can be administered at a dose between 0.0001 and approximately 10 mg/kg. Combination Therapies: The methods described in the current explanation involve, according to some practices, the administration of one or more additional therapeutic agents to the volunteer in combination with an IL-4R antagonist. As used here, the phrase "in combination with" means that additional therapeutic agents are administered before, after, or concurrently with the pharmaceutical formulation containing the IL-4R antagonist. In some applications, the term "in combination with". This involves the sequential or simultaneous administration of an 1L-4R antagonist and a second therapeutic agent. The current description includes methods to treat asthma or a related health problem or complication, or to reduce at least one exacerbation, including the administration of an IL-4R antagonist in combination with a second therapeutic agent to provide additive or synergistic activity. For example, when administered "before" a pharmaceutical formulation containing an IL-4R antagonist, the additional therapeutic agent may be administered approximately 72 hours, approximately 60 hours, approximately 48 hours, approximately 36 hours, approximately 4 hours, approximately 2 hours, approximately 1 hour, approximately 30 minutes, approximately 15 minutes, or approximately 10 minutes before the administration of the pharmaceutical formulation containing the IL-4R antagonist. When administered "after" a pharmaceutical formulation containing an IL-4R antagonist, the additional therapeutic agent may be administered approximately 10 minutes, approximately 15 minutes, approximately 30 minutes, approximately 1 hour, approximately 2 hours, approximately 4 hours, approximately 6 hours, approximately 48 hours, approximately 60 minutes, or approximately 72 hours after the administration of the pharmaceutical formulation containing the IL-4R antagonist. "Concurrent" administration with a pharmaceutical formulation containing an IL-4R antagonist means that the additional therapeutic agent is administered to the subject in a separate dosage form within a minute (before, after, or simultaneously) of the administration of the pharmaceutical formulation containing the IL-4R antagonist, or that the subject is administered a single combined dosage formulation containing both the additional therapeutic agent and the IL-4R antagonist. Additional therapeutic agents could include, for example, another IL-4R antagonist, or an IL-1 antagonist (e.g., US Patent No. 1). including an IL-1 antagonist as described in US Patent No. 6,927,044), an IL-6 antagonist, an IL-6R antagonist (for example, US Patent No. The anti-IL-6R antibody (identified in 7,582,298) may be a TNF antagonist, an IL-8 antagonist, an IL-9 antagonist, salmeterol or formoterol), an inhaled corticosteroid (e.g., fluticasone or budesonide), a systemic corticosteroid (e.g., oral or intravenous), methylxanthine, nedocromil sodium, cromolyn sodium, or combinations thereof. For example, in some applications, a pharmaceutical compound containing an 1L-4R antagonist is administered in combination with a combination containing a long-acting beta-ase agonist and an inhaled corticosteroid (e.g., fluticasone + salmeterol [e.g., Advair® (GlaxoSmithKline)]; or budesonide + formoterol [e.g., Symbicort® (AstraZeneca)]). Administration Regimens According to some applications of the current statement, multiple doses of an IL-4R antagonist may be administered to a subject over a specified period of time. This type of method involves the sequential administration of multiple doses of an IL-4R antagonist to a subject. As used here, "sequential administration" means that each dose of the 1L-4R antagonist is administered to the subject at a different point in time, for example, on different days separated by predetermined intervals (e.g., hours, days, weeks, or months). The current description includes methods involving the sequential administration of a single initial dose of an IL-4R antagonist to a patient, followed by one or more secondary doses of an IL-4R antagonist and optionally one or more tertiary doses of an IL-4R antagonist. The current description includes methods involving the administration of a pharmaceutical compound containing an IL-4R antagonist to a subject approximately four times a week, twice a week, once a week, every two weeks, every three weeks, every four weeks, every five weeks, every six weeks, every eight weeks, every twelve weeks, or less frequently as long as a therapeutic response is achieved. In some treatments involving the administration of a pharmaceutical compound containing an anti-IL-4R antibody, a dosage of approximately 75 mg, 150 mg, or 300 mg once a week may be used. In other applications involving the administration of a pharmaceutical compound containing an anti-IL-4R antibody, a dosage of approximately 75 mg, 150 mg, or 300 mg every two weeks may be administered. In other applications involving the administration of a pharmaceutical compound containing an anti-IL-4R antibody, a dosage of approximately 75 mg, 150 mg, or 300 mg every three weeks may be administered. In other applications involving the administration of a pharmaceutical compound containing an anti-IL-4R antibody, a dosage of approximately 75 mg, 150 mg, or 300 mg every four weeks may be administered. In other applications involving the administration of a pharmaceutical compound containing an anti-IL-4R antibody, a dosage of approximately 75 mg, 150 mg, or 300 mg every five weeks may be administered. In other applications involving the administration of a pharmaceutical compound containing an anti-IL-4R antibody, a dosage of approximately 75 mg, 150 mg, or 300 mg every six weeks may be administered. In other applications involving the administration of a pharmaceutical compound containing an anti-IL-4R antibody, a dosage of approximately 75 mg, 150 mg, or 300 mg every eight weeks may be administered. In other applications involving the administration of a pharmaceutical compound containing an anti-IL-4R antibody, a dosage of approximately 75 mg, 150 mg, or 300 mg every twelve weeks may be administered. The preferred route of administration is subcutaneous. It preferably refers to a period of (n x 7 days), where "n" specifies the number of weeks, for example 1, 2, 3, 4, 5, 6, 8, 12 or more. It refers to the temporal sequence of its implementation. Therefore, the "initial dose" is the dose administered at the beginning of the treatment regimen (also called the "baseline dose"); "secondary doses" are the doses administered after the initial dose; and "tertiary doses" are the doses administered after the secondary doses. Initial, secondary, and tertiary doses may all contain the same amount of IL-4R antagonist, but they may generally differ in terms of frequency of administration. However, in some applications, the amount of IL-4R antagonist included in the initial, secondary and/or tertiary doses varies during the course of treatment (for example, it can be adjusted up or down depending on the situation). In some applications, two or more doses (e.g., 2, 3, 4, or 1000) are administered as "loading doses" at the beginning of the treatment regimen, with subsequent doses given at less frequent intervals (e.g., "maintenance doses"). In some applications, the maintenance dose may be lower than the loading dose. For example, one or more loading doses containing 600 mg of IL-4R antagonist may be administered, followed by maintenance doses of approximately 75 mg to approximately 300 mg. In an example application of the current statement, it is applied after each secondary and/or 14% or more of (weeks). The phrase "immediately preceding dose" means, in a series of administrations involving multiple doses, the dose of IL-4R antagonist administered to a patient immediately before the next dose in the sequence. Methods may involve administering any number of secondary and/or tertiary doses of an IL-4R antagonist to a patient. For example, in some applications, only a single secondary dose is administered to the patient. In other applications, the patient is given two or more (e.g., 2, 3, 4, 5, 6, 7, 8 or more) secondary doses. Similarly, in some applications, only a single tertiary dose is administered to the patient. In other applications, the patient is given two or more (e.g., 2, 3, 4, 5, 6, 7, 8 or more) tertiary doses. In applications involving multiple secondary doses, each secondary dose can be administered at the same frequency as the other secondary doses. For example, each secondary dose might be administered to the patient 1 to 2 weeks after the dose immediately preceding it. Similarly, in applications involving multiple tertiary doses, each tertiary dose can be administered at the same frequency as the other tertiary doses. For example, each third dose can be administered to the patient 2 to 4 weeks after the dose immediately preceding it. Alternatively, the frequency of secondary and/or tertiary doses administered to a patient may vary during the course of the treatment regimen. Following a clinical examination, the frequency of application can be adjusted by a physician during the course of treatment, depending on each patient's needs. The current description includes methods involving the sequential administration of an IL-4R antagonist and a second therapeutic agent to a patient to treat asthma or a related health problem. In some applications, the methods involve administering one or more doses of an IL-4R antagonist followed by one or more doses of a second therapeutic agent (e.g., 2, 3, 4, 5, 6, 7, 8 or more). For example, after administering one or more doses of approximately 75 mg to approximately 300 mg of an IL-4R antagonist, one or more doses (e.g., 2, 3, 4, 5, 6, 7, 8 or more) of a second therapeutic agent (e.g., an inhaled corticosteroid or a beta2-agonist or any other therapeutic agent described elsewhere in this document) may be administered to relieve, reduce, or improve one or more symptoms of asthma. In some applications, an IL-4R antagonist may be administered in one or more doses (e.g., 2, 3, 4, 5, 6, 7, 8 or more) to achieve improvement in one or more asthma-related parameters, after which a second therapeutic agent may be administered to prevent the recurrence of at least one symptom of asthma. Alternative approaches involve the concomitant administration of an IL-4R antagonist and a second therapeutic agent. For example, one or more doses of an IL-4R antagonist (e.g., 2, 3, 4, 5, 6, 7, 8 or more) are administered, and a second therapeutic agent is administered cyclically. In some applications, the second therapeutic agent is administered before, after, or simultaneously with the IL-4R antagonist. Treatment Populations The methods described in the current explanation involve administering a therapeutic compound containing an IL-4R antagonist to a subject in need. The term "subject in need" means a human or non-human animal exhibiting one or more symptoms or signs of asthma (e.g., eosinophilic asthma, including moderate to severe eosinophilic asthma) or having been diagnosed with asthma. For example, "a subject in need," for example, before treatment, for example, impaired FEV1 (e.g., 2. This may include subjects showing (or having shown) one or more asthma-related parameters such as impaired AM PEF (less than 0 L), an ACQ5 score of at least 1, waking up at least once per night, and/or an SNOT-22 score of at least 20. In various applications, these methods can be used to treat mild, moderate to severe, and severe asthma in patients who need it. In a relevant application, a "subject in need" might be a subject who has been prescribed or is currently using a combination of inhaled corticosteroids (ICS)/long-acting beta-adronergic antagonists (LABA) before receiving an IL-4R antagonist. This includes budesonide/formotorol combination therapy. For example, the current description includes methods involving the administration of an IL-4R antagonist to a patient who has been receiving a regular course of ICS/LABA for two weeks or longer, immediately prior to the administration of the IL-4R antagonist (such prior treatments are referred to here as "background therapies"). The current explanation includes therapeutic methods in which background treatments are discontinued during or immediately before (e.g., 1 day to 2 weeks before) the first administration of the IL-4R antagonist. Alternatively, background therapies may be continued in combination with the administration of an IL-4R antagonist. In other applications, the amount of the ICS component, the LABA component, or both is gradually reduced before or after the start of IL-4R antagonist administration. In some applications, the current description includes methods aimed at treating patients with persistent asthma for at least 212 months. In one scenario, a patient with persistent asthma may be resistant to treatment with a therapeutic agent such as a corticosteroid, and according to current methods, may be administered an IL-4R antagonist. In some applications, a "subject in need" might be a subject with elevated levels of an asthma-associated biomarker. Examples of asthma-associated biomarkers include, but are not limited to, IgE, thymus and its activation-modulating chemokine (TARC), eotaxin-S, CEA, YKL-40, and periostin. In some applications, a "subject in need" might be someone with cervical eosinophils of 2,300/µl or sputum eosinophil levels of 2%. In one study, a "subject in need" might be someone with an elevated level of bronchial or airway inflammation, as measured by fractional exhaled nitric oxide (FeNO). For the purposes of this study, a normal IgE level in healthy subjects is less than approximately 100 kU/L (e.g., ImmunoCAP® assay [Phadia, Inc. (as measured using Portage, MI). Therefore, the current explanation. This involves methods that include selecting a subject showing an elevated serum IgE level, i.e., higher than approximately 100 kU/L, higher than approximately 150 kU/L, higher than approximately 3500 kU/L, higher than approximately 4000 kU/L, higher than approximately 4500 kU/L, or higher than approximately 5000 kU/L, and administering a pharmaceutical compound containing a therapeutically effective amount of an IL-4R antagonist to that subject. TARC levels in healthy subjects ranged from 106 ng/L to 431 ng/L, with an average of approximately 239 ng/L. (An example assay system for measuring TARC levels, developed by R&D Systems, Minneapolis, MN.) No. (TARC is a quantitative ELISA kit offered by DDNOO). Therefore, the current description involves methods involving the selection of a subject showing an increased TARC level, i.e., a serum TARC level higher than approximately 3000 ng/L, higher than approximately 3500 ng/L, and the administration of a pharmaceutical compound containing a therapeutically effective amount of an IL-4R antagonist to that subject. Eotaxin-B belongs to a group of chemokines secreted by airway epithelial cells and is upregulated by the Th2 cytokines IL-4 and IL-13 (Lilly et al.). This includes methods involving the administration of an IL-4R antagonist to treat patients with elevated levels, for example, higher than approximately 100 pg/ml, higher than approximately 150 pg/ml, higher than approximately 200 pg/ml, higher than approximately 300 pg/ml, or higher than approximately 350 pg/ml. Serum eotaxin-3 levels. Periostin is an extracellular matrix protein that plays a role in Th2-mediated inflammatory processes. Periostin levels have been found to be upregulated in asthmatic patients, and treatment methods include the administration of an IL-4R antagonist to treat patients with elevated levels. Fractional exhaled NO (FeNO) is a biomarker of bronchial or airway inflammation. FeNO is produced by airway epithelial cells in response to inflammatory cytokines including IL-4 and IL-13 (Alwing et al.). 1993, Eur Respir J 6: 1368- 1370). In healthy adults, FeNO levels range from 2 to 30 parts per billion (ppb). An example of a determination for the measurement of FeNO can be carried out using a NIOX device from Aerocrine AB, Solna, Sweden. This assessment can be performed before spirometry and at least one hour after fasting. The current description includes methods involving the administration of an IL-4R antagonist to patients with elevated exhaled NO (FeNO) levels, e.g., higher than approximately 30 ppb, higher than approximately 31 ppb, higher than approximately 32 ppb, higher than approximately 33 ppb, higher than approximately 34 ppb, or higher than approximately 35 ppb. Carcinoembryogenic antigen (CEA) is a tumor marker found to be associated with non-neoplastic diseases of the lung (Marechal et al.). 1988, Anticancer Res 8:677-680). Serum CEA levels can be measured using ELISA. Current statement. CEA levels have increased, for example, around 1. Higher than 0 ng/ml, approximately 1. Higher than 5 ng/ml, approximately 2. Higher than 0 ng/ml, approximately 2. Higher than 5 ng/ml, approximately 3. Higher than 0 ng/ml, approximately 4. Higher than 0 ng/ml or approximately 5. This includes methods involving the administration of an IL-4R antagonist to patients with levels higher than 0 ng/ml. YKL-40 [so named because its N-terminal amino acids are tyrosine (Y), lysine (K), and leucine (L), and its molecular weight is 40kD], is measured by ELISA of a chitinase-like sample that has been found to be upregulated and associated with asthma exacerbations, IgE, and eosinophils. The current explanation includes methods involving the administration of an 1L-4R antagonist to patients with elevated YKL-40 levels, e.g., higher than approximately 40 ng/ml, higher than approximately 50 ng/ml, higher than approximately 100 ng/ml, higher than approximately 150 ng/ml, higher than approximately 200 ng/ml, or higher than approximately 250 ng/ml. Induced sputum eosinophils and neutrophils are induced by inhalation of a well-known hypertonic saline solution for airway inflammation and processed for cell counting according to known methods in the technique, e.g., according to the guidelines of the European Respiratory Society. The current explanation refers to individuals with elevated levels of sputum eosinophils, for example, approximately 2%. This includes methods involving the administration of an IL-4R antagonist to more than 5% or more than 3% of patients. Pharmacodynamic Methods for Evaluating Asthma-Related Parameters This description includes methods for evaluating one or more pharmacodynamic parameters related to asthma in a subject in need, following administration of a pharmaceutical compound containing an interleukin-4 receptor (IL-4R) antagonist. A decrease in the incidence of an asthma exacerbation (as described above) or an improvement in one or more asthma-related parameters (as described above) may be associated with an improvement in one or more asthma-related pharmacodynamic parameters; however, such an association is not always established by (a) biomarker expression levels; (b) serum protein and RNA analysis; (c) induced sputum eosinophil and neutrophil levels; (d) exhaled nitric oxide (FeNO₃); and (e) erythrocyte eosinophil count. "An improvement in a pharmacodynamic parameter associated with asthma" means, for example, a decrease in one or more biomarkers such as TARC, eotaxin-3 or IgE, a decrease in sputum eosinophils or neutrophils, FeNO or blood eosinophil count compared to baseline. As used here. With respect to a pharmacodynamic parameter associated with asthma, the term "baseline" means the numerical value of a patient's asthma-related pharmacodynamic parameter before or during the administration of a pharmaceutical compound highlighted in the present discovery. To evaluate a pharmacodynamic parameter associated with asthma, the amount of this parameter is taken at baseline and at a time point after administration of the pharmaceutical formulation of the present discovery. For example, a pharmacodynamic parameter associated with asthma might be 1% of the initial treatment with a pharmaceutical component of the present discovery. week 21. week 22. week 23. week 24. It can be measured after a week or a longer period. The difference between the value of a parameter at a specific time point after the start of treatment and its value at baseline is used to determine whether a change, such as an "improvement" (e.g., an increase or decrease depending on the specific parameter being measured), has occurred in the asthma-related pharmacodynamic parameter. In some applications, administering an IL-4R antagonist to a patient results in a change, such as a decrease or increase in the expression of a particular biomarker. Asthma-associated biomarkers include: (a) total IgE; (b) thymus and activation-regulating chemokine (TARC); (c) YKL-40; and (d) carcinoembryonic antigen in serum (CEA, also known as CEA cell adhesion molecule 5 [CEACAM5]); and (e) eotaxin-3 in plasma. For example, administering an IL-4R antagonist to an asthma patient may lead to one or more decreases in TARC or eotaxin-3 levels, or a decrease in total serum IgE levels. This decrease occurred 1 day after administration of the lL-4R antagonist. week 2. week 3. week 4. weekly, . It can be detected after a week or even longer. Biomarker expression can be determined using methods known in the field. For example, protein levels can be measured using ELISA (Enzyme-Linked Immunosorbent Assay) or RNA levels can be measured using polymerase chain reaction-coupled reverse transcription (RT-PCR). As described above, biomarker expression can be determined by detecting protein and RNA in serum. Serum samples can also be used to monitor additional protein or RNA biomarkers related to treatment with an IL-4R antagonist, IL-4/IL-13 signaling, asthma, atopy, or eosinophilic diseases (e.g., by measuring soluble IL-4R0i, IL-4, IL-13, periostin). In some applications, RNA samples are used to determine RNA levels, for example, the RNA levels of biomarkers (non-genetic analysis); and in other applications, RNA sampling is used for transcriptome sequencing (e.g., genetic analysis). EXAMPLES The numbers used (e.g., quantities, temperature, etc.) While great care has been taken to ensure accuracy, some experimental errors and deviations are to be expected. Unless otherwise specified, parts are parts by weight, molecular weight is mean molecular weight, temperature is in degrees Celsius, and pressure is atmospheric or near atmospheric. Example 1. Production of Human Antibodies Against Human IL-4R US Patent No. Human anti-hlL-4R antibodies were produced as described in 7,608,693. Table 1 presents the sequence identifiers for the selected anti-1L-4R antibodies and their corresponding antibody nomenclatures, including the heavy and light chain variable region amino acid sequence pairs and CDR amino acid sequences. SEQ ID Numbers: Antibody Name HCVR HCDR1 HCDR2 HCDR3 LCVR LCDR1 LCDR2 LCDR3 SEQ ID Numbers: Antibody Name HCVR HCDR1 HCDR2 HCDR3 LCVR LCDR1 LCDR2 LCDR3 The sample IL-4R antagonist used in the following samples is the human anti-IL-4R antibody designated H1H098-b in Table 1 (also referred to as "mAb1" here). Example 2: Clinical Trial Study A of Subcutaneously Administered Anti-IL-4R Antibody (mAb1) in Patients with Moderate to Severe Persistent Eosinophilic Asthma, Including Patients with Chronic Hyperplastic Eosinophilic Sinusitis. Study Objectives and Overview A randomized, placebo-controlled, double-blind, parallel-group study was conducted in patients with moderate to severe persistent eosinophilic asthma that was partially or uncontrolled with inhaled corticosteroid (ICS) and long-acting beta2 agonist (LABA) therapy, administering either 300 mg mAb1 or placebo subcutaneously once weekly for 12 weeks. The primary aim of this study was to investigate the effects of mAb1, administered subcutaneously once weekly for 12 weeks, on reducing the incidence of asthma exacerbations in patients with moderate to severe persistent eosinophilic asthma, compared to placebo. The secondary objectives of the study were to evaluate the safety and tolerability of mAb1 administered subcutaneously once weekly for 12 weeks in patients with moderate to severe persistent eosinophilic asthma, and to assess serum mAb1 concentrations after 12 weeks of once-weekly subcutaneous dosing in patients with moderate to severe persistent eosinophilic asthma. Prior to screening, patients were required to be on a stable dose of any of the following doses and formulations of ICS/LABA combination therapy (also referred to as "background therapy") for at least one month: fluticasone/salmeterol combination therapy; budesonide/formoterol combination therapy (Symbicort® 160/9 µg BID or 320/9 µg BID); or mometasone/formoterol combination therapy (Dulera® 200/10 µg BID). Patients receiving budesonide/formoterol or mometasone/formoterol were switched to an equivalent dose of fluticasone/salmeterol at randomization (1. Patients receiving (day) and fluticasone/salmeterol remained in the same background therapy. Patients meeting the inclusion and exclusion criteria (see below) were randomized to receive either of the following treatments: 300 mg mAb1 administered subcutaneously once weekly for 12 weeks; or placebo administered subcutaneously once weekly for 12 weeks. The study included a 2-week screening period, a 12-week treatment period including a 4-week background therapy stabilization phase, an 8-week background therapy withdrawal phase after randomization, and an 8-week post-treatment follow-up period. Algorithm for withdrawing background therapy (ICS/LABA): Patients remained on BID fluticasone/salmeterol background therapy for 4 weeks after initiating supportive therapy or treatment with 300 mg mAb1 (or placebo). 4th after randomization. Weekly, patients receive either fluticasone/salmeterol combination therapy, fluticasone monotherapy equivalent, or Flovent® HFA. The LABA component (i.e., salmeterol) has been removed. 6. Starting weekly, at subsequent examinations, if the patient does not meet any of the asthma exacerbation criteria (as defined below), the fluticasone dose is reduced by approximately 50%. If no asthma exacerbations occurred, ICS withdrawal was performed according to the following dosing schedule: Background therapy stable phase; Background therapy withdrawal phase 4. Week 6. Week 7. Week 4 Fluticasone/salmeterol (DPI): Fluticasone (DPI): 100 pg 50 pg 0 pg 0 pg Fluticasone/salmeterol (DPI): Fluticasone (DPI): 250 pg 100 ug 50 ug 0 pg Fluticasone/salmeterol (MDI): Fluticasone (MDI): 110 ug 44 pg 0 pg 0 ug Background therapy stable phase Background therapy withdrawal phase Week 6. Week 7. Weekly Fluticasone/salmeterol (MDI): Fluticasone (MDI): 220 µg 110 µg 44 µg 0 µg After completion of 12 weeks of treatment with the investigational product (or after early discontinuation), patients were returned to their original fluticasone/salmeterol, budesonide/formoterol, or mometasone/formoterol doses (dose intake at study entry) and given albuterol or levalbuterol as an out-of-study drug as needed to control symptoms for an additional 8 weeks prior to a final safety assessment. Adult patients were included in the study according to the following criteria: (1) a physician-established diagnosis of persistent asthma lasting at least 2 to 12 months according to the Global Asthma Initiative (GINA) 2009 Guidelines, with likely eosinophilic airway inflammation; and (2) the patient's asthma was partially or not controlled with combination therapy including inhaled corticosteroids/long-acting beta-agonists according to the following criteria: (i) stable dose of fluticasone/salmeterol combination therapy (DPI formulation) for at least 1 month prior to screening; or budesonide/formoterol combination therapy (16019 µg BID); or mometasone/formoterol combination therapy (200/10 µg BID); or 2,300 cells/pl blood eosinophils or 2% sputum during the screening phase. eosinophils; (iii) 2 1 in screening. 5 and 5 3. (iv) Juniper Asthma Control Questionnaire (5-question version, ACQ) score; (v) FEV1 2 50% normal estimate during the screening phase (maximum 3 trials) and on the day of randomization before the first dose (maximum 3 trials); (v) treatment with one or more systemic (oral and/or parenteral) steroids or hospitalization or emergency department visit due to worsening asthma within 2 years prior to screening; and (vi) proven reversibility history during the 12-month screening period meeting the criteria - history of at least positive methacholine forcing after 200 µg to 400 µg (2 to 4 inhalations) of albuterol during the screening phase (PD20 methacholine s 8 mg). Patients with moderate to severe asthma, partially or uncontrolled with moderate to high doses of inhaled corticosteroids and long-acting beta-egonists (ADVAIR®, SYMBICORT®, or DULERA®), and who had 300 or more blood eosinophils per microliter or 3% or more sputum eosinophils during the screening phase, were included in the study. Patients meeting all inclusion criteria were screened for the following exclusion criteria: (1) patients under 18 or over 65 years of age; (2) clinically relevant abnormal laboratory values suggestive of an unknown disease requiring further evaluation; (3) chronic obstructive pulmonary disease (COPD) and/or other lung diseases that impair pulmonary function tests; (4) patients requiring beta-adrenergic receptor blockers for any reason; (5) current smoking or having quit smoking within 6 months prior to screening; (6) history of smoking 10 packs of cigarettes per year; (7) hospitalization or emergency care examination due to asthma exacerbation within 2 months prior to screening; (8) plans to begin allergen immunotherapy during the study period. (9) exposure to another investigational antibody within a time period less than 5 half-lives of the antibody but not less than 30 days prior to screening, or if the half-life of the antibody is unknown, within a time period of at least 6 months prior to screening; (10) previous participation in the current study; (11) the patient being a researcher, a family member of a researcher, or an employee in the research area; (12) known or suspected nonconformity, alcohol or drug use; (13) inability to follow the procedures of the study (e.g., due to language problems or psychological disorders); (14) disruption of sleep patterns (e.g., working night shifts); (15) treatment with medications known to prolong the QTc interval; (16) ICS (e.g., active or inactive pulmonary tuberculosis) or LABA (e.g., diabetes, cardiovascular diseases, hypertension, hyperthyroidism, thyrotoxicosis, etc. (17) use of injectable glucocorticosteroids or oral systemic glucocorticosteroids for more than 3 courses within 2 months prior to screening or within 6 months prior to screening; (18) pre-examination with variable ICS doses alone or with a non-steroidal controller (other than fluticasone/salmeterol combination therapy, budesonide/formoterol combination therapy or mometasone/formoterol combination therapy); (19) patients taking concomitant medications (listed below); (20) known allergy to doxycycline or related compounds; (21) being pregnant or intending to become pregnant during the course of the study, breastfeeding or not wanting to use an effective method of contraception; and (22) recent history of parasitic infection or having traveled to a parasitic endemic area within 6 months prior to screening. Patients remained on a constant dose of background asthma therapy for the first four weeks of the study, after which the dose of background therapy was gradually reduced. First, the long-acting beta agonist component of background therapy is 4. withdrawn in week 12, followed by inhaled corticosteroid dose. Until next week, it was halved every two weeks. Patients continued to receive study treatment until the end of the study or until they withdrew due to an asthma exacerbation or for any other reason. B. Study Treatment Investigation Product: A sterile mAb1 150 mg/mL SC injection solution is provided in a 5 mL glass vial. Each vial contained a 2 mL drawable volume. A dose of 300 mg was administered subcutaneously once a week in the mornings at the study site for 12 weeks. Placebo: Likewise, sterile placebo for SC injection is provided in a 5 mL glass vial. Each vial contained a 2 mL drawable volume. Placebo administered once a week in the mornings at the study site for 12 weeks. Concomitant use of the following drugs was not permitted during the study period: fluticasone/salmeterol combination therapy or any other inhaled steroid other than fluticasone administered according to protocol (or budesonide/formoterol or mometasone/formoterol during the screening period); systemic or ocular steroids; LABAs other than the salmeterol component of fluticasone/salmeterol combination therapy administered according to protocol; any other ICS/LABA combination product other than those listed above; any inhaled anticholinergic agent (e.g., ipratropium bromide and tiotropium); methylxanthines (theophylline, aminophyllines); cromones; anti-IgE therapy, inhibitors. C. Treatment Efficacy The primary endpoint of this study was the occurrence of an asthma exacerbation as defined by any of the following: (1) a 30% or greater reduction in morning peak expiratory flow (PEF) from baseline on two consecutive days; or (2) a 24-hour period (compared to baseline) on two consecutive days. Taking six or more additional puffs of albuterol or levalbuterol to provide relief or (3) an exacerbation of asthma as determined by the investigator requires: (a) systemic (oral and/or parenteral) steroid therapy or (b) a 2-4 fold increase in ICS from the last dose taken before discontinuation of the study or (c) hospitalization. Secondary endpoints of the study included mean changes in the following parameters from baseline: (1) forced expiratory volume in liters per second (FEV1) as measured at each examination; (2) morning and evening peak expiratory flow rate in liters/minute as measured daily (AM PEF and PM PEF); (3) daily Albuterol/Levalbuterol use as inhalations/day; (4) Five-Item Asthma Control Questionnaire (ACQ5) score at each examination; (5) nocturnal awakenings (number per night) as measured daily; and (6) upper airway symptoms assessed at baseline and end of treatment (12th day). The 22-item Sino-Nasal Outcome Test (SNOT-22) is assessed (weekly). Secondary endpoints also included the proportion of patients showing a 30% or greater reduction in morning PEF from baseline on two consecutive days, along with a 24-hour period on two consecutive days showing a reduction in albuterol or other drugs compared to baseline. PEF, ACQ5, asthma symptom scores, nighttime awakenings, and medication use for relief were recorded in an electronic journal. The average of daily nighttime awakenings over the previous 7 days was calculated, with a range of 0-10. Morning and evening asthma symptom scores included unvalidated patient-reported results evaluated on a 5-point Likert scale, with higher scores indicating worse outcomes (Table 2). Patients recorded their general symptom scores twice daily before PEF measurement. Data are described as the average of the 7 days preceding the specified time point (see, for example, Figures 26A and 268). Table 2: Asthma Symptom Score Assessment A) Morning symptom score: 0 = No asthma symptoms, slept well during the night 1 = Sleeped well, but experienced some discomfort in the morning. A) Evening symptom score: 0 = Very good, no asthma symptoms 1 = One episode of wheezing, coughing, or shortness of breath 2 = Multiple episodes of wheezing, coughing, or shortness of breath that do not interfere with normal activities 3 = Wheezing, coughing, or shortness of breath for most of the day that interferes with normal activities to some degree 4 = Very bad asthma. The inability to perform daily activities as usual (D). Adverse Event Monitoring: Safety was assessed throughout the study by monitoring adverse events and serious adverse events. An adverse event (AE) is any undesirable medical event in a subject or clinical trial participant who has received a pharmaceutical product. Therefore, an AE can be any undesirable and unintended sign (including abnormal laboratory findings), symptom, or disease that is temporally associated with the use of a medicinal product, whether or not it is considered to be related to a medicinal (research) product. AEs also include: any worsening of a pre-existing health condition (i.e., any clinically significant change in frequency and/or severity) that is temporally associated with the use of the study drug; abnormal laboratory findings considered clinically significant by the investigator; and any adverse medical events. A Serious Adverse Event (SAE) is any adverse medical event that, at any dose, results in death; is life-threatening; requires hospitalization or prolonged hospitalization; causes persistent or significant disability; is a congenital anomaly/birth defect; or is a significant medical event. E. Statistical methods: For the primary analysis of the proportion of patients experiencing an asthma exacerbation, a logistic regression model was used to compare the SAR group with placebo. This model included durations for treatment and stratification factor (previous ICS/LABA combination therapy dose). The primary analysis was performed according to the modified therapeutic intent (mlTT) population, which included all randomized patients who had received at least one dose of the investigational medicinal product (IMP). A stratified chi-square test was also used to strengthen the primary analysis. For secondary efficacy endpoints, excluding SNOT-22, change from baseline was analyzed using a mixed effects model incorporating a repeated measures (MMRM) approach. This model uses baseline values as response variables at level 12. This included changes up to the next week and treatment factors (fixed effects), stratification factor, examination, treatment-examination interaction, baseline value, and baseline-examination interaction. 12. Statistical inferences regarding treatment comparisons for weekly changes from baseline were derived from a mixed-effects model. The change in SNOT-22 from baseline was analyzed using an analysis of covariance (ANCOVA), and end-of-treatment measures were used to estimate missing data. Pharmacodynamic effects were evaluated post hoc using MMRM models. Because there is only one primary endpoint and analysis, no adjustments for multiples have been made. Safety variables, including laboratory parameters, vital signs, ECG, clinical laboratory observations, and physical examinations, were summarized using descriptive statistics. Demographic and clinical characteristics were summarized using descriptive attributes. Graphs of secondary and pharmacodynamic variables are presented as mean change over time from baseline, with standard error. Comparison of treatment effects obtained from MMRM analyses showed a 12-fold increase compared to baseline. The least squares data for the week is based on the mean change (95% confidence intervals [CI]). F. Results The results observed in all 104 randomized patients who completed or discontinued the treatment phase of the study (out of 491 individuals screened) are summarized below. All randomized patients underwent study treatment and were included in the miTT population. Baseline characteristics are similar across groups. Demographic and clinical characteristics were also similar between the two groups (Table 3). As described above, patients were treated with either 300 mg subcutaneous mAb1 once a week or placebo. The study showed that 86% of patients receiving mAb1 and 86% receiving placebo participated in the treatment period. 51% and 67%. It was completed by 3 of them (Figure 25). The most common reason for discontinuing treatment was lack of effectiveness, occurring more frequently with placebo (212%) than with mAb1 (19%). Table 3. Demographic and Clinical Characteristics at Baseline of Treatment Groups. * Variable Placebo (N = mAb1 300 mg (N 52) = 52) Black or African-American 9 (17. 3) 5 (9. 6) Asian 3 (5. 8) 1 (1. 9) Body mass index Variable Placebo (N = 2 30, number (%) 25 (48. 1) Duration of asthma (years) 26. 9 ± 14. 8. Number of asthma exacerbations in the previous 2 years: 1. 4 ± 1. 3 Previous ICS/LABA combination therapy dose, High Dose 41 (78. 8) Low Dose 11 (21. 2) FEV1 (percentage of estimated value) 72. 0 ± 12. 7 PEF (I/minute) ACQS score 2. 1 ± 0. 5 Asthma symptom score: Daily nighttime awakenings 0. 21 ± 0. 50 Albuterol or levalbuterol inhalations/24 0 ± 1. Eotaxin-3 (pg/ml) after an 8-hour period: 117. 3 ± 349. 2 24 (46. 2) 24. 2 ± 12. 6 1. 4±1. 0 42 (80. 8) (19. 2) 0. 55 ± 0. 19 2. 47 ±0. 65 72. 0 ± 12. 6,393. 0 ± 101. 1 414. 6 ± 102. 3 2. 1±0. 5 0. 75 ±0. 81 0. 92 ±0. 71 0. 44 ± 0. 80. 9 ±14. 8 2. 2 ± 2. 4 37. 6 ± 28. 1,496. 1 ± 342. 4 75. 4 ± 44. 0 657. 7 ± 14823 Variable Placebo (N = mAb1 300 mg (N 52) = 52) *Unless otherwise stated, plus or minus values are mean ± SD. ACQS stands for Asthma Control Questionnaire (5-item version); FeNO stands for fractional exhaled nitric oxide; FEVi stands for forced expiratory volume in 1 second; IgE stands for immunoglobulin E; PEF stands for peak expiratory volume; SNOT-22 stands for 22-item Sinonasal Outcome Test; and TARC stands for thymus and activation-regulating chemokine. (i) Primary Efficacy Endpoint: The incidence of asthma exacerbations in the placebo and mAb1 treatment groups is presented in Table 4. Table 4: Incidence of Asthma Exacerbations in the mITT Population Placebo (N=52) mAb1 (N=52) Patients with Asthma Exacerbations 23 (442%) 3 (58%) A total of 26 asthma exacerbations occurred during the treatment period, and no patients were hospitalized due to asthma exacerbations. In the placebo group, 23 patients (442%) experienced asthma exacerbations, while in the mAb1 treatment group, only 3 patients (58%) experienced asthma exacerbations. Risk level is 0. 077 (p < 0.0001) and relative risk reduction approximately. Of the 26 asthma exacerbations encountered during this study, 9 were considered severe, as determined by the need for emergency intervention based on the pre-event dose of 4 or more solid systemic corticosteroids or inhaled corticosteroids. A summary of the incidence of severe asthma exacerbations is presented in Table 5. Table 5: Incidence of Severe Asthma Exacerbations in the mITT Population Placebo (N=52) mAb1 (N=52) Placebo (N=52) mAb1 (N=52) Patients with Severe Asthma Exacerbation 8 (15.4%) 1 (1.9%) Patients with Mild Asthma Exacerbation 15 (28.8%) 2 (3.8%) As shown in Table 5, eight severe asthma exacerbations were observed in the placebo group, while only one severe asthma exacerbation was observed in the mAb1 treatment group. The remaining 15 asthma exacerbations in the placebo group and 2 in the mAb1 group conformed to the exacerbation definition in the protocol based on decreased morning PEF and/or increased albuterole/levalbuterol use. As shown in Table 6, in the active treatment group, despite steroid withdrawal, sustained improvement in all parameters compared to baseline was observed throughout the course of the study. Table 6. Flare-up Events Outcome Placebo (N = 52) 30% decrease compared to baseline albuteroI/levalbuterol inhalation Systemic steroid treatment 5 (9.6) 1 (1.9) 4-fold increase in ICS compared to previous dose 3 (5.8) 0 Hospitalization 0 0 *4 placebo patients met both PEF and systemic steroid treatment criteria, and 1 placebo patient met both PEF and additional albuteroI/levalbuterol use criteria. In mAb1, the time to exacerbation is longer (Figure 1), and an analysis of the time to asthma exacerbation using the Meier plot compared to placebo revealed that the effect of treatment with mAb1 persisted over time, including after 8 weeks, when patients were at a higher risk of developing an exacerbation due to steroid withdrawal (Figure 1). Only 1 patient in the placebo group experienced a compound asthma event. A compound asthma event is defined as taking 26 additional puffs of albuterol or levalbuterol in a 24-hour period (compared to baseline) on 2 consecutive days, with a 30% or greater reduction in morning PEF from baseline on 2 consecutive days. (ii) Other Efficacy Endpoints At each examination, pulmonary function parameters (FEV1, AM PEF, and PM PEF), asthma symptom-related endpoints (ACQ score, nocturnal awakenings), and albuterol use were assessed for each patient. Observed results (change from baseline) for these parameters are shown in Figures 2-7, respectively. In addition, the SNOT-22 score was assessed at baseline and at the end of treatment. For all parameters, the mean values at baseline and at week 12 (LOCF), along with the mean difference between treatment groups (ANOVA model for SNOT-22), are summarized in Table 7. In Table 7, the column labeled "Difference vs. Placebo" reflects the placebo-corrected value compared to baseline, taking into account the changes observed in the parameter's value in the placebo-treated group. Table 7: Secondary Parameters of Lung Function and Symptom Scores Least Squares Baseline Placebo Mean Change - p Mean (SD) vs. Difference 0.27 (0.11, AM PEF (L/minute) Baseline Least Squares Mean Change (SD) vs. Difference 58.5) PM PEF (L/minute) Baseline Least Squares Mean Change (SD) vs. Difference 22.7 (-0 46.0) Albuterol Use (Puff/Day) Placebo 52 0.7 (0.3) -- 2.2 -2.0 (-2.9, (2.4) 1.2) ACQ Score Night Awakenings (number/night) SNOT22 Mean Score T 51 patients with at least 1 assessment after baseline. 1: 50 patients with at least 1 assessment after baseline. Treatment with mAb1 resulted in a significant change in FEV1 from baseline at week 1, and this effect persisted until week 12, even after withdrawal of LABA and ICS, with a slight decrease in FEV1 at week 5 coinciding with LABA withdrawal (Figure 2). Similar improvements were observed in morning PEF, but less so in evening PEF (Figures 3 and 4). The mean least squares (LS) change in FEV1 from baseline until week 12 was -0.22 L for the placebo group and 0.05 L for the mAb1 group (p=0.0009). ACQ5 scores improved in both treatment groups at week 1 (Figure 6). However, while greater improvement in ACQS scores was achieved with mAb1 between weeks 1 and 4, the placebo effect stabilized, and this difference was maintained until week 12. Morning symptom scores increased with placebo until week 12 compared to baseline. With mAb1, there was an increase that remained below baseline until week 12 (Figure 26A). A similar pattern (with greater variability) was observed for evening asthma symptom scores (Figure 268). Nocturnal awakenings remained stable in the placebo group until week 6, then increased between weeks 6 and 12. In contrast, nocturnal awakenings decreased in the mAb1 group until week 1 and remained at a good level compared to baseline until week 12. Changes in albutero1/ievalbuterol use (Figure 5) were similar to other secondary endpoints: an initial decrease was observed, followed by a return to baseline with placebo. The initial increase with mAb1 was maintained over time. A non-significant difference was observed between SNOT-22 values compared to baseline. The mean weekly LS change was a slight increase of 0.23 points in the placebo group and a mean decrease (improvement) of 8.26 points in the mAb1 group. This represents an improvement magnitude of 8.49 points for the mAb1 group (p=0.0027). Table 8. Secondary Endpoints Outcome Placebo (N mAb1 (N Placebo vs P = 52) = 52) Difference (95% CI)** Value Outcome Placebo (N mAb1 (N Placebo vs P = 52) = 52) Difference (95% CI)** Value 60.2) 2.1) change of 0.1 from baseline to week 12 change of 0.1 from baseline to week 12 Table 9. Change in Upper Respiratory Disease-Related SNOT-22 Items from Baseline to Week 12. SNOT-22 Lower Least Squares Mean P-Score Change ± Standard Error Difference (95% CI) Value *At least 1 in 51 and TSO patients assessed post-baseline, respectively. Measurements at week 12 for all secondary endpoints, except evening PEF and nocturnal awakenings, were significantly in favor of mAb1 treatment (Tables 7 and 8). Significant improvements were observed with mAb1 in all three SNOT-22 items related to upper airway disease (Table 9). (iii) Safety mAb1 is generally safe and well tolerated. Treatment-associated adverse events (TEAEs) were reported similarly in patients treated with placebo (769%) and 42 patients treated with mAb1 (808%) (Table 10). TEAEs were non-specific and generally mild to moderate in severity, with most resolving by the end of the study. An increase in the reporting of the following TEAEs was observed for mAb1 compared to placebo: injection site reactions were reported in 15 (28.8%) mAb1 patients and 5 (96%) placebo patients; nasopharyngitis was reported in 7 (135%) mAb1 patients and 2 (3.8%) placebo patients; headache was reported in 6 (115%) mAb1 patients and 3 (5.85%) placebo patients; and nausea was reported in 4 (77%) mAb1 patients and 1 (19%) placebo patients. Table 10. Adverse Events. Adverse Event Placebo (N = 52) Number of patients (%) Any serious adverse event 3 (5.8) 1 (1.9) Termination of study due to adverse event 3 (5.8) 3 (5.8) Most common AEDs* Injection site reactions 5 (9.6) 15 (28.8) Nasopharyngitis 2 (3.8) 7 (13.5) Upper respiratory tract infection 9 (17.3) 7 (13.5) Headache 3 (5.8) 6 (11.5) Arthropod bite 0 3 (5.8) Muscle spasms 0 3 (5.8) Nasal congestion 1 (1.9) 3 (5.8) Rash 1 (1.9) 3 (5.8) Urticaria 0 3 (5.8) Adverse events Placebo (N = mAb1 300 mg (N = 52) Number of patients (%) Viral upper respiratory tract infection 0 3 (5.8) * 2 3 patients in any treatment group according to Preferred Term Injection site reaction includes events reported as follows: pain at injection site, reaction at injection site, erythema at injection site, rash at injection site, hematoma at injection site, urticaria at injection site, dermatitis at injection site, inflammation at injection sites, nodule at injection site, pruritus at injection site and swelling at injection site. No deaths were reported during the study period. Among the 4 reported treatment-induced serious adverse events (SAEs): 1 mAb1 patient experienced bipolar disorder, and 3 placebo patients experienced pneumonia and asthma, gunshot wound with left pneumothorax, and right ankle fracture. None of the SAEs were considered related to IMP, and all, except for the recent ankle fracture, resolved by the end of the study. No deaths occurred. A total of 6 patients discontinued the study due to TEAEs: 3 patients in the mAb1 group (bipolar disorder, asthma with wheezing, and angioedema) and 3 patients in the placebo group (upper respiratory tract infection, psoriasis, and asthma). Angioedema, a TEAE, occurred in a 42-year-old African-American woman following the ninth study treatment dose, presenting as a pruritic, papular rash at and away from the injection site. This lasted for one week and resolved after discontinuation of study treatment and treatment with prednisolone and diphenhydramine. This was considered treatment-related. This AE followed milder rashes at the injection site after the first and sixth study treatment doses. Among the most common AEs (Table 10), occurring in 23 patients in any treatment group, injection site reactions, nasopharyngitis, nausea, and headache occurred more frequently in mAb1 compared to placebo. No clinically significant changes were reported in any vital signs, physical examination, clinical laboratory, or ECG findings in any group. G. Results Significant improvements were observed in lung function and other asthma control parameters. Efficacy was observed early and persisted despite withdrawal of background therapy. Clinically significant and statistically significant (without multiple adjustment) improvements were observed in approximate lung function parameters (FEV1, PEF AM), asthma symptom scores (ACQ), and albuterol use in patients with moderate to severe persistent eosinophilic asthma after 12 weeks of treatment with 300 mg mAb1 once weekly (58%) compared to placebo (442%). A statistically significant improvement (without adjusting for multiples) was also observed in the SNOT-22 score. In the active treatment group, despite withdrawal of LABA and ICS, sustained improvement in all parameters compared to baseline was observed throughout the study. mAb1 is generally safe and well tolerated. Example 3: Biomarker studies Biomarker analysis was performed on samples taken from subjects participating in clinical trials of mAb1 (see Example 2 above). Specifically, serum/plasma biomarkers associated with TH2 inflammation, such as thymus and activation chemokine (TARC, CCL17), immunoglobulin E (IgE), eotandaxin-S, periostin, carcinoembryonic antigen (CEA), YKL-40, and blood eosinophils, were measured in samples taken from patients at baseline and at different time points after the initiation of study treatment(s). Baseline levels of these biomarkers were considered as potential predictors of treatment response. In addition, fractional exhaled NO (FeNO) and induced sputum eosinophils and neutrophils were also measured as biomarkers of bronchial inflammation. Exhaled nitric oxide was assessed using a NIOX device (Aerocrine AB, Solna, Sweden) prior to spirometry and after at least 1 hour of fasting. Biomarkers were analyzed using a mixed model, and the least squares mean derived from the model is reported below. Asthma subjects (N=104) were administered either mAb1 (300 mg) or placebo subcutaneously (see Example 2 here). Samples for biomarker analysis were collected from subjects treated with antibody and placebo at weeks 0, 1, 4, 8, and 12. Antigen-specific IgE was detected using the Phadiat0p® test. TARC, eotaxin-3, and IgE remained unchanged in response to placebo (Figures 8, 9, and ). In contrast, in patients treated with mAb1, TARC levels responded within one week of exposure to 300 mg of subcutaneously administered mAb1 (mean and persisted until week 12: TARC: -26.0% vs. +7.6% in placebo). TARC levels plateaued at approximately 50% of baseline in mAb1-treated subjects despite withdrawal of ICS. The data suggest that TARC expression is more directly dependent on IL-4R signaling than on FEV1 changes (which decrease in parallel with ICS withdrawal [after week 4]), and that IL-4R blockade induces a shift towards a TH1 signature, as observed, for example, with IFN-gamma administration. In patients requiring long-term treatment and those at risk for TH1-type immunodeficiency disorders, titration of the mAb1 dose using TARC (and e.g., CXCL10) may be possible. Total serum IgE also decreased following mAb1 treatment. Compared to the TARC response, the total serum IgE response was more heterogeneous and delayed. The mean (SD) baseline was 206.15. Despite this heterogeneity, a trend towards IgE decrease was observed in patients exposed to mAb1 compared to placebo, starting only at week 4. Serum IgE continued to decrease from week 4 to week 12 in the mAb1 group compared to placebo (mean % change, baseline for FeNO, TARC, eotaxin-3 and IgE). All changes at week 12 compared to placebo were in favor of mAb1 (all in P). <0.001) (Table 11). No difference was observed between YKL-4O or CEA compared to baseline or between treatments. Table 11. Percentage Change in Pharmacodynamic Endpoints at Week 12 from Baseline. Least Squares Mean Percentage Change ± Result Standard Error P Placebo (N = 52) mAb1 (N = 52) eosinophils There was a transient decrease in periostin levels followed by an increase upon withdrawal of LABA/ICS (Figure 11). Administration of mAb1 delayed the increase but did not prevent it from exceeding baseline. No consistent therapeutic effect was observed with CEA (Figure 12) and YKL-4O (Figure 13). Blood eosinophil counts remained unchanged until week 6, but then increased at weeks 8 and 12 (Figure 14). In the placebo group, peripheral blood eosinophil counts remained unchanged throughout treatment. The difference between treatments was not statistically significant, with borderline increases due to higher blood eosinophil increases in only a few patients treated with mAb1. Most patients experienced little or no increase (Table 12). Table 12. Change in Eosinophils in Patients Obtaining Thresholds for Changes in Blood Eosinophil Levels Number of Patients (%) Change in Eosinophils Number of Patients (%) 200% increase 0 4 (9.1) Since only 3 mAb1 patients experienced asthma exacerbations during the study, no conclusion could be drawn about the relationship between baseline biomarker levels and asthma exacerbations. mAb1 treatment was also associated with a significant decrease in FeNO at week 4 compared to baseline, and despite withdrawal of ICS, FeNO remained below baseline until week 12 (mean % change at week 12: -28.7 for mAb1 and remained stable until week 12, followed by an increase coinciding with withdrawal of ICS at week 12). Improvement in forced expiratory volume in 1 second (FEV1) and improvements in AM-PEF and PM-PEF at week 12 were associated with the decrease in FeNO (Figures 17 and 18). Other correlations with FeNO were not significant. See Table 13. Table 13. Correlation between FEV1 and PD endpoints. Result Correlation P Value Eotaxin-3 -0.146 0.34 Blood eosinophils 0.165 0.28 Scatter plot analysis of baseline eosinophils versus change in FEV1 at week 12 relative to baseline did not suggest a relationship between baseline eosinophils and treatment effect, as measured by the change in FEV1 at week 12 relative to baseline in the study population (baseline eosinophils 2 0.3 Giga/L) (Figure 19). Baseline eosinophils were correlated with a decrease in ACQ (Figure ) and a decrease in albutero1/levalbuterol use (Figure 21). Baseline periostin and YKL-40 were correlated with a decrease in ACQ (Figures 22 and 23). Reversal of ICS, baseline According to baseline, it negatively affected the change in FEV1 at week 12 (from week 4 onwards). Similar analyses did not suggest a relationship between baseline TARC or IgE and the change in FEV1 at week 12 in the study population (baseline eosinophils 20.3 Brief Description These results demonstrate that mAbi significantly reduces serum biomarkers associated with Th2 inflammation (TARC, eotaxIn-B, and IgE) and bronchial inflammation (FeNO) in adult asthma patients. The correlation between the decrease in FeNO and the improvement in FEV1 suggests a relationship between IL-4/IL-13-mediated anti-inflammatory activity and improved lung function in moderate to severe, uncontrolled asthma. This suggests. Example 4: Blockade of the IL-4/IL-13 Signaling Pathway Inhibits IgE Production and Airway Remodeling in a Mouse Model of House Dust Mite-Induced Eosinophilic Asthma. House dust mite allergen (HDM) has been shown to induce the Th2 immune response, including the influx of Th2 cells into the lungs and the IL-4-induced trans-endothelial migration of eosinophils into the lungs. Eosinophils are the dominant effector cells in allergic reactions, and the release of granule content (including IL-4) from eosinophils contributes to inflammation. In asthmatic patients, Th2-driven production of IL-4 promotes inflammatory eosinophil migration from the blood to the lungs via eotoxin, a potent eosinophil chemoattractant. When localized in the region, they produce and release IL-4, thus contributing to ongoing Th2-driven inflammation (Bjerke et al., Respi'r. Med., 1996, 90(5):271-277). In patients with allergic asthma, a challenge with HDM increased serum IgE levels and Th2 cytokines for up to 5 weeks after allergen challenge. In this example, an HDM-induced model of chronic asthma was used to evaluate the pharmacodynamic effects of anti-IL-4R antibodies on markers of airway inflammation in mice. Furthermore, the effects of anti-IL-4R antibodies on collagen deposition in the airways were also evaluated in this model, as collagen deposition is correlated with the degree of airway remodeling. MATERIALS AND METHODS In the experiments of this example, two different anti-IL-4R antibodies were used. The following antibodies were used: "mAb1", a fully human monoclonal antibody specific for human IL-4R0i (i.e., the anti-IL-4R antibody used in other study examples presented here), and "anti-mIL-4R0i", a mouse monoclonal antibody specific for mouse IL-4R0i protein. mAb1 does not cross-react with mouse IL-4R0i; therefore, mAb1 was evaluated in humanized mice, where both the ecto domain of human IL-4 and IL-4Rd were engineered to substitute the corresponding murine sequences in mice (IL-4"U/hu IL-4R0ihulhu). On the other hand, the mouse anti-mouse IL-4R0i antibody "anti-mIL-4R0i" was tested in wild-strain (BaIb/c) mice. In these experiments, it also demonstrated activity as a pseudoreceptor. A mouse IL-13R0i2-mFc fusion protein, which blocks IL-13 signaling through cytokine sequestration, was also tested. For the HDM-induced asthma model, mice were sensitized with daily intranasal HDM administration (50 pg per mouse in 20 pL PBS) for 10 days and then rested (2-week weaning period). Allergen challenge was administered with intranasal HDM administration (50 pg per mouse in 20 pL PBS) three times a week for 8 weeks. For each administration of HDM, during the sensitization or challenge period, mice were mildly anesthetized with isoflurane. Mice were acclimatized to the experimental facility for a minimum of 5 days prior to the start of the experimental procedure. For the entire duration of the experiment, animals were kept in the experimental facility under standard conditions within a 12-hour day/night cycle. The animals were housed and allowed access to as much water and food as they wanted. The number of mice in each cage was limited to a maximum number. A total of 48 humanized mice were used for two experiments, in which human IL-4 Iigandi and IL-4R0i were engineered to substitute corresponding murine sequences on the human ecto-domain (IL-4m'/hu IL-4Rdhu/""). In one experiment, IL-4""/hu IL-4R0im'/hu mice were used in a mixed strain of 20 wild-strain mice with the same mixed background. In each experiment, mice were sensitized daily with HDM (or PBS in the control group) for ten days, followed by a dissociation period from day 11 to day 29. From day 30 to day 81, the animals were fed three times a week for 8 weeks. The mice were forced with HDM and then euthanized on day 85 for analysis. The mice were divided into six experimental groups as follows: (1) Unsensitized, untreated: PBS was administered intranasally during sensitization and forcing periods. Mice were not treated with antibodies (IL-4hu/hu IL-4R0ihu/hu mice ri = 9; natural strain consorts n = 5); (2) HDM-walled, untreated: HDM was administered intranasally during sensitization and forcing periods. Mice were not treated with antibodies (IL-4hulhu IL-4R0ihulhu mice n = 7; natural strain consorts n = 5); (3) HDM-walled and treated with anti-mIL-4Rd: During sensitization and coercion periods, HDM was administered intranasally. Mice were injected with anti-mIL-4R0i i.p. at a dose of 50 mg/kg twice weekly from week 7 to week 12 for a total of 12 doses over a 6-week period (natural strain consorts n = 5); (4) HDM sensitized, anti-human mAb1 treated: During sensitization and coercion periods, HDM was administered intranasally. Mice were injected with mAb1 i.p. at a dose of 50 mg/kg twice weekly from week 7 to week 12 for a total of 12 doses over a 6-week period (IL-4R0i mice n = 12); (5) HDM (6) HDM-walled mice treated with isotype control antibody: HDM was administered intranasally during sensitization and coercion periods. Mice were injected with IL-13R02-mFc i.p. at a dose of 25 mg/kg twice weekly from week 7 to week 12 for a total of 12 doses over a 6-week period (IL-4hu/hu IL-4Roihu/hu mice n = 7; natural strain consorts n = 5); HDM-walled mice treated with isotype control antibody: HDM was administered intranasally during sensitization and coercion periods. Mice were injected with IL-13R02-mFc i.p. at a dose of 25 mg/kg twice weekly from week 7 to week 12 for a total of 12 doses over a 6-week period. Isotype control antibodies were injected intraperitoneally at a dose of 50 mg/kg (IL-4hu/hu IL-4R(Jh"/hu mice n = 7). Mice were euthanized on day 85, blood was collected for serum immunoglobulin level determination, and lung (one lobe) was used to produce a sample for i) bronchoalveolar lavage (BAL) fluid, ii) a digested single-cell suspension sample for flow cytometry analysis, iii) a fixed formalin sample for staining and histological analysis, or iv) a sample for analysis using the Sircol™ Collagen Assay to determine the amount of collagen content in each lung lobe. BAL fluid was obtained from euthanized animals by first opening the trachea and inserting a 23G lavage tube into the tracheal wall through a small incision. Subsequently, sterile PES (1 mL) was injected into the lungs, and BAL fluid was recovered from the lavage tube using a syringe. 100 µL of BAL was loaded onto a cytospin, and this cytospin was spun at 500 rpm for 5 minutes to extract the cells onto microscope slides. The slides were dried, and H&E staining was performed to visualize eosinophils. Briefly, serially diluted serum samples were incubated with anti-IgE capture antibody on 96-well plates, and IgE was detected with biotinylated anti-mouse IgE secondary antibody. Purified mouse IgE, which was interacted with HRP, was used as a standard. The quantification of serum IgE levels specific to HDM was determined by ELISA. In short, plates coated with HDM were serially incubated with diluted serum samples, followed by incubation with anti-mouse IgG1-HRP-conjugated antibody. Relative levels of IgG1 serum were represented as titer units (OD450 multiplied by a dilution factor required to obtain OD450 S 0.5). The collected lung tissue was stored at 80°C. To extract collagen, the lung tissue was homogenized in ice-cold NaCl/NaHCO3 solution and centrifuged at 9000xg for 10 minutes. This step was repeated three times, and the resulting pellet was digested with pepsin in acetic acid at 4°C for 18 hours. Samples were centrifuged, the supernatant collected, and mixed with Sircol Dye Reagent for staining collagen content. To remove unbound Sircol dye, samples were washed with Acid-Salt Wash Reagent and then mixed with Alkaline Reagent. 200 µL from each sample was transferred into a 96-well plate, and the OD was measured at 555 nm. A collagen standard was used to determine the final amount of collagen content in each sample. Lungs were obtained from euthanized mice and kept in complete DMEM medium on ice until digested with a collagenase and DNase mixture in HBSS buffer at 37°C for 20 minutes. Collagenase activity was stopped by the addition of 0.5M EDTA, samples were centrifuged, and red blood cells were lysed with ACK buffer. Cell suspensions obtained for each sample were divided into three separate pools and stained with antibody mixture 1 (anti-CD11c-APC Ab, anti-SiglecF-PE Ab, anti-F) or mixture 2 (anti-CDlic-APC Ab, anti-CD11b-PerCp-Cy5.5 Ab, anti-CD103-FITC Ab, anti-MHCll-PE Ab) or mixture 3 (anti-CD19-PE Ab, anti-LyGG-APC Ab, anti-CD3-FITC, anti-CD11b-PerCp-Cy5.5 Ab) for 25 minutes at 4°C. The stained cells were fixed in Cytofix/Cytoperm solution for 30 minutes at 4°C and stored in PBS until flow cytometry analysis with FACSCanto (BD Biosciences). For microdetermination analysis of gene expression using GeneChip® technology, each group was prepared. Left lung lobes were collected from 4 mice in a chronic model of eosinophilic asthma (EA) induced by HDM. Gene expression levels in mice sensitized and challenged with HDM and subsequently treated with an isotype control antibody were compared to gene expression levels in mice sensitized and challenged with a mock (PBS) antibody and not treated with antibodies. The threshold for a change in gene expression was set at 1.5-fold. The population of genes found to be differentially expressed in mice sensitized and challenged with HDM was then analyzed in more detail in the group treated with anti-IL-4R0i compared to the group treated with isotype control. The threshold for a change in gene expression was set at 2-fold in the group treated with IL-4R0i-Ab compared to the group treated with isotype control. RESULTS HDM Sensitization and coercion of HDM resulted in increased levels of IgE and HDM-specific IgG1. The increase in IgE was completely blocked by both anti-IL-4R01 antibodies but not by IL-13R02-Fc treatment (Figures 27A and 278); HDM-specific IgG1 levels were unaffected by any treatment (data not shown). HDM sensitization and coercion also led to an increase in collagen content in the lungs of mice. Collagen content in the lungs of mice treated with both IL-4R01 antibodies and IL-13R02-Fc protein was reduced to levels observed in mice sensitized and coerced with sham treatment (Figures 28A and 288). Additionally, mAb1 treatment led to an increase in collagen content in the lungs. It prevented the flux of eosinophils, neutrophils, and inflammatory dendritic cells (Figure 29, Panels A and B). Microarray analysis of mRNA isolated from lung tissue of HDM-induced IL-4hulhu IL-4Roi""/hu mice treated with an isotype control antibody revealed differential expression of 1468 genes (826 upregulated and 642 downregulated) compared to mice sensitized and challenged with sham treatment. Treatment of HDM-induced IL-4h"/hu IL-4R0i hLi/hu mice with mAb1 resulted in expression changes in only 521 genes (compared to mice sensitized/challenged with sham treatment), compared to HDM-induced mice. It effectively blocked approximately 65% of the genes affected by sensitization/stressing (1.5-fold change, p < 0.05). <0.05). Of particular interest is that mAb1 mediates the downregulation of the specific expression of various members of the IL-1 cytokine family. IL-1β gene expression was not increased in the HDM-induced, isotype-controlled group (compared to mice sensitized with sham treatment), but was decreased (1.5-fold) in the mAb1-treated group. Gene expression of the Th1 inflammatory cytokines IL-12β and lFN-γ was also downregulated by mAb1 compared to the isotype-controlled group. Remarkably, eight genes encoding chemokine ligands involved in cell homing and trafficking were downregulated in the mAb1-treated group compared to the isotype-controlled group: Ccl11 (~9-fold decrease), Ccl8 and Cxcl2 (~5-fold decrease in both), Cxcl1, Ccl7, Ccl1 (~3-fold decrease in all), Ccl2 and Ccl9 (approximately 2-fold decrease). RESULTS This example demonstrates that blocking IL-4 signaling via Type I and Type II receptors by anti-IL-4R0i antibodies suppresses inflammatory and fibrotic changes in the lungs of HDM-stressed mice, as well as HDM-driven gene signature alterations. Other applications are in the works.

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