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 TO TREAT ASTHMA BY ADMINISTRING AN IL-4R ANTAGONIST OR METHODS TO PREVENT FIELD OF THE INVENTION The present invention relates to the treatment and/or prevention of asthma and related health problems.

More specifically, this invention provides an interleukin-4-receptor (lL-4R) It is about its application to treat or prevent asthma in the patient.

INFRASTRUCTURE Asthma, respiratory hypersensitivity, acute and chronic bronchoconstriction, respiratory tract A chronic inflammatory disease of the airways characterized by edema and mucus obstruction. is the disease. The inflammatory component of asthma is affected by mast cells, eosinophils, T lymphocytes, including neutrophils, epithelial cells and their biological products It is thought to contain the cell type. Patients with asthma often experience wheezing, shortness of breath, It shows symptoms of cough and chest tightness. In most asthma patients, a check-up therapy regimen and bronchodilator therapy provide adequate long-term control. inhaled corticosteroids (ICS) as the “gold standard” for controlling asthma symptoms are accepted and inhaled betaZ-agonists are the most effective bronchodilators currently available. Studies have included a combination of an ICS and an inhaled long-acting beta2-agonist (LABA). combination therapy improved asthma compared to higher doses of ICS alone He showed that he had control. As a result, combination therapy alone However, 5% to 10% of the asthmatic population use anti-inflammatory and Despite maximum recommended treatment with combinations of bronchodilator drugs, It is estimated that he has symptomatic disease. Moreover, this severe asthma population; through hospital admission, use of emergency rooms, and unscheduled physician visits. It accounts for up to 50% of the total health cost. This There is an unmet need for a new treatment in the severe asthma population as this Many patients are vulnerable to ICS due to a number of cellular and molecular mechanisms. It answers. Additionally, systemic and inhaled corticosteroids have been shown to cause bone damage in children. long-term adverse effects on metabolism, adrenal function and growth, paving the way for initiatives to minimize the amount of corticosteroid use It is opening. The majority of asthma patients do reasonably well with current treatments. Although maintained, patients with severe corticosteroid refractory asthma There are few therapeutic treatment options that can adequately control the condition.

The consequence of not responding to or adhering to therapy is poor asthma control. loss and, as a result, exacerbation of asthma.

One of the reasons for the poor response to medication in some patients with severe asthma is There may be heterogeneity of the disease. There is increasing interest in understanding these different phenotypes, because targeted therapy is used in patients with similar underlying pathobiological features. The therapy is more likely to be successful. New therapeutic approaches in asthma. T It focuses on trying to control the helper cell-2 response. Interleukin-4 Upregulation of (IL-4) and interleukin-13 (IL-13) is associated with asthma. It has been shown that there is an important inflammatory component to its progression.

J. Corren et al. ("A Randomized, Control/ed, Phase 2 Study of AMG 317, an IL-4R Antagonist, in Patients with Asthma", AMERICAN JOURNAL OF RESPIRATORY AND 796), a human monoclonal antibody against IL-4Ralpha AMG 317 in the treatment of asthma. describes a phase II study in which subcutaneous injection was administered once a week for 12 weeks. in the number of exacerbations in patients taking 150 mg and 300 mg AMG 317 It was noted that there was a decrease in the time until exacerbation.

Accordingly, new targeted techniques are available in the art for the treatment and/or prevention of asthma. therapies are needed.

BRIEF DESCRIPTION OF THE INVENTION According to one aspect of the present invention, preventing asthma exacerbations in a subject in need Pharmaceutical compositions are provided for use in reducing the incidence.

In a related aspect, a subject in need may have one or more asthma-related symptoms. pharmaceutical compositions for use in improving the parameter(s) is provided. In yet another aspect of the present invention, in a subject in need, pharmaceutical compositions to treat asthma, such as moderate to severe eosinophilic asthma is provided.

Pharmaceutical compositions for the uses set forth in the invention include an interleukin-4 It contains a therapeutically effective amount of a receptor (IL-4R) antagonist. binding fragment and the heavy chain variant of SEQ 1D NO: 162 and 164, respectively. heavy chain and light chain regions (HCVR) and light chain variable region (LCVR) chain (complementarity determining region) contains CDR sequences. In the context of the present invention Exemplary anti-IL-4R antibodies that may be used include study Example 1 are described elsewhere in this document.

In one embodiment, a subject suffering from persistent asthma has one or more asthma symptoms. A pharmaceutical composition for use in reducing the incidence of exacerbations of is provided. An asthma exacerbation may be caused by one or more of the following: (a) 30% of baseline in morning peak expiratory flow (PEF) on two consecutive days or greater decrease; (b) on two consecutive days over a 24-hour period (baseline six or more doses of albuterol or Ievalbuterol to provide relief purchasing additional puffs; and (c) a worsening of asthma requires: (i) systemic (oral and/or parenteral) steroid therapy or (ii) taken before discontinuation of therapy. increase of at least 4 times the last inhaled corticosteroid dose or hospitalization.

In another embodiment, a subject suffering from persistent asthma has an asthma-related or A pharmaceutical for use in improving more parameters combination is provided, where the improvement in asthma-related parameters is It is defined as one of: an increase in FEV1 relative to baseline; to baseline an increase in AM PEF relative to an increase in PM PEF relative to baseline; relative to baseline a decrease in the use of albuterol/evalbuterol; night relative to baseline a decrease in arousals; and/or a SNOT-22 score relative to baseline reduction. Examples of asthma-related parameters include the following: (a) 1 forced expiratory volume per second (FEV1); (b) morning PEF (AM PEF) and evening PEF peak expiratory flow rate (PEF), including (PM PEF); (c) albuterol or Questionnaire (ACQ5) score; (d) night awakenings; and (e) 22-item Sino-Nasal Outcome Test (SNOT-22) score. In this application, improvement in an asthma-related parameter selected from the following: an increase in FEV1 of at least 0.10 L from baseline; an increase in AM PEF of at least 10.0 L/min from baseline; relative to baseline An increase in PM PEF of at least 1.0 L/minute; albuterol/Ievalbuterol relative to baseline decrease in use by at least 1 puff(s) per day; highest ACQ5 score compared to baseline a decrease of at least 0.5 points; at least 0.2 per night in night awakenings compared to baseline a one-time reduction; and an increase of at least 5 points in the SNOT-22 score from baseline This finding also provides relief from asthma exacerbations in a subject suffering from persistent asthma. in reducing the incidence of or one or more asthma-related parameter(s) It also provides pharmaceutical compositions for use in achieving healing. wherein the use is an IL-4R antagonist (an anti-IL-4R antibody or A single initial dose of a pharmaceutical composition containing followed by one or more secondary effects of the pharmaceutical composition containing the IL-4R antagonist. It involves the sequential administration of doses to a subject in need. lL-4R The pharmaceutical composition containing the antagonist is administered to the subject in need subcutaneously, intranasally or Can be administered intravenously.

According to some embodiments, the invention prevents asthma exacerbations in a subject in need. in reducing the incidence of or one or more asthma-related parameter(s) provides pharmaceutical compositions for use in achieving healing, The use herein is binding to an antibody or antigen that specifically binds to IL-4R. A sample of approximately 75 to approximately 300 mg of the pharmaceutical composition Containing the fragment includes implementation. According to this aspect, the pharmaceutical composition may be administered, for example, once a week. can be administered to the subject with dosing frequency.

The present description also includes one or more symptoms or signs of asthma. Selecting a subject who shows signs of infection and administering an IL-4R antagonist (e.g., an anti-IL-4R a pharmaceutical composition containing an antibody or antigen-binding fragment thereof) asthma (e.g. eosinophilic asthma, moderate to severe eosinophilic asthma, etc.), where the subject is subjected to the following asthma exhibits one or more of the following symptoms or signs: (1) the subject fluticasone/salmeterol combination therapy (250/50 µg) for at least 3 months before BID or or budesonide/formoterol combination therapy (16019 µg BID or subject, 300 cells/µL or has more blood eosinophils; (3) subjects had sputum equal to or more than 3% has eosinophils; (4) IgE in the subject. thymus and activation regulatory chemokine (TARC), eotaxin-3, carcinoembryonic antigen (CEA), YKL-40 or periostin levels has increased; (5) the subject had increased fractional exhaled nitric oxide (FeNO) level; and/or It has (6) subject points.

The applications featured in this description will be used as described above. for pharmaceutical compositions, said use also with IL-4R antagonist further comprising administering a second therapeutic agent in combination. second therapeutic agent is administered to a subject in need before, after, or concurrently with the IL-4R antagonist. can be applied as. Exemplary second therapeutic agents include, but are not limited to Provided that it contains one or more of the following in combination: IL-1 inhibitors, lL-5 inhibitors, lL-8 inhibitors, IgE inhibitors, tumor necrosis factor (TNF) inhibitors; corticosteroids, long-acting beta2-agonists and leukotrienes inhibitors.

In another aspect of the explanation, an asthma patient's background asthma therapy IL-4R for use in reducing or eliminating addiction related to its antagonists and is not controlled or partially controlled by background asthma therapy selecting a patient with controlled moderate to severe asthma; to this patient, a While the patient's background therapy is continued throughout the initial treatment period, On the other hand, an IL-4R antagonist during an initial treatment period administering a defined dose; and the patient, initial treatment period Continue to administer the IL-4R antagonist at the defined frequency and dose used during while one or more of the background therapies are removed during a subsequent treatment period. It involves gradually reducing or eliminating the dosage of the component.

Background therapy in this application includes an inhaled corticosteroid (ICS), a long-acting beta- agonist (LABA) or a combination of an ICS and a LABA. Some In applications, background therapy is gradually reduced over a period of 2-8 weeks or retreats. In one embodiment, background therapy is gradual over a subsequent treatment period. is reduced as .

Yet another explanation is that thymus and activation regulatory chemokine (TARC), IgE, such as eotaxin-S, periostin, carcinoembryonic antigen (CEA), or YKL-40 an elevated level of the biomarker or an elevated fractional exhale selecting a patient with high nitric oxide (FeNO) levels; and to this patient, IL-4R moderate to severe effects by administration of a therapeutically effective amount of the antagonist. relates to IL-4R antagonists for use in the treatment of persistent asthma.

In another aspect the present disclosure is in a subject, for example (a) TARC or eotaxin-S expression level of a biomarker such as either or both or an IL-4R of IgE in a biological sample taken from the subject prior to treatment with the antagonist. determination of total serum level; (b) After treatment with lL-4R antagonist the expression level of the biomarker in a biological sample taken from the subject determination; (0) the expression level obtained in step (a) and (d) the level determined in step (b) is compared with the level determined in step (a) Judging that the treatment is effective when it is lower than the specified level or the level determined in step (b) is the same as the level determined in step (a), or When it is higher than ten, it is concluded that the treatment is not effective and the treatment is not effective. It highlights a method for monitoring the effectiveness of treatment for severe asthma.

In one embodiment, the biomarker is FeNO and if following administration of the antagonist If FeNO levels decrease, treatment with the lL-4R antagonist is determined to be effective.

The expression level of the biomarker decreases after administration of the lL-4R antagonist, e.g. 1 weeks, 2 weeks, 3 weeks, 4 weeks, 5 weeks or longer, and compared to the expression level before application of the antagonist. IL-4R dose or dosing regimen of the antagonist (e.g., an anti-IL4R antibody), can be adjusted after the determination process. For example, if the expression of the biomarker 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks or 1 week after administration of the antagonist. If it does not decrease after a longer period of time, treatment with the antagonist can be stopped or The dose of the antagonist may be increased. If after administration of the antagonist If the expression of the biomarker decreases, the dosage of the antagonist can be maintained or, for example, a may be reduced to determine the minimal effective dose. In some applications, treatment is minimal is maintained at the effective dose.

In another aspect, the present invention is an enzyme such as either or both of TARC or eotaxin-S. the expression level of a biomarker or an IL-4R antagonist in the subject. total IgE in a biological sample taken from the subject following administration Determination of serum level and comparison with the level before treatment with IL-4R antagonist If the expression level of the biomarker is decreased compared to by providing an indication that a subject should be tested for an IL-4R A method for monitoring the response to treatment with an antagonist is highlighted. wherein the subject has moderate to severe asthma. In one embodiment, the biomarker is FeNO and If FeNO levels are found to decrease following administration of the antibody, IL- An indication for continued treatment with the 4R antagonist is provided.

This statement also applies to asthma as described here (e.g. eosinophilic asthma, moderate to severe eosinophilic asthma, etc.) or as described herein. for the treatment of any other indications or health problems It also contains an IL-4R antagonist for use in the manufacture of the drug.

This statement also applies to asthma as described here (e.g. eosinophilic asthma, moderate for use in the treatment and/or prevention of severe eosinophilic asthma, etc.) or any of the other indications or health conditions described herein It also contains an IL-4R antagonist for treatment and/or prevention.

This statement is not intended for use in the treatment and/or prevention of asthma and related health problems. an anti-IL4R antibody antagonist or its binding to an antigen for use A pharmaceutical composition containing a fragment thereof.

This statement also includes one or more asthma exacerbations in a subject in need. an anti-IL4R antibody antagonist or its own for use in reducing the incidence of It also includes a pharmaceutical composition containing an antigen binding fragment.

Additionally, this statement does not include one or more asthma-related symptoms in a subject in need. An anti-IL4R antibody for use in improving the parameter(s) A pharmaceutical containing an antagonist or an antigen binding fragment thereof. Contains compound.

This description includes thymus and activation regulatory chemokine (TARC), IgE. eotaxin-S, periostin, carcinoembryonic antigen (CEA), YKL-40, and fractional exhaled nitric oxide In a patient with increased levels of a biomarker selected from the group consisting of (FeNO) An anti-IL4R antibody for use in the treatment of asthma and related health problems A pharmaceutical containing an antagonist or an antigen binding fragment thereof. Contains compound.

This statement also applies to a subject in need who has asthma or moderate to severe eosinophilic an anti-IL4R antibody antagonist or a combination thereof for use in the treatment of asthma further comprising a pharmaceutical composition containing the antigen binding fragment, where the treatment is for the patient to maintain a blood eosinophil level of at least 300 cells per microlitre. and/or be tested for the presence of a sputum eosinophil level of at least 3% and if this blood eosinophil level and/or sputum level is found, pharmaceutical It includes initiating/continuing administration of the composition.

Other embodiments of the invention will become apparent upon examination of the detailed description that follows. will come.

BRIEF DESCRIPTION OF THE FIGURES Figure 1 compared to patients treated with anti-IL-4R antibody mAb1 (asterisks). Time to asthma exacerbation in placebo-treated patients (open circles) shows a Kaplan-Meier plot of time. With an anti-IL-4R antibody mAb1 effect of treatment, risk of patients developing flares due to steroid withdrawal including after 8 weeks, when the patient is at higher risk of It continues over time, including Dashed vertical lines indicate LABA retraction shows.

Figure 2 compared to patients treated with anti-IL-4R antibody mAb1 (closed circles). In placebo-treated patients (open triangles), the force per 1 second in liters A measure showing the average change from baseline in expiratory volume (FEV1) is graphic. Dashed vertical lines indicate retraction of LABA.

Figure 3 compared to patients treated with anti-IL-4R antibody mAb1 (closed circles). morning hours in liters per minute in placebo-treated patients (open triangles). Mean change from baseline in peak expiratory flow rate (AM PEF) It is a graph showing .

Figure 4 compared to patients treated with anti-IL-4R antibody mAb1 (closed circles). In placebo-treated patients (open triangles), liters per minute Mean change from baseline in peak expiratory flow rate (PM PEF) It is a graph showing .

Figure 5 compared to patients treated with anti-IL-4R antibody mAb1 (closed circles) In placebo-treated patients (open triangles), daily albuterol as inhalation In its use, it is a graph that shows the average change compared to the baseline. dashed vertical lines indicate withdrawal of LABA.

Figure 6 compared to patients treated with anti-1L-4R antibody mAb1 (closed circles). Five-item asthma control questionnaire in placebo-treated patients (open triangles). It is a graph showing the average change in (ACQ5) score compared to the baseline. Incision vertical lines indicate retraction of LABA.

Figure 7 compared to patients treated with anti-IL-4R antibody mAb1 (closed circles). nightly awakenings in placebo-treated patients (open triangles) It is a chart that shows the average change in numbers relative to the baseline. dashed vertical lines indicate withdrawal of LABA.

Figure 8 compared to patients treated with anti-IL-4R antibody mAb1 (closed squares). of the placebo-treated mlTT population (closed circles), 0, 1, 4, 8, and 12. Average percent TARC relative to baseline by week 2 It is a graph showing the change. Dashed vertical lines indicate LABA retraction shows.

Figure 9 compared to patients treated with anti-IL-4R antibody mAb1 (closed squares). of the placebo-treated mlTT population (closed circles), 0, 1, 4, 8, and 12. Average percent Eotaxin-S relative to baseline by week 2 It is a graph showing the change. Dashed vertical lines indicate LABA retraction shows.

Figure 10 compared to patients treated with anti-IL-4R antibody mAb1 (closed squares). of the placebo-treated mlTT population (closed circles), 0, 1, 4, 8, and 12. Average percentage of total IgE relative to baseline by week 2 It is a graph showing the change. Dashed vertical lines indicate LABA retraction shows.

Figure 11 compared to patients treated with anti-IL-4R antibody mAb1 (closed squares). of the placebo-treated mlTT population (closed circles), 0, 1, 4, 8, and 12. Average percentage of periosteum relative to baseline by week 2 It is a graph showing the change.

Figure 12 compared to patients treated with anti-IL-4R antibody mAb1 (closed squares). of the placebo-treated mITT population (closed circles), 0, 1, 4, 8, and 12. carcinoembryogenic antigen levels relative to baseline until their next week examination. (CEA) is a chart showing the average percentage change.

Figure 13 compared to patients treated with anti-IL-4R antibody mAb1 (closed squares). of the placebo-treated mITT population (closed circles), 0, 1, 4, 8, and 12. until their next week's check-ups. mean percent in YKL-40 relative to baseline It is a graph showing the change.

Figure 14 compared to patients treated with anti-IL-4R antibody mAb1 (closed squares). of the placebo-treated mITT population (closed circles), 0, 1, 2, 4, 6, 8, and 12. mean blood eosinophils from baseline to their week It is a graph showing percentage change.

Figure 15 compared to patients treated with anti-IL-4R antibody mAb1 (closed squares). of the placebo-treated mITT population (closed circles), 0, 4, 8, and 12. fractional exhaled nitric oxide relative to baseline until their next week visit. It is a graph showing the average percentage change in the (NO) level. Dashed vertical lines It shows the withdrawal of LABA.

Figure 16, patients treated with anti-1L-4R antibody mAb1 (plus sign and dashed line) in the placebo-treated mITT population compared to (open circles and solid line) baseline versus fractional exhaled nitric oxide (FeNO) (PPB) at week 12 is a scatter plot of the change in FEV1 (L) from baseline.

Figure 17, patients treated with anti-1L-4R antibody mAb1 (plus sign and dashed line) in the placebo-treated mITT population compared to (open circles and solid line) baseline FeNO (PPB) versus baseline AM-PEF at week 12 (L/minute) is a scatter plot of change.

Figure 18, patients treated with anti-1L-4R antibody mAb1 (plus sign and dashed line) in the placebo-treated mITT population compared to (open circles and solid line) FeNO (PPB) at baseline versus PM-PEF at week 12 (L/minute) is a scatter plot of change.

Figure 19, patients treated with anti-1L-4R antibody mAb1 (plus sign and dashed line) blood in the placebo-treated mITT population (open circles and full line) compared to FEV1 (L) versus baseline eosinophil count (GlGA/L) at week 12 is a scatter plot of change.

Figure 20, patients treated with anti-1L-4R antibody mAb1 (plus sign and dashed line) blood in the placebo-treated mITT population (open circles and full line) compared to ACQ versus baseline eosinophil count (GIGA/L) at week 12 is a scatter plot of change.

Figure 21, patients treated with anti-IL-4R antibody mAb1 (plus sign and dashed line) blood in the placebo-treated mITT population (open circles and full line) compared to daily eosinophil count (GlGA/L) versus baseline at week 12 A scatter plot of the change in albuterol/Ievalbuterol usage.

Figure 22, patients treated with anti-IL-4R antibody mAb1 (plus sign and dashed line) in the placebo-treated mITT population compared to (open circles and solid line) periostein at baseline versus baseline ACQ at week 12 is a scatter plot of change.

Figure 23, patients treated with anti-1L-4R antibody mAb1 (plus sign and dashed line) in the placebo-treated mITT population compared to (open circles and solid line) A scatter plot of the change in ACQ from baseline at week 12 versus YKL-40 graph.

Figure 24 is a summary of timing and dosing regimens for treating asthma patients. is a semantic representation.

Figure 25 with inhaled corticosteroid (ICS) and long-acting beta2 agonist (LABA) therapy partially controlled/uncontrolled moderate to severe persistent eosinophilic asthma Patients were given 300 mg mAb1 or placebo subcutaneously once a week for 12 weeks. A randomized, placebo-controlled, double-blind parallel It is a diagram describing the patient distribution of the group study.

Figures 26A and 26B show administration of placebo (open triangles) or mAb1 (closed circles). then measured morning (A) and evening (B) asthma symptoms over 12 weeks. are scatter plots.

Figure 27 shows house dust mite (HDM) challenge and anti-IL-4R antibody or an IL-4R antibody. Following treatment or sham treatment with the 13Ra2-Fc pseudoreceptor molecule showing serum IgE levels in humanized IL-4/IL-4R mice (IL-4“”lhu lL-4R0ihulhu). is a graph. on samples taken on Day 40 (24 hours before the first dose of treatment) and Day 85.

Measurements were made at the end of the experiment.

Figure 28 shows house dust mite (HDM) challenge and isotype control, anti-1L-4R antibody or following treatment or sham treatment with an IL-13Rα2-Fc pseudoreceptor molecule A graph showing serum IgE levels in wild strain (BaIb/c) mice.

Figure 29, Humanized IL-4/1L-4R after HDM challenge and indicated treatment A study showing the collagen content (expressed in µg/Iob) of mice lungs. is graphic.

Figure 30 shows wild strain mice following HDM challenge and indicated treatment. It is a graph showing the collagen content of your lungs (expressed in pg/Iob).

Figure 31A, Humanized IL-4/IL-4R after HDM challenge and indicated treatment A graph showing the levels of eosinophils and neutrophils in mice and Figure 31B in mice, resident dendritic cells and inflammatory dendritic cells It is a chart showing the levels.

DETAILED DESCRIPTION Before describing the present invention, it should be noted that the specific methods and experiments described is not limited to the terms and conditions, therefore these methods and conditions may change. must be understood. Additionally, terminology used herein describes specific applications only. It should also be understood that it is for the purpose of

Unless otherwise defined, all technical and scientific terms used herein by a person of ordinary skill in the art to which the invention belongs It will carry the meaning as it is understood.

As used herein, the term "approximate" refers to a specific numerical value. When used, this value may differ from the mentioned value by no more than 1%. It will mean that it can show. For example, "about 100" as used here 99.4 etc.).

As used herein, the terms "treat", "treating" or similar terms relieve the symptoms of a given disorder or health problem To temporarily or permanently eliminate the occurrence of symptoms or It means to stop or slow down the appearance.

Preferred methods and materials will now be described.

Methods to Reduce the Incidence of Asthma Exacerbations The present description does not estimate the incidence of asthma exacerbations in a subject in need. These methods include methods to reduce the level of interleukin-4 It involves administering a pharmaceutical composition containing a receptor (IL-4R) antagonist.

As used herein, "asthma exacerbation" refers to one or more episodes of asthma. an increase in the severity and/or frequency and/or duration of the symptom or sign It means. An "asthma exacerbation" may also include changes in a subject's respiratory health, a therapeutic intervention for asthma (e.g. steroid therapy, inhaled corticosteroids) treatment, hospitalization, etc. such as) and or can be treated with this intervention. This includes any deterioration. According to some embodiments of the invention, asthma exacerbation is defined as one or more of the following: (a) successive on two consecutive days at morning peak expiratory flow (see elsewhere in this document). "AM PEF") as defined by a decrease of 30% or more from baseline; (b) provide relief over a 24-hour period (compared to baseline) on two consecutive days taking six or more additional puffs of albuterol or Ievalbuterol; and (c) a worsening of asthma (for example, by a physician or other type of doctor) as specified) and requires at least one of the following: (i) systemic (oral and/or parenteral) steroid therapy or (ii) last inhaled, relative to baseline level increase in corticosteroid dose by at least 4 times or (iii) hospitalization.

In some cases, an asthma exacerbation may be referred to as a "severe asthma exacerbation." can be categorized. A severe asthma exacerbation may last four or more times the pre-event dose. with higher solids of systemic corticosteroids or inhaled corticosteroids It means a case that requires urgent intervention in the form of treatment. Therefore "asthma" The general phrase "exacerbation of asthma" may differ from the more specific term "severe asthma exacerbations". It also includes and covers a subcategory. Accordingly, the present disclosure requires To reduce the incidence of severe asthma exacerbations in a patient with Includes methods.

The phrase "a reduction in the incidence" of an asthma exacerbation is not a part of the present invention. A subject receiving the pharmaceutical composition is more likely to be more active after treatment than before treatment. have a small number of asthma exacerbations (i.e. at least one less exacerbation), or At least 4 days following initiation of treatment with a pharmaceutical composition of the present invention. asthma exacerbation for weeks (e.g., 4, 6, 8, 12, 14 or more weeks) It means not living. Alternatively, an asthma exacerbation then, a subject who has not received a pharmaceutical composition of the present invention at least a 10% chance of experiencing an asthma exacerbation compared to control subjects (e.g., 10%, is coming.

Methods for Improving Asthma-Related Parameters The present disclosure includes one or more asthma-related symptoms in a subject in need. It includes methods for improving the parameter, where the methods are a pharmaceutical composition containing an interleukin-4 receptor (1L-4R) antagonist. involves applying the composition. For the purposes of the invention, an asthma a reduction in the incidence of exacerbations (as described above) associated with asthma may be associated with an improvement in one or more parameters; but such a The correlation need not be observed in all cases. forced expiratory volume (FEV1); (b) morning PEF (AM PEF) and evening PEF (PM PEF) peak expiratory flow rate (PEF), including: (c) drugs such as albuterol or Ievalbuterol use of an inhaled bronchodilator; (d) five-item Asthma Control Questionnaire (ACQ5) score; (d) night awakenings; and (e) 22-item Sino-Nasal Outcome Test (SNOT-22). score “Improvement in an asthma-related parameter” relative to baseline, FEV1, An increase in one or more of AM PEF or PM PEF and/or According to daily albuterol/Ievalbuterol use, ACQö score, average night awakenings or a decrease in one or more of the SNOT-22 scores. Here As used, the term "baseline" in relation to an asthma-related parameter refers to a patient's asthma-related parameter, a pharmaceutical composition of the present invention It means the numerical value before or during its application.

To determine whether there is "improvement" in an asthma-related parameter, this parameter, the baseline and the pharmaceutical composition of the present invention The amount is taken at a time point after administration. For example, associated with asthma a parameter, after initial treatment with a pharmaceutical composition of the present invention. can be measured after some time. At a certain point in time after starting treatment the difference between the value of the parameter and the value of this parameter at the baseline, an "improvement" in an asthma-related parameter (i.e., depending on the specific parameter measured to reveal whether there is an increase or decrease (depending on the situation) is used.

As used herein, the terms "win" or "gain" refer to the use of a physical entity. or ownership of a value, such as a numerical value, that physical entity or value, For example, "direct acquisition" or "indirect acquisition" of the asthma-related parameter refers to the acquisition of physical performing a process (e.g. a synthesis) to obtain the asset or value or the realization of the analysis method). "Indirectly winning", physical asset or value from another person or source (e.g. physical attribute) or from a third party laboratory that has directly earned the value). is cited. The direct acquisition of a physical entity in a physical substance, e.g. carrying out a process that involves a physical change in a starting material Contains. Exemplary changes include one from two or more starting materials. creating a physical entity, cutting or dividing a substance, separation or purification of a substance, a mixture of two or more substances combining into, breaking a covalent or non-covalent bond, or It involves carrying out a chemical reaction that involves the formation of of a value direct acquisition, a physical change in a sample or other substance, a physical change in a substance, such as a sample, analyte, or reagent performing an analytical process (sometimes referred to here as "physical analysis") It involves performing a process that includes (referred to).

Information gained indirectly, for example in the form of a report provided on paper or is obtained from an online database or application (an “Application”) can be provided in electronic form. Report or information, for example, a hospital or clinic a health institution such as; or by a healthcare professional such as a doctor or nurse can be provided. Forced Expiratory Volume in 1 Second (FEV1). According to some embodiments of the invention, a administration of an 1L-4R antagonist to the patient at forced expiratory volume in 1 second (FEV1) leads to an increase compared to the baseline. For measuring FEV1 The methods are known in the art. For example, / A spirometer that meets the recommendations of the European Respiratory Society (ERS) It can be used to measure FEV1. ATS/ERS' Spirometry Standards as a guide can be used. Spirometry usually requires at least 6 hours of albuterol withdrawal. It is then held between 6 and 10 a.m. in the morning. Pulmonary function tests usually measured in a sitting position and for the highest measurement FEV1 (in litres) is recorded.

The present disclosure relates to a pharmaceutical composition comprising an anti-1L-4R antagonist. at week 12 after initiation of treatment, a decrease of at least 0.05 L from baseline It includes therapeutic methods that increase FEV1. For example, according to the invention, an IL-4R administration of the antagonist to a subject in need, increased relative to baseline at week 12. leads to a further increase.

Morning and Evening Peak Expiratory Flow (AM PEF and PM PEF). some of the invention According to practice, administering an IL-4R antagonist to a patient in the morning (AM). and/or evening (PM) peak expiratory flow (AM PEF and/or PM PEF) to baseline It leads to an increase in . Methods for measuring PEF are in the art is known. For example, according to one method of measuring PEF, morning (AM) and evening (PM) PEF (as well as daily albuterol use, morning and evening asthma night due to asthma symptoms requiring symptom scores and rescue medications They were given an electronic PEF meter to measure the number of awakenings. patients The patients were informed about how to use the device and the electronic PEF was given to the patients. Written instructions for using the meter are provided. Additionally, a type of occupation member also explains how to save special variables in the electronic PEF meter. can inform patients. AM PEF, usually after waking up (between 6 a.m. and 10 a.m.) between) within 15 minutes, before any use of albuterol. P.M. PEF, usually in the evening (between 6pm and 10pm) without any albuterol performed before use. Subjects waited at least 6 hours before measuring their PEF. The patient should try not to use albuterol during the treatment period. Three PEF efforts by the patient is performed and all 3 values are recorded by the electronic PEF meter.

The highest value is usually used for evaluation. AM PEF at baseline, can be calculated as the average AM measurement recorded over the previous 7 days and the base PM PEF in line with the first dose of the pharmaceutical composition containing the 1L-4R antagonist as the average PM measurement recorded over the 7 days before application computable.

The present disclosure relates to a pharmaceutical composition comprising an anti-IL-4R antagonist. at least 1.0 from baseline at week 12 after initiation of treatment It includes therapeutic methods that provide a L/minute increase in AM PEF and/or PM PEF. For example, administering an IL-4R antagonist according to the invention to a subject in need thereof, Approximately 0.5 L/min, 1.0 L/min, 1.5 PEF from baseline at week 12 causes an increase.

Use of AlbuteroI/Levalbuterol. According to some embodiments of the invention, a patient is provided with a lL- Administration of the 4R antagonist should be considered as a basis for daily use of albuterol or Ievalbuterol. It causes a decrease according to the line. Albuterol/Ievalbuterol inhalations The number is recorded daily by patients in a diary, PEF meter, or other recording device. can be saved as . During treatment with the pharmaceutical composition of the invention albuterol/evalbuterol use is typically administered regularly or prophylactically. It should be when necessary for symptoms, not when needed. albuteroI/Ievalbuterol at baseline number of inhalations/day, the first dose of the pharmaceutical composition containing the IL-4R antagonist It can be calculated based on the average of the 7 days before application.

The present disclosure relates to a pharmaceutical composition comprising an anti-1L-4R antagonist. At the 12th week after starting treatment, the baseline for albuterol/evalbuterol use It includes therapeutic methods that provide a daily reduction of at least 0.25 puffs according to the line. For example, administering an IL-4R antagonist according to the invention to a subject in need thereof, At week 12, approximately daily reductions in albuterol/levalbuterol use compared to baseline leading to a reduction of 3.00 puffs or more per day.

-Item Asthma Control Questionnaire (ACQ) Score. According to some embodiments of the invention, a administration of an IL-4R antagonist to the patient, five-item Asthma Control Questionnaire It causes a decrease in the (ACQ5) score compared to the baseline. ACQ5, asthma It is a validated questionnaire to evaluate the control of

The present disclosure relates to a pharmaceutical composition comprising an anti-IL-4R antagonist. At week 12 after starting treatment, the ACQ5 score was the lowest compared to baseline. It includes therapeutic methods that provide a reduction of at least 0.10 points. For example, according to the invention, administration of an IL-4R antagonist to a subject in need, at week 12 leading to a decrease of one point or more.

Night Awakenings. According to some embodiments of the invention, a patient is administered an IL-4R administration of the antagonist reduced the mean number of nocturnal awakenings to baseline. It leads to a decrease in .

The present disclosure relates to a pharmaceutical composition comprising an anti-1L-4R antagonist. At week 12 after starting treatment, the average number of night awakenings therapeutic effect providing a reduction of at least approximately 0.10 times per night from baseline Includes methods. For example, according to the invention, an IL-4R antagonist administration, average nocturnal awakenings relative to baseline at week 12 Approximately 0.10 times per night, 0.15 times per night, 0.20 times per night, leading to a reduction of 2.0 times per night or more. 22-Item Sinonasal Outcome Test (SNOT-22) Score. Some applications of the invention According to the 22-item Sinonasal Outcome test, administration of an IL-4R antagonist to a patient It causes a decrease in the test (SNOT-22) score compared to the baseline. SNOT- 22 validated studies to evaluate the impact of chronic rhinosinusitis on quality of life. The present disclosure relates to a pharmaceutical composition comprising an anti-1L-4R antagonist. At week 12 after initiation of treatment, the SNOT-22 score increased from baseline It includes therapeutic methods that provide a reduction of at least 1 point. For example, according to the invention, administration of an IL-4R antagonist to a subject in need, at week 12 or lead to a greater decrease.

Methods for Treating Asthma The present disclosure provides that, according to some embodiments, in a subject in need, such as eosinophilic provides methods for the treatment of asthma, including asthma, wherein the methods include the subject in a drug containing an interleukin-4 receptor (IL-4R) antagonist. involves administering the pharmaceutical composition. In some applications, the current description methods are used if a subject has moderate to severe eosinophilic asthma (e.g., moderate to severe It is useful for the treatment of persistent eosinophilic asthma.

According to the invention, if the subject has a blood eosinophil level of at least 300 cells per microliter and/or shows a sputum eosinophil level of at least 3%, the subject has moderate to moderate He is considered to have severe eosinophilic asthma. Blood and/or sputum eosinophils Any method known and available in the art to measure the level of a subject's that he had moderate to severe eosinophilic asthma and therefore the current statement to determine who is a suitable subject for their therapeutic methods. can be used in context.

According to a related aspect of the present disclosure, methods for treating asthma are provided, which include: (a) a concentration of at least 300 cells per microlitre showing a blood eosinophil level and/or a sputum eosinophil level of at least 3% selecting a patient; and (b) a pharmaceutical composition comprising an 1L-4R antagonist. application to this patient.

In another aspect, during the treatment of moderate to severe asthma, an asthma patient's inhaled dependence on corticosteroids (ICS) and/or long-acting beta agonists (LABA) Methods are provided to reduce or eliminate it. Some In applications, these methods include: control with a background therapy A patient with moderate to severe asthma that is uncontrolled or partially controlled selection; The patient is given this initial treatment during an initial treatment period. While the patient's background therapy is maintained during the preferably administering a determined dose of an anti-IL-4R antibody; and IL-4R background levels in a subsequent treatment period while the antagonist continues to be administered. gradually reducing the dosage of one or more components of therapy. refers to traditional therapeutic agents. In some applications, background therapy is a and/or the dosage of LABA is discontinued or completely reduced after the initial treatment period. retreats. For example, a LABA such as salmeterol or formoterol may be an initial treatment period and is stopped or reversed completely in the subsequent treatment period. is withdrawn.

An example of a treatment regimen for a patient with moderate to severe asthma is shown in Figure 24. shown wherein an IL-4R antagonist is administered to a patient with moderate to severe asthma. is implemented. An initial treatment period (also called the “stable phase”) During this period, the patient is administered a LABA and an ICS as background therapy.

A subsequent treatment period (also called the "withdrawal phase") During LABA administration is stopped, i.e. LABA is withdrawn or discontinued. Following During the treatment period, ICS is gradually tapered and eventually discontinued.

In a related aspect, background with withdrawal of systemic background therapy Asthma treatment methods that include supportive therapy are provided. Some In applications, for a certain period of time (e.g. 1 week, 2 weeks, 3 weeks, 1 week). months, 2 months, 5 months, 12 months, 18 months, 24 months or longer) who is receiving background therapy An 1L-4R antagonist is administered to the asthmatic patient as supportive therapy (also referred to as “stable In some applications, background therapy is an ICS and/or an Contains LABA. The stable phase is followed by a background therapy withdrawal phase. where one or more of the elements that constitute the background therapy are maintained while the supportive therapy is continued. More than one component is withdrawn or reduced or dropped. In some applications background therapy, about 5%, about 10%, about 20% during the withdrawal phase, It can be reduced by about 30%, about 40%, about 50% or more. withdrawal phase It may take weeks, 12 weeks or longer. In one preferred embodiment, background therapy is It can be reduced by approximately 5% during the withdrawal phase and the withdrawal phase can be 1 week, 2 weeks, 3 weeks. or it may take longer. Background therapy, withdrawal in a preferred embodiment It can be reduced by approximately 10% during the withdrawal phase and the withdrawal phase is 1 week, 2 weeks, 3 weeks, 4 weeks. it may take a long time. In a preferred embodiment, background therapy is performed during the withdrawal phase. It can be reduced by approximately 20% and the withdrawal phase is 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks. weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks or longer. One background therapy in the preferred embodiment, approximately 30% during the withdrawal phase May be tapered and withdrawal phase 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, It may take 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks or longer. a preferred In practice, background therapy can be reduced by approximately 40% during the withdrawal phase and Withdrawal phase 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. a preferred In practice, background therapy can be reduced by approximately 50% during the withdrawal phase and Withdrawal phase 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 embodiments, the present disclosure includes chronic rhinosinusitis associated with asthma, allergic rhinitis, allergic fungal rhinosinusitis, allergic broncho-pulmonary aspegilosis, combined airway disease, Churg-Strauss syndrome, vasculitis, chronic obstructive pulmonary disease (COPD) and health problems such as exercise-induced bronchospasm or It covers methods to treat or alleviate complications.

The present disclosure also includes methods for treating persistent asthma.

The term "persistent asthma" as used herein means that the subject has asthma at least once a week. It means showing symptoms during the day and/or at night, including and symptoms may last from a few hours to a few days. In some alternative applications Persistent asthma is "mildly persistent" (e.g., more than twice a week but not always is less than a day and symptoms are severe enough to interfere with daily activities or sleep is severe and/or lung function is normal or with inhalation of a bronchodilator reversible), "moderately persistent" (e.g. symptoms occur every day) sleep is interrupted at least weekly and/or lung function is impaired is moderately abnormal) or "severely persistent" (e.g., Despite proper use, symptoms are persistent and/or lung function is severely affected).

Interleukin-4 Receptor Antagonists The methods of the present disclosure include an interleukin-4 receptor (IL-4R) antagonist. It involves administering a therapeutic composition to a subject in need thereof. Here As used, an "IL-4R antagonist" means a substance that binds to or interacts with the IL-4R. is any agent that expresses IL-4R on a cell in vitro or in vivo When administered, it inhibits the normal biological signaling function of IL-4R. lL-4R Non-limiting examples of categories of antagonists include small molecule lL-4R antagonists, anti-IL-4R aptamers, peptide-based IL-4R antagonists (e.g. Contains antigen binding fragments of antibodies. chain and two light (L) chains, as well as their multimers (e.g. lgM). It refers to immunoglobulin molecules. Each heavy chain, a heavy chain variable region (here abbreviated as HCVR or VH) and a heavy chain constant region.

The heavy chain constant region contains three domains, 0.41, GHZ and CH3. Each light chain a light chain variable region (abbreviated here as LCVR or VL) and a light The chain contains a constant region. The light chain constant region contains a domain (CL1). VH and VL regions can also be subdivided into regions of hypervariability, which are complementarity intertwined with more protected regions called regions (FR) They are called detection regions (CDRs). Each VH and VL, three CDR and four It consists of FR, which are as follows, from amino-terminus to carboxy-terminus. It is arranged in the order: FR1, CDR1, FR2, CDR2, FR3, CDR3, FR4. In different applications FRs of the anti-IL-4R antibody (or the antigen-binding portion thereof). human germ It may be identical to line sequences or modified naturally or artificially. One amino acid consensus sequence based on side-by-side analysis of two or more CDRs can be defined based on . Contains. The "antigen-binding portion" of an antibody is the "antigen-binding portion" of an antibody. "fragment" and similar terms as used herein mean any inherent occurring, enzymatically available, synthetically or genetically engineered administered polypeptide or a complex by specifically binding to an antigen. Contains the glycoprotein that forms Antigen-binding fragments of an antibody manipulation of DNA encoding variable and optionally constant domains and proteolytic digestion or recombinant genetic engineering involving expression using any suitable standard techniques, such as full antibody can be derived from molecules. Such DNA is known and/or commercially available, for example. sources, DNA libraries (including, for example, phage-antibody libraries) can be easily obtained or synthesized. DNA, such as one or more variants and/or arranging the constant domains or codons in a suitable configuration introducing cysteine residues, modifying, adding or adding amino acids delete, etc. chemically or using molecular biological techniques to can be sequenced and manipulated.

Non-limiting examples of antigen binding fragments include: (i) Fab trailers; (ii) F(ab')2 fragments; (iii) Fd fragments; (iv) Fv fragments; (v) single chain Fv (scFv) molecules; (vi) dAb fragments; and (vii) hypervariable of an antibody minimal recognition units consisting of amino acid residues that mimic the an isolated complementarity determining region (CDR) such as a CDR3 peptide) or a restricted FR3-CDR3-FR4 peptide. Domain-specific antibodies, single-domain antibodies, domain-specific antibodies deleted antibodies, chimeric antibodies, CDR-grafted antibodies, diabodies, tribodies, tetrabodies, minibodies, nanobodies (e.g. monovalent nanobodies, bivalent nanobodies, etc.), small modular immunopharmaceuticals (SMIPs) and shark variant IgNAR Other engineered molecules, such as domains, also contain "antigen binding fragments". It falls within the scope of the expression.

An antigen-binding fragment of an antibody typically contains at least one variable domain. It does. The variable domain can be of any size or amino acid composition and usually adjacent to or associated with one or more frame sequences. Contains at least one CDR in it. Antigen having a VH domain associated with a VL domain VH and VL domains in binding fragments in any suitable arrangement. may be related to each other. For example, the variable region may be dimeric and VH-VH, It may contain VH-VL or VL-VL dimers. Alternatively, an antibody binds to the antigen. The fragment may contain a monomeric VH or VL alanine.

In some embodiments, the binding fragment of an antibody to an antigen has at least one constant domain. may contain at least one covalently linked variable domain. One of the current explanations Variables and variables that may be present within an antigen-binding fragment of an antibody The following are exemplary, non-limiting configurations of fixed fields. contains: (i) VH-CHl; (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. Any of variable and fixed fields configuration, any of the exemplary configurations listed above Variable and constant fields can be directly connected to each other, including one or it can be connected with a full or partial hinge or fastener area. a single polypeptide a flexible or semi-structured structure between adjacent variable and/or constant domains within the molecule. or more) amino acids, preferably in the hinge region 2 to 60 It may consist of between, preferably between 5 and 50, or preferably between 10 and 40 amino acids.

Furthermore, an antigen binding fragment of an antibody of the present disclosure is described above. a homo-dimer of any of the variable and constant domain configurations listed or its hetero-dimer (or other multimer), with each other and/or with one or more may contain a non-covalent association with the monomeric VH or VL domain (e.g. with disulfide bond(s).

As with full antibody molecules, antigen-binding fragments are monospecific. or it may be multispecific (e.g. bispecific). An antibody to a multispecific antigen The binding fragment may typically contain at least two different variable domains, where each variable domain corresponds to a separate antigen or a different epitope on the same antigen. It has specific binding ability. Any form of multispecific antibody an antibody of the present disclosure using routine techniques available in the art. can be adapted for use in the context of the antigen binding fragment.

The constant region of an antibody is the part of an antibody that binds to complement and mediator cells. It is important in its ability to repair cytotoxicity. Therefore, the isotope of an antibody is depending on whether the antibody is desired to mediate cytotoxicity can be selected. and antibodies with constant regions. The person featured in the current statement antibodies may still be detected, for example in human germline cells at CDRs and particularly at CDR3. may contain amino acid residues not encoded by immunoglobulin sequences (e.g. mutations introduced in vitro by random or site-specific mutagenesis or in in vivo somatic mutations). However, the term "human antibody" does not apply to other mammalian antibodies, such as mice. CDR sequences derived from the germline of the species were grafted into human framework sequences. Does not contain antibodies. all human antibodies that have been produced, generated or isolated from a host cell, e.g. expressed using a recombinant expression vector transfected into antibodies (described in detail below), a recombinant, combinatorial human antibodies isolated from the antibody library (described in detail below), isolated from an animal (e.g., a mouse) that is transgenic for human immunoglobulin genes or involving the splicing of human immunoglobulin gene sequences into other DNA sequences prepared, expressed, formed or isolated by any other means Contains antibodies. Such recombinant human antibodies contain human germline immunoglobulin It has variable and constant regions derived from its sequences. However, in some applications, These recombinant human antibodies are subjected to in vitro mutagenesis (or When a transgenic animal is used, it is subjected to in vivo somatic mutagenesis) and Thus, the amino acid sequences of the VH and VL regions of the recombinant antibodies are human germ Although the line is derived from and related to the VH and VL sequences, the human antibody germline These are sequences that may not naturally occur in the repertoire in vivo.

Human antibodies can exist in two forms that are associated with hinge heterogeneity. One In this form, an immunoglobulin molecule is a stable, four-chain protein of approximately 150-160 kDa. structure, where dimers are formed by an interchain heavy chain disulfide bond. is kept in between. In a second form, dimers form via interchain disulfide bonds. consists of a light and heavy chain that is non-bonding and covalently coupled antibody) a molecule of approximately 75-80 kDa is created. Separating these forms, affinity It remained extremely difficult even after its purification.

The frequency of occurrence of the second form in various intact IgG isotypes is, but is not limited to, provided that structural differences associated with the hinge region isotype of the antibody It is due to. A single amino acid in the hinge region of the human IgG4 hinge The substitution accounts for the appearance of the second form, typically when a human IgG1 hinge is used. can significantly reduce it to observed levels (Angal et al. (1993) Molecular Immunology 30:105). The current description you have is hinge, CH2 or CH3 It includes antibodies with one or more mutations in this region. mutations are desired in production, for example to improve the yield of the desired form of antibody can be done.

An "isolated antibody" is one that is identified and separated from at least one component in its natural environment. and/or a recovered antibody. For example, if an organism has at least one component or a substance in which the antibody is naturally present or naturally produced. an antibody separated or removed from a tissue or cell, for purposes of the present invention Accordingly, it is an "isolated antibody". An isolated antibody is also a recombinant cell It also contains a resident in situ antibody. Isolated antibodies require at least one purification or These are antibodies that have been subjected to the isolation step. According to some applications, a The isolated antibody may be substantially free of other cellular material and/or chemicals. binding fragment with an antigen that is relatively stable under physiological conditions. It means that it can form a complex. An antibody specific to an antigen Methods for determining whether the device is connected are well known in the art. these include, for example, equilibrium dialysis, surface plasmon resonance, and the like. For example, an antibody that “specifically binds” IL-4R is, in the context of the present invention IL- as used and measured in a surface plasmon resonance assay 4R or part thereof less than about 1000 nM, less than about 500 nM, about less than about 80 nM less than about 70 nM less than about 60 nM about 50 less than mM, 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 little, with a KD of less than about 2 nM, less than about 1 nM, or less than about 0.5 nM Contains binding antibodies. However, there is an isolate that specifically binds human lL-4R. antibody with other antigens, such as IL-4R molecules from other (non-human) species may show cross-reactivity.

Anti-1L-4R antibodies useful for the methods of the present disclosure are those from which the antibodies are derived. framework of the heavy and light chain variable regions compared to the corresponding germline sequences and/or one or more amino acid substitutions in the CDR regions. Such mutations occur when the amino acid sequences described herein are not publicly available, e.g. by comparison with germline sequences available from antibody sequence databases. can be easily understood. The present disclosure does not include any of the amino acid sequences disclosed herein. antibodies and their antigen-binding fragments derived from It includes methods that involve the use of one or more frames. and/or one or more (e.g. 1, 2, 3, 4, 5, 6, for tetrameric antibody) or 6) one or more amino acids within the CDR region (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 amino acids), corresponding to the germline sequence from which the antibody was derived corresponding residue(s) of another human germline sequence a conservative treatment of the residue(s) or the corresponding germline residue(s) amino acid substitution is changed by mutation (such sequence changes are collectively referred to herein as Based on the heavy and light chain variable region sequences described herein, one or a variety of diseases involving more than one individual germline mutation or combination It can easily produce antibodies and their antigen-binding fragments. Some In applications, framework and/or CDR residues within the VH and/or VL domains all by mutation to residues in the original germline sequence from which the antibody was derived. is returned. In other applications, only some residues, such as only FR1 mutation within the first 8 amino acids or the last 8 amino acids of FR4 introduced residues or mutation within CDR1, CDR2 or CDR3 The introduced residue(s) are mutated back to the original germline sequence. Other In embodiments, one or more framework and/or CDR residues originate from a different germline of the sequence (i.e., a gene that differs from the germline sequence from which the antibody was originally derived) The corresponding residue(s) of the germline sequence are changed by mutation. Moreover, The antibodies of the present disclosure contain two or more antibodies within the framework and/or CDR regions. may include any combination of multiple germline mutations, such as here some individual residues mutate into the corresponding residue of a particular germline sequence. While changing, some other residues that differ from the original germline sequence are retained. is removed or replaced by mutation to the corresponding sequence of a different germline sequence. One or antibodies or antigen binding involving more than one germline mutation Once fragments are obtained, improvement in binding specificity, increase in affinity, improvement in antagonistic or agonistic biological properties, or development (depending on the situation), decrease in immunogenicity, etc. One or more features such as can be easily tested for. This generally means that the antibodies obtained in this way and the antigen The use of binding fragments is within the scope of the present disclosure.

The present disclosure also includes HCVR, LCVR and/or CDR amino acids disclosed herein. any of the sequences has one or more conservative substitutions. It also includes methods involving the use of anti-1L-4R antibodies containing variants thereof. For example, the present disclosure includes HCVR, LCVR, and/or CDR amino acids disclosed herein. for any of the following sequences, e.g. 10 or less, 8 or less, 6 or more less, 4 or less, etc. HCVR, LCVR and/or with conservative amino acid substitution It involves the use of anti-1L-4R antibodies containing CDR amino acid sequences.

Healthcare's Biacore Life Sciences division) using a biosensor matrix real-time through detection of changes in protein concentrations It refers to an optical phenomenon that allows the analysis of interactions. Refers to an antigenic determinant that interacts with a specific antigen binding site within is available. A single antigen can have more than one epitope. Therefore, different antibodies It can bind to different sites on an antigen and have different biological effects.

Epitopes can be conformational or linear. A conformational epitope, linear spatially juxtaposed data from different segments of the polypeptide chain It is produced with amino acids. A linear epitope is the adjacent amino acid within a polypeptide chain. It is an epitope produced by acid residues. In some cases, an epitope is located on the antigen. The saccharide moieties may contain phosphoryl groups or sulfonyl groups.

Preparation of Human Antibodies Methods for producing human antibodies in transgenic mice are not known in the art. is known. Any of such known methods, in the context of the present disclosure, can be used to make human antibodies that specifically bind to human IL-4R.

VELOCIMMUNETM technology for producing monoclonal antibodies (see e.g. US 6,596,541, Regeneron Pharmaceuticals) or any other known method. using a human variable region and a mouse constant region, high levels of IL-4R affinity chimeric antibodies are first isolated. VELOCIMMUNE® technology, endogenous human heavy and light chains operatively bound to mouse constant site locations generation of a transgenic mouse with a genome containing variable regions In this way, the mouse develops a human variant in response to antigenic stimulation. region and produce an antibody containing a mouse constant region. Antibody's heavy and light DNA encoding the variable regions of the human heavy and light chain chains is isolated and It binds operatively to the DNA encoding its constant regions. DNA is then completely It is expressed in a cell capable of expressing human antibody.

Usually a VELOCIMMUNE® mouse is challenged with the antigen of interest and lymphatic cells (like B-cells) are recovered from mice expressing antibodies. lymphatic cells, combining with a myeloma cell line to prepare immortal hybridoma cell lines and by screening and selecting these hybridoma cell lines, cells specific to the antigen of interest are identified. Hybridoma cell lines producing antibodies are detected. Heavy chain and light chain DNA encoding the variable regions can be isolated and the heavy chain and light chain It can be connected to isotypic constant regions. Such an antibody protein is present in a cell such as a CHO cell. can be produced within the cell. Alternatively, antigen-specific chimeric antibodies or mild and DNA encoding variable domains of heavy chains is directly antigen-specific can be isolated from lymphocytes.

Initially, it had a human variable region and a mouse fixed region. affinity chimeric antibodies are isolated. Antibodies are known to those skilled in the art. characterized using standard procedures and affinity, selectivity, epitope, etc. like are selected in terms of the desired characteristics. Mouse fixed regions are a desired human fixed A fully human antibody featured in the present disclosure, modified by For example, natural strain or modified IgG1 or IgG4 is produced. The selected fixed region is specific Although it may vary depending on use, high affinity antigen binding and target specificity characteristics are found in the variable region.

In general, antibodies that can be used in the methods of the present disclosure are by binding to antigen in the solid phase or solution phase, as described above It has high affinities when measured. Mouse fixed regions, desired human fixed regions fully human antibodies highlighted in the current statement by modifying their regions is produced. Although the fixed area selected may vary depending on the specific use, High affinity antigen binding and target specificity characteristics vary is located in the region.

specific methods for lL-4R that may be used in the context of the methods of the present disclosure. human antibodies or antigen-binding fragments of antibodies that bind A heavy chain having an amino acid sequence selected from the group consisting of 258 and 262 three heavy chain CDRs (HCDR1, HCDR2 and HCDR3) containing any antibody or antigen binding fragment thereof. three light chain CDRs located within a light chain variable region (LCVR) having May contain (LCVR1, LCVR2, LCVR3). CRDs within the HCVR and LCVR amino acid sequences Methods and techniques for identification are well known in the art and are described herein. CDRs within specified HCVR and/or LCVR amino acid sequences disclosed can be used to define. Can be used to define the boundaries of CDRs exemplary conventions, such as the Kabat definition, the Chothia definition, and the AbM Contains the definition. In general, the definition of Kabat is based on sequence variability, Chothia The definition is based on the location of the structural loop regions and the AbM definition is based on the Kabat and Chothia is a middle ground between approaches. See, for example, Kabat, "Sequences of Proteins of Immunological Interest," National Institutes of Health, Bethesda, Md. There are also publicly available databases for .

In some embodiments of the present disclosure, the antibody or its binding to the antigen six CDRs from light chain variable region amino acid sequence pairs (HCVR/LCVR) Includes (HCDR1, HCDR2, HCDR3, LCDR1, LCDR2 and LCDRB).

In some embodiments of the present disclosure, the antibody or its binding to the antigen six CDRs with amino acid sequences In some embodiments of the present disclosure, the antibody or its binding to the antigen It contains the HCVR/LCVR amino acid sequence pairs.

Pharmaceutical Compositions The present disclosure describes methods comprising administering an IL-4R antagonist to a patient. wherein the IL-4R antagonist is included in a pharmaceutical composition.

The pharmaceutical compositions featured in the invention are prepared with suitable carriers and excipients. together with other agents that ensure appropriate transfer, distribution, tolerance, etc. is formulated. The formula that all pharmaceutical chemists know: Remington's Many in Pharmaceutical Sciences, Mack Publishing Company, Easton, PA suitable formulation can be found. These formulations, such as powders, pastes, ointments, gels, waxes, oils, lipids, containing lipids (cationic or anionic) vesicles (such as LIPOFECTINTTM), DNA conjugates, anhydrous absorption pastes, oil-in-water and water-in-oil emulsions, carbowax emulsions (various molecular weights containing polyethylene glycols), semisolid gels and carbowax Includes semisolid mixtures. See also Powell et al. "Compendium of excipients for According to the methods of the present disclosure, the dose of antibody administered to a patient is age and size, symptoms, health problems, route of administration, etc. may vary depending on the The preferred dose is typically based on body weight or It is calculated based on body surface area. Depending on the severity of the health problem Frequency and duration of treatment can be adjusted. Pharmaceuticals containing anti-IL-4R antibodies Effective dosages and schedules for administering the compositions have not been established empirically. can be determined; For example, the patient's progress can be monitored by periodic evaluation and the dose can be adjusted accordingly. Moreover, using methods well known in the art cross-species scaling of dosages can be achieved (e.g. Mordenti et al., 1991, Pharmaceut. Pic. &1351). into various delivery systems, e.g. liposomes, microparticles, microcapsules encapsulation, recombinant cells capable of expressing mutant viruses, 4432) and these are the pharmaceutical compositions featured in the invention. can be used for implementation. Application methods, but not limited to: intradermal, intramuscular, intraperitoneal, intravenous, subcutaneous, intranasal, Includes intratracheal, epidural and oral routes. Composition by any suitable means, e.g. by infusion or bolus injection, epithelial or mucocutaneous lining (e.g. oral mucosa, rectal and intestinal mucosa, etc.) and other It can be administered together with biologically active agents.

A pharmaceutical composition of the invention may be administered subcutaneously or injected with a standard needle and syringe. can be released intravenously. Additionally, regarding subcutaneous distribution, the invention is a A pen delivery device also has many applications in the delivery of pharmaceutical composition. has. Such a pen dispensing device may be reusable or disposable.

Generally containing a pharmaceutical composition in a reusable pen dispensing device, A replaceable cartridge is used. The entire pharmaceutical composition in the cartridge After administration and the cartridge is empty, the empty cartridge is immediately discarded and the pharmaceutical It can be replaced with a new cartridge containing the compound. The pen dispenser can be used again later. can be used. A replaceable cartridge in a disposable pen dispenser not found. Instead, the disposable pen dispensing device uses a dispenser within the device. It comes filled with pharmaceutical composition held in a reservoir. in the reservoir Once the pharmaceutical composition is finished, the entire device is discarded.

It can be used in a variety of ways for subcutaneous delivery of a pharmaceutical composition of the invention. It can be used in pen and autoinjector dispensing devices. a few of them 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 I, 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, existing inventions disposable with application in the subcutaneous delivery of a pharmaceutical composition Examples of pen dispensing devices include, but are not limited to: SOLOSTART'Vl pen (sanofi-aventis), FLEXPENTM (Novo Nordisk) and KWIKPENT'V' (Eli Lilly), SURECLICKTM Autoinjector (Amgen, Thousand Oaks, CA), PENLETTM (Haselmeier, Stuttgart, Germany), EPIPEN (Dey, L.P.) and HUMIRATM Pen (Abbott Labs, Abbott Park IL).

For direct administration to the sinuses, pharmaceutical compositions of the invention may be used, e.g. microcatheter (e.g. an endoscope and microcatheter), an aerosolizer, a powder dispenser, It can be administered using a nebulizer or an inhaler. Methods, an IL-4R antagonist in an aerosolized formulation to a subject in need. includes implementation. For example, aerosolized IL-4R antibodies may cause asthma in a patient. can be applied to treat. Aerosolized antibodies, e.g. in U88178098 It can be prepared as described.

In some cases, the pharmaceutical composition may be released in a controlled release system. One In practice a pump may be used (see Langer, above; Sefton, 1987, CRC Crit. Ref. Biomed. Eng 14:201). In another application, polymeric materials can be used; see Medical Applications of Controlled Release, Langer and Wise (eds.), 1974, CRC Pres., Boca Raton, Florida. Yet in another application A controlled release system can be placed near the target of the compound so that only a fraction of the systemic dose is needed (see, e.g. Goodson, are considered in the review.

Injectable preparations; intravenous, subcutaneous, intracutaneous and intramuscular injections, drip infusions, etc. May contain dosage forms for It can be injected The preparations can be prepared by known methods. For example, injectable preparations, For example, the antibody described above or its salt may be used for injections. in a conventionally used sterile aqueous medium or an oil medium. It can be prepared by dissolving, suspending or emulsifying.

As aqueous medium for injections, use, for example, glucose and other auxiliary agents, etc. containing an alcohol (e.g. ethanol), a polyalcohol (e.g. propylene glycol, polyethylene glycol), a nonionic surfactant [e.g. polysorbate 80, HCO-SO (hydrogenated castor oil polyoxyethylene (50 mol) adduct)], etc. with a suitable solubilizing agent such as physiological saline, an isotonic solution that can be used in combination There are. As oily media, for example benzyl benzoate, benzyl alcohol, etc. like a sesame oil, soybean oil, which can be used in combination with the solubilizing agent yagi, etc. is used. The injection prepared in this way is poured into a suitable ampoule. Advantageously, pharmaceutical preparations for oral or parenteral use as described above can be used. compositions, dosage in a unit dose suitable to fit into a dose of active ingredients It is prepared in forms. Such dosage forms in a unit dose, such as tablets, pills, capsules, injections (ampoules), suppositories, etc. Contains.

Example containing an anti-IL-4R antibody that can be used in the context of this invention pharmaceutical compositions, such as US Patent Application Publication No.

of the 1L-4R antagonist administered to a subject according to the methods of the present disclosure. The amount (eg, of anti-IL-4R antibody) is generally a therapeutically effective amount.

As used herein, a "therapeutically effective amount" means an IL-4R antagonist, It means an amount that produces one or more of the following: (a) a reduction in the incidence of asthma exacerbations; (b) one or more asthma-related an improvement in the parameter (as defined elsewhere in this document); and/or (c) one or more symptoms related to an inflammatory problem of the upper respiratory tract a detectable improvement in the symptom or sign. "A therapeutically effective amount" Additionally, the IL-4R antagonist inhibits the progression of asthma in a subject. It also includes an amount that reduces or delays.

In the case of an anti-IL-4R antibody, a therapeutically effective amount is approximately May have 600 mg of anti-IL-4R antibody. 300 mg anti-1L-4R antibody in some applications is applied.

The amount of lL-4R antagonist contained in individual doses depends on the patient's body weight. It can be expressed in milligrams of antibody per kilogram (i.e. mg/kg). For example IL-4R antagonist to a patient at approximately 0.0001 to approximately 10 kg of the patient's body weight. It can be administered at a dose between mg/kg.

Combination Therapies According to some embodiments, the methods of the present disclosure include a 1L-4R antagonist. optional use of one or more additional therapeutic agents in combination includes implementation. As used herein, the term "in combination with" means IL- before, after or with the pharmaceutical composition containing the 4R antagonist. This means that additional therapeutic agents are administered simultaneously. Some In applications the term "in combination with". an 1L-4R antagonist and a second It involves sequential or simultaneous administration of the therapeutic agent. The current explanation is to treat asthma or a related health problem or complication, or to treat at least one It includes methods to reduce exacerbation, which may be additive or synergistic. an IL-4R in combination with a second therapeutic agent to provide activity involves the administration of the antagonist. For example, when administered "before" the pharmaceutical composition containing the IL-4R antagonist, additional therapeutic agent, the pharmaceutical composition containing the IL-4R antagonist Approximately 72 hours, approximately 60 hours, approximately 48 hours, approximately 36 hours from application hours, about 4 hours, about 2 hours, about 1 hour, about 30 minutes, about 15 It can be applied minutes or approximately 10 minutes before. Containing lL-4R antagonist When administered "after" the pharmaceutical composition, the additional therapeutic agent contains the IL-4R antagonist. Approximately 10 minutes, approximately 15 minutes after application of the pharmaceutical composition containing minutes, about 30 minutes, about 1 hour, about 2 hours, about 4 hours, about 6 hours, approximately 48 hours, approximately 60 minutes, or approximately 72 hours. PROVINCE- "Simultaneous" administration with the pharmaceutical composition containing the 4R antagonist may provide additional therapeutic benefits. depending on the administration of the agent to the subject, the pharmaceutical composition containing the 1L-4R antagonist. in a separate dosage form (before, after or simultaneously) in less than minutes administered or the subject contains both the additional therapeutic agent and the IL-4R antagonist. This means that it is administered as a single combined dosage formulation.

Additional therapeutic agent such as another IL-4R antagonist, an IL-1 antagonist (e.g. US Patent No. an IL-6 antagonist, including an IL-1 antagonist disclosed in US 6,927,044 antagonist, an IL-6R antagonist (e.g., as disclosed in US Patent No. 7,582,298 an anti-IL-6R antibody), a TNF antagonist, an IL-8 antagonist, an IL-9 antagonist, a 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 embodiments, the pharmaceutical composition containing an IL-4R antagonist is a long-acting betase agonist and an inhaled corticosteroid (e.g. fluticasone + salmeterol [e.g. Advair® (GlaxoSmithKline)]; or budesonide + formoterol [e.g., Symbicort® (Astra It is administered in combination with a combination containing Zeneca)]).

Application Regimes Multiple doses of an IL-4R antagonist according to some embodiments of the present disclosure, a balance may be administered over a specified period of time. Such methods allow one subject to It involves administering multiple doses of the lL-4R antagonist in a sequential manner. Here "Sequential administration" as used means that each dose of the lL-4R antagonist is subject at a different point in time, such as at predetermined intervals (e.g. applied on different days separated by hours, days, weeks or months) It means. The present disclosure indicates that a single initial dose of an IL-4R antagonist followed by one or more secondary doses of the lL-4R antagonist and optional as a sequential dose of one or more tertiary doses of the IL-4R antagonist to a patient. It includes methods that include the application of The present disclosure provides that a pharmaceutical composition containing an IL-4R antagonist is approximately four times a week, twice a week, once a week, once every two weeks, once every three weeks, once every four weeks, once every five weeks, once every six weeks, once every eight weeks, once every ten weeks every two weeks or less frequently as long as therapeutic response is achieved Includes methods involving the application of balance. Contains an anti-1L-4R antibody In some embodiments involving the administration of a pharmaceutical composition, once a week A dosing amount of approximately 75 mg, 150 mg or 300 mg may be applied. An anti-lL-4R another method involving the administration of a pharmaceutical composition containing the antibody In applications, an amount of approximately 75 mg, 150 mg or 300 mg is administered every two weeks. dosing can be applied. A pharmaceutical composition containing an anti-1L-4R antibody In other applications involving the administration of approximately 75 mg, 150 mg every three weeks or a dosage of 300 mg may be applied. Containing an anti-IL-4R antibody In other applications involving administration of a pharmaceutical composition, every four weeks A dosing amount of approximately 75 mg, 150 mg or 300 mg may be applied. An anti-IL-4R another method involving the administration of a pharmaceutical composition containing the antibody In applications, an amount of approximately 75 mg, 150 mg or 300 mg is administered every five weeks. dosing can be applied. A pharmaceutical composition containing an anti-1L-4R antibody In other applications involving the administration of approximately 75 mg, 150 mg every six weeks or a dosage of 300 mg may be applied. Containing an anti-IL-4R antibody In other embodiments involving the administration of a pharmaceutical composition, every eight weeks A dosing amount of approximately 75 mg, 150 mg or 300 mg may be applied. An anti-lL-4R another method involving the administration of a pharmaceutical composition containing the antibody In applications, an amount of approximately 75 mg, 150 mg or 300 mg is administered every twelve weeks. dosing can be applied. A preferred route of administration is subcutaneous. more preferably refers to a period of (n x 7 days), where "n" is, e.g. 1, Indicates the number of weeks, 2, 3, 4, 5, 6, 8, 12 or more. It refers to the temporal sequence of its implementation. Therefore i'beginning dose" is the dose administered at the start of the treatment regimen (also called "baseline dose" also called ); "secondary doses" are doses administered after the initial dose; and "tertiary doses" are doses administered after secondary doses. Initial, secondary and tertiary doses may all contain the same amount of IL-4R antagonist, but in general, They can be distinguished from each other in terms of frequency of application. However, in some applications, the amount of IL-4R antagonist included in the initial, secondary and/or tertiary doses, differ from each other during the course of treatment (e.g. up and down depending on the situation). can be adjusted downwards). In some applications, two or more (e.g. 2, 3, 4 or ) dose is administered as "loading doses" at the beginning of the treatment regimen, subsequent doses are administered on a less frequent basis (e.g. "maintenance doses"). In one application, The maintenance dose may be lower than the loading dose. For example, 600 mg of IL-4R antagonist one or more loading doses, followed by approximately 75 mg to approximately 300 mg Maintenance doses of mg may be administered.

In an exemplary embodiment of the present disclosure, each secondary and/or 14% or more) is applied weeks later. "The dose that immediately precedes it" In a series of multiple administrations, the dose of IL-4R antagonist is the patient is given the next dose immediately in the sequence, without another dose in between. It means the dose applied before administration.

The methods provide a patient with the ability to administer an IL-4R antagonist to any number of secondary and/or may include the administration of tertiary doses. For example, in some applications, the patient Only a single secondary dose is administered. In other applications, the patient is given two or more Secondary doses (e.g. 2, 3, 4, 5, 6, 7, 8 or more) are administered. Likewise some In most applications, only a single tertiary dose is administered to the patient. In other applications give the patient two or more (e.g., 2, 3, 4, 5, 6, 7, 8, or more) tertiary doses is applied.

In applications involving more than one secondary dose, each secondary dose is combined with other secondary doses. It can be applied with the same frequency. For example, each secondary dose is given to the patient immediately It can be administered 1 to 2 weeks after the previous dose. Similarly, more than one In applications involving tertiary doses, each tertiary dose is the same as the other tertiary doses. Can be applied cyclically. For example, each tertiary dose is administered to the patient immediately before It can be administered 2 to 4 weeks after the next dose. Alternatively, secondary and/or tertiary The frequency with which doses are administered to a patient may vary during the course of the treatment regimen. Clinic After the examination, the frequency of application depends on the needs of each patient. It can also be adjusted during the course of treatment.

The present disclosure provides that an IL-4R antagonist and a second therapeutic agent are effective against asthma or administered sequentially to a patient to treat a related health problem Contains methods. In some embodiments, the methods include a combination of an IL-4R antagonist. or multiple doses of a second therapeutic agent followed by one or more It involves administering a dose (e.g., 2, 3, 4, 5, 6, 7, 8 or more). For example one or more doses of approximately 75 mg to approximately 300 mg of IL-4R antagonist After administration, a second therapeutic agent (such as an inhaled corticosteroid or a beta2-agonist or any other described elsewhere in this document. one or more doses (e.g., 2, 3, 4, 5, 6, 7, 8 or more) of the therapeutic agent), to relieve, reduce or improve one or more symptoms of asthma applicable. In some applications, the IL-4R antagonist may be administered in one or more doses. (e.g., 2, 3, 4, 5, 6, 7, 8, or more) to reduce one or more asthma-related symptoms. An improvement in many parameters can be achieved, and then at least one of the asthma symptoms can be improved. A second therapeutic agent may be administered to prevent recurrence of the symptom.

Alternative embodiments include simultaneous administration of an IL-4R antagonist and a second therapeutic agent. regarding its implementation. For example, an IL-4R antagonist has one or more dose (e.g. 2, 3, 4, 5, 6, 7, 8 or more) is administered and a second therapeutic agent, It is applied frequently. In some applications, the second therapeutic agent consists of an IL-4R antagonist. It is applied before, after or simultaneously.

Treatment Populations The methods of the present disclosure employ a therapeutic composition comprising an 1L-4R antagonist, It involves applying a needful balance. The phrase "a subject in need" refers to asthma (e.g. eosinophilic asthma, including moderate to severe eosinophilic asthma) or has more than one symptom or sign or has been diagnosed with asthma It means human or non-human animal. For example, a "subject in need", e.g. before treatment, e.g. impaired FEV1 (e.g. less than 2.0 L), impaired AM PEF (e.g. at least An ACQ5 score of , waking up at least once per night, and/or a SNOT-22 of at least 20 showing (or having shown) one or more parameters associated with asthma, such as score may include subjects. In various applications, methods provide mild, It can be used to treat moderate to severe and severe asthma.

In a related embodiment, a "subject in need" prior to receiving an IL-4R antagonist inhaled corticosteroid (ICS)/long-acting betase-adronergic antagonist (LABA) may be a subject who has been prescribed or is currently using the combination. Includes budesonide/formotorol combination therapy. For example the current description is lL-4R regularly for two weeks or more immediately before administration of the antagonist. involving the administration of an IL-4R antagonist to a patient receiving a course of ICS/LABA. (such previous treatments are referred to herein as "background treatments"). mentioned). The present statement does not apply to the initial administration or initial administration of the IL-4R antagonist. background treatments immediately before application (e.g. 1 day to 2 weeks before) It includes the therapeutic methods used. Alternatively, background treatments, IL-4R may be continued in combination with administration of the antagonist. It's different again In embodiments, the amount of the ICS component, the LABA component, or both, IL-4R It is gradually reduced before or after the start of antagonist administration.

In some practices, the current statement requires patients with persistent asthma to be treated for at least 212 months. Includes methods for doing so. In one embodiment, a patient with persistent asthma is may be resistant to treatment with a therapeutic agent such as a corticosteroid and may be refractory to existing methods IL-4R antagonist can be administered accordingly.

In some embodiments, a "subject in need" may use a biomarker associated with asthma. It may be a subject with increased levels. Examples of biomarkers associated with asthma, including, but not limited to, IgE, thymus, and activation regulatory chemokine (TARC), eotaxin-S, CEA, YKL-40 and periostin. In some applications "need" "a subject with current eosinophils of 2 300/ul or a sputum eosinophil level of 2 3% may be a test subject. In one embodiment, a "subject in need" receives fractional exhaled nitric oxide Increased levels of bronchial or airway inflammation as measured by (FeNO) There may be a subject with

For the purposes of the invention, a normal IgE level in healthy subjects is approximately Less than 100 kU/L (e.g., ImmunoCAP® assay [Phadia, Inc. Portage, MI] as measured using). Hence the current explanation. an increased serum IgE level, i.e. greater than approximately 100 kU/L, greater than approximately 150 kU/L, approximately greater than kU/L, greater than approximately 3500 kU/L, greater than approximately 4000 kU/L, a serum IgE greater than approximately 4500 kU/L or greater than approximately 5000 kU/L Select a subject who shows a level of IL-4R and use an IL-4R antagonist therapeutically. comprising administering to the subject a pharmaceutical composition containing an effective amount of Contains methods that

TARC levels in healthy subjects range from 106 ng/L to 431 ng/L, with an average is approximately 239 ng/L. (An exemplary determination for measuring the TARC level system, Cat. by R&D Systems, Minneapolis MN. No. TARC with DDNOO is a quantitative ELISA kit). Hence the current explanation is an increased TARC level, i.e. greater than ng/L, greater than approximately 3000 ng/L, greater than approximately 3500 ng/L, select a subject showing a serum TARC level greater than ng/L and an IL-4R of a pharmaceutical composition containing a therapeutically effective amount of the antagonist. Includes methods involving the application of balance.

Eotaxin-B belongs to a group of chemokines secreted by airway epithelial cells. It is upregulated by the Th2 cytokines IL-4 and IL-13 (Lilly et al.). elevated, for example, more than about 100 pg/ml, more than about 150 pg/ml, greater than approximately 200 pg/ml, greater than approximately 300 pg/ml, or approximately 350 An IL-4R antagonist should be used to treat patients with levels greater than pg/ml. It includes methods of implementation. Serum eotaxin-3 levels Periostin, an extracellular matrix involved in Th2-mediated inflammatory processes It is protein. Periostin levels have been found to be upregulated in patients with asthma involves administering an IL-4R antagonist to treat patients with elevated Contains methods that

Fractional exhaled NO (FeNO) is a sign of bronchial or airway inflammation. It is a biomarker. In response to inflammatory cytokines including FeNO, IL-4 and IL-13 produced by airway epithelial cells (Alwing et al. 1993, Eur Respir J 6: 1368- 1370). FeNO levels in healthy adults range from 2 to 30 parts per billion (ppb).

An exemplary assay for measuring FeNO is available from Aerocrine AB, Solna, It can be achieved using a Swedish NIOX device. This review It can be performed before spirometry and after fasting for at least one hour. Available explanation is those with elevated exhaled NO (FeNO) levels, i.e. more than about 30ppb high, higher than about 31 ppb, higher than about 32 ppb, higher than about 33ppb High, greater than approximately 34 ppb or greater than approximately 35 ppb It includes methods comprising administering an 1L-4R antagonist.

Carcinoembryogenic antigen (CEA), associated with non-neoplastic diseases of the lung (Marechal et al. 1988, Anticancer Res 8: 677- 680). CEA levels in serum can be measured by ELISA. Current description. CEA levels elevated, such as greater than approximately 1.0 ng/ml, greater than approximately 1.5 ng/ml, greater than approximately 2.0 ng/ml, greater than approximately 2.5 ng/ml, greater than approximately 3.0 ng/ml high, greater than approximately 4.0 ng/ml or greater than approximately 5.0 ng/ml methods comprising administering an IL-4R antagonist to patients.

YKL-40 [N-terminal amino acids are tyrosine (Y), Izine (K) and Iucine (L) and (so named because its molecular weight is 40kD), upregulated chitinase-like enzymes, which have been found to be associated with asthma exacerbation, IgE, and eosinophils. For example, it is measured by ELISA. The current explanation is for patients with elevated YKL-40 levels, e.g. greater than approximately 40 ng/ml, greater than approximately 50 ng/ml, greater than approximately 100 ng/ml high, greater than approximately 150 ng/ml, greater than approximately 200 ng/ml, or approximately It involves administration of an IL-4R antagonist to patients with levels greater than 250 ng/ml. It includes methods that

Induced sputum eosinophils and neutrophils are well-known markers of airway inflammation. It is induced by inhalation of hypertonic saline solution and is produced according to methods known in the art. according to, for example, cell counting according to the guidelines of the European Respiratory Society It is processed in terms of The current explanation is that the level of sputum eosinophils is elevated, For example, patients with more than about 2.5% or more than 3% should receive an IL-4R includes methods comprising administering an antagonist.

Pharmacodynamics for the Evaluation of Asthma-Related Parameters Methods The present disclosure relates to a drug containing an interleukin-4 receptor (IL-4R) antagonist. associated asthma in a subject in need as a result of administration of the pharmaceutical composition. for the evaluation of one or more pharmacodynamic parameters Also includes methods. A reduction in the incidence of an asthma exacerbation (see above as described) or an improvement in one or more asthma-related parameters (as described above) one or more of the pharmacodynamic effects associated with asthma (as described above). may be correlated with improvement in the parameter; However, such a correlation does not exist in all cases. (a) biomarker expression levels; (b) serum protein and RNA analysis; (c) induced sputum eosinophils and neutrophil levels; (d) exhaled nitric oxide (FeNO); and (e) kari eosinophil count. "An improvement in a pharmacodynamic parameter associated with asthma", for example, one or more of these, such as TARC, eotaxin-3, or IgE, relative to baseline a decrease in biomarker, sputum eosinophils or neutrophils, FeNO or blood It means a decrease in eosinophil count. As used here. with asthma The term "baseline" refers to a patient's The asthma-related pharmacodynamic parameter of numerical values before or during the application of the pharmaceutical composition. It means value.

To evaluate a pharmacodynamic parameter associated with asthma, at baseline and after administration of the pharmaceutical composition of the present invention. amount at a point in time is taken. For example, a pharmacodynamics associated with asthma parameter after initial treatment with a pharmaceutical composition of the present invention. week, 21 weeks, 22 weeks, 23 weeks, 24 weeks or longer can then be measured. At a certain point in time after starting treatment the difference between the value of the parameter and the value of this parameter at the baseline, an "improvement" in an asthma-related pharmacodynamic parameter (e.g. measured specific depending on the parameter, an increase or decrease as the case may be) It is used to reveal whether something has occurred or not.

In some embodiments, administration of an IL-4R antagonist to a patient may It causes a change such as a decrease or increase in the expression of the biomarker.

Biomarkers associated with asthma include: (a) total IgE; (b) thymus and activation regulatory 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 asthmatic patient. administration may cause one or more decreases in TARC or eotaxin-3 levels. or may lead to a decrease in total serum IgE levels. This decrease, lL-4R following the administration of the antagonist, at week 1, week 2, week 3, week 4, . can be detected after a week or more. Biomarker expression, can be determined by methods known in the art. For example, protein levels can be measured by ELISA (Enzyme Immunosorbent Determination) or RNA levels, polymerase chain It can be measured by reverse transcription (RT-PCR) coupled to the reaction.

Biomarker expression, protein and RNA detection in serum as described above can be determined by . Serum samples were also subjected to treatment with a lL-4R antagonist, lL-4/lL-13 additional protein or protein related to signaling, asthma, atopy or eosinophilic diseases It can also be used to monitor RNA biomarkers (e.g. soluble lL-4R0i, lL-4, IL- 13, by measuring periostin). In some applications, we can measure RNA levels, such as biomarkers RNA samples are used to determine RNA levels (non-genetic analysis); and RNA sampling for transcriptome sequencing in other applications are used (e.g. genetic analysis). EXAMPLES Care must be taken to ensure that the numbers used (e.g. amounts, temperature, etc.) are correct. Although shown, there may be some experimental errors and deviations. should be expected. Unless otherwise stated, parts are parts by weight, molecular weight is the average molecular weight, the temperature is in Celsius, and the pressure is atmospheric or It is close to the atmosphere. Example 1. Production of Human Antibodies Against Human IL-4R US Patent No. Human anti-hlL-4R antibodies were produced as described in No. 7,608,693.

In Table 1, selected anti-1L-4R antibodies and their corresponding antibody heavy and light chain variable region amino acid sequence pairs and CDR nomenclature Sequence identifiers for amino acid sequences are introduced.

SEQ ID NO's: AntikorAdi HCVR HCDR1 HCDR2 HCDR3 LCVR LCDR1 LCDR2 LCDR3 SEQ ID NO's: Antibody Name HCVR HCDR1 HCDR2 HCDR3 LCVR LCDR1 LCDR2 LCDR3 The exemplary 1L-4R antagonist used in the following Examples is listed in Table 1. It is a human anti-IL-4R antibody designated H1H098-b (here also referred to as "mAb1"). (also referred to as). Example 2: Including Asthma Patients with Chronic Hyperplastic Eosinophilic Sinusitis Subcutaneous administration in patients with moderate to severe persistent eosinophilic asthma Clinical Trial Study of Anti-IL-4R Antibody (mAb1) Administered as A. Study Objectives and Overview Partially with inhaled corticosteroid (ICS) and long-acting beta2 agonist (LABA) therapy Patients with controlled/uncontrolled moderate to severe persistent eosinophilic asthma 300 mg mAb1 or placebo subcutaneously once weekly for 12 weeks A randomized, placebo-controlled, double-blind, parallel group study with has been carried out. The primary aim of the study was to determine the 12-week mAb1 administered subcutaneously once a week for moderate to severe persistent on reducing the incidence of asthma exacerbations in patients with eosinophilic asthma was to investigate its effects. Secondary objectives of the study were to investigate moderate to severe persistent eosinophilic administered subcutaneously once a week for 12 weeks in asthma patients. To evaluate the safety and tolerability of mAb1 and to evaluate moderate to severe persistent subcutaneous dosing once weekly for 12 weeks in patients with eosinophilic asthma The aim was then to evaluate mAb1 serum concentrations.

Prior to screening, patients should be on ICS/LABA combination therapy for at least 1 month. (also referred to as "background therapy") and required to be on a stable dose with any of the formulations: Futicasone/salmeterol combination therapy Budesonide/formoterol combination therapy (Symbicort® 160/9 ug BID or 320/9 ug BID); or Mometasone/formoterol combination therapy (Dulera® 200/10 ug BID or Patients taking budesonide/formoterol or mometasone/formoterol, was switched to an equivalent dose of fluticasone/salmeterol at randomization (Day 1) and Patients receiving fluticasone/salmeterol remained on the same background therapy.

Patients meeting inclusion and exclusion criteria (see below) Randomized to one of the following treatments: once a week for 12 weeks 300 mg mAb1 administered subcutaneously; or once a week for 12 weeks placebo administered subcutaneously. The study included a 2-week screening period, a 4-week background therapy stabilization phase. A 12-week treatment period including a 12-week treatment period and an 8-week background period after randomization. therapy withdrawal phase, followed by an 8-week post-treatment follow-up phase. It includes the period.

Algorithm for Withdrawal of background therapy (ICS/LABA): Patients were assigned to supportive therapy or treatment with 300 mg mAb1 (or placebo). on BID fluticasone/salmeterol background therapy for 4 weeks after initiation continues to remain. At week 4 after randomization, patients were BID from fluticasone/salmeterol combination therapy to an equivalent dose of fluticasone monotherapy. or Flovent® HFA - . LABA component (i.e. salmeterol) has been discontinued. Starting at the 6th week, subsequent During examinations, the patient meets any of the asthma exacerbation criteria (see below: If not met (as defined), the fluticasone dose was reduced by approximately 50%.

If no asthma exacerbations occur, ICS withdrawal It was administered according to the following dosing schedule: Background therapy stable phase Background therapy withdrawal phase Week 4 Week 6 Week 7 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 4 Week 6 Week 7 Fluticasone/salmeterol (MDI): Fluticasone (MDI): 220 ug 110 ug 44 ug 0 ug Following completion of 12 weeks of treatment with the investigational product (or early after discontinuation), patients should be treated with their original fluticasone/salmeterol, budesonide/formoterol or mometasone/formoterol doses (doses at entry into the study) and relieve symptoms for an additional 8 weeks before a final safety assessment. albuterol or Ievalbuterol as needed as an off-study medication to control has been given.

Adult patients were included in the study according to the following criteria: (1) Global Asthma According to the Initiative (GINA) 2009 Guidelines, at least 2 to 12 months prescribed by the physician It is a diagnosis of long-term persistent asthma and the patient probably has airway inflammation. is eosinophilic and (2) the patient has asthma according to the following criteria: Partially with combination therapy including corticosteroids/long-acting beta-agonists controlled or uncontrolled: (i) at least 1 month before screening Stable dose of fluticasone/salmeterol combination therapy (DPI formulation: or budesonide/formoterol combination therapy (16019 µg BID or or mometasone/formoterol combination therapy (200/10 µg BID or blood eosinophils of 2 300 cells/pl or 2 3% during the screening phase sputum eosinophils; (iii) 2 1.5 and 5 3.0 Juniper asthma control questionnaire (5 questions) at screening version, ACQ) score; (iv) during the screening phase (maximum 3 trials) and first dose FEV1 2 50% normal prediction on the day before randomization (maximum 3 trials); (v) one or more systemic diseases due to worsening asthma in the 2 years before screening Treatment with (oral and/or parenteral) steroid administration or hospitalization or emergency room visits due to worsening asthma; and (vi) to meet the criteria Proven reversibility history over 12 months screening phase - screening phase FEV1* after 200 µg to 400 µg (2 to 4 inhalations) of albuterol during positive methacholine challenge history (PD20 methacholine s 8 mg). Inhaled corticosteroids and medium to high doses of long-acting beta egonists (ADVAIR®, SYMBICORT® or DULERA®) and partially controlled or uncontrolled during the screening phase blood eosinophils of 300 cells or more per microliter or 3% or more Moderate to severe asthma patients with sputum eosinophils were included in the study.

Patients who met all inclusion criteria were excluded according to the following exclusion criteria. Screened for: (1) patients younger than 18 years or older than 65 years; (2) Clinical findings that are suggestive of an unknown disease and require more detailed evaluation associated abnormal laboratory values; (3) chronic obstructive pulmonary disease (COPD) and/or other lung diseases that impair respiratory function tests; (4) patients who require beta adrenergic receptor blockers for any reason; (5) current smoker or ex-smoker within 6 months before screening; (6) history of smoking >10 packs of cigarettes per year; (7) asthma within 2 months before screening hospitalization or emergency care examination due to exacerbation; (8) study plans to start allergen immunotherapy during pregnancy; (9) 5 days of antibody before scanning less than the half-life, but not less than 30 days period or, if the half-life of the antibody is unknown, before screening. exposure to another investigational antibody for a period of at least 6 months; (10) having previously participated in the current study; (11) patient, researcher, researcher be a family member or employee in the research field; (12) known or suspected noncompliance, alcohol or drug use; (13) follow the study's procedures inability to do so (for example, due to language problems or psychological disorders); (14) sleep reversal of routine (for example, working the night shift); (15) QTc interval treatment with drugs known to cause prolongation; (16) ICS (e.g., active or inactive lung tuberculosis) or LABA (e.g. diabetes, cardiovascular diseases, hypertension, hyperthyroidism, thyrotoxicosis, etc.) is contraindicated, serious disease(s); (17) within 2 months before screening or within 6 months before screening more than 3 courses of injectable glucocorticosteroids or oral systemic use of glucocorticosteroids; (18) alone or with a non-steroidal controller (fluticasone/salmeterol combination therapy, budesonide/formoterol combination therapy variable ICS (other than mometasone/formoterol combination therapy) preliminary examination with doses; (19) patients taking prohibited concomitant medications (see below listed); (20) known allergy to doxycycline or related compounds; (21) being pregnant or intention to become pregnant, breastfeeding, or using effective birth control during the course of the study unwillingness to use the method; and (22) a recent history of parasitic infection. or having traveled to a parasitic endemic area within 6 months before screening.

Patients were given a constant dose of background asthma therapy during the first four weeks of the study. dose remained, and then the dose of background therapy was gradually increased. has been reduced. First, the long-acting beta agonist component of background therapy was introduced at week 4. withdrawn and then inhaled corticosteroid dose every 2 weeks until week 12 has been halved. Patients were kept until the end of the study or if they had an asthma exacerbation or receive study treatment until withdrawn for any other reason. It continued.

B. Working Treatments Investigational Product: Sterile mAb1 150 mg/mL SC in a 5 mL glass vial solution for injection is provided. Each vial contained a drawable volume of 2 mL. One dose of 300 mg at the study site once a week in the morning for 12 weeks It was administered subcutaneously. Placebo: SC in the same 5 mL glass vial. A sterile placebo for injection was provided. Each vial contains a drawable volume of 2 mL. It contains. Placebo at the study site once a week in the morning for 12 weeks Concomitant use of the following medications was not allowed during the duration of the study: fluticasone/salmeterol combination therapy or fluticasone administered according to protocol (or budesonide/formoterol or mometasone/formoterol during the screening period) another inhaled steroid; systemic or ocular steroids; according to protocol other than the salmeterol component of the administered quticasone/salmeterol combination therapy. LABA's; any other ICS/LABA combination other than those given above product; any inhaled anti-cholinergic agent (e.g. ipratropium bromide and tiotropium); methylxanthines (theophylline, aminophyllines); chromones; anti-IgE therapy, inhibitors.

C. Effectiveness of Treatment The primary endpoint of this study was defined as any of the following: The occurrence of an asthma exacerbation: (1) on two consecutive days, with morning peak decrease in expiratory flow (PEF) of 30% or more from baseline; or (2) over a 24-hour period (compared to baseline) on 2 consecutive days. relaxation Taking six or more additional puffs of albuterol or Ievalbuterol to ensure or (3) a worsening of asthma as determined by the investigator Requires: (a) systemic (oral and/or parenteral) steroid therapy or (b) increase in lCS by 2 to 4 times the last dose taken before discontinuation of the study, or (c) hospitalization. Secondary endpoints of the study were the following parameters: included average changes: (1) 1 in liters as measured at each examination forced expiratory volume per second (FEV1): (2) liters per minute as measured daily Morning and evening peak expiratory flow rate (AM PEF and PM PEF) in terms of (3) Daily Albuterol/Levalbuterol use as inhalation/day; (4) Five at each examination One-item Asthma Control Questionnaire (ACQ5) score and (5) as measured daily night awakenings (number per night) and (6) assess upper airway symptoms as assessed at baseline and at the end of treatment (at Week 12) 22-item Sino-Nasal Outcome Test (SNOT-22). Secondary endpoints also include two consecutive increased daily morning PEF with a decrease of 30% or more from baseline albuterol or albuterol compared to baseline over a 24-hour period on 2 consecutive days It also included the proportion of patients showing PEF, ACQ5, asthma symptom scores, night Awakenings and drug use for relaxation were recorded in an electronic diary. has been recorded. Daily nights for the previous 7 days, ranging from 0 to 10 The average of the awakenings was taken. Morning and evening asthma symptom scores, 5 An unvalidated patient-reported study evaluated on a one-point Likert-type scale. results, higher scores indicate worse results (Table 2). Patients recorded global symptom scores twice daily before measuring PEF. has recorded. Data are averaged over the 7 days prior to the specified time point. has been described (see e.g. Figures 26A and 268).

Table 2: Asthma Symptom Score Evaluation A) Morning symptom score: A) Morning symptom score: 0 = No asthma symptoms, slept through the night 1 = Slept well, but had some complaints in the morning. night waking it didn't happen 2 = Awakened once due to asthma (including early awakening) 3 = Awakened several times due to asthma (including waking up early) 4 = Had a bad night, awake most of the night due to asthma is left out B) Evening symptom score: 0 = Very good, no asthma symptoms 1 = An episode of wheezing, cough, or shortness of breath 2 = More than one wheezing, coughing or wheezing that does not interfere with normal activities. episode of shortness of breath 3 = Most of the day, interfering with normal activities to some extent wheezing, cough, or shortness of breath 4 = I have very bad asthma. Inability to perform daily activities as usual D. Monitoring Adverse Events Safety throughout the study by monitoring Adverse Events and Serious Adverse Events has been evaluated.

An Adverse Event (AE) occurs in a subject or clinical situation to which a pharmaceutical product is administered. It is any undesirable medical event in the research subject. Therefore, an AE is a medical with the use of a medicinal product, whether or not it is considered to be associated with the (investigational) product. any undesirable or unintended sign that is temporally associated (including abnormal laboratory findings), symptom, or disease. AEs also including: temporally associated with the use of study drug, any worsening of a pre-existing health problem (i.e. frequency and/or any clinically significant change in severity): clinically abnormal laboratory findings that are considered significant; and any unwanted medical event.

A Serious Adverse Event (SAE) is any adverse event that results in death at any dose. It is a medical incident; is life-threatening; patient's hospitalization or current requires prolonged hospitalization; persistent or significant disability causes incapacity; It is a congenital anomaly/birth defect; or a significant It is a medical event.

E. Statistical methods For the primary analysis of the proportion of patients experiencing an asthma exacerbation, use the SAR group A logistic regression model was used to compare with placebo. This model for treatment and stratification factor (prior ICS/LABA combination therapy dose) Includes periods. Primary analysis was based on patients who had received at least one dose of the investigational medicinal product (IMP). modified intention-to-treat (mlTT) including all randomized patients with It was carried out according to the population. To strengthen primary analysis Stratified chi-square test was also used.

For secondary efficacy endpoints, compared to baseline, except SNOT-22 A mixed-effects model incorporating a change-repeated measures (MMRM) approach was analyzed using . This model uses baseline values as response variables. changes in values until the 12th week and treatment factors (fixed effects), stratification factor, examination, treatment-examination interaction, baseline value and baseline-examination interaction. Compared to baseline at week 12 Statistical inferences for treatment comparisons for changes mixed effect derived from the model. The change in SNOT-22 from baseline is a covariance Analysis (ANCOVA) was used to estimate missing data. End-of-treatment measurements were used. Pharmacodynamic effects, MMRM models It was evaluated post hoc using Only one primary endpoint and Because this was an analysis, adjustments for multiplicity were not made. AEs, laboratory parameter, vital signs, ECG, clinical laboratory observations, and physical Safety variables including examinations were evaluated using descriptive statistics. has been summarized.

Demographic and clinical characteristics were summarized using descriptive attributes. secondary and Plots of pharmacodynamic variables, time versus baseline with standard error It is presented as the average change within. Treatment derived from MMRM analysis Comparison of effects, least squares mean at week 12 relative to baseline Based on change (95% confidence intervals [CI]).

F. Results 104 randomized patients who completed or discontinued the treatment phase of the study The results observed in all (out of 491 individuals screened) are summarized below. All randomized patients received study treatment and were included in the mITT population has been done. Characteristics at baseline were similar between groups. Demographic and Clinical characteristics were also similar between the two groups (Table 3). As stated above, Patients were treated with 300 mg subcutaneous mAb1 or placebo once weekly. Study treatment period 86.51% and 67.3% of mAb1 and placebo patients, respectively It was completed by (Figure 25). The most common reason for abandoning treatment There was a lack of efficacy, occurring more frequently with placebo (212%) than with mAb1 (19%). It has happened.

Table 3. Baseline Demographic and Clinical Analysis of Treatment Groups Characteristics.* 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 (% of predicted value) 72.0 ± 12.7 PEF (I/minute) ACQS score 2.1 ± 0.5 Asthma symptom score Daily night awakenings 0.21 ± 0.50 Albuterol or levalbuterol inhalations/24 0 ± 1.8 hourly period Eotaxin-3 (pg/ml) 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 and minus values are mean ± SD. ACQS, Asthma Control Questionnaire (5-question version); FeNO, fractional exhaled nitric oxide; FEVi, 1 forced expiratory volume per second; IgE, immunoglobulin E; PEF, peak expiratory volume; SNOT-22, 22-item Sinonasal Outcome Test, TARC stands for thymus and activation regulatory chemokine. (i) Primary Efficacy Endpoint The incidence of asthma exacerbations in the placebo and mAb1 treatment groups is shown in Table 4 is offered.

Table 4: Incidence of Asthma Exacerbations in the mITT population Placebo (N=52) mAb1 (N=52) Patients with Asthma Exacerbation 23 (442%) 3 (58%) A total of 26 asthma exacerbations occurred during the treatment period and no patient developed asthma. He was not hospitalized due to his exacerbation. 23 patients (442%) in the placebo group experienced an asthma exacerbation, and only 3 patients (58%) in the mAb1 treatment group had asthma. experienced an exacerbation. The risk ratio was 0.077 (p < 0.0001) and the relative risk reduction was approx. Among the 26 asthma exacerbations encountered during this study, pre-event Treatment with 4 or more times the dose of systemic corticosteroids or inhaled corticosteroids 9 were considered severe, as identified on the form as needing urgent intervention.

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 Non-Severe Asthma Exacerbations 15 (28.8%) 2 (3.8%) As shown in Table 5, eight severe asthma exacerbations occurred in the placebo group. observed, and only 1 severe asthma exacerbation in the mAb1 treatment group. has been observed. The remaining 15 in the placebo group and 2 in the mAb1 group exacerbation, decrease in morning PEF and/or increase in albuterol/evalbuterol use. based on the definition of exacerbation in the protocol. As shown in Table 6, in the active treatment group, despite steroid withdrawal, during the course of the study. A sustained improvement against baseline was observed in all parameters.

Table 6. Exacerbation Events Result Placebo (N = mAb1 (N = 52) 52) 2 30% reduction from baseline albuteroI/Ievalbuterol inhalation Systemic steroid therapy 5 (9.6) 1 (1.9) 2 4-fold increase in ICS compared to previous dose 3 (5.8) 0 Hospitalization O 0 *4 placebo patients met both PEF and systemic steroid treatment criteria, 1 The placebo patient meets both PEF and additional albuterol/evalbuterol use criteria. has met. With mAb1, time to flare was longer (Figure 1) and An analysis of time to asthma exacerbation using a Meier Plot, steroid withdrawal Patients have a higher risk of developing exacerbations due to withdrawal treatment with mAb1, including after 8 weeks when the patient is at risk. revealed that its effect continued over time (Figure 1).

Only 1 patient in the placebo group showed a combined asthma event. a combined incident asthma, morning PEF 30% or greater above baseline on 2 consecutive days over a 24-hour period on 2 consecutive days with a decrease (compared to baseline) It is defined as taking 26 additional puffs of albuterol or levalbuterol. (ii) Other Efficacy Endpoints Lung function parameters (FEV1, AM PEF) for each patient at each examination and PM PEF), asthma symptom-related endpoints (ACQ score, night awakenings), and The use of albuterol was evaluated. Observed results for these parameters (change from baseline) are shown in Figure 2-7, respectively. Additionally SNOT-22 score was assessed at baseline and at the end of treatment. All For parameters, mean values at baseline and Week 12 (LOCF) Mean difference between co-treatment groups (ANOVA model for SNOT-22) Table It is summarized in 7. In Table 7, the column labeled "Difference vs. Placebo" compared to the changes observed for the parameter in the placebo-treated group. The changes observed in the value of the parameter are taken into account, compared to the baseline It reflects the placebo-corrected value.

Table 7: Secondary Parameters of Lung Function and Symptom Scores Least Squares Baseline Placepaint p Average Change - .

Mean (SD) Versus Difference value 0.27 (0.11, AM PEF (Llminute) Least Squares Baseline Placepaint Average Change Difference Against Mean (SD) 58.5) PM PEF (L/minute) Baseline Least Squares Placebo Mean (SD) Mean Change (SD) Versus Difference 22.7 (-0 46.0) Albuterol Usage (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 Average Score T 51 patients with at least 1 post-baseline evaluation. 1: 50 patients with at least 1 post-baseline evaluation. p value Treatment with mAb1 resulted in a significant change from baseline in FEV1 at Week 1 and this effect coincides with the withdrawal of LABA, despite the withdrawal of LABA and ICS. followed by a small decrease in FEV1 at week 5 until week 12. continued (Figure 2). Similar improvements were observed in PEF in the morning. but in the evening It was less in PEF (Figures 3 and 4). FEV1 compared to baseline by week 12 least squares (LS) mean change -0.22 L for placebo and 0.05 for the mAb1 group It has been L. (p=0.0009).

ACQ5 score improved in both treatment groups at Week 1 (Figure 6). But 1st and 4th.

While more improvement was achieved in ACQS with mAb1 between weeks, the placebo effect stabilized and this difference was maintained until the 12th week.

Morning symptom scores increased from baseline with placebo through Week 12. With mAb1, an increase at baseline that remains below baseline until Week 12 (Figure 26A). A similar pattern for evening asthma symptom scores (more with great variability) has been observed (Figure 268). Night awakenings were stable in the placebo group by Week 6, followed by Weeks 6 to 12. It increased between weeks. In contrast, night awakenings were mAb1 until Week 1. group and remained at a good level compared to baseline until Week 12. Changes in AIbuteroI/Ievalbuterol use (Figure 5) were similar to other secondary endpoints. similar: there was an initial decrease, then increased to baseline with placebo. right back. With mAb1, the initial increase was maintained over time.

A non-significant difference was observed between SNOT-22 values compared to the baseline. Mean change in LS per week, a slight increase of 0.23 points in the placebo group, mAb1 In the group, there was an average decrease (improvement) of 8.26 points. This is the mAb1 group It represents an improvement of 8.49 points for (p=0.0027).

Table 8. Secondary Endpoints Result Placebo (N mAb1 (N Placebo Vs P = 52) = 52) Difference (95% Cl)** Value Result Placebo (N mAb1 (N Placebo Vs P = 52) = 52) Difference (95% CI)** Value 60.2) 2.1) 0.1 from baseline to week 12 change as much 0.1 from baseline to week 12 change as much Table 9. Baseline on SNOT-22 Items Related to Upper Respiratory Tract Disease Change from line to week 12.

SNOT-22 Lower Least Squares Mean P Versus Placebo score Change ± Standard Error Difference (95% CI) Value decreased sensation *At least 1 51 and TSO patients evaluated after baseline, respectively Measurements at Week 12 for all secondary endpoints, evening PEF and nocturnal awakenings Except for mAb1 treatment, it was in favor of mAb1 treatment and was significant (Tables 7 and 8). Significant association with mAb1 in all three SNOT-22 items related to upper airway disease Improvements were observed (Table 9). (iii) Security mAb1 is generally safe and well tolerated. Occurs with treatment Adverse events (TEAEs) occurred in 40 (769%) patients treated with placebo and 40 (769%) in patients treated with mAb1. It was reported similarly in 42 (808%) treated patients (Table 10).

TEAEs are nonspecific and generally mild to moderate in severity. The majority recovered by the end of the study. The following for mAb1 compared to placebo An increase in reporting for TEAEs was observed: injection site reactions mAb1 It was reported as 15 (28.8%) in patients and 5 (96%) in placebo patients; 7 (135%) in nasopharyngitis mAb1 patients and 2 (3.8%) in placebo patients. has been reported; Headache was 6 (115%) in mAb1 patients and 3 (5.85) in placebo patients. and nausea was reported in 4 (77%) cases in mAb1 patients and in placebo patients. It was reported as 1 (19%).

Table 10. Adverse Events.

Adverse event Placebo (N = mAb1 300 mg (N = 52) 52) number of patients (%) Any serious adverse event 3 (5.8) 1 (1.9) 3 (5.8) 3 (5.8) termination Most common AEs* Injection site reactionsT 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 event Placebo (N = mAb1 300 mg (N = 52) 52) number of patients (%) Viral upper respiratory tract infection 0 3 (5.8) * 2 to 3 patients in any supply group by Preferred Term Injection site reaction includes events reported as follows: pain, injection site reaction, injection site erythema, injection site rash, injection site hematoma, injection site urticaria, injection site dermatitis, inflammation at injection sites, nodule at injection site, injection pruritis at the site and swelling at the injection site. No deaths were reported during the study period. With 4 treatments reported Among the serious adverse events (SAEs) that occurred: 1 mAb1 patient with bipolar disorder and 3 placebo patients had pneumonia and asthma, gunshot wound and left pneumothorax, and He experienced right ankle fracture SAEs. None of the SAEs are considered to be associated with IMP. At the end of the study, all except for one untreated and recent ankle fracture. He has recovered. Death did not occur.

A total of 6 patients discontinued the study due to TEAE: 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 TEAE in 42-year-old injection following the ninth study treatment dose in an African American woman as a pruritic, papular rash observed at the site and away from the injection site Happened. This situation lasted a week. discontinuation of study treatment and He recovered following treatment with prednisom and diphenhydramine. This is treatment-related acceptance has been done. This AE occurred after injection following the first and sixth study treatment doses. It was seen after milder rashes in the area.

Most common AEs occurring in 23 patients in any treatment group (Table 10) injection site reactions, nasopharyngitis, nausea and headache, It occurred more frequently with mAb1 compared to placebo. There is no vital element in any group. clinically evident in the sign, physical examination, clinical laboratory or ECG findings. No significant changes were reported.

G. Findings Significant improvements in lung function and other asthma control parameters has been observed. Efficacy was observed early and was reversed after background therapy. It continued despite its withdrawal. 300 mg once weekly compared to placebo (442%) Moderate to severe persistent eosinophilia after 12 weeks of treatment with mAb1 (58%) The primary endpoint of the incidence of asthma exacerbations in asthmatic patients was approximately lung function parameters (FEV1, PEF AM), asthma symptom scores (ACQ) and albuterol use, compared to placebo, clinically significant and Statistically significant (without multiplicity adjustment) improvements were observed. has been observed. It was also statistically significant in the SNOT-22 score (multiplicity adjustment without) improvement was observed. In the active treatment group, LABA and ICS were reversed. Despite withdrawal, all parameters returned to baseline during the course of the study. A steady improvement was observed. mAb1 is generally safe and well tolerated. is done. Example 3: Biomarker studies on samples taken from subjects in clinical trial studies of mAb1. biomarker analysis was performed (see Example 2 above). In particular, the base line and at different times after initiation of study treatment(s). Thymus and activation chemokine (TARC, CCL17), Immunoglobulin E (IgE), eoctaxin-S, periostin, carcinoembryonic antigen Serum/plasma associated with TH2 inflammation such as (CEA), YKL-40 and blood eosinophils biomarkers were measured. Baseline levels of these biomarkers increase before treatment It was considered as a potential predictive value in terms of response. Additionally fractional exhaled NO (FeNO) and induced sputum eosinophils and neutrophils have been measured as biomarkers of bronchial inflammation. Before and after spirometry a NIOX device (Aerocrine AB, Solna, Sweden) after at least 1 hour of fasting Evaluation of exhaled nitric oxide was carried out using Biomarkers are a analyzed using a mixed model and derived least squares The average is reported below. mAb1 (300 mg) or placebo subcutaneously to asthma subjects (N=104) with doses has been implemented (see Example 2 here). Samples for biomarker analysis include antibody and were collected from placebo-treated subjects at weeks 0, 1, 4, 8, and 12. to antigen Detected using the specific IgE Phadiat0p® test.

TARC, eoctaxin-3 and IgE remained unchanged in response to placebo (Figures 8, 9 and ). In contrast, patients treated with mAb1 had an improvement in TARC (mean and continued through week 12: TARC: +7.6% versus -26.0% on placebo TARC within one week after exposure to mAb1 administered at 300 mg subcutaneously levels responded. TARC levels increased with mAb1 despite withdrawal of lCS. plateau at approximately 50% of baseline level in treated subjects has created. Data show that TARC expression correlates with FEV1 changes (reversal of ICS). It is decreasing in parallel with its withdrawal [4. After week]) compared to lL-4R signaling and that IL-4R blockade, such as IFNgamma induces a shift towards a TH1 signature as observed with It makes you think. Especially those requiring long-term treatment and TH1 type immunity TARC (and e.g. CXCL10) in patients at risk for disease It may be possible to titrate the mAb1 dose using Total serum IgE also decreased following mAb1 treatment. Compared to TARC answer The total serum IgE response is more heterogeneous and delayed. Mean (SD) baseline It became 206.15. Despite this heterogeneity, patients exposed to mAb1 compared to placebo There was a trend towards IgE reduction in patients, starting only at week 4. has been observed. Serum IgE decreased in the mAb1 group compared to placebo from week 4 onwards. It continued to decrease until the 12th week (average % change, Week 12 relative to baseline and placebo for FeNO, TARC, eoctaxin-3, and IgE All changes were due to mAb1 (all P<0.001) (Table 11). YKL-4O or No differences in CEA from baseline or between treatments has not been observed.

Table 11. Pharmacodynamic Endpoints at Week 12 Compared to Baseline Percent Change.

Least Squares Mean Percentage Change ± Result Standard Error P Placebo (N = 52) mAb1 (N = 52) eosinophils A transient decrease in periostin levels followed by withdrawal of LABA/ICS There has been an increase (Figure 11). Application of mAb1 delayed the increase, but this increase was at baseline. It did not prevent it from going above the line. With CEA (Figure 12) and YKL-4O (Figure 13) No consistent treatment effect was observed. Number of blood eosinophils by week 6 remained unchanged, but then increased at weeks 8 and 12 (Figure 14).

In placebo, the number of peripheral blood eosinophils did not change throughout treatment. treatments The difference between the patients was not significant and the increase in the limit was observed only in a few patients treated with mAb1. This was due to higher blood eosinophil increases in the patient. In most patients little or no increase was observed (Table 12).

Table 12. Patients Achieving Change Thresholds in Blood Eosinophil Levels Change in eosinophils 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, baseline A study on the relationship between biomarker levels at baseline and asthma exacerbations no conclusion has been reached. mAb1 treatment was also associated with a significant reduction in FeNO from baseline at Week 4. was also associated, and despite the withdrawal of ICS, FeNo remained at baseline until Week 12. remained below the line (average % change at week 12: -28.7 for mAb1 and It remained stable until week 1, after which the lCS retreated at week 12. There has been an increase. Improvement in forced expiratory volume in 1 second (FEVi) and reduction in FeNO at week 12 Improvements in AM-PEF and PM-PEF correlate with reductions in FeNO (Figure 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 Change in FEV1 at week 12 versus baseline Scatterplot analysis of eosinophils relative to baseline in the study population As measured by change at week 12 in FEV1 (baseline eosinophils 2 0.3 Giga/L) (Figure 19) a relationship between eosinophils at baseline and treatment effect It didn't make you think it was. Decrease in eosinophils ACQ at baseline (Figure ) and decreased albuterol/evalbuterol use (Figure 21).

Periostin and YKL-40 at baseline correlated with reductions in ACQ (Figure 22 and 23). Going back lCS negatively affected the FEV1 change at week 12 compared to baseline. affected (starting from the 4th week). Similar analyzes were conducted in the study population at baseline TARC or IgE at baseline and baseline FEV1 at week 12 did not suggest a relationship between changes (baseline eosinophils 20.3 Brief Description These results suggest that mAbi affects Th2 inflammation (TARC, eotaxIn-B and IgE) and serum associated with bronchial inflammation (FeNO) shows that it significantly reduces biomarkers. decrease in FeNO and Correlation between improvement in FEV1 and IL-1 in moderate to severe, uncontrolled asthma Between 4/IL-13-mediated anti-inflammatory activity and improvement in lung function It suggests that there is a relationship. Example 4: Blockade of the lL-4/lL-13 Signaling Pathway Induced by House Dust Mite Increasing IgE Production and Airway Remodeling in a Mouse Model of Eosinophilic Asthma It Inhibits Modeling.

House dust mite allergen (HDM) affects the influx of Th2 cells into the lung and eosinophils. Th2 immunity, including IL-4-induced trans-endothelial migration into the lung It has been shown to induce the response Eosinophils are the dominant effector in allergic reactions cells, and the release of granule contents (including IL-4) from eosinophils contributes to inflammation. There are. In asthmatic patients, Th2-driven production of IL-4 is a potent eosinophil Promotes eosinophil migration from the blood to the lungs through the chemoattractant eotoxin When localized in the inflammatory area, they produce and secrete IL-4 and so on. It contributes to Th2-driven inflammation (Bjerke et al., Respi'r. Med., 1996, 90(5):271-277). In patients with allergic asthma, a challenge with HDM increases serum IgE increased levels and Th2 cytokines for up to 5 weeks after allergen challenge. In this Example, an HDM-induced model of chronic asthma is treated with anti-IL-4R antibodies. Pharmacodynamic effects on markers of airway inflammation in mice was used for evaluation. Additionally, anti-IL-4R antibodies appear in the airways. The effects on collagen deposition were also evaluated in this model, since collagen Its accumulation correlates with the degree of airway remodeling.

MATERIALS AND METHODS Two different anti-IL-4R0i antibodies were used in this Example experiments: for human IL-4R0i "mAb1", a specific fully human monoclonal antibody (i.e. anti-IL-4R antibody used in other study samples) and mouse IL-4R0i "anti-mIL-4R0i", a mouse monoclonal antibody specific for the protein. mAb1, mouse IL- Does not cross-react with 4Roi; hence, mAb1 in humanized mice evaluated, where on the ectodomain of both human IL-4 and IL-4Rd, 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" is a natural strain (BaIb/c) was tested in mice. It was also used as a pseudoreceptor in these experiments. Blocking IL-13 signaling through sequestration of IL-13 cytokinin by showing activity A mouse IL-13R0i2-mFc fusion protein was also tested.

For the HDM-induced asthma model, mice received daily intranasal HDM for 10 days. (50pg per mouse in 20pL PBS) and then was left to rest (2-week decomposition period). Allergen challenge, 8 weeks intranasal administration of HDM (50pg per mouse in 20pL PBS) three times a week for It was implemented with . For each application of HDM. sensitization or coercion During the period, mice were lightly anesthetized with isoflurane.

Mice were transported to the experimental facility for a minimum of 5 days before starting the experimental procedure. has been trained. During the entire duration of the experiment, animals were kept in the experimental facility for 12 hours. housed under standard conditions within a day/night cycle and They were allowed access to water and food. Maximum number of mice in each cage Restricted to mouse.

A total of 48 humanized mice were used for two experiments, where human IL-4 Iigandi and to substitute corresponding murine sequences on the human ectodomain of IL-4R0i. engineered (IL-4m'/hu IL-4Rdhu/"”). IL-4"”/hu IL-4R0im'/hu mice in a mixed In one experiment, 20 inbred mice with the same mixed background were tested. used. In each experiment, mice were fed HDM (or in the control group) were sensitized with PBS), then from day 11 to day 29. A decomposition period was applied. Animals 8 weeks from day 30 to day 81 challenged with HDM three times a week for 10 days and then euthanized for analysis on day 85. has been implemented. Mice were divided into six experimental groups as follows: (1) Non-sensitized, untreated: Sensitization and challenge During the periods, PBS was administered intranasally. Treating mice with antibodies not (IL-4hu/hu IL-4R0ihu/hu mice ri = 9; inbred littermates n = 5); (2) Untreated, walled with HDM: Sensitization and challenge During the periods, HDM was applied intranasally. Treating mice with antibodies not (IL-4hulhu IL-4R0ihulhu mice n = 7; inbred strain littermates n = 5); (3) Those treated with HDM-infused anti-mIL-4Rd: Sensitization and During challenge periods, HDM was administered intranasally. Mice, 6 weeks old twice weekly from weeks 7 to 12 for a total of 12 doses during one period anti-mIL-4R0i at a dose of 50 mg/kg i.p. injected as (natural sus batindaslar n = 5); (4) Those sensitized with HDM, treated with anti-human mAb1: Sensitization and HDM was administered intranasally during challenge periods. mice 6 from weeks 7 to 12 for a total of 12 doses during a one-week period mAb1 i.p. at a dose of 50 mg/kg twice a week. was injected as (IL- 4hu/hu IL-4R0ihulhu mice n = 12); (5) Wallized with HDM. mouse treated with IL-13R02-mFc fusion protein m HDM intranasally during sensitization and challenge periods has been implemented. 7 to mice for a total of 12 doses over a 6-week period. IL-13Roi2- at a dose of 25 mg/kg twice a week from week 12 to week 12. mFc i.p. (IL-4hu/hu IL-4Roihu/hu mice n = 7; inbred strain siblings n = 5); (6) Wallized with HDM. Those treated with isotype control antibody: During the sensitization and challenge periods, HDM was administered intranasally.

Mice were administered from weeks 7 to 12 for a total of 12 doses over a 6-week period. isotype control Ab i.p. at a dose of 50 mg/kg twice a week for up to aspect injected (IL-4hu/hu IL-4R(Jh”/hu mice n = 7).

Mice were euthanized on day 85 for serum immunoglobulin level determinations. blood was collected and lung (one IOB), i) bronchoalveolar Iavage (BAL) fluid, ii) flow cytometry a digested single cell suspension sample for analysis, iii) staining and histology a fixed formalin sample for analysis or iv) collagen in each lung lobe analysis using SircolTM Collagen Assay to quantify its content It was used to produce a sample for

BAL fluid is obtained from euthanized animals by first opening the trachea and Obtained by inserting a 23G IV tube into the tracheal wall through an incision. has been done. Then, sterile PES (1 mL) was injected into the lungs and BAL fluid was It was recovered through the Iavage tube using a syringe. 100 pL HONEY on a cytospin loaded and this Cytospin is used to extract the cells onto the slides of the microscope. It was spun at 500 rpm for 5 minutes. Slides were dried and visualized eosinophils. H&E staining was performed for was determined using . Briefly, serially diluted serum samples were analyzed in 96-well incubated with anti-IgE capture antibody on the plates, and IgE was biotinylated Detected with anti-mouse IgE secondary antibody. Purified enzymes interacted with HRP mouse IgE was used as a standard.

HDM-specific IgG1 serum levels were quantified by ELISA. In short, with HDM coated plates were incubated with serially diluted serum samples, then Incubation was performed with anti-mouse IgG1-HRP-conjugated antibody. IgG1 serum Relative levels of levels are represented as titer units (OD450, OD450 S multiplied by a dilution factor required to obtain 0.5). collected lung Stored at 80°C. Lungs ice cold to extract collagen It was homogenized in NaCl/NaHCOs solution and heated at 9000xg for 10 minutes. centrifuged. This step was repeated three times and the resulting pellet was heated for 18 hours at 4°C. Digested with pepsin in acetic acid for 1 hour. Samples were centrifuged, top The phase was collected and used with Sircol Dye Reagent for staining for collagen content. mixed. Samples for removal of unbound Sircol Dye Acid-Salt Washed with Washing Reagent and then mixed with Alkali Reagent. Each 200 µL of the sample was transferred into a 96-well plate and measured OD at 555 nm. has been measured. To determine the final amount of collagen content in each sample collagen standard was used. Lungs were removed from euthanized mice and incubated in HBSS for 20 min at 37°C. completely on ice until digested with a mixture of collagenase and DNAse in buffer. It was kept in DMEM medium. Collagenase activity with the addition of 0.5M EDTA stopped, samples were centrifuged and red cells were lysed with ACK buffer. has been done. The cell suspensions obtained for each sample were divided into three separate pools. antibody mix 1 (anti-CD11c-APC Ab, anti- SiglecF-PE Ab, anti-F or mix 2 (anti- CDlic-APC Ab, anti-CD11b-PerCp-Cy5.5 Ab, anti-CD103-FITC Ab, anti-MHC11-PE Ab) or mixture 3 (anti-CD19-PE Ab, anti-LyGG-APC Ab, anti-CD3-FITC, anti-CD11b- It was stained with PerCp-Cy5.5 Ab). Stained cells were incubated for 30 min at 4°C. fixed in Cytofix/Cytoperm solution and flow-through with FACSCanto (BD Biosciences). were stored in PBS until cytometric analysis.

For microdetection analysis of gene expression using GeneChip® technology left from 4 mice in the group, HDM-induced chronic model of eosinophilic asthma (EA). Lung lobules were collected. sensitized and challenged with HDM and then an isotype Gene expression levels in control Ab-treated mice versus mock (PBS) Gene expression levels of mice sensitized and challenged and not receiving antibody treatment. compared with . The threshold for a change in gene expression is >1.5-fold is set. It is expressed differently in mice sensitized and challenged with HDM. The population of genes identified as being affected was then treated with isotype control. A more detailed analysis was conducted in the anti-IL-4R0i-treated group compared to the has been done. in the IL-4R0i-Ab-treated group compared to the isotype control-treated group. The threshold for a change in gene expression was set at >2-fold.

RESULTS HDM sensitization and challenge lead to increased levels of IgE and HDM-specific IgG1. It has led to IgE increase was completely blocked by both anti-IL-4R0t Abs however, it could not be blocked by IL-13Rα2-Fc treatment (Figures 27A and 278); HDM specific IgGi levels were not affected by any treatment (data not shown).

HDM sensitization and challenge also increased collagen content in the lungs of mice. It also led to an increase. Treatment with both lL-4R0i Abs and lL-13R02-Fc protein collagen content in the lungs of mice sensitized with sham treatment and was reduced to levels observed in challenged mice (Figures 28A and 288).

Additionally, mAb1 treatment stimulates lung eosinophil, neutrophil, and inflammatory dendritic cell proliferation. (Figure 29, Panel A and B).

HDM-induced IL-4hulhu IL-4Roi””/hu treated with an isotype control antibody Microarray analysis of mRNA isolated from lung tissue of mice with sham treatment Differential expression of 1468 genes compared to mice sensitized and challenged with sham treatment. expression (826 up-regulated and 642 down-regulated are transferred genes). Treatment of HDM-induced IL-4h”/hu IL-4R0i hLi/hu mice with mAb1, by causing expression changes in only 521 genes (with sham treatment compared to sensitized/challenged mice) without sensitization/challenge with HDM effectively blocked approximately 65% affected genes (>1.5-fold change, p<0.05). Of particular interest is the fact that mAb1; Various members of the IL-1 cytokine family have specific It helps to downregulate its expression. lL-1ß gene expression, HDM-induced was not increased in the isotype control-treated group (with sham treatment compared to sensitized mice), but decreased (1.5) in the mAb1-treated group. floor). Gene expression of Th1 inflammatory cytokines IL-12ß and lFN-γ was also affected by isotype. was downregulated by mAb1 compared to the control-treated group. remarkable chemokine ligands that play a role in cell homing and traffic eight genes encoding mAb1-treated group compared to the isotype control-treated group. downregulated in the control group: Ccl11 (~9-fold decrease), Ccl8, and Cxcl2 (both ~5-fold decrease), Cxcl1, Ccl7, Cclö (all ~3-fold decrease), Ccl2 and Ccl9 (about 2-fold decrease in fold decrease).

RESULTS This example shows IL-4 activation via Type I and Type II receptors by anti-IL-4R0i antibodies. blocking signaling in the lungs of HDM-challenged mice inflammatory and fibrotic changes as well as HDM-driven gene signature shows that it suppresses the changes.

Other applications are in the claims.

Claims (1)

CLAIMS A pharmaceutical composition comprising an antibody that specifically binds to the interleukin-4 receptor (IL-4R), or an antigen-binding fragment thereof, for use in reducing the incidence of one or more asthma exacerbations in a subject suffering from persistent asthma, characterized in that the antibody or antigen-binding fragment thereof is It contains the heavy chain and light chain complementarity determining region (CDR) sequences from the SEQ ID NO / light chain variable region (LCVR) sequence pair. The pharmaceutical composition for use according to claim 1, wherein the asthma exacerbation is selected from the group consisting of: (a) a 30% or greater reduction from baseline in morning peak expiratory flow (PEF) on two consecutive days; (b) ingestion of six or more additional puffs of albuterol or levalbuterol in a 24-hour period (compared to baseline) on two consecutive days; and (c) a worsening of asthma requires: (i) systemic (oral and/or parenteral) steroid therapy, or (ii) an increase of at least 4 times the last dose of inhaled corticosteroid received before discontinuation, or (iii) hospitalization. Pharmaceutical composition for use according to claim 1 or 2, characterized in that the pharmaceutical composition has one or more of the following properties: - it contains from 75 mg to 600 mg of antibody or antigen-binding fragment thereof; - the subject is administered at a weekly or bi-weekly dosing frequency; - administered to the subject systemically, subcutaneously, intravenously or intranasally. A pharmaceutical composition comprising an antibody that specifically binds to the interleukin-4 receptor (lL-4R) or an antigen binding fragment thereof, for use in improving one or more asthma-related parameters in a subject suffering from persistent asthma, characterized in that the improvement in the asthma-related parameter consists of: selection from the following groups: (a) an increase in forced expiratory volume in 1 second (FEV1) of at least 0.10 L from baseline; (b) an increase in morning peak expiratory flow rate (AM PEF) of at least 10.0 L/min from baseline; (o) an increase in evening peak expiratory flow rate (PM PEF) of at least 1.0 L/minute from baseline; (d) a decrease in daily albuterol/evalbuterol use by at least 1 inhalation/day from baseline; (e) a decrease of at least 0.5 point from baseline in the five-item Asthma Control Questionnaire (ACQ5) score; (f) a reduction from baseline in night awakenings of at least 0.2 times per night (number per night) as measured daily; and (g) a decrease from baseline of at least 5 points in the 22-item Sino-Nasal Outcome Test (SNOT-22) score, wherein the antibody or antigen binding fragment thereof outweighs the SEQ ID NO / light chain variable region (LCVR) sequence pair chain and light chain complementarity determining region (CDR) sequences. Pharmaceutical composition for use according to claim 4, characterized in that the pharmaceutical composition contains from 75 mg to 600 mg of antibody or antigen binding fragment thereof and/or wherein the pharmaceutical composition is administered to the subject systemically, subcutaneously, intravenously or intranasally. Pharmaceutical composition for use according to any one of claims 1 to 5, characterized in that a second therapeutic agent is administered to the subject before, after or simultaneously with the pharmaceutical composition, where preferably the second therapeutic agent is selected from the group consisting of: a TNF inhibitor, a 1L -1 inhibitor, an IL-5 inhibitor, an IL-8 inhibitor, an IgE inhibitor, a Ieukotriene inhibitor, a corticosteroid, a methylxanthine, an NSAID, nedocromyl sodium, cromolyn sodium, a long-acting beta2 agonist, an anti-fungal agent and a combination of these. A pharmaceutical composition comprising an antibody that specifically binds to the interleukin-4 receptor (IL-4R) or an antigen-binding fragment thereof, for use in improving one or more asthma-related parameters or reducing the incidence of asthma exacerbations in a subject suffering from persistent asthma. of use. comprising sequentially administering to the subject a single initial dose of the pharmaceutical composition, wherein the administration of the single initial dose is followed by one or more secondary doses of the pharmaceutical composition, wherein the antibody or antigen binding fragment thereof is SEQ 1D NO / light chain variable region (LCVR). It contains the heavy chain and light chain complementarity determining region (CDR) sequences from the sequence pair. Pharmaceutical composition for use according to claim 7, characterized in that the initial dose and secondary doses of the pharmaceutical composition each contain from 75 mg to 600 mg of the antibody or antigen binding fragment thereof and/or wherein the pharmaceutical composition is administered to the subject systemically, subcutaneously, intravenously or intranasally. . Pharmaceutical composition for use according to claim 7 or 8, characterized in that a second therapeutic agent is administered to the subject before, after or simultaneously with an initial dose and/or a secondary dose of the pharmaceutical composition, wherein preferably the second therapeutic agent is selected from the group consisting of: a a TNF inhibitor, an IL-1 inhibitor, an IL-5 inhibitor, an IL-8 inhibitor, an IgE inhibitor, a Ieukotriene inhibitor, a corticosteroid, a methylxanthine, an NSAID, nedocromil sodium, cromolyn sodium, a long-acting beta2 agonist, an anti-fungal agent and a combination thereof. Pharmaceutical composition for use according to any one of claims 7 to 9, characterized in that each secondary dose is administered 1 to 8 weeks after the immediately preceding dose or that the antibody that specifically binds an interleukin-4 receptor (IL-4R) or its binding to the antigen is administered 1 to 8 weeks after the immediately preceding dose. administering to the subject at least 8 secondary doses of the fragment, wherein each secondary dose is administered 1 week after the immediately preceding dose. A pharmaceutical composition comprising an antibody or an antigen binding fragment thereof that specifically binds to the interleukin-4 receptor (IL-4R) for use in the treatment of persistent asthma, characterized in that it contains: (a) a blood eosinophil level of at least 300 cells per microliter; and /or selecting a patient showing a sputum eosinophil level of at least 3%; and (b) administering this pharmaceutical composition to such patient, wherein the antibody or antigen binding fragment thereof comprises heavy chain and light chain complementarity determining region (CDR) sequences from the SEQ ID NO / light chain variable region (LCVR) sequence pair. An antibody that specifically binds to the interleukin-4-receptor (IL-4R) for use in reducing or eliminating a persistent asthma patient's dependence on inhaled corticosteroids (ICS) and/or long-acting beta-agonists (LABA) for the treatment of one or more asthma exacerbations. or antigen binding fragment thereof, comprising: (a) selecting a patient with moderate to severe persistent asthma that is partially controlled or uncontrolled by a background asthma therapy comprising an ICS, a LABA, or a combination thereof; (b) administering to the patient a determined dose of the antibody or antigen binding fragment thereof at a determined frequency during an initial treatment period while maintaining the patient's background asthma therapy during the initial treatment period; and (c) gradually reducing or discontinuing the dosage of ICS and/or LABA administered to the patient over the course of a subsequent treatment period, while continuing to administer the antibody or antigen binding fragment thereof to the patient at the specified frequency and dose used during the initial treatment period, wherein the antibody or its antigen binding fragment. SEQ ID includes the heavy chain and light chain complementarity determining region (CDR) sequences from the NO/light chain variable region (LCVR) sequence pair. The antibody or antigen binding fragment thereof for use according to claim 12, wherein the ICS is fluticasone, budesonide or mometasone and/or where the LABA is salmeterol or formoterol and/or where the ICS/LABA combination is fluticasone/salmeterol, budesonide/formoterol or mometasone. /formoterol. The antibody or antigen binding fragment thereof for use according to claim 12 or 13, characterized in that the dosage of LABA is eliminated at the end of the initial treatment period and/or wherein the dosage of LABA and/or ICS is gradually reduced over a course of 2 to 8 weeks. or left. An antibody or antigen-binding fragment thereof that specifically binds to the interleukin-4 receptor (IL-4R) for use in the treatment of moderate to severe persistent asthma. characterized in that said treatment includes: (a) the level of a biomarker selected from the group consisting of thymus and activation regulatory chemokine (TARC), IgE, eotaxin-3, periostin, carcinoembryonic antigen (CEA), YKL-4O and fractional exhaled nitric oxide (FeNO). Selecting a patient with elevated blood pressure; and (b) administering to the patient a therapeutically effective amount of the antibody or antigen-binding fragment thereof, wherein the antibody or antigen-binding fragment thereof consists of the heavy chain and light chain complementarity determining region (CDR) sequence pair SEQ ID NO / light chain variable region (LCVR) ) contains the sequences. Pharmaceutical composition for use according to any one of claims 1 to 11, or the antibody or antigen-binding fragment thereof for use according to any one of claims 13 to 151, characterized in that the antibody or antigen-binding fragment thereof is SEQ ID NO: 148, 150 and 152, respectively. a heavy chain comprising the heavy chain complementarity determining region (HCDR) sequences of , and a light chain comprising the light chain complementarity determining region (LCDR) sequences of SEQ ID NOs: 156, 158, and 160, respectively, wherein more preferably the antibody or its antigen is The binding fragment comprises an HCVR having the amino acid sequence of SEQ ID NO:162 and an LCVR having the amino acid sequence of SEQ ID NO:164. Pharmaceutical composition for use according to any one of claims 7 to 10, characterized in that the initial dose and the secondary doses of the pharmaceutical composition each contain the same amount of antibody or antigen-binding fragment, or wherein the initial dose contains 600 mg of antibody or antigen-binding fragment and each of the secondary doses Contains 75 to 300 mg of antibody or antigen binding fragment.