Metabolite biomarker for predicting therapeutic response of biological agents in asthma

Abstract

The present invention relates to a biomarker for predicting therapeutic response in asthma patients and a use thereof, and specifically, to a method for predicting therapeutic response to an anti-interleukin 4 receptor antibody (anti-IL-4R antibody), an anti-interleukin 5 antibody (anti-IL-5 antibody), or an anti-interleukin 5 receptor antibody (anti-IL-5R antibody), which is being used as a therapeutic agent for asthma, by using eicosanoids, and the like.

Description

Metabolite biomarkers for predicting therapeutic response to biological agents in asthma

[0001] The present invention relates to a biomarker for predicting therapeutic responsiveness in asthma patients and the use thereof. Specifically, it relates to a method for predicting therapeutic responsiveness to anti-interleukin 4 receptor antibodies (anti-IL-4R antibody), anti-interleukin 5 antibodies (anti-IL-5 antibody), or anti-interleukin 5 receptor antibodies (anti-IL-5R antibody) currently used as asthma treatments, using eicosanoids which are metabolites.

[0002] The present application claims priority based on Korean Patent Application No. 10-2024-0159824 filed on November 12, 2024 and Korean Patent Application No. 10-2024-0200627 filed on December 30, 2024, and all contents disclosed in the specification and drawings of said applications are incorporated by reference into the present application.

[0003] Asthma is a chronic airway inflammation disease characterized by bronchial hyperresponsiveness to various stimuli. Clinical symptoms such as wheezing, dyspnea, and coughing occur due to extensive airway stenosis and can improve naturally or reversibly through treatment. Generally, asthma is recognized as a chronic inflammatory disease resulting from the proliferation, differentiation, and activation of inflammatory cells by stimuli, specifically antigens, which then migrate and infiltrate the airways and surrounding tissues. In such cases, inflammatory cells, such as activated eosinophils, mast cells, and alveolar macrophages, play a significant role in inducing strong bronchoconstriction by secreting various inflammatory mediators (cysteine, leukotrienes, prostaglandins, etc.) (Korean Patent Publication No. 10-2021-0119131).

[0004] Asthma is a disease that is not easy to cure completely, and the general goal of asthma treatment is to control the condition well to maintain daily life while minimizing risks such as acute exacerbations, side effects, and death. However, despite these treatment goals, asthma is generally not well controlled and exacerbations recur, so high-dose inhaled corticosteroids are often used. However, because the frequent use of corticosteroids causes significant side effects, the development of new agents to effectively treat asthma has been actively underway recently. In particular, therapeutic agents targeting interleukin 4 or interleukin 5 to reduce side effects and enhance therapeutic efficacy have been developed and are being applied in treatment.

[0005] However, since most of these treatments are not covered by insurance, they are very expensive and generally not easy for individuals to use for treatment. In particular, these treatments can be used under insurance when asthma worsens despite long-term use of various common asthma treatments such as steroids, leukotriene modifiers, and theophylline; however, even in such cases, there are many patients who do not respond to these treatments, and in many cases, the therapeutic effect decreases with repeated administration, so continuous follow-up is required.

[0006] Therefore, if the therapeutic effects of these treatments targeting interleukin 4 or interleukin 5 can be accurately predicted in advance and the decision to proceed with or maintain treatment can be made based on this, it is expected that not only can the cost burden and patient suffering from treatment be significantly reduced, but the therapeutic effect can also be significantly enhanced by selecting a treatment that is suitable for the individual.

[0007] The present invention has been devised to solve the problems of the prior art as described above, comprising: a) leukotriene E4, 2,3-Dinor-11β-Prostaglandin F contained in a biological sample obtained from an asthma patient. 2α , tetranor Prostaglandin E Metabolite, 11-Dehydro-TXB2, 2,3-dinor-8-Iso-Prostaglandin F 2α , Prostaglandin F 2α , 8-Iso-Prostaglandin F 2α The purpose is to provide a method for providing information regarding the prediction of therapeutic responsiveness to a therapeutic agent in asthma patients, comprising: a) measuring the concentration of one or more eicosanoids selected from a group consisting of prostaglandin E2 and 2,3-dinor Thromboxane B2; and b) classifying patients as exhibiting a therapeutic effect to an anti-interleukin 4 receptor antibody (anti-IL-4R antibody), an anti-interleukin 5 antibody (anti-IL-5 antibody), or an anti-interleukin 5 receptor antibody (anti-IL-5R antibody) when the measured concentration of the eicosanoid is higher or lower compared to a control group.

[0008] In addition, the present invention relates to leukotriene E4, 2,3-Dinor-11β-Prostaglandin F 2α , tetranor Prostaglandin E Metabolite, 11-Dehydro-TXB2, 2,3-dinor-8-Iso-Prostaglandin F 2α , Prostaglandin F 2α , 8-Iso-Prostaglandin F 2αThe purpose is to provide a composition for predicting therapeutic responsiveness to a therapeutic agent for asthma patients, comprising as an active ingredient a preparation for measuring the concentration of one or more eicosanoids selected from the group consisting of prostaglandin E2 and 2,3-dinor Thromboxane B2, wherein the therapeutic agent is an anti-interleukin 4 receptor antibody (anti-IL-4R antibody), an anti-interleukin 5 antibody (anti-IL-5 antibody), or an anti-interleukin 5 receptor antibody (anti-IL-5R antibody).

[0009] In addition, the present invention aims to provide a kit for predicting the therapeutic response of an asthma patient to a therapeutic agent, comprising as an active ingredient a composition for predicting the therapeutic response of the asthma patient to the therapeutic agent.

[0010] In addition, the present invention aims to provide a diagnostic device for predicting the therapeutic responsiveness of an asthma patient to a therapeutic agent, comprising as an active ingredient a composition for predicting the therapeutic responsiveness of the asthma patient to the therapeutic agent.

[0011] In addition, the present invention relates to a) leukotriene E4, 2,3-Dinor-11β-Prostaglandin F contained in a biological sample obtained from an asthma patient. 2α , tetranor Prostaglandin E Metabolite, 11-Dehydro-TXB2, 2,3-dinor-8-Iso-Prostaglandin F 2α , Prostaglandin F 2α , 8-Iso-Prostaglandin F 2αThe purpose is to provide a method for treating asthma, comprising: a) measuring the concentration of one or more eicosanoids selected from the group consisting of prostaglandin E2 and 2,3-dinor thromboxane B2; and b) administering a pharmaceutical composition containing an anti-interleukin 4 receptor antibody (anti-IL-4R antibody), an anti-interleukin 5 antibody (anti-IL-5 antibody), or an anti-interleukin 5 receptor antibody (anti-IL-5R antibody) as an active ingredient to an asthma patient when the measured concentration of the eicosanoid is higher or lower compared to a control group.

[0012] However, the technical problems that the present invention aims to solve are not limited to those mentioned above, and other unmentioned problems will be clearly understood by those skilled in the art to which the present invention belongs from the description below.

[0013] The present invention relates to a) leukotriene E4, 2,3-Dinor-11β-Prostaglandin F contained in a biological sample obtained from an asthma patient. 2α , tetranor Prostaglandin E Metabolite, 11-Dehydro-TXB2, 2,3-dinor-8-Iso-Prostaglandin F 2α , Prostaglandin F 2α , 8-Iso-Prostaglandin F 2αThe present invention provides a method for providing information regarding the prediction of therapeutic responsiveness to a therapeutic agent in an asthma patient, comprising: a) measuring the concentration of one or more eicosanoids selected from a group consisting of prostaglandin E2 and 2,3-dinor Thromboxane B2; and b) classifying the patient as exhibiting a therapeutic effect for an anti-interleukin 4 receptor antibody (anti-IL-4R antibody), an anti-interleukin 5 antibody (anti-IL-5 antibody), or an anti-interleukin 5 receptor antibody (anti-IL-5R antibody) when the measured concentration of the eicosanoid is higher or lower compared to a control group.

[0014] In addition, the present invention relates to leukotriene E4, 2,3-Dinor-11β-Prostaglandin F 2α , tetranor Prostaglandin E Metabolite, 11-Dehydro-TXB2, 2,3-dinor-8-Iso-Prostaglandin F 2α , Prostaglandin F 2α , 8-Iso-Prostaglandin F 2α A composition for predicting therapeutic responsiveness to a therapeutic agent for asthma patients, comprising as an active ingredient a preparation for measuring the concentration of one or more eicosanoids selected from the group consisting of prostaglandin E2 and 2,3-dinor Thromboxane B2, wherein the therapeutic agent is an anti-interleukin 4 receptor antibody (anti-IL-4R antibody), an anti-interleukin 5 antibody (anti-IL-5 antibody), or an anti-interleukin 5 receptor antibody (anti-IL-5R antibody).

[0015] In addition, the present invention provides a kit for predicting the therapeutic response of an asthma patient to a therapeutic agent, comprising as an active ingredient a composition for predicting the therapeutic response of the asthma patient to the therapeutic agent.

[0016] In addition, the present invention provides a diagnostic device for predicting the therapeutic response of an asthma patient to a therapeutic agent, comprising as an active ingredient a composition for predicting the therapeutic response of an asthma patient to a therapeutic agent. In one embodiment of the present invention, the diagnostic device may be in the form of a measuring unit for measuring the eicosanoid concentration, or the eicoside concentration and the blood eosinophil concentration; and a judging unit for comparing and judging the pattern of the measured eicosanoid concentration, or the pattern of the measured eicoside concentration and blood eosinophil concentration, with a control group. In another embodiment of the present invention, the diagnostic device may further include an input port for adding a biological sample and an output unit for displaying the measured results.

[0017] In addition, the present invention relates to a) leukotriene E4, 2,3-Dinor-11β-Prostaglandin F contained in a biological sample obtained from an asthma patient. 2α , tetranor Prostaglandin E Metabolite, 11-Dehydro-TXB2, 2,3-dinor-8-Iso-Prostaglandin F 2α , Prostaglandin F 2α , 8-Iso-Prostaglandin F 2α A method for treating asthma is provided, comprising: a) measuring the concentration of one or more eicosanoids selected from the group consisting of prostaglandin E2 and 2,3-dinor Thromboxane B2; and b) administering a pharmaceutical composition comprising an anti-interleukin 4 receptor antibody (anti-IL-4R antibody), an anti-interleukin 5 antibody (anti-IL-5 antibody), or an anti-interleukin 5 receptor antibody (anti-IL-5R antibody) as an active ingredient to an asthma patient when the measured concentration of the eicosanoid is higher or lower compared to a control group.

[0018] In one embodiment of the present invention, the step of measuring the concentration of the eicosanoid may further include the step of measuring the blood eosinophil concentration. And the composition may further include a preparation for measuring the blood eosinophil concentration.

[0019] In another embodiment of the present invention, the control group may be an eicosanoid concentration contained in a biological sample obtained from a non-responder that does not respond to treatment with an anti-interleukin 4 receptor antibody, an anti-interleukin 5 antibody, or an anti-interleukin 5 receptor antibody. Or it may be an eicosanoid concentration and blood eosinophil concentration contained in a biological sample obtained from a non-responder.

[0020] In another embodiment of the present invention, the anti-interleukin 4 receptor antibody may be dupilumab, the anti-interleukin 5 antibody may be mepolizumab or reslizumab, and the anti-interleukin 5 receptor antibody may be benralizumab. However, it is not limited thereto if the antibody targets interleukin 4 or its receptor, or interleukin 5 or its receptor.

[0021] In another embodiment of the present invention, if the biological sample in step a) is a biological sample obtained prior to treatment with an anti-interleukin 4 receptor antibody, an anti-interleukin 5 antibody, or an anti-interleukin 5 receptor antibody, the patient may be classified as exhibiting a therapeutic effect when the eicoside concentration in step b) is higher compared to the control group. The therapeutic effect may appear within 2 to 12 months after administration of the therapeutic agent, preferably within 3 to 10 months, more preferably within 4 to 9 months, and even more preferably within 5 to 8 months. Alternatively, it may appear within 6 to 7 months, more preferably. Preferably, the eicosanoid is leukotriene E4, 2,3-Dinor-11β-Prostaglandin F 2α When it is any one of tetranor Prostaglandin E Metabolite, 11-Dehydro-TXB2, and prostaglandin E2, it may exhibit a therapeutic effect against an anti-interleukin 5 antibody or an anti-interleukin 5 receptor antibody, and more preferably 2,3-Dinor-11β-Prostaglandin F 2α , it may be a tetranor prostaglandin E metabolite, or prostaglandin E2. Or when leukotriene E4 concentration is high compared to the control and blood eosinophil concentration is low compared to the control, or 2,3-Dinor-11β-Prostaglandin F 2α When the concentration is high compared to the control group and the blood eosinophil concentration is low compared to the control group, it may exhibit a therapeutic effect against an anti-interleukin 5 antibody or an anti-interleukin 5 receptor antibody. Preferably, the eicosanoid is leukotriene E4, 2,3-Dinor-11β-Prostaglandin F 2αWhen it is any one of , tetranor Prostaglandin E Metabolite, and 2,3-dinor Thromboxane B2, it may exhibit a therapeutic effect against anti-interleukin 4 receptor antibodies, and more preferably 2,3-Dinor-11β-Prostaglandin F 2α Or it may be a tetranor prostaglandin E metabolite. Or when leukotriene E4 concentration is high compared to the control group and blood eosinophil concentration is low compared to the control group, or 2,3-Dinor-11β-Prostaglandin F 2α When the concentration is high compared to the control group and the blood eosinophil concentration is low compared to the control group, it may exhibit a therapeutic effect against the anti-interleukin 4 receptor antibody. Preferably, the eicosanoid is leukotriene E4, 2,3-Dinor-11β-Prostaglandin F 2α When it is any one of tetranor Prostaglandin E Metabolite, 2,3-dinor-8-Iso-Prostaglandin F2α, prostaglandin F2α, 8-Iso-PGF2α, PGE2, and 2,3-dinor Thromboxane B2, it may exhibit a therapeutic effect against an anti-interleukin 4 receptor antibody, an anti-interleukin 5 antibody, or an anti-interleukin 5 receptor antibody, and more preferably 2,3-Dinor-11β-Prostaglandin F 2α Or it may be 2,3-dinor Thromboxane B2. Or when leukotriene E4 concentration is high compared to the control group and blood eosinophil concentration is low compared to the control group, or 2,3-Dinor-11β-Prostaglandin F 2αWhen the concentration is high compared to the control group and the blood eosinophil concentration is low compared to the control group, it may indicate a therapeutic effect against an anti-interleukin 4 receptor antibody, an anti-interleukin 5 antibody, or an anti-interleukin 5 receptor antibody. Here, the anti-interleukin 4 receptor antibody is dupilumab, the anti-interleukin 5 antibody, or the anti-interleukin 5 receptor antibody is mepolizumab or reslizumab, and the anti-interleukin 4 receptor antibody, the anti-interleukin 5 antibody, or the anti-interleukin 5 receptor antibody is one of dupilumab, mepolizumab, and reslizumab.

[0022] In another embodiment of the present invention, if the biological sample of step a) is a biological sample obtained preferably 3 to 8 months, more preferably 4 to 7 months, or 5 to 6 months after the initiation of treatment with an anti-interleukin 4 receptor antibody, an anti-interleukin 5 antibody, or an anti-interleukin 5 receptor antibody, the patient may be classified as exhibiting a therapeutic effect when the eicoside concentration of step b) is lower compared to the control group. The therapeutic effect may appear within 8 to 24 months after administration of the therapeutic agent, preferably within 10 to 22 months, more preferably within 10 to 20 months, and even more preferably within 10 to 18 months. Or, more preferably, within 10 to 16 months. Preferably, the eicosanoid is 2,3-Dinor-11β-Prostaglandin F 2α When it is either , and prostaglandin E2, it may exhibit a therapeutic effect against anti-interleukin 4 receptor antibodies, and more preferably, it may be prostaglandin E2. Or 2,3-Dinor-11β-Prostaglandin F 2αWhen the concentration and blood eosinophil concentration are low compared to the control group, it may indicate a therapeutic effect against the anti-interleukin 4 receptor antibody. Preferably, the eicosanoid is leukotriene E4, 2,3-Dinor-11β-Prostaglandin F 2α When it is any one of tetranor Prostaglandin E Metabolite, 11-Dehydro-TXB2, 2,3-dinor-8-Iso-Prostaglandin F2α, prostaglandin E2, and 2,3-dinor Thromboxane B2, it may exhibit a therapeutic effect against an anti-interleukin 5 antibody or an anti-interleukin 5 receptor antibody, and more preferably 2,3-Dinor-11β-Prostaglandin F 2α It may be , 11-Dehydro-TXB2, 2,3-dinor-8-Iso-Prostaglandin F2α, prostaglandin E2, and 2,3-dinor Thromboxane B2. Or when leukotriene E4 concentration and blood eosinophil concentration are low compared to the control group, or 2,3-Dinor-11β-Prostaglandin F 2α When the concentration and blood eosinophil concentration are low compared to the control group, it may indicate a therapeutic effect against an anti-interleukin 5 antibody or an anti-interleukin 5 receptor antibody. Preferably, the eicosanoid is 2,3-Dinor-11β-Prostaglandin F 2α When it is any one of , 11-Dehydro-TXB2, 2,3-dinor-8-Iso-Prostaglandin F2α, prostaglandin E2, and 2,3-dinor Thromboxane B2, it may exhibit a therapeutic effect against an anti-interleukin 4 receptor antibody, an anti-interleukin 5 antibody, or an anti-interleukin 5 receptor antibody, and more preferably 2,3-Dinor-11β-Prostaglandin F 2αOr it may be prostaglandin E2. Or when leukotriene E4 concentration and blood eosinophil concentration are low compared to the control group, or 2,3-Dinor-11β-Prostaglandin F 2α When the concentration and blood eosinophil concentration are low compared to the control group, it may indicate a therapeutic effect against an anti-interleukin 4 receptor antibody, an anti-interleukin 5 antibody, or an anti-interleukin 5 receptor antibody. Here, the anti-interleukin 4 receptor antibody is dupilumab, the anti-interleukin 5 antibody, or the anti-interleukin 5 receptor antibody is mepolizumab or reslizumab, and the anti-interleukin 4 receptor antibody, the anti-interleukin 5 antibody, or the anti-interleukin 5 receptor antibody is one of dupilumab, mepolizumab, and reslizumab.

[0023] In another embodiment of the present invention, the biological sample may be urine, saliva, blood, plasma, serum, etc., but is not limited thereto as long as it is a sample that can be obtained non-invasively. More preferably, it is a urine or blood sample.

[0024] In another embodiment of the present invention, the method may further include the step of comparing the eosinophil concentration in a biological sample with a control group, and the eosinophil concentration may be classified as having a therapeutic effect on the therapeutic agent when it is lower compared to the eosinophil concentration of a control group, i.e., a non-responder to the therapeutic agent.

[0025] The method for providing information regarding the prediction of therapeutic responsiveness to a therapeutic agent for asthma patients according to the present invention, the composition for prediction using the same, the kit for prediction including the composition, and the diagnostic device for prediction including the composition can predict therapeutic responsiveness to an anti-interleukin 4 receptor antibody, an anti-interleukin 5 antibody, or an anti-interleukin 5 receptor antibody in advance, thereby significantly reducing the suffering and costs of patients who do not respond to treatment. In addition, by predicting long-term therapeutic effects even during the treatment period, the duration of treatment can be effectively determined, and therapeutic effects can be significantly enhanced because a therapeutic agent predicted to show therapeutic effects according to each patient can be used.

[0026] Figure 1 is a figure showing the results of confirming the accuracy of the degree of prediction of responders and non-responders exhibiting a therapeutic effect 6 months after administration of a therapeutic agent, using AUC, based on the concentrations of eicosanoids and blood eosinophils measured in a sample obtained before administration of any one of mepolizumab, reslizumab, or dupilumab according to an embodiment of the present invention. The x-axis represents the AUC value.

[0027] FIG. 2 is a figure showing the results of confirming the accuracy of the degree of prediction of responders and non-responders exhibiting a therapeutic effect 6 months after administration of a therapeutic agent, using AUC, based on the concentrations of eicosanoids and blood eosinophils measured in a sample obtained before administration of either mepolizumab or reslizumab according to one embodiment of the present invention. The x-axis represents the AUC value.

[0028] Figure 3 is a figure showing the results of confirming the accuracy of the degree of prediction of responders and non-responders exhibiting a therapeutic effect 6 months after administration of the therapeutic agent, using AUC, based on the concentrations of eicosanoids and blood eosinophils measured in a sample obtained before administration of dupilumab according to one embodiment of the present invention. The x-axis represents the AUC value.

[0029] Figure 4 is a figure showing the results of confirming the accuracy of the degree of prediction of responders and non-responders exhibiting a therapeutic effect 12 months after administration of a therapeutic agent, using AUC, based on the concentrations of eicosanoids and blood eosinophils measured in a sample obtained 6 months after the start of administration of any one of mepolizumab, reslizumab, or dupilumab according to an embodiment of the present invention. The x-axis represents the AUC value.

[0030] FIG. 5 is a figure showing the results of confirming the accuracy of the degree of prediction of responders and non-responders exhibiting a therapeutic effect 12 months after administration of a therapeutic agent, using AUC, based on the concentrations of eicosanoids and blood eosinophils measured in a sample obtained 6 months after the start of administration of either mepolizumab or reslizumab according to one embodiment of the present invention. The x-axis represents the AUC value.

[0031] Figure 6 is a figure showing the results of confirming the accuracy of the degree of prediction of responders and non-responders exhibiting a therapeutic effect 12 months after administration of the therapeutic agent, using AUC, based on the concentrations of eicosanoids and blood eosinophils measured in a sample obtained 6 months after the start of administration of dupilumab according to one embodiment of the present invention. The x-axis represents the AUC value.

[0032] A method for providing information regarding the prediction of therapeutic responsiveness to a therapeutic agent for asthma patients according to the present invention is leukotriene E4, 2,3-Dinor-11β-F 2α, tetranor Prostaglandin E Metabolite, 11-Dehydro-TXB2, 2,3-dinor-8-Iso-Prostaglandin F 2α , Prostaglandin F 2α , 8-Iso-Prostaglandin F 2α By measuring the concentration of one or more eicosanoids selected from the group consisting of prostaglandin E2 and 2,3-dinor Thromboxane B2, it is possible to predict in advance the therapeutic responsiveness to anti-interleukin 4 receptor antibodies, anti-interleukin 5 antibodies, or anti-interleukin 5 receptor antibodies before starting treatment, as well as accurately predict in advance whether a long-term therapeutic effect will be sustained during the treatment period. In addition, the accuracy of the prediction can be significantly increased by additionally using blood eosinophil concentrations in addition to the eicosanoids.

[0033]

[0034] In all claims below, when a part is described as "comprising" a certain component, this means that, unless specifically stated otherwise, it does not exclude other components but may include additional components.

[0035] In this specification, including the entire set of claims below, terms of degree such as “about,” “approximately,” “substantially,” “generally,” etc., are used to mean at or near the numerical value when inherent manufacturing and material tolerances are presented in the sense mentioned, and are used to prevent unscrupulous infringers from unfairly exploiting the disclosure regarding the precise or absolute numerical value mentioned to aid in understanding the invention. For example, terms such as “about,” “approximately,” “substantially,” “generally,” etc., may refer to amounts within 10%, within 5%, within 3%, within 1%, within 0.1%, and within 0.01% of the mentioned amount. Additionally, in this specification, including the entire set of claims below, “a step of” or “a step of” does not mean “a step for.”

[0036] In all claims below, the term “combination thereof” included in the Markush-type expression means one or more mixtures or combinations selected from the group consisting of the components described in the Markush-type expression, and means including one or more selected from the group consisting of said components.

[0037] In the entirety of the following claims, the description of "A and / or B" means "A or B, or A and B".

[0038] In the entirety of the following claims, the term "active ingredient" refers to any substance used interchangeably with active drugs, active ingredients, active formulations, drugs, and therapeutic formulations, and used to prevent, alleviate, improve, or treat a target disease, namely asthma.

[0039] In this specification, including all claims below, the term “subject” refers to a target to which the composition of the present invention may be administered, preferably a mammal including humans, and may mean, for example, mammals such as human or non-human primates, mice, rats, dogs, cats, horses, cattle, and pigs, but is not limited thereto. Furthermore, the term “subject in need thereof” may preferably mean a subject having asthma and requiring treatment, but is not limited thereto.

[0040] In all claims below, the term “pharmaceutically effective amount” refers to an amount that produces a response greater than that of a negative control, and means an amount sufficient to treat a disease with a reasonable benefit / risk ratio applicable to medical treatment, and the effective dose level may be determined based on factors including the type and severity of the patient’s disease, drug activity, sensitivity to the drug, time of administration, route of administration and elimination rate, duration of treatment, concurrently used drugs, and other factors well known in the medical field. Preferably, it means an amount sufficient to treat or prevent the target disease, namely asthma.

[0041] In this specification, including all claims below, “asthma” refers to a disease of the “bronchial tubes,” which are the passages leading to the lungs, in which the bronchi become severely narrowed due to inflammation, resulting in recurrent coughing, wheezing, shortness of breath, chest tightness, etc. Asthma may include, but is not limited to, allergic asthma or non-allergic asthma, severe asthma or uncontrolled asthma, adult asthma or pediatric asthma. The “severe asthma” or “uncontrolled asthma” generally corresponds to severe asthma as defined in the guidelines of the American Thoracic Society and the European Respiratory Society (ATS / ERS), but is not limited thereto. The “uncontrolled asthma” refers to asthma in which the asthmatic state is not controlled despite appropriate stepwise treatment for asthma, such as inhaled steroids, tailored to each asthma severity, and may include, but is not limited to, one or more of the following conditions:

[0042] 1) Poor symptom control: Partially controlled according to the Korean Asthma Treatment Guidelines, or a score of less than 20 on the asthma control test,

[0043] 2) Frequent asthma exacerbations: Two or more asthma exacerbations per year severe enough to require systemic steroids for 3 days or more,

[0044] 3) Severe exacerbation: Cases where hospitalization or mechanical ventilation is required due to asthma exacerbation,

[0045] 4) Airflow limitation: FEV1 < 80% after bronchodilator use.

[0046] In the entire specification including the following claims, the term "biological sample" means any sample capable of determining the concentration of eicosanoids in the body, preferably blood, plasma, serum, bone marrow, tissue, cell, saliva, sputum, peritoneal fluid, hair, urine, feces, cerebrospinal fluid, various secretions, etc., but is not limited thereto as long as it is a sample that can be obtained by a non-invasive method containing eicosanoids. The sample may be pretreated through methods such as homogenization, filtration, distillation, extraction, concentration, inactivation of interfering components, and addition of reagents before use for detection or diagnosis.

[0047] In this specification, including all claims below, “eicosanoid” refers to an endogenous compound produced by the action of a cyclooxygenase enzyme system or a lipooxygenase enzyme system on aracadonic acid, which is a carbon-20 unsaturated fatty acid, and exhibits various physiological activities. Examples of eicosanoids include, but are not limited to, prostaglandins, prostacyclins, thromboxanes, leukotrienes, and PUFAs, or other metabolites formed by the enzymatic or non-enzymatic addition of oxygen thereof. Methods for measuring the eicosanoid include, but are not limited to, mass spectrometers, gas chromatography, liquid chromatography, mass spectrometers, columns, mass spectrometers, ELISA, NMR, UV-Vis, HPLC, UPLC, and enzymatic-based colorimetric methods.

[0048] In this specification, including all claims below, “response” may be defined as having “response” to a therapeutic agent if, as a result of performing treatment on an asthma patient, asthma symptoms are prevented, improved, or treated. The prevention, improvement, or treatment of asthma may be measured in various known ways. The term “prevention” refers to a broad concept of blocking the occurrence of asthma and means any act of suppressing asthma-related diseases or delaying their onset by administering a therapeutic agent or a composition according to the present invention. Preferably, it includes both primary prevention, which prevents the onset beforehand, and secondary prevention, which detects the onset early and treats it in a timely manner. The term “treatment” refers to a broad concept of dealing with the occurrence of asthma and means any act of improving or beneficially altering the symptoms of asthma-related diseases by administering a therapeutic agent or a composition according to the present invention. The term “improvement” means an act of at least reducing parameters related to the treated state, such as the severity of symptoms.

[0049] In the entire specification including the following claims, “method for providing information,” that is, “method for providing information,” means a method for providing information regarding the asthma treatment effect of a therapeutic agent, and means a method for obtaining or predicting information regarding the possibility that asthma symptoms will be prevented, improved, or treated when said therapeutic agent is administered to an asthma patient. More specifically, it is a concept that includes all of the following: selecting a therapeutic agent suitable for an asthma patient, determining the asthma patient’s susceptibility to the therapeutic agent, determining the asthma patient’s prognosis, or therametrics (e.g., monitoring the asthma patient’s condition to provide information on treatment efficacy).

[0050] In the entirety of the following claims, the term "kit" refers to a diagnostic device capable of predicting the therapeutic responsiveness of an asthma patient to a therapeutic agent contained within a biological sample, and preferably may be in a form including an antibody, compound, etc. that binds to an eicoside, but is not limited to any form capable of measuring the amount of eicoside from a biological sample isolated from an asthma patient.

[0051] In the entirety of the following claims, the term "diagnosis instrument" refers to equipment capable of measuring therapeutic responsiveness to a therapeutic agent in vitro based on biological samples generated in the human body, such as blood, saliva, or urine. Preferably, it may include an inlet for adding a biological sample, a main body capable of measuring the amount of eicoside, and an output unit for displaying the measured results, but there are no limitations as long as the equipment is of a form capable of measuring the amount of eicoside contained in the biological sample.

[0052] In all claims below, the term "antigen" refers to a substance capable of generating an immune response in a host, preferably but not limited to a substance capable of causing asthma. The antigen may be recognized by and bound to an antibody. The antigen may originate from within the body or from the external environment.

[0053] In all claims below, the term “antibody” may mean an antibody of class IgG, IgM, IgA, IgD, or IgE, including Fab, F(ab')2, Fd, and short-chain antibodies and derivatives thereof, or a fragment, a fragment, or a derivative thereof. The antibody may be an antibody isolated from a mammalian serum sample that exhibits sufficient binding specificity to a desired epitope or a sequence derived therefrom, a polyclonal antibody, an affinity-purified antibody, or a mixture thereof. As used interchangeably herein, the terms “antibody fragment” or “fragment of antibody” mean a portion of an intact antibody comprising an antigen-binding site or a variable region. This portion does not include the constant heavy-chain domain of the Fc region of the intact antibody (i.e., CH2, CH3, or CH4 depending on the antibody isotype). Examples of antibody fragments include, but are not limited to, Fab fragments, Fab' fragments, Fab'-SH fragments, F(ab')2 fragments, Fd fragments, Fv fragments, diabodies, short-chain Fv (scFv) molecules, short-chain polypeptides containing only one light-chain variable domain, short-chain polypeptides containing three CDRs of a light-chain variable domain, short-chain polypeptides containing only one heavy-chain variable domain, and short-chain polypeptides containing three CDRs of a heavy-chain variable domain. "Fragment" may mean a polypeptide fragment of an antibody that is functional, i.e., capable of binding to a desired target, and has the same intended effect as a full-length antibody. A fragment of an antibody may be 100% identical to the full length except that at least one amino acid is missing from the N and / or C terminals, and in each case, may or may not have a signal peptide and / or methionine at position 1.The fragment may comprise a percentage of at least 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, and 99% of the length of a specific full-length antibody, excluding any added non-homologous signal peptide. The fragment may comprise a fragment of polypeptide that is 95%, 96%, 97%, 98%, or 99% identical to the antibody, and additionally may comprise an N-terminal methionine or non-homologous signal peptide that is not included when calculating the identity percentage. The fragment may additionally comprise N-terminal methionine and / or signal peptides, e.g., immunoglobulin signal peptides, e.g., IgE or IgG signal peptides. The N-terminal methionine and / or signal peptides may be linked to the fragment of the antibody. In all claims below, the “percentage of amino acid sequence identity (%)” and “homology” for an antibody sequence are defined as the percentage of amino acid residues within a candidate sequence that are identical to the amino acid residues of a specific peptide or polypeptide sequence, which appear after aligning the sequences and introducing gaps, if necessary, to obtain the maximum percentage of sequence identity, and after not considering any conservative substitutions as part of the sequence identity. Alignment performed for the purpose of determining the percentage of amino acid sequence identity may be achieved in various ways within the common sense of a person skilled in the art, for example, using publicly available computer software, such as BLAST, BLAST-2, ALIGN, or MEGALIGN™ (DNASTAR) software. A person skilled in the art can determine appropriate parameters for measuring alignment, including any algorithm required to achieve maximum alignment over the entire length of the sequences being compared.

[0054] In all claims below, the antibody preferably refers to an antibody used as a treatment for asthma that targets interleukin 4, interleukin 4 receptor, interleukin 5, or interleukin 5 receptor, and more preferably includes, but is not limited to, mepolizumab, reslizumab, benralizumab, dupilumab, etc. The term "target" refers to the intended, i.e., binding to, interacting with, or hybridizing with interleukin 4, interleukin 4 receptor, interleukin 5, or interleukin 5 receptor.

[0055] In this specification, including all claims below, the term “pharmaceutical composition” means a composition comprising a therapeutically effective amount of an antibody targeting said interleukin 4, interleukin 4 receptor, interleukin 5, or interleukin 5 receptor, and may be characterized in that it is in the form of a capsule, tablet, granule, injection, ointment, powder, or beverage, and may be characterized in that the pharmaceutical composition is intended for humans. The pharmaceutical composition of the present invention may include a pharmaceutically acceptable carrier. For oral administration, the pharmaceutically acceptable carrier may use a binder, a lubricant, a disintegrant, an excipient, a solubilizer, a dispersant, a stabilizer, a suspending agent, a colorant, a flavoring agent, etc.; for injections, it may use a mixture of a buffer, a preservative, an analgesic, a solubilizer, an isotonic agent, a stabilizer, etc.; and for topical administration, a base, an excipient, a lubricant, a preservative, etc. The formulations of the pharmaceutical composition of the present invention can be prepared in various ways by mixing with pharmaceutically acceptable carriers as described above. For example, for oral administration, it can be prepared in the form of tablets, troches, capsules, elixirs, suspensions, syrups, wafers, etc., and for injectables, it can be prepared in the form of unit dosing ampoules or multi-dose formulations. Additionally, it may be used in the form of coated tablets, gels, pills, powders, granules, suppositories, topical preparations, solutions, suspensions, sustained-release formulations, slurries, etc. Meanwhile, examples of carriers, excipients, and diluents suitable for formulation include lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, acacia gum, alginate, gelatin, calcium phosphate, calcium silicate, cellulose, methyl cellulose, microcrystalline cellulose, polyvinylpyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate, mineral oil, etc.In addition, it may additionally include fillers, anticoagulants, lubricants, wetting agents, fragrances, emulsifiers, preservatives, etc.

[0056] The administration route of the pharmaceutical composition according to the present invention is not limited to these, but oral or parenteral administration is preferred, and includes, for example, oral, intravenous, intramuscular, intra-articular, intrasynovial, intra-arterial, intramedullary, intradural, intracardiac, transdermal, intradermal, subcutaneous, intraperitoneal, intranasal, intestinal, local, sublingual, rectal, intrasternal, intralesional, intracranial, intracranial, intraocular, etc.

[0057] The dosage of the pharmaceutical composition of the present invention may vary depending on several factors including the activity of the specific compound used, age, body weight, general health, gender, diet, time of administration, route of administration, elimination rate, drug combination, and the severity of the specific disease to be prevented or treated, and may be appropriately selected by a person skilled in the art, depending on the patient's condition, body weight, degree of disease, drug form, route of administration, and duration, and may be administered at a dose of 0.0001 to 500 mg / kg or 0.001 to 500 mg / kg per day. Administration may be administered once a day or divided into several doses. The above dosage does not limit the scope of the present invention in any way.

[0058] Other pharmaceutically acceptable carriers may be referenced as described in the following literature (Remington's Pharmaceutical Sciences, 19th ed., Mack Publishing Company, Easton, PA, 1995). Additionally, the pharmaceutical composition of the present invention may be formulated using methods known in the art to provide rapid, sustained, or delayed release of the active ingredient after administration to mammals.

[0059]

[0060] Preferred embodiments are presented below to aid in understanding the present invention. However, the following embodiments are provided merely to facilitate a better understanding of the invention, and the scope of the invention is not limited by the following embodiments.

[0061]

[0062] [Example]

[0063] Example 1: Quantitative analysis of biological samples from asthma patients

[0064] To identify biomarkers capable of effectively predicting the efficacy of asthma treatment, urine and blood samples were obtained from 199 patients (PRISM study cohort supervised by the Ministry of Science and ICT) who visited the hospital for asthma treatment before the administration of the treatment. Urine and blood samples were then obtained one month and six months after the administration of the treatment, respectively. Of the 199 patients, 130 were treated with dupilumab, an anti-IL-4Rα antibody targeting the interleukin 4 receptor, and 69 were treated with mepolizumab or reslizumab, anti-IL-5R antibodies targeting the interleukin 5 receptor. The frequency and dosage of each treatment were administered according to the prescribed regimen. The amount of eicosanoids, lipid metabolites contained in the collected urine samples, was determined in units of ng / mL. Eicosanoids were analyzed using the Solid-Phase Extraction (SPE) pretreatment method. More specifically, 3cc / 60mg Evolute Express ABN SPE cartridges were used to analyze them using an Extrahera automated instrument, and PG metabolites, thromboxanes, and isoprostans were analyzed using 300μL of urine. Additionally, the tautomer 2,3-dinor-TXB2 was analyzed after performing a derivatization method. The CysLT series LTE4 was analyzed using 1mL of urine. A Waters Acquity UPLC system was used for liquid chromatography, and an AB Sciex Triple Quadrupole 5500 was used for mass spectrometry. An ACQUITY UPLC® HSS T3 column (100 × 2.1mm id, 1.8μm particle size) was used for separation.The amount of blood eosinophils in the blood was measured by the number of eosinophils per 1 mL using the blood luteinization hemomicroscopy method. Since the concentration of metabolites in urine can be affected by body water content, the concentration was corrected using specific gravity relative to water, and the calculation formula is as shown in Equation 1 below. However, the number of patients for whom urine and blood samples could be obtained at 6 months after administration of the treatment was 50 patients administered mepolizumab or reslizumab, and 21 patients administered dupilumab, totaling 71 patients.

[0065] [Equation 1]

[0066] <Concentration corrected = Concentration measured X (1.020 - 1) / (Specific gravity - 1)>

[0067] The quantification range of eicosanoids was verified for quantitative analysis after pretreatment. More specifically, Multiple Reaction Monitoring (MRM) transition values ​​and retention times (RT) were measured for 10 types of eicosides; a highly sensitive Sciex Triple Quad 5500 was used for the measurements to lower the minimum quantification limit. A total of 10 types of eicosanoids (LTE4 (Leukotriene E4), ECO1 (2,3-Dinor-11β-Prostaglandin F) 2α ; 2,3-Dinor-11β-PGF 2α ), ECO2 (tetranor Prostaglandin E Metabolite; Tetranor PGEM), ECO3 (11-Dehydrothromboxane B2; 11-Dehydro-TXB2), ECO4 (8,12-Iso-Isoprostane F 2α -VI; 8,12-Iso-IPF 2α-VI), ECO5(2,3-dinor-8-Iso-Prostaglandin F 2α ; 2,3-dinor-8-Iso-PGF 2α ), ECO6(prostaglandin F 2α ; PGF 2α ), ECO7(8-Iso-Prostaglandin F 2α ;8-Iso-PGF 2α The quantitative ranges of ), ECO8 (prostaglandin F2; PGE2), and TXB2 (2,3-dinor Thromboxane B2) were determined, and samples for quality control (QC) were prepared using the quantitative ranges.

[0068] Treatment response was analyzed by classifying patients into responders (R) and non-responders (NR) based on whether there was a reduction of more than 50% in the annual severity of exacerbation or a reduction of more than 50% in the daily dosage of oral systemic steroids (mOCS) after the start of treatment. To determine whether the difference in eicoside concentration and blood eosinophil concentration between responders and non-responders indicated discriminative accuracy, the predictive accuracy was assessed by calculating the area under the curve (AUC) of the major exposure variable using a multivariate logistic regression model. Statistical analysis was performed using SAS (SAS Institute v.9.4), and a P value < 0.05 was considered statistically significant.

[0069] Figures 1 to 3 show the AUC values ​​for the predicted degree of response and non-responder showing therapeutic effects for each treatment after 6 months using samples obtained before administering the treatment.

[0070] As shown in Figure 1, it was confirmed that LTE4, ECO1, ECO2, ECO5, ECO6, ECO7, ECO8, or TXB2, which have an AUC value of 0.8 or higher, can be used as markers to predict the therapeutic effect after 6 months when either an antibody targeting the interleukin 4 receptor or interleukin 5 is administered as a treatment. Additionally, it was confirmed that using LTE4 or ECO1 together with blood eosinophil concentration as markers can further increase the accuracy of the prediction.

[0071] As shown in Figure 2, it was confirmed that LTE4, ECO1, ECO2, ECO3, or ECO8, which have an AUC value of 0.9 or higher, can be used as markers to predict the therapeutic effect after 6 months when any one of the antibodies targeting interleukin 5 is administered as a treatment. In particular, it was confirmed that the prediction accuracy can be further improved when LTE4 is used together with the blood eosinophil concentration as a marker, and when ECO1 is used together with the blood eosinophil concentration as a marker.

[0072] As shown in Figure 3, it was confirmed that LTE4, ECO1, ECO2, or TXB2 with an AUC value of 0.8 or higher can be used as markers to predict the therapeutic effect after 6 months when an antibody targeting the interleukin 4 receptor is administered as a treatment. It was also confirmed that using LTE4 or ECO1 together with blood eosinophil concentration as markers can further increase the accuracy of the prediction.

[0073] Secondly, using samples obtained 6 months after the start of administration of the therapeutic agent, the AUC values ​​for the predicted degree of response and non-responder showing therapeutic effects for each therapeutic agent after 12 months are shown in Figures 4 to 6.

[0074] As shown in Figure 4, it was confirmed that ECO1, ECO3, ECO5, ECO8, or TXB2 with an AUC value of 0.75 or higher can be used as markers to predict the therapeutic effect after 12 months when either an antibody targeting the interleukin 4 receptor or interleukin 5 is administered as a treatment. In particular, it was confirmed that the prediction accuracy can be further improved when LTE4 and the blood eosinophil concentration are used together as markers, and when LTE4 or ECO1 is used together as markers with the blood eosinophil concentration.

[0075] As shown in Figure 5, it was confirmed that LTE4, ECO1, ECO2, ECO3, ECO5, ECO8, or TXB2, which have an AUC value of 0.8 or higher, can be used as markers to predict the therapeutic effect after 12 months when any one of the antibodies targeting interleukin 5 is administered as a treatment. In particular, it was confirmed that the prediction accuracy can be further improved when LTE4 or ECO1 is used together with the concentration of blood eosinophils as markers.

[0076] As shown in Figure 6, it was confirmed that ECO1 or ECO8 with an AUC value of 0.75 or higher can be used as markers to predict the therapeutic effect after 12 months when an antibody targeting the interleukin 4 receptor is administered as a treatment. In particular, it was confirmed that using ECO1 and blood eosinophil concentration together as markers can further increase the accuracy of the prediction.

[0077] When looking at the quantitative results for each marker, it was confirmed that before the administration of the treatment, the eicosanoid values ​​of responders were higher compared to non-responders, but after 6 months of treatment, the eicosanoid values ​​of responders were significantly reduced compared to non-responders, showing that the eicosanoid values ​​of responders were lower.

[0078] Through the above results, it was confirmed that by using each marker before administering the therapeutic agent, it is possible to predict with high accuracy whether the therapeutic agent will show a therapeutic effect, or which therapeutic agent will show a therapeutic effect. In addition, it was confirmed that by using the marker even 6 months after administering the therapeutic agent, it is possible to predict whether the therapeutic agent will continue to show a therapeutic effect over a long period. Generally, in the case of antibody therapeutic agents, there are many instances where they initially show a therapeutic effect during long-term administration but fail to show a therapeutic effect after adaptation; therefore, it was confirmed that the effect of long-term administration can be predicted in advance by using the method of the present invention.

[0079]

[0080] The foregoing description of the present invention is for illustrative purposes only, and those skilled in the art will understand that other specific forms can be easily modified without altering the technical spirit or essential features of the present invention. Therefore, the embodiments described above should be understood as illustrative in all respects and not restrictive.

[0081] The method for providing information regarding the prediction of therapeutic responsiveness to an asthma patient, the predictive composition using the same, the predictive kit comprising the composition, and the predictive diagnostic device comprising the composition according to the present invention can predict therapeutic responsiveness to an anti-interleukin 4 receptor antibody, an anti-interleukin 5 antibody, or an anti-interleukin 5 receptor antibody in advance. Therefore, it is possible to select patients predicted to show a therapeutic effect with high accuracy and proceed with treatment, and also to play an important role in determining whether to maintain treatment by selecting patients whose therapeutic effect is maintained without decreasing during treatment with high accuracy. Accordingly, it can be widely applied to all fields involved in determining the treatment of biological agents in asthma treatment.

Claims

1. a) Leukotriene E4, 2,3-Dinor-11β-Prostaglandin F contained in biological samples obtained from asthma patients 2α , tetranor Prostaglandin E Metabolite, 11-Dehydro-TXB2, 2,3-dinor-8-Iso-Prostaglandin F 2α , Prostaglandin F 2α , 8-Iso-Prostaglandin F 2α A step of measuring the concentration of one or more eicosanoids selected from the group consisting of , prostaglandin E2, and 2,3-dinor thromboxane B2; and b) a method for providing information on predicting the therapeutic responsiveness of an asthma patient to a therapeutic agent, comprising the step of classifying the patient as exhibiting a therapeutic effect to an anti-interleukin 4 receptor antibody (anti-IL-4R antibody), an anti-interleukin 5 antibody (anti-IL-5 antibody), or an anti-interleukin 5 receptor antibody (anti-IL-5R antibody) when the measured concentration of eicosanoid is higher or lower compared to a control group.

2. The method of claim 1, wherein the control group is an eicosanoid concentration contained in a biological sample obtained from a non-responder that does not respond to treatment with an anti-interleukin 4 receptor antibody, an anti-interleukin 5 antibody, or an anti-interleukin 5 receptor antibody.

3. A method according to claim 1, wherein if the biological sample in step a) is a biological sample obtained prior to treatment with an anti-interleukin 4 receptor antibody, an anti-interleukin 5 antibody, or an anti-interleukin 5 receptor antibody, the patient is classified as exhibiting a therapeutic effect when the eicoside concentration in step b) is higher compared to the control group.

4. A method according to claim 1, wherein if the biological sample in step a) is a biological sample obtained 3 to 8 months after the start of treatment with an anti-interleukin 4 receptor antibody, an anti-interleukin 5 antibody, or an anti-interleukin 5 receptor antibody, the patient is classified as exhibiting a therapeutic effect when the eicoside concentration in step b) is lower compared to the control group.

5. The method according to claim 1, characterized in that the biological sample is urine, saliva, blood, plasma, or serum.

6. The method of claim 1, wherein the anti-interleukin 4 receptor antibody is dupilumab, the anti-interleukin 5 antibody is mepolizumab or reslizumab, and the anti-interleukin 5 receptor antibody is benralizumab.

7. The method of claim 1, wherein the method further comprises the step of comparing the eosinophil concentration in a biological sample with a control group. 8.Leukotriene E4, 2,3-Dinor-11β-Prostaglandin F 2α , tetranor Prostaglandin E Metabolite, 11-Dehydro-TXB2, 2,3-dinor-8-Iso-Prostaglandin F 2α , Prostaglandin F 2α , 8-Iso-Prostaglandin F 2α A composition for predicting therapeutic responsiveness to a treatment for asthma patients, comprising as an active ingredient a preparation for measuring the concentration of one or more eicosanoids selected from the group consisting of prostaglandin E2 and 2,3-dinor thromboxane B2, The above therapeutic agent is a composition in which the anti-interleukin 4 receptor antibody (anti-IL-4R antibody), an anti-interleukin 5 antibody (anti-IL-5 antibody), or an anti-interleukin 5 receptor antibody (anti-IL-5R antibody).

9. A kit for predicting the therapeutic response of an asthma patient to a therapeutic agent, comprising as an active ingredient the composition for predicting the therapeutic response of an asthma patient to a therapeutic agent according to claim 8.

10. A diagnostic device for predicting the therapeutic response of an asthma patient to a therapeutic agent, comprising as an active ingredient the composition for predicting the therapeutic response of an asthma patient to a therapeutic agent according to claim 8. 11.a) Leukotriene E4, 2,3-Dinor-11β-Prostaglandin F contained in biological samples obtained from asthma patients 2α , tetranor Prostaglandin E Metabolite, 11-Dehydro-TXB2, 2,3-dinor-8-Iso-Prostaglandin F 2α , Prostaglandin F 2α , 8-Iso-Prostaglandin F 2α A step of measuring the concentration of one or more eicosanoids selected from the group consisting of , prostaglandin E2, and 2,3-dinor thromboxane B2; and b) a method for treating asthma comprising the step of administering a pharmaceutical composition containing an anti-interleukin 4 receptor antibody (anti-IL-4R antibody), an anti-interleukin 5 antibody (anti-IL-5 antibody), or an anti-interleukin 5 receptor antibody (anti-IL-5R antibody) as an active ingredient to the asthma patient when the measured concentration of eicosanoid is higher or lower compared to the control group.

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