TW201537175A - Method for predicting response of patient with pruritic disease to IL-31 antagonist therapy - Google Patents

Abstract

The present inventors discovered that by measuring the level of expression of at least one marker selected from a group consisting of (1) SERPINB3 and/or SERPINB4, (2) S100A9, (3) CXCL1, (4) SFTPD, (5) TCHH, and (6) CXCL6 in a sample obtained from a patient with a pruritic disease, it is possible to predict very easily and efficiently whether said patient will be a responder or a nonresponder to IL-31 antagonist therapy. They also discovered that by measuring the level of expression of TCHH in the sample obtained from the patient, it is possible to diagnose whether or not said patient has a pruritic disease.

Description

A method for predicting the response of a patient suffering from a skin itching to the treatment of an IL-31 antagonist

The present invention relates to a method of predicting a response to treatment in a patient suffering from a disease of pruritus. Furthermore, the present invention relates to a therapeutic agent for a skin itching disease, a method for treating a patient suffering from a skin itching disease, a method for screening a patient suffering from a skin itching disease, and a method for predicting a disease suffering from skin itching. The patient's response to the treatment. Further, the present invention relates to a method for diagnosing a skin itchy disease and a kit for diagnosing a skin itchy disease.

Itchy skin (itch) is a skin-specific sensation, although it can be found in various skin diseases accompanying inflammation, in certain medical diseases (malignant tumors, diabetes, liver diseases, kidney failure, kidney dialysis, gout, thyroid diseases, blood diseases, Iron deficiency) or pregnancy, parasitic infection is the cause, and sometimes it is caused by pharmacy or psychogenicity. Due to the subjective perception of itch and the difficulty of quantitative assessment, the mechanism of pruritus is still not fully understood. At present, as a stimulating substance causing itching, histamine, substance P, bradykinin, protease, prostaglandin, opioid peptide and the like are known (Non-Patent Document 1).

Itchy skin is a very unpleasant symptom for the patient, and severe conditions are also a major obstacle to maintaining daily life. Treatment of itchy skin, First, it is necessary to treat dermatitis or a basic disease that causes it, especially in the case of skin diseases. Since the symptoms are deteriorated due to smashing, it is necessary to treat the skin itch at the same time. The smashing system may cause damage to the skin barrier function due to skin injury, and is susceptible to invasion by antigens such as physical or chemical stimuli or bacterial infections. As a result, the inflammation is worsened and the itching of the skin is further increased, and most of them repeatedly rupture and fall into a vicious circle. Therefore, in the skin disease accompanied by strong itchy skin, the treatment of skin itching itself is also associated with its direct underlying treatment (Non-Patent Document 2).

In the treatment of such skin itching, an antihistamine, an anti-allergic agent, and the like are mainly used as an internal preparation, and an antihistamine, a renal corticosteroid external preparation, a non-steroidal anti-inflammatory agent, camphor, and mint are used as an external preparation. Alcohol, phenol, salicylic acid, tar, crotamiton, capsaicin, humectant (urea, hirudoid, petrolatum, etc.).

Skin itching becomes a specific skin disease to be treated, and includes atopic dermatitis, neurodermatitis, dermatitis, liposuction dermatitis, auto-sensitive dermatitis, caterpillar dermatitis, sebum deficiency, and old age. Sexual itching, pruritus, photoallergies, urticaria, pruritus, herpes, pus, eczema, ferrets, moss, cognac, warts, non-general sores, etc. Furthermore, as a visceral disease with skin itching, malignant tumor, diabetes, liver disease, kidney failure, kidney dialysis, and pregnancy are particularly problematic.

Among them, atopic dermatitis is known to be easily exacerbated by external stimuli such as sweating, smashing, and rubbing, and skin itching becomes the most important therapeutic target. Atopic dermatitis is a chronic skin disease characterized by inflammation of the skin or contact with dermatitis and eczema, characterized by itchy skin. In addition to bronchial asthma or allergic nose In addition to inflammation, allergic dermatitis and other allergic constitutions (atopic factors), the letter is accompanied by various stimuli. Although the pathogenesis of atopic dermatitis is not fully understood, the result of cross-linking and accompanying activation of IgE of the Fcε receptor present on basophilic spheres or obese cells occurs in association with Th2 cells. The production of hormones (IL-4, IL-13, IL-5, etc.) and chemical carriers (histamine, serotonin, etc.) is important. In the treatment of atopic dermatitis, in addition to steroids, antihistamines, and other medical therapies, there are also PUVA treatments that illuminate UVA (ultraviolet A waves). The incidence of skin itching of diseases such as atopic dermatitis has not been reported not only because of the release of histamine or the like (Non-Patent Document 3), but development of an antipruritic agent based on a new mechanism of action is expected.

IL-31 (interleukin-31) is a newly discovered T cell cytokine, and dermatitis similar to cutaneous itching or atopic dermatitis is known in genetically transgenic mice that overexpress IL-31. Symptoms occur (Non-Patent Document 4). Furthermore, it was found that the IL-31-binding receptor is a heterodimer of IL-31RA (interleukin-31 receptor A) and OSMR (oncinomycin M receptor) (Patent Document 1), IL-31 system. Signals are delivered to the cells via the receptor. It has been reported that human IL-31RA is hyperactive in the hypertrophic epidermis of patients with atopic dermatitis (Non-Patent Document 5).

A method for treating a skin itching disease such as atopic dermatitis using an IL-31 antagonist has been reported in several documents (Patent Documents 2 to 5). Further, as an IL-31 antagonist, IL-31 neutralizing antibody or IL-31RA (NR10) neutralizing antibody has been previously reported in several documents (Patent Documents 6 to 9). However, in addition to reports of elevated levels of IL-31 protein or mRNA in serum of patients with atopic dermatitis (Non-Patent Documents 6 and 7), patients with atopic dermatitis and healthy adults have also been reported. Table of skin IL-31 The current level is different (Patent Document 10), and it is estimated that the skin itching of all patients with atopic dermatitis is not only related to IL-31. Therefore, it is important to select a method in which a patient who is only expected to have a therapeutic effect via an IL-31 antagonist is selected from patients suffering from an itchy disease such as atopic dermatitis. As such methods, as of now, there have been reports of methods for predicting response by measuring IL-31 produced by a single lymphoblastic antigen (CLA)-positive T cell from a patient with atopic dermatitis (Patent Literature) 10), but from the point of view that such operations are very complicated and take time, they cannot be called practical. That is, as of now, there is no known method for predicting the response to treatment with high sensitivity by IL-31 antagonist, and the development of such methods is sought, especially in lieu of the prediction of possible novel biomarkers of IL-31 ( Identification of surrogate markers.

From the current report, it is known that the expression level of most genes varies among atopic dermatitis (Patent Document 11). Further, the genes (SERPINB3 and SERPINB4 (Non-Patent Documents 8 and 9), S100A9 (Patent Document 12, Non-Patent Document 10), CXCL1 (Non-Patent Documents 11 to 13), and SFTPD (Non-Patent Literature) which will be described later in the present specification. 14), CXCL6 (Non-Patent Document 15)), which has been reported to exhibit changes in the level of expression in atopic dermatitis, and any of these suggests only that the onset or pathology of atopic dermatitis is associated with each gene. Possibility, not a predictor of response to treatment via an IL-31 antagonist.

Prior technical literature

Patent literature

Patent Document 1: WO2004/003140

Patent Document 2: WO2006/088855

Patent Document 3: WO2007/133816

Patent Document 4: WO2007/142325

Patent Document 5: WO2009/072598

Patent Document 6: WO2006/122079

Patent Document 7: WO2008/028192

Patent Document 8: WO2009/072604

Patent Document 9: WO2010/064697

Patent Document 10: WO2006/088956

Patent Document 11: WO2004/031386

Patent Document 12: WO2006/063865

Non-patent literature

Non-Patent Document 1: Acta DermVenereol Suppl (1981) 97, 1-34

Non-Patent Document 2: Br J Dermatol (2004) 151, 335-345

Non-Patent Document 3: J Dermatol Sci (2001) 25, 20-28

Non-Patent Document 4: Nat Immunol (2004) 5, 752-760

Non-Patent Document 5: J Allergy Clin Immunol (2006) 117, 418-425

Non-Patent Document 6: J Allergy Clin Immunol (2008) 122, 421-423

Non-Patent Document 7: Ann Dermatol (2011) 23, 468-473

Non-Patent Document 8: Clin Exp Allergy (2005) 35, 1327-1333

Non-Patent Document 9: J Allergy Clin Immunol (2012) 129, 426-433

Non-Patent Document 10: Exp Dermatol (2012) 21, 184-188

Non-Patent Document 11: Methods (2012) 56, 198-203

Non-Patent Document 12: Int Immunol (2010) 22, 453-467

Non-Patent Document 13: PLoS One (2012) 7, e29815

Non-Patent Document 14: Exp Dermatol (2006) 15, 168-174

Non-Patent Document 15: Cytokine (2013) 61, 419-425

The present invention has been made in view of such circumstances, and an object thereof is to provide a method for predicting a response to treatment with an IL-31 antagonist in a patient suffering from a skin itching disease. Furthermore, it is an object of the present invention to provide a therapeutic agent for pruritus characterized by administering an IL-31 antagonist as an active ingredient to a patient judged to be a responder to treatment with an IL-31 antagonist; A method of administering a patient with a skin itching disease to a patient who is judged to be a responder to the treatment of an IL-31 antagonist; whether the treatment of an IL-31 antagonist is a patient suffering from a skin itching disease A screening method for responders; and a kit for predicting the response of a patient suffering from a skin itching to the treatment of an IL-31 antagonist. Further, the object of the present invention is also to provide a method for diagnosing whether a patient suffers from a skin itching disease, and a kit for diagnosing a skin itching disease.

The inventors of the present invention conducted a research on a method for predicting a response to an IL-31 antagonist in a patient suffering from a skin itching disease, and found that an IL-31 antagonist is involved in a patient suffering from a skin itching disease. Treatment of responders and non-responders, from samples taken by patients, by (1) SERPINB3 and / or SERPINB4, (2) S100A9, (3) CXCL1, (4) SFTPD, (5) TCHH and (6) The performance level of at least one marker selected from the group of CXCL6 can be used to predict the patient's IL-31 very easily and efficiently. The treatment of the antagonist is a responder or a non-responder. Furthermore, it has been found in the process that by determining the level of expression of TCHH in a sample taken from a patient, it is possible to diagnose whether the patient has a disease with itchy skin.

The present invention is based on these findings, and in particular, the following invention.

[1] A method for predicting a response to treatment of an IL-31 antagonist in a patient suffering from a skin itching disease, the method comprising: (1) SERPINB3 and a sample obtained from a patient suffering from a skin itching disease / or SERPINB4 (2) S100A9 (3) CXCL1 (4) SFTPD (5) TCHH, and (6) the step of the performance level of at least one of the markers selected in the group of CXCL6.

[2] The method as disclosed in [1], which further comprises the step of determining, in the sample obtained from the patient, that the patient having a high level of expression of the aforementioned marker is a responder to the treatment of the IL-31 antagonist.

[3] The method as disclosed in [1] or [2], wherein the aforementioned label is determined as a polypeptide.

[4] The method as disclosed in any one of [1] to [3] wherein the sample is a blood sample.

[5] The method as disclosed in any one of [1] to [4] wherein the skin itching is skin itching caused by IL-3.

[6] The method disclosed in any one of [1] to [5], wherein the skin has a skin defect The disease of itching is atopic dermatitis.

[7] The method as disclosed in any one of [1] to [6] wherein the IL-31 antagonist is an antibody that blocks the IL-31 signal.

[8] The method as disclosed in [7], wherein the antibody that blocks the IL-31 signal is an anti-IL-31 neutralizing antibody or an anti-IL-31RA neutralizing antibody.

[9] The method as disclosed in [8], wherein the anti-IL-31RA neutralizing antibody comprises the CDR1 revealed by SEQ ID NO: 9, the CDR2 revealed by SEQ ID NO: 10, and the H chain of CDR3 revealed by SEQ ID NO: 11. The variable region, and the CDR2 disclosed in SEQ ID NO: 12, SEQ ID NO: 13 revealed CDR2 and SEQ ID NO: 14 revealed an anti-IL-31RA antibody of the L chain variable region of CDR3.

[10] The method as disclosed in [9], wherein the anti-IL-31RA neutralizing antibody is an anti-IL-containing the H chain variable region revealed by SEQ ID NO: 15 and the L chain variable region revealed by SEQ ID NO: 16. 31RA antibody.

[11] The method as disclosed in [10], wherein the anti-IL-31RA neutralizing antibody is an anti-IL-31RA antibody comprising the H chain revealed by SEQ ID NO: 17 and the L chain revealed by SEQ ID NO: 18.

[12] A therapeutic agent which is a therapeutic agent for a skin itching disease, characterized by comprising an IL-31 antagonist as an active ingredient in a sample obtained from a patient suffering from a skin itching disease, for SERPINB3 and / or SERPINB4 (2) S100A9 (3) CXCL1 (4) SFTPD (5) TCHH, and (6) A patient having a high level of expression of at least one marker selected from the group consisting of CXCL6 is administered.

[13] A therapeutic agent comprising a therapeutic agent for pruritus of the skin, characterized by comprising an IL-31 antagonist as an active ingredient, by the method disclosed in any one of [1] to [11], It is judged that the patient who is the responder to the treatment of the IL-31 antagonist is administered.

[14] A method of treating a patient suffering from a disease of pruritus, in a sample obtained from a patient suffering from a disease of pruritus, for (1) SERPINB3 and/or SERPINB4 (2) S100A9(3)CXCL1(4) SFTPD(5)TCHH, and (6) a step of administering an IL-31 antagonist to a patient having a high level of expression of at least one marker selected from the group consisting of CXCL6.

[15] A method of treating a patient suffering from a disease of pruritus comprising the method disclosed in any one of [1] to [11], for the treatment of an IL-31 antagonist The step of administering an IL-31 antagonist to a patient of the responder.

[16] A method for screening a patient suffering from a skin itching disease, comprising a sample obtained from a patient suffering from a skin itching disease a patient having a high level of expression of at least one marker selected from the group consisting of (1) SERPINB3 and/or SERPINB4(2)S100A9(3)CXCL1(4)SFTPD(5)TCHH, and (6) CXCL6 The step of judging the response to the treatment of the IL-31 antagonist is a reaction.

[17] A kit for predicting a response to treatment of an IL-31 antagonist in a patient suffering from a skin itching disorder, comprising for determining from (1) SERPINB3 and/or SERPINB4 (2) S100A9(3) CXCL1(4) SFTPD(5)TCHH, and (6) a reagent for the expression level of at least one of the markers selected in the group of CXCL6.

[18] The kit disclosed in [17], which further comprises an indication that the patient having a high level of expression of the aforementioned marker in the sample obtained from the patient is judged to be a responder to the treatment of the IL-31 antagonist.

[19] A method for diagnosing a disease of pruritus comprising a step of treating a disease having pruritus in a patient having a high level of TCHH expression in a sample obtained from a patient.

[20] A kit for diagnosing a set of pruritus diseases, characterized by comprising an agent for determining the performance level of TCHH.

[21] The kit according to [20], which further comprises a patient who is found to have a high level of expression of TCHH in the sample obtained from the patient, and is judged to be suffering from a disease with pruritus.

The invention further relates to the following invention.

[A-1] Used in the prediction of the response of patients with pruritus to the treatment of IL-31 antagonists. (1) SERPINB3 and/or SERPINB4(2)S100A9(3)CXCL1(4) SFTPD (5) TCHH, and (6) reagents selected from the group consisting of at least one of CXCL6.

[A-2] In the manufacture of a predictor for response to treatment with an IL-31 antagonist in a patient suffering from a skin itching disease, it is detected from (1) SERPINB3 and/or SERPINB4(2)S100A9(3)CXCL1(4) The use of at least one labeled reagent selected from the group consisting of SFTPD (5) TCHH, and (6) CXCL6.

[A-3] In the prediction of response to treatment with IL-31 antagonist in patients suffering from pruritus, (1) SERPINB3 and/or SERPINB4(2)S100A9(3)CXCL1(4)SFTPD( 5) Use of at least one labeled reagent selected from the group consisting of TCHH, and (6) CXCL6.

[A-4] A method for predicting a response to a response to treatment with an IL-31 antagonist in a patient suffering from a skin itching disease, the method comprising determining (1) SERPINB3 and a sample obtained from the patient / or SERPINB4 (2) S100A9 (3) CXCL1 (4) SFTPD (5) TCHH, and (6) the step of the performance level of at least one of the markers selected in the group of CXCL6.

[A-5] A method for predicting the response of a patient suffering from a skin itching disease to the treatment of an IL-31 antagonist, which method is included in a sample obtained from a patient suffering from a skin itching disease Determination (1) SERPINB3 and / or SERPINB4 (2) S100A9 (3) a step of expressing the level of expression of at least one of the selected ones of the CXCL1 (4) SFTPD (5) TCHH, and (6) CXCL6 groups.

[A-6] A method for evaluating an intermediate result of a response to treatment of an IL-31 antagonist in a patient suffering from a skin itching disease, which is obtained from a patient suffering from a skin itching disease The procedure for determining the expression level of (1) SERPINB3 and/or SERPINB4(2)S100A9(3)CXCL1(4)SFTPD(5)TCHH, and (6) the at least one marker selected from the group of CXCL6 is determined in the sample.

The invention further relates to the invention below.

[B-1] An IL-31 antagonist for use in the treatment of a skin itchy disease characterized by (1) SERPINB3 and/or SERPINB4(2)S100A9 (3) in a sample obtained from a patient receiving the treatment. ) CXCL1 (4) SFTPD (5) TCHH, and (6) CXCL6

The performance level of at least one of the selected markers is high.

[B-2] Use of an IL-31 antagonist for the manufacture of a therapeutic agent for pruritus, characterized by (1) SERPINB3 and/or SERPINB4(2)S100A9 in a sample obtained from a patient who administers the therapeutic agent (3) The performance level of at least one of the selected ones of the CXCL1 (4) SFTPD (5) TCHH, and (6) CXCL6 groups is high.

[B-3] Use of an IL-31 antagonist in the treatment of a disease with pruritus characterized by (1) SERPINB3 and/or SERPINB4(2)S100A9 (3) from a sample obtained from a patient receiving the treatment The performance level of at least one of the selected ones in the group of CXCL1(4)SFTPD(5)TCHH, and (6)CXCL6 is high.

[B-4] A method for producing a therapeutic agent for a skin itching disease, comprising an IL-31 antagonist as an active ingredient, characterized by (1) SERPINB3 and/or SERPINB4 in a sample obtained from a patient who administers the therapeutic agent (2) S100A9 (3) The performance level of at least one of the selected ones of the CXCL1 (4) SFTPD (5) TCHH, and (6) CXCL6 groups is high.

The invention further relates to the following invention

[C-1] Detection of screening for use in patients suffering from pruritus with at least one marker selected from the group consisting of (1) SERPINB3 and/or SERPINB4(2)S100A9(3) CXCL1 (4) SFTPD (5) TCHH, and (6) CXCL6 patients with high levels of expression of this marker were judged to be responders to treatment with an IL-31 antagonist.

[C-2] In the manufacture of a screening agent for the manufacture of a patient suffering from a skin itching disease, the use of at least one of the selected agents selected in the following group is detected, (1) SERPINB3 and/or SERPINB4 (2) S100A9(3)CXCL1(4)SFTPD(5)TCHH, and (6) CXCL6 A patient with a high level of expression of this marker was judged to be a responder to the treatment of an IL-31 antagonist.

[C-3] In the screening of a patient suffering from a skin itching disease, the use of the agent selected from at least one of the following groups is detected, (1) SERPINB3 and/or SERPINB4(2)S100A9(3) CXCL1 (4) SFTPD (5) TCHH, and (6) CXCL6 The patient with a high level of expression of this marker was judged to be a responder to the treatment of the IL-31 antagonist.

[C-4] A method for screening a marker for detecting a patient suffering from a skin itching disease, comprising measuring (1) SERPINB3 and/or SERPINB4(2)S100A9(3)CXCL1 in a sample obtained from the patient ( 4) a step of SFTPD (5) TCHH, and (6) a level of expression of at least one marker selected from the group consisting of CXCL6, and a patient who determines that the marker has a high level of expression is a response to treatment with an IL-31 antagonist Steps.

[C-5] A method for obtaining an intermediate result of screening for a patient suffering from a skin itching disease, comprising measuring (1) SERPINB3 and/or SERPINB4(2)S100A9(3) from a sample obtained from the patient CXCL1(4) SFTPD(5)TCHH, and (6) a step of expressing the level of at least one of the markers in the group of CXCL6, and determining the marker by combining the result of the determined performance level with other information Patients with high levels of performance are the steps of responding to the treatment of IL-31 antagonists.

The invention further relates to the following invention.

[D-1] A method of diagnosing a skin itchy disease comprising the step of determining the performance level of TCHH.

[D-2] A method for diagnosing a disease with pruritus in vivo, comprising the step of determining the expression level of TCHH.

[D-3] A method of detecting a marker of a skin itchy disease, comprising the step of determining the expression level of TCHH.

[D-4] TCHH detection reagent used in the diagnosis of a disease with pruritus.

[D-5] Use of a TCHH detecting reagent in the manufacture of a diagnostic agent for a skin itchy disease.

[D-6] In the diagnosis of a disease with pruritus, the TCHH test reagent use.

[D-7] A method for obtaining an intermediate result of diagnosis of a skin itchy disease in a step of measuring the expression level of TCHH.

Fig. 1 is a graph showing the results of microarray analysis of SERPINB3 and SERPINB4 in NHEK cells. (A) SERPINB3/B4 specific probe was used, (B) (C) SERPINB3-specific probe was used, and (D) SERPINB4-specific probe was used to show the individual measurement results of each group of IL-31 stimulation.

[Fig. 2-1] is a graph showing the results of microarray analysis of SERPINB3 and SERPINB4 in HaCaT cells. (A) SERPINB3/B4 specific probe was used, (B) (C) SERPINB3-specific probe was used, and (D) SERPINB4-specific probe was used to show the individual measurement results of each group of IL-31 stimulation.

[Fig. 2-2] is a graph showing the results of microarray analysis of CXCL1 in HaCaT cells. Individual measurement results of each group showing the presence or absence of IL-31 stimulation.

[Fig. 2-3] is a graph showing the results of microarray analysis of CXCL6 in HaCaT cells. Individual measurement results of each group showing the presence or absence of IL-31 stimulation.

[Fig. 2-4] are graphs showing the results of microarray analysis of TCHH in HaCaT cells. Individual measurement results of each group showing the presence or absence of IL-31 stimulation.

[Fig. 3-1] is a graph showing the results of measurement of the amount of CXCL1 expression in serum samples of healthy adults and patients with atopic dermatitis.

Fig. 3-2 is a graph showing the results of measurement of the amount of CXCL6 expressed in serum samples of healthy adults and patients with atopic dermatitis.

[Fig. 3-3] shows serum in healthy adults and patients with atopic dermatitis A graph showing the results of the measurement of the amount of TCHH in the sample.

[Fig. 4-1] is a graph showing the results of microarray analysis of S100A9 in the skin of cynomolgus monkeys. Individual measurement results of each group showing the presence or absence of IL-31 stimulation.

[Fig. 4-2] is a graph showing the results of microarray analysis of SFTPD in the skin of cynomolgus monkeys. Individual measurement results of each group showing the presence or absence of IL-31 stimulation.

[Fig. 5-1] is a graph showing the expression level of S100A9 in serum samples of healthy adults and patients with atopic dermatitis.

[Fig. 5-2] is a graph showing the expression level of SFTPD in serum samples of healthy adults and patients with atopic dermatitis.

[Fig. 6] Each of atopic dermatitis patients (non-responders/reactors) who showed anti-human inflammatory dermatitis and a human anti-human IL-31 receptor A antibody Concentration map of SERPINB3/B4 in serum.

Fig. 7 is a graph showing the average value and individual values of S100A9 concentrations in serum of patients with atopic dermatitis (non-responders/responders) administered with anti-human IL-31 receptor A antibody.

Fig. 8 is a graph showing the mean value and individual values of TCHH concentrations in serum of patients with atopic dermatitis (non-responders/responders) administered with anti-human IL-31 receptor A antibody.

The present invention relates to a method for predicting a response to treatment of an IL-31 antagonist in a patient suffering from a skin itching disease, which comprises measuring (1) SERPINB3 in a sample obtained from a patient suffering from a skin itching disease. And/or SERPINB4(2)S100A9 (3) a step of expressing the level of expression of at least one of the selected ones of the CXCL1 (4) SFTPD (5) TCHH, and (6) CXCL6 groups.

In the present invention, since the patient who has judged the expression level of the marker from the sample obtained by the patient is a responder to the treatment of the IL-31 antagonist, it is judged that the patient with a low level of expression is a treatment for the IL-31 antagonist. The reaction, the method of the invention may also comprise such steps. In the present invention, when the expression level of the mark is high, it means that the measured value of the mark is higher than a predetermined value set for the mark, and when the expression level of the mark is low, it means that it is equal to or less than a predetermined value set for the mark. Therefore, in the method of the present invention, when the expression level of the marker measured in the sample obtained from the patient is higher than the prescribed value set for the marker, the patient is shown to be a responder to the treatment of the IL-31 antagonist. . In one aspect, the method of the present invention may further comprise the step of comparing the performance level of the marker determined in the sample obtained from the patient with a prescribed value set for the marker, and the performance level of the assay is greater than the specification. When the value is higher, the patient's treatment of the IL-31 antagonist is judged as a responder.

The label of the present invention, which may also be referred to as a biomarker, means that the normal biological process, the pathogenesis or the treatment as a pharmacological reactivity index can objectively determine the specific biochemical substance to be evaluated. The label is used for the assessment of the presence or absence of the disease, the state of the condition, or the ease of the disease, or the effect of the agent, the assessment or prediction of the most appropriate amount or safety, or the prediction of the prognosis. The label of the present invention is specified by a gene name and becomes a labeled gene as a polypeptide. It is preferably measured as a polynucleotide or as a polypeptide.

The measurement of the expression level of the marker can be carried out by measuring the morphology of the desired marker or the expression level of the marker and selecting an appropriate method depending on the type of the sample. When the form of the label is a polypeptide, it is preferably measured by immunological means using an antibody that specifically binds to the polypeptide, and examples of such means include an enzyme immunoassay (ELISA, EIA), and fluorescent immunity. Assay (FIA), radioimmunoassay (RIA), luminescent immunoassay (LIA), electrochemiluminescence (ECL), western blotting, surface plasmon resonance, methods using antibody arrays, immunohistochemical staining, Fluorescence activated cell screening (FACS), immunochromatography, immunoprecipitation, immunoturbidimetry, colloidal agglutination, and the like. When the form of the label is a polynucleotide, it is preferably measured by genetic engineering using an oligonucleotide which specifically binds to the polynucleotide, and as such means, for example, a polymerase chain reaction (PCR) method, reverse transcription PCR (RT-PCR) method, real-time quantitative PCR (Q-PCR) method, northern blot method, hybridization method (including a method using an oligonucleotide such as a DNA microarray), and the like.

The sample of the present invention may also be referred to as a biological sample, and means a mixture of organs, tissues, cells, body fluids or the like contained in the living body. Specific examples include skin, trachea, intestine, urogenital pathway, nerve, tumor, bone marrow, blood cells, blood (whole blood, plasma, serum), lymph, cerebrospinal fluid, intraperitoneal fluid, synovial fluid, and intrapulmonary Liquid, saliva, sputum, urine, etc. Further, those obtained after the washing or the in vitro culture are also included in the sample of the present invention. A preferred sample of the invention is blood, and the extra sample is plasma or serum.

In the present invention, the sample obtained from a patient or the like may be concentrated, refined, extracted, isolated or physically before being measured for the expression level of the label. Processing by methods such as chemical/chemical treatment. For example, blood cells or plasma components can also be separated from blood samples, and DNA or RNA can also be extracted from tissue/cell samples. Alternatively, the unwanted components may be modified/removed by heating or chemical reagents. Such processing is mainly carried out for the purpose of improving the sensitivity or specificity of the expression level of the measurement mark.

The predetermined value of the present invention means a value determined in advance based on any scientific basis, but it can be judged that the patient suffering from a skin itching disease is a responder to the treatment of an IL-31 antagonist based on the value. Or non-responders, any value is acceptable. The predetermined value of the present invention can also be set for each mark as will be described later.

The predetermined value of the present invention can be set, for example, from the measured value of the label of the sample (control sample) obtained from a healthy adult. Due to the measured value of the marker of the present invention, compared with a healthy adult, the increase in the patient suffering from a skin itching disease has been identified in the results of the present study, and as a means of obtaining, it can be obtained from a plurality of healthy adults. The average value of the measured value of the mark in the sample is directly used as a predetermined value. Further, as another means of obtaining, 1.0 times, 1.5 times, 2.0 times, 2.5 times or 3.0 of the standard deviation may be added to the average value of the measured value. The value of the multiple value is used as the specified value. Therefore, in one aspect of the present invention, the level of expression of the marker measured in a sample obtained from a healthy adult (control sample) is determined by a sample obtained from a patient suffering from a disease with pruritus The high level of marker expression indicates that the patient is responding to treatment with an IL-31 antagonist.

Furthermore, the value of the present invention may be based on a clinical trial or the like for the treatment of a patient suffering from a skin itching disease with an IL-31 antagonist. Set as a result. When a difference between the therapeutic effect of the IL-31 antagonist and the patient group below which the measured value of the marker is higher than the measured value is observed, the reference value can be used as the predetermined value of the present invention. At this time, it is expected that statistically significant differences can be observed in the therapeutic effects of the two groups. For example, in one aspect of the present invention, the therapeutic effect on the IL-31 antagonist is low, and the skin is itchy when compared with the level of the marker measured in the sample obtained from a patient suffering from a skin itching disease. The level of marker performance measured in the samples obtained by the patient with the disease is high, indicating that the patient is responding to the treatment of the IL-31 antagonist.

The measured value or the predetermined value of the mark of the present invention means that the measurement result of the mark expression level is numerically determined by any method, and as a numerical value, the straightness (for example, color intensity, etc.) obtained by the measurement result can be directly used, or A positive control sample containing an amount of a known label may be separately prepared, and the measurement result compared with it may be converted to a straight (e.g., concentration, etc.). Further, it is also possible to use a value obtained by the above-described method to be fractionated in a certain range section or the like (for example, classification 1, 2, 3, etc.).

The patient who obtains the sample of the present invention may be a patient suffering from a disease having skin itching. It may be a patient who has not received treatment for a skin itching disease, or a patient who has been treated. In the case of a patient who has been treated with an IL-31 antagonist, the present invention provides a method of monitoring the patient's response to treatment with an IL-31 antagonist, or a method of determining whether the patient can continue treatment with an IL-31 antagonist.

IL-31 (interleukin-31) is a newly discovered cytokine of T cells. In the genetically transgenic mice overexpressing IL-31, dermatitis-like symptoms similar to atopic dermatitis have been observed. Cause itching action, etc., and understand Itchy skin.

The nucleic acid sequence of human IL-31 and the amino acid sequence are disclosed in SEQ ID NO: 1 (RefSeq Accession No. NM_001014336) and SEQ ID NO: 2 (RefSeq Accession No. NP_001014358), respectively.

The receptor for IL-31 is formed by heterodimers of IL-31 receptor A (IL-31RA) and oncostatin M receptor (OSMR) (Nat Immunol (2004) 5, 752-60) . IL-31RA, also known as NR10, is known to have a plurality of splicing variants (see patent WO 00/075314). Among the splice variants, NR10.1 (652 amino acids), NRE 10.2 (252 amino acids), NR10.3 (662 amino acids, also known as IL-31RA4), IL-31RAv3 are known. (764 amino acids), NR10.3 (IL-31RAv4) and IL-31RAv3 are mentioned as preferable IL-31RA. The nucleic acid sequence of human IL-31RA (IL-31RAv4) and the amino acid sequence are disclosed in SEQ ID NO: 3 (RefSeq Accession No. NM_001242638) and SEQ ID NO: 4 (RefSeq Accession No. NP_001229567), Human IL-31RA (IL- The nucleic acid sequence of 31RAv3) and the amino acid sequence are disclosed in SEQ ID NO: 5 (RefSeq Accession No. NM_139017) and SEQ ID NO: 6 (RefSeq Accession No. NP_620586), respectively. Furthermore, the nucleic acid sequence of human OSMR and the amino acid sequence are disclosed in SEQ ID NO: 7 (RefSeq Accession No. NM_003999) and SEQ ID NO: 8 (RefSeq Accession No. NP_003990), respectively.

The IL-31 antagonist in the present invention means to inhibit or block intracellular signal transmission caused by IL-31, and the like, in other words, a compound which blocks the IL-31 signal. These compounds may be naturally occurring compounds and are intended to be synthetic compounds. Further, it may be a low molecular compound, and may be a polymer compound such as a protein.

IL-31, which is present extracellularly, is known to cause intracellular signal transmission via the IL-31 receptor (IL-31RA and OSMR heterodimer) present on the cell surface (Nat Immunol (2004) 5, 752-760). The extracellular domain of the IL-31 receptor contains the IL-31 binding domain. When IL-31 binds to it, the steric structure of the IL-31 receptor changes, and the result is the intracellular domain of the IL-31 receptor. Start intracellular signal communication. Thus, whether or not a compound blocks the IL-31 signal can be confirmed by examining whether the compound inhibits the binding of IL-31 to the IL-31 receptor. Examples of the method for performing such measurement include analysis by ELISA or flow cytometry, analysis using surface plasmon resonance, and the like. For example, in the case of ELISA, a secondary antibody such as an anti-IL-31 antibody identified by an enzyme is prepared by analyzing the amount of the IL-31 receptor (or IL-31RA) protein on the disk and binding the IL-31 protein thereto. In the system for detecting the method, whether or not the amount of the detected IL-31 protein is decreased by adding a compound, whether or not the compound inhibits binding of IL-31 to the IL-31 receptor can be evaluated.

Further, as another method, whether or not a certain compound blocks the IL-31 signal can be confirmed by examining whether the physiological activity caused by the action of IL-31 on the cells is inhibited by the compound. The physiological activity herein is not particularly limited as long as it is quantitatively or qualitatively measured by any method, and examples thereof include cell proliferation activity, protein phosphorylation activity, and gene/protein expression-inducing activity. For example, a cell which exhibits a proliferative activity on the surface of the IL-31 receptor and is induced by IL-31 stimulation from the outside is prepared, and when a compound is added thereto, it is determined whether or not the cell proliferation activity induced by IL-31 is decreased. Evaluate whether the compound blocks the IL-31 signal. As these cells, they can be used to express IL-31 As the natural cells of the body, genetically recombinant cells artificially expressing the IL-31 receptor can also be used. Preferable examples of the genetic recombinant cells include Ba/F3 cells which express the IL-31 receptor. Further, as another method, the method disclosed in Dillon et al. (Nat Immunol (2004) 5, 752-760) can be used.

In the present invention, the degree of inhibition of the IL-31 signal by the IL-31 antagonist is not particularly limited, and is at least 10% or more, preferably 20% or more, 30% or more, 40% or more, 50% or more, or 60% or more. 70% or more, 80% or more, particularly good hindering 90% or more, 95% or more, 98% or more.

In the present invention, as a preferred embodiment of the IL-31 signal blocking compound, a protein which blocks the IL-31 signal can be mentioned. The protein herein is not particularly limited as long as it has a property of specifically binding to IL-31 or IL-31 receptor, and preferred examples thereof include antibodies or antibody-like molecules (Curr Opin Biotechnol (2006) 17, 653-658; Curr Opin Struct Biol (1997) 7, 463-469; Protein Sci (2006) 15, 14-27). Antibodies include monoclonal antibodies (eg, IgG, IgM, IgE, IgA, IgD, etc.), polyclonal antibodies, altered antibodies (eg, chimeric antibodies, humanized antibodies, sugar chain altered antibodies (WO 99/54342, WO 00/61739) ), etc., antibody fragments (eg, Fab, F(ab') 2, Fv, CDR, etc.), multiplex specific antibodies (eg, dual specific antibodies, etc.), conjugated antibodies (eg, addition polyethylene glycol (PEG) , antibodies such as radioisotopes, drugs, etc.). On the other hand, examples of the antibody-like molecule include DARPin (WO 2002/020565), Affibody (WO 1995/001937), Avimer (WO 2004/044011), and Adnectin (WO 2002/032925). More preferred are antibodies that block the IL-31 signal. Further, as another preferred example of the protein which blocks the IL-31 signal, a protein or a package comprising an extracellular domain of IL-31RA may be mentioned. A protein containing each of the extracellular domains of the IL-31 receptor (a heterodimer of IL-31RA and OSMR).

Further, in the present invention, as a preferred aspect of the antibody which blocks the IL-31 signal, an antibody which blocks IL-31 signaling by binding to IL-31 (anti-IL-31 neutralizing antibody) or by using IL The -31 receptor binds to an antibody that blocks IL-31 signaling (anti-IL-31 receptor neutralizing antibody). The anti-IL-31 receptor neutralizing antibody comprises an antibody (anti-IL-31RA neutralizing antibody) that blocks IL-31 signaling by binding to IL-31RA, and an antibody that blocks IL-31 signaling by binding to OSMR (anti-antibody) OSMR neutralizing antibody), or an antibody (anti-IL-31RA/OSMR heterodimeric neutralizing antibody) which blocks IL-31 signaling by binding to a heterodimer of IL-31RA and OSMR, preferably anti-antibody The IL-31RA neutralizing antibody or the anti-IL-31RA/OSMR heterodimer neutralizing antibody, more preferably the anti-IL-31RA neutralizing antibody.

Methods of making antibodies are well known in the art, for example, by fusion microscopy (Nature (1975) 256, 495) or phage antibody library method (Nature 1991) 352, 624-628; J Mol Biol (1991) 222, 581-597. ) Production. The IL-31 protein or the IL-31 receptor protein is used as an immunogen, and an anti-IL-31 antibody or an anti-IL-31 receptor antibody can be obtained in a large amount by these methods. Further, as long as the antibody is used, The method of screening for a compound which blocks the above-mentioned IL-31 signal can be carried out to obtain an anti-IL-31 neutralizing antibody or an anti-IL-31 receptor neutralizing antibody. Proteins such as IL-31 or IL-31 receptors can be modulated by genetic engineering methods well known to those skilled in the art. Specifically, a gene encoding a desired protein is inserted into a expression vector, and the vector is introduced into an appropriate host cell, and then purified by the host cell or the target protein expressed in the culture supernatant of the host cell. Can be modulated.

As preferred examples of the anti-IL-31 neutralizing antibody, an anti-IL-31 antibody disclosed in WO2006/122079 or an anti-IL-31 antibody disclosed in WO2008/028192 can be cited.

Preferred examples of the anti-IL-31RA neutralizing antibody include an anti-IL-31RA (NR10) antibody disclosed in WO2007/142325, an anti-IL-31RA (NR10) antibody disclosed in WO2009/072604, and an anti-IL disclosed in WO2010/064697. -31RA (NR10) antibody or the like. Further, as another preferred example, an anti-IL-31RA antibody recognizing human IL-31RA domain 1 can be mentioned. Human IL-31RA domain 1 herein means the region from the 53th amino acid to the 152th amino acid in the amino acid sequence of SEQ ID NO: 6 (LPAKP to LENIA). More preferably, it comprises CDR1 revealed by SEQ ID NO: 9, CDR2 revealed by SEQ ID NO: 10, and H chain variable region of CDR3 revealed by SEQ ID NO: 12, and CDR1 including SEQ ID NO: 12. SEQ ID NO: 13 revealed CDR2 and SEQ ID NO: 14 revealed an anti-IL-31RA antibody of the L chain variable region of CDR3, and more preferably contains H chain variable region revealed by SEQ ID NO: 15 and SEQ ID NO: 16 reveals The anti-IL-31RA antibody of the L chain variable region is particularly preferably an anti-IL-31RA antibody comprising the H chain variable region disclosed by SEQ ID NO: 17 and the L chain variable region disclosed by SEQ ID NO: 18.

Further, as a definition of the CDR method, a known method of Kabat et al (Sequences of Proteins of Immunological Interest, 5 th Ed (1991), Bethesda, MD), Chothia et al. (Science (1986) 233,755-758) A method based on an antigen-antibody contact region (J Mol Biol (1996) 262, 732-745) and the like.

Specifically, the CDRs are defined by the respective methods as follows.

Therefore, preferred examples of the anti-IL-31RA neutralizing antibody of the present invention include CDR1, CDR2 and CDR3 comprising the H chain variable region disclosed in SEQ ID NO: 15, and the L chain including SEQ ID NO: 16 The CDR1, CDR2 and CDR3 of the variable region are the anti-IL-31RA antibodies of the H chain CDR1, CDR2 and CDR3, and the L chain CDR1, CDR2 and CDR3, respectively. The method for defining the CDRs of the antibodies may be either according to the method of Kabat et al., the method of Chothia et al., the method based on the antigen-antibody contact region, or the combination method.

The sequence of each CDR of the H chain and the L chain, the sequence of the H chain and the L chain variable region, and the sequence of the full length of the H chain and the L chain bind to the same epitope as the specific anti-IL-31RA antibody ( The anti-IL-31RA antibody of epitope is also preferably used as an anti-IL-31RA neutralizing antibody. The epitope-determining antibody recognizes a specific structural unit of the bound antigen, and when the antigen is a polypeptide, it usually contains about 6 to 10 amino acids. The identification of an epitope can be achieved by a method of synthesizing an antigen-fragmented polypeptide, a method of sudden mutation specific to an antigen-introducing site (for example, arginine/glutamic acid scanning, J Biol Chem (1995) 270, 21619-21625; J Biol Chem (2006) 281, 20464-20473), a method of performing crystallization of an antigen-antibody complex, and the like, which are known in the art (Using Antibodied: A Laboratory Manual (1999) , Cold Spring Harbor Laboratory Press, New York). In the present invention, "binding to the same epitope" means that at least a part of the epitopes to which the two types of antibodies bind are repeated. The degree of repetition is not particularly limited, and is at least 10% or more, preferably 20% or more, 30% or more, 40% or more, 50% or more, 60% or more, 70% or more, 80% or more, and particularly preferably 90%. Above, the best is 100% repeat.

Furthermore, the binding to IL-31A competes with the sequence of the H- and L-chain CDR sequences, the H-chain and L-chain variable regions, and the sequence-specific anti-IL-31A antibodies of the full length of the H chain and the L chain. The anti-IL-31RA antibody is also preferably used as an anti-IL-31RA neutralizing antibody. Whether the two types of antibodies compete with each other can be evaluated by competitive binding assay using ELISA or the like. Specifically, among the two types of antibodies, one of the antibodies is previously identified by fluorescence or the like, and a system for detecting the binding of the antibody (labeled antibody) to the antigen is prepared, and then compared with or without another unlabeled antibody ( When the antibody to be tested is coexisting, in the case where the antibody to be detected coexists, when the amount of binding of the labeled antibody to the antigen is lowered, it can be judged that the antibody to be detected by the antibody competes with each other. In the present invention, the degree of competition is not particularly limited, and the competition is at least 10% or more, preferably 20% or more, 30% or more, 40% or more, 50% or more, 60% or more, 70% or more, and 80% or more. Preferably, it is 90% or more, 95% or more, and 98% or more (that is, the amount of antibody binding of the other is decreased).

The skin itching of the present invention may be caused by skin itching caused by any cause, and it is preferably skin itching caused by IL-31.

The skin itch disease of the present invention may be a disease causing itching of the skin as a result of the disease, and may be any disease, and specific examples thereof include atopic dermatitis, contact dermatitis, and neurodermatitis. , liposuction dermatitis, self-sensitive dermatitis, caterpillar dermatitis, sputum dermatitis, acne, sebum deficiency, senile pruritus, nodular pruritus, herpes zoster, urticaria, pus , eczema, sweat rash, rash-like dermatitis, pemphigoid, rosacea, general acne, ferrets, cognac, moss, phlegm, leukoplakia, dry skin, round hair loss, light allergy, biliary obstruction , primary biliary cirrhosis, viral hepatitis, uremia, chronic renal failure, hemodialysis, gout, cutaneous T-cell lymphoma, leukemia, polycythemia, hyperthyroidism, diabetes, visceral cancer, pregnancy, Drug allergy, etc.

Furthermore, the present invention relates to a therapeutic agent for a skin itching disease characterized by comprising an IL-31 antagonist as an active ingredient in a sample obtained from a patient suffering from a skin itching disease (1) SERPINB3 and/or Or a patient with a high level of expression of at least one marker selected from the group consisting of SERPINB4(2)S100A9(3)CXCL1(4)SFTPD(5)TCHH, and (6) CXCL6.

As described above, according to the present invention, since a method for predicting a response to treatment of an IL-31 antagonist in a patient suffering from a skin itching disease is provided, The present invention also provides a therapeutic agent for a skin itching disease characterized by comprising an IL-31 antagonist as an active ingredient, and a therapeutic agent which is judged to be a responder to treatment with an IL-31 antagonist by the method is administered.

Furthermore, the present invention relates to a method for treating a patient suffering from a skin itching disease, which comprises (1) SERPINB3 and/or SERPINB4(2)S100A9 in a sample obtained from a patient suffering from a skin itching disease (1) 3) A step of administering an IL-31 antagonist to a patient having a high level of expression of at least one of the selected ones selected from the group consisting of CXCL1 (4) SFTPD (5) TCHH, and (6) CXCL6.

As described above, according to the present invention, since a method for predicting a response to treatment of an IL-31 antagonist in a patient suffering from a skin itching disease is provided, the present invention also provides a method of treating a patient suffering from a skin itching disease, which A step of administering an IL-31 antagonist to a patient judged to be a responder to treatment with an IL-31 antagonist by the method.

More specifically, the method of the present invention for treating a patient suffering from a skin itching disease may include (a) a step of taking a sample from a patient suffering from a skin itching disease, and (b) measuring in the aforementioned sample (1) )SERPINB3 and / or SERPINB4 (2) a step of S100A9(3)CXCL1(4)SFTPD(5)TCHH, and (6) a level of expression of at least one marker selected from the group of CXCL6, (c) comparing the marker in the sample obtained from the patient The step of measuring the measured value and the predetermined value set for the label, and (d) the step of administering the IL-31 antagonist to the patient whose measured value is higher than the predetermined value, and the like.

Furthermore, the present invention relates to an IL-31 antagonist for use in the treatment of a skin itching disease characterized by (1) SERPINB3 and/or from a sample obtained from a patient suffering from a skin itching disease. SERPINB4(2)S100A9(3)CXCL1(4)SFTPD(5)TCHH, and (6) A patient with a high level of expression of at least one marker selected from the group of CXCL6 is administered an IL-31 antagonist.

As described above, according to the present invention, since a method for predicting a response to treatment of an IL-31 antagonist in a patient suffering from a skin itching disease is provided, The invention relates to an IL-31 antagonist for use in the treatment of a skin itching disease, characterized by an IL-31 antagonist which is judged by the method to be administered to a patient who is a responder to the treatment of an IL-31 antagonist. use.

Furthermore, the present invention relates to the use of an IL-31 antagonist in the manufacture of a therapeutic agent for a skin itching disease, which is characterized in that, from a sample obtained from a patient suffering from a skin itching disease, (1) SERPINB3 and/or Or a patient having a high level of expression of at least one of the selected ones selected from the group consisting of SERPINB4(2)S100A9(3)CXCL1(4)SFTPD(5)TCHH, and (6) CXCL6 is administered to the therapeutic agent.

As described above, according to the present invention, the present invention relates to a method for treating a therapeutic agent for a disease having pruritus in the treatment of an IL-31 antagonist, and the present invention relates to IL-31 in the manufacture of a therapeutic agent for a skin itching disease. Use of an antagonist characterized by the use of an IL-31 antagonist for the administration of a therapeutic agent in a patient who is judged to be a responder to treatment with an IL-31 antagonist.

Furthermore, the present invention relates to a method for screening a patient suffering from a skin itching disease, which comprises a sample obtained from a patient suffering from a skin itching disease, (1) SERPINB3 and/or SERPINB4(2)S100A9. (3) A patient having a high level of expression of at least one of the selected ones selected from the group consisting of CXCL1 (4) SFTPD (5) TCHH and (6) CXCL6 is judged to be a responder to the treatment of the IL-31 antagonist.

More specifically, the method of the present invention for screening a patient suffering from a skin itching disease may include (a) a step of taking a sample from a patient suffering from a skin itching disease, and (b) measuring in the aforementioned sample (1) SERPINB3 and/or SERPINB4(2)S100A9(3)CXCL1(4)SFTPD(5)TCHH, and (6) a step of the performance level of at least one marker selected from the group of CXCL6, (c) compared to the patient a step of measuring a labeled value in the obtained sample and a predetermined value set for the label, and (d) determining a step of administering the IL-31 antagonist as a responder to a patient whose measured value of the labeled label is higher than a predetermined value, Wait for steps.

Furthermore, the present invention relates to a kit for predicting a response to treatment of an IL-31 antagonist in a patient suffering from a skin itching disease, characterized in that Reagents for determining the expression level of at least one marker selected from the group consisting of (1) SERPINB3 and/or SERPINB4(2)S100A9(3)CXCL1(4) SFTPD(5)TCHH, and (6) CXCL6 .

The kit may further include an instruction to describe the method of use of the kit. Among these methods of use, it is desirable to disclose a method for determining the measurement result of the expression level of the marker. Specifically, as a preferred example, a measurement value of a marker in a sample obtained from a patient is compared with a predetermined value set for the marker, and a patient having a higher than a predetermined value is determined to be a treatment for an IL-31 antagonist. For the responder, patients below the prescribed value were judged to be non-responders for the treatment of the segmental IL-31 antagonist.

The reagent contained in the kit of the present invention is not particularly limited as long as the expression level of the label can be measured, and the drug can be appropriately selected depending on the form of the label. In the case where the form of the label is a polypeptide, it is preferably a reagent comprising an antibody which specifically binds to the polypeptide, and further, in the case where the label is in the form of a polynucleotide, it is preferably an oligonucleotide which specifically binds to the polynucleotide. Nucleotide.

Further, the kit of the present invention preferably includes a positive control sample which is a reference when the expression level of the marker is measured. The positive control sample is not particularly limited as long as the amount of the label contained therein is a predetermined sample, and may be according to the set. The morphology of the markers determined by the group is suitably selected. For example, in the case where the form of the label is a polypeptide, it is preferred to include a sample in which the polypeptide is quantified in the same manner as the label as a positive control sample.

In the present invention, a method for predicting a response to treatment of an IL-31 antagonist in a patient suffering from a skin itching disease is, in other words, an evaluation of the effectiveness of treatment of an IL-31 antagonist in a patient suffering from a skin itching disease. method. Furthermore, it is also possible to select a method for treating a patient who is suitable for the treatment of an IL-31 antagonist from a patient suffering from a skin itching disease. Alternatively, in other words, in a patient suffering from a skin itching disease, a method for detecting a marker for predicting a response to treatment with an IL-31 antagonist, a method for assessing the effectiveness of the treatment or A method for screening markers of a patient suitable for the treatment. These methods can be performed in vitro using samples taken from a patient.

In one aspect, the invention provides a method of obtaining intermediate results for assessing the response of a patient suffering from a skin itching disorder to the treatment of an IL-31 antagonist. In another aspect, the invention provides a method of obtaining intermediate results for screening a patient suffering from a skin itchy disease. In still other aspects, the invention provides methods of obtaining intermediate results for the diagnosis of a disease with pruritus. By combining these intermediate results with more information, physicians, caregivers, or other medical practitioners can be assisted in treating patients with pruritus or pruritus with IL-31 antagonists. Responder.

In the present invention, a patient suffering from a skin itching disease is a responder to the treatment of an IL-31 antagonist, meaning that the skin itching is relieved by the treatment of the IL-31 antagonist, and the non-responder means Treatment of IL-31 antagonists The skin itching of the patient was not alleviated. The case of skin itching is a case of atopic dermatitis, and in addition to the effect of reducing skin itching, the responder may also have an effect of treating a skin disease of the underlying disease. Whether or not the skin itching is alleviated can be evaluated by a method known to those skilled in the art. For example, using a Visual Analogue Scale (VAS) or a whiteness severity reference, the degree of skin itching felt by the patient can be scored, and the device for measuring the itching action caused by the acceleration of the wrist movement can be used. The number of night smashes of the patient can be measured by micro-speed far-line photography or video photography.

The following are the marks of the present invention.

(1) SERPINB3 and / or SERPINB4

SERPINB3 (serpin peptidase inhibitor, clade B member 3) and SERPINB4 (serpin peptidase inhibitor, clade B member 4) are proteins with a molecular weight of about 45,000 and belong to the Serpin family of serine protease inhibitors. SERPINB3 and SERPINB4, both of which are Squamous Cell Carcinoma Antigen (SCCA), also known as the aliases SCCA1 and SCCA2, show high blood in patients with cervical cancer, esophageal cancer, lung cancer, skin cancer, etc. The medium concentration can also be used for the diagnosis of cancer. On the other hand, SERPINB3 (SCCA1) and SERPINB4 (SCCA2) are known to be involved in the specific skin of patients with atopic skin, and the levels of genes and proteins are simultaneously increased, indicating the possibility of becoming a marker of atopic dermatitis (Clin Exp Allergy (2005) 35, 1327-1333). Furthermore, it has been reported that SERPINB3 and SERPINB4 have slightly increased mRNA expression levels in keratinocytes stimulated with IL-31 (J Allergy Clin Immunol (2012) 129, 426-433).

The nucleic acid sequence and amino acid sequence of human SERPINB3 are respectively revealed Shown in the serial number: 19 (RefSeq registration number NM_006919) and serial number: 20 (RefSeq registration number NP_008850). The nucleic acid sequence and amino acid sequence of human SERPINB4 are disclosed in SEQ ID NO: 21 (RefSeq Accession No. NM_002974) and SEQ ID NO: 22 (RefSeq Accession No. NP_002965), respectively.

The identity of the nucleic acid sequence and the amino acid sequence of SERPINB3 and SERPINB4 are very high 95% and 91%, respectively. It is not necessarily easy to distinguish the specificity of the two, and there are many in the art that are not different at the same time. Determination. For example, the common portion of the nucleic acid sequences of the two sets the primer for gene amplification or the probe for gene detection, and the two can be simultaneously measured, and further, the amino acid sequence bound to the two is prepared. The antibody is shared and detected by an antigen-antibody reaction such as ELISA, and both can be simultaneously measured.

In the present invention, SERPINB3 or SERPINB4 may also be used alone as a label, or a combination of the two may be used as a label. When the two are labeled, SERPINB3 and SERPINB4 can be separately measured and combined, or SERPINB3 and SERPINB4 can be simultaneously determined by the method described above. In the present specification, the designation "SERPINB3/SERPINB4" indicates SERPINB3 and SERPINB4 when measured by a method that does not distinguish between the two.

The measurement of the expression level of SERPINB3 and/or SERPINB4 can be carried out by using the measurement method disclosed in the present invention, and a commercially available measurement reagent (for example, ARCHITECT.SCC (registered trademark) (ABBOTT Janpan Co., Ltd.)) can also be used. The specific measured value or predetermined value of SERPINB3 and/or SERPINB4 disclosed in the present specification can be interpreted as a value measured using the aforementioned measuring reagent.

The specified value set for SERPINB3 and/or SERPINB4, The sample type of the patient whose SERPINB3 and/or SERPINB4 expression level is measured may vary, and may be set, for example, in the range of 0.1 to 100 ng/mL. Alternatively, 0.2 to 90 ng/mL, 0.3 to 80 ng/mL, 0.4 to 70 ng/mL, 0.5 to 60 ng/mL, 1.0 to 50 ng/mL, 1.5 to 40 ng/mL, 2.0 to 30 ng/mL, 2.5 to 20 ng/ The range of mL, 3.0 to 10 ng/mL, etc. is not limited to these.

Furthermore, the specified values set for SERPINB3 and/or SERPINB4 can be set to 0.1 ng/mL, 0.2 ng/mL, 0.3 ng/mL, 0.4 ng/mL, 0.5 ng/mL, 0.6 ng/mL, 0.7 ng. /mL, 0.8 ng/mL, 0.9 ng/mL, 1.0 ng/mL, 1.5 ng/mL, 2.0 ng/mL, 2.5 ng/mL, 3.0 ng/mL, 3.5 ng/mL, 4.0 ng/mL, 4.5 ng /mL, 5.0 ng/mL, 5.5 ng/mL, 6.0 ng/mL, 6.5 ng/mL, 7.0 ng/mL, 7.5 ng/mL, 8.0 ng/mL, 8.5 ng/mL, 9.0 ng/mL, 10 ng/ mL, 15 ng/mL, 20 ng/mL, 25 ng/mL, 30 ng/mL, 35 ng/mL, 40 ng/mL, 45 ng/mL, 50 ng/mL, 60 ng/mL, 70 ng/mL, 80 ng/mL, 90 ng/mL, 100 ng/mL equivalent, but not limited to these.

(2) S100A9

S100A9 (S100 calcium binding protein A9), a protein with a molecular weight of approximately 14,000, belongs to the EF-hand calcium binding S100 protein family. S100A9, also known as calgranulin B or MRP14 (mobility inhibitory factor-related protein 4), is known to cause inflammation in chronic rheumatoid arthritis, multiple sclerosis, Crohn's disease, and connective tissue diseases. High serum levels are shown in patients with sexually transmitted diseases. On the other hand, S100A9 is known to increase the level of expression of genes in the skin of patients with atopic dermatitis (Exp Dermatol (2012) 21, 184-188). again It has been reported that S100A9 is induced in the expression of mRNA in keratinocytes stimulated with IL-31 (WO 2006/063865).

The nucleic acid sequence and amino acid sequence of human S100A9 are disclosed in SEQ ID NO: 23 (RefSeq Accession No. NM_002965) and SEQ ID NO: 24 (RefSeq Accession No. NP_002956), respectively.

The measurement of the performance level of S100A9 can be carried out using the assay method disclosed in the present invention, or can be carried out using a commercially available assay reagent (for example, CircuLex S100A9/MRP14 ELISA kit (Circulex)). The specific set value or predetermined value of S100A9 disclosed in the present specification can be interpreted as a value measured using the aforementioned measuring reagent.

The predetermined value set in S100A9 can be changed according to the type of the patient who measures the performance level of S100A9, and can be set, for example, in the range of 0.1 to 100 ng/mL. Alternatively, 0.5 to 90 ng/mL, 1.0 to 85 ng/mL, 1.5 to 80 ng/mL, 2.0 to 75 ng/mL, 2.5 to 70 ng/mL, 3.0 to 65 ng/mL, 4.0 to 60 ng/mL, 5.0 to 55 ng/ The range of mL, 10 to 50 ng/mL, etc., but is not limited to these.

Furthermore, the predetermined values set for S100A9 can be set to 0.1 ng/mL, 0.5 ng/mL, 1.0 ng/mL, 1.5 ng/mL, 2.0 ng/mL, 2.5 ng/mL, 3.0 ng/mL, 3.5. Ng/mL, 4.0 ng/mL, 4.5 ng/mL, 5.0 ng/mL, 5.5 ng/mL, 6.0 ng/mL, 6.5 ng/mL, 7.0 ng/mL, 7.5 ng/mL, 8.0 ng/mL, 8.5 Ng/mL, 9.0 ng/mL, 9.5 ng/mL, 10 ng/mL, 15 ng/mL, 20 ng/mL, 25 ng/mL, 30 ng/mL, 35 ng/mL, 40 ng/mL, 45 ng/mL, 50 ng/mL, 55ng/mL, 60ng/mL, 65ng/mL, 70ng/mL, 75ng/mL, 80ng/mL, 85ng/mL, 90ng/mL, 95ng/mL, 100 ng/mL equivalent, but not limited to these.

(3) CXCL1

CXCL1 (chemokine (C-X-C motif) ligand 1) is a protein with a molecular weight of about 7800 and belongs to the CXC family of chemokines, also known as GRO-α (growth regulated oncogene-α). It has been reported that CXCL1 has a change in gene level or protein level in tissues or blood of patients with malignant tumors such as colorectal cancer or ovarian cancer or malignant black tumor. On the other hand, CXCL1 is known to increase protein expression levels in the skin of patients with atopic dermatitis (Methods (2012) 56, 198-203). Furthermore, it has been reported that CXCL1 is induced by administration of IL-31 stimulation due to the co-culture of eosinophils with keratinocytes or fibroblasts (Int Immunol (2010) 22, 453-467, PLoS One (2012) 7, E29815).

The nucleic acid sequence and amino acid sequence of human CXCL1 are disclosed in SEQ ID NO: 25 (RefSeq Accession No. NM_001511) and SEQ ID NO: 26 (RefSeq Accession No. NP_001502), respectively.

The measurement of the expression level of CXCL1 can be carried out using the assay method disclosed in the present invention, or can be carried out using a commercially available assay reagent (for example, Human CXCL1/GRO alpha Quantikine ELISA Kit (R&D Systems)). The specific set value or predetermined value of CXCL1 disclosed in the present specification can be interpreted as a value measured using the aforementioned measuring reagent.

The predetermined value set for CXCL1 can be varied depending on the type of the patient who measures the expression level of CXCL1, and can be set, for example, in the range of 40 to 800 pg/mL. Alternatively, 50 to 780 pg/mL, 60 to 760 pg/mL, 70 to 740 pg/mL, 80 to 720 pg/mL, 90 to 700 pg/mL, It is in the range of 100 to 680 pg/mL, 110 to 660 pg/mL, 120 to 640 pg/mL, 130 to 620 pg/mL, and the like, but is not limited thereto.

Further, the predetermined value set for CXCL1 can be set to 40 pg/mL, 50 pg/mL, 60 pg/mL, 70 pg/mL, 80 pg/mL, 90 pg/mL, 100 pg/mL, 110 pg/mL, 120 pg/mL, 130 pg/mL, 140 pg/mL, 150 pg/mL, 160 pg/mL, 170 pg/mL, 180 pg/mL, 190 pg/mL, 200 pg/mL, 210 pg/mL, 220 pg/mL, 230 pg/mL, 240 pg/mL, 250 pg/ mL, 260 pg/mL, 270 pg/mL, 280 pg/mL, 290 pg/mL, 300 pg/mL, 310 pg/mL, 320 pg/mL, 330 pg/mL, 340 pg/mL, 350 pg/mL, 360 pg/mL, 370 pg/mL, 380pg/mL, 390pg/mL, 400pg/mL, 410pg/mL, 420pg/mL, 410pg/mL, 430pg/mL, 440pg/mL, 450pg/mL, 460pg/mL, 470pg/mL, 480pg/mL, 490pg/ mL, 500 pg/mL, 510 pg/mL, 520 pg/mL, 530 pg/mL, 540 pg/mL, 550 pg/mL, 560 pg/mL, 570 pg/mL, 580 pg/mL, 590 pg/mL, 600 pg/mL, 610 pg/mL, 620pg/mL, 630pg/mL, 640pg/mL, 650pg/mL, 660pg/mL, 670pg/mL, 680pg/mL, 690pg/mL, 700pg/mL, 710pg/mL, 720pg/mL, 730pg/mL, 740pg/ The values are mL, 750 pg/mL, 760 pg/mL, 770 pg/mL, 780 pg/mL, 790 pg/mL, and 800 pg/mL, but are not limited thereto.

(4) SFTPD

SFTPD (surfactant protein D) is a protein having a molecular weight of about 43,000, a protein called a collagen lectin. SFTPD is known as a component of protein on the surface of the lungs, and is provided by the alveolar secretion to maintain the smooth breathing, and is also a factor of natural immunity in the defense of the body. Patients with atopic dermatitis and health When human skin is compared, SFTPD has an increased level of protein expression in the epidermis of patients with atopic dermatitis. When comparing the serum concentrations of SFTPD, it has been reported that patients with atopic dermatitis and healthy adults have not been observed. Difference (Exp Dermatol (2006) 15, 168-174).

The nucleic acid sequence and amino acid sequence of human SFTPD are disclosed in SEQ ID NO: 27 (RefSeq Accession No. NM_003019) and SEQ ID NO: 28 (RefSeq Accession No. NP_003010), respectively.

The measurement of the SFTPD expression level can be carried out by using the measurement method disclosed in the present invention, or by using a commercially available measurement reagent (for example, SP-D Kit "YAMASA" EIAII (YAMASA CORPORATION)). The specific set value or predetermined value of the SFTPD disclosed in the present specification can be interpreted as a value measured using the aforementioned measuring reagent.

The predetermined value set for the SFTPD can be varied depending on the type of the patient who measures the performance level of the SFTPD, and can be set, for example, in the range of 1.0 to 400 ng/mL. Alternatively, 5.0 to 350 ng/mL, 10 to 300 ng/mL, 20 to 250 ng/mL, 25 to 200 ng/mL, 30 to 190 ng/mL, 35 to 180 ng/mL, 40 to 170 ng/mL, 45 to 160 ng/ The range of mL, 50 to 150 ng/mL, etc., but is not limited to these.

Furthermore, the specified values set for SFTPD can be set to 1.0 ng/mL, 2.0 ng/mL, 5.0 ng/mL, 10 ng/mL, 15 ng/mL, 20 ng/mL, 25 ng/mL, 30 ng/mL, 35 ng. /mL, 40ng/mL, 45ng/mL, 50ng/mL, 55ng/mL, 60ng/mL, 65ng/mL, 70ng/mL, 75ng/mL, 80ng/mL, 85ng/mL, 90ng/mL, 95ng/mL , 100 ng/mL, 110 ng/mL, 120 ng/mL, 130 ng/mL, 140 ng/mL, 150 ng/mL, 160 ng/mL, 170 ng/mL, 180 ng/mL, 190 ng/mL, 200 ng/mL, 210 ng/mL, 220 ng/mL, 230 ng/mL, 240 ng/mL, 250 ng/mL, 300 ng/mL, 350 ng/mL, 400 ng/mL, However, it is not limited to these.

(5) TCHH

TCHH (trichohyalin) is a protein having a molecular weight of about 220,000. The site of the inner hair root sheath which is specifically expressed in the hair follicle of the organ called the hair, which is associated with the keratinization of the cells by binding to keratin filaments here. The association with skin itching diseases such as atopic dermatitis has not been reported as of today.

The nucleic acid sequence and amino acid sequence of human TCHH are disclosed in SEQ ID NO: 29 (RefSeq Accession No. NM_007113) and SEQ ID NO: 30 (RefSeq Accession No. NP_009044), respectively.

The measurement of the TCHH expression level can be carried out using the assay method disclosed in the present invention, or can be carried out using a commercially available assay reagent (for example, ELISA Kit for Trichohyalin (TCHH) (USCN)). The specific set value or predetermined value of the SFTPD disclosed in the present specification can be interpreted as a value measured using the aforementioned measuring reagent.

The predetermined value set for the TCHH may vary depending on the type of the patient who measures the expression level of TCHH, and may be set, for example, in the range of 10 to 400 ng/mL. Alternatively, 20 to 380 ng/mL, 30 to 350 ng/mL, 40 to 320 ng/mL, 50 to 300 ng/mL, 60 to 280 ng/mL, 70 to 260 ng/mL, 80 to 240 ng/mL, and 90 to 220 ng/ The range of mL, 100 to 200 ng/mL, etc., is not limited to these.

Furthermore, the specified value set for TCHH can be set to 10ng/mL, 15ng/mL, 20ng/mL, 25ng/mL, 30ng/mL, 35ng/mL, 40ng/mL, 45ng/mL, 50ng/mL, 55ng/mL, 60ng/mL, 65ng/mL, 70ng/ mL, 75 ng/mL, 80 ng/mL, 85 ng/mL, 90 ng/mL, 95 ng/mL, 100 ng/mL, 105 ng/mL, 110 ng/mL, 115 ng/mL, 120 ng/mL, 125 ng/mL, 130 ng/mL, 135 ng/mL, 140 ng/mL, 145 ng/mL, 150 ng/mL, 155 ng/mL, 160 ng/mL, 165 ng/mL, 170 ng/mL, 175 ng/mL, 180 ng/mL, 185 ng/mL, 190 ng/mL, 195 ng/ mL, 200 ng/mL, 205 ng/mL, 210 ng/mL, 215 ng/mL, 220 ng/mL, 225 ng/mL, 230 ng/mL, 235 ng/mL, 240 ng/mL, 245 ng/mL, 250 ng/mL, 255 ng/mL, 260ng/mL, 265ng/mL, 270ng/mL, 275ng/mL, 280ng/mL, 285ng/mL, 290ng/mL, 295ng/mL, 300ng/mL, 305ng/mL, 310ng/mL, 315ng/mL, 320ng/ mL, 325 ng/mL, 330 ng/mL, 335 ng/mL, 340 ng/mL, 345 ng/mL, 350 ng/mL, 355 ng/mL, 360 ng/mL, 365 ng/mL, 370 ng/mL, 375 ng/mL, 380 ng/mL, 385 ng/mL, 390 ng/mL, 395 ng/mL, 400 ng/mL equivalent, but not limited to these.

(6) CXCL6

CXCL6 (chemokine (C-X-C motif) ligand 6) is a protein with a molecular weight of about 12,000 and belongs to the CXC family of chemokines, also known as GCP2 (granulocyte chemotactic protein 2) or SCYB6 (small-inducible cytokine B6). It has been reported that CXCL6 has an increased gene expression in IL-4-stimulated keratinocytes, suggesting a relationship with atopic dermatitis (Cytokine (2013) 61, 419-425).

The nucleic acid sequence and amino acid sequence of human CXCL6 are disclosed in Sequence number: 31 (RefSeq registration number NM_002993) and sequence number: 32 (RefSeq registration number NP_002984).

The measurement of the expression level of CXCL6 can be carried out using the assay method disclosed in the present invention, or can be carried out using a commercially available assay reagent (for example, Human CXCL6/GCP-2 Quantikine ELISA Kit (R&D Systems)). The specific set value or predetermined value of CXCL6 disclosed in the present specification can be interpreted as a value measured using the aforementioned measuring reagent.

The predetermined value set for CXCL6 can be varied depending on the type of the sample of the patient who measures the expression level of CXCL6, and can be set, for example, in the range of 10 to 400 ng/mL. Alternatively, 20 to 390 pg/mL, 30 to 380 pg/mL, 40 to 370 pg/mL, 850 to 360 pg/mL, 60 to 350 pg/mL, 70 to 340 pg/mL, 80 to 330 pg/mL, 90 to 320 pg/ The range of mL, 100 to 310 pg/mL, etc. is not limited to these.

Further, the predetermined value set for CXCL6 can be set to 10 pg/mL, 20 pg/mL, 30 pg/mL, 40 pg/mL, 50 pg/mL, 60 pg/mL, 70 pg/mL, 80 pg/mL, 90 pg/mL, 100 pg/mL, 105 pg/mL, 110 pg/mL, 115 pg/mL, 120 pg/mL, 125 pg/mL, 130 pg/mL, 135 pg/mL, 140 pg/mL, 145 pg/mL, 150 pg/mL, 155 pg/mL, 160 pg/ mL, 165 pg/mL, 170 pg/mL, 175 pg/mL, 180 pg/mL, 185 pg/mL, 190 pg/mL, 195 pg/mL, 200 pg/mL, 205 pg/mL, 210 pg/mL, 215 pg/mL, 220 pg/mL, 225 pg/mL, 230 pg/mL, 235 pg/mL, 240 pg/mL, 245 pg/mL, 250 pg/mL, 255 pg/mL, 260 pg/mL, 265 pg/mL, 270 pg/mL, 275 pg/mL, 280 pg/mL, 285 pg/ mL, 290pg/mL, 295pg/mL, 300pg/mL, 310pg/mL, 320 pg/mL, 330 pg/mL, 340 pg/mL, 350 pg/mL, 360 pg/mL, 370 pg/mL, 380 pg/mL, 390 pg/mL, 400 pg/mL, etc., but not limited thereto.

In the present invention, as the label, IL-31 or IL-31RA other than the above may also be mentioned. The measurement of the expression level of IL-31 or IL-31RA can be carried out using the assay method disclosed in the present invention, or can be carried out using a commercially available assay reagent.

Further, as the mark of the present invention, one of the marks listed in the present specification may be used, or two or more of them may be used in combination.

The present invention relates to a method for diagnosing a skin itching disease, which comprises the step of determining a patient having a high level of expression of TCHH in a sample obtained from a patient as a disease suffering from skin itching.

More specifically, the method for diagnosing a skin itching disease of the present invention may comprise (a) a step of taking a sample from a patient, (b) a step of determining a performance level of TCHH in the aforementioned sample, and (c) a step from the patient. The step of comparing the measured value of the TCHH in the obtained sample with the predetermined value, and (d) the step of determining that the patient having a high predetermined value of the TCHH has a disease of skin itching, and the like.

Furthermore, the present invention relates to a kit for diagnosing a disease with pruritus characterized by a kit comprising reagents for determining the level of expression of TCHH.

The foregoing kit may further include a user who records the set Instructions for the law. Among these methods of use, it is desirable to disclose a method for determining the measurement result of the TCHH performance level. Specifically, a preferred example is a report indicating that the measured value of TCHH in the sample obtained from the patient is compared with a predetermined value, and the patient having a higher than the predetermined value is determined to be suffering from a disease with skin itching.

The animal to be the object of the present invention is not particularly limited, and is preferably a mammal, and particularly preferably a human. The IL-31 antagonist or label of the present invention can be suitably selected in combination with the animal to be targeted. That is, in the case of a patient suffering from a skin itching disease, in order to predict a human response to IL-31 antagonist therapy, a human marker can also be determined.

The therapeutic agent of the present invention can be formulated by combining an IL-31 antagonist of an active ingredient with a pharmaceutically acceptable carrier, and the like by a conventional method. For example, consider an IL-31 antagonist, and a pharmacologically acceptable carrier or vehicle, specifically, sterile water or physiological saline, vegetable oil, emulsifier, suspending agent, surfactant, stabilizer, flavoring agent The excipient, the carrier, the preservative, the binding agent and the like are suitably combined and formulated by mixing the unit dosage forms required for the pharmaceutical practice. Examples of the carrier include light anhydrous citric acid, lactose, crystalline cellulose, mannitol, starch, carmellose calcium, sodium carboxymethylcellulose, hydroxypropylcellulose, and hydroxy group. Propylmethylcellulose, polyvinyl acetal diethylaminoacetate, polyvinylpyrrolidine, gelatin, medium chain fatty acid triglyceride, polyoxyethylene ethyl hardened castor oil 60, white sugar, carboxy Methyl cellulose, corn starch, inorganic salts, and the like. The amount of the active ingredient in the preparations can be appropriately set within the range of the specified amount.

Furthermore, the dosage and administration method of the therapeutic agent of the present invention may vary depending on the patient's body weight, age, symptoms, etc., as long as it is in the technical field. Can be chosen as appropriate. The dosage can be selected, for example, in the range of 0.0001 to 1000 mg per body weight of 1 kg, or in the range of 0.001 to 100,000 mg/body per patient, but is not necessarily limited to these values. As a method of administration, oral administration or parenteral administration can be selected. In general, the case where the active ingredient is a low molecular compound is preferably oral administration, and the case of a polymer compound is preferably a parenteral administration. Examples of the parenteral administration include injection administration, nasal administration, transpulmonary administration, and transdermal administration, and further examples of injections include intravenous injection, intramuscular injection, intraperitoneal injection, subcutaneous injection, and the like. . By the administration methods, the therapeutic agent of the present invention can be administered to the whole body or part.

Moreover, all prior art documents cited in this specification are hereby incorporated by reference.

Example

The present invention is further illustrated by the following examples, but is not limited to the following examples.

[Example 1] Exploration of biomarker candidates using NHEK cells

(1-1) Acquisition of cells and samples

The NHEK of the primary cells of human normal keratinocytes was obtained from Lonza Walkersville Inc. (Product No. C2507A). KGM-Gold SingleQuots (Lonza) was used as a medium, and the cells were cultured in a 37 ° C incubator under an atmosphere containing 5% CO ₂ . For the samples used in the microarray, under the INFγ stimulation condition, the IL-31 stimulation had 2 groups with and without N, and the N number was 3. INFγ is used to induce IL-31RA of the receptor for IL-31. The preparation of the samples was carried out in a 24-well plate (Corning) at 2 × 10 ⁴ cells per well, and after 3 days of culture, the wells were replaced with a medium containing 10 ng/mL of human INFγ (Peprotech) and a medium containing no human INFγ. Medium. Further, human IL-31 (R&D) was added so that the final concentration after one day of culture was 500 n/mL. The same amount of medium was added to the other samples and cultured again. Then, the medium was removed after 1, 3, 6, and 24 hours from the stimulation of human IL-31, and 200 μL of RLT buffer (RNeasy plus 96 kit, Qiagen) was added, and the sample was collected, and total RNA was extracted using RNeasy plus 96 kit (Qiagen). .

(1-2) mRNA microarray experiments of NHEK cells

The amount of total RNA extracted was measured by NanoDrop 1000 (Thermo Scientific), and its quality was confirmed with an Agilent 2100 Bioanalyzer (Agilent Technologies) using an RNA 6000 Pico Kit (Agilent Technologies). The synthesis of the total RNA cDNA and the biotin labeling and fragmentation were carried out by the method recommended by the manufacturer using GeneChip (registered trademark) 3' IVT Express Kit (Affymetrix). Further, the amount of labeled cRNA synthesized before fragmentation was measured by NanoDrop, and the quality was confirmed by Bioanalyzer using an RNA 6000 Pico Kit (Agilent Technologies). Microarray uses GeneChip Human Genome U133 Plus 2.0 Array (Affymetrix), hybridization of arrays and fragmented cRNAs, and washing and staining of arrays using GeneChip (registered trademark) Hybridization, Wash and Stain Kit (Affymetrix), as recommended by the manufacturer The method is carried out. The scanning of the array data was carried out by GeneChip (registered trademark) Scanner 3000 7G upgrade (Affymetrix).

(1-3) mRNA microarray analysis of NHEK cells

Statistical analysis of microarray data using the statistical stylized environment R and Microsoft excel. Hybrid signal and call out, used in R The calculation of the gcrma and affy library of the BioConductor software package is performed. After various stimuli, the difference in the expression levels of the IL-31 stimulated presence and absence of each group 3 sample was compared at the same time, and the difference was found to be 1.5 times or more at any time, and the statistically significant probe (Welch's t -test is p < 0.05) for 151 probes, 141 genes.

(1-4) Limitation of biomarker candidate factors

Among the 141 genes identified by microarray analysis, factors which are measurable in serum and plasma, and which were most strongly induced by IL-31 stimulation, were found to be SERPINB3 and SERPINB4. The results of microarray analysis of SERPINB3 and SERPINB4 are shown in Figure 1. These factors were not induced by induction with INFγ alone, suggesting selectivity for IL-31. From these results, SERPINB3, SERPINB4 were selected as biomarker candidate factors.

[Example 2] Exploration of biomarker candidates using HaCaT cells

(2-1) Acquisition of cells and samples

The HaCaT cell line of human normal keratinocytes was obtained from Deutsches Krebsforschungszentrum. DMEM (GIBCO) supplemented with 10% fetal calf serum (MOREGATE) and 1% penicillin/streptomycin (GIBCO) was used as a medium, and the cells were cultured in an incubator containing 5% CO ₂ in a 37 ° C incubator. For the samples used in the microarray, (1) there were IL-31 stimulation, stimulation with INFγ, (2) stimulation with no IL-31, and stimulation with INFγ, and the number of N was 3. INFγ is used to induce IL-31RA of the receptor for IL-31. The preparation of the samples was carried out by seeding in a 24-well plate (Corning) at 5 × 10 ⁴ cells per well. Then, the medium after the 1-day culture was removed, and 100 ng/mL of human INFγ (Peprotech) DMEM was added for replacement. Further, human IL-31 was added to DMEM in such a manner that the final concentration after one day of culture was 375 ng/mL. Furthermore, the same amount of DMEM was added to the group without IL-31 stimulation and cultured again. Then, the medium was removed after 1, 3, 6, and 24 hours from the stimulation of human IL-31, and 200 μL of RLT buffer (RNeasy plus 96 kit, Qiagen) was added, and the sample was collected, and total RNA was extracted using RNeasy plus 96 kit (Qiagen). .

(2-2) mRNA microarray experiment of HaCaT cells

The amount of total RNA extracted was measured by NanoDrop 1000 (Thermo Scientific), and its quality was confirmed with an Agilent 2100 Bioanalyzer (Agilent Technologies) using an RNA 6000 Pico Kit (Agilent Technologies). The synthesis of the total RNA cRNA and the biotin labeling and fragmentation were carried out by the method recommended by the manufacturer using GeneChip (registered trademark) 3' IVT Express Kit (Affymetrix). Further, the amount of labeled cRNA synthesized before fragmentation was measured by NanoDrop, and the quality was confirmed by Bioanalyzer using an RNA 6000 Pico Kit (Agilent Technologies). Microarray uses GeneChip Human Genome U133 Plus 2.0 Array (Affymetrix), hybridization of arrays and fragmented cRNAs, and washing and staining of arrays using GeneChip (registered trademark) Hybridization, Wash and Stain Kit (Affymetrix), as recommended by the manufacturer The method is carried out. The scanning of the array data was carried out by GeneChip (registered trademark) Scanner 3000 7G upgrade (Affymetrix).

(2-3) mRNA microarray analysis of HaCaT cells

Statistical analysis of microarray data using Perl, statistical stylized environment R and Microsoft excel. Hybridization signals were calculated using the gcrma library of R's BioConductor kit software for output. IL-31 thorn after various stimuli The difference in the amount of expression of each group of 3 samples with and without excitation was compared at the same time, and the difference was found to be 1.5 times or more at any time, and the statistically significant probe (Welch's t-test was p<0.05). For 361 probes, 252 genes. The detection limit value is set to 16.

(2-4) Determination of candidate factors in serum by ELISA

Among the 252 genes identified by microarray analysis, induced by IL-31 stimulation, and considering factors detectable in blood, SERPINB3, SERPINB4, CXCL1, CXCL6, TCHH were found. The results of microarray analysis of SERPINB3 and SERPINB4 are shown in Fig. 2-1, the results of microarray analysis of CXCL1 are shown in Fig. 2-2, and the results of microarray analysis of CXCL6 are shown in Fig. 2-3, and the results of microarray analysis of TCHH are shown. Figure 2-4. Next, serum samples of 18 patients with atopic dermatitis purchased from PROTEOGENEX and serum samples obtained from healthy adults were used to measure the amount of serum in CXCL1, CXCL6, and TCHH by ELISA. The CXCL1 ELISA kit uses R&D Systems (catalog number DGR00), CXCL6 ELISA kit using R&D Systems (catalog number DGC00) ELISA kit, TCHH ELISA kit using Uscn Life Science Inc. (catalog number E96480Hu) ELISA Set the set for measurement. The measurement results of CXCL1, CXCL6, and TCHH are shown in Fig. 3-1, Fig. 3-2, and Fig. 3-3, respectively. Statistical analysis was performed using an un-paired Student's t-test for bilateral assays.

(2-5) Limitation of biomarker candidate factors

The results of CXCL1, CXCL6, and TCHH were measured, and it was confirmed that each factor was significantly higher in serum of patients with atopic dermatitis than healthy adults. From these results, CXCL1, CXCL6, and TCHH were selected as biomarker candidate factors.

[Example 3] Exploration of biomarker candidates using cynomolgus skin

(3-1) Acquisition of tissues and samples

A cynomolgus monkey from Vietnam was obtained from HAMRI. The abdominal skin of the cynomolgus monkey was taken, and after immersing in 70% ethanol in a safety cabinet, the subcutaneous fat was removed in Phosphate buffered saline (PBS). The samples used in the microarray were compared for the four conditions of the presence or absence of stimulation with IL-31 and the presence or absence of stimulation with Staphylococcal enterotoxin B (SEB). For the sample used in the microarray, 50 μL of the stimulant was injected into the skin tissue taken with the injection needle, and the center of the injection site was taken by the biopsy ring saw (Pui Yin Company) with a diameter of Φ 4 mm, and floated in the stimulant by the injection. It was obtained by culturing in an incubator at 37 ° C in an atmosphere of % CO ₂ . Five samples of each group were prepared by performing various stimulating skin tissues, and after freezing, they were quickly frozen in liquid nitrogen, and total RNA was extracted using RNeasy plus 96 kit (Qiagen).

(3-2) mRNA microarray experiment of cynomolgus skin

The amount of total RNA extracted was measured by NanoDrop 1000 (Thermo Scientific), and its quality was confirmed with an Agilent 2100 Bioanalyzer (Agilent Technologies) using an RNA 6000 Pico Kit (Agilent Technologies). The synthesis of cDNA from total RNA was carried out by a method recommended by the manufacturer using a cDNA Synthesis System (Roche Diagnostics), selectively applying T4 DNA polymerase treatment, RNase I treatment, and Proteinase K treatment. The synthesized cDNA was purified by High Pure PCR Product Purification Kit (Roche Diagnostics) column. The amount of cDNA was determined by Quant-iT PicoGreen dsDNA Assay Kit (Life Technologies), and its quality was RNA. The 6000 Pico Kit (Agilent Technologies) was confirmed with Bioanalyzer. The identification of the cDNA was carried out using the NimbleGen One-Color DNA Labeling Kit (Roche NimbleGen) in the manner suggested by the manufacturer. The amount of labeled cDNA was determined by NanoDrop. The microarray system used NimbleGen 12-plex Gene Expression Array for Cynomolgus monkey (135K) (version II microarray in Reference 1). Hybridization and washing of the labeled cDNA with the array was performed using a NimbleGen Hybridization Kit (Roche NimbleGen), a NimbleGen Sample Tracking Control Kit (Roche NimbleGen), and a NimbleGen Wash Buffer Kit (Roche NimbleGen) in the manner suggested by the manufacturer. Array data was acquired by scanning the array with a Roche NimbleGen MS200 Microarray Scanner (Roche NimbleGen).

references

1: Genome-based analysis of the nonhuman primate Macaca fascicularis as a model for drug safety assessment, Genome Res. 2011 Oct; 21 (10); 1746-56

(3-3) mRNA microarray analysis of cynomolgus skin

Statistical analysis of microarray data was performed using Perl, the statistical stylized environment R, and Microsoft excel. The array of scan data of the NimbleGen array was loaded with the digitization of the probe signal, and RMA (Robust Multichip Average) was standardized, and the NimbleScan software attached to the NimbleGen MS 200 Microarray Scanner was used. The RMA.calls file of the signal value data of the gene unit is used in the data analysis. After various stimuli, the group with no IL-31 stimulation and SEB stimulation, and the group with IL-31 stimulation and SEB stimulation, the expression of each group 5 sample The difference was compared at the same time. The IL-31 addition group used the 95% of the Random probe as the detection limit, which was more than 2 times the difference, and the statistically significant genes were combined (Welch's t-test was p<0.05). ) Determine 274.

(3-4) Determination of candidate factors in serum by ELISA

Regarding the 274 genes that were induced by IL-31 stimulation, the secreted protein, IL-31 selective inducer, and the serum derived from patients with atopic dermatitis showed higher values than those derived from healthy adults. Benchmark, IL-31-inducible protein of S100A9 and SFTPD was selected. The results of the microarray analysis of S100A9 are shown in Figure 4-1, and the results of the SFTPD microarray are shown in Figure 4-2. The sera derived from patients with atopic dermatitis were purchased from PROTEOGENEX, Inc., and were reviewed by comparison with those from healthy adults. The measurement of S100A9 was measured using an ELISA kit (Circulex, catalog number CY-8062), and the measurement of SFTPD was measured using an in vitro diagnostic drug (Concord Medex, catalog number 54772-3). The measurement results of S100A9 and SFTPD are shown in Fig. 5-1 and Fig. 5-2, respectively. Statistical analysis was performed using an un-paired Student's t-test for bilateral assays.

(3-5) Limitation of biomarker candidate factors

The results of S100A9 and SFTPD were measured, and it was confirmed that each factor was significantly higher in serum of patients with atopic dermatitis than healthy adults. From these results, S100A9 and SFTPD were selected as biomarker candidate factors.

[Example 4] Review of biomarkers in patients with atopic dermatitis (SERPINB3/B4)

(4-1) Sample collection

By participating in an anti-human IL31 receptor A antibody (H chain SEQ ID NO: 17, L Chain SEQ ID NO: 18) Phase I single-dose trials of healthy adults and patients with atopic dermatitis, taking consent for biomarker review and taking serum samples for evaluation.

The serum sample was administered as a single subcutaneous administration of a placebo or anti-human IL-31 receptor A antibody at 0.3 mg/kg, 1 mg/kg or 3 mg/kg, and serum samples were taken before administration on the day of administration. The number of experimental cases was 24 in healthy adults, 6 in placebo in patients with atopic dermatitis, 5 in anti-human IL-31 receptor A antibody 0.3 mg/kg, and 6 in 1 mg/kg. 7 cases of 3mg/kg administration group. The serum taken was stored at -70 °C until the measurement.

(4-2) Determination of SERPINB3/B4 in serum

In the measurement, the serum was thawed and diluted 10 times with physiological saline, and then the serum SERPINB3/B4 was measured using the clinical examination "ARCHITECT SCC (registered trademark)" (ABBOTT, product number 8D18-26/8D18-36). concentration.

(4-3) Analysis of the results

In the above phase I single administration test, the skin pruritus intensity was evaluated daily, after waking, and at bedtime during the test period of one week prior to administration of the test drug in patients with atopic dermatitis. The assessment of the intensity of pruritus was performed by visual analog scale (VAS). VAS is a straight line of 100 mm, 0 mm is no skin itching, and 100 mm is considered to be the maximum skin itching. The itching intensity at the time of measurement shows that the patient itself is between 0 and 100 mm. As a result, there was a subject who was found to have a significant reduction in skin itching VAS after administration of the anti-human IL-31 receptor A antibody, and it was not possible to confirm that the decrease was significant or the decrease was not confirmed. Therefore, in this trial, the weekly average of itching VAS for 2 weeks (the week of individual itching VAS after getting up and sleeping) When the value of the mean value is compared with the weekly average of 1 week before administration, the subject whose decrease is 50% or more is defined as a subject having high reactivity against the human IL-31 receptor A antibody (reaction) The subjects who did not achieve a 50% reduction were defined as subjects (non-responders) who had low reactivity against the IL-31 receptor A antibody.

The concentration of SERPINB3/B4 in the serum was divided into subjects whose serum SERPINB3/B4 concentration was higher than 5 ng/mL (SERPINB3/B4 high group) and subjects below 5 ng/mL (SERPINB3/B4 low group).

The ratio of SERPINB3/B4 high group and SERPINB3/B4 low group classified above is calculated, and the ratio of responder to non-responder is calculated. Furthermore, the difference between SERPINB3/B4 high group and SERPINB3/B4 low group is based on Fisher's Correctly check the p value and review it.

(4-4) Results

The concentration of SERPINB3/B4 in the serum of all subjects measured in this test is shown in Fig. 6. Further, the ratio of the SERPINB3/B4 high group to the SERPINB3/B4 low group and the non-reactant in the atopic dermatitis patients who received the anti-human IL-31 receptor A antibody are shown in Table 1.

The proportion of responders in the SERPINB3/B4 high population was as high as 80% (4 of 5), while the proportion of responders in the SERPINB3/B4 low population was 23.08% (3 of 13). Also, SERPINB3/B4 high group and The difference in the ratio of responders to non-responders in the SERPINB3/B4 low group was calculated according to Fisher's correct test. The p value on both sides was 0.0474.

From the above, patients with high concentrations of SERPINB3/B4 in serum Among them, there are many patients with high reactivity against human IL-31 receptor A antibody, and on the other hand, in patients with low serum SERPINB3/B4 concentration, the reactivity against anti-human IL-31 receptor A antibody is High patients have a low propensity, and serum SERPINB3/B4 concentrations are shown as biomarkers predictive of pruritus inhibition of human IL-31 receptor A antibodies.

[Example 5] Review of biomarkers in patients with atopic dermatitis (S100A9, TCHH)

(5-1) Sample collection

By taking an anti-human IL31 receptor A antibody (H chain SEQ ID NO: 17, L chain SEQ ID NO: 18) phase I single-dose test for patients with atopic dermatitis, obtaining approval for biomarker review and taking an assessment Serum samples.

The serum sample was administered as a single subcutaneous administration of anti-human IL-31 receptor A antibody at 0.3 mg/kg, 1 mg/kg or 3 mg/kg, and serum samples were taken before administration on the day of administration. The number of administration groups was 5 cases of anti-human IL-31 receptor A antibody 0.3 mg/kg, 6 cases of 1 mg/kg, and 7 cases of 3 mg/kg. The serum taken was stored at -70 °C until the measurement.

(5-2) Determination of S100A9 in serum and TCHH in serum

In the measurement, after the serum was thawed, the serum for S100A9 concentration in serum was diluted 40 times with Sample Dilution Buffer attached to the CircuLe x S100A9/MRP14 ELISA kit (Cyclex, product number CY-8062), and then the same set was used. Serum S100A9 concentration. Again, the dilution line of the calibration line Use Sample Dilution Buffer.

The TCHH concentration in the serum was measured by using a sera diluted 1000-fold with Standard Diluent attached to ELISA Kit For Trichohyalin (TCHH) (USCN LIFE SCIENCES, product number E96480Hu), and the TCHH concentration in the serum was measured using the same kit.

(5-3) Analysis of the results

In the above phase I single administration test, the skin pruritus intensity was evaluated daily, after waking, and at bedtime during the test period of one week prior to administration of the test drug in patients with atopic dermatitis. The assessment of the intensity of pruritus was performed by visual analog scale (VAS). VAS is a straight line of 100 mm, 0 mm is no skin itching, and 100 mm is considered to be the maximum skin itching. The itching intensity at the time of measurement shows that the patient itself is between 0 and 100 mm. As a result, there was a case where the decrease in the skin itching VAS after the administration of the anti-human IL-31 receptor A antibody was confirmed was remarkable, and the subject who could not be confirmed to be significantly reduced or unable to confirm the decrease was confirmed. Therefore, in this test, the weekly mean of the itching VAS for 2 weeks (the average of the weekly average of the individual itching VAS after getting up and at bedtime) was 50% compared with the weekly average of 1 week before administration. The above-mentioned reduced subjects were defined as subjects (reactors) who were highly reactive against human IL-31 receptor A antibodies, and those who did not achieve a 50% decrease were defined as antibodies against IL-31 receptor A. Subjects with low reactivity (non-responders).

The concentration of S100A9 in serum and the concentration of TCHH in serum were compared by the mean value of the concentration between the responder and the non-responder. The p-value study was calculated according to the un-paired Student's t-test.

(5-4) Results

Serum S100A9 concentration in patients with atopic dermatitis as determined by this test As shown in Figure 7, the TCHH concentration in the serum is shown in Figure 8.

S100A9 concentration in serum and TCHH concentration in serum of patients receiving atopic dermatitis with anti-human IL-31 receptor A antibody, any responder was higher than non-responders, t-test results, serum S100A9 concentration The p value on both sides was 0.0200, and the p value on both sides of the TCHH concentration in the serum was 0.0296.

It can be seen from the above that in patients with high S100A9 concentration in serum or high concentration of TCHH in serum, there are many patients with high reactivity against human IL-31 receptor A antibody, and on the other hand, low concentration of S100A9 in serum, TCHH in serum. In patients with high concentrations, patients with high reactivity against human IL-31 receptor A antibodies have a low propensity. Serum S100A9 concentration and serum TCHH concentration are shown to be predictive of anti-human IL-31 receptor A antibodies. Biomarkers for the skin itching inhibition effect.

Industrial availability

According to the present invention, the sample obtained from the patient is obtained by measuring (1) SERPINB3 and/or SERPINB4, (2) S100A9, (3) CXCL1, (4) SFTPD, (5) TCHH and (6) CXCL6. The level of performance of at least one biomarker selected in the cohort demonstrates predictable response to treatment with an IL-31 antagonist. The present invention pre-predicts the response of a patient suffering from a skin itching disease before starting treatment with an IL-31 antagonist, and can screen a patient who can only expect an effect as a treatment target, and individualize the appropriate treatment for an appropriate patient. From a medical point of view, it is extremely useful.

<110> CHUGAI SEIYAKU KABUSHIKI KAISHA

<120> A method for predicting the response of patients with pruritus to the treatment of IL-31 antagonists

<130> C1A1305Y1-TW

<150> JP 2013-136501

<151> 2013-06-28

<150> JP 2013-259918

<151> 2013-12-17

<160> 32

<170> PatentIn version 3.5

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Claims (21)

A method for predicting a response to treatment with an IL-31 antagonist in a patient suffering from a skin itching disease, the method comprising: (1) SERPINB3 and a sample obtained from a patient suffering from a skin itchy disease / or SERPINB4 (2) S100A9 (3) CXCL1 (4) SFTPD (5) TCHH, and (6) the step of the performance level of at least one of the markers selected in the group of CXCL6. The method of claim 1, further comprising the step of determining, in the sample obtained from the patient, that the patient having a high level of expression of the marker has a response to treatment with an IL-31 antagonist. The method of claim 1 or 2, wherein the aforementioned label is determined as a polypeptide. The method of any one of claims 1 to 3 wherein the sample is a blood sample. The method of any one of claims 1 to 4, wherein the itching of the skin is pruritus caused by IL-3. The method of any one of claims 1 to 5, wherein the pruritus is atopic dermatitis. The method of any one of claims 1 to 6, wherein the IL-31 antagonist is an antibody that blocks the IL-31 signal. The method of claim 7, wherein the antibody that blocks the IL-31 signal is an anti-IL-31 neutralizing antibody or an anti-IL-31RA neutralizing antibody. The method of claim 8, wherein the anti-IL-31RA neutralizing antibody comprises the CDR2 disclosed in SEQ ID NO: 9 and the CDR2 disclosed in SEQ ID NO: 10 and the H chain variable region of CDR3 disclosed in SEQ ID NO: 11. And an anti-IL-31RA antibody comprising the CDR2 disclosed in SEQ ID NO: 12, SEQ ID NO: 13 and the L chain variable region of CDR3 revealed by SEQ ID NO: 14. The method of claim 9, wherein the anti-IL-31RA neutralizing antibody is an anti-IL-31RA antibody comprising the H chain variable region revealed by SEQ ID NO: 15 and the L chain variable region revealed by SEQ ID NO: 16. . The method of claim 10, wherein the anti-IL-31RA neutralizing antibody is an anti-IL-31RA antibody comprising the H chain revealed by SEQ ID NO: 17 and the L chain revealed by SEQ ID NO: 18. A therapeutic agent for a skin itching disease characterized by comprising an IL-31 antagonist as an active ingredient in a sample obtained from a patient suffering from a skin itching disease, for (1) SERPINB3 and/or SERPINB4 (2) S100A9 (3) CXCL1 (4) SFTPD (5) TCHH, and (6) a patient with a high level of expression of at least one marker selected from the group of CXCL6 medicine. A therapeutic agent for a skin itching disease characterized by comprising an IL-31 antagonist as an active ingredient, and the treatment of the IL-31 antagonist is judged by the method of any one of claims 1 to 11 The drug is administered to the responder's patient. A method of treating a patient suffering from a skin itching disease, in a sample obtained from a patient suffering from a skin itching disease, for (1) SERPINB3 and/or SERPINB4(2)S100A9(3)CXCL1(4) A step of administering an IL-31 antagonist to a patient having a high level of expression of at least one marker selected from the group consisting of SFTPD (5) TCHH, and (6) CXCL6. A method for treating a patient suffering from a skin itching disease, comprising administering IL-in a patient judged to be a responder to treatment with an IL-31 antagonist by the method of any one of claims 1 to 11 Step 31 of the antagonist. A screening method for a patient suffering from a skin itching disease, which is included in a sample obtained from a patient suffering from a skin itching disease, for (1) SERPINB3 and/or SERPINB4(2)S100A9(3)CXCL1 (4) SFTPD (5) TCHH, and (6) A patient having a high level of expression of at least one marker selected from the group consisting of CXCL6 is a step of judging the response to treatment with an IL-31 antagonist. A kit for predicting the response of a patient suffering from a skin itching disorder to the treatment of an IL-31 antagonist, comprising assays for (1) SERPINB3 and/or SERPINB4(2)S100A9 (3) CXCL1 (4) SFTPD (5) TCHH, and (6) a reagent for the expression level of at least one of the markers selected in the group of CXCL6. The kit of claim 17 further comprising instructions for revealing that the patient having a high level of expression of the aforementioned marker in the sample obtained from the patient is a responder to the treatment of the IL-31 antagonist. A method for diagnosing a disease of pruritus comprising a step of treating a disease with pruritus in a patient having a high level of TCHH expression in a sample obtained from a patient. A kit for diagnosing a set of skin itching disorders, characterized by comprising an agent for determining the performance level of TCHH. For example, if the kit of claim 20 is included, it further includes a patient who has revealed a high level of performance of TCHH in the sample obtained from the patient, and is judged to be suffering. Instructions for skin itching diseases.