JP2021031482A - Itch treatment agent - Google Patents

Abstract

To provide itch treatment agents and compositions for pruritus.SOLUTION: An itch treatment agent contains interleukin 27(IL-27) and/or IL-27 receptor agonist as an active ingredient.SELECTED DRAWING: None

Description

The present invention relates to an antipruritic agent containing interleukin 27 (IL-27) and / or an IL-27 receptor agonist as an active ingredient, and an antipruritic composition containing the antipruritic agent.

Currently, it is estimated that more than 15% of the Japanese people suffer from some form of chronic "itch". Chronic itch significantly reduces the patient's quality of life (QOL), including sleep disorders, resulting in significant economic losses. According to estimates by the Department of Dermatology, Department of Information Integrated Medicine, Graduate School of Medicine, Osaka University, the total economic loss in Japan per month due to the decline in QOL caused by itching is estimated to be 469 billion yen. (Non-Patent Document 1).

Itching is a sensation that occurs on the surface of the skin (the boundary area between the epidermis and dermis) and the mucous membranes, causing the urge to scratch. In itching, the free endings of peripheral nerve fibers (primary afferent sensory nerve C fibers) present in the skin receive histamine released from mast cells and mediators produced by damaged skin and immune cells. , It is recognized by transmitting information to the brain via spinal cord posterior horny nerve cells.

The sensation of itching constitutes a biological defense response that eliminates the invasion of pathogens and harmful environmental stimuli by causing scratching (scratching, scraping). On the other hand, in diseases accompanied by chronic itching, a vicious cycle may occur in which the skin barrier is destroyed by scratching, which worsens the symptoms and induces stronger itching. Therefore, it is necessary to develop effective drugs and treatments for itching not only to improve the QOL of patients but also to prevent further exacerbation of the disease.

Although the standard treatment for itching currently performed has a certain effect of reducing itching, many problems remain as described below.

_{For example, antihistamines (H 1} blockers) are the first choice for the treatment of itching in eczema skin disorders such as urticaria. However, in chronic skin diseases such as atopic dermatitis and psoriasis, antihistamine agents do not respond because factors other than histamine are important for inducing itching (Non-Patent Document 2). Therefore, in the treatment of atopic dermatitis, topical steroids and topical tacrolimus are used in the sense that itching is indirectly suppressed by suppressing inflammation. However, topical steroids cause increased skin infections associated with stretch marks, atrophy, and decreased local immunity, and topical tacrolimus causes a feeling of local burning, and many patients do not have a sufficient antipruritic effect. To do. Short-term oral administration of steroids and cyclosporine is unavoidable for such patient groups, but there are concerns about serious adverse effects such as systemic immunodeficiency, and it cannot be used for a long period of time (Non-Patent Document 3). ..

Further, in recent years, antibody drugs have been introduced for highly severe atopic dermatitis and psoriasis, and their effectiveness has been shown (Non-Patent Documents 4 and 5). However, chronic pruritus is the result of the combined action of various inflammatory mediators and endogenous pruritus substances, and it is theoretically possible to block all of these pathways by targeting a single mediator. difficult. Furthermore, many of the antibody drugs that have appeared in recent years only work to suppress inflammation, and do not directly show the effect of suppressing itching. Therefore, it cannot be expected to be effective for pruritus dermatitis in which there is no background inflammation such as senile pruritus dermatitis (dry skin) and chronic idiopathic pruritis (CIP).

Therefore, it is desired to develop a new therapeutic agent for pruritus, which can effectively suppress itching for various pruritus and has few side effects.

Hiroyuki Murota et al., PROGRESS IN MEDICINE, 2009, 29 (7), 1842-1848. Kido-Nakahara M. et al., Immunol Allergy Clin North Am, 2017, 37 (1), 113-122. Buchman A. L. et al., J Clin Gastroenterol, 2001, 33 (4), 289-94. Paller A. S. et al., J Allergy Clin Immunol, 2017, 140 (3), 633-643. Szepietowski J. C. and Reich A., Curr Probl Dermatol, 2016, 50, 102-10.

An object of the present invention is to provide an agent for treating pruritus and a composition for treating pruritus.

Recently, we have found that in non-inflammatory conditions, skin mechanics in mice deficient in p28 or EBI3, a component of interleukin 27 (IL-27), or WSX-1, a component of its receptor. It was reported that the sensitivity of pain to stimuli and thermal stimuli was increased (Sasaguri, T. et al., Scientific Reports, 2018, 8, 11022).

IL-27 is a cytokine belonging to the IL-12 cytokine family and is a heterodimer protein formed from the p28 protein and the EBI3 protein (Fig. 1). The IL-27 receptor is formed from the specific subunit WSX-1 protein and the signaling subunit gp130 protein (Fig. 1). It has been previously reported that IL-27 is mainly secreted from activated macrophages and dendritic cells (DC) and regulates the differentiation and function of various helper T (Th) cells. In asthma and atopic dermatitis, cytokines produced by Th2 cells and ILC2 (Innate lymphoid cell 2) cells that cause a type 2 immune response are involved in the pathogenesis, but IL-27 acts directly on Th2 cells and ILC2 cells. It has also been reported to suppress its differentiation and cytokine production (Yoshimoto, T. et al., The Journal of Immunology, 2007, 179 (7), 4415-23; Moro, K. et al., Nature Immunology. , 2016, 17 (1). 76-86). However, there has been no report on the function of IL-27 for the suppression of pruritus, and research and development of a therapeutic agent for pruritus for the purpose of suppressing pruritus using IL-27 has not yet been carried out.

Based on the above findings on pain susceptibility to mechanical and thermal stimuli (Sasaguri, T. et al., Scientific Reports, 2018, 8, 11022), we found that IL-27 was independent of inflammation suppression. , I thought that it could directly control the function of peripheral sensory nerves. Based on this idea, the present inventors came up with the idea that IL-27 could be a new therapeutic agent for pruritus.

As a result of intensive studies, the present inventors have conducted atopic dermatitis induced by (1) acute pruritus test by subcutaneous administration of histamine and (2) repeated skin application of hapten (sensitizing compound) using mice. A chronic pruritus test using a dermatitis model was performed, and it was found that subcutaneous inoculation of recombinant IL-27 (rIL-27) significantly suppressed the scraping behavior of mice. The present invention is based on the above research results and provides the following.
(1) An antipruritic agent containing interleukin 27 (IL-27) and / or an IL-27 receptor agonist as an active ingredient.
(2) The IL-27
a) Human wild-type p28 protein having the amino acid sequence shown in SEQ ID NO: 1.
b) A mutant p28 protein having 90% or more identity with respect to the amino acid sequence shown in SEQ ID NO: 1 or
c) A mutant p28 protein in which one or more amino acids have been added, deleted, or substituted with respect to the amino acid sequence shown in SEQ ID NO: 1.
d) Human wild-type EBI3 protein having the amino acid sequence shown in SEQ ID NO: 2,
e) A mutant EBI3 protein having 90% or more identity with respect to the amino acid sequence shown in SEQ ID NO: 2, or
f) Consists of a mutant EBI3 protein in which one or more amino acids have been added, deleted, or substituted with respect to the amino acid sequence shown in SEQ ID NO: 2, and has the activity of human wild-type IL-27, (1). The antipruritic agent described.
(3) The pruritus therapeutic agent according to (1) or (2), wherein the pruritus is histamine-dependent pruritus.
(4) The pruritus therapeutic agent according to (3), wherein the histamine-dependent pruritus is pruritus caused by urticaria, insect bites, or drug eruption.
(5) The pruritus therapeutic agent according to (1) or (2), wherein the pruritus is histamine-independent pruritus.
(6) The pruritus therapeutic agent according to (5), wherein the histamine-independent pruritus is pruritus due to atopic dermatitis or psoriasis, chronic idiopathic pruritus, or senile pruritus dermatitis.
(7) The antipruritic agent according to any one of (1) to (6), as well as an antihistamine agent, a steroid agent, cyclosporin, tacrolimus, a human anti-human IL-4 / IL-13 receptor monoclonal antibody, and an anti-IL-31. A composition for treating pruritus, which comprises one or more selected from the group consisting of a humanized receptor monoclonal antibody and a human anti-human IL-17 receptor A monoclonal antibody.

According to the present invention, itching therapeutic agents and pruritus therapeutic compositions for pruritus can be provided.

It is a figure which shows IL-27 and IL-27 receptor. IL-27 is a heterodimeric protein formed from the p28 and EBI3 proteins. The IL-27 receptor is formed from the specific subunit WSX-1 protein and the signaling subunit gp130 protein. It is a figure which shows the antipruritic effect of IL-27 in the histamine-induced acute pruritus test. In this experiment, pruritus was induced by subcutaneous ingestion of the pruritus substance histamine under the cheek of mice. In the IL-27 administration group shown in the figure, recombinant IL-27 (rIL-27) was co-inoculated with histamine. In the control group, PBS was co-inoculated with histamine. The figure shows the average value of the rate of change in the number of scraping behaviors after histamine inoculation in each group (each n = 7 individuals), and the error bar indicates the standard error. * Indicates P <0.05 (t-test). It is a figure which shows the antipruritic effect of IL-27 in the chronic pruritus test using the atopic dermatitis model induced by repeated skin application of a hapten (sensitizing compound). The polygonal line indicates the number of scraping behaviors of each individual every 10 minutes (n = 5 individuals). The dashed line indicates the time when recombinant IL-27 (rIL-27) was subcutaneously inoculated.

1. 1. Itching remedy 1-1. Overview The first aspect of the present invention is an antipruritic agent.
The pruritus therapeutic agent of this embodiment contains IL-27 and / or an IL-27 receptor agonist as an active ingredient. The pruritus therapeutic agent of this embodiment has an antipruritic effect on histamine-dependent and independent pruritus.

1-2. Definitions The following terms frequently used herein are defined.
As mentioned above, "interleukin 27 (IL-27)" is a cytokine belonging to the interleukin 12 (IL-12) cytokine family and is formed from the p28 protein and the EBI3 (Epstein-Barr virus induced-3) protein. It is a heterodimeric protein that is produced (Fig. 1). The p28 protein is a protein associated with the p35 subunit of IL-12 and is a polypeptide consisting of 243 amino acid residues in humans. The EBI3 protein is a member of the hematopoetin receptor family associated with the p40 subunit of IL-12. The EBI3 protein is a glycoprotein, a polypeptide consisting of 229 amino acid residues in humans.

In the present specification, when simply referred to as "IL-27", wild-type and mutant IL-27 derived from any species (referred to as "wild-type IL-27" and "mutant IL-27", respectively). Shall be included. Similarly, the term "p28 protein" or "EBI3 protein" as used herein refers to wild-type and mutant p28 proteins derived from any species ("wild-type p28 protein" and "variant p28 protein," respectively. (Indicated as) or EBI3 protein (denoted as "wild-type EBI3 protein" and "variant EBI3 protein", respectively). Specific examples of IL-27 include a human-derived wild-type p28 protein consisting of the amino acid sequence shown in SEQ ID NO: 1 (denoted as "human wild-type p28 protein") and a human-derived wild-type p28 protein consisting of the amino acid sequence shown in SEQ ID NO: 2. IL-27 (denoted as "human wild-type IL-27") consisting of the wild-type EBI3 protein (denoted as "human wild-type EBI3 protein").

An "IL-27 receptor" is a receptor to which IL-27 binds as a ligand and is a heterodimer formed from the specific subunit WSX-1 protein and the signaling subunit gp130 (glycoprotein 130) protein. It is a protein (Fig. 1). WSX-1 protein, also called TCCR protein, IL27RA protein, etc., is a glycosylation membrane protein, and in humans, it is a polypeptide consisting of 636 amino acid residues. The gp130 protein is a membrane protein that has five fibronectin type III domains and one immunoglobulin-like domain extracellularly, and is a polypeptide consisting of 918 amino acid residues in humans. As used herein, the term "IL-27 receptor" shall include wild-type and mutant IL-27 receptors derived from any species. Specific examples of the WSX-1 protein and the gp130 protein constituting the IL-27 receptor include a human-derived wild-type WSX-1 protein consisting of the amino acid sequence shown in SEQ ID NO: 3 and a human consisting of the amino acid sequence shown in SEQ ID NO: 4. Included is the wild gp130 protein of origin.

As used herein, the term "receptor agonist" means a substance capable of activating a receptor to induce a completely or partially receptor-mediated response. In the present specification, the receptor agonist includes both an endogenous substance and an exogenous (extrinsic) substance, and is not particularly limited.

As used herein, the term "pruritus" refers to any disease associated with itching (pruritus). As used herein, pruritus includes local skin diseases and systemic pruritus dermatitis caused by abnormalities in the body. Local skin diseases include, for example, atopic dermatitis, eczema, urticaria, insect stinging, mycosis (tinea, cutaneous candidiasis, etc.), psoriasis, psoriasis, chronic idiopathic pruritus, senile pruritus dermatitis. , Hypertrophic scars, and drug eczema. Systemic pruritus dermatitis caused by abnormalities in the body includes, for example, renal diseases such as chronic renal failure and urinary toxin disease, hepatic / biliary tract diseases such as liver cirrhosis and jaundice, blood diseases such as iron deficiency anemia and lymphocytic leukemia. Endocrine / metabolic diseases such as thyroid dysfunction and diabetes, neurological diseases such as multiple sclerosis, psychogenic psychological disorders, visceral malignant tumors, systemic pruritus associated with HIV infection, and morphine , Systemic pruritus associated with the administration of drugs such as aspirin, captopril, β-lactam antibacterial agents and etretinate. As described below, pruritus can also be further classified into histamine-dependent and histamine-independent pruritus.

As used herein, the term "histamine-dependent pruritus" refers to itching that occurs mainly depending on histamine. Histamine is a biological amine mediator that controls a variety of biological reactions, and its receptors have four subtypes, _{H 1 to} H _{4, which belong to the G protein-coupled receptor superfamily. Histamine binds to the histamine H 1 to} H ₄ receptors expressed on target cells and expresses various physiological functions by transmitting information into the cells. In histamine-dependent pruritus, mast cells and basophils are stimulated to release histamine, which is detected by the ends of the itchy nerves present in the skin, causing itching. In the present specification, histamine-dependent pruritus shall include pruritus associated with urticaria, insect bites, drug eruption and the like. Urticaria is caused by foods, drugs such as antibiotics, physical irritation, sweating, stress, and the like. Antihistamines are mainly used for the treatment of histamine-dependent pruritus such as urticaria. The "anti-histamine agent" is generally an agent that acts antagonistically with histamine on histamine receptors and is used for the purpose of suppressing an overreaction involving histamine such as an allergic reaction. _{H 1} receptor antagonists (H ₁ blockers) are mainly used to treat histamine-dependent pruritus such as urticaria.

As used herein, the term "histamine-independent pruritus" refers to pruritus in which factors other than histamine are mainly involved in the induction of itching. As used herein, histamine-independent pruritus shall mean pruritus other than the above-mentioned histamine-dependent pruritus. Histamine-independent pruritus is classified into those with inflammation in the background and those without inflammation. Histamine-independent pruritus with inflammation in the background includes, but is not limited to, chronic skin diseases such as atopic dermatitis and psoriasis. Histamine-independent pruritus in which there is no background inflammation includes, but is not limited to, chronic idiopathic pruritus and senile skin pruritus. In general, antihistamines do not respond to histamine-independent pruritus.

"Atopic dermatitis" is an allergic disease in which abnormalities in the stratum corneum in the epidermis cause dry skin and abnormal barrier function, and its pathological condition is chronic inflammation and pruritus. In atopic dermatitis, the vicious cycle in which the destruction of the skin barrier by scratching induces stronger itching exacerbates the disease and becomes a major barrier to treatment. In atopic dermatitis, interleukin 4 (IL-4), interleukin 5 (IL-5), interleukin 13 (IL-13), interleukin secreted by helper T (Th) 2 cells and ILC2 cells Type 2 inflammatory response is triggered by 31 (IL-31) and TSLP (thymic stromal lymphopoietin) secreted by fibroblasts and skin keratinized cells. For the treatment of atopic dermatitis, topical steroids, topical tacrolimus, cyclosporine, or antibody drugs are usually used in the sense that it is indirectly suppressed by suppressing inflammation.

"Topical steroid" means an external drug containing a steroid as an active ingredient. As used herein, the term "steroid agent" means a steroid hormone or a derivative thereof, particularly a glucocorticoid or a derivative thereof. Steroids have pharmacological actions such as anti-inflammatory action, immunosuppressive action, lymphopenia action, vasoconstriction action, and bronchodilator action, and are known to be effective against various diseases. Topical steroids are known to cause increased skin infections associated with stretch marks / atrophy and decreased local immunity.

"Tacrolimus topical drug" means a topical drug containing tacrolimus as an active ingredient. "Tacrolimus" is an immunosuppressive substance isolated from the soil bacterium Streptomyces tsukubaensis. Tacrolimus is known to suppress the production of cytokines such as interleukin 2 (IL-2) in helper T cells. Topical tacrolimus is known to cause a local burning sensation.

In many patients with atopic dermatitis, topical steroids and topical tacrolimus do not provide sufficient antipruritic effect. Short-term oral administration of steroids and cyclosporine is unavoidable for such patients, but this treatment method cannot be used for a long period of time due to concerns about serious adverse effects such as systemic immunodeficiency. .. Ultraviolet light therapy is also used in severe cases of atopic dermatitis.

"Cyclosporine" is a hydrophobic cyclic polypeptide consisting of 11 amino acids extracted from the fungal Tolypocladium inflatum in soil. Cyclosporine has an immunosuppressive effect and is known to suppress the production of cytokines such as IL-2 in T cells.

An "antibody drug" is a drug that utilizes the functions of an antibody, and in particular, an antibody that specifically binds to a biomolecule that causes a disease is artificially produced and used as a drug. In recent years, antibody drugs have been introduced for highly severe atopic dermatitis, and their effectiveness has been demonstrated. Dupilumab, a human anti-human IL-4 / IL-13 receptor monoclonal antibody, has been developed for patients with severe atopic dermatitis who are not fully treated with topical steroids / tacrolimus. Tolvaptan works to suppress inflammation and is said to be effective in about 40% of patients with high severity. In addition, it is known that IL-31 produced by Th2 cells is involved in the development of itching due to atopic dermatitis, and the anti-IL-31 receptor humanized monoclonal antibody (nemoritumab) is phase II international. In a joint clinical trial, its effectiveness against clinical symptoms and itching has been confirmed.

"Psoriasis" is an inflammatory disease of the skin with infiltration and activation of immune cells and associated epidermal thickening. In psoriasis, the metabolic cycle is shortened in the epidermis, the outermost layer of the skin. That is, the metabolic cycle of normal epidermal cells is about 28 days, whereas that of psoriasis is extremely short, about 4 to 5 days. Typically, white scales are thickly attached to the red rash in various parts of the body, causing the symptoms of desquamation. Itching occurs in more than half of psoriasis patients. Psoriasis includes, for example, psoriasis vulgaris, pustular psoriasis, psoriatic arthritis, guttate psoriasis, and psoriatic erythroderma. There are various treatments for psoriasis, but the main treatment is topical medication. Topical steroids, tacrolimus, cyclosporine, etc. are often used as topical drugs. Ultraviolet light therapy is also used to treat psoriasis. In recent years, biopharmacy has also been introduced for psoriasis. Human anti-human interleukin 17 (IL-17) receptor A monoclonal antibody is known to have an anti-inflammatory effect on psoriasis.

"Chronic idiopathic pruritis (CIP)" refers to pruritus of unknown cause caused by an abnormality in the immune system. The causes of CIP are considered to be skin barrier dysfunction, sensory neuropathy, and / or Th2-type reaction dysfunction associated with aging, but the detailed mechanism has not been elucidated.

"Senile skin pruritus" means pruritus due to senile skin pruritus (dry skin), and refers to pruritus caused by dry skin with aging. Chronic idiopathic pruritus and chronic idiopathic pruritus are skin pruritus in which there is no inflammation in the background, and effective treatment methods are currently limited because anti-inflammatory agents do not respond.

1-3. Composition The antipruritic agent of the present invention contains IL-27 and / or an IL-27 receptor agonist as an essential ingredient as an active ingredient.

1-3-1. Components The components will be described in detail below.
(1) IL-27
When the pruritus therapeutic agent of the present invention contains IL-27 as an active ingredient, the p28 protein and EBI3 protein constituting IL-27 are wild-type or mutant p28 protein and EBI3 protein derived from any species. .. The species from which the p28 protein and EBI3 protein constituting IL-27 included in the antipruritic agent of the present invention are derived are not limited, but for example, humans, domestic animals (cattle, horses, sheep, goats, pigs, chickens, ostriches, etc.). ), Race horses, pet animals (dogs, cats, rabbits, etc.), experimental animals (mouses, rats, guinea pigs, monkeys, marmosets, etc.). For example, the p28 protein constituting IL-27 is a wild-type or mutant p28 protein derived from a human-derived p28 protein having the amino acid sequence shown in SEQ ID NO: 1, and a mouse-derived p28 protein having the amino acid sequence shown in SEQ ID NO: 5. It may be a wild or mutant p28 protein derived from the p28 protein. The EBI3 protein constituting IL-27 is a wild-type or mutant EBI3 protein derived from a human-derived EBI3 protein having the amino acid sequence shown in SEQ ID NO: 2, and a mouse-derived EBI3 protein having the amino acid sequence shown in SEQ ID NO: 6. It may be a wild or mutant EBI3 protein derived from the EBI3 protein. In addition, the species from which the p28 protein and the EBI3 protein constituting IL-27 are derived may be the same species or different species. Preferably, the p28 and EBI3 proteins that make up IL-27 are from the same species as the subject being treated. More preferably, the species from which the p28 and EBI3 proteins that make up IL-27 are derived is human. Preferably, IL-27 has the activity of wild-type IL-27. "Having the activity of wild-type IL-27" means having an activity equal to or higher than the activity of wild-type IL-27. Specifically, it means that when administered to pruritus patients or pruritus model animals, it has an antipruritic effect equal to or higher than that of wild-type IL-27.

In one embodiment, the p28 protein that constitutes IL-27 is
a) Human wild-type p28 protein having the amino acid sequence shown in SEQ ID NO: 1.
b) 70% or more, 75% or more, 80% or more, 85% or more, 90% or more, 95% or more, 96% or more, 97% or more, 98% or more, or 99 with respect to the amino acid sequence shown in SEQ ID NO: 1. Variant p28 protein with% or more identity, or
c) Any polypeptide selected from the mutant p28 protein in which one or more amino acids have been added, deleted, or substituted with respect to the amino acid sequence shown in SEQ ID NO: 1, further constituting IL-27. EBI3 protein
d) Human wild-type EBI3 protein having the amino acid sequence shown in SEQ ID NO: 2,
e) 70% or more, 75% or more, 80% or more, 85% or more, 90% or more, 95% or more, 96% or more, 97% or more, 98% or more, or 99 with respect to the amino acid sequence shown in SEQ ID NO: 2. Mutant EBI3 protein with% or more identity, or
f) Any polypeptide selected from the mutant EBI3 protein in which one or more amino acids have been added, deleted or substituted with respect to the amino acid sequence shown in SEQ ID NO: 2. Preferably, IL-27 has the activity of human wild-type IL-27. "Having the activity of human wild-type IL-27" means having an activity equal to or higher than the activity of human wild-type IL-27. Specifically, it means that when administered to pruritus patients or pruritus model animals, it has an antipruritic effect equal to or higher than that of human wild-type IL-27.

In the present specification, "plurality" means, for example, 2 to 24 pieces, 2 to 22 pieces, 2 to 20 pieces, 2 to 18 pieces, 2 to 16 pieces, 2 to 14 pieces, 2 to 12 pieces, 2 to ~. 10 pieces, 2 to 8 pieces, 2 to 7 pieces, 2 to 6 pieces, 2 to 5 pieces, 2 to 4 pieces or 2 to 3 pieces. Further, in the present specification, "amino acid identity" means the ratio (%) of the number of matching amino acid residues to the total number of amino acid residues of the two amino acid sequences to be compared. Specifically, the two amino acid sequences are aligned, and if necessary, gaps are appropriately inserted in one or both of them. At this time, 1 gap is counted as 1 amino acid residue in the total number of amino acid residues. Amino acid sequence alignment can be performed using known programs such as Blast, FASTA, ClustalW (Karlin, S. et al., 1993, Proc. Natl. Acad. Sci. USA, 90: 5873- 5877; Altschul, S.F. et al., 1990, J. Mol. Biol., 215: 403-410; Pearson, WR et al., 1988, Proc. Natl. Acad. Sci. USA, 85 : 2444-2448). If the total number of amino acid residues differs between the two amino acid sequences to be compared, the longer one is taken as the total number of amino acid residues. It is calculated by dividing the number of the same amino acid residues when the degree of amino acid matching is highest in the two amino acid sequences to be compared by the total number of amino acid residues.

As used herein, "substitution (of amino acids)" refers to a group of conservative amino acids having similar properties such as charge, side chain, polarity, and aromaticity among the 20 amino acids that make up a natural protein. Refers to replacement. For example, uncharged polar amino acids (Gly, Asn, Gln, Ser, Thr, Cys, Tyr) with low side chains, branched amino acids (Leu, Val, Ile), neutral amino acids (Gly, Ile). , Val, Leu, Ala, Met, Pro), neutral amino acids with hydrophilic side chains (Asn, Gln, Thr, Ser, Tyr, Cys), acidic amino acids (Asp, Glu), basic amino acids (Asn, Gln, Thr, Ser, Tyr, Cys), basic amino acids (Asn, Gln, Thr, Ser, Tyr, Cys) Arg, Lys, His), substitutions within the aromatic amino acid group (Phe, Tyr, Trp). Amino acid substitutions within these groups are preferable because it is known that the properties of peptides are unlikely to change.

(2) IL-27 receptor agonist When the antipruritic agent of the present invention contains an IL-27 receptor agonist as an active ingredient, the IL-27 receptor agonist activates the IL-27 receptor to completely or partially. It is not particularly limited as long as it is a substance that induces a receptor-mediated response to the drug and has an antipruritic effect. The IL-27 receptor agonist included in the pruritus therapeutic agent of the present invention may be either an endogenous substance or an exogenous (extrinsic) substance, but does not include IL-27 described in (1) above. The IL-27 receptor agonist may be any compound, but is not limited to, for example, a high molecular compound such as a nucleic acid (including a nucleic acid aptamer), a protein (including an antibody and an antigen-binding fragment), or a polysaccharide. Alternatively, it may be a low molecular weight compound such as a nucleic acid, a nucleotide, an amino acid, a peptide (including a peptide antigener), a sugar, a lipid, a vitamin, or a hormone.

In one embodiment, as a specific example of the IL-27 receptor agonist included in the antipruritic agent of the present invention, isolated or recombinant soluble WSX-1 / p28, as described in JP 2009-543579. Polypeptide complex, isolated or recombinant soluble WSX-1 / EBI3 polypeptide complex, isolated or recombinant soluble WSX-1 / IL-27 complex, isolated or recombinant soluble gp130 / p28 polypeptide complex , Isolated or recombinant soluble gp130 / EBI3 polypeptide complex, isolated or recombinant soluble gp130 / IL-27 complex, or variants thereof. Here, the p28 protein and the EBI3 protein are secreted as separate polypeptides, and are thought to stabilize by associating with the receptors WSX-1 protein and gp130 protein and activate the receptor signal. Since IL-27 is a cytokine belonging to the IL-6 superfamily, the following predictions are made based on the crystal structure of the interaction between IL-6 and the IL-6 receptor (IL-6Rα / gp130). That is, the binding sites between each component in the IL-27 and IL-27 complex are the binding site between the p28 protein and the EBI3 protein (site 1), the p28 / EBI3 complex (IL-27) and the WSX-1 protein. It is considered to be formed by the binding of gp130 protein (site 2) or the binding of p28 protein and gp130 protein (site 3). Therefore, the soluble complex of IL-27 component and IL-27 receptor component that can be formed by these bindings, like IL-27, is finally a complex consisting of p28 / EBI3 / WSX-1 / gp130. May act as an agonist of the IL-27 receptor by promoting the formation of (Boulanger MJ et al., Science, 2003, 27, 300 (5628), 2101-4; Vignali DA and Kuchroo VK, Nat Immunol , 2012, 13 (8), 722-8).

In another embodiment, the IL-27 receptor agonist included in the pruritus therapeutic agent of the present invention may be IL-27 hyperkine. As used herein, the term "IL-27 hypercain" refers to a fusion protein of p28 protein and EBI3 protein. More specifically, it means a fusion protein having an amino acid sequence containing both the amino acid sequence of the p28 protein and the amino acid sequence of the EBI3 protein. In the fusion protein, the p28 protein moiety and the EBI3 protein moiety are present as one continuous polypeptide chain, but may be present in any order. In addition, a linker sequence may be contained between the p28 protein moiety and the EBI3 protein moiety. Preferably, in the IL-27 hyperkine included in the antipruritic agent of the present invention, the amino acid sequence of the p28 protein portion in the IL-27 hyperkine is 70% or more, 75% or more of the amino acid sequence shown in SEQ ID NO: 1. % Or more, 80% or more, 85% or more, 90% or more, 95% or more, 96% or more, 97% or more, 98% or more, or 99% or more identity, or the amino acid sequence shown in SEQ ID NO: 1. One or more amino acids have been added, deleted, or substituted with respect to the amino acid sequence of the EBI3 protein portion in IL-27 hyperkine, which is 70% or more of the amino acid sequence shown in SEQ ID NO: 2. Amino acids having the same identity of 75% or more, 80% or more, 85% or more, 90% or more, 95% or more, 96% or more, 97% or more, 98% or more, or 99% or more, or shown in SEQ ID NO: 2. One or more amino acids have been added, deleted, or substituted to the sequence. More preferably, in the IL-27 hyperkine included in the antipruritic agent of the present invention, the amino acid sequence of the p28 protein portion in the IL-27 hyperkine is the amino acid sequence shown in SEQ ID NO: 1, and the IL-27 hyperkine. The amino acid sequence of the EBI3 protein portion in Cain is the amino acid sequence shown in SEQ ID NO: 2. Preferably, the IL-27 hypercain included in the antipruritic agent of the present invention has the activity of human wild-type IL-27.

In yet another embodiment, the IL-27 receptor agonist included in the pruritus therapeutic agent of the present invention may be an agonist antibody of the IL-27 receptor, or an antigen-binding fragment thereof. As used herein, the term "agonist antibody" refers to an antibody capable of activating a receptor to induce a fully or partially receptor-mediated response. As used herein, the term "antibody" includes any immunoglobulin, monoclonal antibody, polyclonal antibody, multispecific antibody, or bispecific (divalent) antibody that binds to a specific antigen. As used herein, the term "antigen-binding fragment" refers to an antibody fragment formed from a portion of an antibody that contains one or more complementarity determining regions (CDRs), or an antibody fragment that binds to an antigen but is completely natural. Refers to any other antibody fragment that does not contain the antibody structure of. Examples of antigen-binding fragments are, but are not limited to _{, deerbodies, Fabs, Fab', F (ab') 2} , Fv fragments, disulfide-stabilized Fv fragments (dsFv), (dsFv). ) ₂ , bispecific dsFv (dsFv-dsFv'), disulfide-stabilized deerbody (ds deabody), single-chain antibody molecule (scFv), dimer scFv (divalent diabody), multispecific Includes sex antibodies, camelized single domain antibodies, nanobodies, domain antibodies, and divalent domain antibodies.

In one embodiment, the IL-27 receptor agonist included in the pruritus therapeutic agent of the present invention may be an aptamer capable of binding to the IL-27 receptor and functioning as an agonist. As used herein, the term "aptamer" refers to a nucleic acid molecule or peptide that specifically binds to a specific molecule. The aptamer included in the pruritus therapeutic agent of the present invention may be any of a DNA aptamer, an RNA aptamer, or a peptide aptamer.

1-3-2. Dosage Form The dosage form of the antipruritic agent of the present invention does not inactivate or does not easily inactivate the active ingredient IL-27 and / or the IL-27 receptor agonist, and its pharmacological effect is sufficient in vivo after administration. There is no particular limitation as long as it is a dosage form that can be exerted on.

The dosage form can be classified into a liquid dosage form or a solid dosage form (including a semi-solid dosage form such as a gel) depending on the form, and the antipruritic agent of the present invention may be any of them. The dosage form can be roughly classified into an oral dosage form and a parenteral dosage form depending on the administration method, and any of these may be used.

Specific dosage forms include oral dosage forms such as suspensions, emulsions, and liquid dosage forms such as syrups, powders (including powders, powders, and candy powders), granules, and tablets. , And solid dosage forms such as capsules. In the case of parenteral dosage forms, for example, liquid dosage forms such as injections, suspensions, emulsions, eye drops, and nasal drops, and solid preparations such as creams, ointments, ointments, and ship agents. The shape can be mentioned. The preferred dosage form is a parenteral dosage form, more preferably a liquid dosage form of an injection.

1-3-3. Administration Method As the method for administering the pruritus therapeutic agent of the present invention, any method known in the art can be applied as long as it can be administered in an effective amount to a living body for the treatment of pruritus.

The therapeutic agent for pruritus of the present invention, any disease associated with itching (pruritus) is targeted. The pruritus targeted by the pruritus therapeutic agent of the present invention may be either histamine-dependent pruritus or histamine-independent pruritus. For example, atopic dermatitis, eczema, urticaria, insect stings, fungal disease (tinea, cutaneous candidiasis, etc.), psoriasis, pruritus, chronic idiopathic pruritus, senile pruritus dermatitis, hypertrophic scars, or drugs. It may be either rash or pruritus associated with systemic pruritus dermatitis.

As used herein, the term "effective amount" refers to an amount required for the active ingredient to exert its function, that is, an amount required for the pruritus therapeutic agent to suppress pruritus in the present invention. An amount that gives little or no harmful side effects to the body to which it is applied. This effective amount may vary depending on conditions such as subject information, route of administration, and frequency of administration. Here, the "subject" refers to a living body to which the pruritus therapeutic agent of this embodiment or the pruritus therapeutic composition according to the second aspect is applied. For example, humans, domestic animals (cattle, horses, sheep, goats, pigs, chickens, ostriches, etc.), racehorses, pet animals (dogs, cats, rabbits, etc.), laboratory animals (mouses, rats, guinea pigs, monkeys, marmosets, etc.) Etc. are applicable. It is preferably human (in this case, particularly referred to as a "subject"). Further, the "subject information" is various individual information of a living body to which the antipruritic agent of this embodiment or the composition for treating pruritus according to the second aspect is applied, and is, for example, in the case of a subject. Includes general health, disease / disease progression and severity, age, weight, gender, diet, drug susceptibility, presence / absence of concomitant medications, and resistance to treatment. The effective amount and the dose calculated based on the effective amount are determined by the judgment of a doctor or a veterinarian according to the information of individual subjects and the like. When it is necessary to administer a large amount of the pruritus therapeutic agent of the present invention in order to obtain a sufficient effect of suppressing pruritus, it can be administered in several divided doses in order to reduce the burden on the subject.

The method for administering the pruritus therapeutic agent of the present invention may be either systemic administration or local administration. Examples of systemic administration include intravascular injection such as intravenous injection and oral administration. Examples of local administration include local injection such as subcutaneous injection, intradermal administration, and transdermal administration. In the case of oral administration, it is preferable to take appropriate measures such as using an appropriate DDS (drug delivery system) to protect the active ingredient from degradation by degrading enzymes or digestive enzymes. In the case of local injection, it is preferable to administer the pruritus therapeutic agent of the present invention to the pruritic skin. Subcutaneous administration by subcutaneous injection, which can directly deliver the pruritus therapeutic agent of the present invention to an affected area having pruritus, is preferable.

As an example of a specific dose, for example, when administered to a human adult male (body weight 60 kg) with atopic dermatitis, the effective amount of the pruritus therapeutic agent per day is, for example, 1 μg to 1 g, 10 μg to 100 mg, 100 μg to 100 μg. It is in the range of 10 mg, or 1 mg to 10 mg. When the antipruritic agent of the present invention is administered to a subject, the effective dose of the antipruritic agent of the present invention, which is an active ingredient, is, for example, 1 μg to 100 mg, 1 μg to 10 mg, or 10 μg to 1 mg per 1 kg of body weight at a time. Selected by range. Alternatively, a dose of 1 μg to 1 g / body, 10 μg to 100 mg / body, 100 μg to 10 mg / body, or 1 mg to 10 mg / body can be selected per subject. However, it is not limited to these doses.

The administration time of the pruritus therapeutic agent of the present invention is not particularly limited as long as the administration can suppress pruritus, and for example, prophylactic administration, therapeutic administration, and recurrence preventive administration after treatment are possible. ..

1-4. Effect By administering the antipruritic agent of the present invention to a subject having pruritus, an antipruritic effect is exerted on both histamine-dependent pruritus and histamine-independent pruritus. In particular, the anti-histamine agent does not respond to histamine-independent pruritus such as atopic dermatitis, whereas the pruritus therapeutic agent of the present invention also suppresses pruritus to histamine-independent pruritus such as atopic dermatitis. It works.

Since the antipruritic agent of the present invention is effective for both histamine-dependent and independent pruritus, it is considered that the signal common to both of these pathways is blocked.

The antipruritic agent of the present invention is considered to directly control the function of peripheral sensory nerves independently of the suppression of inflammation. Therefore, the pruritus therapeutic agent of the present invention can collectively block various pruritus factors that cause pruritus in a complex manner. Therefore, the therapeutic agent for pruritus of the present invention is considered to be effective for pruritus dermatitis that is not caused by inflammation such as chronic idiopathic pruritus and senile pruritus dermatitis.

The antipruritic agent of the present invention provides a synergistic effect between the above-mentioned antipruritic effect and the previously reported anti-inflammatory effect through suppression of Th2 cytokine production.

In addition, since IL-27, which constitutes the antipruritic agent of the present invention, is a cytokine originally expressed in the living body, it is unlikely to cause serious adverse effects seen in steroids and immunosuppressive drugs, and has few side effects. It has the advantage of.

The pruritus therapeutic agent of the present invention can be used for the treatment of pruritus. In addition, the pruritus therapeutic agent of the present invention can also be used for the treatment of pruritus in combination with a known pruritus treatment method, for example, ultraviolet light therapy.

2. Composition for treating pruritus 2-1. Overview A second aspect of the present invention is a composition for treating pruritus.
The composition for treating pruritus of this embodiment comprises the pruritus therapeutic agent according to the first aspect, a pharmaceutically acceptable carrier, and other active ingredients as selective ingredients. The composition for treating pruritus of this embodiment has an antipruritic effect on histamine-dependent and independent pruritus.

2-2. Composition The composition for treating pruritus according to the first aspect comprises the pruritus therapeutic agent according to the first aspect, a pharmaceutically acceptable carrier, and other active ingredients as selective ingredients.
Hereinafter, each component other than the pruritus therapeutic agent described in the first aspect will be specifically described.

(1) Other Active Ingredients The "other active ingredient" contained in the composition for treating pruritus of the present invention is not limited as long as it is an ingredient having an antipruritic effect. The "other active ingredient" contained in the composition for treating pruritus of the present invention is, in particular, either a component that directly suppresses pruritus without suppressing inflammation or a component that indirectly suppresses pruritus through suppression of inflammation. It may be.

Specific preferable ingredients as "other active ingredients" contained in the pruritus treatment composition of the present invention differ depending on the type of pruritus targeted by the pruritus treatment composition of the present invention, as described below.

When the pruritus targeted by the pruritus treatment composition of the present invention is histamine-dependent pruritus, the pruritus treatment composition of the present invention may contain an antihistamine agent in addition to the pruritus therapeutic agent according to the first aspect. .. The antihistamine agent that can be used in the composition for treating pruritus of this embodiment _{is preferably an H 1} receptor antagonist (H ₁ blocker). H ₁ receptor antagonists can use, but are not limited to, diphenhydramine, chlorpheniramine, mepyramine, triprolidine, mequitazine, terfenadine, dimenhydrinate, promethazine, or salts thereof.

When the pruritus targeted by the pruritus treatment composition of this embodiment is histamine-independent pruritus, in addition to the pruritus therapeutic agent according to the first aspect, a steroid agent, cyclosporin, tacrolimus, human anti-human IL-4. It may contain one or more selected from the group consisting of the / IL-13 receptor monoclonal antibody, the anti-IL-31 receptor humanized monoclonal antibody, and the human anti-human IL-17 receptor A monoclonal antibody.

The steroid agent included in the composition for treating histamine-independent pruritus of the present invention is not limited. For example, clobetasol propionate, diflorazone acetate, mometasone furancarboxylic acid ester, butyric acid propionate betamethasone, dexamethasone dipropionic acid ester, diflupredonato, fluoronide, amcinonide, cortisol, cortisol acetate, hydrocortisone, hydrocortisol acetate, hydrocortisol succinate. , Hydrocortisol butyrate, Hydrocortisol butyrate, Deprodon propionate, Dexamethasone propionate, Dexamethasone valerate, Halcyonide, Betamethasone valerate, Bechrometasone propionate, Fluosinoloneacetonide, Betamethasone, Betamethasone phosphate Betamethasone, betamethasone dipropionate, dexamethasone, dexamethasone acetate, dexamethasone valerate, prednisolone, prednisolone acetate, prednisolone valerate, triamsinolone acetonide, alchrometasone propionate, clobetazone butyrate, methylprednisolone It is selected from, but not limited to, the group consisting of diflucortisol herbate, parameterzone, fluoronide or fluorone asenide, or salts thereof.

The human anti-human IL-4 / IL-13 receptor monoclonal antibody included in the composition for treating histamine-independent pruritus of the present invention is not limited, and for example, dupilumab can be used.

The anti-IL-31 receptor humanized monoclonal antibody included in the composition for treating histamine-independent pruritus of the present invention is not limited, and for example, nemoritumab can be used.

The human anti-human IL-17 receptor A monoclonal antibody included in the composition for treating histamine-independent pruritus of the present invention is not limited, and for example, cosentyx can be used.

(2) Pharmaceutically acceptable carrier The "pharmaceutically acceptable carrier" is a solvent and / or additive that can be usually used in the field of formulation technology and has almost no harm to the living body. Or it means something that does not exist at all.

Pharmaceutically acceptable solvents include, for example, water, ethanol, propylene glycol, ethoxylated isostearyl alcohol, polyoxylated isostearyl alcohol, polyoxyethylene sorbitan fatty acid esters and the like. These are preferably sterilized and preferably adjusted to be isotonic with blood as needed.

In addition, pharmaceutically acceptable additives include, for example, excipients, binders, disintegrants, fillers, emulsifiers, flow addition modifiers, lubricants and the like.

Excipients include, for example, sugars such as monosaccharides, disaccharides, cyclodextrins and polysaccharides (more specifically, but not limited to, glucose, sucrose, lactose, raffinose, mannitol, sorbitol, inositol, dextrin). , Maltodextrin, including starch and cellulose), metal salts (eg, sodium chloride, sodium phosphate or calcium phosphate, calcium sulfate, magnesium sulfate, calcium carbonate), citric acid, tartrate, glycine, low, medium or high molecular weight polyethylene Glucose (PEG), pururonic, kaolin, sucrose, or a combination thereof can be mentioned.

Examples of the binder include starch paste using starch of corn, wheat, rice, or potato, simple syrup, glucose solution, gelatin, tragacant, methyl cellulose, hydroxypropyl methyl cellulose, sodium carboxymethyl cellulose, cellac and / or polyvinylpyrrolidone and the like. Can be mentioned.

Examples of the disintegrant include the starch, lactose, carboxymethyl starch, crosslinked polyvinylpyrrolidone, agar, laminarin powder, sodium hydrogen carbonate, calcium carbonate, alginate or sodium alginate, polyoxyethylene sorbitan fatty acid ester, sodium lauryl sulfate, and stearic acid. Acid monoglycerides or salts thereof can be mentioned.

Examples of the filler include the above-mentioned sugar and / or calcium phosphate (for example, tricalcium phosphate or calcium hydrogen phosphate).

Examples of the emulsifier include sorbitan fatty acid ester, glycerin fatty acid ester, sucrose fatty acid ester, and propylene glycol fatty acid ester.

Examples of the flow addition modifier and lubricant include silicates, talc, stearate or polyethylene glycol.

In addition to the above additives, if necessary, flavoring agents, solubilizing agents (solubilizers), suspending agents, diluents, surfactants, stabilizers, absorption enhancers (for example, quaternary ammonium salts, etc.) Sodium lauryl sulfate), bulking agents, moisturizers to relieve dry skin (eg, vaseline, glycerin, starch), adsorbents (eg, starch, lactose, kaolin, bentonite, colloidal silicic acid), disintegration inhibitors (eg, colloidal silicic acid) It can also contain sucrose, stear, cacao butter, hydrogenated oil), coatings, colorants, preservatives, antioxidants, buffers and the like.

The dosage form of the composition for treating pruritus of the present invention conforms to the dosage form described in "1-3-2. Dosage form" of "1. Itching therapeutic agent". Therefore, the specific description thereof will be omitted here.

The method for administering the composition for treating pruritus of the present invention conforms to the method described in "1-3-3. Administration method" of "1. Therapeutic agent for pruritus". Therefore, the specific description thereof will be omitted here.

2-3. Effect In the composition for treating pruritus of this embodiment, the antipruritic effect is enhanced by adding a component having a further antipruritic effect to the pruritic therapeutic agent according to the first aspect.

The composition for treating pruritus of the present invention can be used for the treatment of pruritus. In addition, the composition for treating pruritus of the present invention can be used for treating pruritus in combination with a known treatment method for pruritus, for example, ultraviolet light therapy.

<Example 1: Histamine-induced acute pruritus test>
(Purpose)
Using an animal model of histamine-dependent pruritus, the antipruritic effect of IL-27 is evaluated using scraping behavior as an index.

(Method)
Itching was induced in the mice by subcutaneously inoculating the itching substance histamine subcutaneously in the cheeks of the mice. Mice used a 9-week-old ICR bred in SPF, and the site to be subcutaneously inoculated with histamine was pre-shaved with hair clippers and shaving cream. For histamine, 2 μL of 50 mM histamine dihydrochloride (Sigma-ALDRICH, H7250) dissolved in PBS was used.

In the IL-27 administration group (n = 7 individuals), 0.1 mg / ml recombinant IL-27 (rIL-27, SEQ ID NO: 5 and SEQ ID NO: 6) dissolved in PBS (BioLegend, Cat # 577406, Recombinant Mouse IL- 27 (carrier-free)) was inoculated with 18 μL at the same time as histamine. In the control group (n = 7 individuals), PBS was inoculated at the same time as histamine.

To assess the pruritus caused by histamine, the number of scraping behaviors of mice was counted 2 hours before histamine inoculation and 2 hours after histamine inoculation. The scraping behavior of mice was measured using an automatic scraping behavior measuring device (scrubarial system) manufactured by Novell Tech. The device can record mouse behavior using a near-infrared LED light panel and a high-speed camera with built-in image processing (image acquisition speed 240 frames / sec), and can automatically detect scraping behavior by image processing. .. The behavior of continuous scraping over 150 frames was defined as one scraping behavior.

(result)
FIG. 2 shows the rate of change in the number of scraping behaviors 1 hour after inoculation with respect to 1 hour before histamine inoculation in the IL-27 administration group and the control group. In the control group (n = 7 individuals), the number of scraping behaviors increased to about 300% after histamine administration (Fig. 2). On the other hand, in the IL-27 administration group (n = 7 individuals), the number of scraping behaviors did not increase after histamine inoculation, and the scraping behaviors due to histamine administration were significantly suppressed (Fig. 2). From this result, it was shown that IL-27 has an antipruritic effect on histamine-dependent pruritus.

<Example 2: Chronic pruritus test using an atopic dermatitis model>
(Purpose)
In a mouse model of atopic dermatitis induced by repeated skin application of a hapten (sensitizing compound), the antipruritic effect of IL-27 is evaluated using the scraping behavior as an index.

(Method)
Sensitization was performed by directly applying 25 μl of 3% oxazolone as a hapten to the abdomen of 5 shaved mice using Pipetman. Atopic dermatitis-like by applying 0.5% oxazolone (Sigma-ALDRICH, E0753) to both cheeks of shaved mice 8 times in total every 3 days (20 μL / one cheek) from one week after sensitization. Caused chronic pruritus due to inflammation of the skin. Twenty-four hours after the last application, 20 μL of rIL-27 dissolved in PBS was subcutaneously inoculated into the cheeks of mice, and the scraping behavior before and after administration was recorded.

Conditions other than the above and the method of counting the scraping behavior of the mouse to be used were based on the method described in Example 1.

(result)
FIG. 3 shows the number of temporal scraping behaviors of each of the five animals in each hour before and after administration of rIL-27. It was clarified that the number of scraping behaviors was significantly reduced by the administration of rIL-27 (Fig. 3).

From the results of Examples 1 and 2, it was shown that the administration of IL-27 had an antipruritic effect on both histamine-dependent pruritus and histamine-independent pruritus. From this result, it is considered that IL-27 blocks a signal common to both histamine-dependent and independent pathways.

Recently, we have reported that IL-27 regulates the susceptibility of skin to mechanical and thermal stimuli, regardless of inflammatory status (Sasaguri, T. et al., Scientific Reports). , 2018, 8, 11022.). Considering this finding together with the results of the present invention, it is considered that IL-27 can control the function of peripheral sensory nerves independently of the anti-inflammatory effect. Therefore, the action of IL-27 is considered to be effective for pruritus dermatitis that is not caused by inflammation such as chronic idiopathic pruritus and senile pruritus dermatitis.

Claims (7)

An antipruritic agent comprising interleukin 27 (IL-27) and / or an IL-27 receptor agonist as an active ingredient. The IL-27
a) Human wild-type p28 protein having the amino acid sequence shown in SEQ ID NO: 1.
b) A mutant p28 protein having 90% or more identity with respect to the amino acid sequence shown in SEQ ID NO: 1 or
c) A mutant p28 protein in which one or more amino acids have been added, deleted, or substituted with respect to the amino acid sequence shown in SEQ ID NO: 1.
d) Human wild-type EBI3 protein having the amino acid sequence shown in SEQ ID NO: 2,
e) A mutant EBI3 protein having 90% or more identity with respect to the amino acid sequence shown in SEQ ID NO: 2, or
f) According to claim 1, which comprises a mutant EBI3 protein in which one or more amino acids are added, deleted or substituted with respect to the amino acid sequence shown in SEQ ID NO: 2 and has the activity of human wild-type IL-27. The antipruritic agent described. The pruritus therapeutic agent according to claim 1 or 2, wherein the pruritus is histamine-dependent pruritus. The pruritus therapeutic agent according to claim 3, wherein the histamine-dependent pruritus is pruritus due to urticaria, insect bites, or drug eruption. The pruritus therapeutic agent according to claim 1 or 2, wherein the pruritus is histamine-independent pruritus. The pruritus therapeutic agent according to claim 5, wherein the histamine-independent pruritus is pruritus due to atopic dermatitis or psoriasis, chronic idiopathic pruritus, or senile pruritus dermatitis. The antipruritic agent according to any one of claims 1 to 6, as well as an antihistamine agent, a steroid agent, cyclosporin, tacrolimus, a human anti-human IL-4 / IL-13 receptor monoclonal antibody, and an anti-IL-31 receptor human. A composition for treating pruritus, which comprises one or more selected from the group consisting of a recombinant monoclonal antibody and a human anti-human IL-17 receptor A monoclonal antibody.

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