Pharmaceutical composition

Abstract

The present disclosure provides a pharmaceutical composition which comprises an anti-IL-31 receptor A antibody as an active ingredient thereof, and which is for the treatment of perforating dermatosis.

Description

Pharmaceutical Composition

[0001] In one aspect, the present disclosure relates to a pharmaceutical composition (prophylactic or therapeutic agent) for preventing or treating perforating skin disease, comprising an antibody against interleukin-31 (hereinafter referred to as IL-31) receptor A as an active ingredient. In another aspect, the present disclosure relates to a method for preventing or treating perforating skin disease, comprising administering an antibody against IL-31 receptor A. In yet another aspect, the present disclosure relates to an antibody against IL-31 receptor A for use in the prevention or treatment of perforating skin disease. In yet another aspect, the present disclosure relates to the use of an antibody against IL-31 receptor A in the manufacture of a medicament for preventing or treating perforating skin disease. In a specific aspect, the perforating skin disease is acquired reactive perforating collagen disease (hereinafter referred to as ARPC). In a specific aspect, the antibody against IL-31 receptor A is nemolizumab.

[0002] Kyrle first reported Kyrle's disease in 1916, Lutz first reported elastosis perforans serpiginosa in 1953, and Mehregan et al. first reported perforating folliculitis and acquired reactive perforating collagenosis (ARPC) in 1968. These diseases are characterized by histopathological findings of transepithelial elimination, a phenomenon in which degenerated dermal components are expelled to the outside of the skin, and are collectively referred to as perforating dermatosis.

[0003] The diagnostic criteria for ARPC are (1) histopathological findings of collagen fibers excreted in a cup-shaped epidermal depression, (2) clinical findings of multiple keratotic papules or nodules with a central umbilicus containing a keratin plug, and (3) onset after the age of 18. Furthermore, systemic diseases such as diabetes and chronic kidney disease are common (Non-Patent Document 1). Lesions are distributed throughout the body, primarily on the limbs and trunk, and are characterized by intense pruritus and Koebner phenomenon. Intense pruritus significantly reduces patients' quality of life (QOL) (Non-Patent Document 2) and can even cause sleep disturbances. Furthermore, the characteristic rash of ARPC is said to affect appearance and limit patients' social activities. Although the etiology of ARPC is unclear, it has been suggested that scratching behavior caused by pruritus can cause abnormalities in the epidermis and dermis.

[0004] Currently, there are no drugs or therapies covered by health insurance for ARPC. ARPC is refractory, often undergoing repeated remissions and relapses, making treatment difficult (Non-Patent Document 2). The Guide to the Management of Perforating Dermatitis (Non-Patent Document 1) proposes topical steroids and ultraviolet light therapy as treatments for ARPC. Antihistamines and antiallergic drugs are used to treat pruritus, but their effectiveness is insufficient. While the use of nalfurafine (a selective kappa opioid receptor agonist), which is indicated for pruritus in dialysis patients and patients with chronic liver disease, has been mentioned, its effectiveness for ARPC has not been verified. Other treatment options, such as dupilumab (Non-Patent Document 3), antibiotics (Non-Patent Document 4), and tricyclic antidepressants (Non-Patent Document 5), have been reported in a few case reports to be effective, but the evidence level is low. Furthermore, these treatments generally do not cure the disease, only improving symptoms such as rash and itching. While several treatments have been considered, none are highly recommended, and novel therapeutic agents are needed.

[0005] Kawakami Tamihiro, Akiyama Masashi, Suga Yasushi, Nakano Hajime, Mitoma Chikage, Yamamoto Akemi, Yoneda Kozo. Guide to the treatment of perforating dermatosis. Journal of the Japanese Dermatological Association. 2020; 130 (9):2007-2016. Kawakami Tamihiro. Comprehensive study of rare, intractable genetic skin diseases: Disease and biostatistical research on perforating dermatosis (reactive perforating collagenosis, Kirle's disease, perforating folliculitis, and perforating elastosis serpiginosa) and Sturge-Weber syndrome. FY2021 Ministry of Health, Labour and Welfare Sciences Research Grant-in-Aid Research Report. May 2022:39-41. Ying Y, Shuang C, Zhen-Ying Z. Dupilumab may be an alternative option in the treatment of acquired reactive perforating collagenosis combined with AD. Immun Inflamm Dis. 2022 Mar;10(3):e574.Muzeyyen G, Seray KC, Ulker G, Arzu K, Gulusan E. Two cases of acquired perforating dermatosis treated with doxycycline therapy. Int J Dermatol. 2006 Dec; 45(12): 1461-3.Yong A, Chong WS, Tey HL. Effective treatment of uremic pruritus and acquired perforating dermatosis with amitriptyline. Australas J Dermatol. 2014;55:e54-57.

[0006] The invention of the present disclosure has been made in view of the above circumstances, and aims to provide, in one aspect, a new means for treating perforating skin disease. Also, in a specific aspect, the invention of the present disclosure aims to provide a new means for treating ARPC.

[0007] The problem to be solved by the present invention is to provide a novel medical use of an anti-IL-31 receptor A antibody. After extensive studies, the present inventors discovered for the first time that the anti-IL-31 receptor A antibody of the present invention is effective in treating or preventing perforating skin disease, and completed the present invention.

[0008] The present inventors explored the efficacy and safety of nemolizumab, a humanized anti-human IL-31 receptor A (IL-31RA) monoclonal antibody.

[0009] The present disclosure is based on such findings, and specifically includes, but is not limited to, the following exemplary embodiments: [A1] A preventive or therapeutic agent for perforating skin disease, comprising an antibody against IL-31 receptor A as an active ingredient. [A2] The preventive or therapeutic agent according to [A1], wherein the perforating skin disease is acquired reactive perforating collagen fibrosis. [A3] The preventive or therapeutic agent according to [A1] or [A2], wherein the antibody has neutralizing activity against IL-31 receptor A. [A4] The preventive or therapeutic agent according to any of [A1] to [A3], wherein the antibody is: (1) an antibody comprising a heavy chain variable region comprising CDR1 having the amino acid sequence set forth in SEQ ID NO: 1, CDR2 having the amino acid sequence set forth in SEQ ID NO: 2, and CDR3 having the amino acid sequence set forth in SEQ ID NO: 3, and a light chain variable region comprising CDR1 having the amino acid sequence set forth in SEQ ID NO: 4, CDR2 having the amino acid sequence set forth in SEQ ID NO: 5, and CDR3 having the amino acid sequence set forth in SEQ ID NO: 6; (2) an antibody comprising a heavy chain variable region having the amino acid sequence set forth in SEQ ID NO: 7 and a light chain variable region having the amino acid sequence set forth in SEQ ID NO: 8; or (3) an antibody comprising a heavy chain having the amino acid sequence set forth in SEQ ID NO: 9 and a light chain having the amino acid sequence set forth in SEQ ID NO: 10. [A5] The preventive or therapeutic agent according to any of [A1] to [A4], wherein the perforating dermatosis is acquired reactive perforating collagen fibrosis accompanied by moderate or severe pruritus. [A6] The preventive or therapeutic agent according to any one of [A1] to [A5], wherein the perforating dermatitis is acquired reactive perforating collagenosis having an itch score of 3 or more. [A7] The preventive or therapeutic agent according to any one of [A1] to [A6], wherein the perforating dermatitis is acquired reactive perforating collagenosis having an edema / papule and excoriation score sum of 3.6 or more. [A8] The preventive or therapeutic agent according to any one of [A1] to [A7], wherein the perforating dermatitis is acquired reactive perforating collagenosis having moderate or more severe pruritus, an itch score of 3 or more, and an edema / papule and excoriation score sum of 3.6 or more. [A9] The preventive or therapeutic agent according to any one of [A1] to [A8], wherein the perforating dermatitis is acquired reactive perforating collagenosis having 20 or more lesions.[A10] The preventive or therapeutic agent according to any one of [A1] to [A9], wherein the perforating dermatitis is acquired reactive perforating collagenosis with a BSA of 5% or more. [A11] The preventive or therapeutic agent according to any one of [A1] to [A10], wherein the perforating dermatitis is acquired reactive perforating collagenosis with a severity classification total score of 8.6 or more. [A12] The preventive or therapeutic agent according to any one of [A1] to [A11], wherein the perforating dermatitis has lesions of acquired reactive perforating collagenosis in at least one site selected from the upper arm, forearm, back, abdomen, thigh, and lower leg. [A13] The prophylactic or therapeutic agent according to any one of [A1] to [A12], wherein the single dose of the antibody against IL-31 receptor A is 0.1 mg to 1000 mg / body, or about 5 mg, about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, or about 90 mg. [A14] The prophylactic or therapeutic agent according to any one of [A1] to [A13], wherein the prophylactic or therapeutic agent is administered to a subject once a week, once every two weeks, once every three weeks, once every four weeks, once every five weeks, once every six weeks, once every seven weeks, or once every eight weeks. [A15] The prophylactic or therapeutic agent according to any one of [A1] to [A12], comprising 30 mg or 60 mg of the antibody against IL-31 receptor A. [A16] The prophylactic or therapeutic agent according to any one of [A1] to [A13], wherein the prophylactic or therapeutic agent is administered to a subject once every four weeks. [A17] The prophylactic or therapeutic agent according to [A1] or [A2], wherein the antibody against IL-31 receptor A is administered to a subject at 60 mg / body dose every four weeks. [A18] The prophylactic or therapeutic agent according to [A1] or [A2], wherein the antibody against IL-31 receptor A is administered to a subject at 60 mg / body dose for the first dose and at 30 mg / body dose every four weeks thereafter. [A19] The prophylactic or therapeutic agent according to [A1] or [A2], wherein the antibody against IL-31 receptor A is administered to a subject at 30 mg / body dose every four weeks.[A20] The preventive or therapeutic agent according to [A1] or [A2], wherein administration of the antibody shows a significant improvement in at least one of the following indices (a) to (g) compared to before administration: (a) Peak pruritus-NRS (PP-NRS); (b) itch score; (c) the sum of the edema / papule score and the scratch score; (d) Body Surface Area (BSA); (e) the number of lesions at the evaluation site; (f) the number of lesions throughout the body; or (g) the total severity classification score. [A21] The preventive or therapeutic agent according to [A1] or [A2], wherein the perforating skin disease is acquired reactive perforating collagen fibrosis with an itch score of 3 or more, and wherein 4 months after administration of the antibody, the itch score improves to 1.8 or improves by 1.2 or more compared to before administration. [A22] The preventive or therapeutic agent according to [A1] or [A2], wherein the perforating dermatitis is acquired reactive perforating collagen fibrosis with an itch NRS score of 5 or more, and the itch NRS score improves by 3 or more four months after administration of the antibody compared to before administration.

[0010] [B1] A method for preventing or treating perforating skin disease, comprising administering an antibody against IL-31 receptor A. [B2] The method according to [B1], wherein the perforating skin disease is acquired reactive perforating collagen fibrosis. [B3] The method according to [B1] or [B2], wherein the antibody has neutralizing activity against IL-31 receptor A. [B4] The method of any of [B1] to [B3], wherein the antibody is: (1) an antibody comprising a heavy chain variable region comprising CDR1 having the amino acid sequence set forth in SEQ ID NO: 1, CDR2 having the amino acid sequence set forth in SEQ ID NO: 2, and CDR3 having the amino acid sequence set forth in SEQ ID NO: 3, and a light chain variable region comprising CDR1 having the amino acid sequence set forth in SEQ ID NO: 4, CDR2 having the amino acid sequence set forth in SEQ ID NO: 5, and CDR3 having the amino acid sequence set forth in SEQ ID NO: 6; (2) an antibody comprising a heavy chain variable region having the amino acid sequence set forth in SEQ ID NO: 7 and a light chain variable region having the amino acid sequence set forth in SEQ ID NO: 8; or (3) an antibody comprising a heavy chain having the amino acid sequence set forth in SEQ ID NO: 9 and a light chain having the amino acid sequence set forth in SEQ ID NO: 10. [B5] The method of any of [B1] to [B4], wherein the perforating dermatosis is acquired reactive perforating collagen fibrosis accompanied by moderate or severe pruritus. [B6] The method of any of [B1] to [B5], wherein the perforating skin disease is acquired reactive perforating collagenosis with an itch score of 3 or more. [B7] The method of any of [B1] to [B6], wherein the perforating skin disease is acquired reactive perforating collagenosis with a sum of the edema / papule score and the excoriation score of 3.6 or more. [B8] The method of any of [B1] to [B7], wherein the perforating skin disease is acquired reactive perforating collagenosis with moderate or more severe pruritus, an itch score of 3 or more, and a sum of the edema / papule score and the excoriation score of 3.6 or more. [B9] The method of any of [B1] to [B8], wherein the perforating skin disease is acquired reactive perforating collagenosis with 20 or more lesions. [B10] The method according to any one of [B1] to [B9], wherein the perforating skin disease is acquired reactive perforating collagen fibrosis having a BSA of 5% or more.[B11] The method according to any one of [B1] to [B10], wherein the perforating skin disease is acquired reactive perforating collagenosis with a total severity classification score of 8.6 or higher. [B12] The method according to any one of [B1] to [B11], wherein the perforating skin disease has lesions of acquired reactive perforating collagenosis in at least one site selected from the upper arm, forearm, back, abdomen, thigh, and lower leg. [B13] The method of any of [B1] to [B12], wherein the single dose of the antibody against IL-31 receptor A is 0.1 mg to 1000 mg / body, or about 5 mg, about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, or about 90 mg. [B14] The method of any of [B1] to [B13], wherein the antibody against IL-31 receptor A is administered to a subject once a week, once every two weeks, once every three weeks, once every four weeks, once every five weeks, once every six weeks, once every seven weeks, or once every eight weeks. [B15] The method of any of [B1] to [B12], wherein the antibody against IL-31 receptor A is administered at a single dose of 30 mg or 60 mg. [B16] The method of any of [B1] to [B13], wherein the antibody against IL-31 receptor A is administered to a subject once every four weeks. [B17] The method of [B1] or [B2], wherein the antibody against IL-31 receptor A is administered to a subject at 60 mg / body dose every four weeks. [B18] The method of [B1] or [B2], wherein the antibody against IL-31 receptor A is administered to a subject at 60 mg / body dose for the first dose, and at 30 mg / body dose every four weeks thereafter. [B19] The method of [B1] or [B2], wherein the antibody against IL-31 receptor A is administered to a subject at 30 mg / body dose every four weeks.[B20] The method of [B1] or [B2], wherein administration of the antibody shows a significant improvement compared to before administration in at least one of the following indicators (a) to (g): (a) Peak pruritus-NRS (PP-NRS); (b) itch score; (c) the sum of the edema / papule score and the scratch score; (d) Body Surface Area (BSA); (e) the number of lesions at the evaluation site; (f) the number of lesions over the whole body; or (g) the severity classification total score. [B21] The method of [B1] or [B2], wherein the perforating skin disease is acquired reactive perforating collagenous fibrosis with an itch score of 3 or more, and 4 months after administration of the antibody, the itch score improves to 1.8 or improves by 1.2 or more compared to before administration. [B22] The method according to [B1] or [B2], wherein the perforating dermatitis is acquired reactive perforating collagen fibrosis with an itch NRS score of 5 or more, and the itch NRS score improves by 3 or more four months after administration of the antibody compared to before administration.

[0011] [C1] An antibody against IL-31 receptor A for use in the prevention or treatment of perforating skin disease. [C2] The antibody of [C1], wherein the perforating skin disease is acquired reactive perforating collagen fibrosis. [C3] The antibody of [C1] or [C2], wherein the antibody has neutralizing activity against IL-31 receptor A. [C4] The antibody according to any of [C1] to [C3], wherein the antibody is: (1) an antibody comprising a heavy chain variable region comprising CDR1 having the amino acid sequence set forth in SEQ ID NO: 1, CDR2 having the amino acid sequence set forth in SEQ ID NO: 2, and CDR3 having the amino acid sequence set forth in SEQ ID NO: 3, and a light chain variable region comprising CDR1 having the amino acid sequence set forth in SEQ ID NO: 4, CDR2 having the amino acid sequence set forth in SEQ ID NO: 5, and CDR3 having the amino acid sequence set forth in SEQ ID NO: 6; (2) an antibody comprising a heavy chain variable region having the amino acid sequence set forth in SEQ ID NO: 7 and a light chain variable region having the amino acid sequence set forth in SEQ ID NO: 8; or (3) an antibody comprising a heavy chain having the amino acid sequence set forth in SEQ ID NO: 9 and a light chain having the amino acid sequence set forth in SEQ ID NO: 10. [C5] The antibody according to any of [C1] to [C4], wherein the perforating dermatosis is acquired reactive perforating collagen fibrosis accompanied by moderate or severe pruritus. [C6] The antibody of any of [C1] to [C5], wherein the perforating dermatitis is acquired reactive perforating collagenosis with an itch score of 3 or more. [C7] The antibody of any of [C1] to [C6], wherein the perforating dermatitis is acquired reactive perforating collagenosis with a sum of the edema / papule score and the excoriation score of 3.6 or more. [C8] The antibody of any of [C1] to [C7], wherein the perforating dermatitis is acquired reactive perforating collagenosis with moderate or more severe pruritus, an itch score of 3 or more, and a sum of the edema / papule score and the excoriation score of 3.6 or more. [C9] The antibody of any of [C1] to [C8], wherein the perforating dermatitis is acquired reactive perforating collagenosis with 20 or more lesions. [C10] The antibody according to any one of [C1] to [C9], wherein the perforating dermatitis is acquired reactive perforating collagen fibrosis having a BSA of 5% or more.[C11] The antibody according to any one of [C1] to [C10], wherein the perforating dermatitis is acquired reactive perforating collagenosis with a severity classification total score of 8.6 or more. [C12] The antibody according to any one of [C1] to [C11], wherein the perforating dermatitis has lesions of acquired reactive perforating collagenosis in at least one site selected from the upper arm, forearm, back, abdomen, thigh, and lower leg. [C13] The antibody according to any one of [C1] to [C12], wherein the antibody against IL-31 receptor A is administered at a single dose of 0.1 mg to 1000 mg / body, or at a dose of about 5 mg, about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, or about 90 mg. [C14] The antibody according to any one of [C1] to [C13], wherein the antibody is administered to a subject once a week, once every two weeks, once every three weeks, once every four weeks, once every five weeks, once every six weeks, once every seven weeks, or once every eight weeks. [C15] The antibody according to any one of [C1] to [C12], wherein the antibody against IL-31 receptor A is administered at a single dose of 30 mg or 60 mg. [C16] The antibody according to any one of [C1] to [C13], wherein the antibody is administered to a subject once every four weeks. [C17] The antibody according to [C1] or [C2], wherein the antibody is administered to a subject at 60 mg / body dose every four weeks. [C18] The antibody according to [C1] or [C2], wherein the antibody is administered to a subject at 60 mg / body dose for the first dose, and at 30 mg / body dose every four weeks thereafter. [C19] The antibody according to [C1] or [C2], wherein the antibody is administered to a subject at 30 mg / body dose every four weeks.[C20] The antibody of [C1] or [C2], wherein administration of the antibody shows significant improvement in at least one of the following indicators (a) to (g) compared to before administration: (a) Peak pruritus-NRS (PP-NRS); (b) itch score; (c) the sum of the edema / papule score and the scratch score; (d) Body Surface Area (BSA); (e) the number of lesions at the evaluation site; (f) the number of lesions throughout the body; or (g) the severity classification total score. [C21] The antibody of [C1] or [C2], wherein the perforating skin disease is acquired reactive perforating collagenous fibrosis with an itch score of 3 or more, and wherein 4 months after administration of the antibody, the itch score improves to 1.8 or improves by 1.2 or more compared to before administration. [C22] The antibody described in [C1] or [C2], wherein the perforating dermatitis is acquired reactive perforating collagen fibrosis with an itch NRS score of 5 or more, and the itch NRS score improves by 3 or more four months after administration of the antibody compared to before administration.

[0012] [D1] Use of an antibody against IL-31 receptor A in the manufacture of a medicament for preventing or treating perforating skin disease. [D2] The use of [D1], wherein the perforating skin disease is acquired reactive perforating collagen fibrosis. [D3] The use of [D1] or [D2], wherein the antibody has neutralizing activity against IL-31 receptor A. [D4] The use according to any of [D1] to [D3], wherein the antibody is: (1) an antibody comprising a heavy chain variable region comprising CDR1 having the amino acid sequence set forth in SEQ ID NO: 1, CDR2 having the amino acid sequence set forth in SEQ ID NO: 2, and CDR3 having the amino acid sequence set forth in SEQ ID NO: 3, and a light chain variable region comprising CDR1 having the amino acid sequence set forth in SEQ ID NO: 4, CDR2 having the amino acid sequence set forth in SEQ ID NO: 5, and CDR3 having the amino acid sequence set forth in SEQ ID NO: 6; (2) an antibody comprising a heavy chain variable region having the amino acid sequence set forth in SEQ ID NO: 7 and a light chain variable region having the amino acid sequence set forth in SEQ ID NO: 8; or (3) an antibody comprising a heavy chain having the amino acid sequence set forth in SEQ ID NO: 9 and a light chain having the amino acid sequence set forth in SEQ ID NO: 10. [D5] The use according to any of [D1] to [D4], wherein the perforating dermatosis is acquired reactive perforating collagenous fibrosis accompanied by moderate or severe pruritus. [D6] The use of any of [D1] to [D5], wherein the perforating skin disease is acquired reactive perforating collagenosis with an itch score of 3 or more. [D7] The use of any of [D1] to [D6], wherein the perforating skin disease is acquired reactive perforating collagenosis with a sum of the edema / papule score and the excoriation score of 3.6 or more. [D8] The use of any of [D1] to [D7], wherein the perforating skin disease is acquired reactive perforating collagenosis with moderate or more pruritus, an itch score of 3 or more, and a sum of the edema / papule score and the excoriation score of 3.6 or more. [D9] The use of any of [D1] to [D8], wherein the perforating skin disease is acquired reactive perforating collagenosis with 20 or more lesions. [D10] The use according to any one of [D1] to [D9], wherein the perforating skin disease is acquired reactive perforating collagen fibrosis having a BSA of 5% or more.[D11] The use according to any one of [D1] to [D10], wherein the perforating skin disease is acquired reactive perforating collagenosis with a severity classification total score of 8.6 or higher. [D12] The use according to any one of [D1] to [D11], wherein the perforating skin disease has lesions of acquired reactive perforating collagenosis in at least one site selected from the upper arm, forearm, back, abdomen, thigh, and lower leg. [D13] The use of any of [D1] to [D12], wherein the single dose of the antibody against IL-31 receptor A is 0.1 mg to 1000 mg / body, or about 5 mg, about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, or about 90 mg. [D14] The use of any of [D1] to [D13], wherein the medicament is administered to a subject once a week, once every two weeks, once every three weeks, once every four weeks, once every five weeks, once every six weeks, once every seven weeks, or once every eight weeks. [D15] The use of any of [D1] to [D12], wherein the antibody against IL-31 receptor A is administered at a single dose of 30 mg or 60 mg. [D16] The use of any of [D1] to [D13], wherein the medicament is administered to a subject once every four weeks. [D17] The use of [D1] or [D2], wherein the antibody against IL-31 receptor A is administered to a subject at a single dose of 60 mg / body every four weeks. [D18] The use of [D1] or [D2], wherein the antibody against IL-31 receptor A is administered to a subject at a first dose of 60 mg / body, and at a single dose of 30 mg / body from the second dose onwards every four weeks. [D19] The use of [D1] or [D2], wherein the antibody against IL-31 receptor A is administered to a subject at a single dose of 30 mg / body every four weeks.[D20] The use of [D1] or [D2], wherein administration of the antibody shows significant improvement compared to before administration in at least one of the following indicators (a) to (g): (a) Peak pruritus-NRS (PP-NRS); (b) itch score; (c) the sum of the edema / papule score and the scratch score; (d) Body Surface Area (BSA); (e) the number of lesions in the evaluation site; (f) the number of lesions in the whole body; or (g) the severity classification total score. [D21] The use of [D1] or [D2], wherein the perforating skin disease is acquired reactive perforating collagenous fibrosis with an itch score of 3 or more, and 4 months after administration of the antibody, the itch score improves to 1.8 or improves by 1.2 or more compared to before administration. [D22] The use described in [D1] or [D2], wherein the perforating dermatitis is acquired reactive perforating collagen fibrosis with an itch NRS score of 5 or more, and the itch NRS score improves by 3 or more four months after administration of the antibody compared to before administration.

[0013] [E1] Nemolizumab for use in the prevention or treatment of acquired reactive perforated collagen fibrosis. [E2] Nemolizumab for use in the prevention or treatment of acquired reactive perforated collagen fibrosis with moderate or severe pruritus. [E3] Nemolizumab for use in the prevention or treatment of acquired reactive perforated collagen fibrosis with an itch score of 3 or greater. [E4] Nemolizumab for use in the prevention or treatment of acquired reactive perforated collagen fibrosis with a sum of edema / papule score and excoriation score of 3.6 or greater. [E5] Nemolizumab for use in the prevention or treatment of acquired reactive perforated collagen fibrosis with moderate or severe pruritus, an itch score of 3 or greater, and a sum of edema / papule score and excoriation score of 3.6 or greater. [E6] Nemolizumab for use in the prevention or treatment of acquired reactive perforated collagen fibrosis with 20 or more skin lesions. [E7] Nemolizumab for use in the prevention or treatment of acquired reactive perforated collagen fibrosis with a BSA of 5% or more. [E8] Nemolizumab for use in the prevention or treatment of acquired reactive perforated collagen fibrosis with a severity classification total score of 8.6 or more. [E9] Nemolizumab for use in the prevention or treatment of acquired reactive perforated collagen fibrosis with acquired reactive perforated collagen fibrosis lesions in at least one site selected from the upper arm, forearm, back, abdomen, thigh, and lower leg. [E10] Nemolizumab for use in the prevention or treatment of acquired reactive perforated collagen fibrosis, wherein the nemolizumab is administered to a subject at a dose of 30 mg once every four weeks. [E11] Nemolizumab for use in the prevention or treatment of acquired reactive perforating collagen fibrosis with moderate or severe pruritus, wherein the nemolizumab is administered to a subject at a dose of 30 mg once every four weeks. [E12] Nemolizumab for use in the prevention or treatment of acquired reactive perforating collagen fibrosis with an itch score of 3 or higher, wherein the nemolizumab is administered to a subject at a dose of 30 mg once every four weeks.[E13] Nemolizumab for use in the prevention or treatment of acquired reactive perforated collagen fibrosis with a sum of edema / papule and excoriation scores of 3.6 or more, wherein the nemolizumab is administered to a subject at a dose of 30 mg once every four weeks. [E14] Nemolizumab for use in the prevention or treatment of acquired reactive perforated collagen fibrosis with moderate or more severe pruritus, an itch score of 3 or more, and a sum of edema / papule and excoriation scores of 3.6 or more, wherein the nemolizumab is administered to a subject at a dose of 30 mg once every four weeks. [E15] Nemolizumab for use in the prevention or treatment of acquired reactive perforated collagen fibrosis with 20 or more skin lesions, wherein the nemolizumab is administered to a subject at a dose of 30 mg once every four weeks. [E16] Nemolizumab for use in the prevention or treatment of acquired reactive perforated collagen fibrosis having a BSA of 5% or more, wherein the nemolizumab is administered to a subject at a dose of 30 mg once every four weeks. [E17] Nemolizumab for use in the prevention or treatment of acquired reactive perforated collagen fibrosis having a severity classification total score of 8.6 or more, wherein the nemolizumab is administered to a subject at a dose of 30 mg once every four weeks. [E18] Nemolizumab for use in the prevention or treatment of acquired reactive perforated collagen fibrosis having acquired reactive perforated collagen fibrosis lesions in at least one site selected from the upper arm, forearm, back, abdomen, thigh, and lower leg, wherein the nemolizumab is administered to a subject at a dose of 30 mg once every four weeks. [E19] Nemolizumab for use in the prevention or treatment of acquired reactive perforated collagen fibrosis, wherein the nemolizumab is administered to a subject at a dose of 60 mg once every four weeks. [E20] Nemolizumab for use in the prevention or treatment of acquired reactive perforated collagen fibrosis with moderate or severe pruritus, wherein the nemolizumab is administered to a subject at a dose of 60 mg once every four weeks.[E21] Nemolizumab for use in the prevention or treatment of acquired reactive perforated collagen fibrosis having an itch score of 3 or more, wherein the nemolizumab is administered to a subject at a dose of 60 mg once every four weeks. [E22] Nemolizumab for use in the prevention or treatment of acquired reactive perforated collagen fibrosis having an edema / papule score and excoriation score sum of 3.6 or more, wherein the nemolizumab is administered to a subject at a dose of 60 mg once every four weeks. [E23] Nemolizumab for use in the prevention or treatment of acquired reactive perforated collagen fibrosis having moderate or more severe itch, an itch score of 3 or more, and an edema / papule score and excoriation score sum of 3.6 or more, wherein the nemolizumab is administered to a subject at a dose of 60 mg once every four weeks. [E24] Nemolizumab for use in the prevention or treatment of acquired reactive perforated collagen fibrosis with 20 or more skin lesions, wherein the nemolizumab is administered to a subject at a dose of 60 mg once every four weeks. [E25] Nemolizumab for use in the prevention or treatment of acquired reactive perforated collagen fibrosis with a BSA of 5% or more, wherein the nemolizumab is administered to a subject at a dose of 60 mg once every four weeks. [E26] Nemolizumab for use in the prevention or treatment of acquired reactive perforated collagen fibrosis with a severity classification total score of 8.6 or more, wherein the nemolizumab is administered to a subject at a dose of 60 mg once every four weeks. [E27] Nemolizumab for use in the prevention or treatment of acquired reactive perforating collagen fibrosis in a subject having acquired reactive perforating collagen fibrosis lesions in at least one site of the upper arm, forearm, back, abdomen, thigh, or lower leg, wherein the nemolizumab is administered to the subject at a dose of 60 mg once every four weeks. [E28] Nemolizumab for use in the prevention or treatment of acquired reactive perforating collagen fibrosis, wherein the nemolizumab is administered to the subject at a dose of 60 mg / body for the first time and at a dose of 30 mg / body for the second and subsequent times once every four weeks.[E29] Nemolizumab for use in the prevention or treatment of acquired reactive perforated collagen fibrosis with moderate or severe pruritus, wherein the nemolizumab is administered to a subject once every four weeks at 60 mg / body dose initially and 30 mg / body doses thereafter. [E30] Nemolizumab for use in the prevention or treatment of acquired reactive perforated collagen fibrosis with an itch score of 3 or greater, wherein the nemolizumab is administered to a subject once every four weeks at 60 mg / body dose initially and 30 mg / body doses thereafter. [E31] Nemolizumab for use in the prevention or treatment of acquired reactive perforated collagen fibrosis with a sum of edema / papule score and excoriation score of 3.6 or greater, wherein the nemolizumab is administered to a subject once every four weeks at 60 mg / body dose initially and 30 mg / body doses thereafter. [E32] Nemolizumab for use in the prevention or treatment of acquired reactive perforating collagen fibrosis with moderate or severe pruritus, an itch score of 3 or greater, and a sum of edema / papule and excoriation scores of 3.6 or greater, wherein the nemolizumab is administered to the subject once every four weeks at 60 mg / body dose initially and 30 mg / body doses thereafter. [E33] Nemolizumab for use in the prevention or treatment of acquired reactive perforating collagen fibrosis with 20 or more skin lesions, wherein the nemolizumab is administered to the subject once every four weeks at 60 mg / body dose initially and 30 mg / body doses thereafter. [E34] Nemolizumab for use in the prevention or treatment of acquired reactive perforated collagen fibrosis having a BSA of 5% or more, wherein the nemolizumab is administered to a subject once every four weeks at 60 mg / body dose for the first time and 30 mg / body doses thereafter. [E35] Nemolizumab for use in the prevention or treatment of acquired reactive perforated collagen fibrosis having a severity classification total score of 8.6 or more, wherein the nemolizumab is administered to a subject once every four weeks at 60 mg / body dose for the first time and 30 mg / body doses thereafter.[E36] Nemolizumab for use in the prevention or treatment of acquired reactive perforating collagen fibrosis in which the subject has lesions of acquired reactive perforating collagen fibrosis in at least one of the following sites: upper arm, forearm, back, abdomen, thigh, and lower leg, wherein the nemolizumab is administered to the subject at 60 mg / body for the first dose and 30 mg / body per dose thereafter once every four weeks.

[0014] DETAILED DESCRIPTION In one aspect, the present disclosure provides a preventive or therapeutic agent for perforating skin disease (also referred to herein as a pharmaceutical composition for preventing or treating perforating skin disease), comprising an antibody against IL-31 receptor A as an active ingredient. In another aspect, the present disclosure relates to a method for preventing or treating perforating skin disease, comprising administering an antibody against IL-31 receptor A. In yet another aspect, the present disclosure relates to an antibody against IL-31 receptor A for use in the prevention or treatment of perforating skin disease. In yet another aspect, the present disclosure relates to the use of an antibody against IL-31 receptor A in the manufacture of a medicament for preventing or treating perforating skin disease. In this specification, the above-mentioned various aspects of the present disclosure may be collectively referred to as the preventive or therapeutic agent of the present disclosure or the preventive or therapeutic method of the present disclosure.

[0015] In certain embodiments, the perforating dermatitis is acquired reactive perforating collagen fibrosis (ARPC). In certain embodiments, the antibody against IL-31 receptor A is (1) an antibody comprising a heavy chain variable region comprising CDR1 having the amino acid sequence set forth in SEQ ID NO: 1, CDR2 having the amino acid sequence set forth in SEQ ID NO: 2, and CDR3 having the amino acid sequence set forth in SEQ ID NO: 3, and a light chain variable region comprising CDR1 having the amino acid sequence set forth in SEQ ID NO: 4, CDR2 having the amino acid sequence set forth in SEQ ID NO: 5, and CDR3 having the amino acid sequence set forth in SEQ ID NO: 6; (2) an antibody comprising a heavy chain variable region having the amino acid sequence set forth in SEQ ID NO: 7 and a light chain variable region having the amino acid sequence set forth in SEQ ID NO: 8; or (3) an antibody comprising a heavy chain having the amino acid sequence set forth in SEQ ID NO: 9 and a light chain having the amino acid sequence set forth in SEQ ID NO: 10. In certain embodiments, the antibody against IL-31 receptor A is nemolizumab. In certain embodiments, the antibody against IL-31 receptor A is administered at 30 mg / body or 60 mg / body per dose (per administration). In certain embodiments, the antibody against IL-31 receptor A is administered every 4 weeks. In certain embodiments, the antibody against IL-31 receptor A is administered subcutaneously. In certain embodiments, the antibody against IL-31 receptor A is administered to patients with moderate or severe pruritus (PP-NRS score of 5 or greater). In certain embodiments, the antibody against IL-31 receptor A is administered to patients with an itch score of 3 or greater. In certain embodiments, the antibody against IL-31 receptor A is administered to patients with a sum of edema / papule score and excoriation score of 3.6 or greater.

[0016] Perforating Dermatitis: "Perforating Dermatitis" refers to diseases characterized by histopathological findings of transepidermal discharge of degenerated dermal components. It is a collective term for four diseases: acquired reactive perforating collagenosis (ARPC), in which collagen fibers are expelled from the epidermis; serpiginous perforating elastosis, in which elastic fibers are expelled from the epidermis; Kirle's disease, in which keratin is expelled from the epidermis; and perforating folliculitis, in which collagen fibers are expelled from hair follicles. Clinical features of all four diseases are often pruritus and Koebner phenomenon. Furthermore, ARPC, Kirle's disease, and perforating folliculitis share commonalities, such as the frequent occurrence of diabetes and chronic kidney disease as coexisting conditions. In Japan, the diagnostic criteria in the 2020 Japanese Dermatological Association's Guidelines for the Management of Perforating Dermatitis are well known, but the number of patients is small.

[0017] [Acquired reactive perforating collagenosis (ARPC)] "Acquired reactive perforating collagenosis (ARPC)" is a type of perforating dermatosis that shows transepidermal excretion of collagen fibers on histopathology. The diagnostic criteria proposed are that all three of the following must be met: (1) histopathological findings show the discharge of collagen fibers in a cup-shaped epidermal depression; (2) clinical findings show multiple keratotic papules or nodules with a central umbilicus containing a keratin plug; and (3) onset of the disease after the age of 18.

[0018] [IL-31] IL-31 is a new member of the IL-6 cytokine family and was initially reported as an inducer of mouse dermatitis. IL-31 is primarily produced by Th2 cells, but is also expressed in a variety of cells, including fibroblasts, keratinocytes, and macrophages. When IL-31 binds to the IL-31 receptor complex on the cell surface, it activates JAK / STAT, PI3K / AKT, and other intracellular signaling pathways, resulting in a broad immune response.

[0019] The IL-31 receptor complex is a heterodimer consisting of IL-31 receptor A (IL-31RA) and oncostatin M receptor. Although oncostatin M receptor is also included in the receptor complex for oncostatin M, IL-31RA is unique to the IL-31 receptor. IL-31 primarily binds to IL-31RA, one of the two receptor subunits.

[0020] [Anti-IL-31 receptor A antibody] As used herein, the terms "anti-IL-31 receptor A antibody" and "antibody against IL-31 receptor A" are used interchangeably and refer to an antibody capable of specifically binding to IL-31 receptor A (IL-31RA). In the context of the presently disclosed invention, an antibody against IL-31 receptor A is preferably an antibody having neutralizing activity against IL-31 receptor A. As used herein, "neutralizing activity against IL-31 receptor A" refers to the activity of inhibiting the binding of IL-31 receptor A to its ligand, IL-31, and preferably refers to the activity of suppressing physiological activity based on IL-31 receptor A. Therefore, an "antibody having neutralizing activity against IL-31 receptor A" inhibits the binding of IL-31RA to IL-31, thereby suppressing, inhibiting, or blocking intracellular signaling mediated by IL-31RA.

[0021] As used herein, the term "antibody" refers to a molecule that specifically binds to a particular antigenic determinant (epitope), and includes various antibody structures, including, but not limited to, monoclonal antibodies (mAbs), polyclonal antibodies (pAbs), and antibody fragments.

[0022] In the context of the presently disclosed invention, the antibody against IL-31RA is preferably an antibody against mammalian IL-31RA, more preferably an antibody against human IL-31RA. An example of a neutralizing antibody against human IL-31RA is nemolizumab. Nemolizumab has been shown in clinical trials to improve the symptoms of atopic dermatitis. Nemolizumab comprises a heavy chain variable region comprising CDR1 having the amino acid sequence set forth in SEQ ID NO: 1, CDR2 having the amino acid sequence set forth in SEQ ID NO: 2, and CDR3 having the amino acid sequence set forth in SEQ ID NO: 3, and a light chain variable region comprising CDR1 having the amino acid sequence set forth in SEQ ID NO: 4, CDR2 having the amino acid sequence set forth in SEQ ID NO: 5, and CDR3 having the amino acid sequence set forth in SEQ ID NO: 6. Nemolizumab also comprises a heavy chain variable region having the amino acid sequence set forth in SEQ ID NO: 7 and a light chain variable region having the amino acid sequence set forth in SEQ ID NO: 8. Nemolizumab also comprises a heavy chain having the amino acid sequence set forth in SEQ ID NO: 9 and a light chain having the amino acid sequence set forth in SEQ ID NO: 10.

[0023] Dosage and Administration: In one embodiment, an anti-IL-31 receptor A antibody is administered to a subject (sometimes referred to herein as a patient or subject) at a dose of about 5 mg / body, about 10 mg / body, about 15 mg / body, about 20 mg / body, about 25 mg / body, about 30 mg / body, about 35 mg / body, about 40 mg / body, about 45 mg / body, about 50 mg / body, about 55 mg / body, about 60 mg / body, about 65 mg / body, about 70 mg / body, about 75 mg / body, about 80 mg / body, about 85 mg / body, or about 90 mg / body per dose. In a specific embodiment, an anti-IL-31 receptor A antibody is administered to a subject at a dose of 30 mg / body or 60 mg / body per dose. In a specific embodiment, an anti-IL-31 receptor A antibody is administered to a subject at a dose of 60 mg / body for the first dose and 30 mg / body per dose thereafter. In one non-limiting embodiment, a subject suffering from or at risk of suffering from ARPC, for example, a human adult and / or child, is administered 0.1 mg to 1000 mg / body, for example, 0.2 mg to 360 mg / body, preferably, for example, 5 mg to 100 mg / body, 5 mg to 75 mg / body, 5 mg to 60 mg / body, 5 mg to 30 mg / body, 5 mg to 20 mg / body, 10 mg to 100 mg / body, 10 mg to 75 mg / body, 10 mg to 60 mg / body, 10 mg to 40 mg / body, 10 mg to 39.5 mg / body, 10 mg to 39 mg / body, 10 mg to 38.5 mg / body body, 10mg to 38mg / body, 10mg to 37.5mg / body, 15mg to 100mg / body, 15mg to 75mg / body, 15mg to 50mg / body, 15mg to 40mg / body, 15mg to 39.5mg / body, 15mg to 39mg / body, 15mg to 38.5mg / b ody, 15mg to 38mg / body, 15mg to 37.5mg / body, 17.5mg to 100mg / body, 17.5mg to 75mg / body, 17.5mg to 50mg / body, 17.5mg to 40mg / body, 17.5mg to 39.5mg / body, 17.5mg to 39mg / body, 17.5mg~38.5mg / body、17.5mg~38mg / body、17.5mg~37.5mg / body、20mg~100mg / body、20mg~75mg / body、20mg~50mg / body、20mg~40mg / body、20mg~39.5mg / body、20mg~39mg / body、20mg~38.5mg / body、20mg~38mg / body、20mg~37.5mg / body、22.5mg~100mg / body、22.5mg~75mg / body、22.5mg~50mg / body、22.5mg~40mg / body、22.5mg~39.5mg / body、22.5mg~39mg / body、22.5mg~38.5mg / body、22.5mg~38mg / body、22.5mg~37.5mg / body、25mg~500mg / body、25mg~200mg / body、25mg~120mg / body、25mg~110mg / body、25mg~100mg / body、25mg~90mg / body、25mg~80mg / body、25mg~79mg / body、25mg~78mg / body、25mg~77mg / body、25mg~76mg / body、25mg~75mg / body、25mg~74mg / body、25mg~73mg / body、25mg~72mg / body、25mg~71mg / body、25mg~70mg / body、25mg~50mg / body、30mg~50mg / body、30mg24~75mg / body、30mg~100mg / body、30mg~150mg / body、30mg~200mg / body、30mg~250mg / body、30mg~300mg / body、40mg~70mg / body、40mg~71mg / body、40mg~72mg / body、40mg~73mg / body、40mg~74mg / body、40mg~75mg / body、40mg~76mg / body、40mg~77mg / body、40mg~78mg / body、40mg~79mg / body、40mg~80mg / body、40mg~90mg / body、40mg~100mg / body、40mg~110mg / body、40mg~120mg / body、42.5mg~70mg / body、42.5mg~71mg / body、42.5mg~72mg / body、42.5mg~73mg / body、42.5mg~74mg / body、42.5mg~75mg / body、42.5mg~76mg / body、42.5mg~77mg / body、42.5mg~78mg / body、42.5mg~79mg / body、42.5mg~80mg / body、42.5mg~90mg / body、42.5mg~100mg / body、42.5mg~110mg / body、42.5mg~120mg / body、45mg~70mg / body、45mg~71mg / body、45mg~72mg / body、45mg~73mg / body、45mg~74mg / body、45mg~75mg / body、45mg~76mg / body、45mg~77mg / body、45mg~78mg / body、45mg~79mg / body、45mg~80mg / body、45mg~90mg / body、45mg~100mg / body、45mg~110mg / body、45mg~120mg / body、47.5mg~70mg / body、47.5mg~71mg / body、47.5mg~72mg / body、47.5mg~73mg / body、47.5mg~74mg / body、47.5mg~75mg / body、47.5mg~76mg / body、47.5mg~77mg / body、47.5mg~78mg / body、47.5mg~79mg / body、47.5mg~80mg / body、47.5mg~90mg / body、47.5mg~100mg / body、47.5mg~110mg / body、47.5mg to 120mg / body, 50mg to 70mg / body, 50mg to 71mg / body, 50mg to 72mg / body, 50mg to 73mg / body, 50mg to 74mg / body, 50mg to 75mg / body, 50mg ~76mg / body, 50mg~77mg / body, 50mg~78mg / body, 50mg~79mg / body, 50mg~80mg / body, 50mg~90mg / body, 50mg~100mg / body, 50mg~110 mg / body, 50mg to 120mg / body, 50mg to 150mg / body, 50mg to 200mg / body, 50mg to 250mg / body, 50mg to 300mg / body, 52.5mg to 70mg / body, 52.5m g~71mg / body, 52.5mg~72mg / body, 52.5mg~73mg / body, 52.5mg~74mg / body, 52.5mg~75mg / body, 52.5mg~76mg / body, 52.5mg~77mg / b ody, 52.5mg to 78mg / body, 52.5mg to 79mg / body, 52.5mg to 80mg / body, 52.5mg to 90mg / body, 52.5mg to 100mg / body, 52.5mg to 110mg / body, 52 .5mg to 120mg / body, 75mg to 100mg / body, 75mg to 150mg / body, 75mg to 200mg / body, 75mg to 250mg / body, 75mg to 300mg / body, 100mg to 150mg / bo A single dose selected from the following may be selected as the dose of the IL-31 antagonist of the present disclosure: 100 mg to 20 / 250 mg / body, 100 mg to 250 mg / body, 100 mg to 300 mg / body, 150 mg to 200 mg / body, 150 mg to 250 mg / body, 150 mg to 300 mg / body, 200 mg to 250 mg / body, 200 mg to 300 mg / body, etc., and may be administered repeatedly at the same dose intervals as described above. In this case, the first administration may be at a different dose from subsequent administrations. In another non-limiting embodiment, a subject suffering from or at risk of suffering from ARPC, e.g., a human adult and / or child, may receive a dose of 0.01 mg to 10 mg / kg, e.g., 0.05 mg to 7.5 mg / kg, 0.075 mg to 5 mg / kg, or 0.1 mg to 3 mg / kg, preferably, for example, 0.1 mg to 0.25 mg / kg, 0.1 mg to 0.3 mg / kg, 0.1 mg to 0.5 mg / kg, 0.1 mg to 0.75 mg / kg, 0.1 mg to 1 mg / kg, 0.1 mg to 1.5 mg / kg, 0.1 mg to 2 mg / kg, 0.1 mg to 3 mg / kg, 0.125 mg to 0.25 mg / kg, 0.125 mg to 0.3 mg / kg, 0.125 mg to 0.5 mg / kg, 0.125 mg to 0.75 mg / kg, 0.125 mg to 1 mg / kg, 0.125 mg to 1.5 mg / kg, 0.125 mg to 2 mg / kg, 0.125 mg to 3 mg / kg, 0.2 mg to 0.3 mg / kg, 0.2 mg to 0.5 mg / kg, 0.2 mg to 0.75 mg / kg, 0.2 mg to 1 mg / kg, 0.2 mg to 1.5 mg / kg, 0.2 mg to 2 mg / kg, 0.2 mg to 3 mg / kg, 0.25 mg to 0.3 mg / kg, 0.25 mg to 0.5 mg / kg, 0.25 mg to 0.75 mg / kg, 0.25 mg to 1 mg / kg, 0.25 mg to 1.5 mg / kg, 0.25 mg to 2 mg / kg, 0.25 mg to 3 mg / kg, 0.3 mg to 0.5 mg / kg, 0.3 mg to 0.75 mg / kg, 0.3 mg to 1 mg / kg, 0.3 mg to 1.5 mg / kg, 0.3 mg to 2 mg / kg, 0.3 mg to 3 mg / kg, 0.5 mg to 0.75 mg / kg, 0.5 mg to 1 mg / kg, 0.5 mg to 1.5 mg / kg, 0.5 mg to 2 mg / kg, 0.5 mg to 3 mg / kg, 0.75 mg to 1 mg / kg, 0.75 mg to 1.5 mg / kg, 0.75 mg to 2 mg / kg, 0.75 mg to 3 mg / kg, 1 mg to 1.5 mg / kg, 1 mg to 2 mg / kg, 1 mg to 3 mg / kg, 1.5 mg to 2 mg / kg, 1.5 mg to 3 mg / kg, 2 mg to 3 mg / kg, 0.15 mg to 2.9 mg / kg, 0.2 mg to 2.8 mg / kg, 0.25 mg to 2.7 mg / kg, 0.3 mg to 2.6 mg / kg, 0.35 mg to 2.5 mg / kg, 0.4 mg to 2.4 mg / kg, 0.425 mg to 2.3 mg / kg, 0.45 mg to 2.2 mg / kg, 0.475 mg to 2.1 mg / kg, 0.5 mg to 2 mg / kg, or 0.5 mg to 1.A single dose selected from 5 mg / kg or 5 mg / kg may be selected as the dose of the IL-31 antagonist of the present disclosure, and may be repeatedly administered at the same dose and at the same administration intervals as described above. In one embodiment, the anti-IL-31 receptor A antibody is administered to a subject about once a week, about once every two weeks, about once every three weeks, about once every four weeks, about once every five weeks, about once every six weeks, about once every seven weeks, or about once every eight weeks. In a specific embodiment, the anti-IL-31 receptor A antibody is administered to a subject about every four weeks. In one embodiment, the anti-IL-31 receptor A antibody is administered subcutaneously. In a specific embodiment, the anti-IL-31 receptor A antibody is administered subcutaneously to a subject at 60 mg / body dose every four weeks. In a specific embodiment, the anti-IL-31 receptor A antibody is administered subcutaneously to a subject at 30 mg / body dose every four weeks. In another specific embodiment, the anti-IL-31 receptor A antibody is administered subcutaneously to a subject every four weeks at a dose of 60 mg / body for the first dose and 30 mg / body per dose thereafter.

[0024] [Severity of Perforating Dermatopathy] In one embodiment, the severity of perforating dermatopathy can be evaluated by the severity of pruritus and / or the severity of skin lesions. The severity of pruritus can be evaluated by the Peak pruritus-NRS (hereinafter referred to as PP-NRS), itch score, etc. The severity of skin lesions can be evaluated by the severity score of each skin finding (edema / papules, excoriation) for skin lesions in each region of the head, upper limbs, trunk, and lower limbs. This evaluation method is known to those skilled in the art; see also the Examples herein. Skin findings can also be evaluated by body surface area (BSA), which indicates the percentage (%) of skin lesion area relative to the body surface area, the number of lesions in specific sites (e.g., upper arms, forearms, back, abdomen, thighs, lower legs), or the number of lesions on the entire body.

[0025] [Treatment Subject] In one embodiment, a patient (sometimes referred to herein as a treatment subject or subject) receiving the administration of a prophylactic or therapeutic agent of the present disclosure or the prevention or treatment method of the present disclosure is a patient with perforating dermatosis (e.g., ARPC) with moderate or severe pruritus (PP-NRS score of 5 or higher). In one embodiment, a patient receiving the administration of a prophylactic or therapeutic agent of the present disclosure or the prevention or treatment method of the present disclosure is a patient with perforating dermatosis (e.g., ARPC) with an itch score of 3 or higher. In a specific embodiment, a patient receiving the administration of a prophylactic or therapeutic agent of the present disclosure or the prevention or treatment method of the present disclosure is a patient with a PP-NRS score of 5 or higher and an itch score of 3 or higher. In one embodiment, a patient receiving the administration of a prophylactic or therapeutic agent of the present disclosure or the prevention or treatment method of the present disclosure is a patient with perforating dermatosis (e.g., ARPC) with skin lesions (e.g., a sum of the edema / papule score and the excoriation score of 3.6 or higher). In certain embodiments, the patient receiving the administration of the prophylactic or therapeutic agent or the prophylactic or therapeutic method of the present disclosure is a patient with perforating dermatopathy (e.g., ARPC) who has moderate or severe pruritus (PP-NRS score of 5 or greater), an itch score of 3 or greater, and a sum of the edema / papule score and the excoriation score of 3.6 or greater.

[0026] In one embodiment, the patient to whom the prophylactic or therapeutic agent of the present disclosure or the prophylactic or therapeutic method of the present disclosure is administered is a patient with perforating skin disease (e.g., ARPC) with 20 or more lesions. In one embodiment, the patient to whom the prophylactic or therapeutic agent of the present disclosure or the prophylactic or therapeutic method of the present disclosure is administered is a patient with perforating skin disease (e.g., ARPC) with a BSA of 5% or more. In one embodiment, the patient to whom the prophylactic or therapeutic agent of the present disclosure or the prophylactic or therapeutic method of the present disclosure is administered is a patient with perforating skin disease (e.g., ARPC) with a total severity classification score of 8.6 or more. In one embodiment, the patient to whom the prophylactic or therapeutic agent of the present disclosure or the prophylactic or therapeutic method of the present disclosure is administered is a patient with acquired reactive perforating collagen fibrosis lesions in at least one site selected from the upper arm, forearm, back, abdomen, thigh, and lower leg.

[0027] In one embodiment, the patient receiving the administration of the prophylactic or therapeutic agent of the present disclosure or the prophylactic or therapeutic method of the present disclosure is a patient with diabetes. In another embodiment, the patient receiving the administration of the prophylactic or therapeutic agent of the present disclosure or the prophylactic or therapeutic method of the present disclosure is a patient without diabetes. In one embodiment, the patient receiving the administration of the prophylactic or therapeutic agent of the present disclosure or the prophylactic or therapeutic method of the present disclosure is a patient with chronic kidney disease. In another embodiment, the patient receiving the administration of the prophylactic or therapeutic agent of the present disclosure or the prophylactic or therapeutic method of the present disclosure is a patient without chronic kidney disease.

[0028] [Efficacy] In one embodiment, the efficacy of the preventive or therapeutic agent or the preventive or therapeutic method of the present disclosure can be evaluated by the severity of perforating skin disease (e.g., ARPC) compared to a control. In the context of the invention of the present disclosure, the control, in one embodiment, refers to the severity of perforating skin disease (e.g., ARPC) in a patient or patient population with perforating skin disease (e.g., ARPC) without administration of the preventive or therapeutic agent of the present disclosure or treatment with the therapeutic method of the present disclosure. In a specific embodiment, the control refers to the severity of perforating skin disease (e.g., ARPC) in a patient or patient population with perforating skin disease (e.g., ARPC) before administration of the preventive or therapeutic agent of the present disclosure or treatment with the therapeutic method of the present disclosure.

[0029] In one embodiment, the prophylactic or therapeutic agent or the prophylactic or therapeutic method of the present disclosure reduces the PP-NRS by 2 to 5. In one embodiment, the prophylactic or therapeutic agent or the prophylactic or therapeutic method of the present disclosure reduces the itch score by 1 to 2 or more. In one embodiment, the prophylactic or therapeutic agent or the prophylactic or therapeutic method of the present disclosure reduces the sum of the edema / papule score and the excoriation score by 3 to 10. In one embodiment, the prophylactic or therapeutic agent or the prophylactic or therapeutic method of the present disclosure reduces the number of skin lesions by 15 to 20. In one embodiment, the prophylactic or therapeutic agent or the prophylactic or therapeutic method of the present disclosure reduces BSA by 5% or more. In one embodiment, the prophylactic or therapeutic agent or the prophylactic or therapeutic method of the present disclosure reduces the total severity classification score by 7 to 10.

[0030] All technical documents cited herein are incorporated herein by reference in their entirety.

[0031] The present disclosure will be specifically described below using examples, but the present disclosure is not limited to these examples.

[0032] [Example 1] Anti-human IL-31RA antibody The anti-human IL-31RA antibody nemolizumab (H chain: identified by the amino acid sequences of SEQ ID NO: 9; L chain: SEQ ID NO: 10) was produced by methods known to those skilled in the art. As described in WO2010 / 064697, nemolizumab has neutralizing activity against human IL-31RA and cynomolgus monkey IL-31RA.

[0033] Example 2: Randomized, placebo-controlled, double-blind, parallel-group, multicenter study of nemolizumab in patients with acquired reactive perforating collagen fibrosis

[0034] (Table 1) Clinical trial design

[0035] If the investigator (sub-investigator) determines that the use of strong topical steroids (TCS) and / or oral antihistamines / antiallergic drugs is necessary for ARPC, the same drugs will be used in a fixed dosage and administration.

[0036] Target disease: Acquired reactive perforating collagen fibrosis (ARPC)

[0037] Inclusion criteria: (1) Patients aged 18 years or older who have been diagnosed with ARPC according to the diagnostic criteria of the Guidelines for the Management of Perforating Dermatitis (2020). (2) Patients who meet all of the following criteria: 1) PP-NRS score of 5 or more; 2) Itching score of 3 or more; (3) Patients with a total edema / papule score and excoriation score of 3.6 or more.

[0038] Exclusion criteria: Patients who have used systemically administered medications such as steroids, immunosuppressants, JAK inhibitors, PDE4 inhibitors, κ-opioid receptor agonists, active vitamin D3 preparations, and medications for the treatment of pruritus will be excluded.

[0039] Investigational drug: nemolizumab Nemolizumab, the investigational drug in this clinical trial, is a humanized anti-human interleukin-31 receptor A (IL-31RA) monoclonal antibody that inhibits the binding of IL-31 to the interleukin-31 (IL-31) receptor and downstream signaling. On March 28, 2022, Mitiga 60 mg Subcutaneous Syringe, an injection containing nemolizumab as the active ingredient, was approved for the treatment of pruritus associated with atopic dermatitis in adults and children aged 13 years and older (only when existing treatments are insufficient).

[0040] The control drug will be a placebo.

[0041] Efficacy evaluation (patient evaluation) Subjects will evaluate the following items: (1) PP-NRS (2) Itch score

[0042] (1) PP-NRS Subjects rate the severity of their worst itch during the past 24 hours on an 11-point scale ranging from "0 = no itch" to "10 = worst itch imaginable."

[0043] (2) Itch Score Subjects will rate the severity of the most severe itch caused by ARPC during the past 24 hours on a 5-point scale from "0 = none" to "4 = severe" according to Table 2.

[0044] (Table 2) Itch score

[0045] Skin findings evaluation The following items were measured: (1) Sum of edema / papule score and scratch score (2) Body Surface Area (hereinafter referred to as BSA)

[0046] (1) Sum of edema / papule score and excoriation score 1) Severity score For ARPC skin lesions in each region of the head, upper limbs, trunk, and lower limbs, the severity score of each skin finding (edema / papule, excoriation) will be evaluated according to Table 3.

[0047] (Table 3) Severity score

[0048] 2) Skin area score The skin area score will be evaluated according to Table 4 based on the proportion of ARPC skin lesions in each area of ​​the head, upper limbs, trunk, and lower limbs.

[0049] (Table 4) Skin area score

[0050] 3) Calculation of the sum of the edema / papule score and the scratch score The sum of the edema / papule score and the scratch score is calculated according to the following formula (see Non-Patent Document 1): Sum of the edema / papule score and the scratch score = Sum of severity scores of the head and neck × skin area score × 0.1 + Sum of severity scores of the trunk × skin area score × 0.3 + Sum of severity scores of the upper limbs × skin area score × 0.2 + Sum of severity scores of the lower limbs × skin area score × 0.4 Maximum 36 points

[0051] (2) Evaluate the percentage (%) of ARPC lesion area relative to the BSA body surface area (100%).

[0052] (3) Total Severity Classification Score The total severity classification score for ARPC is evaluated by summing up the PP-NRS, edema / papule score, and excoriation score (see Non-Patent Document 1).

[0053] Number of eruptions Count the number of eruptions.

[0054] Efficacy evaluation items <Itching> (1) PP-NRS <Skin rash> (2) Edema / papule score and scratch score (3) BSA (4) Number of skin lesions in the evaluation area (5) Number of skin lesions on the whole body <Disease severity> (6) Total severity classification score

[0055] The present invention provides a new means (prophylactic or therapeutic agent, medicament, or pharmaceutical composition) for preventing or treating perforating dermatosis (particularly acquired reactive perforating collagenosis), which comprises as an active ingredient an antibody against IL-31 receptor A. The present invention further provides a method for preventing or treating perforating dermatosis (particularly acquired reactive perforating collagenosis), which comprises administering an antibody against IL-31 receptor A to a subject in need thereof.

Claims

1. A preventive or therapeutic agent for perforating skin disease, which comprises an antibody against IL-31 receptor A as an active ingredient.

2. The preventive or therapeutic agent according to claim 1, wherein the perforating skin disease is acquired reactive perforating collagen fibrosis.

3. The preventive or therapeutic agent according to claim 1 or 2, wherein the antibody has neutralizing activity against IL-31 receptor A.

4. The preventive or therapeutic agent according to claim 1 or 2, wherein the antibody is: (1) an antibody comprising a heavy chain variable region comprising CDR1 having the amino acid sequence set forth in SEQ ID NO:1, CDR2 having the amino acid sequence set forth in SEQ ID NO:2, and CDR3 having the amino acid sequence set forth in SEQ ID NO:3, and a light chain variable region comprising CDR1 having the amino acid sequence set forth in SEQ ID NO:4, CDR2 having the amino acid sequence set forth in SEQ ID NO:5, and CDR3 having the amino acid sequence set forth in SEQ ID NO:6; (2) an antibody comprising a heavy chain variable region having the amino acid sequence set forth in SEQ ID NO:7 and a light chain variable region having the amino acid sequence set forth in SEQ ID NO:8; or (3) an antibody comprising a heavy chain having the amino acid sequence set forth in SEQ ID NO:9 and a light chain having the amino acid sequence set forth in SEQ ID NO:

10.

5. The preventive or therapeutic agent according to claim 2, wherein the perforating skin disease is acquired reactive perforating collagen fibrosis accompanied by moderate to severe pruritus.

6. The preventive or therapeutic agent according to claim 2, wherein the perforating skin disease is acquired reactive perforating collagen fibrosis with an itching score of 3 or more.

7. The preventive or therapeutic agent according to claim 2, wherein the perforating skin disease is acquired reactive perforating collagen fibrosis in which the sum of the edema / papule score and the excoriation score is 3.6 or more.

8. The preventive or therapeutic agent according to claim 2, wherein the perforating skin disease is acquired reactive perforating collagen fibrosis having moderate to severe pruritus, an itch score of 3 or more, and a sum of edema / papule score and excoriation score of 3.6 or more.

9. The preventive or therapeutic agent according to claim 2, wherein the perforating skin disease is acquired reactive perforating collagen fibrosis with 20 or more skin lesions.

10. The preventive or therapeutic agent according to claim 2, wherein the perforating skin disease is acquired reactive perforating collagen fibrosis having a BSA of 5 or more.

11. The preventive or therapeutic agent according to claim 2, wherein the perforating skin disease is acquired reactive perforating collagen fibrosis having a total severity classification score of 8.6 or more.

12. The preventive or therapeutic agent according to claim 1 or 2, wherein the perforating skin disease has a lesion of acquired reactive perforating collagen fibrosis in at least one site selected from the upper arm, forearm, back, abdomen, thigh, and lower leg.

13. The preventive or therapeutic agent according to claim 1 or 2, wherein the dose of the antibody against IL-31 receptor A per administration is 0.1 mg to 1000 mg / body.

14. The preventive or therapeutic agent according to claim 1 or 2, characterized in that the preventive or therapeutic agent is administered to a subject once a week, once every two weeks, once every three weeks, once every four weeks, once every five weeks, once every six weeks, once every seven weeks, or once every eight weeks.

15. The preventive or therapeutic agent according to claim 1 or 2, comprising 30 mg or 60 mg of the antibody against IL-31 receptor A.

16. The preventive or therapeutic agent according to claim 1 or 2, characterized in that the preventive or therapeutic agent is administered to a subject once every four weeks.

17. The preventive or therapeutic agent according to claim 1 or 2, wherein the antibody against IL-31 receptor A is administered to a subject at a dose of 60 mg / body once every 4 weeks.

18. The preventive or therapeutic agent according to claim 1 or 2, wherein the antibody against IL-31 receptor A is administered to a subject at a dose of 60 mg / body for the first administration, and at 30 mg / body per administration from the second administration onwards, every 4 weeks.

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