CN114423455A

CN114423455A - Pharmaceutical composition for the treatment of systemic sclerosis

Info

Publication number: CN114423455A
Application number: CN202080066358.8A
Authority: CN
Inventors: 吉崎步; 深泽毅伦; 佐藤伸一; 青野友纪子; 松户泰树; 吉川由利子
Original assignee: Kyowa Hakko Kirin Co Ltd; University of Tokyo NUC
Current assignee: University of Tokyo NUC; Kyowa Kirin Co Ltd
Priority date: 2019-09-25
Filing date: 2020-09-25
Publication date: 2022-04-29
Also published as: TW202126330A; TWI870471B; WO2021060425A1; JP7093940B2; KR20220070244A; JPWO2021060425A1

Abstract

To provide a new technology useful for the treatment of patients with systemic sclerosis with progressive skin sclerosis, to provide an IL-17 pathway inhibitor as an active ingredient for the treatment of systemic sclerosis with progressive skin sclerosis Symptomatic pharmaceutical composition. The IL-17 pathway inhibitor can be any one or more selected from IL-17RA antagonists and IL-23R antagonists, especially can be selected from bodalumab, secukinumab, ixekizumab , nitracizumab, bimegizumab, ustekinumab, tiralizumab, risalizumab, migelizumab, brekulizumab, and guselkizumab Any one or more of the antibodies or fragments thereof.

Description

Pharmaceutical composition for treating systemic sclerosis

Technical Field

The present invention relates to a pharmaceutical composition for treating systemic sclerosis, which contains an IL-17 pathway inhibitor as an active ingredient. The present invention relates to methods of treatment for systemic sclerosis using inhibitors of the IL-17 pathway.

Background

Systemic sclerosis is a disease characterized by the sclerosis of the skin or internal organs and which progresses chronically. Systemic sclerosis is classified into two types, namely "diffuse cutaneous sclerosis" (dcSSc) in which skin sclerosis affects not only the face but also the proximal extremities (upper arms, thighs) or the trunk, and "localized cutaneous sclerosis" (lcSSc) in which skin sclerosis is limited to the distal extremities (forearms, calves) and the face. In patients with diffuse cutaneous sclerosis type systemic sclerosis, the skin sclerosis progresses within 6 years of onset, and organ diseases such as lung, digestive tract, kidney and heart, and joint flexion contracture progress in accordance with the progress of the skin sclerosis. In addition, 70% of severe skin sclerosis is reported to occur within 3 years of onset.

Systemic sclerosis is a progressive disease which has an unknown pathogenesis, no established treatment method for skin sclerosis and long-term rehabilitation. Therefore, the main treatment is generally symptomatic therapy or use of a drug for inhibiting progression of a disease. In addition, since the lesion site (organ) varies depending on the degree of progression of the disease in each patient, the treatment method is also selected depending on the symptoms of each patient. Typical therapeutic methods for each organ include small amounts of oral adrenocorticosteriods (for cutaneous sclerosis), cyclophosphamide (for pulmonary fibrosis), proton pump inhibitors (for reflux esophagitis), prostacyclin derivatives (for vascular lesions), angiotensin converting enzyme inhibitors (for scleroderma renal crisis), endothelin receptor antagonists (for pulmonary hypertension), and the like. In general, pharmacological therapies using adrenocortical steroid agents and immunosuppressive agents are performed for skin sclerosis, but these pharmacological therapies are expected to establish a new treatment method because side effects due to long-term administration are concerned.

In systemic sclerosis, the possibility that Th17 cells and IL-17A produced by Th17 cells are associated with skin fibrosis and disease progression was suggested. The number of Th17 cells and the IL-17A concentration in blood of systemic sclerosis patients were higher than those of healthy adults, and significant correlation with skin sclerosis was confirmed (non-patent documents 1 to 4). Also, in the bleomycin-induced systemic sclerosis model in mice, correlation between increase in Th17 cell count and IL-17A concentration and inflammation and sclerosis of skin and lung was confirmed (non-patent documents 5 and 6). It is known that the expression levels of mRNA and protein of IL-17RA are increased in the skin of a lesion site of a systemic sclerosis patient. (non-patent document 7)

Cyberrubizumab is an IgG2 monoclonal antibody that binds to human IL-17RA and inhibits the biological activities of IL-17A, IL-17F, IL-17A/F heterodimer and IL-17E (IL-25) (non-patent documents 8 to 10). In Japan, it has been approved as a therapeutic agent for indications of psoriasis vulgaris, psoriatic arthritis, pustular psoriasis and erythrodermic psoriasis, which are not sufficiently effective in the existing therapies.

Documents of the prior art

Patent document

Patent document 1: international publication No. 2008/054603

Non-patent document

Non-patent document 1: arthritis Rheum, 2000, volume 43, p2455-2463

Non-patent document 2: eur Cytokine Netw, 2012, Vol 23, p128-139

Non-patent document 3: arthritis Res Ther, 2013, volume 15, R151

Non-patent document 4: arthritis Res Ther, 2014 16 th volume R4

Non-patent document 5: clin Exp Rheumatol, 2016, Vol.34, Suppl 100 p14-22

Non-patent document 6: arthritis Rheum, 2012, Vol.64, p3726-3735

Non-patent document 7: human Immunology, 2015, volume 76, p22-29

Non-patent document 8: immunity, 2008, volume 28, No. 4, p.454-467

Non-patent document 9: j Allergy Clin Immunol, 2007, Vol.120, No. 6, p.1324-1331

Non-patent document 10: j Immunol, 2005, volume 175, No. 1, p.404-412

Disclosure of Invention

Problems to be solved by the invention

The main object of the present invention is to provide a novel technique useful for treating systemic sclerosis which may be accompanied by progressive skin sclerosis.

Means for solving the problems

In order to solve the above problems, the present invention provides the following [1] to [45 ].

[1] A pharmaceutical composition for treating systemic sclerosis, which contains an IL-17 pathway inhibitor as an active ingredient.

[2] A pharmaceutical composition for treating systemic sclerosis accompanied by progressive skin sclerosis, which contains an IL-17 pathway inhibitor as an active ingredient.

[3] The pharmaceutical composition according to [1] or [2], wherein the IL-17 pathway inhibitor is any one or more selected from the group consisting of IL-17RA antagonists and IL-23R antagonists.

[4] The pharmaceutical composition according to any one of [1] to [3], wherein the IL-17 pathway inhibitor is an antibody or an antibody fragment.

[5] The pharmaceutical composition according to [4], wherein the antibody is an anti-IL-17 RA antibody, an anti-IL-17A/F antibody, an anti-IL-23 p40 subunit antibody and/or an anti-IL-23 p19 subunit antibody, and particularly any one or more selected from the group consisting of Cyberdea mab, Securium Uigumab, Equisiteumab, Nitrarizumab, Bimetrazuzumab, Ustuzumab, Tilatuzumab, Riseduzumab, Mimetuzumab, Blakekumab and Cusseuzumab.

[6] The pharmaceutical composition according to [5], wherein the antibody is Cyberdea praecox.

[7] The pharmaceutical composition according to any one of [1] to [6], wherein the systemic sclerosis is diffuse cutaneous sclerosis (dcSSc).

[8] The pharmaceutical composition according to [1] to [7], which is used for reducing the skin score (mRSS) of a patient by 3 or more within 12 weeks after the start of administration compared to before treatment.

[9] The pharmaceutical composition according to any one of [1] to [8], which is used for reducing the skin score (mRSS) of a patient by 5 or more within 24 weeks after the start of administration compared to before treatment.

[10] The pharmaceutical composition according to any one of [1] to [9], which is for reducing the skin score (mRSS) of a patient by 7 or more within 52 weeks after the start of administration than before treatment.

[11] The pharmaceutical composition according to any one of [1] to [10], which is used for a patient whose skin score before treatment (mRSS) is 20 or more and less than 30.

[12] The pharmaceutical composition according to any one of [1] to [11], wherein the IL-17 pathway inhibitor is administered in an amount of 70mg, 140mg, 210mg or 280mg for 1 administration.

[13] The pharmaceutical composition according to any one of [1] to [12], wherein the IL-17 pathway inhibitor is administered in an amount of 210mg 1 time, subcutaneously after 1 day, 1 week and 2 weeks, and thereafter subcutaneously 1 time every 2 weeks.

[14] The pharmaceutical composition according to any one of [1] to [13], which is for use in combination with a second therapeutic agent other than an IL-17 pathway inhibitor.

[15] The pharmaceutical composition according to [14], wherein the second therapeutic agent is at least one selected from the group consisting of an adrenocorticosteroid, an anti-fibrotic drug, an immunosuppressant, a proton pump inhibitor, a prostacyclin derivative, an angiotensin-converting enzyme inhibitor, an endothelin receptor antagonist and a cannabinoid type 2 receptor antagonist.

[16] A pharmaceutical composition for the treatment of systemic sclerosis comprising an IL-17 pathway inhibitor as an active ingredient, wherein said systemic sclerosis is diffuse cutaneous sclerosis (dcSSc), said IL-17 pathway inhibitor is cedarluumab in an amount of 210mg administered 1 time, and is subcutaneously administered 1 day, 1 week, 2 weeks later, and thereafter subcutaneously administered 1 time every 2 weeks.

[17] An IL-17 pathway inhibitor for use in the treatment of systemic sclerosis.

[18] An IL-17 pathway inhibitor for use in the treatment of systemic sclerosis with progressive skin sclerosis.

[19] The IL-17 pathway inhibitor according to [17] or [18], which is any one or more selected from IL-17RA antagonists and IL-23R antagonists.

[20] The IL-17 pathway inhibitor according to any one of [17] to [19], which is an antibody or an antibody fragment.

[21] The IL-17 pathway inhibitor according to [20], which is an anti-IL-17 RA antibody, an anti-IL-17A/F, an anti-IL-23 p40 subunit antibody and/or an anti-IL-23 p19 subunit antibody or a fragment thereof, particularly any one or more antibodies selected from the group consisting of Cyberdalus, Securium Ustuzumab, Eschlizumab, Netatuzumab, Bimetuzumab, Ussulizumab, Tilatuzumab, Riseduzumab, Migeuzumab, Blakekumab, and Cusiuzumab or a fragment thereof.

[22] The IL-17 pathway inhibitor according to [21], which is cedarlizumab.

[23] The IL-17 pathway inhibitor according to any one of [17] to [22], wherein the systemic sclerosis is diffuse cutaneous sclerosis (dcSSc).

[24] Use of an inhibitor of the IL-17 pathway in the manufacture of a pharmaceutical composition for the treatment of systemic sclerosis.

[25] Use of an inhibitor of the IL-17 pathway for the manufacture of a pharmaceutical composition for the treatment of systemic sclerosis with progressive skin sclerosis.

[26] The use according to [24] or [25], wherein the IL-17 pathway inhibitor is any one or more selected from IL-17RA antagonists and IL-23R antagonists.

[27] The use according to any one of [24] to [26], wherein the IL-17 pathway inhibitor is an antibody or an antibody fragment.

[28] The use according to [27], wherein the antibody is an anti-IL-17 RA antibody, an anti-IL-17A/F antibody, an anti-IL-23 p40 subunit antibody and/or an anti-IL-23 p19 subunit antibody, and particularly any one or more selected from the group consisting of Cyberdea mab, Securium Ustutzumab, Eschlizumab, Netsulizumab, Bimetuzumab, Ussulizumab, Tilatuzumab, Riseduzumab, Migeuzumab, Blakekuzumab, and Cucecurium Ustuzumab.

[29] The use according to [28], wherein the antibody is Cyberdea brauzumab.

[30] The use according to any one of [24] to [29], wherein the systemic sclerosis is diffuse cutaneous sclerosis (dcSSc).

[31] A method for treating systemic sclerosis, comprising the step of administering to a subject a pharmaceutical composition containing an IL-17 pathway inhibitor as an active ingredient.

[32] A method for treating systemic sclerosis associated with progressive skin sclerosis, comprising the step of administering to a subject a pharmaceutical composition containing an IL-17 pathway inhibitor as an active ingredient.

[33] The therapeutic method according to [31] or [32], wherein the IL-17 pathway inhibitor is one or more selected from the group consisting of IL-17RA antagonists and IL-23R antagonists.

[34] The therapeutic method according to any one of [31] to [33], wherein the IL-17 pathway inhibitor is an antibody or an antibody fragment.

[35] The therapeutic method according to [34], wherein the antibody is an anti-IL-17 RA antibody, an anti-IL-17A/F antibody, an anti-IL-23 p40 subunit antibody and/or an anti-IL-23 p19 subunit antibody or a fragment thereof, and particularly, is one or more selected from the group consisting of Cyberdea mab, Securiu Uzumab, Eschlizumab, Netatuzumab, Bimetuzumab, Ussulizumab, Tilatuzumab, Riseduzumab, Migeuzumab, Blakekumab, and Cusiuzumab.

[36] The therapeutic method according to [35], wherein the antibody is cedarlizumab.

[37] The therapeutic method according to any one of [31] to [36], wherein the systemic sclerosis is diffuse cutaneous sclerosis (dcSSc).

[38] The method of treatment according to [31] to [37], wherein the skin score (mRSS) of the subject is reduced by 3 or more from that before the treatment within 12 weeks after the start of the administration.

[39] The therapeutic method according to any one of [31] to [38], wherein the skin score (mRSS) of the subject is reduced by 5 or more within 24 weeks after the start of the administration, as compared with that before the treatment.

[40] The method of treatment according to any one of [31] to [39], wherein the skin score (mRSS) of the subject is reduced by 7 or more within 52 weeks after initiation of the administration, compared to that before the treatment.

[41] The therapeutic method according to any one of [31] to [40], wherein a skin score before treatment (mRSS) of the subject is 20 or more and less than 30.

[42] The therapeutic method according to any one of [31] to [41], wherein the IL-17 pathway inhibitor is administered in an amount of 70mg, 140mg, 210mg or 280mg for 1 time.

[43] The therapeutic method according to any one of [31] to [42], wherein the IL-17 pathway inhibitor is administered in an amount of 210mg 1 time, subcutaneously after 1 day, 1 week and 2 weeks, and thereafter subcutaneously 1 time every 2 weeks.

[44] The therapeutic method according to any one of [31] to [43], further comprising a step of administering a second therapeutic agent other than the IL-17 pathway inhibitor.

[45] The therapeutic method according to [44], wherein the second therapeutic agent is at least one selected from the group consisting of an adrenocorticosteroid, an anti-fibrotic drug, an immunosuppressant, a proton pump inhibitor, a prostacyclin derivative, an angiotensin-converting enzyme inhibitor, an endothelin receptor antagonist, and a cannabinoid type 2 receptor antagonist.

Effects of the invention

The present invention provides a novel technique effective for treating systemic sclerosis which may be accompanied by progressive skin sclerosis.

Drawings

FIG. 1 is a graph showing the change in skin score (mRSS: modified Rodnan total skin thickness score, modified Rodnan total skin thickness score) for each patient after treatment began. The vertical axis represents mRSS (0 is set at the start of treatment). The horizontal axis represents the period (week) from the first administration of cedarvolumab.

Fig. 2 is a graph showing the average value of the variation in mRSS of each patient after the start of treatment. The vertical axis represents mRSS (0 is set at the start of treatment). The horizontal axis represents the period (week) from the first administration of cedarvolumab.

Detailed Description

Preferred embodiments for carrying out the present invention will be described below. The embodiments described below are merely exemplary of representative embodiments of the present invention, and are not intended to narrow the scope of the present invention.

The present invention relates to a pharmaceutical composition for treating a patient with systemic sclerosis which may be accompanied by progressive skin sclerosis, comprising an inhibitor of the IL-17 pathway as an active ingredient.

In addition, the present invention also includes a method of treating a systemic sclerosis patient, the method comprising the step of administering an IL-17 pathway inhibitor to a systemic sclerosis patient who may be accompanied by progressive skin sclerosis.

Systemic sclerosis is a disease characterized by the sclerosis of the skin or internal organs and which progresses chronically. Systemic sclerosis is classified into two types, namely "diffuse cutaneous sclerosis" (dcSSc) in which skin sclerosis affects not only the face but also the proximal extremities (upper arms, thighs) or the trunk, and "localized cutaneous sclerosis" (lcSSc) in which skin sclerosis is limited to the distal extremities (forearms, calves) and the face.

The systemic sclerosis to be treated by the pharmaceutical composition or the therapeutic method of the present invention is not limited to any one of diffuse cutaneous sclerosis and limited cutaneous sclerosis, but is preferably diffuse cutaneous sclerosis.

The systemic sclerosis patient to be treated with the pharmaceutical composition or the treatment method of the present invention may be a patient accompanied by organ disorders of the lung, digestive tract, kidney or heart or symptoms of joint flexion contracture in addition to symptoms of skin sclerosis.

The severity of systemic sclerosis, which is the degree of skin sclerosis, can be evaluated by a known method. For example, the modified Rodnan total skin thickness score (mRSS) can be evaluated by the following method described in the japan skin science institute guidelines.

The body was divided into 17 sites (two fingers, two backs of hands, two forearms, two upper arms, a face, an anterior chest, an abdomen, two thighs, two calves, and two backs of feet), and the degree of hardening of the skin was evaluated in 4 stages of 0 to 3 (0 normal, 1 mild, 2 moderate, and 3 severe) for each site, yielding a skin score of 0 to 51 in total. For evaluation, the skin was held between the two thumbs and the thickness of the skin and the mobility of the underlying layers were observed. The case where the skin completely lacks the activity of the underlying layer was judged as 3, the case where the skin was not significantly hardened but felt slightly thick was judged as 1, and the interval between the two was judged as 2. The severity of skin sclerosis is classified in Japan into 0 (normal: 0), 1 to 9 (mild: 1), 10 to 19 (moderate: 2), 20 to 29 (severe: 3), and 30 or more (very severe: 4) based on the total mRSS (J.Dermatology Association, 126(10), 1831-. Assays for mRSS are described in J Rheumatol, 1993; 20(11) p 1892 + 1896 and J Rheumatotol, 1995; 22: p1281-1285 are also disclosed.

The severity of skin sclerosis to be treated with the pharmaceutical composition or the treatment method of the present invention is not particularly limited, and mRSS is preferably 10 or more, more preferably 20 or more, and most preferably 20 or more and less than 30. That is, the severity of the skin sclerosis is preferably moderate or more, more preferably severe or more, and most preferably moderate to severe.

The subject of the pharmaceutical composition or method of treatment of the invention may be a systemic sclerosis patient who has not been adequately treated by the current treatments.

The subject of the pharmaceutical composition or the method of treatment of the invention may be a systemic sclerosis patient with cutaneous sclerosis, who has insufficient efficacy in the existing treatments.

The subject of the pharmaceutical composition or method of treatment of the invention may be a systemic sclerosis patient with moderate to severe skin sclerosis.

The subject of the pharmaceutical composition or the treatment method of the present invention may be a systemic sclerosis patient with skin sclerosis at the initial stage of onset. The initial stage of onset is within 6 years of onset.

The subject of the pharmaceutical composition or the method of treatment of the present invention may be a systemic sclerosis patient with reversible skin sclerosis. Reversible skin sclerosis refers to a state in which the skin shows edema and sclerosis, and does not reach atrophy.

The improvement of the skin sclerosis can be confirmed by a known method. For example, the reduction in mRSS compared to that before treatment can be confirmed by measuring mRSS over time after administration of the pharmaceutical composition of the present invention, thereby confirming improvement in skin sclerosis.

The improvement of the symptoms of skin sclerosis means: after a specified period of time from administration of the pharmaceutical composition or initiation of the treatment method, the mRSS is reduced by more than 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 as compared to before the treatment. The mRSS can be decreased by 2 or more within 8 weeks from the administration of the pharmaceutical composition of the present invention or the start of the treatment method, by 3 or more within 12 weeks, by 3 or more within 16 weeks, by 4 or more within 20 weeks, by 5 or more within 24 weeks, by 6 or more within 40 weeks, and by 7 or more within 52 weeks.

The pharmaceutical composition and the treatment method of the present invention can improve or treat at least one symptom selected from organ lesions of the lung, digestive tract, kidney or heart or symptoms of joint flexion contracture, in addition to the symptoms of skin sclerosis. In addition, the pharmaceutical compositions and methods of treatment of the present invention may ameliorate or treat symptoms based on systemic or local fibrosis. The improvement of each symptom can be evaluated by a known method. For example, improvement in lung function based on pulmonary fibrosis can be assessed by scoring lung function using a spirometer. The improvement in the symptoms of reflux esophagitis of the digestive tract can be assessed by scoring the patient's symptoms using an F-score questionnaire.

As used herein, the term "administration" refers to one or more administrations (hereinafter also referred to as "continuous administration").

The amount of the IL-17 pathway inhibitor used in the present invention to be administered per one time is not particularly limited, and can be used in an amount that can be used clinically with reference to the specification of each inhibitor and the like. Specifically, when the IL-17 pathway inhibitor is cedarlizumab, the amount to be administered 1 time is preferably 70mg or more, more preferably 140mg or more, and most preferably 210 mg. In the continuous administration of the above-mentioned therapeutic agent, the amount to be administered may be increased or decreased as appropriate. The dosage for 1 administration is typically 70mg, 140mg, 210mg or 280 mg.

The interval between administration of the pharmaceutical composition is not particularly limited, and for example, administration is performed on day 1 (hereinafter also referred to as week 0), week 1 and week 2, and thereafter administration is performed 1 time every 2 weeks or 1 time every 4 weeks. The administration interval may be appropriately lengthened or shortened. With respect to the administration interval, it is preferably set to administer the drug on day 1,

week

2 and 1 dose every 2 weeks thereafter.

The dose and dosing interval are particularly preferably: the dose of 1 administration was 210mg, and 1 administration was performed every 1 day, 1 week, 2 weeks, and every 2 weeks thereafter.

The period of administration of the pharmaceutical composition is not particularly limited, and may be 8, 10, 12, 16, 20, 24, 36, 48 or 52 weeks after the start of administration, or may be longer than 52 weeks. The administration period is preferably longer than 52 weeks. The administration period may include a withdrawal period.

The IL-17 pathway inhibitor of the present invention broadly comprises a substance which inhibits the interaction between IL-17RA and IL-17RA ligands (IL-17A, IL-17F, IL-17A/F, IL-17E, etc.) and blocks a physiologically active signal. Hereinafter, a substance that inhibits the interaction between IL-17RA and an IL-17RA ligand and blocks a physiologically active signal is referred to as an "IL-17 RA antagonist".

IL-23 is known to induce IL-17RA ligand-producing Th17 cells, upstream of the IL-17 pathway (Nature Reviews Drug Discovery 2015, volume14, p 11-12). Therefore, the IL-17 pathway inhibitor of the present invention also includes a substance that inhibits the interaction between IL-23 and IL-23R and blocks a physiologically active signal. Hereinafter, a substance that inhibits the interaction between IL-23 and IL-23R and blocks a physiologically active signal will be referred to as an "IL-23R antagonist".

The IL-17RA antagonist may be, for example, an antagonist having an activity of inhibiting the binding of IL-17RA to an IL-17RA ligand, an antagonist having an activity of inhibiting the activation of IL-17RA induced by the binding of an IL-17RA ligand, or an antagonist having an activity of inhibiting the association between IL-17RA and a heterodimer-forming receptor.

The IL-23R antagonist may be, for example, an antagonist having an activity of inhibiting the binding of IL-23R to IL-23, an antagonist having an activity of inhibiting the association of p19 with p40 which is a subunit of IL-23.

The IL-17RA antagonist and IL-23R antagonist may be, for example, a low molecule, an antibody or a fragment thereof, siRNA, or an antisense oligonucleotide. The IL-17RA antagonist and the IL-23R antagonist are preferably antibodies or antibody fragments.

Specific examples of the antibody against the IL-17RA antagonist include an anti-IL-17 RA antibody, an anti-IL-17A antibody, an anti-IL-17F antibody, an anti-IL-17A/F antibody, an anti-IL-17E antibody, and fragments thereof.

Specific examples of the low-molecular weight IL-17RA antagonist include dihydroorotate dehydrogenase inhibitors. Examples of the dihydroorotate dehydrogenase inhibitor include vidofludimus (vidofludimus).

Specific examples of the antibody against the IL-23R antagonist include an anti-IL-23 p40 subunit antibody and an anti-IL-23 p19 subunit antibody.

Specific examples of anti-IL-23 p40 subunit antibodies include ubsumizumab. Specific examples of anti-IL-23 p19 subunit antibodies include tirab, Risedab, Mijilizab, Blakezumab, and Gusaiqiuzumab.

The IL-17 pathway inhibitor is preferably an IL-17RA antagonist and an IL-23R antagonist, more preferably an IL-17RA antagonist. The IL-17RA antagonist is preferably Cyinduzumab as an anti-IL-17 RA antibody, nitatuzumab, Securiuzumab or Evzelizumab as an anti-IL-17A antibody, bimagruzumab as an anti-IL-17A/F antibody, and most preferably Cyinduzumab.

The pharmaceutical compositions or methods of treatment of the present invention may be used in combination with a second therapeutic agent or a second method of treatment.

The second therapeutic agent is, for example, an adrenocorticosteroid, an anti-fibrotic drug, an immunosuppressant, a proton pump inhibitor, an angiotensin converting enzyme inhibitor, an endothelin receptor antagonist, a prostacyclin derivative, or a cannabinoid type 2 receptor antagonist.

As the adrenal corticosteroid, prednisolone, for example, can be cited.

Examples of the anti-fibrosis drug include pirfenidone and nintedanib.

As the immunosuppressive agent, for example, cyclophosphamide, mycophenolate mofetil, cyclosporine, tacrolimus, azathioprine, mizoribine, and methotrexate may be cited.

As proton pump inhibitors, omeprazole, lansoprazole, rabeprazole and esomeprazole, for example, may be cited.

Examples of angiotensin converting enzyme inhibitors include captopril, enalapril, alacepril, imidapril and temocapril.

Examples of endothelin receptor antagonists include bosentan, ambrisentan and macitentan.

Examples of the prostacyclin derivative include iloprost, beraprost, treprostinil, epoprostenol, and clinoprost.

As the type 2 cannabinoid receptor antagonist, Lenabasum, for example, can be cited.

As the second treatment method, for example, a large dose immunoglobulin intravenous drip therapy (IVIG) or phototherapy may be cited.

In the pharmaceutical composition or the method of treatment of the present invention, two or more IL-17 pathway inhibitors may be used in combination.

Where an IL-17 pathway inhibitor and a second therapeutic agent are used in the pharmaceutical compositions and methods of treatment of the present invention, they may be administered to the patient at the same time or at different times. Accordingly, the pharmaceutical compositions or methods of treatment of the present invention also include means for use in combination with a second therapeutic agent.

The antibody used in the present invention may be either a monoclonal antibody or a polyclonal antibody, and is preferably a monoclonal antibody that binds to a single epitope.

The antibody may be a monoclonal antibody produced by a hybridoma, or may be a recombinant antibody produced by a genetic recombination technique. Examples of the recombinant antibodies include mouse antibodies, rat antibodies, human chimeric antibodies (hereinafter simply referred to as "chimeric antibodies"), humanized antibodies (also referred to as human Complementarity Determining Region (CDR) grafted antibodies), and human antibodies. In order to reduce immunogenicity in humans, chimeric, humanized or human antibodies are preferably used.

Specifically, the monoclonal antibody used in the present invention includes antibodies selected from the following (a) to (F) and fragments thereof.

(A) A monoclonal antibody in which CDR1, CDR2 and CDR3 of the heavy chain variable region (denoted as VH) of the antibody have amino acid sequences represented by

sequence numbers

1, 2 and 3, respectively, and CDR1, CDR2 and CDR3 of the light chain variable region (denoted as VL) of the antibody have amino acid sequences represented by

sequence numbers

4, 5 and 6, respectively;

(B) a monoclonal antibody wherein the VH of the antibody has an amino acid sequence represented by SEQ ID No. 7 and the VL of the antibody has an amino acid sequence represented by SEQ ID No. 8;

(C) a monoclonal antibody in which the heavy chain (H chain) of the antibody contains the amino acid sequence shown in SEQ ID NO. 9 and the L chain of the antibody contains the amino acid sequence shown in SEQ ID NO. 10;

(D) an antibody that competes for binding to IL-17RA with any one of the antibodies selected from the group consisting of (A) to (C) above;

(E) an antibody that binds to an epitope present in IL-17RA to which any one of the antibodies (A) to (C) above binds; and

(F) an antibody having a sequence identity of 90% or more with an amino acid sequence of any one of the antibodies selected from the group consisting of (A) to (C) above, and having binding specificity and binding activity equivalent to those of the antibody.

In the present invention, one embodiment of a monoclonal antibody in which CDR1, CDR2, and CDR3 of VH of the antibody respectively have amino acid sequences represented by

sequence numbers

1, 2, and 3 and CDR1, CDR2, and CDR3 of VL of the antibody respectively have amino acid sequences represented by

sequence numbers

4, 5, and 6, or a monoclonal antibody in which VH of the antibody has an amino acid sequence represented by sequence number 7 and VL of the antibody has an amino acid sequence represented by sequence number 8 is an anti-human IL-17RA human monoclonal antibody AM _H14/AM_L14 (patent document 1) and a genetically recombinant human IL-17RA human antibody, bdavamab.

In the present invention, a "monoclonal antibody" is an antibody secreted from a monoclonal antibody-producing cell, and refers to an antibody that recognizes only one epitope (antigenic determinant) and has a uniform amino acid sequence (primary structure) constituting the monoclonal antibody.

"epitope" means: a single amino acid sequence recognized by a monoclonal antibody for binding; (ii) a steric structure consisting of an amino acid sequence; an amino acid sequence to which a modified residue such as a sugar chain, glycolipid, lipopolysaccharide, amino group, carboxyl group, phosphoric acid, or sulfuric acid is bonded; and a steric structure comprising an amino acid sequence to which the modified residue is bonded. The "steric structure" is a steric structure possessed by a naturally occurring protein, and refers to a steric structure composed of a protein expressed in a cell or a cell membrane.

In the present invention, an antibody molecule is also referred to as an immunoglobulin (hereinafter referred to as Ig). Human antibodies are classified into isotypes of IgA1, IgA2, IgD, IgE, IgG1, IgG2, IgG3, IgG4, and IgM according to the difference between molecular structures. IgG1, IgG2, IgG3, and IgG4, which have high amino acid sequence homology, are also collectively referred to as IgG.

The antibody used in the present invention is preferably an IgG class, and more preferably an IgG class selected from the group consisting of IgG1, IgG2, IgG4, and Fc variants of an antibody of the isotype in which 1 or 2 or more amino acid residue substitutions are added to the Fc region.

In the present invention, an antibody molecule is composed of polypeptides called a heavy chain (H chain) and a light chain (L chain).

Further, the H chain is composed of VH and an H chain constant region (also referred to as CH) from the N-terminal side, and the L chain is composed of VL and an L chain constant region (also referred to as CL) from the N-terminal side.

"chimeric antibody" refers to an antibody composed of VH and VL of an antibody derived from an animal other than a human, and CH and CL of a human antibody. The type of animal from which the variable region is derived is not particularly limited as long as it is an animal that can be used for hybridoma production such as mouse, rat, hamster, and rabbit.

A "humanized antibody" is an antibody obtained by grafting CDRs derived from VH and VL of a non-human animal antibody to the proper positions of VH and VL of a human antibody (human CDR-grafted antibody).

"human antibody" refers to an antibody that can naturally occur in a human body or an antibody consisting of an amino acid sequence encoded by a human gene. Human antibodies also include: antibodies derived from transgenic animals are produced from human antibody phage libraries or human antibodies produced by genetic engineering, cell engineering, and developmental engineering methods.

In the present invention, the type of the antibody fragment is not particularly limited, and examples thereof include Fab, Fab ', and F (ab')₂scFv, diabody, dsFv, CDR-containing peptideAnd the like.

The pharmaceutical composition of the present invention may be a pharmaceutical composition containing only an IL-17 pathway inhibitor as an active ingredient, but is generally preferably provided in the form of a pharmaceutical preparation which is mixed with one or more pharmacologically acceptable carriers and manufactured by any method well known in the art of pharmaceutical formulation technology. Specific examples of the pharmaceutical preparation include: and a pharmaceutical preparation or the like which comprises a 140mg/mL genetically modified anti-human IL-17RA human antibody, e.g., cedarlizumab, as an active ingredient and which is prepared using 10mmol/L of L-glutamic acid, 3% (w/v) of L-proline, and 0.010% (w/v) of polysorbate 20 as additives. In addition, the pharmaceutical formulation further comprises: a pharmaceutical formulation of ph4.8 containing 140mg/mL of the genetically recombinant anti-human IL-17RA human antibody bdavamab and further containing 30 mmol/L-glutamic acid, 2.4% (w/v) L-proline and 0.01% (w/v) polysorbate 20 as additives. The pharmaceutical preparation can be produced, for example, by the method described in International publication No. 2011/088120.

The route of administration of the IL-17 pathway inhibitor in the pharmaceutical composition or the method of treatment of the present invention is preferably set as the most effective route at the time of treatment. Specific examples of the administration route include oral administration, or non-oral administration such as oral administration, intratracheal administration, intrarectal administration, subcutaneous administration, intramuscular administration, or intravenous administration, and subcutaneous administration is preferable, and subcutaneous administration is more preferable. Examples of administration forms include sprays, capsules, tablets, powders, granules, syrups, emulsions, suppositories, injections, ointments, patches and the like, and injections are preferred.

The administration device of the therapeutic agent of the present invention may be appropriately selected during the treatment. As the administration device, a pre-filled syringe and an automatic syringe may be exemplified, but not limited to these.

Examples

[ test example 1: phase I clinical trial of the recombinant anti-human IL-17RA human antibody, Cyberaprozumab, on patients with systemic sclerosis

(1) Test summary

Table 1 shows a summary of phase I clinical trials (hereinafter, also simply referred to as "clinical trials") of a recombinant anti-human IL-17RA human antibody, bdavamab, on systemic sclerosis patients with moderate to severe skin sclerosis. As subjects to be tested in the clinical trial, systemic sclerosis patients satisfying the conditions shown in table 2 were selected, and the safety, efficacy, and the like of administration of cedarlizumab were evaluated. For each subject, 210mg of bdavamab was administered subcutaneously 1 time on day 1, week 1 and week 2, and every 2 weeks thereafter, 1 time subcutaneously, up to week 50.

Cedarvolumab is produced as a CHO cell-derived recombinant human antibody having an amino acid sequence of an antibody variable region described in patent document 1 by a conventional method.

[ Table 1]

[ Table 2]

(2) Test results

For subjects who participated in the treatment, a skin score (mRSS) indicating the degree of skin hardening was determined over time from the first administration of cedarlizumab. The obtained results are shown in fig. 1 and 2. mRSS is a method of evaluating the degree of skin hardening (0 is normal, 1 is mild, 2 is moderate, 3 is severe, and the total is 0 to 51) in 4 stages of 0 to 3 for each part by a doctor pinching 17 skin with two thumbs. The skin severity based on mRSS is classified into 0 normal, 1 to 9 mild, 10 to 19 moderate, 20 to 29 severe, and more than 30 very severe in total.

The information of the subjects who participated in the treatment is shown in table 3. As shown in the table, 8 patients with systemic sclerosis with moderate to severe skin sclerosis showed severe (mRSS 20-29) skin sclerosis in 7 patients.

[ Table 3]

As shown in fig. 1, in 8 cases of systemic sclerosis patients with moderate to severe skin sclerosis, the mRSS at 12 weeks after the start of administration was reduced by 3 or more from the baseline (mRSS at the start of treatment). Similarly, the mRSS decreased by 5 or more from the baseline at 24 weeks after the start of administration, and the mRSS decreased by 7 or more from the baseline at 52 weeks after the start of administration. It was shown that systemic sclerosis patients with moderate to severe skin sclerosis received a significant reduction in skin score at an early stage of 12 weeks, 24 weeks or 52 weeks after the start of treatment by treatment with cedaruzumab.

In the treatment with adrenocorticosteriods (dexamethasone intravenous pulse therapy) which has been applied to the cutaneous sclerosis of systemic sclerosis, it has been reported that a period of 6 months is required to reduce the mRSS by 4.5 (mean) from baseline (rhcumotol lnt,1994,14, 91-94). Further, it has been reported that in the conventional treatment using cyclophosphamide as an immunosuppressant, the decrease in mRSS from baseline 12 months after the start of the treatment was stopped at 3.6(N Engl J Med,2006,354,2655-66), and in the conventional treatment using azathioprine, which is also an immunosuppressant, improvement in skin sclerosis was not observed even 18 months after the start of the treatment (Cin rhcumat, 2006,25, 205-.

On the other hand, in the treatment with cedaruzumab, all systemic sclerosis patients with moderate to severe skin sclerosis were able to achieve a significant reduction in mRSS 12 weeks, 24 weeks, or 52 weeks after the start of the treatment, including 7 patients with severe skin sclerosis. The results indicate that the cedarlizumab is suitable for systemic sclerosis with moderate-to-severe skin sclerosis, and can exert a therapeutic effect at an extremely early stage compared with the existing medicament.

Sequence Listing free text

Sequence number 1: amino acid sequence of Cydamuzumab HCDR1

Sequence number 2: amino acid sequence of Cydamuzumab HCDR2

Sequence number 3: amino acid sequence of Cydamuzumab HCDR3

Sequence number 4: amino acid sequence of Cyberrubiumab LCDR1

Sequence number 5: amino acid sequence of Cyberrubiumab LCDR2

Sequence number 6: amino acid sequence of Cyberrubiumab LCDR3

Sequence number 7: amino acid sequence of Cyberdea mab-VH

Sequence number 8: amino acid sequence of Cyberrubiumab VL

Sequence number 9: amino acid sequence of Cyberabuzumab-H chain

Sequence number 10: amino acid sequence of Cyberabuzumab-L chain

Sequence listing

<110> national University of court Tokyo University (The University of Tokyo)

Kyowa Kirin Co., Ltd.)

<120> PHARMACEUTICAL composition FOR treating systemic SCLEROSIS (PHARMACEUTICAL COMPACTION FOR TREATING SYSTEMIC SCLEOSIS)

<130> PK53-9012WO

<150> JP2019-174734

<151> 2019-09-25

<160> 10

<170> PatentIn version 3.5

<210> 1

<211> 5

<212> PRT

<213> Artificial sequence

<220>

<223> amino acid sequence of HCDR1 of Cydamuzumab

<400> 1

Arg Tyr Gly Ile Ser

1 5

<210> 2

<211> 16

<212> PRT

<213> Artificial sequence

<220>

<223> amino acid sequence of HCDR2 of Cydamuzumab

<400> 2

Trp Ile Ser Thr Tyr Ser Gly Asn Thr Asn Tyr Ala Gln Lys Leu Gln

1 5 10 15

<210> 3

<211> 7

<212> PRT

<213> Artificial sequence

<220>

<223> amino acid sequence of HCDR3 of Cydamuzumab

<400> 3

Arg Gln Leu Tyr Phe Asp Tyr

1 5

<210> 4

<211> 11

<212> PRT

<213> Artificial sequence

<220>

<223> LCDR1 amino acid sequence of Cyberdaluzumab

<400> 4

Arg Ala Ser Gln Ser Val Ser Ser Asn Leu Ala

1 5 10

<210> 5

<211> 7

<212> PRT

<213> Artificial sequence

<220>

<223> LCDR2 amino acid sequence of Cyberdaluzumab

<400> 5

Asp Ala Ser Thr Arg Ala Thr

1 5

<210> 6

<211> 9

<212> PRT

<213> Artificial sequence

<220>

<223> LCDR3 amino acid sequence of Cyberdaluzumab

<400> 6

Gln Gln Tyr Asp Asn Trp Pro Leu Thr

1 5

<210> 7

<211> 116

<212> PRT

<213> Artificial sequence

<220>

<223> amino acid sequence of VH of Cyberdaluzumab

<400> 7

Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala

1 5 10 15

Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Arg Tyr

20 25 30

Gly Ile Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met

35 40 45

Gly Trp Ile Ser Thr Tyr Ser Gly Asn Thr Asn Tyr Ala Gln Lys Leu

50 55 60

Gln Gly Arg Val Thr Met Thr Thr Asp Thr Ser Thr Ser Thr Ala Tyr

65 70 75 80

Met Glu Leu Arg Ser Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Arg Arg Gln Leu Tyr Phe Asp Tyr Trp Gly Gln Gly Thr Leu Val

100 105 110

Thr Val Ser Ser

115

<210> 8

<211> 107

<212> PRT

<213> Artificial sequence

<220>

<223> amino acid sequence of VL of cedarlaruzumab

<400> 8

Glu Ile Val Met Thr Gln Ser Pro Ala Thr Leu Ser Val Ser Pro Gly

1 5 10 15

Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Ser Asn

20 25 30

Leu Ala Trp Phe Gln Gln Lys Pro Gly Gln Ala Pro Arg Pro Leu Ile

35 40 45

Tyr Asp Ala Ser Thr Arg Ala Thr Gly Val Pro Ala Arg Phe Ser Gly

50 55 60

Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Ser

65 70 75 80

Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Asp Asn Trp Pro Leu

85 90 95

Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys

100 105

<210> 9

<211> 442

<212> PRT

<213> Artificial sequence

<220>

<223> amino acid sequence of H chain of Cyberdaluzumab

<400> 9

Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala

1 5 10 15

Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Arg Tyr

20 25 30

Gly Ile Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met

35 40 45

Gly Trp Ile Ser Thr Tyr Ser Gly Asn Thr Asn Tyr Ala Gln Lys Leu

50 55 60

Gln Gly Arg Val Thr Met Thr Thr Asp Thr Ser Thr Ser Thr Ala Tyr

65 70 75 80

Met Glu Leu Arg Ser Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Arg Arg Gln Leu Tyr Phe Asp Tyr Trp Gly Gln Gly Thr Leu Val

100 105 110

Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala

115 120 125

Pro Cys Ser Arg Ser Thr Ser Glu Ser Thr Ala Ala Leu Gly Cys Leu

130 135 140

Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly

145 150 155 160

Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser

165 170 175

Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Asn Phe

180 185 190

Gly Thr Gln Thr Tyr Thr Cys Asn Val Asp His Lys Pro Ser Asn Thr

195 200 205

Lys Val Asp Lys Thr Val Glu Arg Lys Cys Cys Val Glu Cys Pro Pro

210 215 220

Cys Pro Ala Pro Pro Val Ala Gly Pro Ser Val Phe Leu Phe Pro Pro

225 230 235 240

Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys

245 250 255

Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Gln Phe Asn Trp

260 265 270

Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu

275 280 285

Glu Gln Phe Asn Ser Thr Phe Arg Val Val Ser Val Leu Thr Val Val

290 295 300

His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn

305 310 315 320

Lys Gly Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Thr Lys Gly

325 330 335

Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu

340 345 350

Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr

355 360 365

Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn

370 375 380

Asn Tyr Lys Thr Thr Pro Pro Met Leu Asp Ser Asp Gly Ser Phe Phe

385 390 395 400

Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn

405 410 415

Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr

420 425 430

Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys

435 440

<210> 10

<211> 214

<212> PRT

<213> Artificial sequence

<220>

<223> amino acid sequence of L chain of Cyberdaluzumab

<400> 10

Glu Ile Val Met Thr Gln Ser Pro Ala Thr Leu Ser Val Ser Pro Gly

1 5 10 15

Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Ser Asn

20 25 30

Leu Ala Trp Phe Gln Gln Lys Pro Gly Gln Ala Pro Arg Pro Leu Ile

35 40 45

Tyr Asp Ala Ser Thr Arg Ala Thr Gly Val Pro Ala Arg Phe Ser Gly

50 55 60

Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Ser

65 70 75 80

Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Asp Asn Trp Pro Leu

85 90 95

Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys Arg Thr Val Ala Ala

100 105 110

Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly

115 120 125

Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala

130 135 140

Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln

145 150 155 160

Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser

165 170 175

Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr

180 185 190

Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser

195 200 205

Phe Asn Arg Gly Glu Cys

210

Claims

What is claimed is: 1. A pharmaceutical composition for treating systemic sclerosis, comprising an IL-17 pathway inhibitor as an active ingredient.

2 . The pharmaceutical composition according to claim 1 , wherein the IL-17 pathway inhibitor is any one or more selected from the group consisting of IL-17RA antagonists and IL-23R antagonists. 3 .

3. The pharmaceutical composition according to claim 1 or 2, wherein the IL-17 pathway inhibitor is an antibody or an antibody fragment.

4. The pharmaceutical composition according to claim 3, wherein the antibody is selected from the group consisting of bodalumab, secukizumab, ixekizumab, nitracizumab, and bimegizumab Any one or more of the group consisting of , ustekinumab, tiralizumab, resalizumab, migelizumab, brekulizumab, and guselkumab.

5. The pharmaceutical composition of claim 4, wherein the antibody is bodalumab.

The pharmaceutical composition according to any one of claims 1 to 5, wherein the systemic sclerosis is diffuse cutaneous sclerosing systemic sclerosis (dcSSc).

7. The pharmaceutical composition according to any one of claims 1 to 6, which is used to reduce a patient's skin score (mRSS) by 3 or more within 12 weeks after the start of administration compared to before treatment.

8. The pharmaceutical composition according to any one of claims 1 to 7, which is used to reduce a patient's skin score (mRSS) by 5 or more within 24 weeks after the start of administration compared to before treatment.

9. The pharmaceutical composition according to any one of claims 1 to 8, which is used to reduce a patient's skin score (mRSS) by 7 or more within 52 weeks after the start of administration compared to before treatment.

10. The pharmaceutical composition according to any one of claims 1 to 9, which is used for a patient whose skin score (mRSS) before treatment is 20 or more and less than 30.

The pharmaceutical composition according to any one of claims 1 to 10, wherein the dosage of the IL-17 pathway inhibitor for one administration is 70 mg, 140 mg, 210 mg or 280 mg.

12. The pharmaceutical composition according to any one of claims 1 to 11, wherein the dose of the IL-17 pathway inhibitor is 210 mg once administered on the first day, after 1 week, and after 2 weeks Subcutaneous administration was performed, followed by subcutaneous administration every 2 weeks.

13. The pharmaceutical composition according to any one of claims 1 to 12, for use in combination with a second therapeutic agent other than an IL-17 pathway inhibitor.

14. The pharmaceutical composition according to claim 13, wherein the second therapeutic agent is selected from the group consisting of adrenal corticosteroids, anti-fibrotic drugs, immunosuppressants, proton pump inhibitors, prostacyclin derivatives, angiotensin At least one or more selected from the group consisting of a cannabinoid converting enzyme inhibitor, an endothelin receptor antagonist, and a type 2 cannabinoid receptor antagonist.