WO2019156137A1 - 乾癬の治療薬 - Google Patents

乾癬の治療薬 Download PDF

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Publication number
WO2019156137A1
WO2019156137A1 PCT/JP2019/004330 JP2019004330W WO2019156137A1 WO 2019156137 A1 WO2019156137 A1 WO 2019156137A1 JP 2019004330 W JP2019004330 W JP 2019004330W WO 2019156137 A1 WO2019156137 A1 WO 2019156137A1
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WO
WIPO (PCT)
Prior art keywords
psoriasis
peptide
amino acid
acid sequence
day
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/JP2019/004330
Other languages
English (en)
French (fr)
Japanese (ja)
Inventor
克人 玉井
敬史 新保
尊彦 山崎
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
StemRIM Inc
University of Osaka NUC
Original Assignee
Osaka University NUC
StemRIM Inc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Osaka University NUC, StemRIM Inc filed Critical Osaka University NUC
Priority to EP19751078.7A priority Critical patent/EP3750553A4/en
Priority to US16/967,919 priority patent/US20210024594A1/en
Priority to JP2019570787A priority patent/JP7386455B2/ja
Publication of WO2019156137A1 publication Critical patent/WO2019156137A1/ja
Anticipated expiration legal-status Critical
Priority to US17/817,084 priority patent/US12428458B2/en
Ceased legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • C07K14/46—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates
    • C07K14/47—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates from mammals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/19—Cytokines; Lymphokines; Interferons
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/06—Antipsoriatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides

Definitions

  • the present application relates to a pharmaceutical composition for preventing and / or treating psoriasis, comprising a fragment peptide of the High mobility group box 1 (HMGB1) protein.
  • HMGB1 High mobility group box 1
  • Psoriasis is a chronic skin disease characterized by skin inflammation and abnormal proliferation of keratinocytes.
  • the cause of psoriasis has not yet been fully elucidated, but it is thought to develop when various external factors (infection, stress, drugs, etc.) are added to genetic factors. In recent years, it has been shown that abnormal immune functions are involved.
  • Treatment of psoriasis includes corticosteroids, vitamin D3 derivatives, immunosuppressants (such as cyclosporine), vitamin A derivatives (retinoids), biological products (eg anti-TNF- ⁇ antibody, anti-IL-17A antibody, anti-IL- 17 receptor A antibody) and the like are used, but there are cases where sufficient effects cannot be obtained.
  • immunosuppressants such as cyclosporine
  • vitamin A derivatives retinoids
  • biological products eg anti-TNF- ⁇ antibody, anti-IL-17A antibody, anti-IL- 17 receptor A antibody
  • This application aims to provide a novel pharmaceutical effective for the treatment of psoriasis.
  • an HMGB1 fragment peptide having a specific amino acid sequence suppresses erythema, scale (desquamation) and thickening (infiltration) of skin in an animal model of psoriasis. It has been found to show an effect. Therefore, the present application provides a pharmaceutical composition for the prevention and / or treatment of psoriasis containing the specific HMGB1 fragment peptide.
  • a pharmaceutical composition for the prevention and / or treatment of psoriasis comprising the substance according to any one of the following (a) to (c) (hereinafter referred to as substance A): (A) an HMGB1 fragment peptide comprising the amino acid sequence set forth in SEQ ID NO: 1; (B) a peptide comprising an amino acid sequence in which one or a plurality of amino acids are substituted, deleted, inserted or added in the amino acid sequence described in SEQ ID NO: 1; and (c) the amino acid sequence described in SEQ ID NO: 1.
  • a method for preventing and / or treating psoriasis comprising the step of administering to a subject an effective amount of substance A.
  • [A3] A method for suppressing skin symptoms selected from the group consisting of erythema, thickening, and scales or desquamation, comprising administering an effective amount of substance A to a patient with psoriasis.
  • Substance A for use in the prevention and / or treatment of psoriasis.
  • [C1] Use of substance A in the manufacture of a medicament for the prevention and / or treatment of psoriasis.
  • [C2] The use according to [C1], wherein the psoriasis is psoriasis vulgaris.
  • [C3] Use of substance A in the manufacture of a medicament for suppressing erythema, thickening, and skin symptoms selected from the group consisting of scales or desquamation in patients with psoriasis.
  • the PASI score on the 5th day after starting imiquimod (Day 5) was significantly different between the control group (see “IMQ / saline”) and the HMGB1 peptide (1-44) administration group (see “IMQ / 1-44”) was observed (* p ⁇ 0.05).
  • the skin thickness measurement value was not obtained due to a problem with the measuring instrument, so the PASI score was a missing value. It is a graph which shows the score transition of the erythema, scales, and thickening after the application
  • the skin thickness measurement value could not be obtained due to the trouble of the measuring equipment, so the thickening score is a missing value.
  • the present application provides a pharmaceutical composition for the prevention and / or treatment of psoriasis, comprising an HMGB1 fragment peptide comprising the amino acid sequence set forth in SEQ ID NO: 1.
  • psoriasis in the present application examples include, but are not limited to, psoriasis vulgaris, psoriatic arthritis (psoriatic arthritis), droplet psoriasis, psoriatic erythroderma, and generalized pustular psoriasis.
  • the psoriasis of the present application is psoriasis vulgaris.
  • the main symptoms of psoriasis vulgaris are “erythema” that makes the skin red, “thickening (also called infiltration)” that makes the skin swell, “scales” in which excessively grown keratin is piled up in scabs, and scales are peeled off “Desquamation” that falls.
  • pharmaceutical composition is used interchangeably with “medicine”, “drug” or “pharmaceutical composition”.
  • the pharmaceutical composition of the present application is used to suppress skin symptoms selected from the group consisting of erythema, thickening (infiltration), and scales or desquamation in patients with psoriasis.
  • the pharmaceutical composition of the present application can be used to suppress these skin symptoms in patients with psoriasis vulgaris.
  • the HMGB1 fragment peptide containing the amino acid sequence shown in SEQ ID NO: 1 means a peptide comprising a part of the HMGB1 protein and containing the amino acid sequence shown in SEQ ID NO: 1.
  • Such a peptide can be obtained as a recombinant by incorporating DNA encoding the peptide into an appropriate expression system, or can be artificially synthesized.
  • examples of the HMGB1 protein include, but are not limited to, a protein containing the amino acid sequence shown in SEQ ID NO: 2 and a protein encoded by DNA containing the base sequence shown in SEQ ID NO: 3. It is not a thing.
  • one or more amino acid residues in the amino acid sequence described in SEQ ID NO: 1 are modified in place of or together with the HMGB1 fragment peptide containing the amino acid sequence described in SEQ ID NO: 1 (
  • Examples of such peptides include the peptides described as i) to iv) below, and the peptides described as i) to iv) below and having a prophylactic and / or therapeutic effect on psoriasis.
  • Exemplify but are not limited to: i) One or more (for example, 1 to 10, 1 to 9, 1 to 8, 1 to 7, 1 to 6, 1 in the amino acid sequence shown in SEQ ID NO: 1 A peptide comprising an amino acid sequence in which 5 to 1, 1 to 4, 1 to 3, or 1 or 2 amino acids are substituted, deleted, inserted or added; ii) One or more (for example, 1 to 10, 1 to 9, 1 to 8, 1 to 7, 1 to 6, or 1 in the amino acid sequence shown in SEQ ID NO: 1.
  • a peptide or the like An effective amount of the peptide of the present application and a pharmaceutical composition containing the peptide (hereinafter referred to as a peptide or the like) is administered to a subject for the treatment or prevention of the diseases and symptoms described herein.
  • an effective amount refers to an amount sufficient for the treatment or prevention of the diseases and symptoms described herein.
  • Treatment in the present application includes, but is not limited to, reduction, delay, prevention, improvement, remission, cure, complete cure and the like. Further, prevention in the present application includes, but is not limited to, reduction, delay, prevention, and the like.
  • the target in the present application is not particularly limited, and examples include mammals, birds and fish.
  • mammals include humans or non-human animals, and examples include, but are not limited to, humans, mice, rats, monkeys, pigs, dogs, rabbits, hamsters, guinea pigs, horses, sheep, and whales. is not.
  • the term “subject” is used interchangeably with “patient”, “individual” and “animal”.
  • the peptide of the present application can exert its effect even if administered to any site, such as a site far from the site, or a site that is distal and ectopic to the site where symptoms of psoriasis appear. it can.
  • the peptide of the present application is a tissue different from a tissue exhibiting psoriasis symptoms (for example, skin and joints), a tissue distant from a tissue exhibiting psoriasis symptoms, a tissue distal to a tissue exhibiting psoriasis symptoms, or The effect can be exerted even when administered to any tissue, such as a tissue distant from the tissue exhibiting psoriasis symptoms and located at a different site.
  • Examples of the administration method of the peptide of the present application include oral administration and parenteral administration.
  • Examples of the parenteral administration method include intravascular administration (intraarterial administration, intravenous administration, etc.), intramuscular administration, subcutaneous administration, and intradermal administration. Administration, intraperitoneal administration, nasal administration, pulmonary administration, transdermal administration, and the like, but are not limited thereto.
  • the peptide of the present application can be administered systemically or locally (for example, subcutaneously, intradermally, skin surface, eyeball or eyelid conjunctiva, nasal cavity) by injection administration such as intravenous injection, intramuscular injection, intraperitoneal injection, subcutaneous injection, etc. Mucosa, oral cavity and gastrointestinal mucosa, vaginal / intrauterine mucosa, or damaged site).
  • a cell that secretes the peptide of the present application a gene therapy vector into which a DNA encoding the peptide is inserted, and a pharmaceutical composition containing them can also be used.
  • the administration method can be appropriately selected depending on the age and symptoms of the patient.
  • the dose can be selected in the range of 0.0000001 mg to 1000 mg per kg of body weight per administration.
  • the dose can be selected within the range of 0.00001 to 100,000 mg / body per patient.
  • the peptide can be administered so that the amount falls within the above range.
  • the pharmaceutical composition in the present application is not limited to these doses.
  • the pharmaceutical composition of the present application can be formulated according to a conventional method (for example, Remington's Pharmaceutical, Science, Latest Edition, Mark, Publishing Company, Easton, USA) and includes a pharmaceutically acceptable carrier or additive.
  • a pharmaceutically acceptable carrier or additive There may be.
  • surfactants, excipients, coloring agents, flavoring agents, preservatives, stabilizers, buffering agents, suspending agents, tonicity agents, binders, disintegrating agents, lubricants, fluidity promoters, flavoring agents can be used as appropriate.
  • the test substance is administered for 3 days from the first day of application of imiquimod (Day 1), and HMGB1 peptide (1-44) solution adjusted to a concentration of 1 ⁇ g / ⁇ L using physiological saline as a solvent is 100 ⁇ L / day (peptide Was administered by intravenous injection at 5 mg / kg / day.
  • physiological saline was intravenously injected in an amount of 100 ⁇ L / day for 3 days from the first day after the start of imiquimod application.
  • PASI score is the degree of skin (a) erythema, (b) scale (desquamation) and (c) thickening (infiltration) [no symptoms: 0 points, mild: 1 point, moderate: 2 points, altitude: 3 Points, extremely altitude: 4 points], respectively, and calculated by summing the values of (a), (b) and (c) (minimum 0 points-maximum 12 points).
  • the score of erythema was determined by visually comparing the state of the back of the mouse to be evaluated with the photograph of the back of the mouse shown in FIG. 1 as a reference for each score.
  • the scale score was determined by visually comparing the state of the back of the mouse to be evaluated with the photograph of the back of the mouse shown in FIG. 2 as a reference for each score.
  • the thickening score was determined as follows: Two measurement sites were determined on the back of the mouse, the skin was pinched, the thickness was measured with calipers, and the average value of the two locations was the skin thickness (mm) As recorded daily.
  • the relative value of the skin thickness for each day relative to the skin thickness on the first day (before application) of imiquimod is less than 1.1, 0 points, 1.1 to less than -1.3, 1 point, 1.3 to less than -1.5 It was quantified as 2 points, 3 points if 1.5 or more and less than -1.7, and 4 points if 1.7 or more.
  • IL- inflammatory cytokines
  • the PASI score of the HMGB1 peptide (1-44) administration group was significantly lower than that of the control group on the fifth day after the start of imiquimod application.
  • a photograph of the back of the mouse on day 5 after the start of imiquimod application is shown in FIG. 5 (see “IMQ / saline” for the control group and “IMQ / 1-44” for the HMGB1 peptide (1-44) administration group).
  • This result indicates that the skin symptoms in the psoriasis model mouse were suppressed by administration of HMGB1 peptide (1-44).
  • FIG. 8 shows the expression level of inflammatory cytokines in the skin on the fifth day after application of imiquimod ("IMQ / saline" for the control group, "IMQ for the HMGB1 peptide (1-44) administration group” / 1-44 ").
  • IMQ / saline for the control group
  • IMQ for the HMGB1 peptide (1-44) administration group / 1-44 ".
  • the expression of IL-1 ⁇ , IL-6, IL-17A, IL-17F and IL-22 in the HMGB1 peptide (1-44) administration group was all lower than that in the control group.
  • the pharmaceutical composition containing the peptide of the present application is expected to bring great benefits to patients with psoriasis for which sufficient effects cannot be obtained with existing therapeutic agents.

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Medicinal Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Veterinary Medicine (AREA)
  • Engineering & Computer Science (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Public Health (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Zoology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Dermatology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Toxicology (AREA)
  • Biochemistry (AREA)
  • Biophysics (AREA)
  • Genetics & Genomics (AREA)
  • Molecular Biology (AREA)
  • Epidemiology (AREA)
  • Immunology (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Peptides Or Proteins (AREA)
PCT/JP2019/004330 2018-02-08 2019-02-07 乾癬の治療薬 Ceased WO2019156137A1 (ja)

Priority Applications (4)

Application Number Priority Date Filing Date Title
EP19751078.7A EP3750553A4 (en) 2018-02-08 2019-02-07 THERAPEUTIC FOR PSORIASIS
US16/967,919 US20210024594A1 (en) 2018-02-08 2019-02-07 Therapeutic Agent for Psoriasis
JP2019570787A JP7386455B2 (ja) 2018-02-08 2019-02-07 乾癬の治療薬
US17/817,084 US12428458B2 (en) 2018-02-08 2022-08-03 Therapeutic agent for psoriasis

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
JP2018-020687 2018-02-08
JP2018020687 2018-02-08

Related Child Applications (2)

Application Number Title Priority Date Filing Date
US16/967,919 A-371-Of-International US20210024594A1 (en) 2018-02-08 2019-02-07 Therapeutic Agent for Psoriasis
US17/817,084 Continuation US12428458B2 (en) 2018-02-08 2022-08-03 Therapeutic agent for psoriasis

Publications (1)

Publication Number Publication Date
WO2019156137A1 true WO2019156137A1 (ja) 2019-08-15

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PCT/JP2019/004330 Ceased WO2019156137A1 (ja) 2018-02-08 2019-02-07 乾癬の治療薬

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US (2) US20210024594A1 (https=)
EP (1) EP3750553A4 (https=)
JP (1) JP7386455B2 (https=)
WO (1) WO2019156137A1 (https=)

Cited By (9)

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WO2021215375A1 (ja) * 2020-04-20 2021-10-28 塩野義製薬株式会社 Ｈｍｇｂ１部分ペプチドを含有する製剤
US11191786B2 (en) 2009-10-28 2021-12-07 StemRIM Inc. Agents for promoting tissue regeneration by recruiting bone marrow mesenchymal stem cells and/or pluripotent stem cells into blood
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US11298403B2 (en) 2017-12-01 2022-04-12 StemRIM Inc. Therapeutic agent for inflammatory bowel disease
WO2024005133A1 (ja) * 2022-06-30 2024-01-04 国立大学法人大阪大学 半月板の治療薬
US11969459B2 (en) 2017-01-27 2024-04-30 StemRIM Inc. Therapeutic agent for cardiomyopathy, old myocardial infarction and chronic heart failure
US12304933B2 (en) 2018-10-05 2025-05-20 StemRIM Inc. Disease treatment drug based on mesenchymal-stem-cell mobilization
US12421498B2 (en) 2017-12-01 2025-09-23 StemRIM Inc. Ectodermal mesenchymal stem cells and method for producing same
US12428458B2 (en) 2018-02-08 2025-09-30 StemRIM Inc. Therapeutic agent for psoriasis

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CA3117107A1 (en) * 2018-10-25 2020-04-30 Osaka University Therapeutic agent for cartilage disorder

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