WO2019107530A1 - 炎症性腸疾患の治療薬 - Google Patents

炎症性腸疾患の治療薬 Download PDF

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Publication number
WO2019107530A1
WO2019107530A1 PCT/JP2018/044122 JP2018044122W WO2019107530A1 WO 2019107530 A1 WO2019107530 A1 WO 2019107530A1 JP 2018044122 W JP2018044122 W JP 2018044122W WO 2019107530 A1 WO2019107530 A1 WO 2019107530A1
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WIPO (PCT)
Prior art keywords
inflammatory bowel
bowel disease
peptide
amino acid
dss
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Ceased
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PCT/JP2018/044122
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English (en)
French (fr)
Japanese (ja)
Inventor
克人 玉井
敬史 新保
尊彦 山崎
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StemRIM Inc
University of Osaka NUC
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Osaka University NUC
StemRIM Inc
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Publication date
Application filed by Osaka University NUC, StemRIM Inc filed Critical Osaka University NUC
Priority to JP2019557342A priority Critical patent/JPWO2019107530A1/ja
Priority to US16/768,654 priority patent/US11298403B2/en
Priority to CN201880084992.7A priority patent/CN111542335A/zh
Priority to EP18882661.4A priority patent/EP3718561A4/en
Publication of WO2019107530A1 publication Critical patent/WO2019107530A1/ja
Anticipated expiration legal-status Critical
Priority to JP2023114129A priority patent/JP7590724B2/ja
Ceased legal-status Critical Current

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    • 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
    • A61K38/1703—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates
    • A61K38/1709—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
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • 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
    • C07K14/4701—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates from mammals not used
    • C07K14/4702—Regulators; Modulating activity

Definitions

  • the present application relates to a pharmaceutical composition for the prevention and / or treatment of inflammatory bowel disease, which comprises a fragment peptide of High mobility group box 1 (HMGB1) protein.
  • HMGB1 High mobility group box 1
  • IBD Inflammatory bowel disease
  • IBD ulcerative colitis and Crohn's disease.
  • inflammatory bowel disease does not currently have a curative therapy, and remission and relapse are often repeated, requiring long-term medical management.
  • 5-aminosalicylic acid preparations As therapeutic agents for inflammatory bowel disease, 5-aminosalicylic acid preparations, corticosteroid preparations, immunosuppressants, biological preparations (for example, anti-TNF- ⁇ antibody and anti- ⁇ 4 ⁇ 7 integrin antibody) are used. There are cases where sufficient effects can not be obtained. Furthermore, also in terms of side effects, nausea, fever, abdominal pain, anemia, interstitial nephritis and liver dysfunction due to 5-aminosalicylic acid preparations; insomnia due to corticosteroids, osteoporosis, adrenal cortex dysfunction, glucose intolerance and blood pressure elevation And there are problems such as renal dysfunction due to immunosuppressants, liver dysfunction, leukocytopenia and elevated blood pressure, and there is room for improvement. Therefore, development of a more effective and safer therapeutic agent for inflammatory bowel disease, which is a different type from existing therapeutic agents, is desired.
  • the present application aims to provide a novel medicine effective for the treatment of inflammatory bowel disease.
  • HMGB1 fragment peptides having a specific amino acid sequence have an effect of suppressing weight loss in animal models of inflammatory bowel disease and shortening of the large intestine. And it was found to exhibit the effect of suppressing mucosal damage. Accordingly, the present application provides a pharmaceutical composition for the prevention and / or treatment of inflammatory bowel disease, which comprises the specific HMGB1 fragment peptide.
  • compositions for the prevention and / or treatment of inflammatory bowel disease comprising the substance according to any 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 more amino acids are substituted, deleted, inserted or added in the amino acid sequence set forth in SEQ ID NO: 1; and (c) the amino acid sequence set forth in SEQ ID NO: 1 A peptide comprising an amino acid sequence having about 80% or more sequence identity.
  • the pharmaceutical composition according to [1], wherein the inflammatory bowel disease is a nonspecific inflammatory bowel disease.
  • the pharmaceutical composition according to [2], wherein the nonspecific inflammatory bowel disease is ulcerative colitis.
  • the pharmaceutical composition according to [2], wherein the nonspecific inflammatory bowel disease is Crohn's disease.
  • the pharmaceutical composition according to [5], wherein the inflammatory bowel disease is a nonspecific inflammatory bowel disease.
  • a method of preventing and / or treating inflammatory bowel disease comprising the step of administering an effective amount of substance A to a subject.
  • [A2] The method according to [A1], wherein the inflammatory bowel disease is a nonspecific inflammatory bowel disease.
  • [A3] The method according to [A2], wherein the nonspecific inflammatory bowel disease is ulcerative colitis.
  • [A4] The method according to [A2], wherein the nonspecific inflammatory bowel disease is Crohn's disease.
  • [A5] A method of inhibiting weight loss or damage to the intestinal mucosa in a patient, comprising administering an effective amount of substance A to a patient with inflammatory bowel disease.
  • [A6] The method according to [A5], wherein the inflammatory bowel disease is a nonspecific inflammatory bowel disease.
  • Substance A for use in the prevention and / or treatment of inflammatory bowel disease.
  • [C2] The use according to [C1], wherein the inflammatory bowel disease is a nonspecific inflammatory bowel disease.
  • [C3] The use according to [C2], wherein the nonspecific inflammatory bowel disease is ulcerative colitis.
  • [C4] The use according to [C2], wherein the nonspecific inflammatory bowel disease is Crohn's disease.
  • [C5] Use of substance A in the manufacture of a medicament for inhibiting weight loss or damage to the intestinal mucosa in patients with inflammatory bowel disease.
  • [C6] The use according to [C5], wherein the inflammatory bowel disease is a nonspecific inflammatory bowel disease.
  • the present application provides a pharmaceutical composition for the prevention and / or treatment of inflammatory bowel disease, which comprises an HMGB1 fragment peptide comprising the amino acid sequence set forth in SEQ ID NO: 1.
  • the inflammatory bowel disease in the present application includes a disease of unknown cause (nonspecific inflammatory bowel disease) and a disease with a clear relationship with the cause (specific inflammatory bowel disease).
  • Nonspecific inflammatory bowel diseases include, but are not limited to, ulcerative colitis, Crohn's disease and intestinal Behcet's disease.
  • Specific inflammatory bowel diseases include, but are not limited to, infectious enteritis, drug-induced enteritis, ischemic enteritis, intestinal tuberculosis and the like.
  • the inflammatory bowel disease of the present application is a nonspecific inflammatory bowel disease.
  • the non-specific inflammatory bowel disease of the present application is ulcerative colitis or Crohn's disease. In another embodiment, the non-specific inflammatory bowel disease of the present application is ulcerative colitis. In another further aspect, the non-specific inflammatory bowel disease of the present application is Crohn's disease.
  • Ulcerative colitis is an inflammatory disease of unknown cause that causes erosion or ulceration in the mucosa of the large intestine.
  • the main symptoms are symptoms such as bloody stool, mucous bloody stool, diarrhea or bloody diarrhea, abdominal pain, often accompanied by fever and weight loss.
  • Crohn's disease is a chronic inflammatory disease of unknown cause that causes granulomatous inflammatory lesions accompanied by ulceration and fibrosis in the digestive tract.
  • intestinal complications such as fistula, stenosis, and extraintestinal complications such as anemia, arthritis, ulcerados, nodular erythema, anal lesion etc. may occur. is there.
  • pharmaceutical composition is used interchangeably with “medicament”, “drug” or “pharmaceutical composition”.
  • the present application also provides a pharmaceutical composition for suppressing weight loss or damage to the intestinal mucosa in a patient with inflammatory bowel disease, which comprises an HMGB1 fragment peptide comprising the amino acid sequence set forth in SEQ ID NO: 1.
  • the pharmaceutical composition of the present application is for use in suppressing mucosal damage in the large intestine in patients with inflammatory bowel disease.
  • an HMGB1 fragment peptide containing the amino acid sequence set forth in SEQ ID NO: 1 means a peptide consisting of a part of HMGB1 protein and containing the amino acid sequence set forth in SEQ ID NO: 1.
  • Such peptides can be obtained as recombinants by incorporating the DNA encoding the peptides into an appropriate expression system, or can be artificially synthesized.
  • examples of the HMGB1 protein include, but are not limited to, a protein comprising the amino acid sequence set forth in SEQ ID NO: 2 and a protein encoded by a DNA comprising the base sequence set forth in SEQ ID NO: 3 It is not a thing.
  • an HMGB1 fragment peptide consisting of the amino acid sequence set forth in SEQ ID NO: 1 can be exemplified, but it is not limited thereto.
  • one or more amino acid residues are altered in the amino acid sequence described in SEQ ID NO: 1 instead of or in addition to the HMGB1 fragment peptide containing the amino acid sequence set forth in SEQ ID NO: 1 (
  • a peptide functionally equivalent to an HMGB1 fragment peptide comprising the amino acid sequence described in SEQ ID NO: 1, which is a peptide comprising an amino acid sequence substituted, deleted, inserted or added, can also be used.
  • Such peptides include, 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) of the amino acid sequence set forth in SEQ ID NO: 1 A peptide comprising an amino acid sequence in which -5, 1-4, 1-3, 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, 1) of the amino acid sequence set forth in SEQ ID NO: 1 A peptide consisting of an amino acid sequence in which -5, 1-4, 1-3, 1 or 2 amino acids are substituted, deleted, inserted or added; iii) The amino acid sequence set forth in SEQ ID NO: 1 by about 80% or more, for example about 85% or more, about 90% or more, about 91% or more, about 92% or more, about 93% or more, about 94% or more, about 95% or more A peptide comprising an amino acid sequence having a sequence identity of%
  • a peptide or the like An effective amount of the peptide of the present application or a pharmaceutical composition containing the same (hereinafter referred to as a peptide or the like) is administered to a subject for treatment or prevention of the diseases and conditions described herein.
  • An effective amount in the present application 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, alleviation, delay, arrest, amelioration, remission, cure, complete cure, and the like.
  • prevention in the present application includes, but is not limited to, mitigation, delay, arrest and the like.
  • the subject in the present application is not particularly limited, and includes mammals, birds, fish and the like. Mammals include human or non-human animals, and examples thereof include, but are not limited to, humans, mice, rats, monkeys, pigs, dogs, rabbits, hamsters, guinea pigs, horses, sheep, whales, etc. is not.
  • the term "subject” is used interchangeably with "patient”, “individual” and "animal”.
  • the present invention may be administered at any site, such as a site distant from the site of symptoms of inflammatory bowel disease or a site distant from the site of symptoms of inflammatory bowel disease and other sites. And the like can exert their effects.
  • the peptides and the like of the present application may be selected from tissues different from tissues in which symptoms of inflammatory bowel disease appear (for example, digestive tract), tissues separated from tissues in which symptoms of inflammatory bowel disease appear, and tissues in which symptoms of inflammatory bowel disease appear The effect can be exerted even if it is administered to any tissue, such as a tissue located distally or a tissue located distal to and off the tissue presenting a symptom of inflammatory bowel disease.
  • parenteral administration methods include oral administration and parenteral administration, and parenteral administration methods include intravascular administration (intraarterial administration, intravenous administration, etc.), intramuscular administration, subcutaneous administration, intradermal administration Examples include, but are not limited to, administration, intraperitoneal administration, nasal administration, pulmonary administration, percutaneous administration and the like.
  • the peptides and the like of the present invention can be systemically or locally (eg, subcutaneously, intradermal, skin surface, eye or eyelid conjunctiva, nasal cavity) by injection administration, for example, intravenous injection, intramuscular injection, intraperitoneal injection, subcutaneous injection and the like It can be administered to mucous membranes, oral cavity and digestive tract mucous membranes, vaginal / uterine mucous membranes, or injury sites.
  • injection administration for example, intravenous injection, intramuscular injection, intraperitoneal injection, subcutaneous injection and the like It can be administered to mucous membranes, oral cavity and digestive tract mucous membranes, vaginal / uterine mucous membranes, or injury sites.
  • cells secreting the peptide of the present application cells secreting the peptide of the present application, vector for gene therapy into which DNA encoding the peptide is inserted, and pharmaceutical compositions containing these can be used.
  • the administration method can be appropriately selected according to the age and symptoms of the patient.
  • the dosage can be selected, for example, in the range of 0.0000001 mg to 1000 mg per kg of body weight per single administration.
  • the dose can be selected in the range of 0.00001 to 100,000 mg / body per patient.
  • the amount of the peptide can be administered within the above range.
  • the pharmaceutical compositions in the present application are not limited to these dosages.
  • the pharmaceutical composition of the present application can be formulated according to a conventional method (e.g., Remington's Pharmaceutical Science, latest edition, Mark Publishing Company, Easton, USA), which comprises both a pharmaceutically acceptable carrier and additives. It may be.
  • a pharmaceutically acceptable carrier e.g., ethanol, sulfate, sulfate, sulfate, sulfate, sulfate, sulfate, sulfate, sulfate, sulfate, sulfate, sorbito, sorbito, sorbito, sorbito, sorbito, sorbito, sorbito, sorbito, sorbito, sorbito, sorbito, sulfate, sulfate, sulfate, sulfate, sulfate, sulfate, sulfate, sulfate, sulfate, sulfate, sul
  • HMGB1 peptide (1-44), and is abbreviated to “1-44” in the drawings corresponding to the examples.
  • mice ii) Preparation of an inflammatory bowel disease (IBD) model mouse
  • IBD inflammatory bowel disease
  • C57BL / 6 mice 8 to 10 weeks old, male, weight about 20 g
  • RO water purified water
  • Induced colitis drinking of DSS solution continued until removal of the colon.
  • RO water purified water
  • the test substance was administered at 200 ⁇ L / animal of HMGB1 peptide (1-44) solution adjusted to a concentration of 0.5 mg / mL using saline as a solvent on days 6 and 7 after the start of drinking DSS aqueous solution (The dose of the peptide was 5 mg / kg) by intravenous infusion.
  • physiological saline was intravenously infused in an amount of 200 ⁇ L / animal on the 6th and 7th days after initiation of drinking of the DSS aqueous solution.
  • “the Xth day after the drinking start of the DSS aqueous solution” is abbreviated and described as "the DSS drinking Xth day”.
  • mice The body weight change of the mice during the test period is shown in FIG. 1 (“Water” for normal mice, “DSS + saline” for control group, “DSS for HMGB1 peptide (1-44) administration group) + 1-44).
  • the body weight of the control group IBD model mice decreased with the passage of days, and became significantly smaller than that of the normal mice on the 9th day of DSS drinking.
  • the HMGB1 peptide (1-44) -administered group the body weight once lost recovered after administration of the peptide, and became significantly larger than that in the control group on the 9th day of DSS drinking.
  • the test substance was administered at 200 ⁇ L / animal volume of HMGB1 peptide (1-44) solution adjusted to a concentration of 0.5 mg / mL using saline as a solvent on days 1, 3, 5 and 7 of DSS drinking water As a dose of 5 mg / kg).
  • Mucosal tissue HEstaining image of large intestine tissue at day 10 of DSS drinking water is shown in FIG. 6 (“Water” for normal mice, “DSS + saline” for control group, “DSS for HMGB1 peptide (1-44) administration group) + 1-44).
  • the mucosal tissue was damaged in the control group of IBD model mice, whereas the mucosal tissue damage was suppressed in the HMGB1 peptide (1-44) administration group.
  • the administration of the test substance was carried out by embedding the hydrogel containing HMGB1 peptide (1-44) solution prepared as described above on the back of the mouse one day before the start of drinking of the DSS aqueous solution.
  • HMGB1 peptide (1-44) has an effect of mobilizing mesenchymal stem cells in bone marrow to peripheral blood. Therefore, the following experiment was performed in order to compare the effects of administration of mesenchymal stem cells and administration of HMGB1 peptide (1-44).
  • mesenchymal stem cells were obtained as adherent colonies.
  • MSC mesenchymal stem cell
  • C57BL / 6 mice (6-8 weeks old, male) bone marrow was taken from the femoral bone, using the MesenCult as medium (TM) MSC Basal Medium (Mouse) ( STEMCELL Technologies Co., Ltd., including a 10nM Rock inhibitor and MesenPure)
  • TM MesenCult as medium
  • MSC Basal Medium STEMCELL Technologies Co., Ltd., including a 10nM Rock inhibitor and MesenPure
  • HMGB1 peptide (1-44) was used as an inflammatory intestine prepared under the same conditions. It showed an effect of improving symptoms such as weight loss in disease model mice. From this, it is expected that the peptide of the present application is also effective for patients with inflammatory bowel disease in which the administration of mesenchymal stem cells is ineffective.
  • compositions containing the peptides of the present application are expected to provide significant benefits to patients with inflammatory bowel disease for which existing therapeutic agents are not effective.

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PCT/JP2018/044122 2017-12-01 2018-11-30 炎症性腸疾患の治療薬 Ceased WO2019107530A1 (ja)

Priority Applications (5)

Application Number Priority Date Filing Date Title
JP2019557342A JPWO2019107530A1 (ja) 2017-12-01 2018-11-30 炎症性腸疾患の治療薬
US16/768,654 US11298403B2 (en) 2017-12-01 2018-11-30 Therapeutic agent for inflammatory bowel disease
CN201880084992.7A CN111542335A (zh) 2017-12-01 2018-11-30 炎症性肠病的治疗药
EP18882661.4A EP3718561A4 (en) 2017-12-01 2018-11-30 Therapy for inflammatory bowel disease
JP2023114129A JP7590724B2 (ja) 2017-12-01 2023-07-12 炎症性腸疾患の治療薬

Applications Claiming Priority (4)

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US201762593310P 2017-12-01 2017-12-01
US62/593,310 2017-12-01
JP2018-020686 2018-02-08
JP2018020686 2018-02-08

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US (1) US11298403B2 (https=)
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WO (1) WO2019107530A1 (https=)

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WO2020071520A1 (ja) * 2018-10-05 2020-04-09 株式会社ステムリム 間葉系幹細胞の動員活性を有するペプチド
JPWO2021201260A1 (https=) * 2020-04-03 2021-10-07
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
US11197895B2 (en) 2008-04-30 2021-12-14 StemRIM Inc. Method for collecting functional cells in vivo with high efficiency
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
EP4147711A4 (en) * 2020-04-20 2024-04-24 Shionogi & Co., Ltd FORMULATION WITH A HMGB1 PARTIAL PEPTIDE
WO2023138644A1 (zh) * 2022-01-21 2023-07-27 四川好医生攀西药业有限责任公司 多肽化合物及其治疗肠炎的用途
CN116693612B (zh) * 2023-06-28 2025-02-18 禾美生物科技(浙江)有限公司 一种环肽及其用途
CN117224655B (zh) * 2023-09-14 2024-05-14 大连医科大学 蝎毒耐热合成肽(svhrsp)在制备治疗肠道炎症的药物中的应用

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