JP6431541B2 - 出血性障害の治療に対する改変セルピン - Google Patents
出血性障害の治療に対する改変セルピン Download PDFInfo
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- JP6431541B2 JP6431541B2 JP2016538525A JP2016538525A JP6431541B2 JP 6431541 B2 JP6431541 B2 JP 6431541B2 JP 2016538525 A JP2016538525 A JP 2016538525A JP 2016538525 A JP2016538525 A JP 2016538525A JP 6431541 B2 JP6431541 B2 JP 6431541B2
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- 241001515965 unidentified phage Species 0.000 description 1
- 241001430294 unidentified retrovirus Species 0.000 description 1
- 239000003981 vehicle Substances 0.000 description 1
- 210000003462 vein Anatomy 0.000 description 1
- 210000000264 venule Anatomy 0.000 description 1
- 235000019168 vitamin K Nutrition 0.000 description 1
- 239000011712 vitamin K Substances 0.000 description 1
- 150000003721 vitamin K derivatives Chemical class 0.000 description 1
- 229940046010 vitamin k Drugs 0.000 description 1
- 208000012137 von Willebrand disease (hereditary or acquired) Diseases 0.000 description 1
- 230000003442 weekly effect Effects 0.000 description 1
- 210000005253 yeast cell Anatomy 0.000 description 1
Classifications
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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
- C07K14/81—Protease inhibitors
- C07K14/8107—Endopeptidase (E.C. 3.4.21-99) inhibitors
- C07K14/811—Serine protease (E.C. 3.4.21) inhibitors
- C07K14/8121—Serpins
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- 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
- A61K38/43—Enzymes; Proenzymes; Derivatives thereof
- A61K38/46—Hydrolases (3)
- A61K38/48—Hydrolases (3) acting on peptide bonds (3.4)
- A61K38/482—Serine endopeptidases (3.4.21)
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- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L24/00—Surgical adhesives or cements; Adhesives for colostomy devices
- A61L24/001—Use of materials characterised by their function or physical properties
- A61L24/0015—Medicaments; Biocides
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L26/00—Chemical aspects of, or use of materials for, wound dressings or bandages in liquid, gel or powder form
- A61L26/0009—Chemical aspects of, or use of materials for, wound dressings or bandages in liquid, gel or powder form containing macromolecular materials
- A61L26/0028—Polypeptides; Proteins; Degradation products thereof
- A61L26/0047—Specific proteins or polypeptides not covered by groups A61L26/0033 - A61L26/0042
-
- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
- A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
- A61P7/04—Antihaemorrhagics; Procoagulants; Haemostatic agents; Antifibrinolytic agents
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- C07K14/81—Protease inhibitors
- C07K14/8107—Endopeptidase (E.C. 3.4.21-99) inhibitors
- C07K14/811—Serine protease (E.C. 3.4.21) inhibitors
- C07K14/8121—Serpins
- C07K14/8125—Alpha-1-antitrypsin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
- A61L2300/20—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices containing or releasing organic materials
- A61L2300/252—Polypeptides, proteins, e.g. glycoproteins, lipoproteins, cytokines
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
- A61L2300/20—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices containing or releasing organic materials
- A61L2300/258—Genetic materials, DNA, RNA, genes, vectors, e.g. plasmids
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- A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
- A61L2300/40—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a specific therapeutic activity or mode of action
- A61L2300/418—Agents promoting blood coagulation, blood-clotting agents, embolising agents
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- A—HUMAN NECESSITIES
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- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L2400/00—Materials characterised by their function or physical properties
- A61L2400/04—Materials for stopping bleeding
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Description
本発明は、他の凝固プロテアーゼと比べてAPCに対する特異性を増大するためのセルピンの改変に関する。APCに特異的な改変セルピンバリアントは、例えば凝血促進剤として有用な可能性がある。
(1)P4残基がQであり、P2残基がRであり、P1残基がRであり、P1’残基がNである;
(2)P4残基がKであり、P2残基がRであり、P1残基がRであり、P1’残基がHである;
(3)P4残基がSであり、P2残基がLであり、P1残基がRであり、P1’残基がKである;
(4)P4残基がHであり、P2残基がRであり、P1残基がRであり、P1’残基がVである;
(5)P4残基がFであり、P2残基がKであり、P1残基がRであり、P1’残基がKである;
(6)P4残基がFであり、P2残基がRであり、P1残基がRであり、P1’残基がKである;
(7)P4残基がFであり、P2残基がVであり、P1残基がRであり、P1’残基がKである;
(8)P4残基がCであり、P2残基がLであり、P1残基がRであり、P1’残基がKである;
(9)P4残基がFであり、P2残基がFであり、P1残基がRであり、P1’残基がRである;
(10)P4残基がSであり、P2残基がHであり、P1残基がRであり、P1’残基がRである;
(11)P4残基がGであり、P2残基がIであり、P1残基がRであり、P1’残基がRである;
(12)P4残基がRであり、P2残基がQであり、P1残基がRであり、P1’残基がVである;
(13)P4残基がTであり、P2残基がRであり、P1残基がRであり、P1’残基がVである;
(14)P4残基がRであり、P2残基がRであり、P1残基がRであり、P1’残基がIである;
(15)P4残基がVであり、P2残基がRであり、P1残基がRであり、P1’残基がIである;
(16)P4残基がLであり、P2残基がRであり、P1残基がRであり、P1’残基がIである;
(17)P4残基がTであり、P2残基がLであり、P1残基がRであり、P1’残基がYである;
(18)P4残基がAであり、P2残基がQであり、P1残基がRであり、P1’残基がYである;
(19)P4残基がKであり、P2残基がDであり、P1残基がRであり、P1’残基がMである;
(20)P4残基がWであり、P2残基がWであり、P1残基がRであり、P1’残基がNである;
(21)P4残基がAであり、P2残基がKであり、P1残基がRであり、P1’残基がSである;
(22)P4残基がAであり、P2残基がRであり、P1残基がRであり、P1’残基がSである;
(23)P4残基がAであり、P2残基がPであり、P1残基がRであり、P1’残基がEである;
(24)P4残基がAであり、P2残基がPであり、P1残基がRであり、P1’残基がRである;
(25)P4残基がAであり、P2残基がPであり、P1残基がRであり、P1’残基がKである;
(26)P4残基がAであり、P2残基がTであり、P1残基がRであり、P1’残基がMである;
(27)P4残基がAであり、P2残基がTであり、P1残基がRであり、P1’残基がHである;
(28)P4残基がAであり、P2残基がTであり、P1残基がRであり、P1’残基がQである;
(29)P4残基がAであり、P2残基がTであり、P1残基がRであり、P1’残基がNである;
(30)P4残基がAであり、P2残基がTであり、P1残基がRであり、P1’残基がYである;
(32)P4残基がAであり、P2残基がTであり、P1残基がRであり、P1’残基がRである;
(33)P4残基がAであり、P2残基がRであり、P1残基がRであり、P1’残基がAである;
(34)P4残基がAであり、P2残基がRであり、P1残基がRであり、P1’残基がHである;
(35)P4残基がAであり、P2残基がRであり、P1残基がRであり、P1’残基がCである;
(36)P4残基がAであり、P2残基がRであり、P1残基がRであり、P1’残基がNである;
(37)P4残基がAであり、P2残基がSであり、P1残基がRであり、P1’残基がRである;
(38)P4残基がAであり、P2残基がKであり、P1残基がRであり、P1’残基がNである;
(39)P4残基がAであり、P2残基がKであり、P1残基がRであり、P1’残基がHである;
(40)P4残基がAであり、P2残基がKであり、P1残基がRであり、P1’残基がKである;
(41)P4残基がAであり、P2残基がVであり、P1残基がRであり、P1’残基がRである;
(42)P4残基がAであり、P2残基がYであり、P1残基がRであり、P1’残基がRである;
(43)P4残基がAであり、P2残基がAであり、P1残基がRであり、P1’残基がRである;
(44)P4残基がAであり、P2残基がCであり、P1残基がRであり、P1’残基がKである;
(45)P4残基がAであり、P2残基がWであり、P1残基がRであり、P1’残基がNである;
(46)P4残基がAであり、P2残基がHであり、P1残基がRであり、P1’残基がNである;
(47)P4残基がAであり、P2残基がQであり、P1残基がRであり、P1’残基がKである;又は、
(48)P4残基がAであり、P2残基がNであり、P1残基がRであり、P1’残基がNである。
(49)P4残基がFであり、P2残基がFであり、P1残基がRであり、P1’残基がKである。
(50)P4残基がAであり、P2残基がKであり、P1残基がRであり、P1’残基がQである、
(51)P4残基がAであり、P2残基がRであり、P1残基がRであり、P1’残基がQである。
凝固カスケード及びこのカスケードにおけるセルピンの調節的役割を図1に示す。外因系カスケード(すなわち組織因子経路)及び内因系経路(接触活性化経路)の2つの経路が凝固カスケードの活性化をもたらす。活性化の主な生理学的経路は外因系経路であると考えられている。この経路では、組織因子(TF)が損傷した血管の表面に露出される。その後、TFはfVIIa及びfVIIに結合することができる。TF:fVIIaはfVIIを活性化し、同様にTF:fVIIはTF:fVIIaへと自然に活性化する。TF:fVIIaはfXをfXaへと活性化し、これがプロトロンビンを凝固カスケードの中心的なプロテアーゼであるトロンビン(fIIa)へと活性化する。トロンビンはプロテアーゼ活性化受容体(PAR)の開裂によって血小板を活性化し、フィブリノゲンをフィブリンへと開裂する。フィブリンは、それ自体がトロンビンによって活性化されるfXIIIaにより架橋されて安定なフィブリン塊を形成する。さらに、トロンビンはそれ自体の形成を増強するポジティブフィードバック機構を活性化する。トロンビンはfVIIIをfVIIIaへと活性化し、fVをfVaへと活性化する。fVIIIaはfIXaに結合して内因系テナーゼ(Xase)複合体を形成する。内因系XaseはfXをより活性化する。このfXaはfVaに結合してプロトロンビナーゼを形成することができる。プロトロンビナーゼはプロトロンビンをトロンビンへと活性化し、凝固の開始後に生成されるトロンビンの大半を担う。トロンビンのポジティブフィードバック機構に加えて、トロンビンはネガティブフィードバック機構によってそれ自体の活性化を停止することもできる。トロンビンがその補因子であるトロンボモデュリン(TM)に結合すると、トロンビン:TM複合体がプロテインC(PC)を活性化プロテインC(APC)へと活性化することができる。APCは開裂し、fVIIIa及びfVaの両方を不活性化し、トロンビン生成を効果的に停止する。セルピンは凝固カスケードの重要なインヒビターである。セルピンプロテインCインヒビター(PCI)、抗トロンビン(ATIII)、ヘパリン補因子II(HCII)及びα1−抗トリプシン(α1AT)の阻害作用を図1に示す。
プロペプチドを含む成熟タンパク質は残基20〜406に対応する。シグナル配列は残基1〜19に対応する。プロペプチドは残基20〜25に対応する。RCLのP4、P2、P1及びP1’の残基を太字及び下線で示す。
成熟タンパク質は残基26〜423に対応する。RCLのP4、P2、P1、及びP1’の残基を太字及び下線で示す。
成熟タンパク質は残基23〜500に対応する。RCLのP4、P2、P1、及びP1’の残基を太字及び下線で示す。
成熟タンパク質は残基28〜491に対応する。キモトリプシンの阻害に対するRCLのP4、P2、P1及びP1’の残基を太字、プラスミンの阻害に対する残基を下線で示す。
成熟タンパク質は残基33〜464に対応する。RCLのP4、P2、P1、及びP1’の残基を太字及び下線で示す。
成熟タンパク質は残基20〜499に対応する。RCLのP4、P2、P1、及びP1’の残基を太字及び下線で示す。
成熟タンパク質は残基25〜418に対応する。RCLのP4、P2、P1、及びP1’の残基を太字及び下線で示す。
成熟タンパク質は残基21〜427に対応する。RCLのP4、P2、P1、及びP1’の残基を太字及び下線で示す。
成熟タンパク質は残基24〜402に対応する。RCLのP4、P2、P1、及びP1’の残基を太字及び下線で示す。
成熟タンパク質は残基22〜444に対応する。RCLのP4、P2、P1、及びP1’の残基を太字及び下線で示す。
成熟タンパク質は残基20〜398に対応する。RCLのP4、P2、P1、及びP1’の残基を太字及び下線で示す。
成熟タンパク質は残基25〜418に対応する。RCLのP4、P2、P1、及びP1’の残基を太字及び下線で示す。
Claims (10)
- (i)配列番号12の残基25〜418のアミノ酸配列;
(ii)配列番号12の残基25〜418のアミノ酸配列であり、残基256におけるCからSへの変異を有する;
(iii)配列番号12の残基25〜418のアミノ酸配列であり、残基25におけるEからSへの変異を有する;又は
(iv)配列番号12の残基25〜418のアミノ酸配列であり、残基25におけるEからSへの変異、及び残基256におけるCからSへの変異を有する
を含む、改変セルピン。 - 請求項1に記載の改変セルピンをコードする核酸。
- 請求項1に記載の改変セルピンをコードする核酸を含むベクター。
- 請求項1に記載の改変セルピンを発現するベクターを含む組換え細胞。
- 請求項1に記載の改変セルピン、及び薬学的に許容可能な賦形剤を含む、医薬組成物。
- ヒト又は動物の身体の治療用である、請求項5に記載の医薬組成物。
- 個体における出血の治療用若しくは予防用、又は止血の促進用である、請求項5に記載の医薬組成物。
- 前記個体が出血性障害を有する、請求項7に記載の医薬組成物。
- 前記出血性障害が血友病である、請求項8に記載の医薬組成物。
- 前記個体が外傷患者である、請求項7に記載の医薬組成物。
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PCT/EP2014/077783 WO2015086854A1 (en) | 2013-12-13 | 2014-12-15 | Modified serpins for the treatment of bleeding disorders |
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SI (1) | SI3080157T1 (ja) |
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US20100183558A1 (en) | 2008-10-17 | 2010-07-22 | Zhennan Lai | Safe lentiviral vectors for targeted delivery of multiple therapeutic molecules |
GB201322091D0 (en) | 2013-12-13 | 2014-01-29 | Cambridge Entpr Ltd | Modified serpins for the treatment of bleeding disorders |
EP3319631A4 (en) | 2015-07-08 | 2019-01-09 | American Gene Technologies International Inc. | HIV PREMUNICATION AND IMMUNOTHERAPY |
EP3426777B1 (en) | 2016-03-09 | 2022-02-16 | American Gene Technologies International Inc. | Combination vectors and methods for treating cancer |
WO2017213697A1 (en) | 2016-06-08 | 2017-12-14 | American Gene Technologies International Inc. | Non-integrating viral delivery system and methods related thereto |
JP6971492B2 (ja) | 2016-07-08 | 2021-11-24 | アメリカン ジーン テクノロジーズ インターナショナル インコーポレイテッド | Hiv予備免疫化および免疫療法 |
US11851474B2 (en) * | 2017-02-23 | 2023-12-26 | Preclinics Gesellschaft Für Präklinische Forschung Mbh | Modified serpins for the treatment of bradykinin-mediated disease |
US11820999B2 (en) | 2017-04-03 | 2023-11-21 | American Gene Technologies International Inc. | Compositions and methods for treating phenylketonuria |
RU2663464C1 (ru) * | 2018-02-26 | 2018-08-06 | Общество с ограниченной ответственностью "Международный Биотехнологический Центр "Генериум" | Комбинаторная терапия для лечения геморрагического шока |
CN110051830A (zh) * | 2019-03-14 | 2019-07-26 | 苏州新凝生物医药科技有限公司 | 一种protease nexin II\KPI蛋白突变体的应用 |
US20240051991A1 (en) * | 2021-04-20 | 2024-02-15 | University Of Louisville | Recombinant Miropin |
WO2023118150A1 (en) | 2021-12-22 | 2023-06-29 | Royal College Of Surgeons In Ireland | A conjugate for use in localising a molecule to the vascular endothelium. |
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