JP6826980B2 - 血栓症の予防法 - Google Patents
血栓症の予防法 Download PDFInfo
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- JP6826980B2 JP6826980B2 JP2017531593A JP2017531593A JP6826980B2 JP 6826980 B2 JP6826980 B2 JP 6826980B2 JP 2017531593 A JP2017531593 A JP 2017531593A JP 2017531593 A JP2017531593 A JP 2017531593A JP 6826980 B2 JP6826980 B2 JP 6826980B2
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
- C07K16/38—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against protease inhibitors of peptide structure
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K2039/505—Medicinal preparations containing antigens or antibodies comprising antibodies
-
- 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
- A61K38/177—Receptors; Cell surface antigens; Cell surface determinants
- A61K38/1774—Immunoglobulin superfamily (e.g. CD2, CD4, CD8, ICAM molecules, B7 molecules, Fc-receptors, MHC-molecules)
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Medicinal Chemistry (AREA)
- Life Sciences & Earth Sciences (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- General Health & Medical Sciences (AREA)
- Urology & Nephrology (AREA)
- Heart & Thoracic Surgery (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Genetics & Genomics (AREA)
- Biophysics (AREA)
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- Immunology (AREA)
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- Cardiology (AREA)
- Molecular Biology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Peptides Or Proteins (AREA)
Description
本願は、2014年12月22日に出願された米国仮特許出願第62/095,462号の優先権の利益を主張するものであり、上記出願の内容全体が参照により本明細書に組み込まれる。
本発明は、血栓症およびそれに付随する合併症の発生を予防する方法に関する。
本発明は、本明細書の以下に記載する本発明の好ましい実施形態の詳細な説明および実施例を参照することによってさらに容易に理解され得る。ただし、本発明の化合物、組成物および方法を開示および記載する前に、本発明が特定の核酸、特定のポリペプチド、特定の細胞型、特定の宿主細胞、特定の条件または特定の方法などに限定されず、したがって当然のことながら、様々なものであり得、その多数の修正形態および変形形態が当業者に明らかになることが理解されるべきである。また、本明細書で使用される用語は、単に特定の実施形態を説明することを目的とするものであって、限定することを意図するものではないことも理解されるべきである。
材料および方法
方法
動物試験は施設内動物実験委員会(Institutional Animal Use and Care Committee)によって承認されたものである。Sf2レベルが正常な(Sf2+/+)C57Bl6マウスまたはSf2欠乏(Sf2−/−)C57Bl6マウスを試験した。
マウスにノーズコーンを用いて2%イソフルランで麻酔をかけ、1〜2%に維持した。マウスを37℃の加温パッドの上に背殿位で置いた。前腹部を剃毛した。腹部にクロルヘキシジン溶液を噴霧し、手術部位が清潔になるまで滅菌ガーゼで拭いた。正中切開を実施して開腹した。下大静脈(IVC)を可視化した後、イソフルランを1〜2%の維持レベルまで減量し、十分な麻酔を維持しながら酸素速度を0.2リットル/分に維持する。
ニューマン・クールズ補正を用いて一元配置ANOVAによりデータを解析した。p値0.05未満を有意であるとした。
Sf2欠乏が血栓形成を予防する
これまでの試験から、静脈の血塊または血栓は大静脈結紮後から数時間にわたって発生し、約24時間後に最大になることがわかっている8。Sf2が初期の血栓発生に影響を及ぼすかどうかを明らかにするため、大静脈結紮から5時間後にマウスを検査した。大静脈を結紮せずに外科的処置を実施した偽処置マウスには、検出可能な血栓形成は認められなかった(図1Aおよび1B)。対照(Sf2+/+)マウスには大きな血栓が発達し、腸骨静脈に至るまで大静脈を塞いでいた。これに比較して、コンジェニックSf2欠乏(Sf2−/−)マウスでは血栓形成がほとんど消失していた。Sf2+/+マウスの典型的な静脈血栓の横断面を検査したところ、マルチウス・スカーレットブルー染色によって検出されるフィブリンに富む血栓による静脈閉塞が見られたが、Sf2−/−マウスには有意な血栓は認められなかった。静脈重量を考慮に入れると、Sf2+/+マウスの血栓重量は、Sf2−/−マウスに検出された血栓重量の3倍超であった(図1、p<0.001)。以上のデータをまとめると、Sf2欠乏が血栓形成を予防することがわかる。
Sf2抗体はSf2によって直接制御される血栓形成を阻害する
遺伝子欠失があると個体に代償性変化が生じ、これが結果に影響を及ぼすことがある。Sf2が血栓形成に直接寄与することを裏付けるため、静脈結紮の前に生理的レベルのSf2をマウスに投与した。Sf2を投与したSf2−/−マウスを対照Sf2+/+マウスと比較したところ、ほぼ同じ大きさの静脈血栓形成がみられた(図2)。これに対し、生理的量のヒトSf2を投与したSf2−/−マウスにはSf2−/−マウスの3倍超の大きさの血栓がみられた(p<0.001)。
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Claims (14)
- 必要とする個体の血栓形成を予防する医薬を製造するための組成物の使用であって、前記個体に、セルピンf2(Sf2)の活性を阻害するアンタゴニストとして作用する抗Sf2抗体またはその抗原結合フラグメントと薬学的に許容される担体とを含む前記組成物を血栓予防量投与する、使用。
- 前記Sf2抗体またはその抗原結合フラグメントが、モノクローナル抗体、組換え抗体または天然抗体、あるいはキメラ抗体、ヒト抗体またはヒト化抗体である、請求項1に記載の使用。
- 前記抗体が、MAb49もしくはMAb77またはその抗原結合フラグメント、あるいは4h9、27c9もしくはTS23またはその抗原結合フラグメントである、請求項1に記載の使用。
- 血栓形成が、外科手術、臥床、遺伝的異常、癌、外傷をはじめとする危険因子によって引き起こされるものである、請求項1から3のいずれか一項に記載の使用。
- 前記組成物と、抗凝固剤、プラスミノーゲン活性化因子、抗血小板剤および線維素溶解促進剤からなる群より選択される有効量の薬学的に活性な薬剤とを共投与することをさらに含む、請求項1から4のいずれか一項に記載の使用。
- リスクのある患者の血栓形成を予防する組成物であって、血栓予防量の、セルピンf2(Sf2)の活性を阻害するアンタゴニストとして作用する抗Sf2抗体またはその抗原結合フラグメントと、薬学的に許容される担体とを含む、組成物。
- 前記Sf2抗体またはその抗原結合フラグメントが、モノクローナル抗体、組換え抗体または天然抗体、あるいはキメラ抗体、ヒト抗体またはヒト化抗体である、請求項6に記載の組成物。
- 前記抗体が、MAb49もしくはMAb77またはその抗原結合フラグメント、あるいは4h9、27c9もしくはTS23またはその抗原結合フラグメントである、請求項6に記載の組成物。
- 血栓形成が、外科手術、臥床、遺伝的異常、癌、外傷をはじめとする危険因子によって引き起こされるものである、請求項6から8のいずれか一項に記載の組成物。
- 抗凝固剤、プラスミノーゲン活性化因子、抗血小板剤および線維素溶解促進剤からなる群より選択される有効量の薬学的に活性な薬剤をさらに含む、請求項6から9のいずれか一項に記載の組成物。
- リスクのある患者の血栓形成の予防のための組成物であって、血栓予防量の、セルピンf2(Sf2)の活性を阻害するアンタゴニストとして作用する抗Sf2抗体またはその抗原結合フラグメントと、薬学的に許容される担体とを含む、組成物。
- 前記Sf2抗体またはその抗原結合フラグメントが、モノクローナル抗体、組換え抗体または天然抗体、あるいはキメラ抗体、ヒト抗体またはヒト化抗体である、請求項11に記載の組成物。
- 前記抗体が、MAb49もしくはMAb77またはその抗原結合フラグメント、あるいは4h9、27c9もしくはTS23またはその抗原結合フラグメントである、請求項11に記載の組成物。
- 血栓形成が、外科手術、臥床、遺伝的異常、癌、外傷をはじめとする危険因子によって引き起こされるものである、請求項11から13のいずれか一項に記載の組成物。
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