KR960705921A - 사람 활성화 단백질 C제제 및 이의 제조 방법(Human activated protein C preparation and process for producing the same) - Google Patents

사람 활성화 단백질 C제제 및 이의 제조 방법(Human activated protein C preparation and process for producing the same)

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Publication number
KR960705921A
KR960705921A KR1019960702106A KR19960702106A KR960705921A KR 960705921 A KR960705921 A KR 960705921A KR 1019960702106 A KR1019960702106 A KR 1019960702106A KR 19960702106 A KR19960702106 A KR 19960702106A KR 960705921 A KR960705921 A KR 960705921A
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South Korea
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protein
human
thrombin
solution containing
activated protein
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KR1019960702106A
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KR100383063B1 (ko
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요이치 오가타
토시노부 노우치
신지 나카히라
Original Assignee
노나카 사네오
자이단호진 가가꾸 오요비 게세이 료호 겐규쇼
이타가키 히로시
테이진 가부시키가이샤
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Publication of KR960705921A publication Critical patent/KR960705921A/ko
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    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N9/00—Enzymes; Proenzymes; Compositions thereof; Processes for preparing, activating, inhibiting, separating or purifying enzymes
    • C12N9/14—Hydrolases (3)
    • C12N9/48—Hydrolases (3) acting on peptide bonds (3.4)
    • C12N9/50—Proteinases, e.g. Endopeptidases (3.4.21-3.4.25)
    • C12N9/64—Proteinases, e.g. Endopeptidases (3.4.21-3.4.25) derived from animal tissue
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N9/00—Enzymes; Proenzymes; Compositions thereof; Processes for preparing, activating, inhibiting, separating or purifying enzymes
    • C12N9/14—Hydrolases (3)
    • C12N9/48—Hydrolases (3) acting on peptide bonds (3.4)
    • C12N9/50—Proteinases, e.g. Endopeptidases (3.4.21-3.4.25)
    • C12N9/64—Proteinases, e.g. Endopeptidases (3.4.21-3.4.25) derived from animal tissue
    • C12N9/6421—Proteinases, e.g. Endopeptidases (3.4.21-3.4.25) derived from animal tissue from mammals
    • C12N9/6424—Serine endopeptidases (3.4.21)
    • C12N9/6464—Protein C (3.4.21.69)
    • 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
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Y—ENZYMES
    • C12Y304/00—Hydrolases acting on peptide bonds, i.e. peptidases (3.4)
    • C12Y304/21—Serine endopeptidases (3.4.21)
    • C12Y304/21069—Protein C activated (3.4.21.69)
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y10—TECHNICAL SUBJECTS COVERED BY FORMER USPC
    • Y10S—TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y10S530/00—Chemistry: natural resins or derivatives; peptides or proteins; lignins or reaction products thereof
    • Y10S530/827—Proteins from mammals or birds
    • Y10S530/829—Blood
    • Y10S530/83—Plasma; serum
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y10—TECHNICAL SUBJECTS COVERED BY FORMER USPC
    • Y10S—TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y10S530/00—Chemistry: natural resins or derivatives; peptides or proteins; lignins or reaction products thereof
    • Y10S530/855—Proteins from animals other than mammals or birds
    • Y10S530/856—Snakes; venom

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Organic Chemistry (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Wood Science & Technology (AREA)
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  • Zoology (AREA)
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  • General Engineering & Computer Science (AREA)
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  • Microbiology (AREA)
  • Biotechnology (AREA)
  • Molecular Biology (AREA)
  • General Chemical & Material Sciences (AREA)
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  • Chemical Kinetics & Catalysis (AREA)
  • Diabetes (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • Hematology (AREA)
  • Veterinary Medicine (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Peptides Or Proteins (AREA)
  • Preparation Of Compounds By Using Micro-Organisms (AREA)
  • Enzymes And Modification Thereof (AREA)
  • Compounds Of Unknown Constitution (AREA)

Abstract

본 발명은 실질적으로 트롬빈 또는 등가의 프로테아제 및/또는 활성화되지 않은 단백질 C를 함유하지 않으며 높은 비활성을 갖는 사람 활성화 단백질 C 제제 및 그를 제조하는 방법에 관한 것이다.
사람 활성화 단백질 C 제제는 3500U/㎎ 또는 그 이상의 비활성(여기에서 비활성 단위는 정상인 혈장의 활성화된 트롬보플라스틴 시간(APTT)을 2배 연장시키는 APC의 양으로 정의된다)을 나타내며, 실질적으로 트롬빈 또는 등가의 프로테아제 및/또는 활성화되지 않은 단백질 C를 함유하지 않는다. 이 제제는 트롬빈 또는 등가의 프로테아제로 사람 단백질 C를 활성화시킨 후, 사람 활성화 단백질 C를 함유하는 용액을 양이온 교환체와 접촉시켜 트롬빈 및 활성화 단백질 C를 교환체에 흡착시키고, 사람 활성화 단백질 C만을 단독으로 용출 시킴을 특징으로 하는 사람 활성화 단백질 C를 정제하는 방법에 의해 제조된다.

Description

사람 활성화 단백질 C제제 및 이의 제조 방법(Human activated protein C preparation andprocess for producing the same)
본 내용은 요부공개 건이므로 전문내용을 수록하지 않았음
제1도는 본 발명의 제제 및 통상적인 제제에 대한 SDS-PAGE의 결과를 나타낸다.

Claims (5)

  1. 3500U/㎎ 또는 그 이상의 비활성(여기에서 비활성 단위는 정상인 혈장의 활성화된 트롬보플라스틴 시간(APTT)을 2배 연장시키는 APC의 양으로 정의된다)을 갖고, 실질적으로 트롬빈 또는 등가의 프로테아제 및/또는 활성화되지 않은 단백질 C를 함유하지 않은 사람 활성화 단백질 C 제제.
  2. 제1항에 있어서, 비활성이 4000U/㎎ 또는 그 이상의 사람 활성화 단백질 C 제제.
  3. 제1항 또는 2항에 있어서, 활성화되지 않은 단백질 C를 트롬빈 또는 등가의 프로테아제로 활성화시켜 제조한 사람 활성화 단백질 C 제제.
  4. 트롬빈 또는 등가의 프로테아제로 사람 단백질 C를 활성화시킨 후, 사람 활성화 단백질 C를 함유하는 용액을 pH 5.0 내지 6.0 및 80mM 이하의 염 농도의 조건하에서 양이온 교환체와 접촉시켜 트롬빈 및 활성화 단백질 C를 교환체에 흡착시키고, 사람 활성화 단백질 C만을 0.1 내지 0.35M의 농도의 조건하에서 용출시킴을 특징으로 하여, 사람 활성화 단백질 C를 정제하는 방법.
  5. (1) 사람 단백질 C를 함유하는 용액을 음이온 교환체와 접촉시켜 단백질 C를 교환체에 흡착시킨 후, 단백질 C를 용출시켜 Gla 도메인(domain)을 갖는 사람 단백질 C 분획을 제조하고; (2) 사람 단백질 C를 함유하는 용액을 칼슘의 존재하에서, 칼슘 이온에 결합된 단백질 C를 특이적으로 인식하는 항체를 불용성 담체에 결합시켜 형성된 흡착제와 접촉시켜 단백질 C를 흡착시키고, 이로부터 스트레이트 완충용액을 사용하여 단백질 C를 용출시키고; (3) 단백질 C를 함유하는 용액을 음이온 교환체와 접촉시켜 단백질 C를 교환체에 흡착시킨 후, 이로부터 단백질 C를 용출시켜 상기 단백질 C를 함유하는 용액으로부터 단백질 C에 대한 항체를 제고하고; (4) 사람 단백질 C를 함유하는 용액에 pH6.0 내지 8.0의 조건하에서 트롬빈을 트롬빈／단백질 C 1 내지 20U/㎎의 비율로 첨가하여 사람 단백질 C를 트롬빈 또는 등가의 프로테아제로 활성화시키고; (5) 활성화시킨 후 사람 단백질 C를 함유하는 용액을 pH 5.0 내지 6.0 및 80mM 또는 그 미만의 염 농도의 조건하에서 양이온 교환체와 접촉시켜 트롬빈 및 활성화 단백질 C를 모두 교환체에 흡착시킨 후, 0.1 내지 0.35M의 농도의 조건하에서 사람 활성화 단백질 C만을 용출시켜 회수하는 단계를 포함함을 특징으로 하여, 제1항에 따른 사람 활성화 단백질 C를 제조하는 방법.
    ※ 참고사항 : 최초출원 내용에 의하여 공개하는 것임.
KR1019960702106A 1993-10-29 1994-10-27 사람활성화단백질c제제및이의제조방법 KR100383063B1 (ko)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
JP5292499A JP3043558B2 (ja) 1993-10-29 1993-10-29 ヒト活性化プロテインｃ調製物及びその製法
JP292499/1993 1993-10-29

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KR960705921A true KR960705921A (ko) 1996-11-08
KR100383063B1 KR100383063B1 (ko) 2003-07-07

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US (1) US5831025A (ko)
EP (1) EP0726311B1 (ko)
JP (1) JP3043558B2 (ko)
KR (1) KR100383063B1 (ko)
CN (1) CN1123639C (ko)
AT (1) ATE270327T1 (ko)
AU (1) AU680563B2 (ko)
CA (1) CA2175201C (ko)
DE (1) DE69433875T2 (ko)
ES (1) ES2224109T3 (ko)
WO (1) WO1995011966A1 (ko)

Families Citing this family (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2886061B2 (ja) * 1993-10-29 1999-04-26 財団法人化学及血清療法研究所 プロテインｃもしくは活性化プロテインｃの安定化方法及び安定化組成物
IL132325A (en) 1997-04-28 2005-07-25 Lilly Co Eli Activated protein c formulations
US6630137B1 (en) * 1997-04-28 2003-10-07 Eli Lilly And Company Activated protein C formulations
US7204981B2 (en) 2000-03-28 2007-04-17 Eli Lilly And Company Methods of treating diseases with activated protein C
EP1289543A2 (en) 2000-05-24 2003-03-12 Eli Lilly And Company Formulations and methods for treating hypercoagulable states
WO2003007686A2 (en) * 2001-07-19 2003-01-30 Dmi Biosciences, Inc. Use of copper chelators to inhibit the inactivation of protein c
WO2003075834A2 (en) * 2002-03-08 2003-09-18 Eli Lilly And Company Activated protein c formulations
US20060094650A1 (en) * 2002-12-27 2006-05-04 Juridical Foundation The Chemo-Sero- Therapeutic Research Institute Agent for improving life expectancy in therapy of malignant tumor
BR112015000051A2 (pt) 2012-07-04 2017-06-27 Univ Sydney tratamento de distúrbios inflamatórios da pele
CA2946028C (en) 2014-04-16 2022-10-11 Zz Biotech Llc Treatment of abnormal cutaneous scarring

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US4968626A (en) * 1985-08-15 1990-11-06 Board Of Reagents Of The University Of Washington DNA sequence coding for protein C
WO1989012685A1 (en) * 1987-05-18 1989-12-28 Integrated Genetics, Inc. Improved protein c molecules and method for making and activating same
US5084274A (en) * 1987-11-17 1992-01-28 Scripps Clinic And Research Foundation Inhibition of arterial thrombotic occlusion or thromboembolism
WO1991000912A1 (en) * 1989-07-07 1991-01-24 Massachusetts Institute Of Technology Production and use of hybrid protease inhibitors
WO1991012320A1 (en) * 1990-02-09 1991-08-22 Zymogenetics, Inc. Activated protein c with truncated light chain
AT402262B (de) * 1991-06-20 1997-03-25 Immuno Ag Arzneimittel enthaltend aktiviertes protein c
JPH0564588A (ja) * 1991-08-14 1993-03-19 Teijin Ltd 短い重鎖を有するヒトプロテインｃおよび活性化ヒトプロテインｃ

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CA2175201C (en) 2007-06-12
CN1123639C (zh) 2003-10-08
KR100383063B1 (ko) 2003-07-07
WO1995011966A1 (fr) 1995-05-04
DE69433875D1 (de) 2004-08-05
CA2175201A1 (en) 1995-05-04
EP0726311B1 (en) 2004-06-30
JPH07115972A (ja) 1995-05-09
ATE270327T1 (de) 2004-07-15
AU680563B2 (en) 1997-07-31
EP0726311A4 (en) 1997-06-11
AU8003294A (en) 1995-05-22
EP0726311A1 (en) 1996-08-14
DE69433875T2 (de) 2005-07-14
US5831025A (en) 1998-11-03
CN1138349A (zh) 1996-12-18
JP3043558B2 (ja) 2000-05-22
ES2224109T3 (es) 2005-03-01

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