JP4915918B2 - 第ＶＩＩ因子または第ＶＩＩａ因子のＧｌａドメイン変種 - Google Patents
第ＶＩＩ因子または第ＶＩＩａ因子のＧｌａドメイン変種 Download PDFInfo
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- JP4915918B2 JP4915918B2 JP2006515723A JP2006515723A JP4915918B2 JP 4915918 B2 JP4915918 B2 JP 4915918B2 JP 2006515723 A JP2006515723 A JP 2006515723A JP 2006515723 A JP2006515723 A JP 2006515723A JP 4915918 B2 JP4915918 B2 JP 4915918B2
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- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
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- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12Y—ENZYMES
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| DK1499719T3 (da) * | 2002-04-30 | 2011-02-28 | Bayer Healthcare Llc | Faktor VII- eller VIIa-polypeptidvarianter |
| ES2386010T3 (es) * | 2003-03-20 | 2012-08-07 | Bayer Healthcare Llc | Variantes de FVII o FVIIa |
| PL1781782T3 (pl) | 2004-08-17 | 2010-10-29 | Csl Behring Gmbh | Zmodyfikowane polipeptydy zależne od witaminy K |
| EP1893230A2 (en) * | 2005-04-26 | 2008-03-05 | Maxygen Holdings Ltd. | Use of modified factor vii for treating bleeding |
| WO2006134173A2 (en) | 2005-06-17 | 2006-12-21 | Novo Nordisk Health Care Ag | Selective reduction and derivatization of engineered proteins comprising at least one non-native cysteine |
| WO2007006808A1 (en) | 2005-07-13 | 2007-01-18 | Novo Nordisk Health Care Ag | Host cell protein knock-out cells for production of therapeutic proteins |
| US20070129298A1 (en) * | 2005-07-22 | 2007-06-07 | Maxygen Holdings, Ltd. | In-solution activation of factor vii |
| JP5894722B2 (ja) | 2005-09-01 | 2016-03-30 | ノボ ノルディスク ヘルス ケア アーゲー | 第ｖｉｉ因子ポリペプチドの疎水性相互作用クロマトグラフィ精製 |
| WO2007031559A2 (en) | 2005-09-14 | 2007-03-22 | Novo Nordisk Health Care Ag | Human coagulation factor vii polypeptides |
| EP2423307A1 (en) * | 2006-06-19 | 2012-02-29 | Catalyst Biosciences, Inc. | Modified coagulation factor IV polypeptides and use thereof for treatment |
| JP5570809B2 (ja) | 2006-09-01 | 2014-08-13 | ノボ ノルディスク ヘルス ケア アーゲー | 修飾タンパク質 |
| FR2910969B1 (fr) * | 2006-12-29 | 2009-02-27 | Lab Francais Du Fractionnement | Procede de mesure de la concentration de facteur viia (fviia) dans un echantillon |
| EP1952822A1 (en) * | 2007-01-26 | 2008-08-06 | Novo Nordisk A/S | Factor VII polypeptides with increased affinity to platelets |
| SI2147096T1 (sl) | 2007-04-13 | 2015-07-31 | Catalyst Biosciences, Inc., | Modificirani polipeptidi faktorja VII in njihove uporabe |
| TWI465247B (zh) * | 2008-04-11 | 2014-12-21 | Catalyst Biosciences Inc | 經修飾的因子ｖｉｉ多肽和其用途 |
| WO2010149172A2 (en) | 2009-06-24 | 2010-12-29 | Rigshospitalet | SYSTEMIC PRO-HEMOSTATIC EFFECT OF CLOTTING FACTORS IN COMBINATION WITH SYMPATHICOMIMETICS WITH AGONISTIC EFFECTS ON α-ADRENERGIC AND/OR β-ADRENERGIC RECEPTORS OF THE SYMPATHETIC NERVOUS SYSTEM, RELATED TO IMPROVED CLOT STRENGTH. |
| FR2947181B1 (fr) * | 2009-06-26 | 2012-05-04 | Lfb Biotechnologies | Composition de facteur vii |
| US12203113B2 (en) | 2009-07-09 | 2025-01-21 | Opko Biologics Ltd. | Long-acting coagulation factors and methods of producing same |
| TWI595004B (zh) | 2010-11-03 | 2017-08-11 | 介控生化科技公司 | 經修飾之第九因子多胜肽及其用途 |
| PL3165232T3 (pl) * | 2012-12-24 | 2019-12-31 | Coagulant Therapeutics Corporation | Krótko działające polipeptydy czynnika VII |
| FI3524617T3 (fi) | 2013-03-15 | 2023-06-26 | Gladiator Biosciences Inc | Gla-domeenit terapeuttisina aineina |
| CN104211802B (zh) * | 2013-05-29 | 2018-07-27 | 成都渊源生物科技有限公司 | 人凝血因子轻链蛋白及其应用 |
| PE20171380A1 (es) | 2014-12-10 | 2017-09-15 | Opko Biologics Ltd | Metodos de produccion de polipeptidos de hormona de crecimiento modificada por ctp de accion prolongada |
| US20190153119A1 (en) * | 2016-04-14 | 2019-05-23 | Iconic Therapeutics, Inc. | Compositions and methods for treating disorders associated with neovascularization |
| US11976106B2 (en) | 2016-07-11 | 2024-05-07 | Opko Biologics Ltd. | Long-acting coagulation factors and methods of producing same |
| KR20200050961A (ko) | 2017-09-05 | 2020-05-12 | 글래디에이터 바이오사이언시스 인코포레이티드 | 줄기세포로의 페이로드의 전달 |
| CN114728044A (zh) | 2019-08-15 | 2022-07-08 | 介控生化科技公司 | 用于皮下施用和按需求治疗的经修饰的因子vii多肽 |
Family Cites Families (64)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GR860984B (en) * | 1985-04-17 | 1986-08-18 | Zymogenetics Inc | Expression of factor vii and ix activities in mammalian cells |
| ZA862768B (en) * | 1985-04-17 | 1986-12-30 | Zymogenetics Inc | Expression of factor vii and ix activities in mammalian cells |
| US5180583A (en) * | 1985-11-26 | 1993-01-19 | Hedner Ulla K E | Method for the treatment of bleeding disorders |
| US5258288A (en) * | 1986-07-25 | 1993-11-02 | Genzyme Corporation | Vector containing DNA encoding mature human protein S |
| DK323587D0 (da) | 1987-06-25 | 1987-06-25 | Novo Industri As | Protein |
| JP2799316B2 (ja) | 1987-06-12 | 1998-09-17 | ヘキスト・マリオン・ルセル株式会社 | 雑種ヒトプロテインｃおよびその遺伝子工学的製法 |
| US4904584A (en) * | 1987-12-23 | 1990-02-27 | Genetics Institute, Inc. | Site-specific homogeneous modification of polypeptides |
| US5648254A (en) * | 1988-01-15 | 1997-07-15 | Zymogenetics, Inc. | Co-expression in eukaryotic cells |
| JPH0246296A (ja) | 1988-08-09 | 1990-02-15 | Hoechst Japan Ltd | 雑種プロテインｃ及びその製造方法 |
| US5218092A (en) | 1988-09-29 | 1993-06-08 | Kyowa Hakko Kogyo Co., Ltd. | Modified granulocyte-colony stimulating factor polypeptide with added carbohydrate chains |
| US5041376A (en) * | 1988-12-09 | 1991-08-20 | The Board Of Regents Of The University Of Texas System | Method for identifying or shielding functional sites or epitopes of proteins that enter the exocytotic pathway of eukaryotic cells, the mutant proteins so produced and genes encoding said mutant proteins |
| US5093317A (en) * | 1989-06-05 | 1992-03-03 | Cephalon, Inc. | Treating disorders by application of insulin-like growth factor |
| US5580560A (en) * | 1989-11-13 | 1996-12-03 | Novo Nordisk A/S | Modified factor VII/VIIa |
| US5225537A (en) * | 1989-12-29 | 1993-07-06 | Zymogenetics, Inc. | Methods for producing hybrid phospholipid-binding proteins |
| WO1991011519A1 (en) | 1990-01-26 | 1991-08-08 | Immuno Aktiengesellschaft | Recombinantly produced blood factors and process for the expression of said blood factors, as well as vaccinia virus recombinants used in said process |
| AU651573B2 (en) * | 1990-01-29 | 1994-07-28 | Novo Nordisk Health Care Ag | Anticoagulant proteins |
| US5583107A (en) | 1990-09-04 | 1996-12-10 | Cor Therapeutics, Inc. | Agents affecting thrombosis and hemostasis |
| US5531916A (en) * | 1990-10-03 | 1996-07-02 | E. I. Du Pont De Nemours And Company | Hydrofluorocarbon cleaning compositions |
| ES2109336T3 (es) * | 1990-11-26 | 1998-01-16 | Genetics Inst | Expresion de pace en celulas huesped y metodos de utilizacion de la misma. |
| US5861374A (en) * | 1991-02-28 | 1999-01-19 | Novo Nordisk A/S | Modified Factor VII |
| US5817788A (en) * | 1991-02-28 | 1998-10-06 | Zymogenetics, Inc. | Modified factor VII |
| US5788965A (en) * | 1991-02-28 | 1998-08-04 | Novo Nordisk A/S | Modified factor VII |
| US5833982A (en) * | 1991-02-28 | 1998-11-10 | Zymogenetics, Inc. | Modified factor VII |
| EP0575464B1 (en) | 1991-02-28 | 2004-08-11 | Zymogenetics, Inc. | Modified factor vii |
| US5504064A (en) * | 1991-04-10 | 1996-04-02 | Oklahoma Medical Research Foundation | Treatment of bleeding with modified tissue factor in combination with an activator of FVII |
| JPH0720127A (ja) * | 1993-05-07 | 1995-01-24 | Eisai Co Ltd | 各種ｐｉｖｋａの測定方法および測定試薬 |
| HU219682B (hu) | 1993-05-21 | 2001-06-28 | Novo Nordisk A/S. | Módosított VII faktor |
| DE19531637A1 (de) * | 1995-08-28 | 1997-03-06 | Immuno Ag | Pharmazeutische Zusammensetzung zur Behandlung von Blutgerinnungsstörugnen, Verfahren zur Herstellung derselben und deren Verwendung |
| US5847085A (en) * | 1996-11-08 | 1998-12-08 | Oklahoma Medical Research Foundation | Modified protein C and methods of use thereof |
| US5837843A (en) * | 1996-11-08 | 1998-11-17 | Oklahoma Medical Research Foundation | Modified protein C |
| DE69800640T2 (de) | 1997-01-29 | 2001-07-05 | Polymasc Pharmaceuticals Plc, London | Pegylationsverfahren |
| WO1998035026A1 (en) | 1997-02-06 | 1998-08-13 | Novo Nordisk A/S | Polypeptide-polymer conjugates having added and/or removed attachment groups |
| AT407255B (de) * | 1997-06-20 | 2001-02-26 | Immuno Ag | Rekombinanter zellklon mit erhöhter stabilität in serum- und proteinfreiem medium und verfahren zur gewinnung des stabilen zellklons |
| US6475725B1 (en) * | 1997-06-20 | 2002-11-05 | Baxter Aktiengesellschaft | Recombinant cell clones having increased stability and methods of making and using the same |
| EP1881005B1 (en) | 1997-07-14 | 2013-04-03 | Bolder Biotechnology, Inc. | Derivatives of G-CSF and related proteins |
| ES2339196T3 (es) | 1997-07-18 | 2010-05-17 | Novo Nordisk Health Care Ag | Uso de fviia o fviiai para el tratamiento de disfuncion endotelial y para la inhibicion de angiogenesis, respectivamente. |
| US6747003B1 (en) * | 1997-10-23 | 2004-06-08 | Regents Of The University Of Minnesota | Modified vitamin K-dependent polypeptides |
| US7247708B2 (en) * | 1997-10-23 | 2007-07-24 | Regents Of The University Of Minnesota | Modified vitamin K-dependent polypeptides |
| US6693075B1 (en) * | 1997-10-23 | 2004-02-17 | Regents Of The University Of Minnesota | Modified vitamin K-dependent polypeptides |
| US6017882A (en) * | 1997-10-23 | 2000-01-25 | Regents Of The University Of Minnesota | Modified vitamin K-dependent polypeptides |
| AT408613B (de) | 1998-06-17 | 2002-01-25 | Immuno Ag | Pharmazeutisches faktor vii-präparat |
| DE69916306T2 (de) | 1998-10-30 | 2005-05-04 | Novozymes A/S | Niedrigallergene proteinvarianten |
| WO2000026354A1 (en) | 1998-10-30 | 2000-05-11 | Novozymes A/S | Glycosylated proteins having reduced allergenicity |
| AU1262900A (en) | 1998-11-06 | 2000-05-29 | Novo Nordisk A/S | Method for the production of fvii |
| WO2000054787A1 (en) | 1999-03-16 | 2000-09-21 | The Children's Hospital Of Philadelphia | Enhanced gamma-carboxylation of recombinant vitamin k-dependent clotting factors |
| US6806063B2 (en) * | 2000-02-11 | 2004-10-19 | Maxygen Aps | Factor VII or VIIa-like molecules |
| US7220837B1 (en) * | 2000-04-28 | 2007-05-22 | Regents Of The University Of Minnesota | Modified vitamin K-dependent polypeptides |
| JP4455802B2 (ja) | 2000-05-03 | 2010-04-21 | ノボ ノルディスク ヘルス ケア アクチェンゲゼルシャフト | ヒト第ｖｉｉ凝固因子変異型 |
| US20030211094A1 (en) * | 2001-06-26 | 2003-11-13 | Nelsestuen Gary L. | High molecular weight derivatives of vitamin k-dependent polypeptides |
| US7160540B2 (en) * | 2000-06-30 | 2007-01-09 | Regents Of The University Of Minnesota | Methods for detecting activity of clottings factors |
| US6423826B1 (en) | 2000-06-30 | 2002-07-23 | Regents Of The University Of Minnesota | High molecular weight derivatives of vitamin K-dependent polypeptides |
| MXPA03001984A (es) * | 2000-09-13 | 2003-08-29 | Novo Nordisk Healthcare Ag | Variantes de factor vii de coagulacion humano. |
| HUP0301246A3 (en) | 2000-09-13 | 2005-12-28 | Novo Nordisk Healthcare Ag | Human coagulation factor vii variants |
| HUP0301267A3 (en) * | 2000-10-02 | 2005-12-28 | Novo Nordisk Healthcare Ag | Factor vii glycoforms |
| WO2002038162A1 (en) | 2000-11-09 | 2002-05-16 | The Scripps Research Institute | MODIFIED FACTOR VIIa |
| AU2002249096B2 (en) | 2001-03-22 | 2007-06-28 | Novo Nordisk Health Care Ag | Coagulation factor VII derivatives |
| ATE532858T1 (de) | 2001-09-27 | 2011-11-15 | Novo Nordisk Healthcare Ag | Menschliche gerinnungsfaktor-vii-polypeptide |
| AU2002336919A1 (en) | 2001-11-02 | 2003-05-12 | Novo Nordisk Health Care Ag | Human coagulation factor vii polypeptides |
| WO2003055512A1 (en) | 2001-12-21 | 2003-07-10 | Novo Nordisk Health Care Ag | Liquid composition of factor vii polypeptides |
| DK1499719T3 (da) * | 2002-04-30 | 2011-02-28 | Bayer Healthcare Llc | Faktor VII- eller VIIa-polypeptidvarianter |
| JP4472526B2 (ja) | 2002-09-30 | 2010-06-02 | バイエル ヘルスケア エルエルシー | 凝血活性が増加した第ＶＩＩ因子または第ＶＩＩａ因子変種 |
| ES2386010T3 (es) | 2003-03-20 | 2012-08-07 | Bayer Healthcare Llc | Variantes de FVII o FVIIa |
| US20060116324A1 (en) * | 2003-06-13 | 2006-06-01 | Novo Nordisk Healthcare A/G | Novel formulations |
| RU2373282C2 (ru) * | 2003-06-19 | 2009-11-20 | Байер Хелткэр Ллк | ВАРИАНТЫ ДОМЕНА GLA ФАКТОРА VII ИЛИ VIIa |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2012105650A (ja) * | 2003-06-19 | 2012-06-07 | Bayer Healthcare Llc | 第ＶＩＩ因子または第ＶＩＩａ因子のＧｌａドメイン変種 |
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