JP2013532176A - 安定化させた第ｖｉｉｉ因子バリアント - Google Patents
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- A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
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- A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
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- A61K47/61—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule the organic macromolecular compound being a polysaccharide or a derivative thereof
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- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
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Landscapes
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- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Medicines Containing Material From Animals Or Micro-Organisms (AREA)
- Medicinal Preparation (AREA)
Applications Claiming Priority (5)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| EP10169592 | 2010-07-15 | ||
| EP10169592.2 | 2010-07-15 | ||
| US36547810P | 2010-07-19 | 2010-07-19 | |
| US61/365,478 | 2010-07-19 | ||
| PCT/EP2011/061349 WO2012007324A2 (en) | 2010-07-15 | 2011-07-06 | Stabilized factor viii variants |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JP2013532176A true JP2013532176A (ja) | 2013-08-15 |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2023542388A (ja) * | 2020-09-23 | 2023-10-06 | アブレヴィア バイオテック ゲーエムベーハー | 第ｖｉｉｉ因子補充療法の有効性を増加させるための化合物 |
Families Citing this family (23)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US7855279B2 (en) | 2005-09-27 | 2010-12-21 | Amunix Operating, Inc. | Unstructured recombinant polymers and uses thereof |
| DK3178835T3 (da) | 2009-02-03 | 2019-06-24 | Amunix Pharmaceuticals Inc | Forlængede rekombinante polypeptider og sammensætninger omfattende samme |
| CN102741422B (zh) | 2009-08-24 | 2016-06-08 | 阿穆尼克斯运营公司 | 凝血因子ⅶ组合物及其制备和使用方法 |
| US20130017997A1 (en) * | 2010-08-19 | 2013-01-17 | Amunix Operating Inc. | Factor VIII Compositions and Methods of Making and Using Same |
| JP6141834B2 (ja) | 2011-06-06 | 2017-06-07 | ノヴォ ノルディスク アー／エス | 治療抗体 |
| EP2814840B1 (en) * | 2012-02-15 | 2019-11-13 | Bioverativ Therapeutics Inc. | Factor viii compositions and methods of making and using same |
| JP6383666B2 (ja) | 2012-02-15 | 2018-08-29 | バイオベラティブ セラピューティクス インコーポレイテッド | 組換え第ｖｉｉｉ因子タンパク質 |
| EP2841091A1 (en) * | 2012-04-24 | 2015-03-04 | Novo Nordisk A/S | Pharmaceutical composition suitable for treatment of haemophilia |
| CN104661685A (zh) | 2012-10-15 | 2015-05-27 | 诺和诺德保健Ag（股份有限公司） | 因子vii缀合物 |
| UY35343A (es) * | 2013-02-26 | 2014-09-30 | Bayer Healthcare Llc | Formulaciones y procedimientos para la producción de proteína recombinante aumentada |
| EP3904376B1 (en) | 2013-06-24 | 2024-11-13 | Xiao, Weidong | Mutant factor viii compositions and methods |
| EP3033097B1 (en) | 2013-08-14 | 2021-03-10 | Bioverativ Therapeutics Inc. | Factor viii-xten fusions and uses thereof |
| US9371370B2 (en) | 2013-10-15 | 2016-06-21 | Novo Nordisk Healthcare Ag | Coagulation factor VII polypeptides |
| US20160252519A1 (en) * | 2013-10-18 | 2016-09-01 | Dr. Reddy's Laboratories Limited | In-vitro method for determining fate of polypeptide variant |
| WO2015132724A1 (en) | 2014-03-05 | 2015-09-11 | Pfizer Inc. | Improved muteins of clotting factor viii |
| DK3177317T3 (en) | 2014-08-04 | 2020-06-15 | Csl Ltd | Factor viii formulation |
| AU2016231327B2 (en) | 2015-03-06 | 2018-08-09 | CSL Behring Lengnau AG | Modified von Willebrand factor having improved half-life |
| WO2017024060A1 (en) | 2015-08-03 | 2017-02-09 | Biogen Ma Inc. | Factor ix fusion proteins and methods of making and using same |
| IL266972B2 (en) | 2016-12-02 | 2024-04-01 | Bioverativ Therapeutics Inc | Methods of treating hemophilic arthropathy using chimeric clotting factors |
| CA3099049A1 (en) | 2018-05-18 | 2019-11-21 | Bioverativ Therapeutics Inc. | Methods of treating hemophilia a |
| JP7780341B2 (ja) | 2019-07-04 | 2025-12-04 | ツェー・エス・エル・ベーリング・レングナウ・アクチエンゲゼルシャフト | 第ＶＩＩＩ凝固因子のｉｎ ｖｉｔｒｏでの安定性を向上させるための切断型フォン・ヴィレブランド因子（ＶＷＦ） |
| EP4051703A1 (en) * | 2019-11-01 | 2022-09-07 | Freeline Therapeutics Limited | Factor viii polypeptide |
| JP7680442B2 (ja) | 2019-11-11 | 2025-05-20 | ツェー・エス・エル・ベーリング・レングナウ・アクチエンゲゼルシャフト | 第ｖｉｉｉ因子に対する寛容を誘導するためのポリペプチド |
Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2005500831A (ja) * | 2001-06-14 | 2005-01-13 | ザ スクリプス リサーチ インスティチュート | 操作されたジスルフィド結合を有する安定化蛋白質 |
| JP2008546670A (ja) * | 2005-06-17 | 2008-12-25 | 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 | 少なくとも１つの非天然のシステインを含んでいる操作されたタンパク質の選択的な還元および誘導体化 |
| JP2008546671A (ja) * | 2005-06-17 | 2008-12-25 | ノボ ノルディスク ヘルス ケア アーゲー | 二量体及び多量体ＦＶＩＩａ化合物 |
| WO2009108806A1 (en) * | 2008-02-27 | 2009-09-03 | Novo Nordisk A/S | Conjugated factor viii molecules |
| JP2009532351A (ja) * | 2006-03-31 | 2009-09-10 | バクスター・インターナショナル・インコーポレイテッド | ペグ化第ｖｉｉｉ因子 |
| WO2010045568A1 (en) * | 2008-10-17 | 2010-04-22 | Baxter International Inc. | Modified blood factors comprising a low degree of water soluble polymer |
Family Cites Families (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| AU2645588A (en) | 1987-12-04 | 1989-06-15 | Scripps Clinic And Research Foundation | The von willebrand factor binding domain of factor viii |
| US5824784A (en) | 1994-10-12 | 1998-10-20 | Amgen Inc. | N-terminally chemically modified protein compositions and methods |
| PL193352B1 (pl) | 1998-04-28 | 2007-02-28 | Applied Research Systems | Koniugat poliol-interferon ß, sposób jego wytwarzania i jego zastosowanie oraz kompozycja farmaceutyczna |
| DK2322229T3 (en) | 2001-10-10 | 2017-03-27 | Novo Nordisk As | Remodeling and Glycoconjugation of Factor IX |
| AU2006226782B2 (en) | 2005-03-24 | 2011-12-08 | Ratiopharm Gmbh | Expression of soluble, active eukaryotic glycosyltransferases in prokaryotic organisms |
| WO2006103298A2 (en) * | 2005-04-01 | 2006-10-05 | Novo Nordisk Health Care Ag | Blood coagulation fviii analogues |
| US20090048440A1 (en) | 2005-11-03 | 2009-02-19 | Neose Technologies, Inc. | Nucleotide Sugar Purification Using Membranes |
| US20080248959A1 (en) * | 2006-07-21 | 2008-10-09 | Neose Technologies, Inc. | Glycosylation of peptides via o-linked glycosylation sequences |
-
2011
- 2011-07-06 CN CN2011800348298A patent/CN102971006A/zh not_active Withdrawn
- 2011-07-06 US US13/808,204 patent/US20130183280A1/en not_active Abandoned
- 2011-07-06 JP JP2013519027A patent/JP2013532176A/ja not_active Ceased
- 2011-07-06 EP EP11735405.0A patent/EP2593130A2/en not_active Withdrawn
- 2011-07-06 WO PCT/EP2011/061349 patent/WO2012007324A2/en not_active Ceased
-
2016
- 2016-06-01 US US15/170,502 patent/US20160264645A1/en not_active Abandoned
Patent Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2005500831A (ja) * | 2001-06-14 | 2005-01-13 | ザ スクリプス リサーチ インスティチュート | 操作されたジスルフィド結合を有する安定化蛋白質 |
| JP2008546670A (ja) * | 2005-06-17 | 2008-12-25 | 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 | 少なくとも１つの非天然のシステインを含んでいる操作されたタンパク質の選択的な還元および誘導体化 |
| JP2008546671A (ja) * | 2005-06-17 | 2008-12-25 | ノボ ノルディスク ヘルス ケア アーゲー | 二量体及び多量体ＦＶＩＩａ化合物 |
| JP2009532351A (ja) * | 2006-03-31 | 2009-09-10 | バクスター・インターナショナル・インコーポレイテッド | ペグ化第ｖｉｉｉ因子 |
| WO2009108806A1 (en) * | 2008-02-27 | 2009-09-03 | Novo Nordisk A/S | Conjugated factor viii molecules |
| WO2010045568A1 (en) * | 2008-10-17 | 2010-04-22 | Baxter International Inc. | Modified blood factors comprising a low degree of water soluble polymer |
Non-Patent Citations (4)
| Title |
|---|
| JPN6015028291; Ａ． Ｊ． ＧＡＬＥ: 'Ｉｎｔｒｉｎｓｉｃ ｓｔａｂｉｌｉｔｙ ａｎｄ ｆｕｎｃｔｉｏｎａｌ ｐｒｏｐｅｒｔｉｅｓ ｏｆ ｄｉｓｕｌｆｉｄｅ ｂｏｎｄ-ｓｔａｂｉｌｉｚｅｄ ｃｏａｇｕｌａｔｉｏｎ ｆａｃｔｏｒ ＶＩＩＩａ' Ｊｏｕｒｎａｌ ｏｆ Ｔｈｒｏｍｂｏｓｉｓ ａｎｄ Ｈａｅｍｏｓｔａｓｉｓ Ｖｏｌ．４, 2006, Ｐａｇｅｓ １３１５-１３２２ * |
| JPN6015028292; Ａ． Ｊ． ＧＡＬＥ: 'Ａｎ ｅｎｇｉｎｅｅｒｅｄ ｉｎｔｅｒｄｏｍａｉｎ ｄｉｓｕｌｆｉｄｅ ｂｏｎｄ ｓｔａｂｉｌｉｚｅｓ ｈｕｍａｎ ｂｌｏｏｄ ｃｏａｇｕｌａｔｉｏｎ ｆａｃｔｏｒ ＶＩＩＩａ' Ｊｏｕｒｎａｌ ｏｆ Ｔｈｒｏｍｂｏｓｉｓ ａｎｄ Ｈａｅｍｏｓｔａｓｉｓ Ｖｏｌ．１, 2003, Ｐａｇｅｓ １９６６-１９７１ * |
| JPN6015028294; Ｋ． Ｐ． ＲＡＤＴＫＥ: 'Ｄｉｓｕｌｆｉｄｅ ｂｏｎｄ-ｓｔａｂｉｌｉｚｅｄ ｆａｃｔｏｒ ＶＩＩＩ ｈａｓ ｐｒｏｌｏｎｇｅｄ ｆａｃｔｏｒ ＶＩＩＩａ ａｃｔｉｖｉｔｙ ａｎｄ ｉｍｐｒｏｖｅｄ ｐｏｔｅｎｃｙ ｉｎ ｗｈ' Ｊｏｕｒｎａｌ ｏｆ Ｔｈｒｏｍｂｏｓｉｓ ａｎｄ Ｈａｅｍｏｓｔａｓｉｓ Ｖｏｌ．５, 2007, Ｐａｇｅｓ １０２-１０８ * |
| JPN6015028295; Ｈ． ＷＡＫＡＢＡＹＡＳＨＩ: 'Ｃｏｍｂｉｎｉｎｇ ｍｕｔａｔｉｏｎｓ ｏｆ ｃｈａｒｇｅｄ ｒｅｓｉｄｕｅｓ ａｔ ｔｈｅ Ａ２ ｄｏｍａｉｎ ｉｎｔｅｒｆａｃｅ ｅｎｈａｎｃｅｓ ｆａｃｔｏｒ ＶＩＩＩ ｓｔａｂｉｌｉｔｙ ｏｖ' Ｊｏｕｒｎａｌ ｏｆ Ｔｈｒｏｍｂｏｓｉｓ ａｎｄ Ｈａｅｍｏｓｔａｓｉｓ Ｖｏｌ．７, 2009, Ｐａｇｅｓ ４３８-４４４ * |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2023542388A (ja) * | 2020-09-23 | 2023-10-06 | アブレヴィア バイオテック ゲーエムベーハー | 第ｖｉｉｉ因子補充療法の有効性を増加させるための化合物 |
Also Published As
| Publication number | Publication date |
|---|---|
| CN102971006A (zh) | 2013-03-13 |
| EP2593130A2 (en) | 2013-05-22 |
| US20160264645A1 (en) | 2016-09-15 |
| WO2012007324A3 (en) | 2012-03-08 |
| WO2012007324A2 (en) | 2012-01-19 |
| US20130183280A1 (en) | 2013-07-18 |
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