CA2586379C - Site-directed modification of fviii - Google Patents
Site-directed modification of fviii Download PDFInfo
- Publication number
- CA2586379C CA2586379C CA2586379A CA2586379A CA2586379C CA 2586379 C CA2586379 C CA 2586379C CA 2586379 A CA2586379 A CA 2586379A CA 2586379 A CA2586379 A CA 2586379A CA 2586379 C CA2586379 C CA 2586379C
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- CA
- Canada
- Prior art keywords
- factor viii
- amino acid
- fviii
- conjugate
- mutein
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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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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- A61P7/04—Antihaemorrhagics; Procoagulants; Haemostatic agents; Antifibrinolytic agents
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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
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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
- C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- C07K14/745—Blood coagulation or fibrinolysis factors
- C07K14/755—Factors VIII, e.g. factor VIII C (AHF), factor VIII Ag (VWF)
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- C07—ORGANIC CHEMISTRY
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- C07K17/00—Carrier-bound or immobilised peptides; Preparation thereof
- C07K17/02—Peptides being immobilised on, or in, an organic carrier
- C07K17/08—Peptides being immobilised on, or in, an organic carrier the carrier being a synthetic polymer
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K19/00—Hybrid peptides, i.e. peptides covalently bound to nucleic acids, or non-covalently bound protein-protein complexes
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- C07—ORGANIC CHEMISTRY
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PCT/US2005/041205 WO2006053299A2 (en) | 2004-11-12 | 2005-11-14 | Site-directed modification of fviii |
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CA2586379A1 CA2586379A1 (en) | 2006-05-18 |
CA2586379C true CA2586379C (en) | 2012-04-03 |
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CA2586379A Active CA2586379C (en) | 2004-11-12 | 2005-11-14 | Site-directed modification of fviii |
Country Status (32)
Families Citing this family (106)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
NZ542586A (en) | 2003-04-09 | 2009-11-27 | Biogenerix Ag | Method of forming a covalent conjugate between a G-CSF peptide and PEG |
WO2005012484A2 (en) | 2003-07-25 | 2005-02-10 | Neose Technologies, Inc. | Antibody-toxin conjugates |
US20080305992A1 (en) | 2003-11-24 | 2008-12-11 | Neose Technologies, Inc. | Glycopegylated erythropoietin |
MXPA06015234A (es) * | 2004-06-30 | 2007-11-22 | Nektar Therapeutics Al Corp | Conjugados de fraccion polimero-factor ix. |
EP1771066A2 (en) | 2004-07-13 | 2007-04-11 | Neose Technologies, Inc. | Branched peg remodeling and glycosylation of glucagon-like peptide-1 glp-1 |
JP5948627B2 (ja) | 2004-10-29 | 2016-07-20 | レイショファーム ゲーエムベーハー | 線維芽細胞成長因子(fgf)のリモデリングと糖質ペグ化 |
BRPI0517795B8 (pt) | 2004-11-12 | 2021-05-25 | Bayer Healthcare Llc | conjugado apresentando atividade pró-coagulante de fator viii, seu uso, métodos para sua preparação e para peguilação sítio-dirigida de uma muteína de fator viii, e composição farmacêutica |
ES2449195T3 (es) | 2005-01-10 | 2014-03-18 | Ratiopharm Gmbh | Factor estimulante de colonias de granulocitos glicopegilado |
US20070154992A1 (en) | 2005-04-08 | 2007-07-05 | Neose Technologies, Inc. | Compositions and methods for the preparation of protease resistant human growth hormone glycosylation mutants |
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 |
US20070105755A1 (en) | 2005-10-26 | 2007-05-10 | Neose Technologies, Inc. | One pot desialylation and glycopegylation of therapeutic peptides |
US7855279B2 (en) | 2005-09-27 | 2010-12-21 | Amunix Operating, Inc. | Unstructured recombinant polymers and uses thereof |
US20090048440A1 (en) | 2005-11-03 | 2009-02-19 | Neose Technologies, Inc. | Nucleotide Sugar Purification Using Membranes |
RU2008145084A (ru) * | 2006-05-24 | 2010-06-27 | Ново Нордиск Хелс Кеа Аг (Ch) | Аналоги фактора ix, имеющие пролонгированное время полужизни in vivo |
US20080248959A1 (en) | 2006-07-21 | 2008-10-09 | Neose Technologies, Inc. | Glycosylation of peptides via o-linked glycosylation sequences |
JP2010505874A (ja) | 2006-10-03 | 2010-02-25 | ノヴォ ノルディスク アー/エス | ポリペプチドコンジュゲートの精製方法 |
EP3323430A1 (en) | 2006-12-15 | 2018-05-23 | Baxalta GmbH | Factor viia-(poly)sialic acid conjugate having prolonged in vivo half-life |
PL2144923T3 (pl) | 2007-04-03 | 2013-12-31 | Biogenerix Ag | Sposoby leczenia z użyciem glikopegilowanego G-CSF |
CN101778859B (zh) | 2007-06-12 | 2014-03-26 | 诺和诺德公司 | 改良的用于生产核苷酸糖的方法 |
CA2704234A1 (en) * | 2007-11-09 | 2009-05-14 | Baxter International Inc. | Modified recombinant factor viii and von willebrand factor and methods of use |
CN103497246B (zh) | 2008-02-27 | 2016-08-10 | 诺沃—诺迪斯克有限公司 | 缀合的因子viii分子 |
JP5997443B2 (ja) | 2008-05-16 | 2016-09-28 | バイエル・ヘルスケア・エルエルシーBayer HealthCare LLC | 標的化凝固因子およびそれを使用する方法 |
JP5674650B2 (ja) * | 2008-06-04 | 2015-02-25 | バイエル・ヘルスケア・エルエルシー | フォン・ヴィレブランド病の処置のためのfviii変異タンパク質 |
EP2865760B1 (en) | 2008-06-24 | 2017-10-11 | CSL Behring GmbH | Factor viii, von willebrand factor or complexes thereof with prolonged in vivo half-life |
WO2010019263A2 (en) * | 2008-08-15 | 2010-02-18 | Genzyme Corporation | Soluble flt constructs for treating cancers |
DK2349342T3 (en) * | 2008-10-17 | 2018-10-08 | Baxalta GmbH | MODIFIED BLOOD FACTORS INCLUDING A LOW DEGREE OF WATER SOLUBLE POLYMER |
WO2010062768A1 (en) * | 2008-11-03 | 2010-06-03 | Bayer Healthcare Llc | Method for the treatment of hemophilia |
WO2010060081A1 (en) * | 2008-11-24 | 2010-05-27 | Bayer Healthcare Llc | Method of determining pegylated blood coagulation factor activity in a silica-based activated partial thromboplastin time assay |
US20120121613A1 (en) * | 2009-01-19 | 2012-05-17 | Bayer Healthcare Llc | Protein conjugate having an endopeptidase- cleavable bioprotective moiety |
SI2393828T1 (sl) | 2009-02-03 | 2017-01-31 | Amunix Operating Inc. | Podaljšani rekombinantni polipetidi in sestavki, ki jih obsegajo |
EP2398822B1 (en) * | 2009-02-19 | 2013-01-02 | Novo Nordisk A/S | Modification of factor viii |
PL2408800T3 (pl) * | 2009-03-20 | 2016-11-30 | Sposób wytwarzania koniugatu miejscowo-specyficznego, fizjologicznie aktywnego polipeptydu | |
CN102427823A (zh) * | 2009-03-24 | 2012-04-25 | 拜耳医药保健有限公司 | 因子viii变体及使用方法 |
NZ623810A (en) | 2009-07-27 | 2015-10-30 | Lipoxen Technologies Ltd | Glycopolysialylation of non-blood coagulation proteins |
DK2459224T3 (en) | 2009-07-27 | 2016-07-25 | Baxalta GmbH | Blodstørkningsproteinkonjugater |
US8642737B2 (en) | 2010-07-26 | 2014-02-04 | Baxter International Inc. | Nucleophilic catalysts for oxime linkage |
EP2459226B1 (en) | 2009-07-27 | 2016-06-29 | Lipoxen Technologies Limited | Glycopolysialylation of proteins other than blood coagulation proteins |
US8809501B2 (en) | 2009-07-27 | 2014-08-19 | Baxter International Inc. | Nucleophilic catalysts for oxime linkage |
EP3222287A1 (en) | 2009-08-24 | 2017-09-27 | Amunix Operating Inc. | Coagulation factor ix compositions and methods of making and using same |
ME02964B (me) | 2009-12-06 | 2018-07-20 | Himerni i hibridni polipeptidi faktora viii-fc, i postupci za njihovu upotrebu | |
WO2011075185A1 (en) | 2009-12-18 | 2011-06-23 | Oligasis | Targeted drug phosphorylcholine polymer conjugates |
CN105524164A (zh) | 2010-02-16 | 2016-04-27 | 诺沃—诺迪斯克有限公司 | 具有降低的vwf结合的因子viii分子 |
US9254336B2 (en) * | 2010-02-21 | 2016-02-09 | Bayer Healthcare Llc | Method for activation and conjugation of biomolecules |
KR20200067958A (ko) | 2010-04-15 | 2020-06-12 | 코디악 사이언시스 인코포레이티드 | 고분자량 쌍성이온-함유 중합체 |
GB201007356D0 (en) | 2010-04-30 | 2010-06-16 | Leverton Licence Holdings Ltd | Conjugated factor VIIa |
GB201007357D0 (en) * | 2010-04-30 | 2010-06-16 | Leverton Licence Holdings Ltd | Conjugated factor VIII |
US9611310B2 (en) | 2010-07-09 | 2017-04-04 | Bioverativ Therapeutics Inc. | Systems for factor VIII processing and methods thereof |
KR101948337B1 (ko) * | 2010-11-05 | 2019-02-14 | 박스알타 인코퍼레이티드 | 증가된 특이 활성도를 갖는 항혈우병 인자 viii의 신규 변이체 |
RU2013131911A (ru) * | 2010-12-16 | 2015-01-27 | Ново Нордиск А/С | Водный раствор фактора viii |
EA032056B1 (ru) | 2010-12-22 | 2019-04-30 | Баксалта Инкорпорейтид | Конъюгат терапевтического белка и производного жирной кислоты, способы получения конъюгата терапевтического белка и производного жирной кислоты (варианты) |
US20120329127A1 (en) * | 2011-05-27 | 2012-12-27 | Baxter Healthcare S.A. | Therapeutic proteins with increased half-life and methods of preparing same |
PT2717898T (pt) | 2011-06-10 | 2019-05-20 | Bioverativ Therapeutics Inc | Compostos pró-coagulantes e processos para a sua utilização |
AU2012280474A1 (en) | 2011-07-01 | 2014-01-16 | Bayer Intellectual Property Gmbh | Relaxin fusion polypeptides and uses thereof |
KR102110736B1 (ko) | 2011-07-08 | 2020-05-14 | 바이오버라티브 테라퓨틱스 인크. | Viii 인자 키메라 및 하이브리드 폴리펩타이드, 그리고 이들의 사용 방법 |
MX354705B (es) | 2011-09-23 | 2018-03-16 | Novo Nordisk As | Analogos de glucagon novedosos. |
KR20130049671A (ko) * | 2011-11-04 | 2013-05-14 | 한미사이언스 주식회사 | 생리활성 폴리펩타이드 결합체 제조 방법 |
NZ628014A (en) * | 2012-02-15 | 2016-09-30 | Biogen Ma Inc | Recombinant factor viii proteins |
EP2814502B1 (en) | 2012-02-15 | 2017-09-13 | CSL Behring GmbH | Von willebrand factor variants having improved factor viii binding affinity |
AU2012327217B2 (en) | 2012-02-15 | 2016-05-12 | Bioverativ Therapeutics Inc. | Factor VIII compositions and methods of making and using same |
EP2666782A1 (en) | 2012-05-22 | 2013-11-27 | Imnate Sarl | Coagulation factor VIII with reduced immunogenicity. |
EP4079316A1 (en) | 2012-06-08 | 2022-10-26 | Bioverativ Therapeutics Inc. | Procoagulant compounds |
EP3404105A1 (en) | 2012-07-06 | 2018-11-21 | Bioverativ Therapeutics Inc. | Cell line expressing single chain factor viii polypeptides and uses thereof |
HK1213767A1 (zh) | 2012-10-18 | 2016-07-15 | Bioverativ Therapeutics Inc. | 使用固定劑量凝血因子的方法 |
US20150266944A1 (en) | 2012-10-30 | 2015-09-24 | Biogen Idec Ma Inc. | Methods of Using FVIII Polypeptide |
RS60003B1 (sr) | 2013-03-15 | 2020-04-30 | Bioverativ Therapeutics Inc | Formulacije polipeptida faktora viii |
US20160030524A1 (en) * | 2013-03-15 | 2016-02-04 | Bayer Healthcare Llc | Recombinant factor viii formulations |
CA2899089C (en) | 2013-03-15 | 2021-10-26 | Biogen Ma Inc. | Factor ix polypeptide formulations |
RU2683039C2 (ru) | 2013-04-18 | 2019-03-26 | Ново Нордиск А/С | Стабильные совместные агонисты рецептора глюкагоноподобного пептида-1/глюкагона пролонгированного действия для медицинского применения |
DK2796145T3 (da) | 2013-04-22 | 2018-01-29 | Csl Ltd | Et kovalent kompleks af von Willebrand-faktor og faktor VIII linket af en disulfidbro |
TW201519900A (zh) * | 2013-04-28 | 2015-06-01 | Bayer Healthcare Llc | 用於誘導對凝血因子蛋白之免疫耐受性的組成物及方法 |
EP4108254A1 (en) | 2013-08-14 | 2022-12-28 | Bioverativ Therapeutics Inc. | Recombinant factor viii proteins |
TWI667255B (zh) | 2013-08-14 | 2019-08-01 | 美商生物化學醫療公司 | 因子viii-xten融合物及其用途 |
US10702608B2 (en) | 2013-09-08 | 2020-07-07 | Kodiak Sciences Inc. | Factor VIII zwitterionic polymer conjugates |
KR20160090810A (ko) * | 2013-10-22 | 2016-08-01 | 디비브이 테크놀로지스 (소시에떼 아노님) | 혈액 인자에 대한 관용 유도에 의한 혈우병의 치료 방법 |
US10584147B2 (en) | 2013-11-08 | 2020-03-10 | Biovertiv Therapeutics Inc. | Procoagulant fusion compound |
RU2546297C1 (ru) * | 2013-11-19 | 2015-04-10 | Федеральное государственное бюджетное учреждение "Научно-исследовательский институт фармакологии" Сибирского отделения Российской академии медицинских наук | Средство, улучшающее реологические свойства крови |
US10325687B2 (en) | 2013-12-06 | 2019-06-18 | Bioverativ Therapeutics Inc. | Population pharmacokinetics tools and uses thereof |
ES2688144T3 (es) | 2014-01-20 | 2018-10-31 | Octapharma Ag | Procedimiento de fabricación de Factor VIII que tiene una relación mejorada de FVIII:C/FVIII:AG |
NZ722391A (en) | 2014-02-04 | 2022-12-23 | Biogen Ma Inc | Use of cation-exchange chromatography in the flow-through mode to enrich post-translational modifications |
WO2015132724A1 (en) | 2014-03-05 | 2015-09-11 | Pfizer Inc. | Improved muteins of clotting factor viii |
MA39779A (fr) | 2014-03-24 | 2017-02-01 | Biogen Ma Inc | Formulations de facteur ix lyophilisées |
WO2015154090A1 (en) * | 2014-04-04 | 2015-10-08 | Bloodworks | Routine laboratory and point-of-care (poc) testing for hemostasis |
PE20161326A1 (es) | 2014-04-10 | 2016-12-11 | Bayer Healthcare Llc | Formulacion en polvo de medio de compuesto y metodo de preparacion de medio liquido para cultivo celular |
EP3151852A1 (en) | 2014-06-04 | 2017-04-12 | Novo Nordisk A/S | Glp-1/glucagon receptor co-agonists for medical use |
KR20170026580A (ko) | 2014-07-02 | 2017-03-08 | 씨에스엘 리미티드 | 변형된 폰 빌레브란트 인자 |
MA40864A (fr) | 2014-10-31 | 2017-09-05 | Biogen Ma Inc | Hypotaurine, gaba, bêta-alanine et choline pour la régulation de l'accumulation de sous-produits résiduaires dans des procédés de culture de cellules mammifères |
AU2016231327B2 (en) | 2015-03-06 | 2018-08-09 | CSL Behring Lengnau AG | Modified von Willebrand factor having improved half-life |
CA2986626A1 (en) | 2015-05-22 | 2016-12-01 | Csl Behring Recombinant Facility Ag | Truncated von willebrand factor polypeptides for treating hemophilia |
CA2986625A1 (en) | 2015-05-22 | 2016-12-01 | Csl Behring Recombinant Facility Ag | Methods for preparing modified von willebrand factor |
BR112018002150A2 (pt) | 2015-08-03 | 2018-09-18 | Bioverativ Therapeutics Inc | proteínas de fusão do fator ix e métodos de fabricação e uso das mesmas |
US9849125B1 (en) | 2015-11-03 | 2017-12-26 | Banner Lifie Sciences LLC | Anti-overingestion dosage forms |
WO2017117630A1 (en) | 2016-01-07 | 2017-07-13 | Csl Limited | Mutated von willebrand factor |
WO2017117631A1 (en) | 2016-01-07 | 2017-07-13 | Csl Limited | Mutated truncated von willebrand factor |
US20230151078A1 (en) * | 2016-06-24 | 2023-05-18 | Mogam Instiitute For Biomedical Research | Recombinant single-chain fviii and chemical conjugate thereof |
SG10201912768YA (en) | 2016-11-11 | 2020-02-27 | CSL Behring Lengnau AG | Truncated von willebrand factor polypeptides for extravascular administration in the treatment or prophylaxis of a blood coagulation disorder |
KR20190085021A (ko) | 2016-11-11 | 2019-07-17 | 체에스엘 베링 렝나우 아게 | 혈우병을 치료하기 위한 절단된 폰 빌레브란트 인자 폴리펩타이드 |
AR110079A1 (es) | 2016-11-16 | 2019-02-20 | Bayer Healthcare Llc | Factor viii direccionado a los glóbulos rojos y método para su uso |
US12257288B2 (en) | 2016-12-02 | 2025-03-25 | Bioverativ Therapeutics Inc. | Methods of inducing immune tolerance to clotting factors |
US12161696B2 (en) | 2016-12-02 | 2024-12-10 | Bioverativ Therapeutics Inc. | Methods of treating hemophilic arthropathy using chimeric clotting factors |
MA47416A (fr) | 2017-01-31 | 2019-12-11 | Bioverativ Therapeutics Inc | Protéine de fusion du facteur ix et procédés de fabrication et d'utilisation associés |
US10335375B2 (en) | 2017-05-30 | 2019-07-02 | Patheon Softgels, Inc. | Anti-overingestion abuse deterrent compositions |
KR20190086269A (ko) * | 2018-01-12 | 2019-07-22 | 재단법인 목암생명과학연구소 | 체내 지속형 재조합 당단백질 및 이의 제조방법 |
EP4585260A3 (en) | 2018-05-18 | 2025-08-13 | Bioverativ Therapeutics Inc. | Methods of treating hemophilia a |
CA3157509A1 (en) | 2019-10-10 | 2021-04-15 | Kodiak Sciences Inc. | Methods of treating an eye disorder |
WO2021091881A1 (en) * | 2019-11-04 | 2021-05-14 | The Trustees Of Columbia University In The City Of New York | High concentration cell penetrating caspase inhibitor conjugates compositions and methods thereof |
US20220403005A1 (en) * | 2019-12-06 | 2022-12-22 | The Children's Hospital Of Philadelphia | Compositions and methods for modulating factor viii function |
Family Cites Families (67)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPS59172425A (ja) * | 1983-03-18 | 1984-09-29 | Nippon Chemiphar Co Ltd | 新規な血液凝固因子誘導体およびその製造法ならびにそれを含有する血液凝固促進剤 |
US7138505B1 (en) | 1984-01-12 | 2006-11-21 | Novartis Vaccines And Diagnostics, Inc. | Factor VIII:C nucleic acid molecules |
US4970300A (en) | 1985-02-01 | 1990-11-13 | New York University | Modified factor VIII |
US5422260A (en) | 1986-05-29 | 1995-06-06 | Genetics Institute, Inc. -Legal Affairs | Human factor VIII:c muteins |
US5451521A (en) | 1986-05-29 | 1995-09-19 | Genetics Institute, Inc. | Procoagulant proteins |
US6346513B1 (en) | 1987-06-12 | 2002-02-12 | Baxter Trading Gmbh | Proteins with factor VIII activity: process for their preparation using genetically-engineered cells and pharmaceutical compositions containing them |
EP0690126B1 (en) | 1987-06-12 | 2001-11-28 | Baxter Aktiengesellschaft | Novel proteins with factor VIII activitiy: process for their preparation using genetically-engineered cells and pharmaceutical compositions containing them |
US5171844A (en) | 1987-06-12 | 1992-12-15 | Gist-Brocades N.W. | Proteins with factor viii activity: process for their preparation using genetically-engineered cells and pharmaceutical compositions containing them |
AU2473388A (en) * | 1987-11-16 | 1989-06-22 | Scripps Clinic And Research Foundation | Treatment of factor viii inhibitors |
US5166322A (en) | 1989-04-21 | 1992-11-24 | Genetics Institute | Cysteine added variants of interleukin-3 and chemical modifications thereof |
SE465222C5 (sv) | 1989-12-15 | 1998-02-10 | Pharmacia & Upjohn Ab | Ett rekombinant, humant faktor VIII-derivat och förfarande för dess framställning |
US5766897A (en) | 1990-06-21 | 1998-06-16 | Incyte Pharmaceuticals, Inc. | Cysteine-pegylated proteins |
US6376463B1 (en) | 1992-04-07 | 2002-04-23 | Emory University | Modified factor VIII |
US6037452A (en) | 1992-04-10 | 2000-03-14 | Alpha Therapeutic Corporation | Poly(alkylene oxide)-Factor VIII or Factor IX conjugate |
EP1652534A3 (en) | 1992-10-02 | 2007-05-02 | Genetics Institute, LLC | Composition comprising coagulation factor VIII formulation, process for its preparation and use of a surfactant as stabilizer |
WO1994015625A1 (en) | 1993-01-15 | 1994-07-21 | Enzon, Inc. | Factor viii - polymeric conjugates |
SE504074C2 (sv) | 1993-07-05 | 1996-11-04 | Pharmacia Ab | Proteinberedning för subkutan, intramuskulär eller intradermal administrering |
AU685187B2 (en) | 1993-10-29 | 1998-01-15 | Incyte Pharmaceuticals, Inc. | Chimeric proteins including protease nexin-1 variants |
IL113010A0 (en) | 1994-03-31 | 1995-10-31 | Pharmacia Ab | Pharmaceutical formulation comprising factor VIII or factor ix with an activity of at least 200 IU/ml and an enhancer for improved subcutaneous intramuscular or intradermal administration |
BE1008491A3 (fr) * | 1994-07-14 | 1996-05-07 | Croix Rouge De Belgique Depart | Sequence polypeptidique antigenique du facteur viii, fragments et/ou epitopes de celle-ci. |
CA2204726A1 (en) | 1994-11-09 | 1996-12-27 | Robin E. Offord | Functionalized polymers for site-specific attachment |
WO1997001197A1 (en) * | 1995-06-21 | 1997-01-09 | Motorola Inc. | Method and antenna for providing an omnidirectional pattern |
WO1997003195A1 (en) | 1995-07-11 | 1997-01-30 | Chiron Corporation | Novel factor viii:c polypeptide analogs with altered protease sites |
SE9503380D0 (sv) * | 1995-09-29 | 1995-09-29 | Pharmacia Ab | Protein derivatives |
AT403438B (de) | 1996-05-24 | 1998-02-25 | Immuno Ag | Pharmazeutische präparation mit faktor viii prokoagulationsaktivität und vwf-bindungsaktivität |
US6458563B1 (en) * | 1996-06-26 | 2002-10-01 | Emory University | Modified factor VIII |
AU3908597A (en) * | 1996-08-02 | 1998-02-25 | Ortho-Mcneil Pharmaceutical, Inc. | Polypeptides having a single covalently bound n-terminal water-soluble polymer |
CA2225189C (en) | 1997-03-06 | 2010-05-25 | Queen's University At Kingston | Canine factor viii gene, protein and methods of use |
US6753165B1 (en) * | 1999-01-14 | 2004-06-22 | Bolder Biotechnology, Inc. | Methods for making proteins containing free cysteine residues |
EP1881005B1 (en) | 1997-07-14 | 2013-04-03 | Bolder Biotechnology, Inc. | Derivatives of G-CSF and related proteins |
CN1113656C (zh) * | 1997-10-17 | 2003-07-09 | 丰收技术股份有限公司 | 从富含血小板的血浆中沉淀富集生长因子的纤维蛋白原浓缩物 |
EP0922446A1 (en) | 1997-12-03 | 1999-06-16 | Applied Research Systems Ars Holding N.V. | Solution-phase site-specific preparation of GRF-PEG conjugates |
CA2329768C (en) | 1998-04-27 | 2008-06-10 | Opperbas Holding B.V. | Pharmaceutical composition comprising factor viii and neutral liposomes |
US6759216B1 (en) | 1998-11-06 | 2004-07-06 | Emory University | Glycosylated, low antigenicity low immunogenicity factor VIII |
DK1129186T4 (da) | 1998-11-10 | 2017-02-06 | Stichting Sanquin Bloedvoorziening | Et faktor VIII-polypeptid med faktor VIII:C-aktivitet |
US6358703B1 (en) | 1998-12-10 | 2002-03-19 | Bayer Corporation | Expression system for factor VIII |
US6136599A (en) | 1998-12-10 | 2000-10-24 | Bayer Corporation | Human hybrid host cell for mammalian gene expression |
CN1210400C (zh) * | 1999-01-14 | 2005-07-13 | 博尔德生物技术公司 | 制备含游离半胱氨酸残基的蛋白质的方法 |
AU5282200A (en) | 1999-05-24 | 2000-12-12 | American National Red Cross, The | Methods of reducing factor viii clearance and compositions therefor |
EP2319541A1 (en) * | 2000-02-11 | 2011-05-11 | Bayer HealthCare LLC | Factor VII or VIIA-like conjugates |
KR100638184B1 (ko) | 2000-09-19 | 2006-10-26 | 에모리 유니버시티 | 변형된 인자 ⅷ |
AU2002248329B2 (en) | 2001-01-12 | 2007-06-28 | The American National Red Cross | Methods and compositions for reducing heparan sulfate proteoglycan-mediated clearance of factor VIII |
AU2002249096B2 (en) * | 2001-03-22 | 2007-06-28 | Novo Nordisk Health Care Ag | Coagulation factor VII derivatives |
WO2002096454A1 (en) | 2001-05-31 | 2002-12-05 | D. Collen Research Foundation Vzw | Recombinant molecules with reduced immunogenicity, methods and intermediates for obtaining them and their use in pharmaceutical compositions and diagnostic tools |
WO2002098454A2 (en) | 2001-05-31 | 2002-12-12 | D. Collen Research Foundation Vzw Onderwijsen Navorsing Campus Gasthuisberg K.U. Leuven | Recombinant molecules with reduced immunogenicity, methods and intermediates for obtaining them and their use in pharmaceutical compositions and diagnostic tools |
WO2002103024A2 (en) | 2001-06-14 | 2002-12-27 | The Scripps Research Institute | Stabilized proteins with engineered disulfide bonds |
EP1572889B1 (en) | 2001-10-05 | 2008-12-17 | Expression Therapeutics, LLC | Nucleic acid and amino acid sequences encoding high-level expressor factor viii polypeptides and methods of use |
ES2319758T3 (es) | 2002-04-18 | 2009-05-12 | Merck Patent Gmbh | Factor viii modificado. |
US8003117B2 (en) | 2002-11-20 | 2011-08-23 | Nof Corporation | Polyalkylene glycol derivative and modified bio-related substance |
JP4412461B2 (ja) | 2002-11-20 | 2010-02-10 | 日油株式会社 | 修飾された生体関連物質、その製造方法および中間体 |
KR101031206B1 (ko) | 2002-12-31 | 2011-04-27 | 넥타르 테라퓨틱스 | 말레암산 중합체 유도체 및 이의 바이오컨쥬게이트 |
AU2003300133B2 (en) | 2002-12-31 | 2008-11-13 | Nektar Therapeutics | Hydrolytically stable maleimide-terminated polymers |
AU2004204136B2 (en) | 2003-01-06 | 2008-10-09 | Nektar Therapeutics | Thiol-selective water-soluble polmer derivatives |
BRPI0407882B1 (pt) * | 2003-02-26 | 2021-07-27 | Nektar Therapeutics | Composição compreendendo conjugados de polímero-porção de fator viii e seu método de fabricação |
US20040180054A1 (en) * | 2003-03-13 | 2004-09-16 | Hanmi Pharm. Co., Ltd. | Physiologically active polypeptide conjugate having prolonged in vivo half-life |
US20050176108A1 (en) * | 2003-03-13 | 2005-08-11 | Young-Min Kim | Physiologically active polypeptide conjugate having prolonged in vivo half-life |
AU2004238869B2 (en) * | 2003-05-12 | 2009-06-25 | Affymax, Inc. | Novel poly(ethylene glycol) modified compounds and uses thereof |
EP2644206B1 (en) | 2003-05-23 | 2019-04-03 | Nektar Therapeutics | PEG derivatives containing two PEG chains |
EP1502921A1 (en) | 2003-07-29 | 2005-02-02 | ZLB Behring GmbH | Recombinant mutated human factor VIII (FVIII) with improved stability |
EP1682106A4 (en) | 2003-10-30 | 2008-06-11 | Univ Emory | MODIFIED FVIII WITH REDUCED IMMUNOGENICITY BY MUTAGENESIS OF A2 AND C2 EPITOPES |
US7211559B2 (en) | 2003-10-31 | 2007-05-01 | University Of Maryland, Baltimore | Factor VIII compositions and methods |
DE602004026474D1 (de) | 2003-12-03 | 2010-05-20 | Univ Rochester | Rekombinanter faktor viii mit erhöhter spezifischer aktivität |
WO2006027111A1 (en) | 2004-09-06 | 2006-03-16 | Zlb Behring Gmbh | Modified coagulation factor viii with enhanced stability |
BRPI0517795B8 (pt) | 2004-11-12 | 2021-05-25 | Bayer Healthcare Llc | conjugado apresentando atividade pró-coagulante de fator viii, seu uso, métodos para sua preparação e para peguilação sítio-dirigida de uma muteína de fator viii, e composição farmacêutica |
WO2006103298A2 (en) | 2005-04-01 | 2006-10-05 | Novo Nordisk Health Care Ag | Blood coagulation fviii analogues |
US7645860B2 (en) * | 2006-03-31 | 2010-01-12 | Baxter Healthcare S.A. | Factor VIII polymer conjugates |
MX2008012600A (es) * | 2006-03-31 | 2008-12-12 | Baxter Int | Factor viii pegilado. |
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