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1. 发明申请

WO2007144173A1 PROTEOLYTICALLY CLEAVABLE FUSION PROTEIN COMPRISING A BLOOD COAGULATION FACTOR 审中-公开
标题翻译：包含血液凝血因子的蛋白质可溶性融合蛋白
公开(公告)号：WO2007144173A1
公开(公告)日：2007-12-21
申请号：PCT/EP2007/005246
申请日：2007-06-14
申请人： CSL BEHRING GMBH , METZNER, Hubert , WEIMER, Thomas , SCHULTE, Stefan
发明人： METZNER, Hubert , WEIMER, Thomas , SCHULTE, Stefan
IPC分类号： C07K19/00 , C12N15/62
CPC分类号： C07K14/755 , A61K38/00 , C07K14/745 , C07K2319/31 , C12N9/6472
摘要： The invention relates to therapeutic fusion proteins in which a coagulation factor is fused to a half-life enhancing polypeptide, and both are connected by a linker peptide that is proteolytically cleavable. The cleavage of such linkers liberates the coagulation factor from any activity-compromising steric hindrance caused by the half-life enhancing polypeptide and, thereby, allows the generation of fusion proteins with high molar specific activity when tested in coagulation-related assays. Furthermore, the fact that the linker is cleavable can enhance the rates of inactivation and/or elimination after proteolytic cleavage of the peptide linker compared to the corresponding therapeutic fusion protein linked by the non- cleavable linker having the amino acid sequence GGGGGGV.
摘要翻译：本发明涉及治疗融合蛋白，其中凝血因子与半衰期增强多肽融合，并且两者通过可蛋白水解切割的接头肽连接。这种接头的切割将凝血因子从由半衰期增强多肽引起的任何活性受损的空间位阻释放，从而当在凝血相关测定中测试时允许产生具有高摩尔比活性的融合蛋白。此外，与通过具有氨基酸序列GGGGGGV的不可切割接头连接的相应的治疗融合蛋白相比，接头可切割的事实可增强肽接头的蛋白水解切割后的失活和/或消除速率。

2. 发明申请

WO2008077616A1 MODIFIED COAGULATION FACTORS WITH PROLONGED IN VIVO HALF-LIFE 审中-公开
标题翻译：改良的凝血因子与生殖健康生活息息相关
公开(公告)号：WO2008077616A1
公开(公告)日：2008-07-03
申请号：PCT/EP2007/011356
申请日：2007-12-21
申请人： CSL BEHRING GMBH , SCHULTE, Stefan , WEIMER, Thomas , METZNER, Hubert
发明人： SCHULTE, Stefan , WEIMER, Thomas , METZNER, Hubert
IPC分类号： A61K38/37 , A61K38/38 , C07K14/755 , C07K14/76 , C12N15/09
CPC分类号： C07K14/755 , C07K14/745 , C07K14/765 , C07K16/18 , C07K2319/31
摘要： The present invention relates to modified nucleic acid sequences coding for coagulation factors preferably coagulation factor VIII and their derivatives, recombinant expression vectors containing such nucleic acid sequences, host cells transformed with such recombinant expression vectors, recombinant polypeptides and derivatives coded for by said nucleic acid sequences which recombinant polypeptides and derivatives do have biological activities and prolonged in vivo half-life compared to the unmodified wild-type protein. The invention also relates to corresponding sequences that result in improved in vitro stability. The present invention further relates to processes for the manufacture of such recombinant proteins and their derivatives are covered. The invention also relates to a transfer vector for use in human gene therapy, which comprises such modified nucleic acid sequences.
摘要翻译：本发明涉及编码凝血因子，优选凝血因子VIII及其衍生物的修饰的核酸序列，含有此类核酸序列的重组表达载体，用此类重组表达载体转化的宿主细胞，重组多肽和由所述核酸序列编码的衍生物与未修饰的野生型蛋白质相比，重组多肽和衍生物确实具有生物学活性和延长的体内半衰期。本发明还涉及导致体外稳定性改善的相应序列。本发明还涉及制备这种重组蛋白及其衍生物的方法。本发明还涉及用于人基因治疗的转移载体，其包含这种修饰的核酸序列。

3. 发明申请

WO2009156137A1 FACTOR VIII, VON WILLEBRAND FACTOR OR COMPLEXES THEREOF WITH PROLONGED IN VIVO HALF-LIFE 审中-公开
标题翻译：因子VIII，VON WILLEBRAND因子或其复合物与生殖健康生活息息相关
公开(公告)号：WO2009156137A1
公开(公告)日：2009-12-30
申请号：PCT/EP2009/004549
申请日：2009-06-24
申请人： CSL BEHRING GMBH , WEIMER, Thomas , SCHULTE, Stefan , METZNER, Hubert , KRONTHALER, Ulrich , LIND, Holger , LANG, Wiegand
发明人： WEIMER, Thomas , SCHULTE, Stefan , METZNER, Hubert , KRONTHALER, Ulrich , LIND, Holger , LANG, Wiegand
IPC分类号： C12N15/12 , C07K14/755 , A61K38/37 , C12N5/10 , G01N33/86
CPC分类号： C07K14/76 , A61K38/00 , C07K14/755 , C07K2319/31
摘要： The present invention relates to modified nucleic acid sequences coding for coagulation factor VIII (FVIII) and for von Willebrand factor (VWF) as well as complexes thereof and their derivatives, recombinant expression vectors containing such nucleic acid sequences, host cells transformed with such recombinant expression vectors, recombinant polypeptides and derivatives coded for by said nucleic acid sequences which recombinant polypeptides and derivatives do have biological activities together with prolonged in vivo half-life and/or improved in vivo recovery compared to the unmodified wild-type protein. The invention also relates to corresponding FVIII sequences that result in improved expression yield. The present invention further relates to processes for the manufacture of such recombinant proteins and their derivatives. The invention also relates to a transfer vector for use in human gene therapy, which comprises such modified nucleic acid sequences.
摘要翻译：本发明涉及编码凝血因子VIII（FVIII）和von Willebrand因子（VWF）的修饰的核酸序列及其复合物及其衍生物，含有此类核酸序列的重组表达载体，用这种重组表达转化的宿主细胞载体，重组多肽和由所述核酸序列编码的衍生物，所述重组多肽和衍生物与未修饰的野生型蛋白质相比具有生物活性以及延长的体内半衰期和/或改善的体内恢复。本发明还涉及导致表达产量提高的相应FVIII序列。本发明还涉及制备这些重组蛋白及其衍生物的方法。本发明还涉及用于人基因治疗的转移载体，其包含这种修饰的核酸序列。

4. 发明申请

WO2007115724A2 METHOD OF INCREASING THE IN VIVO RECOVERY OF THERAPEUTIC POLYPEPTIDES 审中-公开
标题翻译：增加治疗性多发性硬化症的方法
公开(公告)号：WO2007115724A2
公开(公告)日：2007-10-18
申请号：PCT/EP2007/002948
申请日：2007-04-02
申请人： CSL BEHRING GMBH , WEIMER, Thomas , METZNER, Hubert , SCHULTE, Stefan , LANG, Wiegand , WORMSBÄCHER, Wilfried
发明人： WEIMER, Thomas , METZNER, Hubert , SCHULTE, Stefan , LANG, Wiegand , WORMSBÄCHER, Wilfried
IPC分类号： C12N9/64 , C12N9/14 , A61K47/48
CPC分类号： C12N9/644 , A61K47/62 , A61K47/643 , C07K2319/31 , C12N9/14 , C12N9/6424 , C12N9/6437
摘要： The present invention relates to the field of modified therapeutic polypeptides with increased in vivo recovery compared to their non-modified parent polypeptide. I.e., the invention relates to fusions of therapeutic polypeptides with recovery enhancing polypeptides connected directly or optionally connected by a linker peptide.
摘要翻译：本发明涉及与其未修饰的亲本多肽相比具有增加的体内恢复的修饰的治疗性多肽的领域。即，本发明涉及治疗性多肽与通过连接肽直接或任选连接的恢复增强多肽的融合。

5. 发明申请

WO2008098720A1 THERAPEUTIC APPLICATION OF KAZAL-TYPE SERINE PROTEASE INHIBITORS 审中-公开
标题翻译：卡氏型丝氨酸蛋白酶抑制剂的治疗应用
公开(公告)号：WO2008098720A1
公开(公告)日：2008-08-21
申请号：PCT/EP2008/001009
申请日：2008-02-11
申请人： CSL BEHRING GMBH , SCHULTE, Stefan , KRONTHALER, Ulrich , SCHMIDBAUER, Stefan , WEIMER, Thomas , HOFMANN, Kay
发明人： SCHULTE, Stefan , KRONTHALER, Ulrich , SCHMIDBAUER, Stefan , WEIMER, Thomas , HOFMANN, Kay
IPC分类号： A61K38/57 , A61P7/02 , C07K14/81
CPC分类号： C07K14/8135 , A61K38/00 , A61K47/64 , A61K47/643
摘要： The subject of the present invention is, in the most general aspect, the therapeutic application of the Kazal-type serine protease inhibitor lnfestin or domains thereof or modified Kazal-type serine protease inhibitors based on lnfestin homologs, which prevent the formation and/or stabilization of three-dimensional arterial or venous thrombi by interfering with proteins involved in activation of the so-called intrinsic coagulation pathway. In particular the present invention relates to the use of said Kazal-type serine protease inhibitors or fragments thereof or modified Kazal-type serine protease inhibitors, in the treatment or prophylaxis of a condition or disorder related to arterial thrombus formation, i. e. stroke or myocardial infarction, inflammation, complement activation, fibrinolysis, angiogenesis and/or diseases linked to pathological kinin formation such as hypotonic shock, edema including hereditary angioedema, bacterial infections, arthritis, pancreatitis, or articular gout, Disseminated Intravasal Coagulation (DIC) and sepsis.
摘要翻译：本发明的主题在最一般的方面是基于伊斯匹林同系物的Kazal型丝氨酸蛋白酶抑制剂腹膜内酯或其结构域或修饰的Kazal型丝氨酸蛋白酶抑制剂的治疗应用，其阻止形成和/或稳定化通过干扰参与所谓的内在凝血途径的激活的蛋白质的三维动脉或静脉血栓。特别地，本发明涉及所述Kazal型丝氨酸蛋白酶抑制剂或其片段或修饰的Kazal型丝氨酸蛋白酶抑制剂在治疗或预防与动脉血栓形成相关的病症或障碍中的用途，即中风或心肌梗塞，炎症，补体激活，纤维蛋白溶解，血管生成和/或与病理激肽形成相关的疾病，例如低渗休克，包括遗传性血管性水肿，细菌感染，关节炎，胰腺炎或关节痛风的水肿，弥散性内皮内凝血（DIC）和败血症。

6. 发明申请

WO2005111074A1 MODIFIED COAGULATION FACTORS WITH ENHANCED STABILITY AND THEIR DERIVATIVES 审中-公开
标题翻译：改进的凝血因子与增强的稳定性及其衍生物
公开(公告)号：WO2005111074A1
公开(公告)日：2005-11-24
申请号：PCT/EP2005/005291
申请日：2005-05-13
申请人： ZLB BEHRING GMBH , WEIMER, Thomas , SCHULTE, Stefan , HOFMANN, Kay , HAUSER, Hans-Peter
发明人： WEIMER, Thomas , SCHULTE, Stefan , HOFMANN, Kay , HAUSER, Hans-Peter
IPC分类号： C07K14/745
CPC分类号： C07K14/811 , C07K14/755 , C12N9/0091 , C12Y116/03001
摘要： The present invention relates to modified nucleic acid sequences coding for coagulation Factors, in particular human FV and human Factor VIII and their derivatives with improved stability, recombinant expression vectors containing such nucleic acid sequences, host cells transformed with such recombinant expression vectors, recombinant polypeptides and derivatives which do have biological activities of the unmodified wild type protein but having improved stability and processes for the manufacture of such recombinant proteins and their derivatives. The invention also covers a transfer vector for use in human gene therapy, which comprises modified DNA sequences.
摘要翻译：本发明涉及编码凝血因子的修饰的核酸序列，特别是具有改善的稳定性的人FV和人因子VIII及其衍生物，含有这种核酸序列的重组表达载体，用这种重组表达载体转化的宿主细胞，重组多肽和确实具有未修饰的野生型蛋白质的生物活性但具有改进的稳定性的衍生物和用于制备这些重组蛋白质及其衍生物的方法。本发明还涵盖用于人基因治疗的转移载体，其包含修饰的DNA序列。

7. 发明申请

WO2007090584A1 MODIFIED COAGULATION FACTOR VILA WITH EXTENDED HALF-LIFE 审中-公开
标题翻译：改进的凝血因子维拉与延伸的生命
公开(公告)号：WO2007090584A1
公开(公告)日：2007-08-16
申请号：PCT/EP2007/000937
申请日：2007-02-03
申请人： ZLB BEHRING GMBH , WEIMER, Thomas , SCHULTE, Stefan , KRONTHALER, Ulrich , LANG, Wiegand , LIEBING, Uwe , WORMSBÄCHER, Wilfried
发明人： WEIMER, Thomas , SCHULTE, Stefan , KRONTHALER, Ulrich , LANG, Wiegand , LIEBING, Uwe , WORMSBÄCHER, Wilfried
IPC分类号： C12N15/62 , C07K14/76 , C12N9/64 , C07K19/00 , A61K38/48
CPC分类号： A61K38/4846 , A61K9/0019 , A61K38/00 , A61K38/385 , C07K14/76 , C07K2319/00 , C07K2319/31 , C12N9/6437 , C12N9/96 , C12N15/62 , C12Y304/21021
摘要： The present invention relates to the fields of Factor VII (FVII) and Factor Vila (FVIIa) albumin linked polypeptides. More specifically, the invention relates to cDNA sequences coding for human Factor VII and Factor Vila and derivatives genetically fused to a cDNA coding for human serum albumin which may be linked by oligonucleotides which code for intervening peptidic linkers such encoded derivatives exhibiting improved stability and extended functional plasma half-life, recombinant expression vectors containing such cDNA sequences, host cells transformed with such recombinant expression vectors, recombinant polypeptides and derivatives which do have biological activities of the unmodified wild type protein but having improved stability and prolonged shelf-life and processes for the manufacture of such recombinant proteins and their derivatives. The invention also covers a transfer vector for use in human gene therapy, which comprises such modified DNA sequences.
摘要翻译：本发明涉及因子VII（FVII）和因子VIIa（FVIIa）白蛋白连接多肽的领域。更具体地，本发明涉及编码人因子VII和因子VIIa的cDNA序列和与编码人血清白蛋白的cDNA遗传融合的衍生物，其可以通过寡核苷酸连接，所述寡核苷酸编码插入的肽接头体，所述衍生物表现出改善的稳定性和延伸的功能血浆半衰期，含有这些cDNA序列的重组表达载体，用这种重组表达载体转化的宿主细胞，确实具有未修饰的野生型蛋白的生物活性但具有改善的稳定性和延长的保存期限的重组多肽和衍生物制备这些重组蛋白及其衍生物。本发明还涵盖用于人基因治疗的转移载体，其包含这种修饰的DNA序列。

8. 发明申请

WO2006128668A2 COAGULATION FACTOR X POLYPEPTIDES WITH MODIFIED ACTIVATION PROPERTIES 审中-公开
标题翻译：凝血因子X多肽具有改性活性
公开(公告)号：WO2006128668A2
公开(公告)日：2006-12-07
申请号：PCT/EP2006/005131
申请日：2006-05-30
申请人： ZLB BEHRING GMBH , SCHULTE, Stefan , HAUSER, Hans-Peter , KALINA, Uwe , WEIMER, Thomas
发明人： SCHULTE, Stefan , HAUSER, Hans-Peter , KALINA, Uwe , WEIMER, Thomas
IPC分类号： C07K14/00 , C12N15/00 , C12N9/00
CPC分类号： C12N9/6432 , C12Y304/21006
摘要： The present invention relates to modified cDNA sequences coding for human Factor X and their derivatives with improved stability and modified activation sequences, recombinant expression vectors containing such cDNA sequences and host cells transformed with such recombinant expression vectors. The invention also relates to recombinant factor X polypeptides and derivatives which do have biological activities of the unmodified wild type protein but with improved stability and processes for the manufacture of such recombinant proteins and their derivatives. The invention also covers a transfer vector for use in human gene therapy, which comprises such modified DNA.
摘要翻译：本发明涉及编码具有改善的稳定性和修饰的活化序列的人因子X及其衍生物的修饰cDNA序列，含有此类cDNA序列的重组表达载体和用这些重组表达载体转化的宿主细胞。本发明还涉及确实具有未修饰的野生型蛋白质的生物活性但具有改进的稳定性的重组因子X多肽和衍生物，以及制备这些重组蛋白及其衍生物的方法。本发明还涵盖用于人基因治疗的转移载体，其包含这种修饰的DNA。

9. 发明申请

WO2007096116A1 COAGULATION FACTOR X POLYPEPTIDES WITH MODIFIED ACTIVATION PROPERTIES 审中-公开
标题翻译：凝血因子X多肽具有改性活性
公开(公告)号：WO2007096116A1
公开(公告)日：2007-08-30
申请号：PCT/EP2007/001417
申请日：2007-02-19
申请人： ZLB BEHRING GMBH , SCHULTE, Stefan , HAUSER, Hans-Peter , KALINA, Uwe , WEIMER, Thomas
发明人： SCHULTE, Stefan , HAUSER, Hans-Peter , KALINA, Uwe , WEIMER, Thomas
IPC分类号： A61K38/36 , C07K14/745 , A61P7/04 , C12N9/00
CPC分类号： C12N9/647 , A61K38/012 , A61K38/36 , C12N9/6432 , C12Y304/21006
摘要： The present invention relates to modified cDNA sequences coding for factor X polypeptides, in particular human factor X and its derivatives which can bypass the need for either factor Vllla/FIXa or factor Vlla/TF for activation. The invention relates further to recombinant expression vectors containing such modified cDNA sequences, host cells transformed with such recombinant expression vectors, recombinant polypeptides and derivatives which do have biological activities of the unmodified wild type protein but having altered activation properties, and processes for the manufacture of such recombinant proteins and their derivatives. The invention also covers a transfer vector for use in human gene therapy, which comprises such modified DNA sequences.
摘要翻译：本发明涉及编码因子X多肽，特别是人因子X及其衍生物的修饰的cDNA序列，其可以绕过对因子Vllla / FIXa或因子Vlla / TF进行活化的需要。本发明还涉及含有这种修饰的cDNA序列的重组表达载体，用这种重组表达载体转化的宿主细胞，确实具有未修饰的野生型蛋白的生物活性但具有改变的活化性质的重组多肽和衍生物，以及制备这些重组蛋白及其衍生物。本发明还涵盖用于人基因治疗的转移载体，其包含这种修饰的DNA序列。

10. 发明申请

WO2006018204A1 MODIFIED VITAMIN K DEPENDENT POLYPEPTIDES 审中-公开
标题翻译：改性维生素K依赖性多糖
公开(公告)号：WO2006018204A1
公开(公告)日：2006-02-23
申请号：PCT/EP2005/008678
申请日：2005-08-10
申请人： ZLB BEHRING GMBH , WEIMER, Thomas , SCHULTE, Stefan , HOFMANN, Kay , HAUSER, Hans-Peter
发明人： WEIMER, Thomas , SCHULTE, Stefan , HOFMANN, Kay , HAUSER, Hans-Peter
IPC分类号： C12N9/64 , C12N15/57 , A61K38/36 , A61P7/04
CPC分类号： C12N15/62 , C12N9/6424
摘要： The present invention relates to modified cDNA sequences coding for vitamin K-dependent polypeptides, in particular human Factor VII, human Factor Vlla, human Factor IX and human protein C and their derivatives with improved stability and extended plasma half life, recombinant expression vectors containing such cDNA sequences, host cells transformed with such recombinant expression vectors, recombinant polypeptides and derivatives which do have biological activities of the unmodified wild type protein but having improved stability and processes for the manufacture of such recombinant proteins and their derivatives. The invention also covers a transfer vector for use in human gene therapy, which comprises such modified DNA sequences.
摘要翻译：本发明涉及编码维生素K依赖性多肽，特别是人因子VII，人因子Vlla，人因子IX和人蛋白C及其衍生物的修饰cDNA序列，其具有改善的稳定性和延长的血浆半衰期，含有这些的重组表达载体 cDNA序列，用这种重组表达载体转化的宿主细胞，确实具有未修饰的野生型蛋白质的生物活性但具有改进的稳定性的生物活性的重组多肽和衍生物，以及制备这些重组蛋白质及其衍生物的方法。本发明还涵盖用于人基因治疗的转移载体，其包含这种修饰的DNA序列。

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