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1. 发明申请

US20100120664A1 MODIFIED COAGULATION FACTORS WITH PROLONGED IN VIVO HALF-LIFE 有权
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：US20100120664A1
公开(公告)日：2010-05-13
申请号：US12520840
申请日：2007-12-21
申请人： Stefan Schulte , Thomas Weimer , Hubert Metzner
发明人： Stefan Schulte , Thomas Weimer , Hubert Metzner
IPC分类号： A61K38/16 , C07K14/745 , C07K14/755 , C07H21/00 , C12N15/74 , C12N5/10 , C12P21/00 , A61P7/04
CPC分类号： C07K14/755 , C07K14/745 , C07K14/765 , C07K16/18 , C07K2319/31
摘要： The present invention relates to nucleic acid sequences coding for modified 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; and recombinant polypeptides and derivatives coded for by said nucleic acid sequences, whereby said recombinant polypeptides and derivatives have biological activities and prolonged in vivo half-lives compared to the unmodified wild-type proteins. 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. The invention also relates to a transfer vector for use in human gene therapy, which comprises such nucleic acid sequences.
摘要翻译：本发明涉及编码改性凝血因子，优选凝血因子VIII及其衍生物的核酸序列; 含有该核酸序列的重组表达载体; 用这些重组表达载体转化的宿主细胞; 和由所述核酸序列编码的重组多肽和衍生物，其中与未修饰的野生型蛋白相比，所述重组多肽和衍生物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，其包含这样的核酸序列。

2. 发明申请

US20080260755A1 Proteolytically cleavable fusion proteins with high molar specific activity 有权
标题翻译：具有高摩尔比活性的蛋白水解切割融合蛋白
公开(公告)号：US20080260755A1
公开(公告)日：2008-10-23
申请号：US12000739
申请日：2007-12-17
申请人： Hubert Metzner , Thomas Weimer , Stefan Schulte
发明人： Hubert Metzner , Thomas Weimer , Stefan Schulte
IPC分类号： A61K39/395 , C07K16/18 , C07K14/00 , C12N15/11 , A61K31/70 , A61P7/00 , A61K38/00 , C12N15/00 , C12N5/06 , C12P21/04
CPC分类号： C12N9/6437 , A61K38/00 , A61K48/00 , C07K14/745 , C07K14/755 , C07K14/76 , C07K14/765 , C07K2319/31 , C07K2319/50 , C12N9/6424 , C12N9/6443 , C12N9/6472 , C12Y304/21021 , C12Y304/21022
摘要： The invention relates to therapeutic fusion proteins in which a coagulation factor is fused to a half-life enhancing polypeptide, and in which both are connected by a linker peptide that is proteolytically cleavable. The cleavage of such linkers liberates the coagulation factor from activity-compromising steric hindrance caused by the half-life enhancing polypeptide and thereby allows the generation of fusion proteins may show relatively 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 rates measured for corresponding therapeutic fusion proteins 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，并且其中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半衰期增强多肽引起的活性损害的空间位阻释放，从而允许融合蛋白的产生在凝血相关测定中测试时可显示相对高的摩尔比活性。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治疗性融合蛋白测量的速率相比，接头可切割的事实可增加肽接头的蛋白水解切割后的失活和/或消除速率。

3. 发明申请

US20130337532A1 THERAPEUTIC POLYPEPTIDES WITH INCREASED IN VIVO RECOVERY 审中-公开
标题翻译：治疗性多糖在体重恢复中增加
公开(公告)号：US20130337532A1
公开(公告)日：2013-12-19
申请号：US13921815
申请日：2013-06-19
申请人： Thomas Weimer , Hubert Metzner , Stefan Schulte , Wiegand Lang , Wilfried Wormsbacher
发明人： Thomas Weimer , Hubert Metzner , Stefan Schulte , Wiegand Lang , Wilfried Wormsbacher
IPC分类号： C12N9/64
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. For example, 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。例如，本发明涉及治疗性多肽与通过连接肽直接连接或任选连接的恢复增强多肽的融合。

4. 发明申请

US20100222554A1 Method of Increasing the In Vivo Recovery of Therapeutic Polypeptides 审中-公开
标题翻译：增加治疗性多肽体内复原的方法
公开(公告)号：US20100222554A1
公开(公告)日：2010-09-02
申请号：US12226188
申请日：2007-04-02
申请人： Thomas Weimer , Hubert Metzner , Stefan Schulte , Wiegand Lang , Wilfried Wormsbächer
发明人： Thomas Weimer , Hubert Metzner , Stefan Schulte , Wiegand Lang , Wilfried Wormsbächer
IPC分类号： C07K1/107
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

US20090042787A1 Proteolytically cleavable fusion proteins with high molar specific activity 审中-公开
标题翻译：具有高摩尔比活性的蛋白水解切割融合蛋白
公开(公告)号：US20090042787A1
公开(公告)日：2009-02-12
申请号：US11812016
申请日：2007-06-14
申请人： Hubert Metzner , Thomas Weimer , Stefan Schulte
发明人： Hubert Metzner , Thomas Weimer , Stefan Schulte
IPC分类号： A61K38/16 , C07K19/00 , C07H21/04 , C12N15/63 , A61P7/00 , A61K31/711 , C12N5/10 , C12P21/00
CPC分类号： C07K14/745 , A61K38/00 , C07K14/755 , C07K2319/31 , C12N9/6424 , 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 in which both are connected by a linker peptide that is proteolytically cleavable. The cleavage of such linkers liberates the coagulation factor from activity-compromising steric hindrance caused by the half-life enhancing polypeptide and thereby allows the generation of fusion proteins may show relatively 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 rates measured for corresponding therapeutic fusion proteins linked by the non-cleavable linker having the amino acid sequence GGGGGGV (SEQ ID NO: 94).
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，并且其中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半衰期增强多肽引起的活性损害的空间位阻释放，从而允许融合蛋白的产生在凝血相关测定中测试时可显示相对高的摩尔比活性。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治疗性融合蛋白的测量速率相比，接头可切割的事实可增加肽接头的蛋白水解切割后的失活和/或消除速率（ SEQ ID NO：94）。

6. 发明授权

US08754194B2 Modified coagulation factors with prolonged in vivo half-life 有权
标题翻译：改性凝血因子具有延长的体内半衰期
公开(公告)号：US08754194B2
公开(公告)日：2014-06-17
申请号：US12520840
申请日：2007-12-21
申请人： Stefan Schulte , Thomas Weimer , Hubert Metzner
发明人： Stefan Schulte , Thomas Weimer , Hubert Metzner
IPC分类号： A61K38/37 , C07K1/00
CPC分类号： C07K14/755 , C07K14/745 , C07K14/765 , C07K16/18 , C07K2319/31
摘要： The present invention relates to nucleic acid sequences coding for modified 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; and recombinant polypeptides and derivatives coded for by said nucleic acid sequences, whereby said recombinant polypeptides and derivatives have biological activities and prolonged in vivo half-lives compared to the unmodified wild-type proteins. 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. The invention also relates to a transfer vector for use in human gene therapy, which comprises such nucleic acid sequences.
摘要翻译：本发明涉及编码改性凝血因子，优选凝血因子VIII及其衍生物的核酸序列; 含有该核酸序列的重组表达载体; 用这些重组表达载体转化的宿主细胞; 和由所述核酸序列编码的重组多肽和衍生物，其中与未修饰的野生型蛋白相比，所述重组多肽和衍生物具有生物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，其包含这样的核酸序列。

7. 发明授权

US08575104B2 Factor VIII, von willebrand factor or complexes thereof with prolonged in vivo half-life 有权
标题翻译：因子VIII，血管性血友病因子或其复合物具有延长的体内半衰期
公开(公告)号：US08575104B2
公开(公告)日：2013-11-05
申请号：US13000938
申请日：2009-06-24
申请人： Thomas Weimer , Stefan Schulte , Hubert Metzner , Ulrich Kronthaler , Holger Lind , Wiegand Lang
发明人： Thomas Weimer , Stefan Schulte , Hubert Metzner , Ulrich Kronthaler , Holger Lind , Wiegand Lang
IPC分类号： A61K38/37 , A61K38/36 , A61K38/16 , A61K35/14 , C07K1/00 , C12N5/00
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。

8. 发明申请

US20110189182A1 PROTEOLYTICALLY CLEAVABLE FUSION PROTEINS WITH HIGH MOLAR SPECIFIC ACTIVITY 审中-公开
标题翻译：具有高度特异性活性的蛋白质可溶蛋白融合蛋白
公开(公告)号：US20110189182A1
公开(公告)日：2011-08-04
申请号：US13074153
申请日：2011-03-29
申请人： Hubert METZNER , Thomas Weimer , Stefan Schulte
发明人： Hubert METZNER , Thomas Weimer , Stefan Schulte
IPC分类号： A61K39/395 , C07K19/00 , C12N9/64 , C07H21/00 , C12N15/63 , C12P21/00 , A61K48/00 , C12N5/10 , A61P7/00 , A61P7/04
CPC分类号： C12N9/6437 , A61K38/00 , A61K48/00 , C07K14/745 , C07K14/755 , C07K14/76 , C07K14/765 , C07K2319/31 , C07K2319/50 , C12N9/6424 , C12N9/6443 , C12N9/6472 , C12Y304/21021 , C12Y304/21022
摘要： The invention relates to therapeutic fusion proteins in which a coagulation factor is fused to a half-life enhancing polypeptide, and in which both are connected by a linker peptide that is proteolytically cleavable. The cleavage of such linkers liberates the coagulation factor from activity-compromising steric hindrance caused by the half-life enhancing polypeptide and thereby allows the generation of fusion proteins may show relatively 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 rates measured for corresponding therapeutic fusion proteins 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，并且其中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半衰期增强多肽引起的活性损害的空间位阻释放，从而允许融合蛋白的产生在凝血相关测定中测试时可显示相对高的摩尔比活性。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治疗性融合蛋白测量的速率相比，接头可切割的事实可增加肽接头的蛋白水解切割后的失活和/或消除速率。

9. 发明授权

US09290561B2 Factor VIII, von Willebrand factor or complexes thereof with prolonged in vivo half-life 有权
标题翻译：因子VIII，血管性血友病因子或其复合物具有延长的体内半衰期
公开(公告)号：US09290561B2
公开(公告)日：2016-03-22
申请号：US14028869
申请日：2013-09-17
申请人： Thomas Weimer , Stefan Schulte , Hubert Metzner , Ulrich Kronthaler , Holger Lind , Wiegand Lang
发明人： Thomas Weimer , Stefan Schulte , Hubert Metzner , Ulrich Kronthaler , Holger Lind , Wiegand Lang
IPC分类号： A61K38/37 , A61K38/36 , A61K38/38 , A61K38/16 , A61K35/14 , C07K1/00 , C07K14/76 , C07K14/755 , A61K38/00
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。

10. 发明申请

US20140072561A1 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：US20140072561A1
公开(公告)日：2014-03-13
申请号：US14028869
申请日：2013-09-17
申请人： Thomas Weimer , Stefan Schulte , Hubert Metzner , Ulrich Kronthaler , Holger Lind , Wiegand Lang
发明人： Thomas Weimer , Stefan Schulte , Hubert Metzner , Ulrich Kronthaler , Holger Lind , Wiegand Lang
IPC分类号： C07K14/76 , C07K14/755
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。

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