公开(公告)号：US20090175828A1

公开(公告)日：2009-07-09

申请号：US12224182

申请日：2007-02-19

申请人： Stefan Schulte ,  Hans-Peter Hauser ,  Uwe Kalina ,  Thomas Weimer

发明人： Stefan Schulte ,  Hans-Peter Hauser ,  Uwe Kalina ,  Thomas Weimer

IPC分类号： A61K38/36 ,  C07K14/745 ,  C12N15/12 ,  C12N15/63 ,  C12N5/10 ,  C12P21/00 ,  A61P7/02

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 VIIIa/factor IXa or factor VIIa/tissue factor 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VIIIa /因子IXa或因子VIIa /组织因子进行活化的需要。 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。

公开(公告)号：US20090053185A1

公开(公告)日：2009-02-26

申请号：US11921399

申请日：2006-05-30

申请人： Stefan Schulte ,  Hans-Peter Hauser ,  Uwe Kalina ,  Thomas Weimer

发明人： Stefan Schulte ,  Hans-Peter Hauser ,  Uwe Kalina ,  Thomas Weimer

IPC分类号： A61K48/00 ,  C07K2/00 ,  C07H21/04 ,  C12N15/63 ,  C12N5/00 ,  C12P21/06 ,  A61K38/00 ,  A61K31/7088

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 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及其衍生物的修饰的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。 本发明还涉及具有未修饰的野生型蛋白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，以及用于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。

公开(公告)号：US09347051B2

公开(公告)日：2016-05-24

申请号：US12224182

申请日：2007-02-19

申请人： Stefan Schulte ,  Hans-Peter Hauser ,  Uwe Kalina ,  Thomas Weimer

发明人： Stefan Schulte ,  Hans-Peter Hauser ,  Uwe Kalina ,  Thomas Weimer

IPC分类号： C07K19/00 ,  C07K4/12 ,  C07K14/745 ,  C12N9/64 ,  A61K38/01 ,  A61K38/36

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 VIIIa/factor IXa or factor VIIa/tissue factor 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VIIIa /因子IXa或因子VIIa /组织因子进行活化的需要。 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。

公开(公告)号：US09249404B2

公开(公告)日：2016-02-02

申请号：US11921399

申请日：2006-05-30

申请人： Stefan Schulte ,  Hans-Peter Hauser ,  Uwe Kalina ,  Thomas Weimer

发明人： Stefan Schulte ,  Hans-Peter Hauser ,  Uwe Kalina ,  Thomas Weimer

IPC分类号： C12N9/64 ,  C12N15/57 ,  A61K38/48

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 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。 本发明还涉及具有未修饰的野生型蛋白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，以及用于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。

公开(公告)号：US08828939B2

公开(公告)日：2014-09-09

申请号：US11632552

申请日：2005-08-10

申请人： Thomas Weimer ,  Stefan Schulte ,  Kay Hofmann ,  Hans-Peter Hauser

发明人： Thomas Weimer ,  Stefan Schulte ,  Kay Hofmann ,  Hans-Peter Hauser

IPC分类号： A61K38/36 ,  C07K14/745 ,  C12N15/62 ,  C12N9/64

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 VIIa, 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依赖多肽，特别是人因子VII，人因子VIIa，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，含有这样的重组表达载体 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。

公开(公告)号：US20090130060A1

公开(公告)日：2009-05-21

申请号：US11632552

申请日：2005-08-10

申请人： Thomas Weimer ,  Stefan Schulte ,  Kay Hofmann ,  Hans-Peter Hauser

发明人： Thomas Weimer ,  Stefan Schulte ,  Kay Hofmann ,  Hans-Peter Hauser

IPC分类号： A61K35/74 ,  C07K1/00 ,  C07K14/00 ,  C12N9/50 ,  C12N15/11 ,  C12N15/00 ,  C12N1/21 ,  C12P21/04 ,  A61K38/16 ,  A61K31/7088

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 VIIa, 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依赖多肽，特别是人因子VII，人因子VIIa，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，含有这样的重组表达载体 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。

公开(公告)号：US20150150911A2

公开(公告)日：2015-06-04

申请号：US14116491

申请日：2012-05-14

申请人： Stefan Schulte ,  Uwe Kalina ,  Michael Moses ,  Annette Feussner

发明人： Stefan Schulte ,  Uwe Kalina ,  Michael Moses ,  Annette Feussner

IPC分类号： A61K35/16

CPC分类号： A61K35/16 ,  A61K31/727 ,  A61K38/385 ,  A61K38/57 ,  C12Y304/21008 ,  C12Y304/21027 ,  C12Y304/21038

摘要： The instant invention provides a method to reduce adverse events caused by a pharmaceutical preparation derived from a plasma fraction said plasma fraction comprising antithrombin III wherein the method comprises contacting the plasma fraction with heparin or a heparin-like substance thereby reducing the activity of at least one activated serine protease per ml of the plasma fraction.

摘要翻译： 本发明提供了一种减少由衍生自血浆级分的药物制剂引起的不良事件的方法，所述血浆级分包含抗凝血酶III，其中所述方法包括使血浆级分与肝素或肝素样物质接触，从而降低至少一种 每毫升血浆级分活化丝氨酸蛋白酶。

公开(公告)号：US20140161899A1

公开(公告)日：2014-06-12

申请号：US14116491

申请日：2012-05-14

申请人： Stefan Schulte ,  Uwe Kalina ,  Michael Moses ,  Annette Feussner

发明人： Stefan Schulte ,  Uwe Kalina ,  Michael Moses ,  Annette Feussner

IPC分类号： A61K35/16

CPC分类号： A61K35/16 ,  A61K31/727 ,  A61K38/385 ,  A61K38/57 ,  C12Y304/21008 ,  C12Y304/21027 ,  C12Y304/21038

摘要： The instant invention provides a method to reduce adverse events caused by a pharmaceutical preparation derived from a plasma fraction wherein the method comprises contacting the plasma fraction with heparin or a heparin-like substance thereby reducing the activity of at least one activated serine proteaseper ml of the plasma fraction.

摘要翻译： 本发明提供了一种减少由衍生自血浆级分的药物制剂引起的不良事件的方法，其中所述方法包括使血浆级分与肝素或肝素样物质接触，从而降低至少一种活化丝氨酸蛋白酶的活性 血浆分数。

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。

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。