公开(公告)号：US5411871A

公开(公告)日：1995-05-02

申请号：US179059

申请日：1994-01-07

申请人： Stephen Anderson ,  William F. Bennett ,  David Botstein ,  Deborah L. Higgins ,  Nicholas F. Paoni ,  Mark J. Zoller

发明人： Stephen Anderson ,  William F. Bennett ,  David Botstein ,  Deborah L. Higgins ,  Nicholas F. Paoni ,  Mark J. Zoller

IPC分类号： A61K38/00 ,  A61K38/48 ,  C07H21/04 ,  C12N1/21 ,  C12N5/10 ,  C12N9/64 ,  C12N9/72 ,  C12N15/55 ,  C12N15/58 ,  C12N15/63 ,  C12N15/70 ,  C12N15/86 ,  C12Q1/37

CPC分类号： C12N9/6456 ,  A61K38/00

摘要： Tissue plasminogen activator (t-PA) zymogens and variants are prepared, including a fibrinolytically active variant of t-PA that has an amino acid alteration at a site within the protease domain of t-PA as compared with the corresponding wild-type t-PA, which alteration renders the variant zymogenic in the presence of plasmin-degraded fibrinogen, and/or fibrin (or plasma clot) specific, as compared to the corresponding wild-type t-PA. DNA sequences can be prepared that encode the zymogens and variants, as well as expression vectors incorporating the DNA sequences, and host cells transformed with the expression vectors. The zymogens and variants may be used in a pharmaceutical preparation to treat a vascular disease or condition or to prevent fibrin deposition or adhesion formation or reformation in mammals.

摘要翻译： 制备组织纤溶酶原激活剂（t-PA）酶原和变体，包括t-PA的纤维蛋白溶解活性变体，其在t-PA的蛋白酶结构域内的位置具有氨基酸改变，与相应的野生型t- PA，与相应的野生型t-PA相比，其改变使纤维蛋白溶酶原纤维蛋白原和/或纤维蛋白（或血浆凝块）存在下的变形酶原。 可以制备编码酶原和变体的DNA序列，以及掺入DNA序列的表达载体和用表达载体转化的宿主细胞。 酶原和变体可用于药物制剂中以治疗血管疾病或病症或预防纤维蛋白沉积或哺乳动物中的粘附形成或重新形成。

公开(公告)号：US5728567A

公开(公告)日：1998-03-17

申请号：US662891

申请日：1996-08-01

申请人： Stephen Anderson ,  William F. Bennett ,  David Botstein ,  Deborah L. Higgins ,  Nicholas F. Paoni ,  Mark J. Zoller

发明人： Stephen Anderson ,  William F. Bennett ,  David Botstein ,  Deborah L. Higgins ,  Nicholas F. Paoni ,  Mark J. Zoller

IPC分类号： A61K38/00 ,  A61K38/48 ,  C07H21/04 ,  C12N1/21 ,  C12N5/10 ,  C12N9/64 ,  C12N9/72 ,  C12N15/55 ,  C12N15/58 ,  C12N15/63 ,  C12N15/70 ,  C12N15/86

CPC分类号： C12N9/6456 ,  A61K38/00

摘要： Tissue plasminogen activator (t-PA) zymogens and variants are prepared, including a fibrinolytically active variant of t-PA that has an amino acid alteration at a site within the protease domain of t-PA as compared with the corresponding wild-type t-PA, which alteration renders the variant zymogenic in the presence of plasmin-degraded fibrinogen, and/or fibrin (or plasma clot) specific, as compared to the corresponding wild-type t-PA. DNA sequences can be prepared that encode the zymogens and variants, as well as expression vectors incorporating the DNA sequences, and host cells transformed with the expression vectors. The zymogens and variants may be used in a pharmaceutical preparation to treat a vascular disease or condition or to prevent fibrin deposition or adhesion formation or reformation in mammals.

公开(公告)号：US5108901A

公开(公告)日：1992-04-28

申请号：US384608

申请日：1989-07-24

申请人： Stephen Anderson ,  William F. Bennett ,  David Botstein ,  Deborah L. Higgins ,  Nicholas F. Paoni ,  Mark J. Zoller

发明人： Stephen Anderson ,  William F. Bennett ,  David Botstein ,  Deborah L. Higgins ,  Nicholas F. Paoni ,  Mark J. Zoller

IPC分类号： C12N15/09 ,  A61K38/00 ,  A61K38/46 ,  A61K38/48 ,  A61P7/02 ,  C07K14/00 ,  C07K14/47 ,  C12N1/19 ,  C12N1/21 ,  C12N5/10 ,  C12N9/64 ,  C12N9/72 ,  C12N15/58 ,  C12P21/02 ,  C12Q1/37

CPC分类号： C12N9/6456 ,  A61K38/00

摘要： Tissue plasminogen activator (t-PA) zymogens and variants are prepared, including a fibrinolytically active variant of t-PA that has an amino acid alteration at a site within the protease domain of t-PA as compared with the corresponding wild-type t-PA, which alteration renders the variant zymogenic in the presence of plasmin-degraded fibrinogen, and/or fibrin (or plasma clot) specific, as compared to the corresponding wild-type t-PA. DNA sequences can be prepared that encode the zymogens and variants, as well as expression vectors incorporating the DNA sequences, and host cells transformed with the expression vectors. The zymogens and variants may be used in a pharmaceutical preparation to treat a vascular disease or condition or to prevent fibrin deposition or adhesion formation or reformation in mammals.

摘要翻译： 制备组织纤溶酶原激活剂（t-PA）酶原和变体，包括t-PA的纤维蛋白溶解活性变体，其在t-PA的蛋白酶结构域内的位置具有氨基酸改变，与相应的野生型t- PA，与相应的野生型t-PA相比，其改变使纤维蛋白溶酶原纤维蛋白原和/或纤维蛋白（或血浆凝块）存在下的变形酶原。 可以制备编码酶原和变体的DNA序列，以及掺入DNA序列的表达载体和用表达载体转化的宿主细胞。 酶原和变体可用于药物制剂中以治疗血管疾病或病症或预防纤维蛋白沉积或哺乳动物中的粘附形成或重新形成。

公开(公告)号：US5770426A

公开(公告)日：1998-06-23

申请号：US660986

申请日：1996-06-12

申请人： Stephen Anderson ,  William F. Bennett ,  David Botstein ,  Deborah L. Higgins ,  Nicholas F. Paoni ,  Mark J. Zoller

发明人： Stephen Anderson ,  William F. Bennett ,  David Botstein ,  Deborah L. Higgins ,  Nicholas F. Paoni ,  Mark J. Zoller

IPC分类号： A61K38/00 ,  A61K38/48 ,  C07H21/04 ,  C12N1/21 ,  C12N5/10 ,  C12N9/64 ,  C12N9/72 ,  C12N15/55 ,  C12N15/58 ,  C12N15/63 ,  C12N15/70 ,  C12N15/86

CPC分类号： C12N9/6456 ,  A61K38/00

摘要： Tissue plasminogen activator (t-PA) zymogens and variants are prepared, including a fibrinolytically active variant of t-PA that has an amino acid alteration at a site within the protease domain of t-PA as compared with the corresponding wild-type t-PA, which alteration renders the variant zymogenic in the presence of plasmin-degraded fibrinogen, and/or fibrin (or plasma clot) specific, as compared to the corresponding wild-type t-PA. DNA sequences can be prepared that encode the zymogens and variants, as well as expression vectors incorporating the DNA sequences, and host cells transformed with the expression vectors. The zymogens and variants may be used in a pharmaceutical preparation to treat a vascular disease or condition or to prevent fibrin deposition or adhesion formation or reformation in mammals.

公开(公告)号：US5714145A

公开(公告)日：1998-02-03

申请号：US733353

申请日：1996-10-17

申请人： Stephen Anderson ,  William F. Bennett ,  David Botstein ,  Deborah L. Higgins ,  Nicholas F. Paoni ,  Mark J. Zoller

发明人： Stephen Anderson ,  William F. Bennett ,  David Botstein ,  Deborah L. Higgins ,  Nicholas F. Paoni ,  Mark J. Zoller

IPC分类号： A61K38/49 ,  C12N9/64 ,  C12N15/58 ,  C12N15/70

CPC分类号： A61K38/49 ,  C12N15/70 ,  C12N9/64

摘要： Tissue plasminogen activator (t-PA) zymogens and variants are prepared, including a fibrinolytically active variant of t-PA that has an amino acid alteration at a site within the protease domain of t-PA as compared with the corresponding wild-type t-PA, which alteration renders the variant zymogenic in the presence of plasmin-degraded fibrinogen, and/or fibrin (or plasma clot) specific, as compared to the corresponding wild-type t-PA. DNA sequences can be prepared that encode the zymogens and variants, as well as expression vectors incorporating the DNA sequences, and host cells transformed with the expression vectors. The zymogens and variants may be used in a pharmaceutical preparation to treat a vascular disease or condition or to prevent fibrin deposition or adhesion formation or reformation in mammals.

公开(公告)号：US5616486A

公开(公告)日：1997-04-01

申请号：US422736

申请日：1995-04-14

申请人： Stephen Anderson ,  William F. Bennett ,  David Botstein ,  Deborah L. Higgins ,  Nicholas F. Paoni ,  Mark J. Zoller

发明人： Stephen Anderson ,  William F. Bennett ,  David Botstein ,  Deborah L. Higgins ,  Nicholas F. Paoni ,  Mark J. Zoller

IPC分类号： A61K38/00 ,  A61K38/48 ,  C07H21/04 ,  C12N1/21 ,  C12N5/10 ,  C12N9/64 ,  C12N9/72 ,  C12N15/55 ,  C12N15/58 ,  C12N15/63 ,  C12N15/70 ,  C12N15/86

CPC分类号： C12N9/6456 ,  A61K38/00

摘要： Tissue plasminogen activator (t-PA) zymogens and variants are prepared, including a fibrinolytically active variant of t-PA that has an amino acid alteration at a site within the protease domain of t-PA as compared with the corresponding wild-type t-PA, which alteration renders the variant zymogenic in the presence of plasmin-degraded fibrinogen, and/or fibrin (or plasma clot) specific, as compared to the corresponding wild-type t-PA. DNA sequences can be prepared that encode the zymogens and variants, as well as expression vectors incorporating the DNA sequences, and host cells transformed with the expression vectors. The zymogens and variants may be used in a pharmaceutical preparation to treat a vascular disease or condition or to prevent fibrin deposition or adhesion formation or reformation in mammals.

公开(公告)号：US5262170A

公开(公告)日：1993-11-16

申请号：US770510

申请日：1991-10-03

申请人： Stephen Anderson ,  William F. Bennett ,  David Botstein ,  Deborah L. Higgins ,  Nicholas F. Paoni ,  Mark J. Zoller

发明人： Stephen Anderson ,  William F. Bennett ,  David Botstein ,  Deborah L. Higgins ,  Nicholas F. Paoni ,  Mark J. Zoller

IPC分类号： A61K38/00 ,  A61K38/48 ,  C07H21/04 ,  C12N1/21 ,  C12N5/10 ,  C12N9/64 ,  C12N9/72 ,  C12N15/55 ,  C12N15/58 ,  C12N15/63 ,  C12N15/70 ,  C12N15/86 ,  A61K37/547

CPC分类号： C12N9/6456 ,  A61K38/00

摘要： Tissue plasminogen activator (t-PA) zymogens and variants are prepared, including a fibrinolytically active variant of t-PA that has an amino acid alteration at a site within the protease domain of t-PA as compared with the corresponding wild-type t-PA, which alteration renders the variant zymogenic in the presence of plasmin-degraded fibrinogen, and/or fibrin (or plasma clot) specific, as compared to the corresponding wild-type t-PA. DNA sequences can be prepared that encode the zymogens and variants, as well as expression vectors incorporating the DNA sequences, and host cells transformed with the expression vectors. The zymogens and variants may be used in a pharmaceutical preparation to treat a vascular disease or condition or to prevent fibrin deposition or adhesion formation or reformation in mammals.

摘要翻译： 制备组织纤溶酶原激活剂（t-PA）酶原和变体，包括t-PA的纤维蛋白溶解活性变体，其在t-PA的蛋白酶结构域内的位置具有氨基酸改变，与相应的野生型t- PA，与相应的野生型t-PA相比，其改变使纤维蛋白溶酶原纤维蛋白原和/或纤维蛋白（或血浆凝块）存在下的变形酶原。 可以制备编码酶原和变体的DNA序列，以及掺入DNA序列的表达载体和用表达载体转化的宿主细胞。 酶原和变体可用于药物制剂中以治疗血管疾病或病症或预防纤维蛋白沉积或哺乳动物中的粘附形成或重新形成。

公开(公告)号：US5756093A

公开(公告)日：1998-05-26

申请号：US275335

申请日：1994-07-14

申请人： Herbert L. Heyneker ,  Gordon A. Vehar ,  Nicholas F. Paoni ,  William F. Bennett

发明人： Herbert L. Heyneker ,  Gordon A. Vehar ,  Nicholas F. Paoni ,  William F. Bennett

IPC分类号： A61K38/00 ,  C12N1/21 ,  C12N9/72 ,  A61K38/48 ,  C07H21/04 ,  C12N9/48

CPC分类号： C12N9/6459 ,  C12Y304/21069 ,  A61K38/00

摘要： Biologically active variant tissue plasminogen activators are disclosed. The disclosure focuses on position 276 variants that exhibit enhanced fibrin specificity.

摘要翻译： 公开了生物活性变体组织纤溶酶原激活剂。 本公开集中于显示增强的纤维蛋白特异性的位置276变体。

公开(公告)号：US5612029A

公开(公告)日：1997-03-18

申请号：US436697

申请日：1995-05-08

申请人： William F. Bennett ,  Bruce A. Keyt ,  Nicholas F. Paoni

发明人： William F. Bennett ,  Bruce A. Keyt ,  Nicholas F. Paoni

IPC分类号： C12N15/09 ,  A61K38/00 ,  A61K38/46 ,  A61P7/02 ,  C12N9/64 ,  C12N9/72 ,  C12N15/58 ,  C12R1/19 ,  A61K38/49 ,  C12N9/48

CPC分类号： C12N9/6459 ,  C12Y304/21069 ,  A61K38/00

摘要： The invention concerns tissue plasminogen activator (t-PA) variants which are glycosylated at any of positions 103-105, and are devoid of functional carbohydrate structure at position 117 of wild-type human t-PA amino acid sequence. The variants have extended circulatory half-life and substantially retained fibrin binding, or improved in vivo fibrinolytic potency, as compared to wild-type human t-PA.

摘要翻译： 本发明涉及在103-105任何位置糖基化并且在野生型人t-PA氨基酸序列的117位没有功能性碳水化合物结构的组织纤溶酶原激活剂（t-PA）变体。 与野生型人t-PA相比，变体具有延长的循环半衰期和基本上保留的纤维蛋白结合或体内纤维蛋白溶解效力的改善。

公开(公告)号：US20110184712A1

公开(公告)日：2011-07-28

申请号：US12682579

申请日：2008-10-10

申请人： Steve Rosenberg ,  Susan Daniels ,  Michael R. Elashoff ,  James A. Wingrove ,  Whittemore G. Tingley ,  Amy J. Sehnert ,  Nicholas F. Paoni

发明人： Steve Rosenberg ,  Susan Daniels ,  Michael R. Elashoff ,  James A. Wingrove ,  Whittemore G. Tingley ,  Amy J. Sehnert ,  Nicholas F. Paoni

IPC分类号： G06G7/60

CPC分类号： C12Q1/6883 ,  C12Q2600/112 ,  C12Q2600/158

摘要： Biomarkers useful for diagnosing and assessing the extent of coronary artery disease (CAD) are provided, along with kits for measuring their expression. The invention also provides predictive models, based on the biomarkers, as well as computer systems, and software embodiments of the models for scoring and optionally classifying samples. In a preferred embodiment, the biomarkers are organized into clustered groups. The expression level of the biomarkers within a group are highly correlated to each other in normal and disease states. Expression values of genes chosen from each of two, three, four or five of the clustered gene groups, A, B, C, D, E may be used. Alternatively, expression values of genes chosen from the groups are combined into a metagene. Preferred biomarkers include S100A12, S100A8, S100A9, BCL2A1, and F5 (group A); XK, P62, and FECH (group B); TUBB2 (group C); IFNG, PDGFB, VSIG4, and TNF (group D); CSF3R, TLR5, CD46, and NCF1 (group E); S100A12, S100A9, BCL2A1, TXN and CSTA (group I); OLIG1, OLIG2, ADORA3, CLC, and SLC29A1 (group II); and CBS and ARG1 (group IV).

摘要翻译： 提供了有助于诊断和评估冠状动脉疾病（CAD）程度的生物标志物，以及用于测量其表达的试剂盒。 本发明还提供了基于生物标志物的预测模型，以及用于评分和可选地分类样品的模型的计算机系统和软件实施方案。 在优选的实施方案中，生物标志物被组织成聚集的组。 一组中生物标志物的表达水平在正常和疾病状态下彼此高度相关。 可以使用从两个，三个，四个或五个聚簇基因组A，B，C，D，E中的每一个中选择的基因的表达值。 或者，选自组中的基因的表达值被组合成元源。 优选的生物标志物包括S100A12，S100A8，S100A9，BCL2A1和F5（组A）; XK，P62和FECH（B组）; TUBB2（C组）; IFNG，PDGFB，VSIG4和TNF（D组）; CSF3R，TLR5，CD46和NCF1（组E）; S100A12，S100A9，BCL2A1，TXN和CSTA（组I）; OLIG1，OLIG2，ADORA3，CLC和SLC29A1（组II）; 和CBS和ARG1（组IV）。