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公开(公告)号：US08940297B2
公开(公告)日：2015-01-27
申请号：US13331109
申请日：2011-12-20
申请人： Enrico Di Cera , Andras Gruber , Prafull Gandhi , Leslie Pelc , Nicola Pozzi , David Collier Wood
发明人： Enrico Di Cera , Andras Gruber , Prafull Gandhi , Leslie Pelc , Nicola Pozzi , David Collier Wood
CPC分类号： C12N9/6429 , A61K38/4833 , C12Y304/21005 , Y02A50/473
摘要： One aspect of the invention contemplates a mutant E-WE thrombin precursor that contains the SEQ ID NO:1 amino acid residue sequence. Another aspect contemplates a thrombin precursor that contains the amino acid residue sequence Asp/Glu-Gly-Arg at positions 325, 326 and 327 based on the preprothrombin sequence. A third aspect contemplates a thrombin precursor that contains the SEQ ID NO:1 amino acid residue sequence as well as the amino acid residue sequence Asp/Glu Gly Arg at positions 325, 326 and 327 based on the preprothrombin sequence. Also contemplated is a composition that contains an effective amount of mutant thrombin dissolved or dispersed in a pharmaceutically acceptable carrier. A method is also disclosed for enhancing treating and preventing thrombosis in a mammal in need using that composition.
摘要翻译： 本发明的一个方面考虑了含有SEQ ID NO：1氨基酸残基序列的突变E-WE凝血酶前体。 另一方面考虑了基于前凝血酶原序列在325,326和327位含有氨基酸残基序列Asp / Glu-Gly-Arg的凝血酶前体。 第三方面考虑了基于前凝血酶原序列的含有SEQ ID NO：1氨基酸残基序列以及位置325,326和327的氨基酸残基序列Asp / Glu Gly Arg的凝血酶前体。 还考虑了包含溶解或分散在药学上可接受的载体中的有效量的突变凝血酶的组合物。 还公开了一种用于增强使用该组合物治疗和预防需要的哺乳动物血栓形成的方法。
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公开(公告)号：US20120164129A1
公开(公告)日：2012-06-28
申请号：US13331109
申请日：2011-12-20
申请人： Enrico Di Cera , Andras Gruber , Prafull Gandhi , Leslie Pelc , Nicola Pozzi , David Collier Wood
发明人： Enrico Di Cera , Andras Gruber , Prafull Gandhi , Leslie Pelc , Nicola Pozzi , David Collier Wood
CPC分类号： C12N9/6429 , A61K38/4833 , C12Y304/21005 , Y02A50/473
摘要： One aspect of the invention contemplates a mutant E-WE thrombin precursor that contains the SEQ ID NO:1 amino acid residue sequence. Another aspect contemplates a thrombin precursor that contains the amino acid residue sequence Asp/Glu-Gly-Arg at positions 325, 326 and 327 based on the preprothrombin sequence. A third aspect contemplates a thrombin precursor that contains the SEQ ID NO:1 amino acid residue sequence as well as the amino acid residue sequence Asp/Glu Gly Arg at positions 325, 326 and 327 based on the preprothrombin sequence. Also contemplated is a composition that contains an effective amount of mutant thrombin dissolved or dispersed in a pharmaceutically acceptable carrier. A method is also disclosed for enhancing treating and preventing thrombosis in a mammal in need using that composition.
摘要翻译： 本发明的一个方面考虑了含有SEQ ID NO：1氨基酸残基序列的突变E-WE凝血酶前体。 另一方面考虑了基于前凝血酶原序列在325,326和327位含有氨基酸残基序列Asp / Glu-Gly-Arg的凝血酶前体。 第三方面考虑了基于前凝血酶原序列的含有SEQ ID NO：1氨基酸残基序列以及位置325,326和327的氨基酸残基序列Asp / Glu Gly Arg的凝血酶前体。 还考虑了包含溶解或分散在药学上可接受的载体中的有效量的突变凝血酶的组合物。 还公开了一种用于增强使用该组合物治疗和预防需要的哺乳动物血栓形成的方法。
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3.发明申请USE OF THROMBIN MUTANTS TO INHIBIT THE ANTICOAGULATION EFFECT OF THROMBIN INHIBITORS 审中-公开使用凝血酶抑制剂抑制血红蛋白抑制剂的抗凝作用公开(公告)号：US20100158890A1
公开(公告)日：2010-06-24
申请号：US12282695
申请日：2007-03-15
CPC分类号： A61K38/4833 , G01N33/86 , G01N2333/7452
摘要： The present invention provides methods for inhibiting the anticoagulation effect of a thrombin inhibitor in a patient in need thereof comprising administration of a therapeutically effective amount of a variant prothrombin or thrombin that is capable of binding the thrombin inhibitor and that has reduced procoagulant activity. Variant prothrombins or thrombins of use in the methods of the present invention include thrombin mutants W215A, W215A/E217A, or variants thereof in which the amino acids at positions 215 and/or 217 are alanine. Methods are also provided in which the thrombin mutants are administered with an additional active agent, particularly hemostatic agents such as activated factor VII or activated prothrombin complex concentrate. In one embodiment of the invention, the methods are useful in the treatment of patients in which a direct thrombin inhibitor has been administered, particularly argatroban. The present invention further provides a method for quantifying the concentration of an anticoagulant in the plasma or whole blood of a patient using a variant prothrombin or thrombin titration assay.
摘要翻译： 本发明提供了抑制凝血酶抑制剂在有需要的患者中的抗凝效果的方法，其包括施用治疗有效量的能够结合凝血酶抑制剂并降低促凝血活性的变体凝血酶原或凝血酶。 在本发明的方法中使用的变体前血栓素或血栓素包括其中215位和/或217位的氨基酸为丙氨酸的凝血酶突变体W215A，W215A / E217A或其变体。 还提供了其中凝血酶突变体与另外的活性剂，特别是止血剂如活化因子VII或活化的凝血酶原复合物浓缩物一起施用的方法。 在本发明的一个实施方案中，所述方法可用于治疗已经施用直接凝血酶抑制剂的患者，特别是阿加曲班。 本发明还提供了使用变体凝血酶原或凝血酶滴定测定来定量患者血浆或全血中抗凝血剂浓度的方法。
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公开(公告)号：US20080219998A1
公开(公告)日：2008-09-11
申请号：US10486159
申请日：2002-05-08
申请人： Andras Gruber
发明人： Andras Gruber
IPC分类号： A61K39/395 , A61K38/02 , A61K31/7052 , A61K38/48 , A61K38/10 , C07K16/00 , C07K2/00 , C07H21/00 , C12N9/48 , C12N9/74 , C07K7/08 , G01N33/68 , A61P7/02
CPC分类号： A61K38/10 , A61K38/55 , A61K2039/505 , G01N33/6893 , G01N33/86
摘要： The present invention embodies: methods; compounds, their pharmaceutically acceptable analogs, isomer, salts, hydrates, solvates and prodrug derivatives, and pharmaceutically acceptable compositions thereof that have particular biological properties; devices; diagnostic and other assays; and the uses of such methods, compounds, devices and assays. Common throughout these embodiments is specific selective reduction of intravascular thromboplastin antecedent activity, which results in a safe antithrombotic effect. A particularly prominent application or the invention relates to diagnosis and treatment of patients which have, or are at risk of, developing thrombosis, thrombotic injury, or vaso-occlusive diseases, such as myocardial infarction, stroke, restenosis after angioplasty, thrombotic diseases, etc. Another particularly prominent feature of the present invention is its high level of hemostatic safety at optimal efficacy. Also, the present invention is compatible for use in combination with other traditional therapeutic agent such as another antithrombotic, antiplatelet, thrombolytic, or anticoagulant agents.
摘要翻译： 本发明体现了：方法; 化合物，其药学上可接受的类似物，异构体，盐，水合物，溶剂合物和前药衍生物及其药学上可接受的组合物; 设备; 诊断和其他测定; 以及这些方法，化合物，装置和测定法的用途。 在这些实施方案中通常是具体选择性降低血管内凝血激酶前体活性，其导致安全的抗血栓形成作用。 特别突出的应用或本发明涉及具有或具有发生血栓形成，血栓形成性损伤或血管闭塞性疾病如血管成形术中的心肌梗死，中风，再狭窄，血栓形成疾病等或有风险的患者的诊断和治疗 本发明的另一个特别突出的特征是其在最佳功效下具有高水平的止血安全性。 此外，本发明可与其它传统治疗剂如另一抗血栓形成剂，抗血小板剂，溶栓剂或抗凝血剂联合使用。
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公开(公告)号：US08236316B2
公开(公告)日：2012-08-07
申请号：US12744037
申请日：2008-11-21
IPC分类号： A61K39/395
CPC分类号： C07K16/36 , A61K39/3955 , A61K45/06 , A61K2039/505 , C07K2316/96 , C07K2317/24 , C07K2317/32 , C07K2317/54 , C07K2317/55 , C07K2317/56 , C07K2317/565 , C07K2317/622 , C07K2317/624 , C07K2317/76 , C07K2317/92
摘要： The present invention relates to compositions and methods for inhibiting thrombosis without compromising hemostasis. Compositions include anti-factor XI monoclonal antibodies (aXIMabs) capable of binding to an epitope on the heavy chain of human FXI, particularly the A3 domain of the heavy chain of human FXI. Compositions also include epitope-binding fragments, variants, and derivatives of the monoclonal antibodies, cell lines producing these antibody compositions, and isolated nucleic acid molecules encoding the amino acid sequences of the antibodies. The invention further includes pharmaceutical compositions comprising the anti-factor XI monoclonal antibodies of the invention, or epitope-binding fragments, variants, or derivatives thereof, in a pharmaceutically acceptable carrier. Methods of the invention comprise administering the compositions described above to a subject in need thereof for the purpose of inhibiting thrombosis, reducing a required dose of an antithrombotic agent in the treatment of thrombosis, treating metastatic cancer, or treating an acute inflammatory reaction. Methods for making an anti-factor XI monoclonal antibody, or epitope-binding fragments, variants, or derivatives thereof, are also provided.
摘要翻译： 本发明涉及在不危及止血的情况下抑制血栓形成的组合物和方法。 组合物包括能够结合人FXI重链上的表位的抗因子XI单克隆抗体（aXIMab），特别是人FXI重链的A3结构域。 组合物还包括单克隆抗体的表位结合片段，变体和衍生物，产生这些抗体组合物的细胞系和编码抗体氨基酸序列的分离的核酸分子。 本发明还包括在药学上可接受的载体中包含本发明的抗因子XI单克隆抗体或其表位结合片段，变体或衍生物的药物组合物。 本发明的方法包括将上述组合物施用于有需要的受试者，以抑制血栓形成，减少治疗血栓形成，治疗转移性癌症或治疗急性炎症反应所需的抗血栓形成剂量。 还提供了制备抗因子XI单克隆抗体或表位结合片段，变体或其衍生物的方法。
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6.发明授权Assay methods for detecting serum proteases, particularly activated protein C 失效用于检测血清蛋白酶，特别是活化蛋白C的测定方法
公开(公告)号：US5288612A
公开(公告)日：1994-02-22
申请号：US725359
申请日：1991-07-03
申请人： John H. Griffin , Andras Gruber
发明人： John H. Griffin , Andras Gruber
IPC分类号： C07K16/40 , C12Q1/37 , G01N33/573 , G01N33/86
CPC分类号： C07K16/40 , C12Q1/37 , G01N33/573 , G01N33/86 , G01N2333/96461
摘要： The invention describes diagnostic methods and compositions for determining the amount of protease in a body fluid sample. In particular, the invention detects proteases by a method in which both a reversible inhibitor of the protease and an irreversible inhibitor of interfering proteases during the detection step are employed to increase the sensitivity of the enzyme capture assay. The assay detects normal serum levels of activated protein C.
摘要翻译： 本发明描述了用于测定体液样品中蛋白酶的量的诊断方法和组合物。 特别地，本发明通过一种方法来检测蛋白酶，其中采用在检测步骤期间蛋白酶的可逆抑制剂和干扰蛋白酶的不可逆抑制剂两者来提高酶捕获测定的灵敏度。 该检测法检测活化蛋白C的正常血清水平
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公开(公告)号：US5084274A
公开(公告)日：1992-01-28
申请号：US121702
申请日：1987-11-17
CPC分类号： C12N9/6464 , A61K38/166 , A61K38/49 , C12Y304/21069 , A61K38/00
摘要： The method of preventing arterial thrombotic occulsion or thromboembolism by administering plasma-derived or recombinate produced protein C alone or in combination with a thrombolytic agent or combinations of thrombolytic agents.
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公开(公告)号：US20120276112A1
公开(公告)日：2012-11-01
申请号：US13446320
申请日：2012-04-13
IPC分类号： A61K39/395 , C12N15/63 , C12N1/21 , A61P7/02 , C12N5/10 , A61P35/04 , A61P29/00 , C12N15/13 , C12N1/19
CPC分类号： C07K16/36 , A61K39/3955 , A61K45/06 , A61K2039/505 , C07K2316/96 , C07K2317/24 , C07K2317/32 , C07K2317/54 , C07K2317/55 , C07K2317/56 , C07K2317/565 , C07K2317/622 , C07K2317/624 , C07K2317/76 , C07K2317/92
摘要： The present invention relates to compositions and methods for inhibiting thrombosis without compromising hemostasis. Compositions include anti-factor XI monoclonal antibodies (aXIMabs) capable of binding to an epitope on the heavy chain of human FXI, particularly the A3 domain of the heavy chain of human FXI. Compositions also include epitope-binding fragments, variants, and derivatives of the monoclonal antibodies, cell lines producing these antibody compositions, and isolated nucleic acid molecules encoding the amino acid sequences of the antibodies. The invention further includes pharmaceutical compositions comprising the anti-factor XI monoclonal antibodies of the invention, or epitope-binding fragments, variants, or derivatives thereof, in a pharmaceutically acceptable carrier. Methods of the invention comprise administering the compositions described above to a subject in need thereof for the purpose of inhibiting thrombosis, reducing a required dose of an antithrombotic agent in the treatment of thrombosis, treating metastatic cancer, or treating an acute inflammatory reaction.
摘要翻译： 本发明涉及在不危及止血的情况下抑制血栓形成的组合物和方法。 组合物包括能够结合人FXI重链上的表位的抗因子XI单克隆抗体（aXIMab），特别是人FXI重链的A3结构域。 组合物还包括单克隆抗体的表位结合片段，变体和衍生物，产生这些抗体组合物的细胞系和编码抗体氨基酸序列的分离的核酸分子。 本发明还包括在药学上可接受的载体中包含本发明的抗因子XI单克隆抗体或其表位结合片段，变体或衍生物的药物组合物。 本发明的方法包括将上述组合物施用于有需要的受试者，以抑制血栓形成，减少治疗血栓形成，治疗转移性癌症或治疗急性炎症反应所需的抗血栓形成剂量。
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公开(公告)号：US20110250207A1
公开(公告)日：2011-10-13
申请号：US13140115
申请日：2009-12-18
申请人： Andras Gruber , Erik I. Tucker , David Gailani
发明人： Andras Gruber , Erik I. Tucker , David Gailani
CPC分类号： C07K16/36 , A61K2039/505 , C07K2317/24 , C07K2317/569 , C07K2317/73 , C07K2317/76
摘要： Disclosed herein are monoclonal antibodies specific for factor XI (fXI) that prevent activation of fXI by factor XIIa (fXIIa). The monoclonal antibodies are universal fXI antibodies, capable of binding all mammalian species tested. The anti-fXI monoclonal antibodies prolong clotting time in mammalian plasmas. Moreover, administration of the fXI monoclonal antibodies disclosed herein results in inhibition of thrombosis without altering hemostasis in animal models of thrombosis. Thus, provided herein are monoclonal antibodies specific for fXI that block activation of fXI by fXIIa, compositions and immunoconjugates comprising such antibodies and their methods of use.
摘要翻译： 本文公开的是针对因子XIIa（fXIIa）防止fXI激活的因子XI（fXI）特异性的单克隆抗体。 单克隆抗体是通用的fXI抗体，能够结合所有被检测的哺乳动物。 抗FXI单克隆抗体延长哺乳动物血浆中的凝血时间。 此外，本文公开的fXI单克隆抗体的施用导致血栓形成的抑制，而不改变血栓形成的动物模型中的止血。 因此，本文提供的是针对fXI特异性的阻断fXIIa的fXI活化的单克隆抗体，包含此类抗体的组合物和免疫缀合物及其使用方法。
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公开(公告)号：US20100184672A1
公开(公告)日：2010-07-22
申请号：US12665540
申请日：2008-06-18
CPC分类号： A61K38/4866
摘要： It is disclosed herein that protein C functions as a hemostatic agent. Thus, provided is a method of preventing, treating or ameliorating abnormal bleeding in a subject, comprising administering to the subject a protein C polypeptide or polynucleotide. Abnormal bleeding can result from a bleeding disorder, such as hemophilia or a platelet disorder, or from a bleeding episode, such as from a traumatic injury.
摘要翻译： 本文公开了蛋白C作为止血剂。 因此，提供了预防，治疗或改善受试者异常出血的方法，其包括对受试者施用蛋白C多肽或多核苷酸。 异常出血可能是出血性疾病，如血友病或血小板疾病，或出血发作，如创伤性损伤。
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