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    Mutant plasminogen activator-inhibitor type 1 (PAI-1) proteins
    1.
    发明授权
    Mutant plasminogen activator-inhibitor type 1 (PAI-1) proteins 有权
    突变型纤溶酶原激活物抑制剂1型（PAI-1）蛋白

    公开(公告)号：US06489143B1

    公开(公告)日：2002-12-03

    申请号：US09324494

    申请日：1999-06-02

    申请人： Daniel A. Lawrence ,  Steingrimur P. Stefansson

    发明人： Daniel A. Lawrence ,  Steingrimur P. Stefansson

    IPC分类号： C12N1509

    CPC分类号： C07K16/28 ,  A61K38/00 ,  C07K14/8132 ,  C07K2317/77

    摘要： Mutants of the human PAI-1 protein are described which are inhibitors of neutrophil elastase or are inhibitors of vitronectin (Vn)-dependent cell migration These mutants preferably comprise one or two amino acid substitutions in the reactive center loop of PAI-1, particularly at positions 331 and 346 of the mature protein. These mutants are notable in being resistant to inactivation by elastase, having high affinity for Vn, or both properties. These mutant proteins as pharmaceutical compositions are used to inhibit elastase in a subject, thereby treating a number of disorders associated with elastase activity, most notably emphysema, ARDS, inflammatory lung injury and cystic fibrosis. The mutants which interact with Vn are used to inhibit cell migration in a subject, thereby treating diseases or conditions associated with undesired cell migration and proliferation, particularly of smooth muscle cells. Such conditions include atherosclerosis, post angioplasty restenosis, fibrosis associated with chronic inflammation or chemotherapy, tumor invasion and metastasis and conditions in which angiogenesis is pathogenic. Also disclosed are peptides of such mutant proteins, mutant-specific antibodies, nucleic acid molecules, particularly DNA, encoding the mutant protein and host cells transformed by such nucleic acids.

    摘要翻译： 描述了人PAI-1蛋白的突变体，其是中性粒细胞弹性蛋白酶抑制剂或玻连蛋白（Vn）依赖性细胞迁移的抑制剂。这些突变体优选在PAI-1的反应性中心环中包含一个或两个氨基酸取代，特别是在 成熟蛋白质的位置331和346。 这些突变体在抵抗对Vn具有高亲和力的弹性蛋白酶的失活或两种性质方面是显着的。 这些作为药物组合物的突变蛋白质用于抑制受试者中的弹性蛋白酶，从而治疗与弹性蛋白酶活性相关的许多病症，最明显的是肺气肿，ARDS，炎性肺损伤和囊性纤维化。 与Vn相互作用的突变体用于抑制受试者中的细胞迁移，从而治疗与不期望的细胞迁移和增殖相关的疾病或病症，特别是平滑肌细胞的增殖。 这些病症包括动脉粥样硬化，血管成形术后再狭窄，与慢性炎症或化学疗法相关的纤维化，肿瘤浸润和转移以及血管发生是致病性的病症。 还公开了这样的突变蛋白质，突变体特异性抗体，核酸分子，特别是DNA，编码由这种核酸转化的突变蛋白质和宿主细胞的肽。

    Mutant plasminogen activator-inhibitor type 1 (PAI-1) and uses thereof
    2.
    发明授权
    Mutant plasminogen activator-inhibitor type 1 (PAI-1) and uses thereof 失效
    突变型纤溶酶原激活物抑制剂1型（PAI-1）及其用途

    公开(公告)号：US6103498A

    公开(公告)日：2000-08-15

    申请号：US840204

    申请日：1997-04-11

    申请人： Daniel A. Lawrence ,  Steingrimur P. Stefansson

    发明人： Daniel A. Lawrence ,  Steingrimur P. Stefansson

    IPC分类号： A61K38/00 ,  C07K14/81 ,  C07K16/28 ,  C12P21/06 ,  C07H21/04 ,  C07K1/00 ,  C12N9/66

    CPC分类号： C07K16/28 ,  C07K14/8132 ,  A61K38/00 ,  C07K2317/77

    摘要： Mutants of the human PAI-1 protein are described which are inhibitors of neutrophil elastase or are inhibitors of vitronectin (Vn)-dependent cell migration. These mutants preferably comprise one or two amino acid substitutions in the reactive center loop of PAI-1, particularly at positions 331 and 346 of the mature protein. These mutants are notable in being resistant to inactivation by elastase, having high affinity for Vn, or both properties. These mutant proteins as pharmaceutical compositions are used to inhibit elastase in a subject, thereby treating a number of disorders associated with elastase activity, most notably emphysema, ARDS, inflammatory lung injury and cystic fibrosis. The mutants which interact with Vn are used to inhibit cell migration in a subject, thereby treating diseases or conditions associated with undesired cell migration and proliferation, particularly of smooth muscle cells. Such conditions include atherosclerosis, post angioplasty restenosis, fibrosis associated with chronic inflammation or chemotherapy, tumor invasion and metastasis and conditions in which angiogenesis is pathogenic. Also disclosed are peptides of such mutant proteins, mutant-specific antibodies, nucleic acid molecules, particularly DNA, encoding the mutant protein and host cells transformed by such nucleic acids.

    摘要翻译： 描述了人PAI-1蛋白的突变体，其是嗜中性粒细胞弹性蛋白酶抑制剂或玻连蛋白（Vn）依赖性细胞迁移的抑制剂。 这些突变体优选在PAI-1的反应性中心环中，特别是成熟蛋白的位置331和346处包含一个或两个氨基酸取代。 这些突变体在抵抗对Vn具有高亲和力的弹性蛋白酶的失活或两种性质方面是显着的。 这些作为药物组合物的突变蛋白质用于抑制受试者中的弹性蛋白酶，从而治疗与弹性蛋白酶活性相关的许多病症，最明显的是肺气肿，ARDS，炎性肺损伤和囊性纤维化。 与Vn相互作用的突变体用于抑制受试者中的细胞迁移，从而治疗与不期望的细胞迁移和增殖相关的疾病或病症，特别是平滑肌细胞的增殖。 这些病症包括动脉粥样硬化，血管成形术后再狭窄，与慢性炎症或化学疗法相关的纤维化，肿瘤浸润和转移以及血管发生是致病性的病症。 还公开了这样的突变蛋白质，突变体特异性抗体，核酸分子，特别是DNA，编码由这种核酸转化的突变蛋白质和宿主细胞的肽。

    Mutant proteinase-inhibitors and uses thereof
    4.
    发明授权
    Mutant proteinase-inhibitors and uses thereof 失效
    突变蛋白酶抑制剂及其用途

    公开(公告)号：US07264953B2

    公开(公告)日：2007-09-04

    申请号：US10197258

    申请日：2002-07-18

    申请人： Daniel A. Lawrence ,  Natalia Gorlatova ,  David L. Crandall

    发明人： Daniel A. Lawrence ,  Natalia Gorlatova ,  David L. Crandall

    IPC分类号： C12N9/99

    CPC分类号： C07K14/8121 ,  C07K14/81 ,  C07K14/8132 ,  C07K16/38 ,  C12Q1/37 ,  G01N2333/81 ,  G01N2500/04

    摘要： A library of mutants of metastable proteins, such as proteinase inhibitors, can be screened for the specific loss of a wild-type capability to bind an antibody, yielding valuable drug-design information which otherwise is unavailable. By this approach, for example, a mutant proteinase inhibitor can be obtained that has the amino acid sequence of a wild-type protein, or an active fragment thereof, save for the presence of one or more mutations in at least one epitope, thereby altering interaction of the mutant with an anti-proteinase inhibitor antibody.

    摘要翻译： 可以筛选亚稳态蛋白质突变体的文库，例如蛋白酶抑制剂，以便特异性丧失结合抗体的野生型能力，产生否则不可用的有价值的药物设计信息。 通过这种方法，例如，可以获得具有野生型蛋白质的氨基酸序列或其活性片段的突变蛋白酶抑制剂，除了在至少一个表位中存在一个或多个突变，从而改变 突变体与抗蛋白酶抑制剂抗体的相互作用。

    Mutant plasminogen activator-inhibitor type 1 (PAI-1) and uses thereof
    8.
    发明授权
    Mutant plasminogen activator-inhibitor type 1 (PAI-1) and uses thereof 有权
    突变型纤溶酶原激活物抑制剂1型（PAI-1）及其用途

    公开(公告)号：US07388074B2

    公开(公告)日：2008-06-17

    申请号：US10259609

    申请日：2002-09-30

    申请人： Daniel A. Lawrence ,  Steingrimor P. Stefansson

    发明人： Daniel A. Lawrence ,  Steingrimor P. Stefansson

    IPC分类号： A61K38/00

    CPC分类号： C07K16/28 ,  A61K38/00 ,  C07K14/8132 ,  C07K2317/77

    摘要： Mutants of the human PAI-1 protein are described which are inhibitors of neutrophil elastase or are inhibitors of vitronectin (Vn)-dependent cell migration. These mutants preferably comprise one or two amino acid substitutions in the reactive center loop of PAI-1, particularly at positions 331 and 346 of the mature protein. These mutants are notable in being resistant to inactivation by elastase, having high affinity for Vn, or both properties. These mutant proteins as pharmaceutical compositions are used to inhibit elastase in a subject, thereby treating a number of disorders associated with elastase activity, most notatably emphysema, ARDS, inflammatory lung injury and cystic fibrosis. The mutants which interact with Vn are used to inhibit cell migration in a subject, thereby treating diseases or conditions associated with undesired cell migration and proliferation, particularly of smooth muscle cells. Such conditions include atherosclerosis, post angioplasty restenosis, fibrosis associated with chronic inflammation or chemotherapy, tumor invasion and metastasis and conditions in which angiogenesis is pathogenic. Also disclosed are peptides of such mutant proteins, mutant-specific antibodies, nucleic acid molecules, particularly DNA, encoding the mutant protein and host cells transformed by such nucleic acids.

    摘要翻译： 描述了人PAI-1蛋白的突变体，其是嗜中性粒细胞弹性蛋白酶抑制剂或玻连蛋白（Vn）依赖性细胞迁移的抑制剂。 这些突变体优选在PAI-1的反应性中心环中，特别是成熟蛋白的位置331和346处包含一个或两个氨基酸取代。 这些突变体在抵抗对Vn具有高亲和力的弹性蛋白酶的失活或两种性质方面是显着的。 作为药物组合物的这些突变蛋白质用于抑制受试者中的弹性蛋白酶，从而治疗与弹性蛋白酶活性，大多数不明显的肺气肿，ARDS，炎症性肺损伤和囊性纤维化相关的许多病症。 与Vn相互作用的突变体用于抑制受试者中的细胞迁移，从而治疗与不期望的细胞迁移和增殖相关的疾病或病症，特别是平滑肌细胞的增殖。 这些病症包括动脉粥样硬化，血管成形术后再狭窄，与慢性炎症或化学疗法相关的纤维化，肿瘤浸润和转移以及血管发生是致病性的病症。 还公开了这样的突变蛋白质，突变体特异性抗体，核酸分子，特别是DNA，编码由这种核酸转化的突变蛋白质和宿主细胞的肽。

    Methods for treating conditions associated with the accumulation of excess extracellular matrix
    9.
    发明授权
    Methods for treating conditions associated with the accumulation of excess extracellular matrix 有权
    治疗与过量细胞外基质积累有关的病症的方法

    公开(公告)号：US07713924B2

    公开(公告)日：2010-05-11

    申请号：US10887378

    申请日：2004-07-08

    申请人： Nancy A. Noble ,  Wayne A. Border ,  Daniel A. Lawrence

    发明人： Nancy A. Noble ,  Wayne A. Border ,  Daniel A. Lawrence

    IPC分类号： A61K38/14 ,  A61K38/55 ,  A61K31/401 ,  C12Q1/68

    CPC分类号： A61K31/573 ,  A61K31/401 ,  A61K31/4178 ,  A61K38/49 ,  A61K38/556 ,  A61K45/06 ,  A61K2300/00

    摘要： The present invention is methods and compositions for reducing and preventing the excess accumulation of extracellular matrix in a tissue and/or organ or at a wound site using a combination of agents that inhibit TGFβ, or using agents that inhibit TGFβ in combination with agents that degrade excess accumulated extracellular matrix. The compositions and methods of the invention are used to treat conditions such as fibrotic diseases and scarring that result from excess accumulation of extracellular matrix, impairing tissue or organ function or skin appearance in a subject.

    摘要翻译： 本发明是减少和预防组织和/或器官或伤口部位的细胞外基质过量积累的方法和组合物，其使用抑制TGFβb的试剂的组合;或使用抑制TGFβb的试剂; 与降解过量积累的细胞外基质的试剂组合。 本发明的组合物和方法用于治疗由受试者的细胞外基质的过量积累，损伤组织或器官功能或皮肤外观而导致的纤维化疾病和瘢痕形成等疾病。

    Brain-associated inhibitor of tissue-type plasminogen activator
    10.
    发明授权
    Brain-associated inhibitor of tissue-type plasminogen activator 有权
    脑组织型纤溶酶原激活物抑制剂

    公开(公告)号：US06191260B1

    公开(公告)日：2001-02-20

    申请号：US09348817

    申请日：1999-07-08

    申请人： Gregg A. Hastings ,  Timothy A. Coleman ,  Daniel A. Lawrence ,  Patrick J. Dillon

    发明人： Gregg A. Hastings ,  Timothy A. Coleman ,  Daniel A. Lawrence ,  Patrick J. Dillon

    IPC分类号： C07K1481

    CPC分类号： C07K14/8132 ,  A61K38/00 ,  C07K14/8121

    摘要： The present invention relates to a novel BAIT protein which is a member of serpin superfamily which is expressed primarily in brain tissue. In particular, isolated nucleic acid molecules are provided encoding the human BAIT protein. BAIT polypeptides are also provided as are vectors, host cells and recombinant methods for producing the same. The invention further relates to screening methods for identifying agonists and antagonists of BAIT activity. Also provided are diagnostic methods for detecting nervous system-related disorders and therapeutic methods for treating nervous system-related disorders.

    摘要翻译： 本发明涉及一种新的BAIT蛋白，其是主要在脑组织中表达的丝氨酸蛋白酶超家族的成员。 特别地，提供编码人BAIT蛋白的分离的核酸分子。 还提供了BAIT多肽，载体，宿主细胞以及用于制备它们的重组方法。 本发明还涉及鉴定BAIT活性的激动剂和拮抗剂的筛选方法。 还提供了用于检测神经系统相关疾病的诊断方法和用于治疗神经系统相关疾病的治疗方法。