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    Targeting of molecules to large vessel endothelium using EPCR
    3.
    发明授权
    Targeting of molecules to large vessel endothelium using EPCR 失效
    使用EPCR将分子靶向大血管内皮

    公开(公告)号：US06953568B1

    公开(公告)日：2005-10-11

    申请号：US09139425

    申请日：1998-08-25

    申请人： Charles T. Esmon ,  Jun Xu

    发明人： Charles T. Esmon ,  Jun Xu

    IPC分类号： A61K45/06 ,  A61K31/4188 ,  A61K31/711 ,  A61K38/00 ,  A61K39/395 ,  A61K47/48 ,  A61K48/00 ,  A61K51/10 ,  A61P7/02 ,  A61P9/10 ,  A61P43/00 ,  A61K49/00 ,  A61K31/70 ,  A61K39/40 ,  C12N15/63

    CPC分类号： B82Y5/00 ,  A61K47/6843 ,  A61K47/6898 ,  A61K51/1018

    摘要： Endothelial protein C receptor (EPCR) is found primarily on endothelial cells of large vessels. EPCR translocates from the plasma membrane surface to the nucleus. Molecules which bind to EPCR can be carried from the plasma membrane surface to the nucleus. These molecules include antibodies to EPCR and activated protein C. Protein C, which also binds to EPCR, can be internalized by endothelial cells, but does not enter the nucleus. Thus, EPCR translocation from the plasma membrane to the nucleus provides a means of delivering nucleic acid such as DNA, proteins such as transcription factors, diagnostic agents or other types of drugs to the nucleus of endothelial cells, particularly those on large blood vessels. Conjugates of the materials to be delivered to the nucleus can be formed by ionic or covalent coupling. For example, proteins, including fusion proteins, can be directly conjugated to an anti-EPCR monoclonal antibody. Covalent attachment of positively charged polymers, such as polylysine, to an anti-EPCR antibody allows nucleic acid to bind by ionic charges. Steptavidin and biotin can also be used to conjugate molecules to anti-EPCR antibodies. These conjugated antibodies are transported to the nucleus by EPCR. Eamples demonstrate selective transport to the nucleus which is mediated by EPCR. Molecules transported include activated protein C, antibodies to EPCR, and steptavidin-biotin conjugates. Modification of anti-EPCR monoclonal antibodies by covalently coupling to polylysine allows binding of an expression vector to the modified antibody and translocation to the nucleus.

    摘要翻译： 内皮蛋白C受体（EPCR）主要发现在大血管的内皮细胞上。 EPCR从质膜表面转移到细胞核。 与EPCR结合的分子可以从质膜表面携带到细胞核。 这些分子包括EPCR和活化蛋白C的抗体。也可以结合EPCR的蛋白C可被内皮细胞内化，但不进入细胞核。 因此，从质膜到细胞核的EPCR易位提供了将核酸如DNA，转录因子，诊断剂或其他类型的药物的蛋白质递送到内皮细胞的细胞核，特别是在大血管上的方法。 可以通过离子或共价偶联形成待递送到细胞核的材料的共轭物。 例如，蛋白质，包括融合蛋白，可以直接缀合到抗EPCR单克隆抗体。 带正电的聚合物如聚赖氨酸的共价连接到抗EPCR抗体允许核酸通过离子电荷结合。 抗生蛋白链菌素和生物素也可用于将分子与抗EPCR抗体结合。 这些缀合的抗体通过EPCR转运到细胞核。 示例表明选择性转运到由EPCR介导的细胞核。 转运的分子包括活化的蛋白C，EPCR的抗体和步骤抗生物素 - 生物素缀合物。 通过共聚偶联到聚赖氨酸来修饰抗EPCR单克隆抗体允许表达载体与经修饰的抗体结合并且转移到细胞核。

    Calcium binding recombinant antibody against protein C
    4.
    发明授权
    Calcium binding recombinant antibody against protein C 失效
    钙蛋白C结合重组抗体

    公开(公告)号：US07247453B1

    公开(公告)日：2007-07-24

    申请号：US08259321

    申请日：1994-06-10

    申请人： Alireza Rezaie ,  Charles T. Esmon

    发明人： Alireza Rezaie ,  Charles T. Esmon

    IPC分类号： C12P21/08 ,  A61K39/395 ,  C07K16/18

    CPC分类号： C07K16/40 ,  C07K2317/55

    摘要： A Ca2+ dependent recombinant antibody that specifically binds to a specific twelve peptide sequence (E D Q V D P R L I D G K) in the activation region of the Protein C has been constructed. The antibody does not bind to Activated Protein C and can be used to inhibit activation of Protein C by thrombin-thrombomodulin, in purification of Protein C, and in treatment of tumors.

    摘要翻译： 已经构建了在蛋白C的活化区域中特异性结合特异性十二肽序列（E D Q V D P R L I D G K）的Ca 2+ 2 + >重组抗体。 抗体不结合活化蛋白C，可用于通过凝血酶 - 血栓调节蛋白，蛋白C的纯化和肿瘤的治疗来抑制蛋白C的活化。

    Cloning and regulation of an endothelial cell protein C/activated protein C receptor
    5.
    发明授权
    Cloning and regulation of an endothelial cell protein C/activated protein C receptor 失效
    克隆和调节内皮细胞蛋白C /活化蛋白C受体

    公开(公告)号：US07063843B1

    公开(公告)日：2006-06-20

    申请号：US09378261

    申请日：1999-08-20

    申请人： Kenji Fukudome ,  Charles T. Esmon

    发明人： Kenji Fukudome ,  Charles T. Esmon

    IPC分类号： A61K39/395 ,  A61K39/00

    CPC分类号： C07K14/70539 ,  A61K38/00

    摘要： Human protein C and activated protein C were shown to bind to endothelium specifically, selectively and saturably (Kd=30 nM, 7000 sites per cell) in a Ca2+ dependent fashion. Expression cloning revealed a 1.3 kb cDNA that coded for a novel type I transmembrane glycoprotein capable of binding protein C. This protein appears to be a member of the CD1/MHC superfamily. Like thrombomodulin, the receptor involved in protein C activation, the endothelial cell protein C receptor (EPCR) function and message are both down regulated by exposure of endothelium to TNF. Identification of EPCR as a member of the CD1/MHC superfamily provides insights into the role of protein C in regulating the inflammatory response, and determination of methods for pharmaceutical use in manipulating the inflammatory response.

    摘要翻译： 显示人C蛋白和活化蛋白C特异性，选择性和饱和（Kd = 30nM，每个细胞7000个位点）以依赖于Ca 2+的方式结合内皮。 表达克隆显示编码能够结合蛋白C的新型I型跨膜糖蛋白的1.3kb cDNA。该蛋白质似乎是CD1 / MHC超家族的成员。 与血栓调节蛋白一样，参与蛋白C活化的受体，内皮细胞蛋白C受体（EPCR）功能和信息都通过内皮对TNF的暴露而下调。 作为CD1 / MHC超家族成员的EPCR的鉴定提供了对蛋白C在调节炎症反应中的作用的了解，以及用于操作炎症反应的药物用途的方法的确定。

    Cloning and regulation of an endothelial cell protein C/activated protein C receptor
    6.
    发明授权
    Cloning and regulation of an endothelial cell protein C/activated protein C receptor 失效

    公开(公告)号：US5852171A

    公开(公告)日：1998-12-22

    申请号：US878283

    申请日：1997-06-18

    申请人： Kenji Fukudome ,  Charles T. Esmon

    发明人： Kenji Fukudome ,  Charles T. Esmon

    IPC分类号： A61K38/00 ,  C07K14/74 ,  C12N15/12 ,  C07K14/705

    CPC分类号： C07K14/70539 ,  A61K38/00

    摘要： Human protein C and activated protein C were shown to bind to endothelium specifically, selectively and saturably (Kd=30 nM, 7000 sites per cell) in a Ca.sup.2+ dependent fashion. Expression cloning revealed a 1.3 kb CDNA that coded for a novel type I transmembrane glycoprotein capable of binding protein C. This protein appears to be a member of the CD1/MHC superfamily. Like thrombomodulin, the receptor involved in protein C activation, the endothelial cell protein C receptor (EPCR) function and message are both down regulated by exposure of endothelium to TNF. Identification of EPCR as a member of the CD1/MHC superfamily provides insights into the role of protein C in regulating the inflammatory response, and determination of methods for pharmaceutical use in manipulating the inflammatory response.

    Modified protein C and methods of use thereof
    7.
    发明授权
    Modified protein C and methods of use thereof 失效
    改性蛋白C及其使用方法

    公开(公告)号：US5847085A

    公开(公告)日：1998-12-08

    申请号：US965832

    申请日：1997-11-07

    申请人： Charles T. Esmon ,  Mikhail D. Smirnov

    发明人： Charles T. Esmon ,  Mikhail D. Smirnov

    IPC分类号： C12N15/09 ,  A61K38/00 ,  A61K38/48 ,  A61P7/02 ,  A61P43/00 ,  C07K14/745 ,  C07K19/00 ,  C12N9/64 ,  C12N9/74 ,  A61K35/14

    CPC分类号： C12N9/6464 ,  C12N9/6429 ,  C12Y304/21005 ,  C12Y304/21069 ,  A61K38/00 ,  C07K2319/00

    摘要： Modified Protein C molecules have been made which substitute the gamma carboxylglutamic acid (Gla) region of another Vitamin K dependent protein, most preferably prothrombin, for the native region of the Protein C. A modified protein C molecules has been made which substitutes the gamma carboxyglutamic acid (Gla) region with the corresponding region of prothrombin. The modified or chimeric protein C has advantages over the wild-type protein C since it is less sensitive to inhibition by some natural antibody inhibitors of protein C (which would otherwise decrease the ability of the protein C to act as an anticoagulant) and which do not need the same cofactors or same amounts of cofactors, and can therefore be effective in patients with lowered levels of the cofactors such as protein S or the lipids present in elevated levels in platelets such as phosphatidyl ethanolamine (PE). The anticoagulant activity of the chimera was tested in normal and factor V Leiden plasma. The chimera was approximately ten times more effective in inhibiting factor V Leiden plasma clotting.

    摘要翻译： 已经制备了修饰的蛋白C分子，其替代了另一种维生素K依赖性蛋白（最优选凝血酶原）的γ-羧基谷氨酸（Gla）区域用于蛋白C的天然区域。已经制备了修饰的蛋白质C分子，其代替γ羧基谷氨酸 酸（Gla）区域与凝血酶原的相应区域。 修饰或嵌合蛋白C具有优于野生型蛋白C的优点，因为它对蛋白质C的某些天然抗体抑制剂的抑制作用较不敏感（否则会降低蛋白C作为抗凝血剂的能力） 不需要相同的辅因子或相同量的辅因子，因此可以在血小板例如磷脂酰乙醇胺（PE）中存在的升高水平的蛋白S或辅助因子水平降低的患者中有效。 在正常和因子V莱顿等离子体中测试嵌合体的抗凝血活性。 嵌合体在抑制因子V莱顿血浆凝血中的效力大约是十倍。

    Method for regulating inflammation and tumor growth with calmodulin, calmodulin analogues or calmodulin antagonists
    8.
    发明授权
    Method for regulating inflammation and tumor growth with calmodulin, calmodulin analogues or calmodulin antagonists 失效
    用钙调蛋白，钙调蛋白类似物或钙调蛋白拮抗剂调节炎症和肿瘤生长的方法

    公开(公告)号：US5698518A

    公开(公告)日：1997-12-16

    申请号：US220814

    申请日：1994-03-30

    申请人： Craig W. Carson ,  Charles T. Esmon ,  Donald S. Houston

    发明人： Craig W. Carson ,  Charles T. Esmon ,  Donald S. Houston

    IPC分类号： A61K38/17 ,  C07K14/435 ,  C07K14/525

    CPC分类号： A61K38/1709 ,  Y10S930/144

    摘要： A method of treating patients to inhibit inflammation is disclosed. In the method, an effective amount of calmodulin, a calmodulin analogue or calmodulin receptor agonist is administered to a patient to inhibit production of tumor necrosis factor and/or augment elastase. In another method, an effective amount of calmodulin antagonist is administered to a patient to stimulate immune response or inhibit elastase release. In another embodiment, a diagnostic test is disclosed to be used on patient blood samples to determine individual propensity to regulate tumor necrosis factor and/or elastase by calmodulin, its analogues or receptor agonists.

    摘要翻译： 公开了一种治疗患者抑制炎症的方法。 在该方法中，向患者施用有效量的钙调素，钙调蛋白类似物或钙调蛋白受体激动剂以抑制肿瘤坏死因子的产生和/或增加弹性蛋白酶。 在另一种方法中，向患者施用有效量的钙调蛋白拮抗剂以刺激免疫应答或抑制弹性蛋白酶释放。 在另一个实施方案中，公开了用于患者血液样品的诊断测试，以通过钙调蛋白，其类似物或受体激动剂来确定调节肿瘤坏死因子和/或弹性蛋白酶的个体倾向。

    Method for detecting antibodies to thrombomodulin in patients
    9.
    发明授权
    Method for detecting antibodies to thrombomodulin in patients 失效
    检测患者血栓调节蛋白抗体的方法

    公开(公告)号：US5639625A

    公开(公告)日：1997-06-17

    申请号：US312870

    申请日：1994-09-26

    申请人： Craig W. Carson ,  Charles T. Esmon

    发明人： Craig W. Carson ,  Charles T. Esmon

    IPC分类号： G01N33/564 ,  G01N33/86 ,  G01N33/53

    CPC分类号： G01N33/564 ,  G01N33/86 ,  G01N2333/7452 ,  Y10S435/961 ,  Y10S435/962 ,  Y10S435/967 ,  Y10S435/968

    摘要： A novel method of detecting antibodies to thrombomodulin in plasma or serum as an indication of an individual's propensity to thrombosis or inflammation is disclosed. A method for identifiying patients at risks of thrombosis or glomerular nephritis by monitoring autoantibodies to truncated soluble thrombomodulin is revealed. A preferred method is an ELISA assay to detect antibodies to thrombomodulin.

    摘要翻译： 公开了一种检测血浆或血清中血栓调节素抗体的新方法，作为个体血栓形成或炎症倾向的指征。 揭示了通过监测截短的可溶性血栓调节素的自身抗体来鉴定患有血栓形成或肾小球肾炎风险的患者的方法。 优选的方法是检测血栓调节素抗体的ELISA测定。

    Assay for detection of selective Protein C inhibition by patients
    10.
    发明授权
    Assay for detection of selective Protein C inhibition by patients 失效
    用于检测患者选择性蛋白C抑制的测定

    公开(公告)号：US5472852A

    公开(公告)日：1995-12-05

    申请号：US121944

    申请日：1993-09-15

    申请人： Mikhail D. Smirnov ,  Charles T. Esmon

    发明人： Mikhail D. Smirnov ,  Charles T. Esmon

    IPC分类号： G01N33/86 ,  G01N33/92 ,  C12Q1/56 ,  C12Q1/00

    CPC分类号： G01N33/86 ,  G01N33/92 ,  G01N2333/96461 ,  G01N2405/04

    摘要： An assay useful for detecting the propensity of patients for thrombotic disease, especially patients having the lupus anticoagulant or antiphospholipid antibodies, is described. The assay is conducted on patient and control plasma in the presence and absence of exogenous Protein C with a membrane source comprising phosphatidylethanolamine and phosphatidylserine. Patients at risk exhibit test results indicating activated Protein C function is inhibited.

    摘要翻译： 描述了用于检测患者血栓形成疾病倾向的测定法，特别是具有狼疮抗凝血剂或抗磷脂抗体的患者。 在含有磷脂酰乙醇胺和磷脂酰丝氨酸的膜源的存在和不存在外源蛋白C的情况下，对患者和对照血浆进行测定。 有风险的患者显示测试结果，表明活化的蛋白C功能被抑制。