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41. 发明授权

US5474765A Preparation and use of steroid-polyanionic polymer-based conjugates targeted to vascular endothelial cells 失效
标题翻译：针对血管内皮细胞的类固醇 - 聚阴离子聚合物基缀合物的制备和使用
公开(公告)号：US5474765A
公开(公告)日：1995-12-12
申请号：US856018
申请日：1992-03-23
申请人： Philip E. Thorpe
发明人： Philip E. Thorpe
IPC分类号： A61K47/48 , C08L5/12 , A61K31/74
CPC分类号： A61K47/48176 , A61K47/4823
摘要： This invention discloses new targeted conjugates for the delivery of a compound, and particularly, a steroid, to vascular endothelial cells. The conjugates comprise two components, preferably linked by a selectively-hydrolyzable bond, such as an acid-labile bond or enzyme-sensitive bond. The first component, a polyanionic polymer, and preferably, a polysulphated polymer such as a heparin-derivative, specifically directs the conjugate to vascular endothelial cells. The second component is a selected agent, such as asteroid, which exerts a specific effect on the target cell following its release. In particular, the present invention provides novel conjugated angiogenesis inhibitors, for use in the treatment of pathogenic conditions including cancer, arthritis, and diabetic blindness. An inhibitor comprising a heparin derivative and the anti-angiogenic steroid, cortisol, is herein shown to be markedly acid-labile, to suppress DNA synthesis and cell migration in human umbilical vein endothelial cells, to retard or abolish (depending on the route of injection) the vascularization of sponges in vivo and to retard lung tumor growth in mice by 65%. No adverse effects of the conjugate were detected, and equivalent treatments with a mixture of heparin plus cortisol were significantly less effective in all cases.
摘要翻译：本发明公开了用于向血管内皮细胞递送化合物，特别是类固醇的新靶向缀合物。缀合物包含两个组分，优选通过选择性可水解键连接，例如酸不稳定键或酶敏感键。第一组分，聚阴离子聚合物，优选多硫酸化聚合物如肝素衍生物，特异性地将缀合物引导至血管内皮细胞。第二个组件是所选择的试剂，例如小行星，其在释放后对靶细胞发挥特定的作用。特别地，本发明提供了用于治疗包括癌症，关节炎和糖尿病失明的病原性病症的新型共轭血管生成抑制剂。本文显示包含肝素衍生物和抗血管生成类固醇皮质醇的抑制剂显着酸性不稳定，以抑制人脐静脉内皮细胞中的DNA合成和细胞迁移，以延缓或消除（取决于注射途径）海绵体内血管化，并将小鼠肺肿瘤生长阻滞65％。没有检测到结合物的不良反应，并且在所有情况下用肝素加皮质醇的混合物的等效处理显着较差。

42. 发明授权

US07976868B2 Liposomes comprising duramycin and anti-viral agents 有权
标题翻译：包含耐久霉素和抗病毒剂的脂质体
公开(公告)号：US07976868B2
公开(公告)日：2011-07-12
申请号：US12717295
申请日：2010-03-04
申请人： Philip E. Thorpe
发明人： Philip E. Thorpe
IPC分类号： A61K9/127
CPC分类号： A61K39/395 , A61K39/39558 , A61K47/62 , A61K47/6811 , A61K47/6835 , A61K47/6849 , A61K2039/505 , C07K16/18 , C07K16/2836 , C07K16/44 , C07K2317/24 , C07K2317/622 , C07K2317/73 , C07K2317/732 , C07K2317/77 , A61K2300/00
摘要： Disclosed are surprising discoveries concerning the role of anionic phospholipids and aminophospholipids in tumor vasculature and in viral entry and spread, and compositions and methods for utilizing these findings in the treatment of cancer and viral infections. Also disclosed are advantageous antibody, immunoconjugate and duramycin-based compositions and combinations that bind and inhibit anionic phospholipids and aminophospholipids, for use in the safe and effective treatment of cancer, viral infections and related diseases.
摘要翻译：公开了关于阴离子磷脂和氨基磷脂在肿瘤脉管系统和病毒进入和扩散中的作用的令人惊奇的发现，以及将这些发现用于治疗癌症和病毒感染的组合物和方法。还公开了结合和抑制阴离子磷脂和氨基磷脂的有利的抗体，免疫缀合物和基于杜氏霉素的组合物和组合，用于安全和有效治疗癌症，病毒感染和相关疾病。

43. 发明授权

US07951356B1 Tissue factor compositions and kits for coagulation and tumor treatment 失效
标题翻译：用于凝血和肿瘤治疗的组织因子组合物和试剂盒
公开(公告)号：US07951356B1
公开(公告)日：2011-05-31
申请号：US09573835
申请日：2000-05-18
申请人： Philip E. Thorpe , Steven W. King , Boning Gao
发明人： Philip E. Thorpe , Steven W. King , Boning Gao
IPC分类号： A61K38/16 , A61K38/36 , A61K38/37 , A61K47/30 , A61K47/48
CPC分类号： A61K47/6813 , A61K47/6435 , Y10S514/834 , Y10S530/827 , Y10S530/829
摘要： The invention embodies the surprising discovery that Tissue Factor (TF) compositions and variants thereof specifically localize to the blood vessels within a vascularized tumor following systemic administration. The invention therefore provides methods and compositions comprising coagulant-deficient Tissue Factor for use in effecting specific coagulation and for use in tumor treatment. The TF compositions and methods of present invention may be used alone, as TF conjugates with improved half-life, or in combination with other agents, such as conventional chemotherapeutic drugs, targeted immunotoxins, targeted coaguligands, and/or in combination with Factor VIIa (FVIIa) or FVIIa activators.
摘要翻译：本发明体现了惊人的发现：组织因子（TF）组合物及其变体在全身给药后特异性定位于血管化肿瘤内的血管。因此，本发明提供了用于实现特异性凝结和用于肿瘤治疗的用于组合凝血剂的组织因子的方法和组合物。本发明的TF组合物和方法可以单独使用，作为具有改善的半衰期的TF缀合物，或与其它试剂（例如常规化学治疗药物，靶向免疫毒素，靶向凝固配体）和/或与因子VIIa组合 FVIIa）或FVIIa激活剂。

44. 发明授权

US07691380B2 Combined methods for tumor coagulation and tumor treatment 失效
标题翻译：肿瘤凝固和肿瘤治疗的联合方法
公开(公告)号：US07691380B2
公开(公告)日：2010-04-06
申请号：US10375716
申请日：2003-02-27
申请人： Philip E. Thorpe , Thomas S. Edgington
发明人： Philip E. Thorpe , Thomas S. Edgington
IPC分类号： A61K39/395 , C12P21/08
CPC分类号： C07K16/3015 , A61K38/00 , A61K47/6817 , A61K47/6849 , A61K47/6851 , A61K47/6877 , A61K2039/505 , A61K2123/00 , C07K16/22 , C07K16/28 , C07K16/2818 , C07K16/2833 , C07K16/2896 , C07K16/30 , C07K2317/31 , C07K2317/34 , C07K2317/55
摘要： Disclosed are various compositions and methods for use in achieving specific blood coagulation. This is exemplified by the specific in vivo coagulation of tumor vasculature, causing tumor regression, through the site-specific delivery of a coagulant using a bispecific antibody.
摘要翻译：公开了用于实现特定凝血的各种组合物和方法。这是通过使用双特异性抗体通过凝固剂的位点特异性递送的肿瘤脉管系统的特异性体内凝血引起肿瘤消退的。

45. 发明授权

US07572448B2 Combined cancer treatment methods using selected antibodies to aminophospholipids 有权
标题翻译：使用氨基磷脂选择抗体的联合癌症治疗方法
公开(公告)号：US07572448B2
公开(公告)日：2009-08-11
申请号：US10642058
申请日：2003-08-15
申请人： Philip E. Thorpe , Xianming Huang , Sophia Ran
发明人： Philip E. Thorpe , Xianming Huang , Sophia Ran
IPC分类号： A61K39/395 , A61K39/00
CPC分类号： A61K39/395 , A61K39/39558 , A61K47/62 , A61K47/6811 , A61K47/6835 , A61K47/6849 , A61K2039/505 , C07K16/18 , C07K16/2836 , C07K16/44 , C07K2317/24 , C07K2317/622 , C07K2317/73 , C07K2317/732 , C07K2317/77 , A61K2300/00
摘要： Disclosed are surprising discoveries concerning the role of anionic phospholipids and aminophospholipids in tumor vasculature and in viral entry and spread, and compositions and methods for utilizing these findings in the treatment of cancer and viral infections. Also disclosed are advantageous antibody, immunoconjugate and duramycin-based compositions and combinations that bind and inhibit anionic phospholipids and aminophospholipids, for use in the safe and effective treatment of cancer, viral infections and related diseases.
摘要翻译：公开了关于阴离子磷脂和氨基磷脂在肿瘤脉管系统和病毒进入和扩散中的作用的令人惊奇的发现，以及将这些发现用于治疗癌症和病毒感染的组合物和方法。还公开了结合和抑制阴离子磷脂和氨基磷脂的有利的抗体，免疫缀合物和基于杜氏霉素的组合物和组合，用于安全和有效治疗癌症，病毒感染和相关疾病。

46. 发明授权

US07550141B2 Methods for imaging tumor vasculature using conjugates that bind to aminophospholipids 有权
标题翻译：使用结合氨磷脂的结合物成像肿瘤脉管系统的方法
公开(公告)号：US07550141B2
公开(公告)日：2009-06-23
申请号：US10988245
申请日：2004-11-12
申请人： Philip E. Thorpe , Sophia Ran , Rolf A. Brekken
发明人： Philip E. Thorpe , Sophia Ran , Rolf A. Brekken
IPC分类号： A61K39/395
CPC分类号： A61K51/1027 , A01K2217/05 , A61K39/395 , A61K47/6849 , C07K2317/24 , C07K2317/31 , C07K2319/00 , A61K2300/00
摘要： Disclosed is the surprising discovery that aminophospholipids, such as phosphatidylserine and phosphatidylethanolamine, are specific, accessible and stable markers of the luminal surface of tumor blood vessels. The present invention thus provides aminophospholipid-targeted diagnostic and therapeutic constructs for use in tumor intervention. Antibody-therapeutic agent conjugates and constructs that bind to aminophospholipids are particularly provided, as are methods of specifically delivering therapeutic agents, including toxins and coagulants, to the stably-expressed aminophospholipids of tumor blood vessels, thereby inducing thrombosis, necrosis and tumor regression.
摘要翻译：公开了令人惊奇的发现，氨基磷脂，例如磷脂酰丝氨酸和磷脂酰乙醇胺，是肿瘤血管的腔表面的特异性，可接近和稳定的标记物。因此，本发明提供用于肿瘤干预的氨基磷脂靶向诊断和治疗构建体。特别是提供了结合氨磷磷脂的抗体治疗剂缀合物和构建体，以及向肿瘤血管的稳定表达的氨基磷脂特异性递送治疗剂（包括毒素和凝结剂）的方法，从而诱导血栓形成，坏死和肿瘤消退。

47. 发明授权

US07056509B2 Antibody methods for selectively inhibiting VEGF 失效
公开(公告)号：US07056509B2
公开(公告)日：2006-06-06
申请号：US10373561
申请日：2003-02-24
申请人： Philip E. Thorpe , Rolf A. Brekken
发明人： Philip E. Thorpe , Rolf A. Brekken
IPC分类号： A61K39/395 , C12P21/08 , C07K16/00
CPC分类号： C07K16/22 , A61K39/3955 , A61K47/6811 , A61K47/6815 , A61K47/6817 , A61K47/6845 , A61K47/6849 , A61K2039/505 , C07K5/101 , C07K14/52 , C07K16/24 , C07K2317/73 , C07K2319/00 , C07K2319/30 , Y10S435/81 , Y10S530/809 , Y10S530/864 , Y10S530/865 , Y10S530/866 , A61K2300/00
摘要： Disclosed are antibodies that specifically inhibit VEGF binding to only one (VEGFR2) of the two VEGF receptors. The antibodies effectively inhibit angiogenesis and induce tumor regression, and yet have improved safety due to their specificity. The present invention thus provides new antibody-based compositions, methods and combined protocols for treating cancer and other angiogenic diseases. Advantageous immunoconjugate and prodrug compositions and methods using the new VEGF-specific antibodies are also provided.

48. 发明授权

US06783760B1 Combined cancer treatment methods using therapeutic conjugates that bind to aminophospholipids 有权
标题翻译：使用结合氨磷脂的治疗性缀合物的联合癌症治疗方法
公开(公告)号：US06783760B1
公开(公告)日：2004-08-31
申请号：US09819386
申请日：2001-03-28
申请人： Philip E. Thorpe , Sophia Ran , Rolf A. Brekken
发明人： Philip E. Thorpe , Sophia Ran , Rolf A. Brekken
IPC分类号： A61K39395
CPC分类号： A61K47/48561 , A01K2217/05 , A61K39/395 , A61K47/6835 , A61K47/6849 , A61K49/04 , A61K51/1027 , A61N5/10 , C07K16/2836 , C07K2317/24 , C07K2317/31 , C07K2319/00 , A61K2300/00
摘要： Disclosed is the surprising discovery that aminophospholipids, such as phosphatidylserine and phosphatidylethanolamine, are specific, accessible and stable markers of the luminal surface of tumor blood vessels. The present invention thus provides aminophospholipid-targeted diagnostic and therapeutic constructs for use in tumor intervention. Antibody-therapeutic agent conjugates and constructs that bind to aminophospholipids are particularly provided, as are methods of specifically delivering therapeutic agents, including toxins and coagulants, to the stably-expressed aminophospholipids of tumor blood vessels, thereby inducing thrombosis, necrosis and tumor regression.
摘要翻译：公开了令人惊奇的发现，氨基磷脂，例如磷脂酰丝氨酸和磷脂酰乙醇胺，是肿瘤血管的腔表面的特异性，可接近和稳定的标记物。因此，本发明提供用于肿瘤干预的氨基磷脂靶向诊断和治疗构建体。特别是提供了结合氨磷磷脂的抗体治疗剂缀合物和构建体，以及向肿瘤血管的稳定表达的氨基磷脂特异性递送治疗剂（包括毒素和凝结剂）的方法，从而诱导血栓形成，坏死和肿瘤消退。

49. 发明授权

US06749853B1 Combined methods and compositions for coagulation and tumor treatment 失效
标题翻译：用于凝血和肿瘤治疗的组合方法和组合物
公开(公告)号：US06749853B1
公开(公告)日：2004-06-15
申请号：US09483679
申请日：2000-01-14
申请人： Philip E. Thorpe , Thomas S. Edgington
发明人： Philip E. Thorpe , Thomas S. Edgington
IPC分类号： A61K3942
CPC分类号： C07K16/3015 , A61K38/00 , A61K47/6817 , A61K47/6849 , A61K47/6851 , A61K47/6877 , A61K2039/505 , A61K2123/00 , C07K16/22 , C07K16/28 , C07K16/2818 , C07K16/2833 , C07K16/2896 , C07K16/30 , C07K2317/31 , C07K2317/34 , C07K2317/55
摘要： Disclosed are various compositions and methods for use in achieving specific blood coagulation. This is exemplified by the specific in vivo coagulation of tumor vasculature, causing tumor regression, through the site-specific delivery of a coagulant using a bispecific antibody.
摘要翻译：公开了用于实现特定凝血的各种组合物和方法。这是通过使用双特异性抗体通过凝固剂的位点特异性递送的肿瘤脉管系统的特异性体内凝血引起肿瘤消退的。

50. 发明授权

US06703020B1 Antibody conjugate methods for selectively inhibiting VEGF 有权
标题翻译：用于选择性抑制VEGF的抗体共轭方法
公开(公告)号：US06703020B1
公开(公告)日：2004-03-09
申请号：US09561005
申请日：2000-04-28
申请人： Philip E. Thorpe , Rolf A. Brekken
发明人： Philip E. Thorpe , Rolf A. Brekken
IPC分类号： A61K39395
CPC分类号： C07K5/101 , A61K39/3955 , A61K47/6811 , A61K47/6815 , A61K47/6817 , A61K47/6845 , A61K47/6849 , A61K2039/505 , C07K14/52 , C07K16/22 , C07K2319/00 , C07K2319/30 , A61K2300/00
摘要： Disclosed are antibodies that specifically inhibit VEGF binding to only one (VEGFR2) of the two VEGF receptors. The antibodies effectively inhibit angiogenesis and induce tumor regression, and yet have improved safety due to their specificity. The present invention thus provides new antibody-based compositions, methods and combined protocols for treating cancer and other angiogenic diseases. Advantageous immunoconjugate and prodrug compositions.
摘要翻译：公开了特异性抑制VEGF仅与两种VEGF受体（VEGFR2）结合的抗体。抗体有效抑制血管生成并诱导肿瘤消退，但由于其特异性而具有改善的安全性。因此，本发明提供了新的基于抗体的组合物，用于治疗癌症和其它血管生成疾病的方法和组合方案。有益的免疫偶联物和前药组合物。

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