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1. 发明授权

US6010680A Thiolation of proteins for radionuclide-based radioimmunodetection and radioimmunotherapy 失效
标题翻译：基于放射性核素的放射免疫检测和放射免疫治疗的蛋白质硫酸化
公开(公告)号：US6010680A
公开(公告)日：2000-01-04
申请号：US106140
申请日：1998-06-29
申请人： Seregulam V. Govindan , Ruth Grebenau , Gary L. Griffiths , Hans J. Hansen
发明人： Seregulam V. Govindan , Ruth Grebenau , Gary L. Griffiths , Hans J. Hansen
IPC分类号： A61K38/00 , A61K39/395 , A61K51/00 , A61K51/08 , A61K51/10 , A61P9/08 , A61P9/10 , A61P31/00 , A61P35/00 , A61P37/00 , C07B59/00 , C07K1/13 , C07K14/00 , C07K16/00 , C09K3/00 , A61M36/14
CPC分类号： A61K51/1093 , A61K51/1048 , A61K2121/00 , A61K2123/00
摘要： A method of radiolabeling a protein with a radionuclide including contacting the protein with a protected tertiary thiol-containing bifunctional chelating agent that is capable of reacting with the protein at one end of the agent and is capable of complexing with a radionuclide at the other end of the agent, to form a protein-acetyl-t-thiol-containing conjugate. The protein-acetyl-t-thiol-containing conjugate then is deprotected and admixed with a reducing agent for the radionuclide, where the radionuclide is added in a subsequent step, to form a mixture of reducing agent and protein-t-thiol-containing conjugate. This mixture then is reacted with a radionuclide whereby the radionuclide reacts with pendant sulfhydryl groups present on the protein-t-thiol-containing conjugate. Methods of radioimmunotherapy and diagnostic kits suitable for forming a composition to be administered to a human patient also are disclosed.
摘要翻译：一种用放射性核素放射性标记蛋白质的方法，包括使蛋白质与受保护的含叔硫醇的双功能螯合剂接触，所述螯合剂能够在所述试剂的一端与蛋白质反应，并且能够与另一端的放射性核素络合以形成含有蛋白质 - 乙酰基-t-硫醇的缀合物。然后将含蛋白质 - 乙酰基-t-硫醇的缀合物脱保护并与用于放射性核素的还原剂混合，其中在随后的步骤中加入放射性核素，以形成还原剂和含蛋白质-T-硫醇的共轭物的混合物。然后将该混合物与放射性核素反应，由此放射性核素与存在于蛋白质-T-硫醇的缀合物上的侧链巯基反应。还公开了放射免疫治疗方法和适合于形成待给予人类患者的组合物的诊断试剂盒。

2. 发明授权

US5772981A Thiolation of proteins for radionuclide-based radioimmunodetection and radioimmunotherapy 失效
标题翻译：基于放射性核素的放射免疫检测和放射免疫治疗的蛋白质硫酸化
公开(公告)号：US5772981A
公开(公告)日：1998-06-30
申请号：US779556
申请日：1997-01-08
申请人： Seregulam V. Govindan , Ruth Grebenau , Gary L. Griffiths , Hans J. Hansen
发明人： Seregulam V. Govindan , Ruth Grebenau , Gary L. Griffiths , Hans J. Hansen
IPC分类号： A61K38/00 , A61K39/395 , A61K51/00 , A61K51/08 , A61K51/10 , A61P9/08 , A61P9/10 , A61P31/00 , A61P35/00 , A61P37/00 , C07B59/00 , C07K1/13 , C07K14/00 , C07K16/00 , C09K3/00 , A61M36/14
CPC分类号： A61K51/1093 , A61K51/1048 , A61K2121/00 , A61K2123/00
摘要： A method of radiolabeling a protein with a radionuclide including contacting the protein with a protected tertiary thiol-containing bifunctional chelating agent that is capable of reacting with the protein at one end of the agent and is capable of complexing with a radionuclide at the other end of the agent, to form a protein-acetyl-t-thiol-containing conjugate. The protein-acetyl-t- thiol-containing conjugate then is deprotected and admixed with a reducing agent for the radionuclide, where the radionuclide is added in a subsequent step, to form a mixture of reducing agent and protein-t-thiol-containing conjugate. This mixture then is reacted with a radionuclide whereby the radionuclide reacts with pendant sulfhydryl groups present on the protein-t-thiol-containing conjugate. Methods of radioimmunotherapy and diagnostic kits suitable for forming a composition to be administered to a human patient also are disclosed.
摘要翻译：一种用放射性核素放射性标记蛋白质的方法，包括使蛋白质与受保护的含叔硫醇的双功能螯合剂接触，所述双功能螯合剂能够在所述试剂的一端与所述蛋白质反应，并且能够与另一端的放射性核素络合形成蛋白质 - 乙酰基-E，不含t + EE-硫醇的缀合物。然后将蛋白质 - 乙酰基 - + E，非t + EE-含硫醇的缀合物脱保护并与用于放射性核素的还原剂混合，其中在随后的步骤中加入放射性核素，以形成还原剂和蛋白质 - + E，uns t + EE-含硫醇的缀合物。然后将该混合物与放射性核素反应，由此放射性核素与存在于蛋白质+ E，非t + EE-硫醇的缀合物上的侧链巯基反应。还公开了放射免疫治疗方法和适合于形成待给予人类患者的组合物的诊断试剂盒。

3. 发明授权

US5635603A Preparation and use of immunoconjugates 失效
标题翻译：免疫缀合物的制备和使用
公开(公告)号：US5635603A
公开(公告)日：1997-06-03
申请号：US352715
申请日：1994-12-05
申请人： Hans J. Hansen , Shui-on Leung , Jerry Shevitz , Gary L. Griffiths , Seregulam V. Govindan
发明人： Hans J. Hansen , Shui-on Leung , Jerry Shevitz , Gary L. Griffiths , Seregulam V. Govindan
IPC分类号： G01N33/53 , A61K38/00 , A61K39/395 , A61K49/00 , A61K51/10 , C07H21/04 , C07K16/00 , C07K16/30 , C07K17/00 , C12N15/09 , C12P21/08 , C12R1/91 , G01N33/532 , G01N33/563 , G01N33/68
CPC分类号： G01N33/6857 , A61K51/1048 , A61K51/1069 , A61K51/1093 , C07K16/00 , C07K16/30 , C07K16/3007 , C07K16/3061 , G01N33/532 , A61K2121/00 , A61K2123/00 , A61K38/00
摘要： The present invention relates to immunoconjugates comprising an antibody fragment which is covalently bound to a diagnostic or therapeutic principle through a carbohydrate moiety in the light chain variable region of the antibody fragment. The invention also relates to immunoconjugates comprising an antibody moiety that is an intact antibody containing a glycosylation site in the light chain variable domain which has been introduced into the antibody by mutating the nucleotide sequence encoding the light chain. The resultant immunoconjugates retain the immunoreactivity of the antibody fragment or intact antibody, and target the diagnostic or therapeutic principle to a target tissue where the diagnostic or therapeutic effect is realized. Thus, the invention contemplates the use of such immunoconjugates for diagnosis and immunotherapy. The invention further relates to methods for preparing such immunoconjugates.
摘要翻译：本发明涉及包含通过抗体片段的轻链可变区中的碳水化合物部分与诊断或治疗原理共价结合的抗体片段的免疫缀合物。本发明还涉及包含抗体部分的免疫缀合物，所述抗体部分是通过突变编码轻链的核苷酸序列而被引入抗体的包含轻链可变结构域中的糖基化位点的完整抗体。所得的免疫偶联物保留抗体片段或完整抗体的免疫反应性，并将诊断或治疗原理靶向实现诊断或治疗效果的靶组织。因此，本发明考虑使用这种免疫缀合物进行诊断和免疫治疗。本发明还涉及制备这种免疫缀合物的方法。

4. 发明授权

US07833528B2 Use of multispecific, non-covalent complexes for targeted delivery of therapeutics 有权
标题翻译：使用多特异性非共价复合物进行靶向递送治疗
公开(公告)号：US07833528B2
公开(公告)日：2010-11-16
申请号：US11553814
申请日：2006-10-27
申请人： Gary L. Griffiths , Serengulam V. Govindan , Hans J. Hansen
发明人： Gary L. Griffiths , Serengulam V. Govindan , Hans J. Hansen
IPC分类号： A61K39/395 , C12P21/04 , C12P21/08 , C07K16/00
CPC分类号： C07K16/44 , A61K47/665 , A61K47/67 , B82Y5/00 , C07K16/3007 , C07K2317/31 , C07K2317/55
摘要： Embodiments of the invention relate to a method for treating target cells, tissues or pathogens in a subject, comprising administering a non-covalently bound complex which comprises a multispecific targeting protein and a hapten-enzyme covalent conjugate, followed by administration of a prodrug that is converted to an active drug by the enzyme. Other embodiments of the invention further relate to kits comprising the non-covalently bound complex or the components to prepare the complex.
摘要翻译：本发明的实施方案涉及用于治疗受试者中靶细胞，组织或病原体的方法，包括施用包含多特异性靶向蛋白质和半抗原酶共价缀合物的非共价结合复合物，然后施用前药，其为通过酶转化为活性药物。本发明的其它实施方案还涉及包含非共价结合复合物或制备复合物的组分的试剂盒。

5. 发明授权

US07300644B2 Targeted combination immunotherapy 有权
标题翻译：靶向组合免疫治疗
公开(公告)号：US07300644B2
公开(公告)日：2007-11-27
申请号：US10361026
申请日：2003-02-10
申请人： Gary L. Griffiths , Hans J. Hansen , David M. Goldenberg
发明人： Gary L. Griffiths , Hans J. Hansen , David M. Goldenberg
IPC分类号： A61K51/00 , A61M36/14
CPC分类号： A61K33/22 , A61K31/7088 , A61K33/24 , A61K38/465 , A61K45/06 , A61K47/645 , A61K47/665 , A61K47/6853 , A61K47/6893 , A61K47/6898 , A61K51/0497 , A61K51/065 , A61K51/10 , A61K51/1096 , B82Y5/00 , Y02A50/463 , A61K2300/00
摘要： The present invention is directed to methods for treating cancer wherein more than one therapeutic agent is used, with each of the therapeutic agents having different tumor-killing capabilities, and wherein the therapeutic agents are delivered to the tumor sites using combined targeting and pre-targeting methods. The methods of the present invention achieve good tumor to non-tumor ratios of the therapeutic agents, and are effective for cancer therapy.
摘要翻译：本发明涉及用于治疗癌症的方法，其中使用多于一种治疗剂，每种治疗剂具有不同的杀伤能力，并且其中使用组合靶向和预靶向将治疗剂递送至肿瘤部位方法。本发明的方法实现了治疗剂的非肿瘤比例的良好肿瘤，并且对于癌症治疗是有效的。

6. 发明授权

US07052872B1 Bi-specific antibodies for pre-targeting diagnosis and therapy 有权
标题翻译：用于预定位诊断和治疗的双特异性抗体
公开(公告)号：US07052872B1
公开(公告)日：2006-05-30
申请号：US09382186
申请日：1999-08-23
申请人： Hans J. Hansen , Gary L. Griffiths , Shui-on Leung , William J. McBride , Zhengxing Qu
发明人： Hans J. Hansen , Gary L. Griffiths , Shui-on Leung , William J. McBride , Zhengxing Qu
IPC分类号： A61K39/395 , C07K16/00 , C12P21/04
CPC分类号： A61K51/109 , A61K47/6853 , A61K47/6893 , A61K47/6897 , A61K47/6899 , B82Y5/00 , C07K16/3007 , C07K16/44 , C07K2317/24 , C07K2317/31 , C07K2317/34 , C07K2317/55 , C07K2317/622 , C07K2319/00
摘要： The present invention relates to a bi-specific antibody or antibody fragment having at least one arm that specifically binds a targeted tissue and at least one other arm that specifically binds a targetable conjugate. The targetable conjugate comprises a carrier portion which comprises or bears at least one epitope recognizable by at least one arm of said bi-specific antibody or antibody fragment. The targetable conjugate further comprises one or more therapeutic or diagnostic agents or enzymes. The invention provides constructs and methods for producing the bi-specific antibodies or antibody fragments, as well as methods for using them.
摘要翻译：本发明涉及具有特异性结合目标组织的至少一个臂和特异性结合可靶向缀合物的至少一个其他臂的双特异性抗体或抗体片段。可靶向缀合物包含载体部分，其包含或携带至少一个可被所述双特异性抗体或抗体片段的至少一个臂识别的表位。可靶向缀合物还包含一种或多种治疗剂或诊断剂或酶。本发明提供用于产生双特异性抗体或抗体片段的构建体和方法，以及使用它们的方法。

7. 发明授权

US06361774B1 Methods and compositions for increasing the target-specific toxicity of a chemotherapy drug 有权
标题翻译：用于增加化疗药物的靶标特异性毒性的方法和组合物
公开(公告)号：US06361774B1
公开(公告)日：2002-03-26
申请号：US09399221
申请日：1999-09-17
申请人： Gary L. Griffiths , Hans J. Hansen
发明人： Gary L. Griffiths , Hans J. Hansen
IPC分类号： A61K39395
CPC分类号： B82Y5/00 , A61K47/6815 , A61K47/6863 , A61K47/6867 , A61K47/6879 , A61K47/6895 , A61K47/6899
摘要： A method for increasing the target-specific toxicity of a drug is effected by pretargeting an enzyme to a mammalian target site, and then administering a cytotoxic drug known to act at the target site or a prodrug form thereof which is converted to the drug in situ, which drug is also detoxified to form an intermediate of lower toxicity using said mammal's ordinary metabolic processes, whereby the detoxified intermediate is reconverted to its more toxic form by the pretargeted enzyme and thus has enhanced cytotoxicity at the target site. Further enhancement can be achieved by pretargeting an enzyme which converts the prodrug to the cytotoxic drug at the target site. Kits for use with the method also are provided. The method and kits permit lower doses of cytotoxic agents, maximize target site activity and minimize systemic side effects.
摘要翻译：通过将酶靶向到哺乳动物靶位点，然后施用已知在靶位点起作用的细胞毒性药物或其前体药物形式，将其转化为药物来实现增加药物的靶特异性毒性的方法，使用所述哺乳动物的普通代谢过程，该药物也被解毒以形成毒性较低的中间体，由此解毒中间体被预靶向的酶再转化为其更有毒的形式，因此在靶位点具有增强的细胞毒性。可以通过预靶向在靶位点将前药转化为细胞毒性药物的酶来实现进一步增强。还提供了与该方法一起使用的套件。该方法和试剂盒允许较低剂量的细胞毒剂，最大限度地提高目标部位活性并最大程度减少全身副作用。

8. 发明授权

US5922302A Detection and therapy of lesions with biotin/avidin-metal chelating protein conjugates 失效
标题翻译：用生物素/抗生物素蛋白金属螯合蛋白缀合物检测和治疗病变
公开(公告)号：US5922302A
公开(公告)日：1999-07-13
申请号：US440652
申请日：1995-05-15
申请人： David Milton Goldenberg , Gary L. Griffiths , Hans J. Hansen
发明人： David Milton Goldenberg , Gary L. Griffiths , Hans J. Hansen
IPC分类号： A61K38/00 , A61K38/16 , A61K38/22 , A61K38/27 , A61K38/43 , A61K39/44 , A61K45/00 , A61K47/48 , A61K49/00 , A61K51/00 , A61K51/10 , A61P9/00 , A61P17/00 , A61P29/00 , A61P35/00 , A61P35/02 , C07K16/00
CPC分类号： B82Y5/00 , A61K47/48353 , A61K47/48753 , A61K51/1093 , A61K2121/00 , A61K2123/00
摘要： Improved methods of detecting and/or treating lesions in a patient are provided. The improved methods comprise the steps of (a) parenterally injecting a subject with a targeting composition comprised of a conjugate of biotin and targeting protein or of an avidin and targeting protein, wherein the targeting protein preferentially binds to a marker substance produced or associated with the targeted lesion, and allowing the targeting protein conjugate to preferentially accrete at the targeted lesion; (b) then parenterally injecting a clearing composition comprised of (i) avidin, when the targeting composition is a biotin-targeting protein conjugate, or (ii) biotin, when the targeting composition is a avidin-targeting protein conjugate, and allowing the clearing composition to substantially clear the targeting composition from non-targeted sites and to bind to the targeting composition accreted at the targeted lesion; (c) parenterally injecting a localization agent which may be the same or different form the clearing agent; (d) parenterally injecting a detection or therapeutic composition comprised of a conjugate of (i) avidin and naturally occurring metal-ion chelating protein chelated with chelatable metal detection or therapeutic agent when the clearing composition is biotin, or (ii) biotin and naturally occurring metal-ion carry protein chelated with chelatable a metal detection or therapeutic agent when the clearing agent is avidin, and allowing the composition to accrete at the targeted lesion. The improvement is that the use of the chelating protein to chelate a chelatable metal therapeutic or detection agent amplifies the amount of detection or therapeutic agent at the targeted site.
摘要翻译：提供改进的检测和/或治疗患者病变的方法。改进的方法包括以下步骤：（a）用由生物素和靶向蛋白质的缀合物或抗生物素蛋白和靶向蛋白质的缀合物组成的靶向组合物肠胃外注射受试者，其中所述靶向蛋白质优先结合生成或与之相关的标记物质靶向性损伤，并允许靶向蛋白质缀合物优先在目标病变处分泌; （b）然后当靶向组合物为抗生物素蛋白靶向蛋白质缀合物时，肠胃外注射由（i）抗生物素蛋白组成的清除组合物，当靶向组合物为生物素靶向蛋白质缀合物或（ii）生物素时，组合物以从非靶位点基本上清除靶向组合物，并结合靶向组合物，其靶向病变呈现; （c）肠胃外注射定位剂，所述定位剂可以相同或不同，形成清除剂; （d）当清除组合物为生物素时，肠胃外注射由（i）抗生物素蛋白和螯合螯合金属螯合蛋白和天然存在的金属离子螯合蛋白的缀合物组成的检测或治疗组合物，或（ii）生物素和天然存在的当清除剂为抗生物素蛋白时，金属离子携带蛋白质与可螯合的金属检测或治疗剂螯合，并允许组合物在靶向病变处进入。改进之处在于使用螯合蛋白螯合螯合金属治疗剂或检测剂可以扩增目标部位的检测量或治疗剂量。

9. 发明授权

US5328679A Methods for technetium/rhenium labeling of proteins 失效
标题翻译：蛋白质锝/铼标记方法
公开(公告)号：US5328679A
公开(公告)日：1994-07-12
申请号：US760466
申请日：1991-09-17
申请人： Hans J. Hansen , Gary L. Griffiths , Anastasia Lentine-Jones
发明人： Hans J. Hansen , Gary L. Griffiths , Anastasia Lentine-Jones
IPC分类号： A61K51/10 , A61K51/12 , A61K49/02 , A61K39/395 , A61K43/00 , C07K15/28
CPC分类号： A61K51/1048 , A61K51/10 , A61K51/1282 , A61K2123/00
摘要： A method for radiolabeling a protein with a radioisotope of technetium or rhenium is disclosed which comprises the steps of contacting a solution of a protein containing a plurality of adjacent free sulfhydryl groups, or in particular cases, intact protein containing at least one disulfide group, with stannous ions, and then with radiopertechnetate or radioperrhenate, the amount of stannous ion being sufficient to substantially completely reduce the radiopertechnetate or radioperrhenate, and recovering radiolabeled protein.A rapid and quantitative method for producing a sterile, injectable solution of Tc-99m-labeled monovalent antibody fragment is also disclosed which comprises the step of mixing a sterile solution containing a monovalent antibody fragment having at least one free sulfhydryl group, stannous chloride and excess tartrate, at mildly acidic pH, or a sucrose-stabilized lyophilizate of such solution, with a sterile solution of Tc-99m-pertechnetate, whereby substantially quantitative labeling of the antibody fragment with Tc-99m is effected in about 5 minutes at ambient temperature, the resultant sterile solution of Tc-99m-labeled monovalent antibody fragment being suitable for immediate injection into a patient for scintigraphic imaging.
摘要翻译：公开了用锝或铼的放射性同位素放射性标记蛋白质的方法，其包括将含有多个相邻游离巯基的蛋白质溶液或特别是含有至少一个二硫基的完整蛋白质溶液与亚锡离子，然后用锝铁或无铼酸盐，亚锡离子的量足以基本上完全降低玄武岩或无纶珍珠岩，并回收放射性标记的蛋白质。还公开了用于生产Tc-99m标记的单价抗体片段的无菌注射溶液的快速和定量的方法，其包括将含有至少一个游离巯基，氯化亚锡和过量的一价抗体片段的无菌溶液混合的步骤用温和酸性pH的酒石酸盐或这种溶液的蔗糖稳定的冻干物，用Tc-99m-高锝酸盐的无菌溶液，由此在约5分钟内在环境温度下对Tc-99m的抗体片段进行基本上定量的标记，所得到的Tc-99m标记的单价抗体片段的无菌溶液适于立即注射到患者中用于闪烁照相成像。

10. 发明申请

US20090246131A1 Production and Use of Novel Peptide-Based Agents for Use with Bi-Specific Antibodies 有权
标题翻译：用于双特异性抗体的新型基于肽的试剂的生产和使用
公开(公告)号：US20090246131A1
公开(公告)日：2009-10-01
申请号：US12481233
申请日：2009-06-09
申请人： Hans J. Hansen , Gary L. Griffiths , Shui-on Leung , William J. McBride , Zhengxing Qu
发明人： Hans J. Hansen , Gary L. Griffiths , Shui-on Leung , William J. McBride , Zhengxing Qu
IPC分类号： A61K51/10 , A61K47/42
CPC分类号： C07K16/468 , A61K47/6863 , A61K47/6899 , A61K51/1048 , A61K51/1063 , A61K2039/505 , B82Y5/00 , C07K16/18 , C07K16/30 , C07K16/3007 , C07K16/3046 , C07K16/44 , C07K2317/12 , C07K2317/13 , C07K2317/24 , C07K2317/31 , C07K2317/55 , C07K2317/622 , C07K2319/00
摘要： The present invention relates to a bi-specific antibody or antibody fragment having at least one arm that is reactive against a targeted tissue and at least one other arm that is reactive against a targetable conjugate. The targetable conjugate encompasses a hapten to which antibodies have been prepared. In preferred embodiments, the hapten is histamine-succinyl-glycine (HSG). In more preferred embodiments, the at least one arm comprises the CDR sequences of the HSG-binding 679 antibody. The targetable conjugate is attached to one or more therapeutic and/or diagnostic agents. The invention provides constructs and methods for producing the bispecific antibodies or antibody fragments, as well as methods for using them and kits comprising them.
摘要翻译：本发明涉及一种双特异性抗体或抗体片段，该双特异性抗体或抗体片段具有至少一个对目标组织有反应性的臂和至少一种其它可靶向缀合物反应的其他臂。可靶向缀合物包含已制备抗体的半抗原。在优选的实施方案中，半抗原是组胺 - 琥珀酰甘氨酸（HSG）。在更优选的实施方案中，所述至少一个臂包含HSG结合679抗体的CDR序列。可靶向缀合物连接至一种或多种治疗和/或诊断剂。本发明提供了用于产生双特异性抗体或抗体片段的构建体和方法，以及使用它们的方法和包含它们的试剂盒。

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