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41. 发明授权

US06929946B1 Gene delivery vectors provided with a tissue tropism for smooth muscle cells, and/or endothelial cells 有权
标题翻译：为平滑肌细胞和/或内皮细胞提供组织嗜性的基因递送载体
公开(公告)号：US06929946B1
公开(公告)日：2005-08-16
申请号：US09444284
申请日：1999-11-19
申请人： Ronald Vogels , Menzo J. E. Havenga , Abraham Bout
发明人： Ronald Vogels , Menzo J. E. Havenga , Abraham Bout
IPC分类号： A61K38/00 , A61K48/00 , C07K14/075 , C12N15/861 , C12N15/00 , A01N63/00 , C07H21/04 , C12N15/63
CPC分类号： C07K14/005 , A61K38/00 , A61K48/00 , C07K2319/00 , C12N15/86 , C12N2710/10322 , C12N2710/10343 , C12N2710/10345 , C12N2810/6018
摘要： A gene delivery vehicle having been provided with at least a tissue tropism for cells selected from the group of smooth muscle cells, endothelial cells, and/or liver cells. The tissue tropism is generally provided by a virus capsid, such as one comprising protein fragments from at least two different viruses, such as two different adenoviruses, including adenovirus of subgroup C or subgroup B (for example, adenovirus 16). The protein fragments can comprises a tissue tropism determining fragment of a fiber protein derived from a subgroup B adenovirus. Also, cells for producing such gene delivery vehicles and pharmaceutical compositions containing said gene delivery vehicles. Further, a method of delivering nucleic acid to cells such as smooth muscle cells and/or endothelial cells which involves administering to the cells an adenovirus capsid having proteins from at least two different adenoviruses and wherein at least a tissue tropism determining fragment of a fiber protein is derived from a subgroup B adenovirus. Particular construct are also disclosed.
摘要翻译：具有至少一种选自平滑肌细胞，内皮细胞和/或肝细胞的细胞的组织嗜性的基因递送载体。组织向性通常由病毒衣壳提供，例如包含来自至少两种不同病毒的蛋白质片段的病毒衣壳，例如两种不同的腺病毒，包括亚组C或亚组B的腺病毒（例如，腺病毒16）。蛋白质片段可以包含衍生自亚组B腺病毒的纤维蛋白质的组织向性确定片段。此外，用于产生这种基因递送载体的细胞和含有所述基因递送载体的药物组合物。此外，将核酸递送到诸如平滑肌细胞和/或内皮细胞的细胞的方法，其涉及向细胞施用具有来自至少两种不同腺病毒的蛋白质的腺病毒衣壳，并且其中至少一种纤维蛋白质的组织向性确定片段来源于亚组B腺病毒。还公开了特定的构建体。

42. 发明授权

US06913922B1 Serotype of adenovirus and uses thereof 有权
标题翻译：腺病毒血清型及其用途
公开(公告)号：US06913922B1
公开(公告)日：2005-07-05
申请号：US09573740
申请日：2000-05-18
申请人： Abraham Bout , Menzo Havenga , Ronald Vogels
发明人： Abraham Bout , Menzo Havenga , Ronald Vogels
IPC分类号： A61K48/00 , C12N5/02 , C12N5/10 , C12N7/00 , C12N15/00 , C12N15/09 , C12N15/35 , C12N15/63 , C12N15/70 , C12N15/74 , C12N15/861
CPC分类号： C07K14/005 , C12N7/00 , C12N15/86 , C12N2710/10321 , C12N2710/10322 , C12N2710/10343 , C12N2710/10345 , C12N2710/10352 , C12N2810/6018 , C12N2830/00
摘要： Adenovirus serotypes differ in their natural tropism. The adenovirus serotypes 2, 4, 5, and 7 all have a natural affiliation towards lung epithelia and other respiratory tissues. In contrast, serotypes 40 and 41 have a natural affiliation towards the gastrointestinal tract. The serotypes described, differ in at least capsid proteins (penton-base, hexon), proteins responsible for cell binding (fiber protein), and proteins involved in adenovirus replication. This difference in tropism and capsid protein among serotypes has led to the many research efforts aimed at redirecting the adenovirus tropism by modification of the capsid proteins.
摘要翻译：腺病毒血清型的自然向性不同。腺病毒血清型2,4,5和7都具有与肺上皮细胞和其他呼吸组织的天然亲和关系。相比之下，血清型40和41与胃肠道具有天然的联系。所描述的血清型至少在衣壳蛋白（penton-base，hexon），负责细胞结合的蛋白质（纤维蛋白）以及涉及腺病毒复制的蛋白质中不同。血清型中对向性和衣壳蛋白的这种差异导致了许多研究工作，旨在通过修饰衣壳蛋白来重新定向腺病毒向性。

43. 发明授权

US06878549B1 Packaging systems for human recombinant adenovirus to be used in gene therapy 有权
标题翻译：用于基因治疗的人重组腺病毒的包装系统
公开(公告)号：US06878549B1
公开(公告)日：2005-04-12
申请号：US09332803
申请日：1999-06-14
申请人： Ronald Vogels , Abraham Bout
发明人： Ronald Vogels , Abraham Bout
IPC分类号： C12N15/09 , A61K48/00 , C07K14/075 , C12N5/10 , C12N7/00 , C12N7/01 , C12N15/861 , C12R1/01 , C12N15/63 , C12N15/64
CPC分类号： C12N7/00 , A61K48/00 , C07K14/005 , C12N15/86 , C12N2710/10322 , C12N2710/10343 , C12N2710/10352 , C12N2830/00 , C12N2830/15 , C12N2830/38 , C12N2830/60
摘要： Methods and corresponding compounds for generating adenoviral vectors. One such method entails a method for generating an adenoviral vector comprising welding together two nucleic acid molecules wherein the molecules comprise partially overlapping sequences capable of combining with each other allowing the generation of a physically linked nucleic acid comprising at least two functional adenovirus inverted terminal repeats, a functional encapsulation signal and a nucleic acid of interest or functional parts, derivatives and/or analogues thereof. Further disclosed are nucleic acid molecules for generating adenoviral vectors.
摘要翻译：用于产生腺病毒载体的方法和相应的化合物。一种这样的方法需要一种产生腺病毒载体的方法，包括将两个核酸分子焊接在一起，其中分子包含能够彼此组合的部分重叠的序列，从而产生包含至少两个功能性腺病毒反向末端重复的物理连接的核酸，功能性封装信号和感兴趣的核酸或其功能部分，衍生物和/或类似物。还公开了用于产生腺病毒载体的核酸分子。

44. 发明申请

US20050074885A1 Packaging systems for human recombinant adenovirus to be used in gene therapy 失效
标题翻译：用于基因治疗的人重组腺病毒的包装系统
公开(公告)号：US20050074885A1
公开(公告)日：2005-04-07
申请号：US10396548
申请日：2003-03-25
申请人： Ronald Vogels , Abraham Bout
发明人： Ronald Vogels , Abraham Bout
IPC分类号： C12N15/09 , A61K48/00 , C07K14/075 , C12N5/10 , C12N7/00 , C12N7/01 , C12N15/861 , C12R1/01 , C12N5/06
CPC分类号： C12N7/00 , A61K48/00 , C07K14/005 , C12N15/86 , C12N2710/10322 , C12N2710/10343 , C12N2710/10352 , C12N2830/00 , C12N2830/15 , C12N2830/38 , C12N2830/60
摘要： The invention provides improved methods and products based on adenoviral materials which can advantageously be used in gene therapy. In one aspect, an adenoviral vector is provided having no overlap with a suitable packaging cell line. The suitable packaging cell line is another aspect. The combination excludes the possibility of homologous recombination, thereby excluding the possibility of the formation of replication competent adenovirus. Another aspect embodies an adenovirus based helper construct which by its size is incapable of being encapsidated. This helper virus can be transferred into any suitable host cell making it a packaging cell. Furthermore, a number of useful mutations to adenoviral based materials and combinations of such mutations are disclosed, all of which have in common the safety of the methods and the products, in particular avoiding the production of replication competent adenovirus and/or interference with the immune system.
摘要翻译：本发明提供了可以有利地用于基因治疗的基于腺病毒材料的改进的方法和产品。在一个方面，提供了与合适的包装细胞系不重叠的腺病毒载体。合适的包装细胞系是另一个方面。该组合不包括同源重组的可能性，从而排除形成复制型腺病毒的可能性。另一方面体现了一种基于腺病毒的辅助构建体，其大小不能被包裹。这种辅助病毒可以转移到任何合适的宿主细胞中，使其成为包装细胞。此外，公开了对基于腺病毒的材料和这种突变的组合的许多有用的突变，所有这些都具有方法和产品的安全性，特别是避免生产复制有关的腺病毒和/或免疫的干扰系统。

45. 发明授权

US06783980B2 Packaging systems for human recombinant adenovirus to be used in gene therapy 有权
标题翻译：用于基因治疗的人重组腺病毒的包装系统
公开(公告)号：US06783980B2
公开(公告)日：2004-08-31
申请号：US09918029
申请日：2001-07-30
申请人： Frits Jacobus Fallaux , Robert Cornelis Hoeben , Alex Jan van der Eb , Abraham Bout , Domenico Valerio
发明人： Frits Jacobus Fallaux , Robert Cornelis Hoeben , Alex Jan van der Eb , Abraham Bout , Domenico Valerio
IPC分类号： C12N1500
CPC分类号： C12N7/00 , A61K48/00 , A61K48/0091 , C07K14/005 , C12N5/0621 , C12N15/86 , C12N2710/10322 , C12N2710/10343 , C12N2710/10351 , C12N2710/10352 , C12N2830/42
摘要： Presented are ways to address the problem of replication competent adenovirus in adenoviral production for use with, for example, gene therapy. Packaging cells having no overlapping sequences with a selected vector and are suited for large scale production of recombinant adenoviruses. A system for use with the invention produces adenovirus incapable of replicating. The system includes a primary cell containing a nucleic acid based on or derived from adenovirus and an isolated recombinant nucleic acid molecule for transfer into the primary cell. The isolated recombinant nucleic acid molecule is based on or derived from an adenovirus, and further has at least one functional encapsidating signal, and at least one functional Inverted Terminal Repeat. The isolated recombinant nucleic acid molecule lacks overlapping sequences with the nucleic acid of the cell. Otherwise, the overlapping sequences would enable homologous recombination leading to replication competent adenovirus in the primary cell into which the isolated recombinant nucleic acid molecule is to be transferred.
摘要翻译：提出了解决在例如基因治疗中用于腺病毒生产中的复制型有效腺病毒的问题的方法。包装细胞与选定的载体不具有重叠序列，并且适合大规模生产重组腺病毒。本发明使用的系统产生不能复制的腺病毒。该系统包括含有基于或衍生自腺病毒的核酸的原代细胞和用于转移至原代细胞的分离的重组核酸分子。分离的重组核酸分子基于或衍生自腺病毒，并且还具有至少一个功能性包封信号和至少一个功能性反向终止重复。分离的重组核酸分子与细胞的核酸缺少重叠序列。否则，重叠序列将实现同源重组，导致要转移分离的重组核酸分子的原代细胞中的复制感受态腺病毒。

46. 发明授权

US06204052B1 Adenoviral vectors with reduced TNF response and partial E3 region deletion 失效
标题翻译：具有降低的TNF反应和部分E3区缺失的腺病毒载体
公开(公告)号：US06204052B1
公开(公告)日：2001-03-20
申请号：US08515495
申请日：1995-08-15
申请人： Abraham Bout , Dirk W. Van Bekkum , Domenico Valerio
发明人： Abraham Bout , Dirk W. Van Bekkum , Domenico Valerio
IPC分类号： C12N500
CPC分类号： C12N15/86 , A61K38/00 , A61K48/00 , C07K14/5403 , C07K14/545 , C12N9/1211 , C12N2710/10343
摘要： Adenoviral vectors with a deletion of the E3 region such that the remaining E3 region reduces the TNF response of a host mammalian cell infected with the virus. The portion of the E3 region remaining in these vectors encodes the 14.7 kD protein, and may also contain a deletion of at least the E1a promoter. These partially deleted E3 vectors will inhibit the host cell's immune response so that the infected cell will live longer. Any non-adenoviral gene expressed from these vectors in the infected cell will be produced for a longer length of time and achieve a higher concentration than when adenoviral vectors not expressing function 14.7 kD protein are used. These 14.7 kD expressing adenoviral vectors will be useful for gene therapy and especially in cancer gene therapy where the non-adenoviral DNA sequence being expressed are preferably cytokine genes, such as IL-1, and suicide genes, such as HSV-tk. The vectors also are useful for antisense therapy.
摘要翻译：具有E3区缺失的腺病毒载体使得剩余的E3区降低了感染病毒的宿主哺乳动物细胞的TNF反应。保留在这些载体中的E3区域的部分编码14.7kD蛋白，并且还可以含有至少E1a启动子的缺失。这些部分缺失的E3载体将抑制宿主细胞的免疫应答，使感染的细胞寿命更长。在感染细胞中从这些载体表达的任何非腺病毒基因将产生更长的时间长度，并且比使用不表达14.7kD蛋白质的腺病毒载体时获得更高的浓度。这些14.7kD表达的腺病毒载体可用于基因治疗，特别是在癌基因治疗中，其中表达的非腺病毒DNA序列优选为细胞因子基因，如IL-1，以及自杀基因，如HSV-tk。载体也可用于反义治疗。

47. 发明授权

US07932360B2 Recombinant production of mixtures of antibodies 有权
公开(公告)号：US07932360B2
公开(公告)日：2011-04-26
申请号：US11593280
申请日：2006-11-06
申请人： Patrick H. C. Van Berkel , Ronald Hendrik Peter Brus , Ton Logtenberg , Abraham Bout
发明人： Patrick H. C. Van Berkel , Ronald Hendrik Peter Brus , Ton Logtenberg , Abraham Bout
IPC分类号： C12P21/08 , A61K39/395
CPC分类号： C12P21/005 , A61K39/39558 , C07K16/00 , C07K16/10 , C07K16/2803 , C07K16/2833 , C07K16/2851 , C07K16/2896 , C07K16/30 , C07K16/32 , C07K2317/12 , C07K2317/21 , C07K2317/31 , C07K2317/50 , C07K2317/51 , C07K2317/56 , C07K2317/622 , C07K2317/626 , C07K2317/73 , C07K2317/732 , C07K2317/734 , C07K2319/30 , Y02P20/582
摘要： The invention provides methods for producing mixtures of antibodies from a single host cell clone, wherein, a nucleic acid sequence encoding a light chain and nucleic acid sequences encoding different heavy chains are expressed in a recombinant host cell. The recombinantly produced antibodies in the mixtures according to the invention suitably comprise identical light chains paired to different heavy chains capable of pairing to the light chain, thereby forming functional antigen-binding domains. Mixtures of the recombinantly produced antibodies are also provided by the invention. Such mixtures can be used in a variety of fields.

48. 发明授权

US07927834B2 Recombinant production of mixtures of antibodies 有权
标题翻译：重组产生抗体混合物
公开(公告)号：US07927834B2
公开(公告)日：2011-04-19
申请号：US12221021
申请日：2008-07-29
申请人： Patrick H. C. Van Berkel , Ronald Hendrik Peter Brus , Ton Logtenberg , Abraham Bout
发明人： Patrick H. C. Van Berkel , Ronald Hendrik Peter Brus , Ton Logtenberg , Abraham Bout
IPC分类号： C12N15/00 , C12N5/06 , C12N5/16 , C12P21/06 , C12P21/02
CPC分类号： C12P21/005 , A61K39/39558 , C07K16/00 , C07K16/10 , C07K16/2803 , C07K16/2833 , C07K16/2851 , C07K16/2896 , C07K16/30 , C07K16/32 , C07K2317/12 , C07K2317/21 , C07K2317/31 , C07K2317/50 , C07K2317/51 , C07K2317/56 , C07K2317/622 , C07K2317/626 , C07K2317/73 , C07K2317/732 , C07K2317/734 , C07K2319/30 , Y02P20/582
摘要： The invention provides methods for producing mixtures of antibodies from a single host cell clone, wherein, a nucleic acid sequence encoding a light chain and nucleic acid sequences encoding different heavy chains are expressed in a recombinant host cell. The recombinantly produced antibodies in the mixtures according to the invention suitably comprise identical light chains paired to different heavy chains capable of pairing to the light chain, thereby forming functional antigen-binding domains. Mixtures of the recombinantly produced antibodies are also provided by the invention. Such mixtures can be used in a variety of fields.
摘要翻译：本发明提供从单个宿主细胞克隆产生抗体混合物的方法，其中编码轻链的核酸序列和编码不同重链的核酸序列在重组宿主细胞中表达。根据本发明的混合物中重组产生的抗体适当地包含与能够与轻链配对的不同重链配对的相同的轻链，从而形成功能性抗原结合结构域。重组产生的抗体的混合物也由本发明提供。这种混合物可用于各种领域。

49. 发明授权

US07820440B2 Means and methods for producing adenovirus vectors 有权
标题翻译：用于产生腺病毒载体的方法和方法
公开(公告)号：US07820440B2
公开(公告)日：2010-10-26
申请号：US11800871
申请日：2007-05-07
申请人： Ronald Vogels , Abraham Bout
发明人： Ronald Vogels , Abraham Bout
IPC分类号： C12N15/861 , C12N15/63 , C12N15/11 , C12N15/00 , C12N15/34 , C12N5/00
CPC分类号： C12N15/86 , A61K48/00 , A61K2039/525 , A61K2039/5256 , C12N2710/10343 , C12N2810/6018 , C12N2830/002
摘要： The invention relates to methods and means for producing adenoviral vectors on complementing cell lines, wherein the early region 4 open reading frame 6 (E4-orf6) encoding nucleic acid is present in the adenoviral vector and wherein the E4-orf6 gene product is compatible with one or more products of the E1 gene products provided by the complementing cell, such that the adenoviral vector can be efficiently produced by the complementing cell.
摘要翻译：本发明涉及在补体细胞系上产生腺病毒载体的方法和方法，其中编码核酸的早期区域4开放阅读框6（E4-orf6）存在于腺病毒载体中，其中E4-orf6基因产物与由补体细胞提供的E1基因产物的一种或多种产物，使得腺病毒载体可以通过补体细胞有效产生。

50. 发明授权

US07785833B2 Methods and means for producing proteins with predetermined post-translational modifications 有权
标题翻译：用预定的翻译后修饰产生蛋白质的方法和方法
公开(公告)号：US07785833B2
公开(公告)日：2010-08-31
申请号：US11657202
申请日：2007-01-24
申请人： Dirk Jan Elbertus Opstelten , Johan Christiaan Kapteyn , Petrus Christianius Johannes Josephus Passier , Ronald Hendrik Peter Brus , Abraham Bout
发明人： Dirk Jan Elbertus Opstelten , Johan Christiaan Kapteyn , Petrus Christianius Johannes Josephus Passier , Ronald Hendrik Peter Brus , Abraham Bout
IPC分类号： C12N5/00 , C12N15/00 , G01N33/53 , C07K14/475
CPC分类号： C07K14/005 , A61K38/00 , C07K14/505 , C12N2710/10322 , C12N2710/10343 , C12P21/005
摘要： Described are methods for identifying, selecting, and obtaining mammalian cells capable of producing proteinaceous molecules having predetermined post-translational modifications, wherein the post-translational modifications are brought about by the mammalian cell in which the proteinaceous molecule is expressed. Preferably, the predetermined post-translational modifications include glycosylation. Also described are methods for obtaining and producing proteinaceous molecules, using mammalian cells obtainable by a method of the present invention. Preferably, the proteinaceous molecules include erythropoietin (EPO), since EPO's effect depends heavily on its glycosylation pattern. Mammalian cells that have been obtained on the basis of their ability to produce proteins and/or post-translational modifications that are indicative for a predetermined post-translational modification that is desired are also provided. Preferably, the mammalian cells have neural characteristics and properties such that significant amounts of recombinant proteins can be produced that harbor “neural- or brain-type” properties.
摘要翻译：描述了用于鉴定，选择和获得能够产生具有预定的翻译后修饰的蛋白质分子的哺乳动物细胞的方法，其中翻译后修饰由其中表达蛋白质分子的哺乳动物细胞产生。优选地，预定的翻译后修饰包括糖基化。还描述了使用可通过本发明的方法获得的哺乳动物细胞获得和产生蛋白质分子的方法。优选地，蛋白质分子包括促红细胞生成素（EPO），因为EPO的作用很大程度上取决于其糖基化模式。还提供了基于其产生蛋白质的能力获得的哺乳动物细胞和/或指示期望的预定的翻译后修饰的翻译后修饰。优选地，哺乳动物细胞具有神经特征和性质，使得可以产生具有“神经或脑型”特性的显着量的重组蛋白。

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