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。

公开(公告)号：US07968087B2

公开(公告)日：2011-06-28

申请号：US12455086

申请日：2009-05-28

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： A01N63/00 ,  A61K48/00 ,  C12N15/00 ,  C12N15/63 ,  C07H21/04

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 comprise 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 these gene delivery vehicles are provided. Further, a method is disclosed for 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 constructs 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决定片段。 此外，提供了用于产生这种基因递送载体的细胞和含有这些基因递送载体的药物组合物。 此外，公开了一种用于将核酸递送至诸如平滑肌细胞和/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，并且其中至少一种组织向性确定片段 纤维蛋白源自B亚型腺病毒亚组。 还公开了特定的构建体。

公开(公告)号：US20090253207A1

公开(公告)日：2009-10-08

申请号：US12455086

申请日：2009-05-28

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： C12N15/86

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 comprise 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 these gene delivery vehicles are provided. Further, a method is disclosed for 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 constructs 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决定片段。 此外，提供了用于产生这种基因递送载体的细胞和含有这些基因递送载体的药物组合物。 此外，公开了一种用于将核酸递送至诸如平滑肌细胞和/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，并且其中至少一种组织向性确定片段 纤维蛋白源自B亚型腺病毒亚组。 还公开了特定的构建体。

公开(公告)号：US06974695B2

公开(公告)日：2005-12-13

申请号：US10002750

申请日：2001-11-15

申请人： Ronald Vogels ,  Menzo J. E. Havenga ,  Majid Mehtali

发明人： Ronald Vogels ,  Menzo J. E. Havenga ,  Majid Mehtali

IPC分类号： C12N15/09 ,  A61K48/00 ,  C12N5/02 ,  C12N5/08 ,  C12N5/10 ,  C12N7/00 ,  C12N7/01 ,  C12N7/02 ,  C12N15/00 ,  C12N15/35 ,  C12N15/63 ,  C12N15/70 ,  C12N15/74 ,  C12N15/861

CPC分类号： C12N15/86 ,  C12N7/00 ,  C12N7/025 ,  C12N15/861 ,  C12N2710/10041 ,  C12N2710/10051 ,  C12N2710/10343 ,  C12N2710/10352 ,  C12N2830/00 ,  C12N2840/20

摘要： A packaging cell line capable of complementing recombinant adenoviruses based on serotypes from subgroup B, preferably adenovirus type 35. The cell line is preferably derived from primary, diploid human cells (e.g., primary human retinoblasts, primary human embryonic kidney cells and primary human amniocytes) which are transformed by adenovirus E1 sequences either operatively linked on one DNA molecule or located on two separate DNA molecules, the sequences being operatively linked to regulatory sequences enabling transcription and translation of encoded proteins. Also disclosed is a cell line derived from PER.C6 (ECACC deposit number 96022940), which cell expresses functional Ad35 E1B sequences. The Ad35-E1B sequences are driven by the E1B promoter or a heterologous promoter and terminated by a heterologous poly-adenylation signal. The new cell lines are useful for producing recombinant adenoviruses designed for gene therapy and vaccination. The cell line can also be used for producing human recombinant therapeutic proteins such as human growth factors and human antibodies. In addition, the cell lines are useful for producing human viruses other than adenovirus such as influenza virus, herpes simplex virus, rotavirus, measles virus.

摘要翻译： 能够基于来自亚组B，优选腺病毒35的血清型补充重组腺病毒的包装细胞系。细胞系优选衍生自原代，二倍体人细胞（例如，原代人成视网膜细胞，原代人胚胎肾细胞和原代人羊膜细胞） 其通过可操作地连接在一个DNA分子上或位于两个分离的DNA分子上的腺病毒E1序列转化，所述序列可操作地连接到能够转录和翻译编码的蛋白质的调控序列。 还公开了衍生自PER.C6（ECACC保藏号96022940）的细胞系，该细胞表达功能性Ad35 E1B序列。 Ad35-E1B序列由E1B启动子或异源启动子驱动，并通过异源多聚腺苷酸化信号终止。 新的细胞系可用于产生用于基因治疗和疫苗接种的重组腺病毒。 细胞系也可用于生产人重组治疗蛋白，如人生长因子和人抗体。 此外，细胞系可用于生产除腺病毒如流感病毒，单纯疱疹病毒，轮状病毒，麻疹病毒之外的人类病毒。

公开(公告)号：US20080113409A1

公开(公告)日：2008-05-15

申请号：US11809697

申请日：2007-06-01

申请人： Guus Hateboer ,  Menzo J. E. Havenga ,  Ronald Vogels ,  Lennart Holterman

发明人： Guus Hateboer ,  Menzo J. E. Havenga ,  Ronald Vogels ,  Lennart Holterman

IPC分类号： C12P21/02

CPC分类号： C12N15/86 ,  C07K14/005 ,  C07K14/505 ,  C12N7/00 ,  C12N2710/10343 ,  C12N2760/16122

摘要： Described is a method for producing a protein of interest, the method comprising: a) providing a recombinant adenoviral vector comprising nucleic acid encoding the protein of interest under control of a promoter, wherein the adenoviral vector has deletions in a first region and in a second region of the adenovirus genome, wherein each of the first region and the second region is required for adenoviral genome replication and/or adenovirus particle formation, b) propagating the adenoviral vector in a first type of complementing cells that express proteins from the first and from the second region of the adenovirus genome so as to complement the deletions of the recombinant adenoviral vector, to obtain recombinant adenovirus particles, c) infecting a culture of a second type of complementing cells with the recombinant adenovirus particles, wherein the second type of complementing cells express protein from the first region of the adenovirus genome but not protein from the second region of the adenovirus genome, to produce the protein of interest, and d) harvesting the protein of interest.

摘要翻译： 描述了用于产生目的蛋白质的方法，所述方法包括：a）提供重组腺病毒载体，所述重组腺病毒载体包含编码在启动子控制下的感兴趣蛋白质的核酸，其中所述腺病毒载体在第一区域和第二区域中具有缺失 腺病毒基因组的区域，其中腺病毒基因组复制和/或腺病毒颗粒形成所需的第一区域和第二区域中的每一个，b）将腺病毒载体扩增到第一类型的互补细胞中，所述互补细胞从第一种和第 腺病毒基因组的第二区域，以补充重组腺病毒载体的缺失，以获得重组腺病毒颗粒，c）用重组腺病毒颗粒感染第二种补体细胞的培养物，其中第二种类型的补体细胞 从腺病毒基因组的第一区域表达蛋白质，但不表示来自第二区域的蛋白质 f产生感兴趣的蛋白质，以及d）收获感兴趣的蛋白质。

公开(公告)号：US08012467B2

公开(公告)日：2011-09-06

申请号：US11667975

申请日：2005-11-15

申请人： Menzo J. E. Havenga ,  Ronald Vogels ,  Jerald Sadoff ,  David Hone ,  Yasir A. W. Skeiky ,  Katarina Radosevic

发明人： Menzo J. E. Havenga ,  Ronald Vogels ,  Jerald Sadoff ,  David Hone ,  Yasir A. W. Skeiky ,  Katarina Radosevic

IPC分类号： A61K39/00 ,  A61K39/04 ,  A61K39/235 ,  C12N15/31

CPC分类号： A61K39/04 ,  A61K35/761 ,  A61K2039/523 ,  A61K2039/5256 ,  A61K2039/53 ,  A61K2039/55544 ,  C07K14/35 ,  C07K2319/00 ,  C12N2710/10343

摘要： The invention relates to vaccines comprising recombinant vectors, such as recombinant adenoviruses. The vectors comprise heterologous nucleic acids encoding for at least two antigens from one or more tuberculosis-causing bacilli. The invention also relates to the use of specific protease recognition sites linking antigens through which the encoded antigens are separated upon cleavage. After cleavage, the antigens contribute to the immune response in a separate manner. The recombinant vectors may comprise a nucleic acid encoding the protease cleaving the linkers and separating the antigens. The invention furthermore relates to the use of genetic adjuvants encoded by the recombinant vectors, wherein such genetic adjuvants may also be cleaved through the presence of the cleavable linkers and the specific protease.

摘要翻译： 本发明涉及包含重组载体例如重组腺病毒的疫苗。 载体包含编码来自一种或多种结核分枝杆菌的至少两种抗原的异源核酸。 本发明还涉及连接抗原的特异性蛋白酶识别位点的用途，通过该抗原将经编码的抗原在切割后分离。 在切割后，抗原以单独的方式有助于免疫应答。 重组载体可以包含编码切割接头并分离抗原的蛋白酶的核酸。 本发明还涉及由重组载体编码的遗传佐剂的用途，其中这种遗传佐剂也可以通过存在可切割接头和特异性蛋白酶来切割。

公开(公告)号：US07604960B2

公开(公告)日：2009-10-20

申请号：US11809697

申请日：2007-06-01

申请人： Guus Hateboer ,  Menzo J. E. Havenga ,  Ronald Vogels ,  Lennart Holterman

发明人： Guus Hateboer ,  Menzo J. E. Havenga ,  Ronald Vogels ,  Lennart Holterman

IPC分类号： C12P21/06 ,  C12N15/00 ,  C12N15/861

CPC分类号： C12N15/86 ,  C07K14/005 ,  C07K14/505 ,  C12N7/00 ,  C12N2710/10343 ,  C12N2760/16122

摘要： Described is a method for producing a protein of interest, the method comprising: a) providing a recombinant adenoviral vector comprising nucleic acid encoding the protein of interest under control of a promoter, wherein the adenoviral vector has deletions in a first region and in a second region of the adenovirus genome, wherein each of the first region and the second region is required for adenoviral genome replication and/or adenovirus particle formation, b) propagating the adenoviral vector in a first type of complementing cells that express proteins from the first and from the second region of the adenovirus genome so as to complement the deletions of the recombinant adenoviral vector, to obtain recombinant adenovirus particles, c) infecting a culture of a second type of complementing cells with the recombinant adenovirus particles, wherein the second type of complementing cells express protein from the first region of the adenovirus genome but not protein from the second region of the adenovirus genome, to produce the protein of interest, and d) harvesting the protein of interest.

摘要翻译： 描述了用于产生目的蛋白质的方法，所述方法包括：a）提供重组腺病毒载体，所述重组腺病毒载体包含编码在启动子控制下的感兴趣蛋白质的核酸，其中所述腺病毒载体在第一区域和第二区域中具有缺失 腺病毒基因组的区域，其中腺病毒基因组复制和/或腺病毒颗粒形成所需的第一区域和第二区域中的每一个，b）将腺病毒载体扩增到第一类型的互补细胞中，所述互补细胞从第一种和第 腺病毒基因组的第二区域，以补充重组腺病毒载体的缺失，以获得重组腺病毒颗粒，c）用重组腺病毒颗粒感染第二种补体细胞的培养物，其中第二种类型的补体细胞 从腺病毒基因组的第一区域表达蛋白质，但不表示来自第二区域的蛋白质 f产生感兴趣的蛋白质，以及d）收获感兴趣的蛋白质。

公开(公告)号：US08221971B2

公开(公告)日：2012-07-17

申请号：US11980222

申请日：2007-10-29

申请人： Abraham Bout ,  Menzo Jans Emco Havenga ,  Ronald Vogels

发明人： Abraham Bout ,  Menzo Jans Emco Havenga ,  Ronald Vogels

IPC分类号： C12Q3/00 ,  C12Q1/70 ,  C12N15/00 ,  C12N15/01 ,  C12N15/09 ,  C12N7/00

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。

公开(公告)号：US06905678B2

公开(公告)日：2005-06-14

申请号：US10010645

申请日：2001-11-13

申请人： Menzo Jans Emco Havenga ,  Abraham Bout ,  Ronald Vogels

发明人： Menzo Jans Emco Havenga ,  Abraham Bout ,  Ronald Vogels

IPC分类号： C12N15/09 ,  A01N63/00 ,  A61K35/28 ,  A61K35/76 ,  A61K39/235 ,  A61K48/00 ,  A61P9/00 ,  A61P19/02 ,  A61P19/08 ,  A61P25/00 ,  C12N5/00 ,  C12N5/08 ,  C12N5/10 ,  C12N7/00 ,  C12N15/00 ,  C12N15/63 ,  C12N15/86 ,  C12N15/861 ,  C12N21/06

CPC分类号： C12N15/86 ,  A61K48/00 ,  C12N2710/10343

摘要： Methods and associated materials for transducing mesenchymal stem cells with a desired nucleic acid. Mesenchymal stem cells are a recently discovered kind of stem cell for which suitable transfer vehicles are still desired. Typical gene delivery vehicles such as the adenoviruses or adeno associated viruses have no particular tropism for mesenchymal stem cells. Also disclosed is gene therapy using adenoviruses provided with tropism for mesenchymal stem cells.

摘要翻译： 用所需核酸转导间充质干细胞的方法和相关材料。 间充质干细胞是最近发现的干细胞，其中仍然需要合适的转运载体。 典型的基因递送载体如腺病毒或腺相关病毒对间充质干细胞没有特异性的向性。 还公开了使用提供间质干细胞向性的腺病毒的基因治疗。

公开(公告)号：US06803234B2

公开(公告)日：2004-10-12

申请号：US09928262

申请日：2001-08-10

申请人： Menzo Havenga ,  Ronald Vogels ,  Abraham Bout

发明人： Menzo Havenga ,  Ronald Vogels ,  Abraham Bout

IPC分类号： C12N1586

CPC分类号： C12N15/86 ,  A61K48/00 ,  C12N2710/10322 ,  C12N2710/10343 ,  C12N2710/10345 ,  C12N2810/6018

摘要： The present invention relates to a gene delivery vehicle comprising a recombinant adenovirus having a tropism for a primary human chondrocyte. By efficiently transducing a nucleic acid of interest into a primary chondrocytes, the gene delivery vehicle is able to at least in part improve the counteraction of cartilage disease. In one embodiment the recombinant adenovirus comprises a deletion in the gene encoding for fiber protein, which is replaced by a nucleic acid sequence encoding at least part of a fiber protein of a B-type adenovirus.

摘要翻译： 本发明涉及包含对于初级人软骨细胞具有向性的重组腺病毒的基因递送载体。 通过将感兴趣的核酸有效地转导到原代软骨细胞中，基因递送载体能够至少部分地改善软骨疾病的反作用。 在一个实施方案中，重组腺病毒在编码纤维蛋白的基因中包含缺失，其被编码B型腺病毒的纤维蛋白的至少一部分的核酸序列替代。