公开(公告)号：US07749493B2

公开(公告)日：2010-07-06

申请号：US11207626

申请日：2005-08-18

申请人： Menzo Havenga ,  Ronald Vogels ,  Abraham Bout

发明人： Menzo Havenga ,  Ronald Vogels ,  Abraham Bout

IPC分类号： A61K48/00 ,  C12N15/00 ,  C12N15/09 ,  C12N15/11 ,  C12N15/34

CPC分类号： C12N15/86 ,  C07K14/005 ,  C12N2710/10322 ,  C12N2710/10344 ,  C12N2760/20134

摘要： The present invention provides methods and vector systems for the generation of chimeric recombinant adenoviruses. These hybrid adenoviruses contain a genome that is derived from different adenovirus serotypes. In particular, novel hybrid adenoviruses are disclosed with improved properties for gene therapy purposes. These properties include: a decreased sensitivity towards neutralizing antibodies, a modified host range, a change in the titer to which adenovirus can be grown, the ability to escape trapping in the liver upon in vivo systemic delivery, and absence or decreased infection of antigen presenting cells (APC) of the immune system, such as macrophages or dendritic cells. These chimeric adenoviruses thus represent improved tools for gene therapy and vaccination since they overcome the limitations observed with the currently used serotype subgroup C adenoviruses.

摘要翻译： 本发明提供用于产生嵌合重组腺病毒的方法和载体系统。 这些杂合腺病毒含有衍生自不同腺病毒血清型的基因组。 特别地，公开了具有改进的用于基因治疗目的的性质的新型杂合腺病毒。 这些性质包括：对中和抗体的降低的敏感性，修饰的宿主范围，可以生长腺病毒的滴度的变化，在体内全身递送时逃避捕获在肝脏中的能力，以及抗原呈递的不存在或减少的感染 免疫系统的细胞（APC），例如巨噬细胞或树突状细胞。 因此，这些嵌合腺病毒代表了用于基因治疗和疫苗接种的改进工具，因为它们克服了目前使用的血清型亚型C腺病毒所观察到的限制。

公开(公告)号：US20080171018A1

公开(公告)日：2008-07-17

申请号：US11980222

申请日：2007-10-29

申请人： Abraham Bout ,  Menzo Havenga ,  Ronald Vogels

发明人： Abraham Bout ,  Menzo Havenga ,  Ronald Vogels

IPC分类号： A61K48/00

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：US07250293B2

公开(公告)日：2007-07-31

申请号：US10272041

申请日：2002-10-15

申请人： Ronald Vogels ,  Menzo Havenga ,  Majid Mehtali

发明人： Ronald Vogels ,  Menzo Havenga ,  Majid Mehtali

IPC分类号： C12N5/10 ,  C12N5/08 ,  C12N15/63 ,  C12N15/861 ,  C12N15/87 ,  A61K48/00

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 transformed by adenovirus E1 sequences either operatively linked on one or two DNA molecules, the sequences operatively linked to regulatory sequences enabling transcription and translation of encoded proteins. Also, a cell line derived from PER.C6 that expresses functional Ad35-E1B sequences. The Ad35-E1B sequences are driven by the E1B promoter and terminated by a heterologous poly-adenylation signal. The new cell lines are useful for producing recombinant adenoviruses. The cell lines can be used to produce human recombinant therapeutic proteins such as human antibodies. In addition, the cell lines are useful for producing human viruses other than adenovirus such as influenza, herpes simplex, rotavirus, and measles.

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。细胞系优选衍生自由一个或两个DNA分子可操作地连接的腺病毒E1序列转化的原代二倍体人细胞，所述序列可操作地 与能够转录和翻译编码蛋白质的调控序列相关联。 此外，衍生自PER.C6的表达功能性Ad35-E1B序列的细胞系。 Ad35-E1B序列由E1B启动子驱动并通过异源多聚腺苷酸化信号终止。 新的细胞系可用于生产重组腺病毒。 细胞系可用于产生人类重组治疗蛋白，如人抗体。 此外，细胞系可用于产生除腺病毒如流感，单纯疱疹，轮状病毒和麻疹以外的人类病毒。

公开(公告)号：US20050277194A1

公开(公告)日：2005-12-15

申请号：US11165697

申请日：2005-06-24

申请人： Ronald Vogels ,  Menzo Havenga ,  Majid Mehtali

发明人： Ronald Vogels ,  Menzo 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 that complements recombinant adenoviruses based on serotypes from subgroup B, preferably adenovirus type 35. The cell line is preferably derived from primary, diploid human cells that 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 that 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 cell lines are useful for producing recombinant adenoviruses designed for gene therapy and vaccination. The cell lines can also be used for producing human recombinant therapeutic proteins such as human growth factors and human antibodies. Also, the cell lines are useful for producing human viruses other than adenovirus such as influenza virus, herpes simplex virus, rotavirus, and measles virus.

摘要翻译： 一种包装细胞系，其基于来自亚组B，优选腺病毒35的血清型补充重组腺病毒。细胞系优选衍生自通过腺病毒E1序列转化的原代二倍体人细胞，所述腺病毒E1序列可操作地连接在一个DNA分子上或位于两个 分离的DNA分子，该序列可操作地连接到能够转录和翻译编码蛋白质的调控序列。 还公开了衍生自表达功能性Ad35 E1B序列的PER.C6的细胞系。 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。 细胞系可用于生产设计用于基因治疗和疫苗接种的重组腺病毒。 细胞系也可以用于生产人重组治疗蛋白质，例如人生长因子和人抗体。 此外，细胞系可用于生产除了腺病毒如流感病毒，单纯疱疹病毒，轮状病毒和麻疹病毒之外的人类病毒。

公开(公告)号：US20050169891A1

公开(公告)日：2005-08-04

申请号：US11018669

申请日：2004-12-20

申请人： Ronald Vogels ,  Menzo Havenga ,  Abraham Bout

发明人： Ronald Vogels ,  Menzo Havenga ,  Abraham Bout

IPC分类号： A61K38/00 ,  A61K48/00 ,  C07K14/075 ,  C12N15/861

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：US20050232900A1

公开(公告)日：2005-10-20

申请号：US11140418

申请日：2005-05-27

申请人： Ronald Vogels ,  Angelique Lemckert ,  Menzo Havenga

发明人： Ronald Vogels ,  Angelique Lemckert ,  Menzo Havenga

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 ,  C12N2740/15034 ,  C12N2810/6018 ,  C12N2830/00 ,  C12N2830/003

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上有所不同。 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：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。

公开(公告)号：US07906113B2

公开(公告)日：2011-03-15

申请号：US11586316

申请日：2006-10-25

申请人： Abraham Bout ,  Menzo Havenga ,  Ronald Vogels

发明人： Abraham Bout ,  Menzo Havenga ,  Ronald Vogels

IPC分类号： A01N63/00 ,  C12N15/00 ,  C12N15/33 ,  C12N15/34

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：US20070041946A1

公开(公告)日：2007-02-22

申请号：US11586316

申请日：2006-10-25

申请人： Abraham Bout ,  Menzo Havenga ,  Ronald Vogels

发明人： Abraham Bout ,  Menzo Havenga ,  Ronald Vogels

IPC分类号： A61K48/00 ,  C12N15/861 ,  C07H21/02 ,  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：US20050201985A1

公开(公告)日：2005-09-15

申请号：US11064910

申请日：2005-02-24

申请人： Stefan Kostense ,  Olga Johanna Alberdina Elisa Ophorst ,  Menzo Havenga

发明人： Stefan Kostense ,  Olga Johanna Alberdina Elisa Ophorst ,  Menzo Havenga

IPC分类号： A61K38/57 ,  A61K39/00 ,  A61K48/00 ,  C12N5/0781 ,  C12N5/0784 ,  C12N5/22 ,  C12N15/86 ,  C12N15/861 ,  C12N5/08

CPC分类号： A61K48/00 ,  A61K38/57 ,  A61K2039/5256 ,  C12N5/0635 ,  C12N5/0639 ,  C12N15/86 ,  C12N2710/10343 ,  C12N2810/6018

摘要： The present invention provides novel methods and means for influencing the CTL-sensitivity of antigen presenting cells (such as dendritic cells) upon viral infections. The invention provides gene delivery vehicles useful in different therapeutic settings such as vaccination and/or gene therapy.

摘要翻译： 本发明提供了用于影响病毒感染时抗原呈递细胞（例如树突状细胞）的CTL敏感性的新颖方法和手段。 本发明提供了可用于不同治疗设置例如疫苗接种和/或基因治疗的基因递送载体。