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1. 发明授权

US06475756B1 Development of viruses resistant to inactivation by the human complement system 失效
标题翻译：开发抗人类补体系统灭活的病毒
公开(公告)号：US06475756B1
公开(公告)日：2002-11-05
申请号：US09554838
申请日：2000-07-21
申请人： Dagmar Wirth , Dirk Spitzer , Hansjoerg Hauser
发明人： Dagmar Wirth , Dirk Spitzer , Hansjoerg Hauser
IPC分类号： C12P2104
CPC分类号： C07K14/005 , A61K48/00 , C07K14/70596 , C07K2319/00 , C12N15/86 , C12N2740/13022 , C12N2740/13043 , C12N2740/13045 , C12N2740/13052 , C12N2810/60 , C12N2810/855
摘要： Murine retroviruses are the most important transfer systems for human gene therapy. However, their application is currently limited. One of the major restrictions both for an application in vivo resides in the problem that this virus type is sensitive to inactivation by human complement factors. Our invention overcomes this limitation. We have modified murine recombinant retroviruses in a way that they are resistant to human complement factors. This was achieved by genetic modification of the retroviral surface protein env which is responsible for receptor interaction: the receptor interacting domain of env was fused to catalytically active domains of human complement inactivation factors. These modified env were expressed in complement-sensitive cells and specifically integrated into virus particles. By this strategy cells and viruses are generated that are fully resistant to complement attack. Thus, this strategy provides a tool for establishment of complement resistant cells and generation of viruses for in vivo gene therapy.
摘要翻译：鼠逆转录病毒是人类基因治疗最重要的转移系统。但是，它们的应用目前是有限的。在体内应用的主要限制之一在于这种病毒类型对人补体因子的失活敏感的问题。我们的发明克服了这个限制。我们已经修改了鼠重组逆转录病毒，使其具有抗人补体因子的作用。这是通过负责受体相互作用的逆转录病毒表面蛋白env的遗传修饰实现的：env的受体相互作用结构域融合到人补体失活因子的催化活性结构域。这些修饰的env在补体敏感细胞中表达并且特异性整合到病毒颗粒中。通过这种策略，产生完全抵抗补体攻击的细胞和病毒。因此，该策略提供了建立补体抗性细胞和产生用于体内基因治疗的病毒的工具。

2. 发明授权

US08461311B2 TRAIL trimers, methods and uses therefor 有权
标题翻译： TRAIL三聚体，方法和用途
公开(公告)号：US08461311B2
公开(公告)日：2013-06-11
申请号：US13155577
申请日：2011-06-08
申请人： William G. Hawkins , Dirk Spitzer , Richard S. Hotchkiss
发明人： William G. Hawkins , Dirk Spitzer , Richard S. Hotchkiss
IPC分类号： C07K14/52 , C07K14/47 , C07K16/46
CPC分类号： C07K14/4747 , C07K14/52
摘要： Disclosed are TNF-related apoptosis-inducing ligand (TRAIL) trimers (TR3) and nucleic acids encoding covalently linked TRAIL trimers. A TRAIL trimer can have greater stability compared to native TRAIL, and can retain the native killing ability of TRAIL. Target specificity of a TR3 can be shown by blocking its activity with soluble death receptor 5 (DR5-Fc). Also disclosed are modified TRAIL trimers and nucleic. acids encoding them. These modifications include additional functional domains, such as antibody fragments (scFvs). A TR3 comprising an additional functional domain can allow for cell-specific delivery of the TR3. The inventors disclose TR3-decorated RBCs that target cell killing in a model of pancreatic cancer.
摘要翻译：公开了TNF相关凋亡诱导配体（TRAIL）三聚体（TR3）和编码共价连接的TRAIL三聚体的核酸。与天然TRAIL相比，TRAIL三聚体可以具有更高的稳定性，并且可以保留TRAIL的天然杀伤能力。可通过用可溶性死亡受体5（DR5-Fc）阻断其活性来显示TR3的靶特异性。还公开了修饰的TRAIL三聚体和核酸。编码它们的酸。这些修饰包括额外的功能域，例如抗体片段（scFv）。包含附加功能域的TR3可以允许TR3的细胞特异性递送。本发明人公开了在胰腺癌模型中靶向细胞杀伤的TR3装饰的RBC。

3. 发明授权

US10072061B2 Tumor targeted TNF-related apoptosis inducing ligand fusion polypeptide, methods and uses therefor 有权
公开(公告)号：US10072061B2
公开(公告)日：2018-09-11
申请号：US15730441
申请日：2017-10-11
申请人： Dirk Spitzer , William G Hawkins
发明人： Dirk Spitzer , William G Hawkins
IPC分类号： C07K14/52 , C07K14/525 , A61K38/16 , A61K38/17 , A61K38/19 , C07K14/705 , C07K14/47 , C12N15/63 , C12N15/62 , C12N15/79 , C12N15/70 , C12N15/74 , A61K38/00
CPC分类号： C07K14/705 , A61K38/00 , A61K38/17 , A61K38/1761 , A61K38/1764 , A61K38/177 , A61K38/191 , A61K39/0001 , C07K14/4747 , C07K14/4748 , C07K14/525 , C07K14/70575 , C07K2319/00 , C07K2319/21 , C07K2319/33 , C07K2319/43 , C07K2319/74 , C12N15/62 , C12N15/63 , C12N15/70 , C12N15/74 , C12N15/79
摘要： Fusion polypeptides comprising a TRAIL trimer and a targeting domain are disclosed. The targeting domain can be, in some embodiments, a sequence that binds MUC16, which is prevalent on some tumor cells such as pancreatic and ovarian tumor cells. A sequence that binds MUC 16 can be mesothelin or a MUC16-binding fragment thereof, such as amino acids 1-64 of mesothelin. A fusion polypeptide of the present teachings can induce apoptosis in a target cell such as a MUC16-expressing cancer cell. Also disclosed are nucleic acids encoding the fusion polypeptides, and methods of use of the fusion polypeptides and nucleic acids.

4. 发明申请

US20180030109A1 TUMOR TARGETED TNF-RELATED APOPTOSIS INDUCING LIGAND FUSION POLYPEPTIDE, METHODS AND USES THEREFOR 审中-公开
公开(公告)号：US20180030109A1
公开(公告)日：2018-02-01
申请号：US15730441
申请日：2017-10-11
申请人： Dirk Spitzer , William G Hawkins
发明人： Dirk Spitzer , William G Hawkins
IPC分类号： C07K14/705 , C12N15/63 , C07K14/47 , C12N15/62 , A61K38/17 , C12N15/74 , A61K38/19 , C12N15/70 , A61K38/00 , C12N15/79 , C07K14/525
CPC分类号： C07K14/705 , A61K38/00 , A61K38/17 , A61K38/1761 , A61K38/1764 , A61K38/177 , A61K38/191 , C07K14/4747 , C07K14/4748 , C07K14/525 , C07K14/70575 , C07K2319/00 , C07K2319/21 , C07K2319/33 , C07K2319/43 , C07K2319/74 , C12N15/62 , C12N15/63 , C12N15/70 , C12N15/74 , C12N15/79
摘要： Fusion polypeptides comprising a TRAIL trimer and a targeting domain are disclosed. The targeting domain can be, in some embodiments, a sequence that binds MUC16, which is prevalent on some tumor cells such as pancreatic and ovarian tumor cells. A sequence that binds MUC 16 can be mesothelin or a MUC16-binding fragment thereof, such as amino acids 1-64 of mesothelin. A fusion polypeptide of the present teachings can induce apoptosis in a target cell such as a MUC16-expressing cancer cell. Also disclosed are nucleic acids encoding the fusion polypeptides, and methods of use of the fusion polypeptides and nucleic acids.

5. 发明申请

US20130302270A1 TUMOR TARGETED TNF-RELATED APOPTOSIS INDUCING LIGAND FUSION POLYPEPTIDE, METHODS AND USES THEREFOR 有权
标题翻译：肿瘤靶向性TNF相关性炎症诱导配体融合多肽，其方法及其用途
公开(公告)号：US20130302270A1
公开(公告)日：2013-11-14
申请号：US13892238
申请日：2013-05-10
申请人： Dirk Spitzer , William G. Hawkins
发明人： Dirk Spitzer , William G. Hawkins
IPC分类号： C07K14/47
CPC分类号： C07K14/705 , A61K38/00 , A61K38/17 , A61K38/1761 , A61K38/1764 , A61K38/177 , A61K38/191 , C07K14/4747 , C07K14/4748 , C07K14/525 , C07K14/70575 , C07K2319/00 , C07K2319/21 , C07K2319/33 , C07K2319/43 , C07K2319/74 , C12N15/62 , C12N15/63 , C12N15/70 , C12N15/74 , C12N15/79
摘要： Fusion polypeptides comprising a TRAIL trimer and a targeting domain are disclosed. The targeting domain can be, in some embodiments, a sequence that binds MUC16, which is prevalent on some tumor cells such as pancreatic and ovarian tumor cells. A sequence that binds MUC 16 can be mesothelin or a MUC16-binding fragment thereof, such as amino acids 1-64 of mesothelin. A fusion polypeptide of the present teachings can induce apoptosis in a target cell such as a MUC16-expressing cancer cell. Also disclosed are nucleic acids encoding the fusion polypeptides, and methods of use of the fusion polypeptides and nucleic acids.
摘要翻译：公开了包含TRAIL三聚体和靶向结构域的融合多肽。在一些实施方案中，靶向结构域可以是结合MUC16的序列，其在一些肿瘤细胞如胰腺和卵巢肿瘤细胞上是普遍存在的。结合MUC16的序列可以是间皮素或其MUC16结合片段，例如间皮素的第1-64位氨基酸。本教导的融合多肽可以在靶细胞例如表达MUC16的癌细胞中诱导凋亡。还公开了编码融合多肽的核酸，以及融合多肽和核酸的使用方法。

6. 发明申请

US20110300629A1 TRAIL trimers, methods and uses therefor 有权
标题翻译： TRAIL三聚体，方法和用途
公开(公告)号：US20110300629A1
公开(公告)日：2011-12-08
申请号：US13155577
申请日：2011-06-08
申请人： William G. Hawkins , Dirk Spitzer , Richard S. Hotchkiss
发明人： William G. Hawkins , Dirk Spitzer , Richard S. Hotchkiss
IPC分类号： C12N5/09 , C07H21/00 , C07K19/00 , C12N15/63 , C07K14/52
CPC分类号： C07K14/4747 , C07K14/52
摘要： Disclosed are TNF-related apoptosis-inducing ligand (TRAIL) trimers (TR3) and nucleic acids encoding covalently linked TRAIL trimers. A TRAIL trimer can have greater stability compared to native TRAIL, and can retain the native killing ability of TRAIL. Target specificity of a TR3 can be shown by blocking its activity with soluble death receptor 5 (DR5-Fc). Also disclosed are modified TRAIL trimers and nucleic acids encoding them. These modifications include additional functional domains, such as antibody fragments (scFvs). A TR3 comprising an additional functional domain can allow for cell-specific delivery of the TR3. In some configurations, a modification such as the addition of a functional domain can be stoichiometrically controlled. In some configurations, a modification can be inconsequential with regard to the bioactivity of TRAIL. In various embodiments, a TR3, including a modified TR3, can be a cancer-selective drug. In some configurations, a TR3 that comprises an additional biologically active moiety such as a functional domain of a protein can have fewer off-target toxicities compared to TRAIL alone. In some configurations, a TR3 that comprises an additional biologically active moiety such as a functional domain of a protein can have enhanced killing capacities compared to the moiety alone. In some aspects, TR3 activity can be targeted to an RBC membrane. The inventors disclose TR3-decorated RBCs that target cell killing in a model of pancreatic cancer.
摘要翻译：公开了TNF相关凋亡诱导配体（TRAIL）三聚体（TR3）和编码共价连接的TRAIL三聚体的核酸。与天然TRAIL相比，TRAIL三聚体可以具有更高的稳定性，并且可以保留TRAIL的天然杀伤能力。可通过用可溶性死亡受体5（DR5-Fc）阻断其活性来显示TR3的靶特异性。还公开了修饰的TRAIL三聚体和编码它们的核酸。这些修饰包括额外的功能域，例如抗体片段（scFv）。包含附加功能域的TR3可以允许TR3的细胞特异性递送。在一些配置中，可以化学计量地控制诸如添加功能域的修饰。在一些配置中，关于TRAIL的生物活性，修饰可能是无关紧要的。在各种实施方案中，包括修饰的TR3的TR3可以是癌症选择性药物。在一些配置中，与单独的TRAIL相比，包含另外的生物活性部分如蛋白质的功能结构域的TR3可以具有较少的靶外毒性。在一些构型中，与单独的部分相比，包含另外的生物活性部分如蛋白质的功能结构域的TR3可以具有增强的杀伤能力。在一些方面，TR3活性可以靶向RBC膜。本发明人公开了在胰腺癌模型中靶向细胞杀伤的TR3装饰的RBC。

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