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1. 发明授权

US06468547B1 Enhancement of tumor cell chemosensitivity and radiosensitivity using single chain secretory antibodies 失效
标题翻译：使用单链分泌抗体增强肿瘤细胞化学敏感性和放射敏感性
公开(公告)号：US06468547B1
公开(公告)日：2002-10-22
申请号：US09499543
申请日：2000-02-07
申请人： Donald J. Buchsbaum , David T. Curiel , Murray Stackhouse
发明人： Donald J. Buchsbaum , David T. Curiel , Murray Stackhouse
IPC分类号： A61K3900
CPC分类号： C07K16/30 , A61K48/00 , A61K2039/505 , A61K2039/51 , C07K16/18 , C07K16/2863 , C07K16/32 , C07K16/40 , C07K2317/622 , C07K2317/73 , C12N2799/022
摘要： The present invention provides a method of enhancing the chemosensitivity and radiosensitivity of a neoplastic cell expressing an oncoprotein that stimulates proliferation of the cell, comprising introducing into the cell a nucleic acid molecule encoding an antibody homologue, wherein the antibody homologue is expressed intracellularly and binds to the oncoprotein intracellularly in the endoplasmic reticulum of the cell. The present invention is also directed to a method for enhancing the inhibition of proliferation of a neoplastic cell expressing an oncoprotein that stimulates proliferation of the cell, comprising the steps of: introducing into the cell a nucleic acid molecule encoding an antibody homologue, wherein the antibody homologue is expressed intracellularly and binds to the protein intracellularly; and contacting said cell with an anti-neoplastic agent.
摘要翻译：本发明提供增强表达刺激细胞增殖的癌蛋白的肿瘤细胞的化学敏感性和放射敏感性的方法，包括将编码抗体同系物的核酸分子导入细胞，其中抗体同系物在细胞内表达并结合胞内胞内蛋白质细胞内质网。本发明还涉及一种用于增强表达癌细胞增殖的肿瘤细胞增殖抑制的方法，所述方法包括以下步骤：将编码抗体同系物的核酸分子导入细胞，其中所述抗体同源物在细胞内表达并在细胞内结合蛋白; 并使所述细胞与抗肿瘤剂接触。

2. 发明授权

US5902583A Genetic induction of receptors for targeted radiotherapy 失效
标题翻译：用于靶向放射治疗的受体的遗传诱导
公开(公告)号：US5902583A
公开(公告)日：1999-05-11
申请号：US739826
申请日：1997-02-11
申请人： Donald J. Buchsbaum , David T. Curiel , Mohammad B. Khazaell , David Raben , Murray Stackhouse
发明人： Donald J. Buchsbaum , David T. Curiel , Mohammad B. Khazaell , David Raben , Murray Stackhouse
IPC分类号： C12N15/09 , A61K31/00 , A61K31/135 , A61K31/138 , A61K31/22 , A61K31/223 , A61K35/76 , A61K38/00 , A61K38/04 , A61K38/17 , A61K38/22 , A61K39/395 , A61K48/00 , A61K51/00 , A61K51/08 , A61K51/10 , A61M36/00 , A61P35/00 , C07K14/705 , C07K14/82 , C07K16/30 , A01N43/04
CPC分类号： A61K51/1036 , A61K38/105 , A61K38/1796 , A61K51/08 , A61K51/088 , A61K51/10 , C07K14/70503 , C07K14/82 , C07K16/3007 , A61K2123/00 , A61K38/00 , A61K48/00 , C07K2317/77
摘要： The present invention provides a method to achieve radioisotopic localization at tumor sites, i.e., a method of enhancing radiolabeled ligand localization to a tumor in an individual in need of such treatment, comprising the steps of: transducing the tumor with a gene encoding a membrane expressed protein unique to the tumor; and administering to said individual a radiolabeled ligand which specifically binds to the protein. The use of gene therapy technology to induce expression of high affinity membrane molecules/receptors can enhance the specificity of radioisotope localization while the use of radioactive isotopes with the ability to deliver radiation damage across several cell diameters will compensate for less than perfect transduction efficiency.
摘要翻译：本发明提供了一种在肿瘤部位实现放射性同位素定位的方法，即一种增强放射性标记的配体定位于需要这种治疗的个体中的肿瘤的方法，包括以下步骤：用编码膜表达的基因转导肿瘤蛋白质独特的肿瘤; 并向所述个体施用特异性结合蛋白质的放射性标记的配体。使用基因治疗技术诱导高亲和力膜分子/受体的表达可以增强放射性同位素定位的特异性，而使用具有在几个细胞直径上传递辐射损伤的能力的放射性同位素将补偿不到完美的转导效率。

3. 发明授权

US6074640A Enhancement of tumor cell radiosensitivity using single chain intracellular antibodies 失效
标题翻译：使用单链细胞内抗体增强肿瘤细胞放射敏感性
公开(公告)号：US6074640A
公开(公告)日：2000-06-13
申请号：US961327
申请日：1997-10-30
申请人： David T. Curiel , Murray Stackhouse , Donald J. Buchsbaum
发明人： David T. Curiel , Murray Stackhouse , Donald J. Buchsbaum
IPC分类号： A61K48/00 , A61P35/00 , C07K16/18 , C07K16/30 , C07K16/32 , A61K39/395 , C07H21/04
CPC分类号： C07K16/32 , C07K16/18 , C07K16/30 , A61K2039/505 , A61K48/00 , C07K2317/622 , C07K2317/73
摘要： The present invention provides a method of enhancing the chemosensitivity and radiosensitivity of a neoplastic cell expressing an oncoprotein that stimulates proliferation of the cell, comprising introducing into the cell a nucleic acid molecule encoding an antibody homologue, wherein the antibody homologue is expressed intracellularly and binds to the oncoprotein intracellularly in the endoplasmic reticulum of the cell. The present invention is also directed to a method for enhancing the inhibition of proliferation of a neoplastic cell expressing an oncoprotein that stimulates proliferation of the cell, comprising the steps of: introducing into the cell a nucleic acid molecule encoding an antibody homologue, wherein the antibody homologue is expressed intracellularly and binds to the protein intracellularly; and contacting said cell with an anti-neoplastic agent.
摘要翻译：本发明提供增强表达刺激细胞增殖的癌蛋白的肿瘤细胞的化学敏感性和放射敏感性的方法，包括将编码抗体同系物的核酸分子导入细胞，其中抗体同系物在细胞内表达并结合胞内胞内蛋白质细胞内质网。本发明还涉及一种用于增强表达癌细胞增殖的肿瘤细胞增殖抑制的方法，所述方法包括以下步骤：将编码抗体同系物的核酸分子导入细胞，其中所述抗体同源物在细胞内表达并在细胞内结合蛋白; 并使所述细胞与抗肿瘤剂接触。

4. 发明授权

US5981504A Genetic induction of receptors for targeted radiotherapy 失效
标题翻译：用于靶向放射治疗的受体的遗传诱导
公开(公告)号：US5981504A
公开(公告)日：1999-11-09
申请号：US948132
申请日：1997-10-09
申请人： Donald J. Buchsbaum , David Raben , Mohammad B. Khazaeli , David T. Curiel , Murray Stackhouse
发明人： Donald J. Buchsbaum , David Raben , Mohammad B. Khazaeli , David T. Curiel , Murray Stackhouse
IPC分类号： A61K51/08 , A61K51/10 , A61P35/00 , A61K48/00
CPC分类号： A61K51/1036 , A61K51/08 , A61K51/083 , A61K51/10 , A61K2123/00
摘要： The present invention provides a method to achieve radioisotopic localization at tumor sites, i.e., a method of enhancing radiolabeled ligand localization to a tumor in an individual in need of such treatment, comprising the steps of: transducing said tumor with a gene encoding a membrane expressed protein unique to said tumor; and administering to said individual a radiolabeled ligand which specifically binds to said protein. The use of gene therapy technology to induce expression of high affinity membrane molecules/receptors can enhance the specificity of radioisotope localization while the use of radioactive isotopes with the ability to deliver radiation damage across several cell diameters will compensate for less than perfect transduction efficiency.
摘要翻译：本发明提供了一种在肿瘤部位实现放射性同位素定位的方法，即在需要这种治疗的个体中增强对肿瘤的放射性标记配体定位的方法，包括以下步骤：用编码膜表达的基因转导所述肿瘤所述肿瘤独特的蛋白质; 并向所述个体施用特异性结合所述蛋白质的放射性标记的配体。使用基因治疗技术诱导高亲和力膜分子/受体的表达可以增强放射性同位素定位的特异性，而使用具有在几个细胞直径上传递辐射损伤的能力的放射性同位素将补偿不到完美的转导效率。

5. 发明授权

US06599909B1 Molecular chemotherapy enhancement of radiotherapy 失效
标题翻译：分子化疗放疗增强
公开(公告)号：US06599909B1
公开(公告)日：2003-07-29
申请号：US09408055
申请日：1999-09-29
申请人： Donald J. Buchsbaum , David T. Curiel , Murray A. Stackhouse , Lee C. Pederson
发明人： Donald J. Buchsbaum , David T. Curiel , Murray A. Stackhouse , Lee C. Pederson
IPC分类号： A61K31505
CPC分类号： C12N15/86 , A61K38/45 , A61K38/50 , A61K41/00 , A61K48/00 , C12N2710/10343 , C12N2810/859 , Y02A50/473
摘要： The present invention provides a new approach for cancer treatment by utilizing gene therapy combined with radiation therapy to enhance cytotoxicity in malignant cells. Specifically, the present invention demonstrates that molecular chemotherapy with the cytosine deaminase gene and 5-fluorocytosine is an effective radiosensitizing strategy which may lead to substantial improvement in tumor control, with less normal tissue toxicity than conventional systemic administration of 5-fluorouracil, that would translate into improved cure rates and better survival. Also provided is a noninvasive method for continuous in vivo monitoring of 5-fluorouracil production via magnetic resonance spectroscopy.
摘要翻译：本发明通过利用与放射治疗相结合的基因治疗来增强恶性细胞中的细胞毒性提供了一种新的癌症治疗方法。具体来说，本发明表明，具有胞嘧啶脱氨酶基因和5-氟胞嘧啶的分子化学疗法是一种有效的放射增敏策略，其可以导致肿瘤控制的显着改善，具有比常规全身施用5-氟尿嘧啶更少的正常组织毒性，这将翻译改善治愈率和更好的生存。还提供了一种用于通过磁共振光谱法连续体内监测5-氟尿嘧啶生产的非侵入性方法。

6. 发明授权

US06613563B1 Viral vectors with modified tropism 失效
标题翻译：具有改良趋向性的病毒载体
公开(公告)号：US06613563B1
公开(公告)日：2003-09-02
申请号：US09039060
申请日：1998-03-13
申请人： Barbara A. Sosnowski , Andrew Baird , Glenn F. Pierce , David T. Curiel , Joanne T. Douglas , Buck E. Rogers
发明人： Barbara A. Sosnowski , Andrew Baird , Glenn F. Pierce , David T. Curiel , Joanne T. Douglas , Buck E. Rogers
IPC分类号： C12N1500
CPC分类号： C12N15/86 , A61K48/00 , C07K14/50 , C07K16/081 , C07K2317/74 , C12N2710/10343 , C12N2710/10345 , C12N2810/851 , C12N2810/859
摘要： The present invention relates to gene therapy. In particular, therapeutic agents, therapeutic gene products, and compositions are disclosed. Various systems and methods useful in targeting and delivering non-native nucleotide sequences to specific cells are disclosed, wherein virus-antibody-ligand conjugates are used to facilitate targeting and delivery.
摘要翻译：本发明涉及基因治疗。特别地，公开了治疗剂，治疗基因产物和组合物。公开了用于将非天然核苷酸序列靶向和递送至特定细胞的各种系统和方法，其中使用病毒 - 抗体 - 配体缀合物来促进靶向和递送。

7. 发明授权

US5521291A Conjugates for introducing nucleic acid into higher eucaryotic cells 失效
标题翻译：用于将核酸引入高级真核细胞的缀合物
公开(公告)号：US5521291A
公开(公告)日：1996-05-28
申请号：US166899
申请日：1993-12-15
申请人： David T. Curiel , Ping-chuan Hu , Max L. Birnstiel , Matthew Cotten , Ernst Wagner
发明人： David T. Curiel , Ping-chuan Hu , Max L. Birnstiel , Matthew Cotten , Ernst Wagner
IPC分类号： A61K47/48 , C07K16/08 , C12N15/87 , A61K39/42 , C07H19/00 , C12N7/00
CPC分类号： C12N15/87 , A61K47/48692 , A61K47/48776 , C07K16/081
摘要： Conjugates in which a virus is bound via an antibody to a substance having an affinity for nucleic acid, for transporting gene constructs into higher eucaryotic cells. Complexes of the conjugates and nucleic acid are internalized in the cell, whilst the virus as part of the complex brings about the internalization and the release of the contents of the endosomes, in which the complexes are located after entering the cell. Pharmaceutical preparations in which the nucleic acid is a therapeutically active gene construct, particularly for use in gene therapy.
摘要翻译：通过抗体将病毒结合到对核酸具有亲和性的物质，用于将基因构建体转运到较高真核细胞中的缀合物。缀合物和核酸的复合物被内化在细胞中，而作为复合物的一部分的病毒导致内含体的内化和释放，其中复合物在进入细胞后位于其中。其中核酸是治疗活性基因构建体，特别是用于基因治疗的药物制剂。

8. 发明授权

US06824771B1 Infectivity-enhanced conditionally-replicative adenovirus and uses thereof 有权
标题翻译：感染性增强的条件复制型腺病毒及其用途
公开(公告)号：US06824771B1
公开(公告)日：2004-11-30
申请号：US09569789
申请日：2000-05-12
申请人： David T. Curiel , Victor Krasnykh , Ramon Alemany , Igor Dmitriev
发明人： David T. Curiel , Victor Krasnykh , Ramon Alemany , Igor Dmitriev
IPC分类号： A61K3576
CPC分类号： C12N15/86 , A61K31/522 , A61K31/70 , A61K31/7076 , A61K35/761 , A61K38/45 , A61K45/06 , A61K48/00 , A61K48/0058 , A61K2300/00 , C12N7/00 , C12N2710/10332 , C12N2710/10343 , C12N2710/10345 , C12N2810/40 , C12N2810/405 , C12N2810/6018 , C12N2810/851 , C12N2810/859 , C12N2830/008
摘要： A modified adenovirus capable of overcoming the problem of low level of coxsackle-adenovirus receptor (CAR) expression on tumor cells and methods of using such adenovirus are provided. The fiber protein of the adenovirus is modified by insertion or replacement so as to target the adenovirus to tumor cells, and the replication of the modified adenovirus is limited to tumor cells due to mutations in E1a or E1b genes.
摘要翻译：提供能够克服肿瘤细胞上的柯萨奇 - 腺病毒受体（CAR）表达低水平的问题的修饰的腺病毒和使用这种腺病毒的方法。通过插入或替换来修饰腺病毒的纤维蛋白，以将腺病毒靶向肿瘤细胞，由于E1a或E1b基因突变，修饰的腺病毒的复制受到肿瘤细胞的限制。

9. 发明授权

US06716823B1 Noninvasive genetic immunization, expression products therefrom, and uses thereof 有权
公开(公告)号：US06716823B1
公开(公告)日：2004-04-06
申请号：US09533149
申请日：2000-03-23
申请人： De-chu C. Tang , Donald H. Marks , David T. Curiel , Zhongkai Shi
发明人： De-chu C. Tang , Donald H. Marks , David T. Curiel , Zhongkai Shi
IPC分类号： A61K3170
CPC分类号： A61K39/00 , A61K39/0011 , A61K39/08 , A61K39/12 , A61K39/145 , A61K48/00 , A61K2039/53 , A61K2039/54 , A61K2039/541 , A61K2039/542 , A61K2039/543 , A61K2039/55522 , A61K2039/55555 , A61K2039/60 , C12N2710/10043 , C12N2760/16134 , C12N2760/16171
摘要： Disclosed and claimed are methods of non-invasive genetic immunization in an animal and/or methods of inducing a systemic immune or therapeutic response in an animal, products therefrom and uses for the methods and products therefrom. The methods can include contacting skin of the animal with a vector in an amount effective to induce the systemic immune or therapeutic response in the animal. The vector can include and express an exogenous nucleic acid molecule encoding an epitope or gene product of interest. The systemic immune response can be to or from the epitope or gene product. The nucleic acid molecule can encode an epitope of interest and/or an antigen of interest and/or a nucleic acid molecule that stimulates and/or modulates an immunological response and/or stimulates and/or modulates expression, e.g., transcription and/or translation, such as transcription and/or translation of an endogenous and/or exogenous nucleic acid molecule; e.g., one or more of influenza hemagglutinin, influenza nuclear protein, influenza M2, tetanus toxin C-fragment, anthrax protective antigen, anthrax lethal factor, rabies glycoprotein, HBV surface antigen, HIV gp 120, HIV gp 160, human carcinoembryonic antigen, malaria CSP, malaria SSP, malaria MSP, malaria pfg, and mycobacterium tuberculosis HSP; and/or a therapeutic, an immunomodulatory gene, such as co-stimulatory gene and/or a cytokine gene. The immune response can be induced by the vector expressing the nucleic acid molecule in the animal's cells. The animal's cells can be epidermal cells. The immune response can be against a pathogen or a neoplasm. A prophylactic vaccine or a therapeutic vaccine or an immunological composition can include the vector. The animal can be a vertebrate, e.g., a mammal, such as human, a cow, a horse, a dog, a cat, a goat, a sheep or a pig; or fowl such as turkey, chicken or duck. The vector can be one or more of a viral vector, including viral coat, e.g., with some or all viral genes deleted therefrom, bacterial, protozoan, transposon, retrotransposon, and DNA vector, e.g., a recombinant vector; for instance, an adenovirus, such as an adenovirus defective in its E1 and/or E3 and/or E4 region(s). The method can encompass applying a delivery device including the vector to the skin of the animal, as well as such a method further including disposing the vector in and/or on the delivery device. The vector can have all viral genes deleted therefrom. The vector can induce a therapeutic and/or an anti-tumor effect in the animal, e.g., by expressing an oncogene, a tumor-suppressor gene, or a tumor-associated gene. Immunological products generated by the expression, e.g., antibodies, cells from the methods, and the expression products, are likewise useful in in vitro and ex vivo applications, and such immunological and expression products and cells and applications are disclosed and claimed. Methods for expressing a gene product in vivo and products therefor and therefrom including mucosal and/or intranasal administration of an adenovirus, advantageously an E1 and/or E3 and/or E4 defective or deleted adenovirus, such as a human adenovirus or canine adenovirus, are also disclosed and claimed.

10. 发明授权

US06689605B1 Controlling immune response to specific antigens 失效
标题翻译：控制对特定抗原的免疫应答
公开(公告)号：US06689605B1
公开(公告)日：2004-02-10
申请号：US09424281
申请日：2000-01-02
申请人： John D. Mountz , David T. Curiel , Huang-Ge Zhang
发明人： John D. Mountz , David T. Curiel , Huang-Ge Zhang
IPC分类号： C12N1563
CPC分类号： C07K14/70575 , A61K48/00 , A61K48/005 , A61K2039/5154 , C12N2799/022
摘要： One major problem with adenovirus gene therapy has been the T-cell mediated immune response elicited by inoculation of adenovirus, which leads to rapid clearance of the virus and loss of transgene expression. In the instant invention, the immune response to a virus is prevented by pre-treatment with adenovirus, adenoassociated virus or herpes virus infected antigen-presenting cell (APC) expressing Fas ligand with induced T-cell tolerance. Administration of AdCMVLacZ after tolerance resulted in prolonged expression of LacZ in tolerized animals compared to control treated animals. In control, but not tolerized animals, there was proliferation of CD3+ T-cell in the spleen in response to AdCMVLacZ treatment. Tolerance induction is also indicated by decreased production of interferon-&ggr; and IL-2 by peripheral T-cells isolated from treated animals after stimulation with the adenovirus infected APCs. T-cell tolerance is specific for the virus as the T-cell responses to an irrelative virus, mouse cytomegalovirus (MCMV) remained unimpaired. The instant invention utilizes virus specific T-cell tolerance, which is induced by APCs that co-express Fas ligand and virus antigens. The instant invention involves novel vectors and methods to induce tolerance to a viral vector gene therapy and prolong expression of a transgene in a viral host.
摘要翻译：腺病毒基因治疗的一个主要问题是通过接种腺病毒引起的T细胞介导的免疫应答，这导致病毒的快速清除和转基因表达的丧失。在本发明中，通过用表达具有诱导的T细胞耐受性的Fas配体的腺病毒，腺相关病毒或疱疹病毒感染的抗原呈递细胞（APC）预处理来防止对病毒的免疫应答。 ADMVLacZ的耐受性导致与对照处理的动物相比，耐受性动物中LacZ的表达延长。在控制但不能耐受的动物中，响应于AdCMVLacZ处理，脾脏中CD3 + T细胞增殖。通过用腺病毒感染的APC刺激后从处理的动物分离的外周T细胞的干扰素-γ和IL-2的产生减少也表示耐受性诱导。 T细胞耐受性对于病毒是特异性的，因为T细胞对不相关病毒的反应，小鼠巨细胞病毒（MCMV）保持不受损害。本发明利用由共表达Fas配体和病毒抗原的APC诱导的病毒特异性T细胞耐受性。本发明涉及诱导对病毒载体基因治疗的耐受并延长病毒宿主中转基因表达的新型载体和方法。

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