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1. 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.

2. 发明授权

US06348450B1 Noninvasive genetic immunization, expression products therefrom and uses thereof 有权
标题翻译：无创遗传免疫，其表达产物及其用途
公开(公告)号：US06348450B1
公开(公告)日：2002-02-19
申请号：US09563826
申请日：2000-05-03
申请人： De-chu C. Tang , Donald H. Marks , David T. Curiel , Zhongkai Shi , Kent Rigby van Kampen
发明人： De-chu C. Tang , Donald H. Marks , David T. Curiel , Zhongkai Shi , Kent Rigby van Kampen
IPC分类号： A61K4800
CPC分类号： A61K39/08 , A61K39/00 , A61K39/0011 , A61K39/12 , A61K39/145 , A61K48/00 , A61K2039/53 , A61K2039/54 , A61K2039/541 , A61K2039/542 , A61K2039/543 , A61K2039/55555 , A61K2039/60 , C12N2710/10343 , C12N2760/16134
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, tetanus toxin C-fragment, anthrax protective antigen, HIV gp 120, human carcinoembryonic antigen, 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 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.
摘要翻译：公开和要求的是在动物中非侵入性遗传免疫的方法和/或在动物中诱导全身性免疫或治疗反应的方法，其产品及其用途。所述方法可以包括使动物的皮肤与有效诱导动物体内免疫或治疗反应的量的载体接触。载体可以包括并表达编码感兴趣的表位或基因产物的外源核酸分子。全身免疫应答可以来自表位或基因产物。核酸分子可以编码感兴趣的表位和/或感兴趣的抗原和/或刺激和/或调节免疫应答和/或刺激和/或调节表达的核酸分子，例如转录和/或翻译，例如内源和/或外源核酸分子的转录和/或翻译; 例如流感血凝素，流感核蛋白，破伤风毒素C片段，炭疽保护性抗原，HIV gp120，人癌胚抗原和/或治疗性免疫调节基因中的一种或多种，例如共刺激基因和/或细胞因子基因。可以通过在动物细胞中表达核酸分子的载体诱导免疫应答。免疫应答可以针对病原体或肿瘤。预防性疫苗或治疗性疫苗或免疫组合物可以包括载体。

3. 发明授权

US06706693B1 Vaccination by topical application of genetic vectors 有权
标题翻译：通过局部应用遗传载体接种疫苗
公开(公告)号：US06706693B1
公开(公告)日：2004-03-16
申请号：US09402527
申请日：2000-01-03
申请人： De-chu Tang , Donald H. Marks , David T. Curiel , Zhongkai Shi
发明人： De-chu Tang , Donald H. Marks , David T. Curiel , Zhongkai Shi
IPC分类号： A61K4800
CPC分类号： A61K39/0011 , A61K39/00 , A61K2039/54 , A61K2039/55516 , A61K2039/55522 , A61K2039/55555 , A61K2039/57 , C12N2799/02 , C12N2799/022
摘要： The present invention provides a method of inducing an immune response in a non-invasive mode, comprising the step of: contacting skin of an individual in need of such treatment topically by applying to said skin an immunologically effective concentration of a genetic vector encoding a gene of interest. Also provided is a method of inducing an anti-tumor immune response in an animal in need of such treatment, comprising the step of: contacting skin of said animal topically by applying to said skin an immunologically effective concentration of a vector encoding a gene which encodes an antigen which induces an anti-tumor effect in said animal following administration. The genetic vector may include adenovirus recombinants, DNA/adenovirus complexes, DNA/liposome complexes, or any other vectors capable of expressing transgenes. Topical application of geneticvectors may preferably include a device as designed therein.
摘要翻译：本发明提供以非侵入性模式诱导免疫应答的方法，其包括以下步骤：通过向所述皮肤施用免疫有效浓度的编码基因的遗传载体，接触需要这种治疗的个体的皮肤，出于兴趣。还提供了在需要这种治疗的动物中诱导抗肿瘤免疫应答的方法，包括以下步骤：通过向所述皮肤施用免疫有效浓度的编码编码的基因的载体来局部接触所述动物的皮肤在给药后在所述动物中诱导抗肿瘤作用的抗原。遗传载体可以包括腺病毒重组体，DNA /腺病毒复合物，DNA /脂质体复合物或能够表达转基因的任何其他载体。遗传医生的局部应用可以优选地包括其中设计的装置。

4. 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。

5. 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。

6. 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。

7. 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。

8. 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。

9. 发明授权

US06210946B1 Modified adenovirus containing a fiber replacement protein 有权
标题翻译：含有纤维替代蛋白的修饰型腺病毒
公开(公告)号：US06210946B1
公开(公告)日：2001-04-03
申请号：US09250580
申请日：1999-02-16
申请人： David T. Curiel , Victor N. Krasnykh
发明人： David T. Curiel , Victor N. Krasnykh
IPC分类号： C12N1500
CPC分类号： C12N15/86 , A61K35/761 , A61K38/45 , A61K48/00 , C12N7/00 , C12N2710/10321 , C12N2710/10332 , C12N2710/10343 , C12N2710/10345 , C12N2810/40 , C12N2810/60 , C12N2810/80 , C12N2810/859 , A61K2300/00
摘要： The present invention provides means to modify the tropism of recombinant adenoviral vectors using genetic methods to alter the adenoviral fiber cell-binding protein while maintaining the native trimeric protein biosynthesis profile. The present invention further provides means to specifically target particular cell types for infection with recombinant adenoviral vectors using genetic methods to alter the adenoviral fiber cell-binding protein.
摘要翻译：本发明提供了使用遗传方法修饰重组腺病毒载体向性来改变腺病毒纤维细胞结合蛋白同时保持天然三聚体蛋白质生物合成特征的方法。本发明还提供了使用遗传方法来改变腺病毒纤维细胞结合蛋白质来特异性靶向用重组腺病毒载体感染的特定细胞类型的方法。

10. 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。

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