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11. 发明申请

WO1994023050A1 TARGETED DELIVERY OF GENES ENCODING ANTISENSE POLYRIBONUCLEOTIDES 审中-公开
标题翻译：编码抗反义寡核苷酸的基因的定向递送
公开(公告)号：WO1994023050A1
公开(公告)日：1994-10-13
申请号：PCT/US1994003643
申请日：1994-04-04
申请人： UNIVERSITY OF CONNECTICUT , TARGETECH, INC.
发明人： UNIVERSITY OF CONNECTICUT , TARGETECH, INC. , CHIOU, Henry, C. , INNAIMO, Steven, F. , WU, George, Y.
IPC分类号： C12N15/87
CPC分类号： C12N15/1131 , A61K47/645 , A61K48/00 , C12N15/87 , C12N2310/12 , C12N2310/3513
摘要： Molecular complexes for targeting a gene encoding an antisense polyribonucleotide to a specific cell in vivo obtaining production of the polyribonucleotide within the targeted cell, and effecting specific inhibition of the expression of cellular or noncellular genes are disclosed. An expressible gene encoding a desired antisense polyribonucleotide is complexed to a conjugate of a cell-specific binding agent and a gene-binding agent. The cell-specific binding agent is specific for a cellular surface structure which mediates internalization of ligands by endocytosis. An example is the asialoglycoprotein receptor of hepatocytes. The gene-binding agent is a compound such as a polycation which stably complexes the gene under extracellular conditions and releases the gene under intracellular conditions so that it can function within a cell. The molecular complex is stable and soluble in physiological fluids and can be used in antisense gene therapy to selectively transfect cells in vivo or in vitro to provide for production of the antisense polyribonucleotide within the targeted cell, and inhibition of the expression of cellular or noncellular genes.
摘要翻译：分子复合物用于将编码反义多核糖核苷酸的基因靶向特定细胞体内获得靶向细胞内的多核糖核苷酸的产生，并且对细胞或非细胞基因的表达进行特异性抑制。编码所需反义多核糖核苷酸的可表达基因与细胞特异性结合剂和基因结合剂的缀合物复合。细胞特异性结合剂对通过内吞作用介导配体内化的细胞表面结构是特异性的。一个例子是肝细胞的脱唾液酸糖蛋白受体。基因结合剂是诸如聚阳离子的化合物，其在细胞外条件下稳定地复合基因并在细胞内条件下释放基因，使得其可以在细胞内起作用。分子复合物是稳定的并且可溶于生理液体，可用于反义基因治疗，以在体内或体外选择性转染细胞，以提供靶向细胞内反义多核糖核苷酸的产生，抑制细胞或非细胞基因的表达。

12. 发明申请

WO9220316A3 TARGETED DELIVERY OF GENES ENCODING IMMUNOGENIC PROTEINS 审中-公开
标题翻译：定点递送编码免疫原性蛋白的基因
公开(公告)号：WO9220316A3
公开(公告)日：1993-01-21
申请号：PCT/US9203875
申请日：1992-05-14
申请人： UNIV CONNECTICUT , TARGETECH INC
发明人： WU GEORGE Y , SPITALNY GEORGE L , FINDEIS MARK A
IPC分类号： A61K38/00 , A61K39/29 , A61K39/395 , A61K47/48 , A61K48/00 , C07K16/00 , C07K16/08 , C12N15/87 , C12P21/08 , A61K
CPC分类号： C12N15/87 , A61K39/12 , A61K39/292 , A61K47/645 , A61K48/00 , A61K2039/53 , A61K2039/6093 , C07K16/00 , C07K16/082 , C12N2730/10134
摘要： Molecular complexes can be used to target a gene encoding an immunogenic protein or polypeptide to a specific cell in vivo. The gene is incorporated into the target cell, expressed and the gene-encoded product is secreted and an immune response against the immunogenic protein or polypeptide is elicited. The molecular complex comprises an expressible gene encoding a desired immunogenic protein or polypeptide complexed with a carrier of a cell-specific binding agent and a gene-binding agent. The cell-specific binding agent is specific for a cellular surface structure which mediates internalization of ligands by endocytosis. An example is the asialoglycoprotein receptor of hepatocytes. The gene-binding agent is a compound such as a polycation which stably complexes the gene under extracellular conditions and releases the gene under intracellular conditions so that it can function within a cell. The molecular complex is stable and soluble in physiological fluids and can be used to elicit an immune response against a variety of immunogens in an organism for the purpose of vaccination or for the production of antibodies.

13. 发明申请

WO1995019433A3 ANTI-HEPATITIS B POLY- AND OLIGONUCLEOTIDES 审中-公开
公开(公告)号：WO1995019433A3
公开(公告)日：1995-07-20
申请号：PCT/US1995000508
申请日：1995-01-11
申请人： TARGETECH, INC.
发明人： TARGETECH, INC. , CARMICHAEL, Ellen
IPC分类号： C12N15/11

14. 发明专利

AU668870B2 Targeted delivery of genes encoding immunogenic proteins 未知
公开(公告)号：AU668870B2
公开(公告)日：1996-05-23
申请号：AU2155092
申请日：1992-05-14
申请人： UNIV CONNECTICUT , TARGETECH INC
发明人： WU GEORGE Y , SPITALNY GEORGE L , FINDEIS MARK A
IPC分类号： A61K38/00 , A61K39/29 , A61K39/395 , A61K47/48 , A61K48/00 , C07K16/00 , C07K16/08 , C12N15/87 , C12P21/08 , C07K15/18 , C12N15/51 , C12N15/85

15. 发明专利

AU2950295A Use of a bacterial component to enhance targeted delivery of polynucleotides to cells 未知
公开(公告)号：AU2950295A
公开(公告)日：1996-01-25
申请号：AU2950295
申请日：1995-06-27
申请人： TARGETECH INC , UNIVERSITY OF CONNECTICUT THE
发明人： WU GEORGE Y , WU CATHERINE H , ZHANG YING , SPITALNY GEORGE L , CARMICHAEL ELLEN
IPC分类号： C12N15/09 , A61K47/48 , C12N15/87
摘要： An improved soluble molecular complex for targeting a polynucleotide to a specific cell is disclosed. The molecular complex comprises (a) a polynucleotide (b) a carrier made up of a polynucleotide binding agent and a cell-specific binding agent which binds to a surface molecule of the cell and is internalized into an endosome, and (c) a bacterial component or fragment thereof which lyses the endosome and causes the polynucleotide to be released into the cytoplasm of the cell. In a preferred embodiment of the invention the polynucleotide binding agent is polylysine, the cell-specific binding agent is an asialoglycoprotein, and the bacterial component is listeriolysin O. The disclosed soluble molecular complex and methods of use can be used therapeutically to deliver genes and antisense polynucleotides to specific cells in vivo.

16. 发明专利

CA2180347A1 ANTI-HEPATITIS B POLY- AND OLIGONUCLEOTIDES 未知
公开(公告)号：CA2180347A1
公开(公告)日：1995-07-20
申请号：CA2180347
申请日：1995-01-11
申请人： TARGETECH INC
发明人： CARMICHAEL ELLEN
IPC分类号： G01N33/566 , A61K38/00 , A61K47/48 , A61K48/00 , A61P1/16 , A61P31/12 , C07H21/04 , C12N15/00 , C12N15/09 , C12N15/113 , C12R1/92 , G01N33/576 , C12N15/87 , A61K31/70 , C07H21/00 , C12N15/11 , C12Q1/68
摘要： Poly- and oligonucleotides which inhibit virai replication, particularly hepatitis virus replication, such as hepatitis B virus (HBV) replication, are disclosed. Preferred antiviral oligonucleotides include the following: an antiviral poly- or oligonucleotide which hybridizes to at least a portion of an RNA primer-binding region of a viral nucleic acid, preferably a DRII region of HBV DNA; an antiviral polyor oligonucleotide which hybridizes to at least a portion of an RNA primer which binds a viral nucleic acid, preferably a DRII region of HBV DNA, an antiviral poly- or oligonucleotide which hybridizes to a hepatitis virus mRNA encoding a DNA polymerase, preferably an HBV mRNA; an antiviral poly- or oligonucleotide which hybridizes to a hepatitis virus mRNA encoding an envelope protein essential for viral attachment to a target cell, preferably an HBV mRNA encoding a pre-S1 protein; and an antiviral poly- or oligonucleotide which hybridizes to an encapsidation signal of a viral nucleic acid, preferably an HBV cis-encapsidation signal, thereby inhibiting encapsidation of the viral nucleic acid. The disclosed poly- or oligonucleotides can be used for detection of the presence of viral nucleic acid, particularly HBV DNA, in a cell and can be used to treat viral infection in a subject.

17. 发明申请

WO9519433A2 ANTI-HEPATITIS B POLY- AND OLIGONUCLEOTIDES 审中-公开
标题翻译：抗生素B多肽和寡核苷酸
公开(公告)号：WO9519433A2
公开(公告)日：1995-07-20
申请号：PCT/US9500508
申请日：1995-01-11
申请人： TARGETECH INC
发明人： CARMICHAEL ELLEN
IPC分类号： G01N33/566 , A61K38/00 , A61K47/48 , A61K48/00 , A61P1/16 , A61P31/12 , C07H21/04 , C12N15/00 , C12N15/09 , C12N15/113 , C12R1/92 , G01N33/576 , C12N15/11 , A61K31/70
CPC分类号： C12N15/1131 , A61K47/645
摘要： Poly- and oligonucleotides which inhibit viral replication, particularly hepatitis virus replication, such as hepatitis B virus (HBV) replication, are disclosed. Preferred antiviral oligonucleotides include the following: an antiviral poly- or oligonucleotide which hybridizes to at least a portion of an RNA primer-binding region of a viral nucleic acid, preferably a DRII region of HBV DNA; an antiviral poly- or oligonucleotide which hybridizes to at least a portion of an RNA primer which binds a viral nucleic acid, preferably a DRII region of HBV DNA; an antiviral poly- or oligonucleotide which hybridizes to a hepatitis virus mRNA encoding a DNA polymerase, preferably an HBV mRNA; an antiviral poly- or oligonucleotide which hybridizes to a hepatitis virus mRNA encoding an envelope protein essential for viral attachment to a target cell, preferably an HBV mRNA encoding a pre-S1 protein; and an antiviral poly- or oligonucleotide which hybridizes to an encapsidation signal of a viral nucleic acid, preferably an HBV cis-encapsidation signal, thereby inhibiting encapsidation of the viral nucleic acid. The disclosed poly- or oligonucleotides can be used for detection of the presence of viral nucleic acid, particularly HBV DNA, in a cell and can be used to treat viral infection in a subject.
摘要翻译：公开了抑制病毒复制的多核苷酸和寡核苷酸，特别是肝炎病毒复制，如乙型肝炎病毒（HBV）复制。优选的抗病毒寡核苷酸包括以下：与病毒核酸，优选HBV DNA的DRII区域的RNA引物结合区域的至少一部分杂交的抗病毒多核苷酸或寡核苷酸; 与至少部分结合病毒核酸，优选HBV DNA的DRII区域的RNA引物杂交的抗病毒多核苷酸或寡核苷酸; 与编码DNA聚合酶，优选HBV mRNA的肝炎病毒mRNA杂交的抗病毒多核苷酸或寡核苷酸; 与编码对靶细胞病毒附着必需的包膜蛋白的肝炎病毒mRNA杂交的抗病毒多核苷酸或寡核苷酸，优选编码前S1蛋白的HBV mRNA; 以及与病毒核酸的壳化信号，优选HBV顺 - 壳化信号杂交的抗病毒多核苷酸或寡核苷酸，从而抑制病毒核酸的壳化。所公开的多核苷酸或寡核苷酸可用于检测细胞中病毒核酸，特别是HBV DNA的存在，并可用于治疗受试者的病毒感染。

18. 发明申请

WO1995018636A2 HEPATOCYTE-TARGETED DRUG CONJUGATES 审中-公开
标题翻译： HEPATOCYTE定向药物联合
公开(公告)号：WO1995018636A2
公开(公告)日：1995-07-13
申请号：PCT/US1995000448
申请日：1995-01-11
申请人： TARGETECH, INC.
发明人： TARGETECH, INC. , PLOURDE, Robert, Jr. , CARMICHAEL, Ellen , SPITALNY, George, L. , FINDEIS, Mark, A. , ERNST, Michael, F. , ROBINSON, Brett
IPC分类号： A61K47/48
CPC分类号： A61K47/62 , A61K47/61
摘要： The invention provides conjugates for targeting a therapeutic agent to a cell with asialoglycoprotein receptors. The conjugates comprise a therapeutic agent and ligand for the asialoglycoprotein receptor, wherein the therapeutic agent and the ligand are linked by a bridging agent. The bridging agent can be a crosslinker, a polyfunctional carrier molecule or a crosslinker and a polyfunctional carrier molecule. In a preferred embodiment, the therapeutic agent is a nucleoside analog or colchicine and the ligand is asialoorosomucoid, arabinogalactan or a Tris-(N-acetyl galactosamine aminohexyl glycoside) amide of tyrosyl(glutamyl)-glutamate. Preferred crosslinkers include aminoacyl derivatives, carboxyacyl derivatives, phosphate, peptides and reductively-labile crosslinkers. Preferred polyfunctional carrier molecules include polyamino acids and polysaccharides. The conjugates of the invention can be used to target a therapeutic agent to a cell, for example to inhibit viral DNA replication in a virally-infected hepatocyte.
摘要翻译：本发明提供用于将治疗剂靶向具有脱唾液酸糖蛋白受体的细胞的缀合物。缀合物包含用于脱唾液酸糖蛋白受体的治疗剂和配体，其中治疗剂和配体通过桥连剂连接。桥连剂可以是交联剂，多官能载体分子或交联剂和多官能载体分子。在一个优选的实施方案中，治疗剂是核苷类似物或秋水仙素，并且配体是阿糖胞苷类，阿拉伯半乳聚糖或酪氨酰（谷氨酰）谷氨酸的三 - （N-乙酰半乳糖胺氨基己基糖苷）酰胺。优选的交联剂包括氨基酰基衍生物，羧酰基衍生物，磷酸酯，肽和还原不稳定的交联剂。优选的多官能载体分子包括聚氨基酸和多糖。本发明的缀合物可用于将治疗剂靶向细胞，例如以抑制病毒感染的肝细胞中的病毒DNA复制。

19. 发明申请

WO1992020316A2 TARGETED DELIVERY OF GENES ENCODING IMMUNOGENIC PROTEINS 审中-公开
标题翻译：定点递送编码免疫原性蛋白的基因
公开(公告)号：WO1992020316A2
公开(公告)日：1992-11-26
申请号：PCT/US1992003875
申请日：1992-05-14
申请人： UNIVERSITY OF CONNECTICUT , TARGETECH, INC.
发明人： UNIVERSITY OF CONNECTICUT , TARGETECH, INC. , WU, George, Y. , SPITALNY, George, L. , FINDEIS, Mark, A.
IPC分类号： A61K0
CPC分类号： C12N15/87 , A61K39/12 , A61K39/292 , A61K47/645 , A61K48/00 , A61K2039/53 , A61K2039/6093 , C07K16/00 , C07K16/082 , C12N2730/10134
摘要： Molecular complexes can be used to target a gene encoding an immunogenic protein or polypeptide to a specific cell in vivo. The gene is incorporated into the target cell, expressed and the gene-encoded product is secreted and an immune response against the immunogenic protein or polypeptide is elicited. The molecular complex comprises an expressible gene encoding a desired immunogenic protein or polypeptide complexed with a carrier of a cell-specific binding agent and a gene-binding agent. The cell-specific binding agent is specific for a cellular surface structure which mediates internalization of ligands by endocytosis. An example is the asialoglycoprotein receptor of hepatocytes. The gene-binding agent is a compound such as a polycation which stably complexes the gene under extracellular conditions and releases the gene under intracellular conditions so that it can function within a cell. The molecular complex is stable and soluble in physiological fluids and can be used to elicit an immune response against a variety of immunogens in an organism for the purpose of vaccination or for the production of antibodies.
摘要翻译：分子复合物可用于将编码免疫原性蛋白或多肽的基因靶向体内特定细胞。该基因被并入目标细胞中，表达并且分泌基因编码的产物，并引发针对免疫原性蛋白质或多肽的免疫应答。分子复合物包含编码与细胞特异性结合剂和基因结合剂的载体复合的所需免疫原性蛋白质或多肽的可表达基因。细胞特异性结合剂对通过内吞作用介导配体内化的细胞表面结构是特异性的。一个例子是肝细胞的脱唾液酸糖蛋白受体。基因结合剂是诸如聚阳离子的化合物，其在细胞外条件下稳定地复合基因并在细胞内条件下释放基因，使得其可以在细胞内起作用。分子复合物是稳定的并且可溶于生理液体，并且可以用于在生物体内引发针对各种免疫原的免疫应答以用于疫苗接种或产生抗体。

20. 发明公开

EP0584279A1 TARGETED DELIVERY OF GENES ENCODING IMMUNOGENIC PROTEINS 失效转让
标题翻译：展望基因免疫原性蛋白CODE供应。
公开(公告)号：EP0584279A1
公开(公告)日：1994-03-02
申请号：EP92913964.0
申请日：1992-05-14
申请人： THE UNIVERSITY OF CONNECTICUT , TARGETECH, INC.
发明人： WU, George, Y. , SPITALNY, George, L. , FINDEIS, Mark, A.
IPC分类号： A61K38 , A61K39 , A61K47 , A61K48 , C07K16 , C12N15 , C12P21
CPC分类号： C12N15/87 , A61K39/12 , A61K39/292 , A61K47/645 , A61K48/00 , A61K2039/53 , A61K2039/6093 , C07K16/00 , C07K16/082 , C12N2730/10134
摘要： Des complexe moléculaires peuvent être utilisés pour donner comme cible à un gène codant une protéine ou un polypeptide immunogène une cellule spécifique in vivo. Ledit gène est incorporé à une cellule cible et primé, puis le produit codé par le gène est sécrété et une réponse immunitaire à la protéine ou au polypeptide immunogène est obtenue. Le complexe moléculaire comprend un gène exprimable codant une protéine ou un polypeptide immunogène désiré(e) complexé(e) avec un porteur qui est un conjugué d'un agent de fixation spécifique à la cellule et d'un agent de fixation du gène. L'agent de fixation spécifique à la cellule est spécifique à la structure de la surface cellulaire qui induit l'internalisation de ligands par endocytose. Cet agent de fixation peut être par exemple le récepteur d'asialoglycoprotéine d'hépatocytes. L'agent de fixation du gène est un composé tel qu'un polycation qui complexe de façon stable le gène dans des conditions extracellulaires et libère le gène dans des conditions intracellulaires de façon qu'il puisse fonctionner à l'intérieur d'une cellule. Le complexe moléculaire est stable et soluble dans des liquides physiologiques et il peut être utilisé pour créer une réponse immunitaire à toute une variété d'immunogène dans un organisme, à des fins de vaccination ou pour la production d'anticorps.

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