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1. 发明专利

IL261438D0 Polymalic acid based nanoimmunoconjugates and uses thereof 未知
公开(公告)号：IL261438D0
公开(公告)日：2018-10-31
申请号：IL26143818
申请日：2018-08-28
申请人： CEDARS SINAI MEDICAL CENTER , LJUBIMOVA JULIA Y , BLACK KEITH L , HOLLER EGGEHARD , LJUBIMOV ALEXANDER , DING HUI
发明人： LJUBIMOVA JULIA Y , BLACK KEITH L , HOLLER EGGEHARD , LJUBIMOV ALEXANDER , DING HUI
IPC分类号： A61K20060101
摘要： Nanoimmunoconjugates including a polymalic acid-based molecular scaffold, targeting ligands, anti-tumor immune response stimulators and anti-cancer agents are provided. Methods for treating cancer in a subject by administering the nanoimmunoconjugates that provide both systemic and local immune responses and synergistic anticancer effect are described.

2. 发明申请

WO2005055980A3 POLYMALIC ACID-BASED MULTIFUNCTIONAL DRUG DELIVERY SYSTEM 审中-公开
标题翻译：基于聚合酸的多功能药物递送系统
公开(公告)号：WO2005055980A3
公开(公告)日：2006-01-05
申请号：PCT/US2004040660
申请日：2004-12-03
申请人： ARROGENE INC , LJUBIMOVA JULIA Y , BLACK KEITH L , HOLLER EGGEHARD
发明人： LJUBIMOVA JULIA Y , BLACK KEITH L , HOLLER EGGEHARD
IPC分类号： A61K47/48
CPC分类号： A61K47/6883 , A61K47/593 , A61K47/60
摘要： A structured drug system that is useful for delivering a drug payload to a specific tissue or cell type is disclosed. The system is based on purified polymalic acid. This polymer isolated from natural sources is biocompatible, biodegradable and of very low toxicity. The polymer is extremely water soluble and contains a large number of free carboxyl groups which can used to attach a number of different active molecules. In the examples disclosed N-hydroxysuccinimide esters of the carboxyl groups are used to attach such molecules. The active molecules include monoclonal antibodies to promote specific cellular uptake and specific pro-drugs such as antisense nucleic acids designed to modify the cellular metabolism of a target cell. The pro-drugs are advantageously linked by a somewhat labile bond so that they will be released under specific conditions. In addition, the system contains amide-linked valine to encourage membrane disruption under lysosomal conditions. Polyethylene glycol groups are attached to extend the drug system's circulation half-life. In addition, fluorescent reported groups can be readily included to aid in visualizing and confirming drug system targeting. The drug system can deliver treatments for a wide range of diseases and is specially advantageous for treatment of neoplasms.
摘要翻译：公开了一种用于将药物有效载荷递送到特定组织或细胞类型的结构化药物系统。该系统基于纯化的聚丙酸。从天然来源分离的聚合物是生物相容的，可生物降解的和非常低的毒性。聚合物极易水溶，并含有大量游离羧基，可用于连接许多不同的活性分子。在实施例中，羧基的N-羟基琥珀酰亚胺酯用于附着这些分子。活性分子包括促进特异性细胞摄取的单克隆抗体和特异性前体药物，例如旨在修饰靶细胞的细胞代谢的反义核酸。前药有利地通过稍微不稳定的键连接，使得它们将在特定条件下释放。此外，该系统含有酰胺键缬氨酸，以促进溶酶体条件下的膜破坏。连接聚乙二醇基团以延长药物系统的循环半衰期。此外，可以容易地包括荧光报告的组以帮助可视化和确认药物系统靶向。药物系统可以为广泛的疾病提供治疗，特别有利于治疗肿瘤。

3. 发明申请

WO2005028617A2 ANTISENSE INHIBITION OF LAMININ-8 EXPRESSION TO INHIBIT HUMAN GLIOMAS 审中-公开
标题翻译：抑制LAMININ-8表达抑制人类GLIOMAS的抗原性
公开(公告)号：WO2005028617A2
公开(公告)日：2005-03-31
申请号：PCT/US2004029956
申请日：2004-09-13
申请人： ARROGENE INC , LJUBIMOVA JULIA Y , LJUBIMOVA ALEXANDER V , BLACK KEITH L
发明人： LJUBIMOVA JULIA Y , LJUBIMOVA ALEXANDER V , BLACK KEITH L
IPC分类号： A01N43/04 , A61K31/00 , A61K31/07 , A61K31/7088 , C07H21/04 , C12N20060101 , C12N15/113 , C12Q1/68 , C12N
CPC分类号： A61K31/07 , A61K31/00 , A61K31/7088 , C12N15/113 , C12N2310/11 , C12N2310/3233
摘要： Using gene array technology, we observed that an increase of the alpha4 chain- containing Laminin-8 correlated with poor prognosis for patients with brain gliomas. We established that inhibition of Laminin-8 expression by a new generation of highly specific and stable antisense oligonucleotides (Morpholino ) against chains of Laminin-8 could slow or stop the spread of glioma. This was demonstrated in an in vitro model using human glioblastoma multiforme cell lines M059K and U-87MG co-cultured with normal human brain microvascular endothelial cells (HBMVEC). Using Western blot analysis and immunohistochemistry, we confirmed that antisense treatment effectively blocked laminin-8 protein synthesis. Antisense oligonucleotides against both alpha4 and ß1 chains of laminin-8 blocked significantly the invasion of co-cultures through Matrigel. The results show that Laminin-8 may not only contribute to glioma progression and recurrence as part of the neovascularization process but also by directly increasing the invasive potential of tumor cells.
摘要翻译：使用基因阵列技术，我们观察到含有α4链的层粘连蛋白-8的增加与脑胶质瘤患者的预后差。我们确定了通过针对Laminin-8链的新一代高度特异性和稳定的反义寡核苷酸（Morpholino TM TM）抑制层粘连蛋白-8表达的抑制可以减缓或停止胶质瘤的扩散。这在使用与正常人脑微血管内皮细胞（HBMVEC）共培养的人多形性细胞瘤M059K和U-87MG细胞系的体外模型中证明。使用Western印迹分析和免疫组织化学，我们证实反义治疗有效阻断了层粘连蛋白-8蛋白的合成。针对层粘连蛋白-8的α4和β1链的反义寡核苷酸通过Matrigel显着阻断了共培养物的侵袭。结果表明，层粘连蛋白-8可能不仅有助于神经胶质瘤进展和复发作为新生血管形成过程的一部分，而且还通过直接增加肿瘤细胞的侵袭潜力。

4. 发明专利

JP2009242428A Antisense inhibition of laminin-8 expression to inhibit human gliomas 审中-公开
标题翻译：抑制LAMININ-8表达抑制人类GLIOMAS的抗原性
公开(公告)号：JP2009242428A
公开(公告)日：2009-10-22
申请号：JP2009167047
申请日：2009-07-15
申请人： Cedars-Sinai Medical Center , セダーズ−シナイメディカルセンター
发明人： LJUBIMOVA JULIA Y , LJUBIMOV ALEXANDER V , BLACK KEITH L
IPC分类号： A61K31/7105 , A01N43/04 , A61K31/00 , A61K31/07 , A61K31/7088 , A61K31/7125 , A61K39/395 , A61P35/00 , A61P43/00 , C07H21/04 , C12N20060101 , C12N15/09 , C12N15/113 , C12Q1/68
CPC分类号： A61K31/07 , A61K31/00 , A61K31/7088 , C12N15/113 , C12N2310/11 , C12N2310/3233
摘要： PROBLEM TO BE SOLVED: To provide antisense oligonucleotides which bind a specific RNA arrangement and also inactivate this. SOLUTION: Using gene array technology, it is observed that an increase in α4 chain-containing Laminin-8 associated with poor prognosis for patients with brain gliomas. It is established that inhibition of Laminin-8 expression by new generation of highly specific and stable antisense oligonucleotides (Morpholino TM ) against chains of Laminin-8 can slow or stop the spread of glioma. This has been demonstrated in an in vitro model using human glioblastoma multiforme cell lines M059K and U-87MG co-cultured with normal human brain microvascular endothelial cells (HBMVEC). Using Western blot analysis and immunohistochemistry, it has been confirmed that antisense treatment effectively blocks Laminin-8 protein synthesis. COPYRIGHT: (C)2010,JPO&INPIT
摘要翻译：要解决的问题：提供结合特异性RNA排列并使其失活的反义寡核苷酸。解决方案：使用基因阵列技术，观察到与脑胶质瘤患者预后不良相关的含α4链的层粘连蛋白-8的增加。确定通过新一代高度特异性和稳定的反义寡核苷酸（Morpholino TM SPM TM）对层粘连蛋白-8的链抑制层粘连蛋白-8表达可以减缓或停止胶质瘤的扩散。这已经在使用与正常人脑微血管内皮细胞（HBMVEC）共培养的人类成胶质细胞瘤多形态细胞系M059K和U-87MG的体外模型中证明。使用蛋白质印迹分析和免疫组织化学，已经证实反义治疗有效阻断层粘连蛋白-8蛋白的合成。版权所有（C）2010，JPO＆INPIT

5. 发明专利

JP2010163468A Polymalic acid-based multifunctional drug delivery system 审中-公开
标题翻译：基于聚合酸的多功能药物递送系统
公开(公告)号：JP2010163468A
公开(公告)日：2010-07-29
申请号：JP2010107780
申请日：2010-05-07
申请人： Arrogene Inc , Cedars-Sinai Medical Center , アロジーン, インコーポレイテッド , セダーズ−シナイメディカルセンター
发明人： LJUBIMOVA JULIA Y , BLACK KEITH L , HOLLER EGGEHARD
IPC分类号： A61K47/42 , A61K31/711 , A61K47/34 , A61K47/48 , A61P35/00 , A61P43/00
CPC分类号： A61K47/6883 , A61K47/593 , A61K47/60
摘要： PROBLEM TO BE SOLVED: To provide a structured drug system that is useful for delivering a drug payload to a specific tissue or cell type. SOLUTION: The system is based on purified polymalic acid. This polymer isolated from natural sources is biocompatible, biodegradable and of very low toxicity. The polymer is extremely water soluble and contains a large number of free carboxyl groups which can be used to attach a number of different active molecules. In the examples disclosed N-hydroxysuccinimide esters of the carboxyl groups are used to attach such molecules. The active molecules include monoclonal antibodies to promote specific cellular uptake and specific pro-drugs such as antisense nucleic acids designed to modify the cellular metabolism of a target cell. The pro-drugs are advantageously linked by a somewhat labile bond so that they will be released under specific conditions. COPYRIGHT: (C)2010,JPO&INPIT
摘要翻译：要解决的问题：提供可用于将药物有效载荷递送到特定组织或细胞类型的结构化药物系统。解决方案：该系统基于纯化的聚丙酸。从天然来源分离的聚合物是生物相容的，可生物降解的，毒性非常低。该聚合物极易溶于水并含有大量游离羧基，可用于连接许多不同的活性分子。在实施例中，羧基的N-羟基琥珀酰亚胺酯用于附着这些分子。活性分子包括促进特异性细胞摄取的单克隆抗体和特异性前体药物，例如旨在修饰靶细胞的细胞代谢的反义核酸。前药有利地通过稍微不稳定的键连接，使得它们将在特定条件下释放。版权所有（C）2010，JPO＆INPIT

6. 发明专利

ES2710463T3 Acido poli(beta málico) con tripéptido colgante Leu-Leu-Leu para la administración eficaz del fármaco citoplasmático 未知
公开(公告)号：ES2710463T3
公开(公告)日：2019-04-25
申请号：ES09730249
申请日：2009-04-10
申请人： CEDARS SINAI MEDICAL CENTER
发明人： DING HUI , LJUBIMOVA JULIA Y , HOLLER EGGEHARD , BLACK KEITH L
IPC分类号： A61K38/00 , A61K9/00 , A61K9/48 , A61K31/711 , A61K39/00 , A61K47/59 , A61K47/60 , A61K49/00
摘要： Una molécula de administración de fármacos que comprende un andamio molecular de ácido polimálico unido covalentemente a uno o más módulos moleculares biológicamente activos, en donde uno de los uno o más módulos moleculares biológicamente activos comprende una unidad de escape de endosoma, Lleucilleucilleucina (LLL).

7. 发明专利

AU2017201353B2 Polymalic acid based nanoconjugates for imaging 未知
公开(公告)号：AU2017201353B2
公开(公告)日：2019-01-31
申请号：AU2017201353
申请日：2017-03-04
申请人： CEDARS SINAI MEDICAL CENTER
发明人： BLACK KEITH L , LJUBIMOVA JULIA Y , LJUBIMOV ALEXANDER V , HOLLER EGGEHARD
IPC分类号： C07C211/00 , A61K49/00
摘要： A method of diagnostic imaging of a brain in a subject comprising: administering to the subject a composition comprising a polymalic acid-based molecular scaffold having a plurality of pendant carboxyl groups, at least one imaging moiety, and at least one targeting module, wherein the polymalic acid-based molecular scaffold is a homopolymer, each of the at least one imaging moiety is conjugated to the polymalic acid based molecular scaffold through one of the plurality of the pendant carboxyl groups, each of the at least one targeting module is conjugated to the polymalic-acid based molecular scaffold through one of the plurality of the pendant carboxyl group, the at least one imaging moiety comprises a contrast agent, and the at least one targeting module comprises an antibody, a peptide, an oligonucleotide, or a therapeutic chemical; and providing that the imaging moiety is visualized by an MRI imaging technique. -38- WO 2012/139030 PCT/US2012/032573 coo o o

8. 发明专利

AU2012239933B2 Polymalic acid based nanoconjugates for imaging 未知
公开(公告)号：AU2012239933B2
公开(公告)日：2017-01-05
申请号：AU2012239933
申请日：2012-04-06
申请人： CEDARS SINAI MEDICAL CENTER
发明人： BLACK KEITH L , LJUBIMOVA JULIA Y , LJUBIMOV ALEXANDER V , HOLLER EGGEHARD
IPC分类号： C07C211/00 , A61K49/00
摘要： Nanoconjugates include a polymalic-based molecular scaffold with one or more imaging moiety and one or more targeting modules attached to the scaffold. At least one imaging moiety and at least one targeting module is conjugated to the polymalicacid based molecular scaffold. Methods of synthesizing the nanoconjugate involve providing a polymalic acid having a plurality of pendant carboxyi groups. The method reacts a compound containing sulfhydryl groups and amino acid groups through the pendant carboxyi groups to add sulfhydryl groups to the polymalic acid to form an activated polymalic acid. The method reacts at least one imaging moiety containing a sulfhydryl binding group to the activated polymalic acid to form a preconjugate. The method may involve administering to the subject a nanoconjugate that includes a polymalic acid-based molecular scaffold, at least one imaging moiety, and at least one targeting module.

9. 发明专利

AU2012239933A1 Polymalic acid based nanoconjugates for imaging 未知
公开(公告)号：AU2012239933A1
公开(公告)日：2013-10-24
申请号：AU2012239933
申请日：2012-04-06
申请人： CEDARS SINAI MEDICAL CENTER
发明人： BLACK KEITH L , LJUBIMOVA JULIA Y , LJUBIMOV ALEXANDER V , HOLLER EGGEHARD
IPC分类号： C07C211/00 , A61K49/00
摘要： Nanoconjugates include a polymalic-based molecular scaffold with one or more imaging moiety and one or more targeting modules attached to the scaffold. At least one imaging moiety and at least one targeting module is conjugated to the polymalicacid based molecular scaffold. Methods of synthesizing the nanoconjugate involve providing a polymalic acid having a plurality of pendant carboxyi groups. The method reacts a compound containing sulfhydryl groups and amino acid groups through the pendant carboxyi groups to add sulfhydryl groups to the polymalic acid to form an activated polymalic acid. The method reacts at least one imaging moiety containing a sulfhydryl binding group to the activated polymalic acid to form a preconjugate. The method may involve administering to the subject a nanoconjugate that includes a polymalic acid-based molecular scaffold, at least one imaging moiety, and at least one targeting module.

10. 发明专利

NO20032781L 未知
公开(公告)号：NO20032781L
公开(公告)日：2003-08-18
申请号：NO20032781
申请日：2003-06-18
申请人： CEDARS SINAI MEDICAL CENTER
发明人： LJUBIMOVA JULIA Y , LJUBIMOV ALEXANDER V , BLACK KEITH L
IPC分类号： C12Q1/68 , G01N33/574

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