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81. 发明授权

US08486908B2 Immune regulatory oligonucleotide (IRO) compounds to modulate toll-like receptor based immune response 有权
公开(公告)号：US08486908B2
公开(公告)日：2013-07-16
申请号：US13299555
申请日：2011-11-18
申请人： Ekambar R. Kandimalla , Daqing Wang , Ireneusz Nowak , Sudhir Agrawal
发明人： Ekambar R. Kandimalla , Daqing Wang , Ireneusz Nowak , Sudhir Agrawal
IPC分类号： A01N61/00 , A61K39/00 , A61K45/00 , C12Q1/68 , C07H21/02
CPC分类号： C12N15/117 , A61K31/7115 , A61K31/7125 , A61K45/06 , C12N2310/17 , C12N2310/31 , C12N2310/317 , C12N2310/321 , C12N2310/3341 , C12N2310/336 , C12N2310/51 , C12N2310/52 , Y02A50/401 , Y02A50/411 , Y02A50/414 , A61K2300/00
摘要： The invention provides novel immune regulatory oligonucleotides (IRO) as antagonist of TLRs and methods of use thereof. These IROs have unique sequences that inhibit or suppress TLR-mediated signaling in response to a TLR ligand or TLR agonist. The methods may have use in the prevention and treatment of cancer, an autoimmune disorder, airway inflammation, inflammatory disorders, infectious disease, skin disorders, allergy, asthma or a disease caused by a pathogen.

82. 发明授权

US06372427B1 Cooperative oligonucleotides 失效
标题翻译：合作寡核苷酸
公开(公告)号：US06372427B1
公开(公告)日：2002-04-16
申请号：US08420672
申请日：1995-04-12
申请人： Ekambar R. Kandimalla , Sudhir Agrawal
发明人： Ekambar R. Kandimalla , Sudhir Agrawal
IPC分类号： C12Q168
CPC分类号： C12N15/113 , A61K38/00 , C07K2319/00 , C12N15/1131 , C12N15/1132 , C12N2310/315 , C12N2310/351 , C12N2310/53
摘要： Disclosed is a composition comprising at least two synthetic, cooperative oligonucleotides, each comprising a region complementary to one of tandem, non-overlapping regions of a target single-stranded nucleic acid, and each further comprising a dimerization domain at a terminus of each of the oligonucleotides, the dimerization domains of the oligonucleotides being complementary to each other. Also disclosed are duplex structures, ternary complexes, pharmaceutical formulations, and methods utilizing the cooperative oligonucleotides of the invention.
摘要翻译：公开了包含至少两个合成的合作寡核苷酸的组合物，每个寡核苷酸包含与靶单链核酸的串联，非重叠区域之一互补的区域，并且每个还包含在每个的每个末端的二聚化结构域寡核苷酸，寡核苷酸的二聚化结构域彼此互补。还公开了双重结构，三元配合物，药物制剂和利用本发明的合作寡核苷酸的方法。

83. 发明申请

US20120128699A1 IMMUNE REGULATORY OLIGONUCLEOTIDE (IRO) COMPOUNDS TO MODULATE TOLL-LIKE RECEPTOR BASED IMMUNE RESPONSE 有权
标题翻译：免疫调节寡核苷酸（IRO）化合物，以调节基于类似感受器的免疫应答
公开(公告)号：US20120128699A1
公开(公告)日：2012-05-24
申请号：US13299555
申请日：2011-11-18
申请人： Ekambar R. Kandimalla , Daqing Wang , Ireneusz Nowak , Sudhir Agrawal
发明人： Ekambar R. Kandimalla , Daqing Wang , Ireneusz Nowak , Sudhir Agrawal
IPC分类号： A61K39/395 , A61K31/7115 , A61K39/00 , A61P37/06 , A61P31/00 , A61P19/02 , A61P7/06 , A61P11/00 , A61P25/00 , C07H21/02 , A61P17/06
CPC分类号： C12N15/117 , A61K31/7115 , A61K31/7125 , A61K45/06 , C12N2310/17 , C12N2310/31 , C12N2310/317 , C12N2310/321 , C12N2310/3341 , C12N2310/336 , C12N2310/51 , C12N2310/52 , Y02A50/401 , Y02A50/411 , Y02A50/414 , A61K2300/00
摘要： The invention provides novel immune regulatory oligonucleotides (IRO) as antagonist of TLRs and methods of use thereof. These TROs have unique sequences that inhibit or suppress TLR-mediated signaling in response to a TLR ligand or TLR agonist. The methods may have use in the prevention and treatment of cancer, an autoimmune disorder, airway inflammation, inflammatory disorders, infectious disease, skin disorders, allergy, asthma or a disease caused by a pathogen.
摘要翻译：本发明提供作为TLR拮抗剂的新型免疫调节寡核苷酸（IRO）及其使用方法。这些TRO具有独特的序列，其响应于TLR配体或TLR激动剂抑制或抑制TLR介导的信号传导。该方法可用于预防和治疗癌症，自身免疫性疾病，气道炎症，炎症性疾病，感染性疾病，皮肤病，变态反应，哮喘或由病原体引起的疾病。

84. 发明授权

US07713535B2 Modulation of immunostimulatory properties by small oligonucleotide-based compounds 失效
标题翻译：通过小寡核苷酸类化合物调节免疫刺激性质
公开(公告)号：US07713535B2
公开(公告)日：2010-05-11
申请号：US10852598
申请日：2004-05-24
申请人： Sudhir Agrawal , Fu-Gang Zhu , Ekambar R. Kandimalla
发明人： Sudhir Agrawal , Fu-Gang Zhu , Ekambar R. Kandimalla
IPC分类号： A61K45/00
CPC分类号： C12N15/117 , A61K39/39 , A61K2039/55561 , C12N2310/17 , C12N2310/315 , C12N2310/318 , C12N2310/3183 , C12N2310/32 , C12N2310/33 , C12N2310/336 , C12N2310/52
摘要： The invention relates to the therapeutic use of oligonucleotides as immunostimulatory agents in immunotherapy applications. More particularly, the invention provides immunomers for use in methods for generating an immune response or for treating a patient in need of immunostimulation. The immunomers of the invention comprise at least two oligonucleotides linked at their 3′ ends, internucleoside linkages or functionalized nucleobase or sugar to a non-nucleotidic linker, at least one of the oligonucleotides being an immunostimulatory oligonucleotide and having an accessible 5′ end.
摘要翻译：本发明涉及在免疫治疗应用中寡核苷酸作为免疫刺激剂的治疗用途。更具体地，本发明提供了用于产生免疫应答的方法或用于治疗需要免疫刺激的患者的免疫
性。本发明的免疫体包含至少两个在其3'末端连接的寡核苷酸，核苷间键或官能化核碱基或糖与非核苷酸连接体，至少一个寡核苷酸是免疫刺激性寡核苷酸并具有可接近的5'端。

85. 发明授权

US07671035B2 Epidermal growth factor receptor antisense oligonucleotides 失效
标题翻译：表皮生长因子受体反义寡核苷酸
公开(公告)号：US07671035B2
公开(公告)日：2010-03-02
申请号：US10140228
申请日：2002-05-07
申请人： Sudhir Agrawal , Ekambar R. Kandimalla
发明人： Sudhir Agrawal , Ekambar R. Kandimalla
IPC分类号： A01N43/04 , A61K31/70
CPC分类号： A61K31/7088 , A61K31/337 , A61K31/4745 , A61K31/704 , A61K33/24 , A61K38/00 , A61K45/06 , C12N15/111 , C12N15/1138 , C12N2310/11 , C12N2310/315 , C12N2310/321 , C12N2310/346 , C12N2320/31 , A61K2300/00 , C12N2310/3527
摘要： Disclosed are synthetic oligonucleotides complementary to nucleic acids encoding epidermal growth factor and methods of their use.
摘要翻译：公开了与编码表皮生长因子的核酸互补的合成寡核苷酸及其使用方法。

86. 发明授权

US07176296B2 Modulation of oligonucleotide CpG-mediated immune stimulation by positional modification of nucleosides 失效
标题翻译：通过核苷位置修饰调节寡核苷酸CpG介导的免疫刺激
公开(公告)号：US07176296B2
公开(公告)日：2007-02-13
申请号：US10365834
申请日：2003-02-13
申请人： Sudhir Agrawal , Ekambar R. Kandimalla
发明人： Sudhir Agrawal , Ekambar R. Kandimalla
IPC分类号： C07H21/02 , C07H21/00 , C07H19/00
CPC分类号： A61K39/39 , A61K2039/55561
摘要： The invention provides compounds having increased or reduced immunostimulatory effect, said compounds comprising a CpG dinucleotide and an immunomodulatory moiety wherein the increased or reduced immunomodulatory effect is relative to a similar compound lacking the immunomodulatorv moiety.
摘要翻译：本发明提供具有增加或降低的免疫刺激作用的化合物，所述化合物包含CpG二核苷酸和免疫调节部分，其中增加或减少的免疫调节作用相对于缺乏免疫调节剂部分的相似化合物。

87. 发明授权

US07105495B2 Modulation of oligonucleotide CpG-mediated immune stimulation by positional modification of nucleosides 失效
公开(公告)号：US07105495B2
公开(公告)日：2006-09-12
申请号：US10406015
申请日：2003-04-03
申请人： Sudhir Agrawal , Ekambar R. Kandimalla
发明人： Sudhir Agrawal , Ekambar R. Kandimalla
IPC分类号： A01N43/04 , C12Q1/68 , C12N15/63
CPC分类号： A61K39/39 , A61K38/00 , A61K2039/55561 , C07H21/00 , C12N15/113 , C12N15/117 , C12N2310/18 , C12N2310/315 , C12N2310/317 , C12N2310/3183 , C12N2310/33 , C12N2310/332 , C12N2310/334 , C12N2310/335 , C12N2310/336 , Y10S514/885
摘要： The invention provides methods for modulating the immune response caused by CpG dinucleotide-containing compounds. The methods according to the invention enables both decreasing the immunostimulatory effect for antisense applications, as well as increasing the immunostimulatory effect for immunotherapy applications.

88. 发明授权

US06383752B1 Pseudo-cyclic oligonucleobases 失效
标题翻译：伪循环寡核苷酸
公开(公告)号：US06383752B1
公开(公告)日：2002-05-07
申请号：US09540699
申请日：2000-03-31
申请人： Sudhir Agrawal , Ekambar R. Kandimalla
发明人： Sudhir Agrawal , Ekambar R. Kandimalla
IPC分类号： C12Q168
CPC分类号： C12Q1/6816 , C12Q1/6853 , C12Q2525/125 , C12Q2525/197 , C12Q2525/301
摘要： The present invention comprises a new class of oligonucleobases (e.g., oligonucleotides), which we call “pseudo-cyclic oligonucleotides” (PCOs). PCOs contain two oligonucleotide segments attached through their 3′-3′ or 5′-5′ ends. One of the segments (the “functional segment”) of the PCO has some functionality (e.g., an antisense oligonucleotide complementary to a target mRNA). Another segment (the “protective segment”) is complementary to the 3′- or 5′-terminal end of the functional segment (depending on the end through which it is attached to the functional segment). As a result of complementarity between the functional and protective segment segments, PCOs form intramolecular pseudo-cyclic structures in the absence of the target nucleic acids (e.g., RNA). PCOs are more stable than conventional antisense oligonucleotides because of the presence of 3′-3′ or 5′-5′ linkages and the formation of intramolecular pseudo-cyclic structures. Pharmacokinetic, tissue distribution, and stability studies in mice suggest that PCOs have higher in vivo stability than and, pharmacokinetic and tissue distribution profiles similar to, those of PS-oligonucleotides in general, but rapid elimination from selected tissues. When a fluorophore and quencher molecules are appropriately linked to the PCOs of the present invention, the molecule will fluoresce when it is in the linear configuration, but the fluorescence is quenched in the cyclic conformation. Such oligos are useful for diagnostic purposes.
摘要翻译：本发明包括一类新的寡核苷酸（例如寡核苷酸），我们称之为“伪环寡核苷酸”（PCO）。 PCOs含有通过其3'-3'或5'-5'末端连接的两个寡核苷酸片段。 PCO的一个区段（“功能区段”）具有一些功能（例如，与靶mRNA互补的反义寡核苷酸）。另一段（“保护段”）与功能区段的3'末端或5'末端互补（取决于其连接到功能区段的末端）。由于功能和保护性片段之间的互补性，PCO在不存在靶核酸（例如RNA）的情况下形成分子内假环状结构。由于存在3'-3'或5'-5'键并形成分子内假结构，PCO比常规反义寡核苷酸更稳定。小鼠的药物代谢动力学，组织分布和稳定性研究表明，PCOs的体内稳定性高于药代动力学和组织分布曲线，与通常的PS寡核苷酸类似，但是从选择的组织快速消除。当荧光团和猝灭剂分子适当地连接到本发明的PCO时，当分子处于线性构型时，分子将发荧光，但荧光在循环构象中淬灭。这样的寡核苷酸可用于诊断目的。

89. 发明授权

US5912332A Affinity-based purification of oligonucleotides using soluble multimeric oligonucleotides 失效
标题翻译：使用可溶性多聚寡核苷酸的亲和纯化寡核苷酸
公开(公告)号：US5912332A
公开(公告)日：1999-06-15
申请号：US690300
申请日：1996-07-26
申请人： Sudhir Agrawal , Ivan Habus , Ekambar R. Kandimalla
发明人： Sudhir Agrawal , Ivan Habus , Ekambar R. Kandimalla
IPC分类号： C07H1/06 , C07H21/00 , C12Q1/68
CPC分类号： C07H21/00 , C07H1/06
摘要： The present invention provides novel compounds and methods for purifying oligonucleotides. The compounds according to the invention are multimeric oligonucleotides comprising a multimerization domain for inducing multimeric oligonucleotide aggregation, a hybridization domain that is complementary to a target oligonucleotide whose isolation is desired, and a linker domain connecting the multimerization domain and the hybridization domain. Other compounds of the invention comprise dendrimers having oligonucleotides with hybridization domains linked thereto.The methods of the invention comprise contacting the compounds of the invention with a solution containing a target oligonucleotide whose purification is desired. The target oligonucleotide hybridizes to the hybridization domain of the inventive compounds, thereby forming an aggregate. Synthetic failure sequences (N-1, N-2, etc.) and other oligonucleotides not complementary to the hybridization domain do not hybridize with the hybridization domain of the compounds and remain free in solution. Conventional size exclusion chromatography or small pore filter membranes are then used to separate the aggregate (and hence target oligonucleotide) from the other oligonucleotides. The aggregate is denatured and the target oligonucleotide separated once again by size exclusion chromatography or with a small pore filter membrane.
摘要翻译：本发明提供了用于纯化寡核苷酸的新型化合物和方法。根据本发明的化合物是多聚寡核苷酸，其包含用于诱导多聚寡核苷酸聚集的多聚化结构域，与需要分离的靶寡核苷酸互补的杂交结构域和连接多聚化结构域和杂交结构域的连接体结构域。本发明的其它化合物包含具有与其连接的杂交结构域的寡核苷酸的树枝状大分子。本发明的方法包括使本发明的化合物与含有需要纯化的靶寡核苷酸的溶液接触。靶寡核苷酸与本发明化合物的杂交结构域杂交，从而形成聚集体。合成失败序列（N-1，N-2等）和与杂交结构域不互补的其他寡核苷酸不与化合物的杂交结构域杂交并且在溶液中保持游离。然后使用常规尺寸排阻色谱法或小孔过滤膜将聚集体（因此靶寡核苷酸）与其他寡核苷酸分离。聚集体变性，并且目标寡核苷酸再次通过尺寸排阻色谱法或用小孔滤膜分离。

90. 发明授权

US07709617B2 Synergistic stimulation of the immune system using immunostimulatory oligonucleotides and/or immunomer compounds in conjunction with cytokines and/or chemotherapeutic agents or radiation therapy 失效
标题翻译：使用免疫刺激性寡核苷酸和/或免疫化合物与细胞因子和/或化学治疗剂或放射治疗联合使用免疫系统的协同刺激
公开(公告)号：US07709617B2
公开(公告)日：2010-05-04
申请号：US11173983
申请日：2005-07-01
申请人： Ekambar R. Kandimalla , Sudhir Agrawal
发明人： Ekambar R. Kandimalla , Sudhir Agrawal
IPC分类号： C07H21/04 , C07H21/00 , A61K31/7088 , A61K31/7115
CPC分类号： A61K39/39 , A61K38/2013 , A61K2039/55533 , A61K2039/55561 , A61N2005/1098 , C12N15/111 , C12N15/117 , C12N2310/17 , C12N2320/31 , A61K2300/00
摘要： The invention provides optimized methods and compositions for enhancing the immune response caused by immunostimulatory compounds used for the treatment of disease such as, but not limited to, treatment of cancer, autoimmune disorders, asthma, respiratory allergies, food allergies and infectious diseases in a patient. The optimized methods according to the invention provide synergy between the therapeutic effects of immunostimulatory oligonucleotides and immunomer compounds in accordance with the invention, and the therapeutic effect of cytokine immunotherapy and/or chemotherapeutic agents and/or radiation.
摘要翻译：本发明提供了用于增强用于治疗疾病的免疫刺激化合物引起的免疫应答的优化方法和组合物，所述免疫刺激化合物用于治疗疾病，例如但不限于在患者中治疗癌症，自身免疫疾病，哮喘，呼吸道过敏，食物过敏和感染性疾病。根据本发明的优化方法提供了根据本发明的免疫刺激性寡核苷酸和免疫化合物的治疗效果以及细胞因子免疫治疗和/或化学治疗剂和/或辐射的治疗效果之间的协同作用。

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