CN106535876A - 免疫调节剂通过脂质体球形核酸的多价递送以用于预防或治疗应用 - Google Patents
免疫调节剂通过脂质体球形核酸的多价递送以用于预防或治疗应用 Download PDFInfo
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- CN106535876A CN106535876A CN201580038173.5A CN201580038173A CN106535876A CN 106535876 A CN106535876 A CN 106535876A CN 201580038173 A CN201580038173 A CN 201580038173A CN 106535876 A CN106535876 A CN 106535876A
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Abstract
根据本发明提供了用作多价免疫调节剂的脂质体球形核酸。本发明的脂质体球形核酸是有用的预防性和治疗性应用以及研究和诊断指征。
Description
相关应用
本申请根据35U.S.C.§119(e)要求于2014年6月4日提交的标题为“免疫调节剂通过脂质体球形核酸的多价递送以用于预防或治疗应用”的美国临时申请系列号No.62/007,528的优先权,其通过引用整体并入本文。
发明背景
免疫系统是细胞和体液组分的复杂网络,所述细胞和体液组分一致地作用以识别身体中的外来和潜在危险物质,并以高度靶向和受控的方式消除它们。它通常可以分为先天性和适应性免疫系统。先天免疫系统是种系编码的,并且被设计为对病原体上存在的保守基序进行应答。适应性免疫系统通过受控的体细胞重组过程产生其抗原特异性集库,并可以以精确的特异性对广泛多样的抗原类型进行应答。刺激先天和适应性免疫应答已被证明是治疗或预防动物、动物疾病模型和人类中的广泛多样的疾病的有效策略。
免疫调节方法在治疗或预防各种传染病中的成功是非凡的。尽管如此,可能有可以使用免疫治疗方法来解决的更多的疾病。两个关键的限制仍然是:(1)用在最佳时间和以最佳比例递送的正确信号适当地引导先天免疫细胞,以安全地增强其功能,同时还提供诱导适应性免疫应答的合适环境,和(2)鉴定应该由自适应性应答靶向的正确的抗原或抗原组合。
用于刺激免疫应答的当前方法很大程度上取决于已知单独地为免疫调节性的化合物的混合物。目前,在临床中使用的化合物是免疫刺激剂的成批混合物,任选地与抗原组合,其已经根据经验被确定分别诱导先天和适应性免疫应答。尽管近一个世纪的发展,常规方法仅产生了两种FDA批准的免疫刺激剂:(1)明矾,其是铝盐的组合,和(2)单磷酰脂质A。虽然明矾特别地具有令人印象深刻的安全记录和在感染性疾病上的功效,但越来越清楚的是,这些药剂不足以诱导有效的免疫应答以对抗更复杂的疾病,例如细胞内病原体、癌症、过敏和过敏性疾病等。开发新的免疫刺激剂的努力在很大程度上是不成功的,主要是由于缺乏效力或由于安全性问题。
免疫系统经过几千年发展以对病原体如细菌、病毒、真菌和蠕虫进行应答。因此,大多数免疫细胞被优化以识别、吞噬、加工和然后响应存在于微生物上的基序,并且具有被“调节”至通常存在于这些生物体上的比例的受体。
发明概述
根据本发明的方面提供了用作多价免疫调节剂的脂质体球形核酸。在一些方面,本发明基于纳米结构,其包含具有脂质双层的脂质体核心,其中免疫刺激剂或免疫抑制剂与脂质双层结合,以及位于脂质体核心外部的寡核苷酸。
在一些实施方案中,纳米结构包含具有脂质双层的脂质体核心,其中免疫刺激剂或免疫抑制剂与脂质双层结合,以及位于脂质体核心外部的寡核苷酸,其中寡核苷酸形成寡核苷酸壳。
在其它实施方案中,纳米结构包含具有脂质双层的脂质体核心,其中免疫刺激剂或免疫抑制剂与脂质双层结合,以及位于脂质体核心外部的寡核苷酸,其中寡核苷酸形成寡核苷酸壳,其中寡核苷酸壳包含至少一种模式识别受体调节寡核苷酸。
在一些实施方案中,纳米结构包含具有脂质双层的脂质体核心,其中免疫刺激剂或免疫抑制剂与脂质双层结合,以及位于脂质体核心外部的寡核苷酸,其中寡核苷酸形成寡核苷酸壳,其中寡核苷酸壳包含至少一种模式识别受体调节寡核苷酸,其中模式识别受体调节寡核苷酸是TLR激动剂。
在其它实施方案中,纳米结构包含具有脂质双层的脂质体核心,其中免疫刺激剂或免疫抑制剂与脂质双层结合,以及位于脂质体核心外部的寡核苷酸,其中寡核苷酸形成寡核苷酸壳,其中寡核苷酸壳包含至少一种模式识别受体调节寡核苷酸,其中模式识别受体调节寡核苷酸是TLR拮抗剂。
在其它实施方案中,TLR选自TLR3、TLR7、TLR8、TLR9和TLR13。
在一些实施方案中,纳米结构包含具有脂质双层的脂质体核心,其中免疫刺激剂或免疫抑制剂与脂质双层结合,以及位于脂质体核心外部的寡核苷酸,其中寡核苷酸形成寡核苷酸壳,其中寡核苷酸壳包含至少一种模式识别受体调节寡核苷酸,其中模式识别受体调节寡核苷酸是RIG-I激动剂。
在其它实施方案中,纳米结构包含具有脂质双层的脂质体核心,其中免疫刺激剂或免疫抑制剂与脂质双层结合,以及位于脂质体核心外部的寡核苷酸,其中寡核苷酸形成寡核苷酸壳,其中寡核苷酸壳包含至少一种模式识别受体调节寡核苷酸,其中模式识别受体调节寡核苷酸是RIG-I拮抗剂。
在一些实施方案中,寡核苷酸壳包含寡核苷酸和载体分子。
在一些实施方案中,其中寡核苷酸壳完全由寡核苷酸组成。
在一些实施方案中,寡核苷酸包含单链或双链DNA寡核苷酸。
在其它实施方案中,寡核苷酸包含单链或双链RNA寡核苷酸。
在其它实施方案中,寡核苷酸包含嵌合RNA-DNA寡核苷酸。
在另一个实施方案中,寡核苷酸包含单链或双链DNA、RNA或嵌合RNA-DNA寡核苷酸的组合。
在另一个实施方案中,寡核苷酸壳的寡核苷酸具有结构相同的寡核苷酸。
在一些实施方案中,寡核苷酸壳的寡核苷酸具有至少两种结构不同的寡核苷酸。
在其它实施方案中,寡核苷酸壳的寡核苷酸具有2-10个不同的核苷酸序列。
在一些实施方案中,寡核苷酸具有至少一个硫代磷酸酯键。
在其它实施方案中,寡核苷酸不具有硫代磷酸酯键。
在另一个实施方案中,纳米结构包含具有脂质双层的脂质体核心,其中免疫刺激剂或免疫抑制剂与脂质双层结合,以及位于脂质体核心外部的寡核苷酸,其中寡核苷酸包含含CpG基序的寡核苷酸。
在一些实施方案中,CpG寡核苷酸选自A类、B类和C类CpG寡核苷酸。
在另一个实施方案中,纳米结构包含具有脂质双层的脂质体核心,其中免疫刺激剂或免疫抑制剂与脂质双层结合,以及位于脂质体核心外部的寡核苷酸,其中寡核苷酸包含免疫刺激性单链或双链RNA。
在一些实施方案中,至少一种寡核苷酸的5'-末端暴露于纳米结构的外表面。
在其它实施方案中,所有寡核苷酸的5'-末端暴露于纳米结构的外表面。
在另一个实施方案中,寡核苷酸直接连接至脂质体核心。
在一些实施方案中,寡核苷酸通过接头间接连接至脂质体核心。
在其它实施方案中,寡核苷酸通过多于一个接头间接连接至脂质体核心。
在另一个实施方案中,接头是一个或多个以下接头:生育酚,鞘脂如鞘氨醇、鞘氨醇磷酸酯、甲基化鞘氨醇和二氢鞘氨醇,神经酰胺,神经酰胺磷酸酯,1-0酰基神经酰胺,二氢神经酰胺,2-羟基神经酰胺,鞘磷脂,糖基化鞘脂,硫苷脂,神经节苷脂,鞘磷脂,和各种长度和饱和状态的植物鞘氨醇及其衍生物,磷脂如磷脂酰胆碱,溶血磷脂酰胆碱,磷脂酸,溶血磷脂酸,环状LPA,磷脂酰乙醇胺,溶血磷脂酰乙醇胺,磷脂酰甘油,溶血磷脂酰甘油,磷脂酰丝氨酸,溶血磷脂酰丝氨酸,磷脂酰肌醇,肌醇磷酸酯,LPI,心磷脂,溶血心磷脂,双(单酰基甘油)磷酸酯,(二酰基甘油)磷酸酯,醚脂,二植烷醚脂质,和各种长度和饱和状态的缩醛磷脂及其衍生物,甾醇如胆固醇,去氢胆甾醇,豆甾醇,羊毛甾醇,烯胆甾烷醇,薯蓣皂苷配基,谷甾醇,酵母甾醇,zymostenol,14-脱甲基-羊毛甾醇,胆甾醇硫酸酯,DHEA,DHEA硫酸酯,14-脱甲基-14-脱氢羊毛甾醇,谷甾烷醇,菜油甾醇,醚阴离子脂质,醚阳离子脂质,镧系螯合脂质,A-环取代氧化甾醇,B-环取代氧化甾醇,D-环取代氧化甾醇,侧链取代氧化甾醇,双取代氧化甾醇,胆甾烷酸衍生物,氟化甾醇,荧光甾醇,磺化甾醇,磷酸化甾醇,不同长度、饱和状态的多不饱和甾醇,饱和C8-C22脂肪酸,甘油的饱和C8-C22醚衍生物,C8-C22脂肪酸的饱和和不饱和酰胺衍生物以及单-和1,2-或1,3-二氨基甘油及其衍生物。
在另一个实施方案中,寡核苷酸包含2-1,000个寡核苷酸。
在一些实施方案中,脂质体核心包含选自以下的一种或多种脂质:鞘脂如鞘氨醇、鞘氨醇磷酸酯、甲基化鞘氨醇和二氢鞘氨醇,神经酰胺,神经酰胺磷酸酯,1-0酰基神经酰胺,二氢神经酰胺,2-羟基神经酰胺,鞘磷脂,糖基化鞘脂,硫苷脂,神经节苷脂,鞘磷脂,和各种长度和饱和状态的植物鞘氨醇及其衍生物,磷脂如磷脂酰胆碱,溶血磷脂酰胆碱,磷脂酸,溶血磷脂酸,环状LPA,磷脂酰乙醇胺,溶血磷脂酰乙醇胺,磷脂酰甘油,溶血磷脂酰甘油,磷脂酰丝氨酸,溶血磷脂酰丝氨酸,磷脂酰肌醇,肌醇磷酸酯,LPI,心磷脂,溶血心磷脂,双(单酰基甘油)磷酸酯,(二酰基甘油)磷酸酯,醚脂,二植烷醚脂质,和各种长度和饱和状态的缩醛磷脂及其衍生物,甾醇如胆固醇,去氢胆甾醇,豆甾醇,羊毛甾醇,烯胆甾烷醇,薯蓣皂苷配基,谷甾醇,酵母甾醇,zymostenol,14-脱甲基-羊毛甾醇,胆甾醇硫酸酯,DHEA,DHEA硫酸酯,14-脱甲基-14-脱氢羊毛甾醇,谷甾烷醇,菜油甾醇,醚阴离子脂质,醚阳离子脂质,镧系螯合脂质,A-环取代氧化甾醇,B-环取代氧化甾醇,D-环取代氧化甾醇,侧链取代氧化甾醇,双取代氧化甾醇,胆甾烷酸衍生物,氟化甾醇,荧光甾醇,磺化甾醇,磷酸化甾醇,不同长度、饱和状态的多不饱和甾醇,饱和C8-C22脂肪酸,甘油的饱和C8-C22醚衍生物,C8-C22脂肪酸的饱和和不饱和酰胺衍生物以及单-和1,2-或1,3-二氨基甘油及其衍生物。
在另一个实施方案中,脂质体核心包含一种类型的脂质。
在一些实施方案中,脂质体核心包含2-10种不同的脂质。
在其它实施方案中,其中免疫刺激剂选自单磷酰脂质A,来自细菌来源的脂质A,22:0海藻糖,二甲基双十八烷基铵,Kdo2脂质A,肌醇磷酸酯,包括IP3(1,3,4),IP3(1,3,5),IP3(1,4,5),IPR(1,3,4,5),LPA/S1P受体选择性激动剂,PAF和PAF类似物,脂核苷酸,环状LPA,生物活性神经酰胺,内源性大麻素,大麻素,脂质氧化产物,二酰基甘油磷酸酯,细菌膜脂质,N-酰基甘氨酸脂质,酰基肉碱脂质,分枝菌酸,植物脂质提取物,FSL-1,PAM3CSK4,HKLM,LPS,FLA-ST,咪喹莫特,瑞喹莫德,C12-IE-DAP,L18-MDP toll样受体激动剂,NOD受体激动剂,和促炎免疫受体激动剂。
在另一个实施方案中,纳米结构还包含抗原。
在一些实施方案中,抗原与纳米结构混合在一起。
在其它实施方案中,抗原直接连接至寡核苷酸壳。
在一些实施方案中,抗原通过接头与寡核苷酸壳间接连接。
在其它实施方案中,抗原直接直接连接至脂质体核心。
在另一个实施方案中,抗原通过接头间接连接至脂质体核心。
在另一个实施方案中,其中抗原-寡核苷酸缀合物通过寡核苷酸杂交连接至脂质体核心。
在一些实施方案中,纳米结构包含具有脂质双层的脂质体核心,其中免疫刺激剂或免疫抑制剂与脂质双层结合,以及位于脂质体核心外部的寡核苷酸,其中所述免疫刺激剂通过嵌入脂质体核心内与脂质体核心结合。
在其它实施方案中,纳米结构包含具有脂质双层的脂质体核心,其中免疫刺激剂或免疫抑制剂与脂质双层结合,以及位于脂质体核心外部的寡核苷酸,其中免疫刺激剂通过间接连接至脂质体核心而与脂质体核心结合。
在一些实施方案中,纳米结构包含具有脂质双层的脂质体核心,其中免疫刺激剂或免疫抑制剂与脂质双层结合,以及位于脂质体核心外部的寡核苷酸,其中免疫刺激剂通过直接连接至脂质体核心而与脂质体核心结合。
在一些实施方案中,纳米结构包含具有脂质双层的脂质体核心,其中免疫刺激剂或免疫抑制剂与脂质双层结合,以及位于脂质体核心外部的寡核苷酸,其中寡核苷酸形成寡核苷酸壳,其中寡核苷酸壳的寡核苷酸径向向外定向。
在其它实施方案中,接头选自生育酚,鞘脂如鞘氨醇、鞘氨醇磷酸酯、甲基化鞘氨醇和二氢鞘氨醇,神经酰胺,神经酰胺磷酸酯,1-0酰基神经酰胺,二氢神经酰胺,2-羟基神经酰胺,鞘磷脂,糖基化鞘脂,硫苷脂,神经节苷脂,鞘磷脂,和各种长度和饱和状态的植物鞘氨醇及其衍生物,磷脂如磷脂酰胆碱,溶血磷脂酰胆碱,磷脂酸,溶血磷脂酸,环状LPA,磷脂酰乙醇胺,溶血磷脂酰乙醇胺,磷脂酰甘油,溶血磷脂酰甘油,磷脂酰丝氨酸,溶血磷脂酰丝氨酸,磷脂酰肌醇,肌醇磷酸酯,LPI,心磷脂,溶血心磷脂,双(单酰基甘油)磷酸酯,(二酰基甘油)磷酸酯,醚脂,二植烷醚脂质,和各种长度和饱和状态的缩醛磷脂及其衍生物,甾醇如胆固醇,去氢胆甾醇,豆甾醇,羊毛甾醇,烯胆甾烷醇,薯蓣皂苷配基,谷甾醇,酵母甾醇,zymostenol,14-脱甲基-羊毛甾醇,胆甾醇硫酸酯,DHEA,DHEA硫酸酯,14-脱甲基-14-脱氢羊毛甾醇,谷甾烷醇,菜油甾醇,醚阴离子脂质,醚阳离子脂质,镧系螯合脂质,A-环取代氧化甾醇,B-环取代氧化甾醇,D-环取代氧化甾醇,侧链取代氧化甾醇,双取代氧化甾醇,胆甾烷酸衍生物,氟化甾醇,荧光甾醇,磺化甾醇,磷酸化甾醇,不同长度、饱和状态的多不饱和甾醇,饱和C8-C22脂肪酸,甘油的饱和C8-C22醚衍生物,C8-C22脂肪酸的饱和和不饱和酰胺衍生物以及单-和1,2-或1,3-二氨基甘油及其衍生物。
在一些实施方案中,抗原在内部水层中包封在脂质体核心内。
在其它实施方案中,抗原非共价地连接至寡核苷酸壳的寡核苷酸上。
在其它实施方案中,抗原选自癌抗原、细菌抗原、病毒抗原、寄生虫抗原、半抗原和过敏原。
在一些实施方案中,纳米结构是自组装纳米结构。
本发明的另一方面包括用于治疗受试者的方法,包括向受试者施用有效量的核酸纳米结构以促进免疫应答。
在一个实施方案中,所述受试者患有病症,并且其中所述方法是用于治疗所述病症的方法。
在另一个实施方案中,所述病症是癌症。
在一些实施方案中,所述病症是传染病。
在其它实施方案中,感染性疾病是病毒感染。
在一些实施方案中,感染性疾病是细菌感染。
在另一个实施方案中,所述病症是过敏症。
在一些实施方案中,所述病症是哮喘。
在另一个实施方案中,所述病症是自身免疫疾病。
在一些实施方案中,进一步包括对受试者施用治疗方案。
在另一个实施方案中,治疗方案是手术。
在一些实施方案中,治疗方案是放射。
在其它实施方案中,治疗方案是药物。
在一个实施方案中,所述方法还包括施用佐剂。
在一个实施方案中,所述受试者患有病症,并且其中所述方法是用于治疗所述病症的方法,其中所述纳米结构与靶向分子结合。
在一个实施方案中,受试者患有病症,并且其中所述方法是治疗所述病症的方法,其中所述纳米结构通过选自口服、鼻、舌下、静脉内、皮下、粘膜、呼吸、直接注射、灌肠和皮肤的途径递送。
在另一方面,用于治疗疾病的组合物包含核酸纳米结构及其实施方案。
本发明的每个限制可以包括本发明的各种实施方案。因此,预期涉及任何一个元件或元件组合的本发明的每个限制可以包括在本发明的每个方面中。本发明在其应用中不限于在以下描述中阐述或在附图中示出的构造的细节和组分的布置。本发明能够实现其它实施方案并且能够以各种方式实践或执行。在所附的详细描述、实施例、权利要求和附图中示出了本发明的一个或多个实施方案的细节。本发明的其它特征、目的和优点将根据本说明书和权利要求书而变得明显。
附图说明
附图不旨在按比例绘制。在附图中,在各个图中示出的每个相同或几乎相同的组分由相似的附图标记表示。为了清楚起见,不是每个组分都可以在每个附图中标记。在附图中:
图1显示了用于共递送寡核苷酸和亲脂性免疫刺激剂的本发明的示例性脂质体纳米结构的一般结构。纳米结构包括:(1)脂质体核心,其含有连接至并可能嵌入脂质双层中的亲脂性免疫刺激剂(TLR1,TLR2,TLR4,TLR5,TLR6等),和(2)寡核苷酸壳,其具有双重功能,因为其有助于将整个构建体靶向至免疫细胞,并且还用于刺激可识别核酸的免疫受体(TLR3、TLR7、TLR8、TLR9,TLR13,RIG-I等)。
图2显示了用于共递送寡核苷酸和亲脂性免疫刺激剂和抗原的另一示例性抗原缀合的脂质体纳米结构的一般结构。该构建体与图1所示的构建体相似,但包括另外的修饰,其中抗原缀合的寡核苷酸非共价地连接至母体结构。抗原通过与寡核苷酸壳的相互作用与脂质体SNA缀合。
图3显示了用于共递送寡核苷酸和亲脂性免疫刺激剂和抗原的抗原-缀合的脂质体纳米结构的另一种通用结构。抗原也可以包封在脂质体核心中。
图4是显示通过脂质体纳米结构刺激TLR4和TLR9两者诱导比单独的任一诱导更大的活化的图。携带TLR4和TLR9的激动剂的脂质体纳米结构诱导比单独的任一诱导更大的RAW Blue细胞的活化。
图5A-5B是一组柱状图,其显示MPLA对NF-kB的活化依赖于功能性TLR4。通过含MPLA的脂质体SNA对NF-kB的活化依赖于功能性TLR4,因为RAW Blue细胞系(图5A)而不是Ramos Blue细胞系(图5B)显示响应于刺激的NF-kB活化。单因素ANOVA****p<0.0001,***p<0.001,**p<0.01。
图6A-6B是一组柱状图,其显示CpG和MPLA的纳米结构共递送最佳地活化MyD88-依赖性和非依赖性途径。在单一构建体中递送CpG 1826和MPLA两者的脂质体纳米结构显示不能通过单独递送每一个或通过在相同的孔中而在非相同构建体上递送两种组分重复的升高的TNF(图6A)和IFN-α(图6B)水平。ANOVA,**p<0.01,****p<0.0001。
图7A-7B是一组柱状图,其显示MPLA的脂质体纳米结构递送改善NF-kB的活化,即使没有CpG基序。图7A显示NF-kB活化,图7B显示TNF(OD)。单因素ANOVA****p<0.0001。
图8是显示MPLA进料至纳米结构制剂中在3.8%以上但不超过7.7%的增加提高活性的图。在RAW Blue细胞系中,观察到将MPLA进料增加至7.7%MPLA但不高至11.5%增加了脂质体SNA的活化效力。
图9是一组图表,其显示在11.5%MPLA(上图)或7.7%MPLA(下图),在鼠免疫细胞中硫代磷酸酯(PS)键增加效力但不增加最大刺激。在RAW Blue细胞中,在脂质体纳米结构的效力中观察到偏移,但是在最大刺激中没有观察到偏移,尽管预期这是物种依赖性的。
图10是显示抗原缀合的脂质体纳米结构显示免疫细胞活化的图。
图11是显示纳米结构比游离PS寡核苷酸和明矾更有效地诱导细胞应答的图。在第0天和第21天使用卵白蛋白作为模型抗原,用指定的制剂免疫C57BL/6小鼠(N=4/组)。在第28天,收集脾细胞,并在具有1uM OVA(257-264)的IFN-γELISPOT板上孵育过夜。使用自动化ELISPOT计数器定量IFN-γ斑点的数量。*p<0.05,NS=非显著性
图12是显示具有抗原的中空纳米结构降低肿瘤生长速率的图。在第0天用1×106E.G7-OVA细胞接种C57BL/6小鼠(N=10/组),然后在第3、7、10天用指定化合物处理。
本发明的某些实施方案的详细描述
Toll样受体(TLR)是模式识别受体(PRR)家族,其触发先天免疫细胞的活化,促进其效应子功能和桥接先天和适应性免疫。刺激TLR的药剂作为潜在的治疗和预防化合物被广泛研究,因为这些受体在协调免疫应答中起着中心作用。类似于当免疫细胞处理病原体时刺激多种TLR和免疫受体的方式,已经显示用多种化合物刺激多种TLR可以产生更大的功效。然而,有效地组合递送多种TLR激动剂可能是相当困难的,原因如下:(1)通常仅在两种化合物之间的固定浓度比的窄窗口中观察到协同作用,这是由于它们通常具有不同的IC50或EC50值,(2)不同的物理化学性质(例如不同的大小、电荷和疏水性)可以使它们彼此的连接变得困难或使它们具有完全不同的PK/PD/ADME性质,(3)化合物的毒性水平倾向于是不同的,和(4)一种或多种不同化合物的靶受体可能是不可接近的,例如胞质溶胶,或位于降解区室如内体或溶酶体中。
根据本发明已经开发了具有意想不到的高免疫调节活性的新型纳米结构。这些纳米结构是超分子组装体,其是免疫调节脂质体球形核酸(有时称为SNA)。这些纳米结构可以以高度时空受控的方式向细胞递送免疫调节材料的组合(实例显示在图1-3中)。这些纳米结构的显著特征是在外壳内以及在核心内掺入免疫调节材料,其协同作用以在免疫反应的量级和质量方面实现意想不到的免疫调节效应。这些免疫调节效应不能通过单独地或组合地递送材料而不是在相同构建体中物理地结合在一起来实现。根据本发明已经证明,将所有组分组装成单个结构对于实现最佳效果是至关重要的(数据在图6-7中示出)。
除了上述以外,还开发了用于实现抗原与多价免疫调节结构的共递送的方法(实例描述于图2-3中)。这使得这些构建体能够递送抗原和共刺激信号以桥接先天和适应性免疫以诱导针对各种疾病的强力免疫应答(刺激应用)或通过在不存在共刺激的情况下递送抗原来引发抗原特异性耐受,通过缺乏刺激信号或通过用拮抗剂分子阻断免疫信号传导来实现,从而导致效应细胞无反应或调节性T细胞的诱导(调节应用)。
目前,在临床中用于诱导免疫效应的方法通常分为两类:1)活化或加强免疫应答的化合物,例如疫苗和佐剂,toll样受体的小分子激动剂如咪喹莫特和瑞喹莫德,或寡核苷酸如ISS 1018(Dynavax Technologies Corporation,等,以及2)用于减少不想要的免疫应答的化合物,例如皮质类甾醇、环孢菌素和他克莫司。这些化合物具有本领域技术人员已知的显著限制。
一般来说,现有技术中的免疫刺激尝试受到缺乏活化针对靶抗原的强烈的细胞免疫应答的能力的限制,导致不能开发用于各种感染性疾病(例如HIV,结核病,疟疾,登革热,衣原体等)的有效和成本有效的疫苗。类似地,用于癌症的各种实验疫苗化合物在晚期临床试验中未能达到其主要终点。尚未令人满意地满意的关键挑战是能够获得优异结果的抗原和免疫刺激剂的制剂。本发明的纳米结构实现了这些目标,在体内产生对抗原的强细胞应答的活化,提供了肿瘤负荷的显著(95%)减少的证据(图12)。
本发明的纳米结构包含:(1)具有脂质双层的脂质体核心,其含有嵌入或连接至脂质双层的免疫刺激物,和(2)寡核苷酸层,其可以是寡核苷酸壳,并且其具有双重功能,因为它们有助于将纳米结构靶向至免疫细胞,并且还起到刺激可以识别核酸的免疫受体的作用(图1)。抗原也可以偶联到该构建体,使得其将与共刺激信号一起递送(图2)。与图1所示的构建体相似的构建体经历另外的修饰,由此将抗原缀合的寡核苷酸连接至纳米结构。或者或另外,可将水溶性免疫刺激剂或抗原包封在核心中。
本发明的纳米结构包括脂质体核心。本文使用的脂质体核心是指由形成脂质双层的脂质或磷脂的组分形成的位于中心的核心区室。“脂质体”是各种大小和结构的人工的、自闭的囊泡结构,其中一个或几个膜包封水性核心。最通常地,脂质体膜由脂质双层膜形成,其中亲水性头部基团朝向水性环境定向,并且脂质链嵌入在亲脂性核心中。脂质体也可以由其它两亲性单体和聚合物分子(例如聚合物,如嵌段共聚物或多肽)形成。单层囊泡是由包封水性空间的单个膜限定的脂质体。相比之下,寡层或多层囊泡由几个膜构成。通常,膜大约4nm厚并且包含天然或合成来源的两亲性脂质(例如磷脂)。任选地,膜性质可以通过掺入其它脂质例如甾醇或胆酸衍生物来改变。
脂质双层包含两层脂质分子。层中的每个脂质分子基本上平行于相邻脂质双层定向,并且形成双层的两个层具有其分子的暴露于水相的极性末端和彼此相邻的非极性末端,如图1-3中所示。脂质体核心的中心含水区可以是空的或用水、水性乳液、抗原、免疫刺激剂、免疫抑制剂或其它治疗剂或诊断剂完全或部分填充。
“脂质”是指其常规含义,其是包括不溶于水的原生质的醇-醚可溶性成分、脂肪、脂质的通用术语。脂质通常由亲水部分和疏水部分组成。在水中,脂质可以自组织以形成双层膜,其中亲水部分(头基)朝向水相定向,并且亲脂部分(酰基链)嵌入双层核心中。脂质还可以包含两个亲水部分(bola两亲物)。在这种情况下,膜可以由单个脂质层而不是双层形成。在本文中脂质的典型实例是脂肪,脂肪油,精油,蜡,类甾醇,甾醇,磷脂,糖脂,硫脂,氨基脂,色脂和脂肪酸。该术语包括天然存在的和合成的脂质。与本发明相关的优选脂质是:类甾醇和甾醇,特别是胆甾醇,磷脂,包括磷脂酰,磷脂酰胆碱和磷脂酰乙醇胺和鞘磷脂。当存在脂肪酸时,它们可以是长度为约12-24个碳的链,含有至多6个双键。脂肪酸连接至主链,其可以源自甘油。一种脂质中的脂肪酸可以是不同的(不对称的),或者可以仅存在1个脂肪酸链,例如溶血卵磷脂。混合制剂也是可能的,特别是当非阳离子脂质来源于天然来源时,例如从蛋黄、牛心、脑、肝或大豆纯化的卵磷脂(磷脂酰胆碱)。
脂质体核心可以由本领域技术人员已知的一种或多种脂质构建,包括但不限于:鞘脂如鞘氨醇、鞘氨醇磷酸酯、甲基化鞘氨醇和二氢鞘氨醇,神经酰胺,神经酰胺磷酸酯,1-0酰基神经酰胺,二氢神经酰胺,2-羟基神经酰胺,鞘磷脂,糖基化鞘脂,硫苷脂,神经节苷脂,鞘磷脂,和各种长度和饱和状态的植物鞘氨醇及其衍生物,磷脂如磷脂酰胆碱,溶血磷脂酰胆碱,磷脂酸,溶血磷脂酸,环状LPA,磷脂酰乙醇胺,溶血磷脂酰乙醇胺,磷脂酰甘油,溶血磷脂酰甘油,磷脂酰丝氨酸,溶血磷脂酰丝氨酸,磷脂酰肌醇,肌醇磷酸酯,LPI,心磷脂,溶血心磷脂,双(单酰基甘油)磷酸酯,(二酰基甘油)磷酸酯,醚脂,二植烷醚脂质,和各种长度和饱和状态的缩醛磷脂及其衍生物,甾醇如胆固醇,去氢胆甾醇,豆甾醇,羊毛甾醇,烯胆甾烷醇,薯蓣皂苷配基,谷甾醇,酵母甾醇,zymostenol,14-脱甲基-羊毛甾醇,胆甾醇硫酸酯,DHEA,DHEA硫酸酯,14-脱甲基-14-脱氢羊毛甾醇,谷甾烷醇,菜油甾醇,醚阴离子脂质,醚阳离子脂质,镧系螯合脂质,A-环取代氧化甾醇,B-环取代氧化甾醇,D-环取代氧化甾醇,侧链取代氧化甾醇,双取代氧化甾醇,胆甾烷酸衍生物,氟化甾醇,荧光甾醇,磺化甾醇,磷酸化甾醇,不同长度、饱和状态的多不饱和甾醇及其衍生物。
免疫刺激剂与脂质体核心的脂质双层结合。如本文所使用的免疫刺激剂是引起免疫系统的刺激以使得诱导或活化一种或多种免疫因子(即细胞因子,免疫细胞,抗体,趋化因子)的物质。免疫应答可以包括细胞和/或体液应答。免疫刺激剂可以是例如小分子,核酸,蛋白质或其组合。免疫刺激剂还可以能够活化局部微环境的细胞上的免疫刺激分子的表达。
并入双层中的免疫刺激剂可以是广泛多样的分子,包括但不限于:单磷酰脂质A,来自细菌来源的脂质A,22:0海藻糖,二甲基双十八烷基铵,Kdo2脂质A,肌醇磷酸酯,包括IP3(1,3,4),IP3(1,3,5),IP3(1,4,5),IPR(1,3,4,5),LPA/S1P受体选择性激动剂,PAF和PAF类似物,脂核苷酸,环状LPA,生物活性神经酰胺,内源性大麻素,大麻素,脂质氧化产物,二酰基甘油磷酸酯,细菌膜脂质,N-酰基甘氨酸脂质,酰基肉碱脂质,分枝菌酸,植物脂质提取物,FSL-1,PAM3CSK4,HKLM,LPS,FLA-ST,咪喹莫特,瑞喹莫德,C12-IE-DAP,L18-MDP toll样受体激动剂,NOD受体激动剂,和对于诱导免疫应答会是有效的其它促炎免疫受体激动剂。
免疫刺激剂与脂质体核心结合。其可以通过嵌入在核心内结合或其可以间接(即通过其它分子如接头非共价地或共价地)或直接(即共价地)附接或连接。
本发明的纳米结构还包括优选为治疗性寡核苷酸的寡核苷酸。本文所用的寡核苷酸是指任何含有核酸的分子。核酸可以是DNA,RNA,PNA,LNA,ENA或其组合或修饰。它也可以是单链、双链或三链。治疗性寡核苷酸是可以用作治疗剂和/或诊断剂的寡核苷酸。
寡核苷酸位于脂质体核心的外部。至少一个寡核苷酸在外部。在一些实施方案中,至少25、50、75、100、200、300、400、500、600、700、800、900或1,000个寡核苷酸或其任何范围组合位于脂质体核心的外部。在一些实施方案中,1-1000、10-500、50-250或50-300个寡核苷酸存在于表面上。在一些情况下,寡核苷酸形成寡核苷酸壳。当脂质体的外表面的至少50%的可用表面积包括寡核苷酸时,形成寡核苷酸壳。在一些实施方案中,脂质体外表面的可用表面积的至少60%,70%,80%,90%,95%,96%,97%,98%或99%包括寡核苷酸。寡核苷酸壳的寡核苷酸可以以多个方向定向。在一些实施方案中,寡核苷酸径向向外定向。
寡核苷酸可以直接或通过接头间接地连接至核心或彼此连接和/或连接至其它分子如抗原。寡核苷酸可以通过5'端或3'端与接头缀合。例如。[序列,5'-3']-接头或接头-[序列,5'-3']。纳米结构的一些或所有寡核苷酸可以通过共价或非共价键直接或间接地彼此连接。一个寡核苷酸与另一个寡核苷酸的连接可以是该寡核苷酸与脂质体核心的连接的补充或替代。一个或多个寡核苷酸还可以与其它分子如抗原连接。寡核苷酸可以直接或间接地通过共价或非共价键连接至核心的抗原。
寡核苷酸壳可以是广泛多样的分子,包括但不限于:单链脱氧核糖核苷酸、核糖核苷酸和掺入本领域技术人员已知的一种或多种修饰的其它单链寡核苷酸,双链脱氧核糖核苷酸、核糖核苷酸,和掺入本领域技术人员已知的一种或多种修饰的其它双链寡核苷酸,掺入脱氧核糖核苷酸、核糖核苷酸或掺入本领域技术人员已知的一种或多种修饰的寡核苷酸的寡核苷酸三链体。在另一个实施方案中,一种或多种不同的寡核苷酸存在于单个脂质体纳米结构的相同表面上。
寡核苷酸壳可以通过与一个或多个接头分子缀合而锚定到脂质体核心的表面,所述接头分子包括但不限于:生育酚,鞘脂如鞘氨醇、鞘氨醇磷酸酯、甲基化鞘氨醇和二氢鞘氨醇,神经酰胺,神经酰胺磷酸酯,1-0酰基神经酰胺,二氢神经酰胺,2-羟基神经酰胺,鞘磷脂,糖基化鞘脂,硫苷脂,神经节苷脂,鞘磷脂,和各种长度和饱和状态的植物鞘氨醇及其衍生物,磷脂如磷脂酰胆碱,溶血磷脂酰胆碱,磷脂酸,溶血磷脂酸,环状LPA,磷脂酰乙醇胺,溶血磷脂酰乙醇胺,磷脂酰甘油,溶血磷脂酰甘油,磷脂酰丝氨酸,溶血磷脂酰丝氨酸,磷脂酰肌醇,肌醇磷酸酯,LPI,心磷脂,溶血心磷脂,双(单酰基甘油)磷酸酯,(二酰基甘油)磷酸酯,醚脂,二植烷醚脂质,和各种长度和饱和状态的缩醛磷脂及其衍生物,甾醇如胆固醇,去氢胆甾醇,豆甾醇,羊毛甾醇,烯胆甾烷醇,薯蓣皂苷配基,谷甾醇,酵母甾醇,zymostenol,14-脱甲基-羊毛甾醇,胆甾醇硫酸酯,DHEA,DHEA硫酸酯,14-脱甲基-14-脱氢羊毛甾醇,谷甾烷醇,菜油甾醇,醚阴离子脂质,醚阳离子脂质,镧系螯合脂质,A-环取代氧化甾醇,B-环取代氧化甾醇,D-环取代氧化甾醇,侧链取代氧化甾醇,双取代氧化甾醇,胆甾烷酸衍生物,氟化甾醇,荧光甾醇,磺化甾醇,磷酸化甾醇,不同长度、饱和状态的多不饱和甾醇及其衍生物。寡核苷酸可以是与分子或分子的复合物相互作用的核酸,所述分子或分子的复合物在被刺激时,响应于该相互作用产生免疫应答。分子或分子的复合物可以是受体。在一些实施方案中,寡核苷酸可以是模式识别受体(PRR)调节寡核苷酸。PRR是包含由先天免疫系统的细胞表达以鉴定与微生物病原体或细胞应激相关的病原体相关分子模式(PAMP)以及与在细胞损伤期间释放的细胞组分相关的损伤相关分子模式(DAMP)的蛋白质的免疫系统的原始部分。PRR包括但不限于膜结合的PRR,例如受体激酶,toll样受体(TLR)和C型凝集素受体(CLR)(甘露糖受体和脱唾液酸糖蛋白受体);细胞质PRR例如RIG-I样受体(RLR),RNA解旋酶,植物PRR和NonRD激酶;和分泌的PRR。PRR调节寡核苷酸包括但不限于TLR激动剂,RIG-I的激动剂或拮抗剂,转录因子,细胞翻译机构,细胞转录机构,核酸作用酶和结合核酸的自身抗原。该实施方案的一个实例是使用未甲基化的5'-胞嘧啶-磷酸-鸟苷-3'(CpG)基序。另一个是使用5'-UUG-3'或5'-UUA-3'基序。另一个是使用长双链RNA。
本文所用的TLR激动剂是与TLR相互作用并刺激TLR活性的核酸分子。Toll样受体(TLR)是在哺乳动物的先天免疫中起关键作用的高度保守的多肽家族。已经鉴定了至少10个家族成员,命名为TLR1-TLR10。各种TLR的胞质结构域的特征在于Toll-白细胞介素1(IL-1)受体(TIR)结构域。Medzhitov R等人(1998)Mol Cell 2:253-8。通过TLR的微生物侵入的识别触发在果蝇(Drosophila)和哺乳动物中进化保守的信号级联的活化。据报道,含有TIR域的衔接蛋白MyD88与TLR结合,并将IL-1受体相关激酶(IRAK)和肿瘤坏死因子(TNF)受体相关因子6(TRAF6)募集至TLR。认为MyD88依赖性信号传导途径导致NF-κB转录因子和c-JunNH2末端激酶(Jnk)丝裂原活化蛋白激酶(MAPK)的活化,这是免疫活化和炎症细胞因子的产生的关键步骤。关于综述,参见Aderem A等人(2000)Nature 406:782-87。
认为TLR在各种组织中和在各种类型的免疫细胞上差异表达。例如,已报道人TLR7在胎盘、肺、脾、淋巴结、扁桃体中和在浆细胞样前体树突细胞(pDC)上表达。Chuang T-H等人(2000)Eur Cytokine Netw 11:372-8);Kadowaki N等人(2001)J Exp Med 194:863-9。据报道,人TLR8在肺、外周血白细胞(PBL)、胎盘、脾、淋巴结中和在单核细胞上表达。Kadowaki N等人(2001)J Exp Med 194:863-9;Chuang T-H等人(2000)Eur Cytokine Netw11:372-8。人TLR9据报道在脾、淋巴结、骨髓、PBL中和在pDC和B细胞上表达。Kadowaki N等人(2001)J Exp Med 194:863-9;Bauer S等人(2001)Proc Natl Acad Sci USA 98:9237-42;Chuang T-H等人(2000)Eur Cytokine Netw 11:372-8。
人和鼠TLR7的核苷酸和氨基酸序列是已知的。参见例如GenBank登录号AF240467,AF245702,NM_016562,AF334942,NM_133211;和AAF60188,AAF78035,NP_057646,AAL73191和AAL73192,其全部内容通过引用并入本文。人TLR7被报道为1049个氨基酸长。鼠TLR7被报道为1050个氨基酸长。TLR7多肽包括具有富含亮氨酸的重复区的胞内结构域、跨膜结构域和包括TIR结构域的胞外结构域。
人和鼠TLR8的核苷酸和氨基酸序列是已知的。参见例如GenBank登录号AF246971,AF245703,NM_016610,XM_045706,AY035890,NM_133212;和AAF64061,AAF78036,NP_057694,XP_045706,AAK62677和NP_573475,其全部内容通过引用并入本文。据报道,人TLR8以至少两种同种型存在,一个1041个氨基酸长,另一个1059个氨基酸长。鼠TLR8的长度为1032个氨基酸。TLR8多肽包括具有富含亮氨酸的重复区的胞内结构域、跨膜结构域和包括TIR结构域的胞外结构域。
人和鼠TLR9的核苷酸和氨基酸序列是已知的。参见例如GenBank登录号NM_017442,AF259262,AB045180,AF245704,AB045181,AF348140,AF314224,NM_031178;和NP_059138,AAF72189,BAB19259,AAF78037,BAB19260,AAK29625,AAK28488和NP_112455,其全部内容通过引用并入本文。据报道,人TLR9以至少两种同种型存在,一个为1032个氨基酸,另一个为1055个氨基酸。鼠TLR9的长度为1032个氨基酸。TLR9多肽包括具有富含亮氨酸的重复区的胞内结构域、跨膜结构域和包括TIR结构域的胞外结构域。
如本文所用,术语“TLR信号传导”是指与通过TLR的信号传导相关的细胞内信号传导的任何方面。如本文所用,术语“TLR介导的免疫应答”是指与TLR信号传导相关的免疫应答。TLR信号传导的水平可以被增强超过预先存在的信号传导水平,或者可以被诱导超过信号传导的背景水平。
TLR3介导的免疫应答是与TLR3信号传导相关的应答。TLR3激动剂包括但不限于dsRNA,例如具有多个AU基序的dsRNA。
TLR7介导的免疫应答是与TLR7信号传导相关的应答。TLR7介导的免疫应答通常特征在于诱导IFN-α和IFN诱导性细胞因子例如IP-10和I-TAC。在TLR7介导的免疫应答中诱导的细胞因子IL-1α/β、IL-6、IL-8、MIP-1α/β和MIP-3α/β的水平小于在TLR8介导的免疫应答中诱导的水平。TLR7配体包括但不限于鸟苷类似物例如C8-取代的鸟苷,基本上由G和U组成的核糖核苷的混合物,鸟苷核糖核苷酸和RNA或RNA样分子(PCT/US03/10406)和基于腺苷的化合物(例如,6-氨基-9-苄基-2-(3-羟基-丙氧基)-9H-嘌呤-8-醇和由Sumitomo制备的类似化合物(例如CL-029))。
如本文所用,术语“鸟苷类似物”是指具有牵涉鸟嘌呤碱基、鸟苷核苷糖或鸟嘌呤碱基和鸟苷核苷糖两者的化学修饰的鸟苷样核苷酸(不包括鸟苷)。鸟苷类似物具体包括但不限于7-脱氮-鸟苷。
鸟苷类似物还包括C8-取代的鸟苷,例如7-硫杂-8-氧代鸟苷(immunosine),8-巯基鸟苷,8-溴鸟苷,8-甲基鸟苷,8-氧代-7,8-二氢鸟苷,C8-芳基氨基-2'-脱氧鸟苷,C8-丙炔基-鸟苷,C8-和N7-取代的鸟嘌呤核糖核苷例如7-烯丙基-8-氧代鸟苷(洛索立宾)和7-甲基-8-氧代鸟苷,8-氨基鸟苷,8-羟基-2'-脱氧鸟苷,8-羟基鸟苷和7-脱氮8-取代的鸟苷。
TLR8介导的免疫应答是与TLR8信号传导相关的应答。该应答的特征还在于促炎细胞因子例如IFN-γ、IL-12p40/70、TNF-α、IL-1α/β、IL-6、IL-8、MIP-1α/β和MIP-3α/β的诱导。TLR8配体包括基本上由G和U组成的核糖核苷的混合物,鸟苷核糖核苷酸和RNA或RNA样分子(PCT/US03/10406)。另外的TLR8配体也公开于Gorden等人J.Immunol.2005,174:1259-1268。
如本文所用,“TLR7/8激动剂”共同地指能够增加TLR7和/或TLR8信号传导的任何核酸(即,TLR7和/或TLR8的激动剂)。一些TLR7/8配体单独诱导TLR7信号传导(例如TLR7特异性激动剂),一些诱导单独的TLR8信号传导(例如TLR8特异性激动剂),以及其它诱导TLR7和TLR8信号传导两者。
TLR9介导的免疫应答是与TLR9信号传导相关的应答。该应答的特征至少进一步在于IFN-γ和IL-12的产生/分泌,尽管其水平低于通过TLR8介导的免疫应答实现的水平。如本文所用,术语“TLR9激动剂”是指能够增加TLR9信号传导的任何试剂(即,TLR9的激动剂)。TLR9激动剂特别包括但不限于免疫刺激性核酸,特别是CpG免疫刺激性核酸。
“免疫刺激性CpG核酸”或“免疫刺激性CpG寡核苷酸”是指能够活化免疫细胞的任何含CpG的核酸。至少CpG二核苷酸的C通常但不一定是未甲基化的。免疫刺激性CpG核酸描述于许多授权的专利和公开的专利申请中,包括美国专利号6,194,388;6,207,646;6,218,371;6,239,116;6,339,068;6,406,705;和6,429,199。
TLR13介导的免疫应答是与TLR13信号传导相关的应答。TLR13激动剂是细菌23SrRNA。
寡核苷酸还可以是视黄酸诱导型基因-I(RIG-I)激动剂或拮抗剂。RIG-I对应于GenBank登录号AF038963。RIG-I激动剂包括但不限于dsRNA,例如聚(I:C)。RIG-I拮抗剂包括短的5'三磷酸DNA或RNA。
“免疫刺激性寡核苷酸”是含有能够诱导免疫应答的免疫刺激基序或主链的任何核酸(DNA或RNA)。免疫应答的诱导是指免疫细胞的数量或活性的任何增加,或免疫因子例如细胞因子的表达或绝对水平的增加。免疫细胞包括但不限于NK细胞,CD4+T淋巴细胞,CD8+T淋巴细胞,B细胞,树突状细胞,巨噬细胞和其它抗原呈递细胞。细胞因子包括但不限于白细胞介素,TNF-α,IFN-α,β和γ,Flt-配体和共刺激分子。免疫刺激基序包括但不限于CpG基序和富含T的基序。
免疫刺激性寡核苷酸的非限制性集合包括:
dsRNA:
聚(A:C)和聚(I:C)
ssRNA:
CCGUCUGUUGUGUGACUC(SEQ ID NO:4)
GCCACCGAGCCGAAGGCACC(SEQ ID NO:6)
UAUAUAUAUAUAUAUAUAUA(SEQ ID NO:7)
UUAUUAUUAUUAUUAUUAUU(SEQ ID NO:8)
UUUUAUUUUAUUUUAUUUUA(SEQ ID NO:9)
UGUGUGUGUGUGUGUGUGUG(SEQ ID NO:10)
UUGUUGUUGUUGUUGUUGUU(SEQ ID NO:11)
UUUGUUUGUUUGUUUGUUUG(SEQ ID NO:12)
UUAUUUAUUUAUUUAUUUAUUUAU(SEQ ID NO:13)
UUGUUUGUUUGUUUGUUUGUUUGU(SEQ ID NO:14)
GCCCGUCUGUUGUGUGACUC(SEQ ID NO:15)
GUCCUUCAAGUCCUUCAA(SEQ ID NO:16)
DNA:
GGTGCATCGATGCAGGGGGG(SEQ ID NO:5)
TCCATGGACGTTCCTGAGCGTT(SEQ ID NO:17)
TCGTCGTTCGAACGACGTTGAT(SEQ ID NO:18)
TCGTCGACGATCCGCGCGCGCG(SEQ ID NO:19)
GGGGTCAACGTTGAGGGGGG(SEQ ID NO:20)
TCGTCGTTTTGTCGTTTTGTCGTT(SEQ ID NO:21)
TCGTCGTTGTCGTTTTGTCGTT(SEQ ID NO:22)
GGGGGACGATCGTCGGGGGG(SEQ ID NO:23)
GGGGACGACGTCGTGGGGGGG(SEQ ID NO:24)
TCGTCGTTTTCGGCGCGCGCCG(SEQ ID NO:25)
TCGTCGTCGTTCGAACGACGTTGAT(SEQ ID NO:26)
术语“寡核苷酸”和“核酸”可互换使用,是指多个核苷酸(即,包含连接至磷酸基团和可交换有机碱基的糖(例如,核糖或脱氧核糖)的分子,所述碱基是取代的嘧啶(例如胞嘧啶(C),胸苷(T)或尿嘧啶(U))或取代的嘌呤(例如腺嘌呤(A)或鸟嘌呤(G))。因此,该术语包括DNA和RNA寡核苷酸。该术语应还包括寡核苷(即减去磷酸酯的寡核苷酸)和任何其它含有机碱基的聚合物。寡核苷酸可以从现有的核酸来源(例如基因组或cDNA)获得,但是优选是合成的(例如,通过核酸合成产生的)。
寡核苷酸可以是单链或双链的。双链寡核苷酸在本文中也称为双链体。本发明的双链寡核苷酸可以包含两条分开的互补核酸链。
如本文所用,“双链体”包括其中互补序列或部分互补序列彼此氢键键合的双链核酸分子。互补序列可以包括有义链和反义链。反义核苷酸序列可以与靶基因相同或充分相同,以介导对靶基因序列的有效靶基因抑制(例如,至少约98%相同,96%相同,94%,90%相同,85%相同或80%相同)。
双链寡核苷酸可以在其整个长度上是双链的,意味着它没有突出的单链序列,因此是平端的。在其它实施方案中,双链寡核苷酸的两条链可具有不同长度,从而产生一个或多个单链突出端。本发明的双链寡核苷酸可以含有错配和/或环或凸起。在一些实施方案中,其在寡核苷酸长度的至少约70%、80%、90%、95%、96%、97%、98%或99%上是双链的。在一些实施方案中,本发明的双链寡核苷酸含有至少或至多1、2、3、4、5、6、7、8、9、10、11、12、13、14或15个错配。
与本发明相关的寡核苷酸可以被修饰,例如在糖部分、磷酸二酯键和/或碱基处。如本文所用,“糖部分”包括天然的、未修饰的糖,包括戊糖、核糖和脱氧核糖,修饰的糖和糖类似物。糖部分的修饰可以包括用卤素、杂原子或脂族基团置换羟基,并且可以包括羟基官能化为例如醚、胺或硫醇。
糖部分的修饰可包括被称为“甲基化”的2'-O-甲基核苷酸。在一些情况下,与本发明相关的寡核苷酸可仅含有修饰的或未修饰的糖部分,而在其它情况下,寡核苷酸含有一些被修饰的糖部分和一些未被修饰的部分。
在一些情况下,修饰的核苷酸单体包括糖-或主链-修饰的核糖核苷酸。修饰的核糖核苷酸可以含有非天然存在的碱基,例如在5'-位修饰的尿苷或胞苷,例如5'-(2-氨基)丙基尿苷和5'-溴尿苷;在8-位修饰的腺苷和鸟苷,例如8-溴鸟苷;脱氮核苷酸,例如7-脱氮-腺苷;和N-烷基化核苷酸,例如N6-甲基腺苷。此外,糖修饰的核糖核苷酸可以具有被H、烷氧基(或OR)、R或烷基、卤素、SH、SR、氨基(例如NH2,NHR,NR2)、或CN基团取代的2'-OH基团,其中R是低级烷基、烯基或炔基。在一些实施方案中,修饰的核糖核苷酸可以具有修饰基团例如硫代磷酸酯基团取代的连接至相邻核糖核苷酸的磷酸二酯基团。
在一些方面,2'-O-甲基修饰对于减少不期望的细胞应激反应例如对双链核酸的干扰素反应可以是有益的。修饰的糖可以包括D-核糖,2'-O-烷基(包括2'-O-甲基和2'-O-乙基),即2'-烷氧基,2'-氨基,2'-S-烷基,2′-卤代(包括2'-氟代),2'-甲氧基乙氧基,2'-烯丙氧基(-OCH2CH=CH2),2'-炔丙基,2'-丙基,乙炔基,乙烯基,丙烯基和氰基等。糖部分也可以是己糖。
术语“烷基”包括饱和脂肪族基,包括直链烷基(例如甲基,乙基,丙基,丁基,戊基,己基,庚基,辛基,壬基,癸基等),支链烷基(异丙基,叔丁基,异丁基等),环烷基(脂环族)基团(环丙基,环戊基,环己基,环庚基,环辛基),烷基取代的环烷基和环烷基取代的烷基。在一些实施方案中,直链或支链烷基在其主链中具有6个或更少的碳原子(例如,对于直链为C1-C6,对于支链为C3-C6),更优选为4个或更少。类似地,优选的环烷基在其环结构中具有3-8个碳原子,更优选在环结构中具有5或6个碳。术语C1-C6包括含有1至6个碳原子的烷基。
除非另有说明,术语烷基包括“未取代的烷基”和“取代的烷基”,其中后者是指具有独立选择的取代烃主链的一个或多个碳上的氢的取代基的烷基部分。术语“烯基”包括在长度和可能的取代上类似于上述烷基但含有至少一个双键的不饱和脂族基团。除非另有说明,术语烯基包括“未取代的烯基”和“取代的烯基”,其中后者是指具有独立选择的取代烃主链的一个或多个碳上的氢的取代基的烯基部分。
术语“碱基”包括已知的嘌呤和嘧啶杂环碱基,脱氮嘌呤和类似物(包括杂环取代的类似物,例如氨基乙氧基吩恶嗪),其衍生物(例如1-烷基-、1-烯基-、杂芳族-和1-炔基衍生物)和互变异构体。嘌呤的实例包括腺嘌呤,鸟嘌呤,肌苷,二氨基嘌呤和黄嘌呤以及其类似物(例如8-氧代-N6-甲基腺嘌呤或7-二氮杂黄嘌呤)和衍生物。嘧啶包括例如胸腺嘧啶、尿嘧啶和胞嘧啶及其类似物(例如5-甲基胞嘧啶,5-甲基尿嘧啶,5-(1-丙炔基)尿嘧啶,5-(1-丙炔基)胞嘧啶和4,4-乙烷基胞嘧啶)。合适的碱基的其它实例包括非嘌呤基和非嘧啶基碱基例如2-氨基吡啶和三嗪。
在一些方面,本发明的寡核苷酸的核苷酸单体是RNA核苷酸,包括修饰的RNA核苷酸。
术语“核苷”包括与糖部分(优选核糖或脱氧核糖)共价连接的碱基。优选的核苷的实例包括核糖核苷和脱氧核糖核苷。核苷还包括与可包含游离羧基、游离氨基或保护基的氨基酸或氨基酸类似物连接的碱基。合适的保护基团是本领域熟知的(参见P.G.M.Wutsand T.W.Greene,“Protective Groups in Organic Synthesis”,2nd Ed.,Wiley-Interscience,New York,1999)。
如本文所用,在核苷酸间键联的上下文中使用的术语“键联”包括共价偶联相邻核苷酸单体的天然存在的未修饰的磷酸二酯部分(-O-(PO2-)-O-)。如本文所用,术语“替代键联接”或“修饰的键联”或“修饰的核苷酸间键联”包括共价偶联相邻核苷酸单体的天然磷酸二酯基团的任何类似物或衍生物。取代键联包括磷酸二酯类似物,例如硫代磷酸酯,二硫代磷酸酯,和P-ethyoxyphosphodiester,P-乙氧基磷酸二酯,P-烷氧基磷酸三酯,甲基膦酸酯,和不含磷的键联,例如缩醛和酰胺。这种替代键联是本领域已知的(例如,Bjergarde等人1991.Nucleic Acids Res.19:5843;Caruthers等人 1991.NucleosidesNucleotides.10:47)。在某些实施方案中,优选不可水解的键联,例如硫代磷酸酯键联。
在一些方面,本发明的寡核苷酸包含3'和5'末端(除了环状寡核苷酸)。寡核苷酸的3'和5'末端可以基本上保护免于核酸酶,例如通过修饰3'或5'键联(例如,美国专利号5,849,902和WO 98/13526)。寡核苷酸可以通过包含“封闭基团”而具有抗性。如本文所用的术语“封闭基团”是指可以连接至寡核苷酸或核苷酸单体的取代基(例如,除OH基团之外的基团),作为保护基团或用于合成的偶联基团(例如FITC,丙基(CH2-CH2-CH3),二醇(-O-CH2-CH2-O-)磷酸酯(PO3 2-),膦酸氢酯或亚磷酰胺。“封闭基团”还包括保护寡核苷酸的5'和3'末端的“末端封闭基团”或“外切核酸酶封闭基团”,包括修饰的核苷酸和非核苷酸外切核酸酶抗性结构。
示例性的末端封闭基团包括帽结构(例如7-甲基鸟苷帽),反向核苷酸单体,例如具有3'-3'或5'-5'末端倒置(参见,例如Ortiagao等人1992.Antisense Res.Dev.2:129),膦酸甲酯,亚磷酰胺,非核苷酸基团(例如,非核苷酸接头,氨基接头,缀合物)等。3'末端核苷酸单体可包含修饰的糖部分。3'末端核苷酸单体包含3'-O,其可以任选地被阻止寡核苷酸的3'-外切核酸酶降解的封闭基团取代。例如,3'-羟基可以通过3'→3'核苷酸间键联被酯化成核苷酸。例如,烷氧基自由基可以是甲氧基,乙氧基或异丙氧基,优选是乙氧基。任选地,3'端的3'→3'连接的核苷酸可以通过替代键联连接。为了降低核酸酶降解,最5'的3'→5'键联可以是修饰的键联,例如硫代磷酸酯或P-烷基氧基磷酸三酯键联。优选地,两个最5'的3'→5'键联是修饰的键联。任选地,5'末端羟基部分可以用含磷部分例如磷酸酯、硫代磷酸酯或P-乙氧基磷酸酯化。
在一些方面,寡核苷酸可以是包括DNA和RNA二者的嵌合RNA-DNA寡核苷酸。
寡核苷酸的长度优选为6至100个碱基。然而,如果存在足够的刺激基序,则大于4个核苷酸(甚至许多kb长)的任何大小的核酸能够诱导根据本发明的生物应答。优选地,核酸的大小在8至100个之间,并且在一些实施方案中在8至50或8至30个核苷酸之间的范围内。
在一些实施方案中,寡核苷酸具有修饰的主链,例如硫代磷酸酯(PS)主链。在其它实施方案中,寡核苷酸具有磷酸二酯(PO)主链。在其它实施方案中,寡核苷酸具有混合或嵌合的PO和PS主链。
纳米结构还可以包含抗原。本文所用的抗原是能够在体内引发免疫应答,特别是产生抗体的分子。抗原包括但不限于细胞,细胞提取物,蛋白质,多肽,肽,多糖,多糖缀合物,多糖和其它分子的肽和非肽模拟物,小分子,脂质,糖脂,碳水化合物,病毒和病毒提取物和多细胞生物体如寄生虫和过敏原。术语抗原广泛地包括被宿主免疫系统识别为外源的任何类型的分子。抗原包括但不限于癌抗原,微生物抗原和过敏原。
抗原可以通过向外朝向的寡核苷酸共价或非共价(例如Watson/Crick杂交)连接至结构。或者或另外,可以通过与疏水部分缀合将抗原掺入脂质体双层中(图2-3)。本文提供的数据证明,这种形式的抗原递送在体外诱发了意想不到的更强的免疫刺激效应诱导(图10),并诱导有效的抗原加工和呈递,从而导致在体内以高度意想不到的水平有效诱导抗肿瘤免疫应答(图11-12)。在另一个实施方案中,可以将抗原掺入脂质体的内部水层内(图3)。
在一个实施方案中,抗原通过与寡核苷酸壳的相互作用与脂质体纳米结构缀合(图2)。在一些情况下,抗原-寡核苷酸缀合物通过寡核苷酸杂交与脂质体核心连接。换句话说,寡核苷酸与互补或部分互补的寡核苷酸杂交以形成双链体或部分双链体。双链体的一个或两个寡核苷酸直接连接至脂质体核心并且面向外部(在脂质双层的外部)或在内部(在内部水层中)且不直接连接至脂质体核心的抗原连接至双链体中的一个或两个寡核苷酸。在另一个实施方案中,抗原通过与脂质体核心的直接相互作用与脂质体纳米结构缀合(图3)。抗原可以通过与一个或多个接头分子缀合而锚定到脂质体核心的表面,所述接头分子包括但不限于:生育酚,鞘脂如鞘氨醇、鞘氨醇磷酸酯、甲基化鞘氨醇和二氢鞘氨醇,神经酰胺,神经酰胺磷酸酯,1-0酰基神经酰胺,二氢神经酰胺,2-羟基神经酰胺,鞘磷脂,糖基化鞘脂,硫苷脂,神经节苷脂,鞘磷脂,和各种长度和饱和状态的植物鞘氨醇及其衍生物,磷脂如磷脂酰胆碱,溶血磷脂酰胆碱,磷脂酸,溶血磷脂酸,环状LPA,磷脂酰乙醇胺,溶血磷脂酰乙醇胺,磷脂酰甘油,溶血磷脂酰甘油,磷脂酰丝氨酸,溶血磷脂酰丝氨酸,磷脂酰肌醇,肌醇磷酸酯,LPI,心磷脂,溶血心磷脂,双(单酰基甘油)磷酸酯,(二酰基甘油)磷酸酯,醚脂,二植烷醚脂质,和各种长度和饱和状态的缩醛磷脂及其衍生物,甾醇如胆固醇,去氢胆甾醇,豆甾醇,羊毛甾醇,烯胆甾烷醇,薯蓣皂苷配基,谷甾醇,酵母甾醇,zymostenol,14-脱甲基-羊毛甾醇,胆甾醇硫酸酯,DHEA,DHEA硫酸酯,14-脱甲基-14-脱氢羊毛甾醇,谷甾烷醇,菜油甾醇,醚阴离子脂质,醚阳离子脂质,镧系螯合脂质,A-环取代氧化甾醇,B-环取代氧化甾醇,D-环取代氧化甾醇,侧链取代氧化甾醇,双取代氧化甾醇,胆甾烷酸衍生物,氟化甾醇,荧光甾醇,磺化甾醇,磷酸化甾醇,不同长度、饱和状态的多不饱和甾醇及其衍生物。
本文使用的癌抗原是与肿瘤或癌细胞表面相关的化合物,例如肽或蛋白质,其当在MHC分子的背景下在抗原呈递细胞的表面上表达时能够引发免疫应答。癌抗原可以通过制备癌细胞的粗提取物来从癌细胞制备,例如,如Cohen,等人,1994,Cancer Research,54:1055中所述,通过部分纯化抗原来制备,通过重组技术来制备,或通过从头合成已知抗原来制备。癌抗原包括但不限于重组表达的抗原,肿瘤或癌症的免疫原性部分或整个肿瘤或癌症。此类抗原可以重组地或通过本领域已知的任何其它手段分离或制备。
本文所用的微生物抗原是微生物的抗原,包括但不限于病毒、细菌、寄生虫和真菌。这样的抗原包括完整的微生物以及其天然分离物和片段或衍生物,以及与天然微生物抗原相同或相似并且诱导对该微生物特异的免疫应答的合成化合物。如果化合物诱导针对天然微生物抗原的免疫应答(体液的和/或细胞的),则该化合物类似于天然微生物抗原。此类抗原在本领域中常规使用,并且是本领域普通技术人员公知的。
已经在人类中发现的病毒的实例包括但不限于:逆转录病毒(Retroviridae)(例如人免疫缺陷病毒,例如HIV-1(也称为HDTV-III,LAVE或HTLV-III/LAV或HIV-III;以及其它分离株,例如HIV-LP;细小RNA病毒(Picornaviridae)(例如脊髓灰质炎病毒,甲型肝炎病毒,肠道病毒,人柯萨奇病毒,鼻病毒,埃可病毒);杯状病毒(Calciviridae)(例如,导致胃肠炎的毒株);披盖病毒(Togaviridae)(例如,马脑炎病毒、风疹病毒);黄病毒(Flaviridae)(例如,登革热病毒、脑炎病毒、黄热病病毒);日冕形病毒(Coronoviridae)(例如,冠形病毒);弹状病毒(Rhabdoviradae)(例如,水泡性口炎病毒、狂犬病病毒);纤丝病毒(Filoviridae)(例如,埃博拉病毒);副黏病毒(Paramyxoviridae)(例如,副流行性感冒病毒,腮腺炎病毒、麻疹病毒、呼吸道合胞体病毒);正粘病毒(Orthomyxoviridae)(例如,流感病毒);布尼亚病毒(Bungaviridae)(例如,汉坦病毒、本呷(bunga)病毒、白蛉病毒和内罗(Nairo)病毒);沙状病毒(Arena viridae)(出血热病毒);呼肠病毒(Reoviridae)(例如,呼肠病毒、环状病毒和轮状病毒);双股双节RNA病毒(Bimaviridae);肝DNA病毒(Hepadnaviridae)(乙肝病毒);微小病毒(Parvovirida)(细小病毒);乳头泡病毒(Papovaviridae)(乳头瘤病毒、多瘤病毒);腺病毒(Adenoviridae)(大多数腺病毒);疱疹病毒(Herpesviridae)(1型和2型单纯疱疹病毒(HSV)、水痘带状疱疹病毒、巨细胞病毒(CMV)、疱疹病毒);痘病毒(Poxviridae)(天花病毒、牛痘病毒、痘病毒);和虹彩病毒(Iridoviridae)(例如,非洲猪瘟病毒);和其它病毒(例如,丁型肝炎(被认为是乙肝病毒的缺陷卫星型)、丙型肝炎的媒介物;诺瓦克(Norwalk)和相关病毒以及星状病毒)。
革兰氏阴性和革兰氏阳性细菌用作脊椎动物的抗原。这样的革兰氏阳性细菌包括但不限于巴斯德氏菌属(Pasteurella)物种,葡萄球菌属(Staphylococci)物种和链球菌属(Streptococcus)物种。革兰氏阴性细菌包括但不限于大肠杆菌(Escherichia coli),假单胞菌属(Pseudomonas)物种和沙门氏菌属(Salmonella)物种。感染性细菌的具体实例包括但不限于幽门螺杆菌(Helicobacter pyloris),伯氏疏螺旋体(Borelia burgdorferi),嗜肺军团杆菌(Legionella pneumophilia),分枝杆菌属的种(Mycobacteria sps)(例如结核分枝杆菌(M.tuberculosis),鸟分枝杆菌(M.avium),胞内分枝杆菌(M.intracellulare),堪萨斯分枝杆菌(M.kansaii),戈氏分枝杆菌(M.gordonae),金黄色葡萄球菌(Staphylococcus aureus),淋病奈瑟球菌(Neisseria gonorrhoeae),脑膜炎奈瑟菌(Neisseria meningitidis),单核细胞增多性李斯特菌(Listeria monocytogenes),化脓性链球菌(Streptococcus pyogenes)(A组链球菌),无乳链球菌(Streptococcusagalactiae)(B组链球菌),链球菌(Streptococcus)(草绿色链球菌组),粪链球菌(Streptococcus faecalis),牛链球菌(Streptococcus bovis),链球菌(厌氧菌),肺炎链球菌(Streptococcus pneumoniae),致病性弯曲杆菌属的种(Campylobacter sp.),肠球菌属的种(Enterococcus sp.),流感嗜血杆菌(Haemophilus influenzae),炭疽杆菌(Bacillus antracis),白喉棒状杆菌(corynebacterium diphtheriae),棒状杆菌属的种(corynebacterium sp.),猪红斑丹毒丝菌(Erysipelothrix rhusiopathiae),产气荚膜梭菌(Clostridium perfringers),破伤风梭菌(Clostridium tetani),产气肠杆菌(Enterobacter aerogenes),肺炎克雷伯杆菌(Klebsiella pneumoniae),多杀巴斯德杆菌(Pasturella multocida),拟杆菌属的种(Bacteroides sp.),核梭杆菌(Fusobacteriumnucleatum),念珠状链杆菌(Streptobacillus moniliformis),苍白密螺旋体(Treponemapallidium),细弱密螺旋体(Treponema pertenue),钩端螺旋体属(Leptospira),立克次氏体属(Rickettsia)和伊色列氏放线菌(Actinomyces israelli)。
真菌的实例包括新型隐球菌(Cryptococcus neoformans),荚膜组织胞浆菌(Histoplasma capsulatum),粗球孢子菌(Coccidioides immitis),皮炎芽孢杆菌(Blastomyces dermatitidis),沙眼衣原体(Chlamydia trachomatis),白色念珠菌(Candida albicans)。
其它传染性生物体(即原生生物)包括疟原虫属的种(Plasmodium spp.)例如恶性疟原虫(Plasmodium falciparum),三日疟原虫(Plasmodium malariae),卵形疟原虫(Plasmodium ovale)和间日疟原虫(Plasmodium vivax)和刚地弓形虫(Toxoplasmagondii)。血源性和/或组织寄生虫包括疟原虫属的种,微小巴贝虫(Babesia microti),分歧巴贝虫(Babesia divergens),热带利什曼原虫(Leishmania tropica),利什曼原虫属的种(Leishmania spp.),巴西利什曼原虫(Leishmania braziliensis),杜氏利什曼虫(Leishmania donovani),冈比亚锥虫(Trypanosoma gambiense)和罗德西亚锥虫(Trypanosoma rhodesiense)(非洲昏睡病),克氏锥虫(Trypanosoma cruzi)(美洲锥虫病),和刚地弓形虫(Toxoplasma gondii)。
其它医学相关微生物已经在文献中广泛描述,例如参见C.G.A Thomas,MedicalMicrobiology,Bailliere Tindall,Great Britain 1983,其全部内容通过引用并入本文。
如本文所用,术语“癌抗原”和“肿瘤抗原”可互换使用,是指由癌细胞差异表达并因此可被利用以靶向癌细胞的抗原。癌抗原是可以潜在地刺激明显的肿瘤特异性免疫应答的抗原。这些抗原中的一些由正常细胞编码,但不一定表达。这些抗原可以表征为在正常细胞中通常沉默(即,不表达)的那些、仅在分化的某些阶段表达的那些和暂时表达的那些,例如胚胎和胎儿抗原。其它癌抗原由突变细胞基因如癌基因(例如活化的ras致癌基因)、抑制基因(例如突变p53)、由内部缺失或染色体易位产生的融合蛋白编码。其它癌抗原可以由病毒基因编码,例如在RNA和DNA肿瘤病毒上携带的那些。
本发明的纳米结构可以体内或离体地递送给受试者用于治疗和/或诊断用途,或者可以在体外、离体或体内用于研究目的。或者,纳米结构可用于激发免疫应答的目的以用于产生可以被收获的试剂例如抗体或细胞因子。
纳米结构可以单独施用或在用于体内施用的任何合适的药物载体(例如液体,例如盐水或粉末)中施用。它们也可以与较大的载体颗粒共同递送或在施用装置内。纳米结构可以是经配制的或未经配制的。本发明的制剂可以在药学上可接受的溶液中施用,所述溶液可以常规地含有药学上可接受的浓度的盐、缓冲剂、防腐剂、相容的载体、佐剂和任选地其它治疗成分。在一些实施方案中,纳米结构与诸如洗剂(例如,水凝胶)的物质混合并施用于受试者的皮肤,由此纳米结构通过受试者的皮肤递送。应当理解,本领域已知的任何递送纳米颗粒的方法可以与本发明的各方面相容。纳米结构也可以是无菌的。
为了在治疗中使用,可以通过将纳米结构递送到所需细胞的任何模式向受试者施用有效量的纳米结构。施用药物组合物可以通过本领域技术人员已知的任何方法完成。施用途径包括但不限于口服,肠胃外,肌内,静脉内,皮下,粘膜,鼻内,舌下,气管内,吸入,眼,阴道,皮肤,直肠和直接注射。
因此,本发明在一个方面涉及本发明的纳米结构在介导免疫刺激效应上高度有效的发现。这些纳米结构(刺激和调节性的)在调节免疫系统以治疗癌症、感染性疾病、过敏症、哮喘、自身免疫疾病和其它疾病和帮助保护避免癌症化疗后的机会性感染中是治疗和预防上有用的。
因此,本发明的纳米结构可用作用于治疗处于发展风险的受试者或患有过敏或哮喘、感染性生物体的感染或其中已鉴定特定癌抗原的癌症的受试者的疫苗。纳米结构也可以配制成不含抗原或过敏原以用于保护避免感染、过敏或癌症,在这种情况下,重复剂量可允许更长期的保护。如本文所用的处于风险中的受试者是具有暴露于引起感染的病原体或癌症或过敏原或发展癌症的风险的任何风险的受试者。例如,处于危险中的受试者可以是计划前往发现特定类型的传染原的区域的受试者,或者可以是通过生活方式或医疗程序暴露于可能含有传染性生物体的体液的受试者或直接暴露于生物体或甚至生活在已经鉴定出感染性生物体或过敏原的区域中的任何受试者。处于发展感染风险的受试者还包括医疗机构推荐用特定感染性生物体抗原接种的一般人群。如果抗原是过敏原,并且受试者对该特定抗原产生过敏反应,并且受试者可能暴露于抗原,即在花粉季节,则该受试者处于暴露于抗原的风险。
具有感染的受试者是已经暴露于感染性病原体并且在体内具有急性或慢性可检测水平的病原体的受试者。纳米结构可以与抗原一起使用或不与抗原一起使用,以产生能够降低传染性病原体的水平或根除传染性病原体的抗原特异性全身性或粘膜免疫应答。本文所用的传染病是由外源微生物在体内的存在引起的疾病。特别重要的是开发有效的疫苗策略和治疗以保护身体的粘膜表面,其是病原体进入的主要部位。
患有癌症的受试者是具有可检测的癌细胞的受试者。癌症可以是恶性或非恶性癌症。癌症或肿瘤包括但不限于胆管癌;脑癌;乳腺癌;宫颈癌;绒毛膜癌;结肠癌;子宫内膜癌;食道癌;胃癌;上皮内瘤;淋巴瘤;肝癌;肺癌(例如小细胞和非小细胞);黑素瘤;神经母细胞瘤;口腔癌;卵巢癌;胰腺癌;前列腺癌;直肠癌;肉瘤;皮肤癌;睾丸癌;甲状腺癌;和肾癌,以及其它癌和肉瘤。在一个实施方案中,癌症是毛细胞白血病,慢性骨髓性白血病,皮肤T细胞白血病,多发性骨髓瘤,滤泡性淋巴瘤,恶性黑色素瘤,鳞状细胞癌,肾细胞癌,前列腺癌,膀胱细胞癌或结肠癌。
受试者是指人或脊椎动物,包括但不限于狗,猫,马,牛,猪,绵羊,山羊,火鸡,鸡,灵长类动物例如猴子和鱼(水产养殖物种)例如三文鱼。因此,本发明还可用于治疗非人受试者中的癌症和肿瘤、感染、自身免疫疾病和过敏/哮喘。
如本文所使用的,当针对病症诸如感染性疾病、自身免疫性疾病、癌症、过敏症或哮喘使用时,术语治疗、被治疗或经治疗是指增加受试者对发展疾病(例如,感染病原体)的耐受性的预防性治疗或者换句话说,降低受试者将发展疾病(例如,变得被病原体感染)的可能性,以及受试者已发展疾病后的治疗以抵抗疾病(例如,减少或消除感染)或防止疾病变得更糟。
本发明的纳米结构还可以用抗微生物剂包被或与抗微生物剂结合施用。本文所用的抗微生物剂是指能够杀死或抑制感染性微生物的天然存在的或合成的化合物。根据本发明有用的抗微生物剂的类型将取决于受试者感染的或处于感染风险的微生物的类型。抗微生物剂包括但不限于抗细菌剂,抗病毒剂,抗真菌剂和抗寄生虫剂。短语诸如“抗感染剂”、“抗细菌剂”、“抗病毒剂”、“抗真菌剂”、“抗寄生虫剂”和“杀虫剂”等具有对于本领域普通技术人员而言良好建立的含义并且在标准医学文本中被定义。简言之,抗细菌剂杀死或抑制细菌,并且包括抗生素以及具有类似功能的其它合成或天然化合物。抗生素是低分子量分子,其作为次级代谢产物被细胞如微生物产生。通常,抗生素干扰对微生物特异的且不存在于宿主细胞中的一种或多种细菌功能或结构。抗病毒剂可以从天然来源分离或被合成,并且可用于杀死或抑制病毒。抗真菌剂用于治疗表面真菌感染以及机会性和原发性全身性真菌感染。抗寄生虫剂杀死或抑制寄生虫。
本发明的纳米结构还可用于调节免疫应答,以使得一些免疫因子的水平降低。实现特异性免疫下调或“耐受性”是重大挑战,因为现有技术通常通过广泛下调免疫应答而起作用。这种非特异性方法可导致高的副作用发生率、毒性、以及获得传染病的增加的风险等。没有市售化合物或结构已经证明在临床上诱导有效和特异性抗炎作用的能力。挑战是在不存在额外的共刺激信号的情况下向免疫细胞递送适当的信号例如抗原。
本发明的纳米结构解决了现有技术遇到的这些问题中的一些。在一些实施方案中,抗原可以通过与本发明的纳米结构缀合而以实现或促进耐受性的方式在细胞内高效递送。所述方法可涉及在抗原递送过程期间拮抗toll样受体,以便增强诱导抗原特异性耐受的能力。用于本发明的这些实施方案的纳米结构包括连接至免疫抑制子例如TLR4免疫抑制子的脂质体核心,和位于核心外部的寡核苷酸。
这些调节性纳米结构可用于下调免疫应答或在需要诱导耐受性的任何时候使用。例如,它们可用于治疗和预防自身免疫性疾病、过敏症、哮喘或其中病理的组分牵涉过度活性免疫应答的其它病症(例如肝纤维化或特发性肺纤维化)。
具有过敏症的受试者是具有响应于过敏原的过敏反应或发生响应于过敏原的过敏反应的风险的受试者。过敏症是指对物质(过敏原)的获得性超敏反应。过敏性病症包括但不限于湿疹,过敏性鼻炎或鼻粘膜炎,花粉症,结膜炎,支气管哮喘,风疹(荨麻疹)和食物过敏症以及其它特应性疾病。
过敏原是指可以在易感受试者中诱导过敏或哮喘反应的物质(抗原)。过敏原的列表是巨大的,并且可以包括花粉,昆虫毒液,动物皮屑,真菌孢子和药物(例如青霉素)。天然、动物和植物过敏原的实例包括但不限于特异于以下属的蛋白:犬(Canine)(家犬(Canisfamiliaris));尘螨属(Dermatophagoides)(例如粉尘螨(Dermatophagoides farinae));猫属(Felis)(猫(Felis domesticus));豕草属(Ambrosia)(Ambrosia artemiisfolia;黑麦草属(Lolium)(例如多年生黑麦草(Lolium perenne)或多花黑麦草(Loliummultiflorum));柳杉属(Cryptomeria)(日本柳杉(Cryptomeria japonica));链格孢属(Alternaria)(链格孢(Alternaria alternata));桤木(Alder);赤杨(Alnus)(Alnusgultinoasa);桦木属(Betula)(疣皮桦(Betula verrucosa));栎树属(Quercus)(白橡木(Quercus alba));木犀榄属(Olea)(Olea europa);蒿属(Artemisia)(艾莴(Artemisiavulgaris));车前属(Plantago)(例如长叶车前(Plantago lanceolata));墙草属(Parietaria)(例如药用墙草(Parietaria officinalis)或欧蓍草(Parietariajudaica));蜚蠊(Blattella)(例如德国蜚蠊(Blattella germanica));蜜蜂属(Apis)(例如Apis multiflorum);柏属(Cupressus)(例如地中海柏木(Cupressus sempervirens),绿干柏(Cupressus arizonica)和大果柏木(Cupressus macrocarpa));刺柏属(Juniperus)(例如Juniperus sabinoides,维吉尼亚雪松(Juniperus virginiana),刺柏(Juniperuscommunis)和Juniperus ashei);金钟柏(Thuya)(例如Thuya orientalis);扁柏属(Chamaecyparis)(例如日本扁柏(Chamaecyparis obtuse));大蠊属(Periplaneta)(例如美洲大蠊(Periplaneta americana));冰草属(Agropyron)(例如偃麦草(Agropyronrepens));黑麦属(Secale)(例如黑麦(Secale cereale));小麦属(Triticum)(例如小麦(Triticum aestivum));鸭茅属(Dactylis)(例如鸭茅(Dactylis glomerata));羊茅属(Festuca)(例如牛尾草(Festuca elatior));早熟禾属(Poa)(例如草地早熟禾(Poapratensis)或加拿大早熟禾(Poa compressa));燕麦属(Avena)(例如燕麦(Avenasativa));绒毛草属(Holcus)(例如绒毛草(Holcus lanatus));黄花茅属(Anthoxanthum)(例如黄花茅(Anthoxanthum odoratum));燕麦草属(Arrhenatherum)(例如燕麦草(Arrhenatherum elatius));剪股颖属(Agrostis)(例如白翦股颖(Agrostis alba));梯牧草属(Phleum)(例如猫尾草(Phleum pratense));虉草属(Phalaris)(例如虉草(Phalarisarundinacea));雀稗属(Paspalum)(例如百喜草(Paspalum notatum));高梁属(Sorghum)(例如Sorghum halepensis);和雀麦属(Bromus)(例如无芒雀麦(Bromus inermis))。
自身免疫性疾病是其中受试者自身的抗体与宿主组织反应或其中免疫效应T细胞与内源自体肽自身反应并引起组织破坏的一类疾病。因此,针对受试者自身抗原(被称为自身抗原)发生免疫应答。自身免疫性疾病包括但不限于类风湿性关节炎,克罗恩病,多发性硬化,系统性红斑狼疮(SLE),自身免疫性脑脊髓炎,重症肌无力(MG),桥本氏甲状腺炎,古德帕斯彻综合征,天疱疮(例如寻常型天疱疮),格雷夫斯病,自身免疫性溶血性贫血,自身免疫性血小板减少性紫癜,具有抗胶原抗体的硬皮病,混合性结缔组织病,多发性肌炎,恶性贫血,特发性艾迪生病,自身免疫相关不孕症,肾小球性肾炎(例如新月体性肾小球肾炎,增殖性肾小球肾炎),大疱性类天疱疮,干燥综合征,胰岛素耐受性和自身免疫性糖尿病。
本文所用的“自身抗原”是指正常宿主组织的抗原。正常的宿主组织不包括癌细胞。因此,在自身免疫性疾病的情况下针对自身抗原发生的免疫应答是不期望的免疫应答,并且促成正常组织的破坏和损伤,而针对癌抗原发生的免疫应答是期望的免疫应答,并且促成肿瘤或癌症的破坏。因此,在本发明的旨在治疗自身免疫性疾病的一些方面,不推荐将纳米结构与自身抗原,特别是作为自身免疫性疾病的靶标的那些自身抗原一起配制。
在其它情况下,纳米结构可以包括少量的自身抗原。许多动物研究已经证明,低剂量抗原的粘膜施用可导致免疫低反应性或“耐受性”的状态。活性机制似乎是从Th1朝向主要地Th2和Th3(即,TGF-β主导的)应答的细胞因子介导的免疫偏差。使用低剂量抗原递送的主动抑制还可抑制不相关的免疫应答(旁观者抑制),其在自身免疫疾病(例如类风湿性关节炎和SLE)的治疗中具有相当大的益处。旁观者抑制涉及在其中促炎性和Th1细胞因子以抗原特异性或抗原非特异性方式释放的局部环境中的Th1反调节性抑制细胞因子的分泌。本文使用的“耐受性”用于指这种现象。实际上,口服耐受性在治疗动物中的许多自身免疫性疾病中已经是有效的,这些疾病包括:实验性自身免疫性脑脊髓炎(EAE),实验性自身免疫性重症肌无力,胶原诱导的关节炎(CIA)和胰岛素依赖性糖尿病。在这些模型中,自身免疫性疾病的预防和抑制与从Th1到Th2/Th3应答的抗原特异性体液和细胞应答的变化相关。
在另一方面,本发明涉及包括一种或多种前述组合物的试剂盒。本文所用的“试剂盒”通常定义包装或组件,其包括一种或多种本发明的组合物,和/或与本发明相关的其它组合物,例如,如前所述的。试剂盒的每种组合物(如果存在)可以液体形式(例如,以溶液形式)或以固体形式(例如干燥粉末)提供。在某些情况下,一些组合物可以是可组合的或可以其它方式加工的(例如,至活性形式),例如通过加入合适的溶剂或其它物质,其可以或可以不与试剂盒一起提供。可与本发明相关的其它组合物的实例包括但不限于溶剂,表面活性剂,稀释剂,盐,缓冲剂,乳化剂,螯合剂,填充剂,抗氧化剂,粘合剂,疏松剂,防腐剂,干燥剂,抗菌剂,针,注射器,包装材料,管,瓶,烧瓶,烧杯,盘,釉料,过滤器,环,夹子,包裹材料,贴剂,容器,带,粘着剂,等等,其例如用于使用、施用、修饰、组装、储存、包装、制备、混合、稀释和/或保存组合物组分用于特定用途例如用于样品和/或受试者。
在一些实施方案中,与本发明相关的试剂盒包括纳米结构的一种或多种组分。例如,试剂盒可以包括用于形成脂质体核心的脂质体、免疫刺激剂或TLR4免疫抑制剂和/或用于纳米结构外部的寡核苷酸。试剂盒还可以包括一种或多种抗原和/或其它治疗剂。
在一些情况下,本发明的试剂盒可以包括以与本发明的组合物相关联的方式提供的任何形式的说明书,以使得本领域普通技术人员将认识到所述说明书将与本发明的组合物相关。例如,说明书可包括用于与试剂盒相关的组合物和/或其它组合物的使用、修饰、混合、稀释、保存、施用、组装、储存、包装和/或制备的说明。在一些情况下,说明书还可包括使用组合物的说明,例如用于特定用途,例如用于样品。说明书可以以本领域普通技术人员可识别的任何形式提供为用于包含这样的说明的以任何方式提供的合适的媒介物,例如书面或出版的、语言的、可听的(例如电话)、数字的、光学的、觉的(例如,录像带,DVD等)或电子通信(包括因特网或基于网络的通信)。
实施例
为了可以更充分地理解本文所述的本发明,示出了以下实施例。本申请中描述的实施例被提供来举例说明本文提供的化合物、药物组合物和方法,且不以任何方式被解释为限制其范围。
实施例1
在一个被简化以进行实践的实施方案中,将序列为5’-TCCATGACGTTCCTGACGTT-3’(SEQ ID NO:1;命名为“CpG 1826”)的寡核苷酸用α-生育酚3'-修饰并掺入包含与(8%w/w)单磷酰脂质A混合的(92%w/w)1,2-二油酰基-sn-甘油基-3-磷脂酰胆碱(DOPC)的小单层囊泡(图1)。在一个子实施方案中,这些结构通过卵白蛋白-寡核苷酸构建体的Watson-Crick类型杂交与卵白蛋白(模型蛋白抗原)进一步缀合,其中寡核苷酸部分与CpG 1826(5’-AACGTCAGGAACGTCATGGA-3’SEQ ID NO:2)互补(图2)。基于其刺激TLR9的能力选择本文中的寡核苷酸,而根据刺激TLR4的能力选择MPLA。
脂质体SNA(纳米结构)合成
将溶解在4mL二氯甲烷(DCM)中的25mg 1,2-二油酰基-sn-甘油基-3-磷脂酰胆碱(DOPC)与溶解在1mL氯仿中的1mg单磷酰脂质A(MPLA)在玻璃容器中混合。然后通过在氩气下温和干燥直到所有溶剂蒸发将脂质以薄膜干燥到玻璃容器的壁上。通过冷冻干燥过夜除去任何残留的溶剂。第二天,通过涡旋和超声处理将脂质重建在10mL脂质体缓冲液(150mMNaCl,20mM HEPES)中,然后通过2-5个冻融循环,然后通过100nm、50nm和随后30nm挤出膜进行连续挤出。挤出后,将1umol具有共价连接的3'-α-生育酚基团的寡核苷酸(5’-TCCATGACGTTCCTGACGTT-3’SEQ ID NO:1)与26mg脂质混合,并在4℃孵育过夜以形成脂质体SNA。第二天,使用300kDa膜截留滤器,利用>5倍体积的1x PBS交换,通过切向流过滤来纯化脂质体SNA。
通过将卵白蛋白首先缀合至与CpG 1826互补的寡核苷酸(5’-AACGTCAGGAACGTCATGGA-3’SEQ ID NO:2),将一些脂质体SNA另外修饰为含有卵白蛋白。然后通过在脂质体SNA上以相对于寡核苷酸2倍过量的卵白蛋白-寡核苷酸缀合物在37℃下孵育3小时,然后在4℃下孵育过夜,将该卵白蛋白-寡核苷酸偶联物与脂质体SNA杂交。通过切向流过滤除去过量的卵白蛋白-寡核苷酸缀合物。
体外测试
化合物以1:4连续稀释。将20μL该混合物一式两份接种在96孔板中。将Raw Blue细胞(InvivoGen)(源自含有NF-kB诱导型分泌型碱性磷酸酶(SEAP)的RAW 264.7细胞的报道鼠巨噬细胞细胞系)以100k细胞/孔接种于180uL/孔中并加入到96孔板中的测试化合物。将Ramos Blue细胞(InvivoGen)(源自含有NF-kB诱导型SEAP的Ramos细胞的报道人B细胞系)以306k细胞/孔接种于180uL/孔中,并加入到96孔板中的测试化合物。重要的是,RamosBlue细胞不具有通过TLR4的功能信号传导。将细胞与测试化合物在37℃、5%CO2下在潮湿室中孵育过夜。第二天,使用QuantiBlue试剂(InVivoGen)根据制造商推荐的方案探测上清液的SEAP活性。结果显示,携带TLR4和TLR9的激动剂的脂质体SNA诱导比任一单独诱导的更高的RAW Blue细胞活化(图4)。重要的是,结果显示,含有MPLA的脂质体SNA对NF-kB的活化取决于功能性TLR4,因为RAW Blue细胞系而不是Ramos Blue细胞系表现出响应于刺激的NF-kB活化(图5)。
为了进一步分析由包含TLR9和TLR4激动剂的脂质体SNA触发的反应,测试脂质体SNA诱导MyD88依赖性和MyD88非依赖性途径活化的能力,分别通过TNF和IFN-α的活化水平测量。为此,将6x106人外周血单核细胞(PBMC)以1x106/mL重悬于补充有10%FBS和1%青霉素/链霉素的RPMI-1640中,并以180k/孔接种20uL测试化合物。孵育过夜后,通过ELISA检测上清液的TNF和IFN-α水平。结果显示,在单一构建体中递送CpG 1826和MPLA两者的脂质体SNA显示升高的TNF和IFN-α水平,其不能通过单独递送每一种或通过在相同的孔而非相同的构建体中递送两种组分来重复(图6)。即使当不活化TLR9的序列(命名为“CTL-ps”:5’-TCCATGAGCTTCCTGAGCTT-3’SEQ ID NO:3)用于构建脂质体SNA时,观察到MPLA的增强的活性(图7),表明脂质体SNA比脂质体制剂更有效地递送MPLA。
接下来,鉴定可能调节脂质体SNA的功效的参数。进入脂质体配制步骤的MPLA进料的量以及核苷酸间键联化学(PO相对PS)可能发挥作用。因此,脂质体SNA用从3.8%(w/w)增加至11.5%(w/w)的MPLA进料和含有PO和PS键联的构建体开发,并测试它们在RAW Blue细胞中的活性。在该细胞系中,观察到将MPLA进料增加至7.7%MPLA但不高达11.5%增加了脂质体SNA的活化效力(图8)。在RAW Blue细胞中,在脂质体SNA的效力中观察到偏移,但是在最大刺激中没有观察到偏移(图9),尽管这预期是物种依赖性的。
最后,测试了抗原缀合的脂质体SNA活化免疫细胞的能力。将卵白蛋白负载的脂质体SNA如用RAW Blue细胞所述的以通过QuantiBlue测定法探测的SEAP水平孵育过夜。抗原与脂质体SNA的缀合似乎增加其活性(图10)。这可能是由于存在与CpG 1826形成双链体的由连接至卵白蛋白的互补寡核苷酸引入的额外的CpG基序引起的。
体内测试
已显示这种形式的抗原递送在体外诱导更强的免疫刺激效应诱导(图10),并诱导有效的抗原加工和呈递,从而导致体内抗肿瘤免疫应答的有效诱导(图11-12)。
在第0和21天使用卵白蛋白作为模型抗原(图11),用指定的制剂免疫(200μLs.c.,100μg卵白蛋白当量剂量)C57BL/6小鼠(N=4/组)。在第28天,收集脾细胞,并在具有1uM OVA(257-264)的IFN-γELISPOT板上孵育过夜。使用自动化ELISPOT计数器定量IFN-γ斑点的数量。这项研究表明SNA比游离PS寡核苷酸和明矾更有效地诱导细胞反应。*p<0.05,NS=非显著。
在另一个实验中,在第0天用1×106E.G7-OVA细胞(ATCC#CRL-2113)接种C57BL/6小鼠(N=11/组),然后在第3、7、10天用指定的制剂处理(200μL s.c.,100μg卵清蛋白当量剂量)。通过测量皮下肿瘤的长度和宽度并应用公式“肿瘤体积=(长度)×(宽度)×(宽度)/2”计算肿瘤体积。结果证明了对抗原的强细胞应答的体内活化,具有肿瘤负荷显著(95%)减少的证据(图12)。
在权利要求中,冠词例如“一”、“一个”和“该”可以表示一个或多于一个,除非相反指示或者另外地从上下文显而易见。包括在组的一个或多个成员之间的“或”的权利要求或描述被认为满足是否一个、多于一个或所有组成员存在于、使用于或以其它方式相关于给定产品或过程,除非相反指示或另外地从上下文显而易见。本发明包括其中组中仅一个成员存在于、使用于或以其它方式相关于给定产品或过程的实施方案。本发明包括其中多于一个或所有组成员存在于、使用于或以其它方式相关于给定产品或过程的实施方案。
此外,本发明包括其中来自一个或多个所列权利要求的一个或多个限制、元素、条款和描述性术语被引入到另一个权利要求中的所有变化、组合和排列。例如,可以修改从属于另一个权利要求的任何权利要求,以包括在从属于相同的基本权利要求的任何其它权利要求中找到的一个或多个限制。在元素被呈现为列表(例如,以马库什组格式)的情况下,还公开了元素的每个亚组,并且可以从组中移除任何元素。应当理解,一般来说,当本发明或本发明的方面被称为包括特定元素和/或特征时,本发明的某些实施方案或本发明的方面由以下组成或基本上由这样的元素和/或特征组成或基本上由其组成。为了简单起见,这些实施方案在这里没有具体地阐述。还应注意,术语“包括”和“包含”旨在是开放的,并且允许包括其它的元素或步骤。在给出范围的情况下,包括端点。此外,除非另有说明或者从上下文和本领域普通技术人员的理解中显而易见,否则表示为范围的值可以采取本发明不同实施方案中所述范围内的任何具体值或子范围,直到该范围的下限的单位的十分之一,除非上下文另有明确规定。
本申请引用各种已授权的专利、公开的专利申请、期刊文章和其它出版物,所有这些通过引用并入本文。如果任何所并入的参考文献和本说明书之间存在冲突,则以说明书为准。另外,可以从任何一个或多个权利要求中明确排除落入现有技术内的本发明的任何特定实施方案。因为这样的实施方案被认为是本领域普通技术人员已知的,即使排除物没有在本文中明确阐述,它们也可以被排除。本发明的任何特定实施方案可以出于任何原因从任何权利要求中排除,无论是否与现有技术的存在相关。
本领域技术人员将通过使用不超过常规实验来认识或能够确定本文所述的具体实施方案的许多等同物。本文描述的本实施方案的范围不旨在限于以上描述,而是如所附权利要求中所阐述的。本领域的普通技术人员将理解,在不脱离如所附权利要求中限定的本发明的精神或范围的情况下,可以对本描述进行各种改变和修改。
序列表
<110> AuraSense, LLC
<120> 免疫调节剂通过脂质体球形核酸的多价递送以用于预防或治疗应用
<130> A1107.70003WO00
<140> Not Yet Assigned
<141> Concurrently Herewith
<150> US 62/007,528
<151> 2014-06-04
<160> 26
<170> PatentIn version 3.5
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<211> 20
<212> DNA
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<220>
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tcgtcgtcgt tcgaacgacg ttgat 25
Claims (66)
1.一种纳米结构,其包含
具有脂质双层的脂质体核心,以及位于脂质体核心外部的寡核苷酸,其中免疫刺激剂或免疫抑制剂与所述脂质双层结合。
2.根据权利要求1所述的纳米结构,其中所述寡核苷酸形成寡核苷酸壳。
3.根据权利要求2所述的纳米结构,其中所述寡核苷酸壳包含至少一种模式识别受体调节寡核苷酸。
4.根据权利要求3所述的纳米结构,其中所述模式识别受体调节寡核苷酸是TLR激动剂。
5.根据权利要求3所述的纳米结构,其中所述模式识别受体调节寡核苷酸是TLR拮抗剂。
6.根据权利要求4-5中任一项所述的纳米结构,其中所述TLR选自TLR3、TLR7、TLR8、TLR9和TLR13。
7.根据权利要求3所述的纳米结构,其中所述模式识别受体调节寡核苷酸是RIG-I激动剂。
8.根据权利要求3所述的纳米结构,其中所述模式识别受体调节寡核苷酸是RIG-I拮抗剂。
9.根据权利要求2-8中任一项所述的纳米结构,其中所述寡核苷酸壳包含寡核苷酸和载体分子。
10.根据权利要求2-8中任一项所述的纳米结构,其中所述寡核苷酸壳完全由寡核苷酸组成。
11.根据权利要求1-9中任一项所述的纳米结构,其中所述寡核苷酸包含单链或双链DNA寡核苷酸。
12.根据权利要求1-9中任一项所述的纳米结构,其中所述寡核苷酸包含单链或双链RNA寡核苷酸。
13.根据权利要求1-9中任一项所述的纳米结构,其中所述寡核苷酸包含嵌合RNA-DNA寡核苷酸。
14.根据权利要求1-9中任一项所述的纳米结构,其中所述寡核苷酸包含单链或双链DNA、RNA或嵌合RNA-DNA寡核苷酸的组合。
15.根据权利要求2-14中任一项所述的纳米结构,其中所述寡核苷酸壳的寡核苷酸具有结构相同的寡核苷酸。
16.根据权利要求2-14中任一项所述的纳米结构,其中所述寡核苷酸壳的寡核苷酸具有至少两种结构上不同的寡核苷酸。
17.根据权利要求2-14中任一项所述的纳米结构,其中所述寡核苷酸壳的寡核苷酸具有2-10个不同的核苷酸序列。
18.根据权利要求1-17中任一项所述的纳米结构,其中所述寡核苷酸具有至少一个硫代磷酸酯键。
19.根据权利要求1-17中任一项所述的纳米结构,其中所述寡核苷酸不具有硫代磷酸酯键。
20.根据权利要求1所述的纳米结构,其中所述寡核苷酸包含含CpG基序的寡核苷酸。
21.根据权利要求20所述的纳米结构,其中所述CpG寡核苷酸选自A类、B类和C类CpG寡核苷酸。
22.根据权利要求1所述的纳米结构,其中所述寡核苷酸包含免疫刺激性单链或双链RNA。
23.根据权利要求1-22中任一项所述的纳米结构,其中至少一个寡核苷酸具有暴露于所述纳米结构的外表面的5'-末端。
24.根据权利要求1-22中任一项所述的纳米结构,其中所有寡核苷酸具有暴露于所述纳米结构的外表面的5'-末端。
25.根据权利要求1-24中任一项所述的纳米结构,其中所述寡核苷酸直接连接至脂质体核心。
26.根据权利要求1-24中任一项所述的纳米结构,其中所述寡核苷酸通过接头间接连接至脂质体核心。
27.根据权利要求1-24中任一项所述的纳米结构,其中所述寡核苷酸通过多于一个接头间接连接至脂质体核心。
28.根据权利要求26或27中任一项所述的纳米结构,其中所述接头是一个或多个以下接头:生育酚,鞘脂如鞘氨醇、鞘氨醇磷酸酯、甲基化鞘氨醇和二氢鞘氨醇,神经酰胺,神经酰胺磷酸酯,1-0酰基神经酰胺,二氢神经酰胺,2-羟基神经酰胺,鞘磷脂,糖基化鞘脂,硫苷脂,神经节苷脂,鞘磷脂,和各种长度和饱和状态的植物鞘氨醇及其衍生物,磷脂如磷脂酰胆碱,溶血磷脂酰胆碱,磷脂酸,溶血磷脂酸,环状LPA,磷脂酰乙醇胺,溶血磷脂酰乙醇胺,磷脂酰甘油,溶血磷脂酰甘油,磷脂酰丝氨酸,溶血磷脂酰丝氨酸,磷脂酰肌醇,肌醇磷酸酯,LPI,心磷脂,溶血心磷脂,双(单酰基甘油)磷酸酯,(二酰基甘油)磷酸酯,醚脂,二植烷醚脂质,和各种长度和饱和状态的缩醛磷脂及其衍生物,甾醇如胆固醇,去氢胆固醇,豆甾醇,羊毛甾醇,烯胆甾烷醇,薯蓣皂苷配基,谷甾醇,酵母甾醇,zymostenol,14-脱甲基-羊毛甾醇,胆甾醇硫酸酯,DHEA,DHEA硫酸酯,14-脱甲基-14-脱氢羊毛甾醇,谷甾烷醇,菜油甾醇,醚阴离子脂质,醚阳离子脂质,镧系螯合脂质,A-环取代氧化甾醇,B-环取代氧化甾醇,D-环取代氧化甾醇,侧链取代氧化甾醇,双取代氧化甾醇,胆甾烷酸衍生物,氟化甾醇,荧光甾醇,磺化甾醇,磷酸化甾醇,不同长度、饱和状态的多不饱和甾醇,饱和C8-C22脂肪酸,甘油的饱和C8-C22醚衍生物,C8-C22脂肪酸的饱和和不饱和酰胺衍生物以及单-和1,2-或1,3-二氨基甘油及其衍生物。
29.根据权利要求1-28中任一项所述的纳米结构,其中所述寡核苷酸包含2-1,000个寡核苷酸。
30.权利要求1-29中任一项的纳米结构,其中所述脂质体核心包含选自以下的一种或多种脂质:鞘脂如鞘氨醇、鞘氨醇磷酸酯、甲基化鞘氨醇和二氢鞘氨醇,神经酰胺,神经酰胺磷酸酯,1-0酰基神经酰胺,二氢神经酰胺,2-羟基神经酰胺,鞘磷脂,糖基化鞘脂,硫苷脂,神经节苷脂,鞘磷脂,和各种长度和饱和状态的植物鞘氨醇及其衍生物,磷脂如磷脂酰胆碱,溶血磷脂酰胆碱,磷脂酸,溶血磷脂酸,环状LPA,磷脂酰乙醇胺,溶血磷脂酰乙醇胺,磷脂酰甘油,溶血磷脂酰甘油,磷脂酰丝氨酸,溶血磷脂酰丝氨酸,磷脂酰肌醇,肌醇磷酸酯,LPI,心磷脂,溶血心磷脂,双(单酰基甘油)磷酸酯,(二酰基甘油)磷酸酯,醚脂,二植烷醚脂质,和各种长度和饱和状态的缩醛磷脂及其衍生物,甾醇如胆固醇,去氢胆甾醇,豆甾醇,羊毛甾醇,烯胆甾烷醇,薯蓣皂苷配基,谷甾醇,酵母甾醇,zymostenol,14-脱甲基-羊毛甾醇,胆甾醇硫酸酯,DHEA,DHEA硫酸酯,14-脱甲基-14-脱氢羊毛甾醇,谷甾烷醇,菜油甾醇,醚阴离子脂质,醚阳离子脂质,镧系螯合脂质,A-环取代氧化甾醇,B-环取代氧化甾醇,D-环取代氧化甾醇,侧链取代氧化甾醇,双取代氧化甾醇,胆甾烷酸衍生物,氟化甾醇,荧光甾醇,磺化甾醇,磷酸化甾醇,不同长度、饱和状态的多不饱和甾醇,饱和C8-C22脂肪酸,甘油的饱和C8-C22醚衍生物,C8-C22脂肪酸的饱和和不饱和酰胺衍生物以及单-和1,2-或1,3-二氨基甘油及其衍生物。
31.根据权利要求1-30中任一项所述的纳米结构,其中所述脂质体核心包含一种类型的脂质。
32.根据权利要求1-30中任一项所述的纳米结构,其中所述脂质体核心包含2-10种不同脂质。
33.根据权利要求1-32中任一项所述的纳米结构,其中所述免疫刺激剂选自单磷酰脂质A,来自细菌来源的脂质A,22:0海藻糖,二甲基双十八烷基铵,Kdo2脂质A,肌醇磷酸酯,包括IP3(1,3,4),IP3(1,3,5),IP3(1,4,5),IPR(1,3,4,5),LPA/S1P受体选择性激动剂,PAF和PAF类似物,脂核苷酸,环状LPA,生物活性神经酰胺,内源性大麻素,大麻素,脂质氧化产物,二酰基甘油磷酸酯,细菌膜脂质,N-酰基甘氨酸脂质,酰基肉碱脂质,分枝菌酸,植物脂质提取物,FSL-1,PAM3CSK4,HKLM,LPS,FLA-ST,咪喹莫特,瑞喹莫德,C12-IE-DAP,L18-MDP toll样受体激动剂,NOD受体激动剂,和促炎免疫受体激动剂。
34.根据权利要求1-33中任一项所述的纳米结构,其还包含抗原。
35.根据权利要求34所述的纳米结构,其中所述抗原与所述纳米结构混合在一起。
36.根据权利要求34所述的纳米结构,其中所述抗原直接连接至所述寡核苷酸壳。
37.根据权利要求34所述的纳米结构,其中所述抗原通过接头与所述寡核苷酸壳间接连接。
38.根据权利要求34所述的纳米结构,其中所述抗原直接连接至所述脂质体核心。
39.根据权利要求34所述的纳米结构,其中所述抗原通过接头间接连接至所述脂质体核心。
40.根据权利要求34所述的纳米结构,其中抗原-寡核苷酸缀合物通过寡核苷酸杂交连接至脂质体核心。
41.根据权利要求1所述的纳米结构,其中所述免疫刺激剂通过嵌入所述脂质体核心内与所述脂质体核心结合。
42.如权利要求1所述的纳米结构,其中所述免疫刺激剂通过间接连接至所述脂质体核心而与所述脂质体核心结合。
43.根据权利要求1所述的纳米结构,其中所述免疫刺激剂通过直接连接至所述脂质体核心而与所述脂质体核心结合。
44.根据权利要求2所述的纳米结构,其中所述寡核苷酸壳的寡核苷酸径向向外定向。
45.权利要求37或39的纳米结构,其中所述接头选自生育酚,鞘脂如鞘氨醇、鞘氨醇磷酸酯、甲基化鞘氨醇和二氢鞘氨醇,神经酰胺,神经酰胺磷酸酯,1-0酰基神经酰胺,二氢神经酰胺,2-羟基神经酰胺,鞘磷脂,糖基化鞘脂,硫苷脂,神经节苷脂,鞘磷脂,和各种长度和饱和状态的植物鞘氨醇及其衍生物,磷脂如磷脂酰胆碱,溶血磷脂酰胆碱,磷脂酸,溶血磷脂酸,环状LPA,磷脂酰乙醇胺,溶血磷脂酰乙醇胺,磷脂酰甘油,溶血磷脂酰甘油,磷脂酰丝氨酸,溶血磷脂酰丝氨酸,磷脂酰肌醇,肌醇磷酸酯,LPI,心磷脂,溶血心磷脂,双(单酰基甘油)磷酸酯,(二酰基甘油)磷酸酯,醚脂,二植烷醚脂质,和各种长度和饱和状态的缩醛磷脂及其衍生物,甾醇如胆固醇,去氢胆甾醇,豆甾醇,羊毛甾醇,烯胆甾烷醇,薯蓣皂苷配基,谷甾醇,酵母甾醇,zymostenol,14-脱甲基-羊毛甾醇,胆甾醇硫酸酯,DHEA,DHEA硫酸酯,14-脱甲基-14-脱氢羊毛甾醇,谷甾烷醇,菜油甾醇,醚阴离子脂质,醚阳离子脂质,镧系螯合脂质,A-环取代氧化甾醇,B-环取代氧化甾醇,D-环取代氧化甾醇,侧链取代氧化甾醇,双取代氧化甾醇,胆甾烷酸衍生物,氟化甾醇,荧光甾醇,磺化甾醇,磷酸化甾醇,不同长度、饱和状态的多不饱和甾醇,饱和C8-C22脂肪酸,甘油的饱和C8-C22醚衍生物,C8-C22脂肪酸的饱和和不饱和酰胺衍生物以及单-和1,2-或1,3-二氨基甘油及其衍生物。
46.根据权利要求34所述的纳米结构,其中所述抗原在内部水层中包封在所述脂质体核心内。
47.根据权利要求34所述的纳米结构,其中所述抗原非共价地连接至所述寡核苷酸壳的寡核苷酸。
48.根据权利要求32-47中任一项所述的纳米结构,其中所述抗原选自癌抗原、细菌抗原、病毒抗原、寄生虫抗原、半抗原和过敏原。
49.根据权利要求1-48中任一项所述的纳米结构,其中所述纳米结构是自组装纳米结构。
50.一种治疗受试者的方法,包括:
以有效量给受试者施用权利要求1-44中任一项的核酸纳米结构,以促进免疫应答。
51.根据权利要求50所述的方法,其中所述受试者患有病症,并且其中所述方法是治疗所述病症的方法。
52.根据权利要求51所述的方法,其中所述病症是癌症。
53.根据权利要求51所述的方法,其中所述病症是传染病。
54.根据权利要求53所述的方法,其中所述传染病是病毒感染。
55.根据权利要求53所述的方法,其中所述传染病是细菌感染。
56.根据权利要求51所述的方法,其中所述病症是过敏症。
57.根据权利要求51所述的方法,其中所述病症是哮喘。
58.根据权利要求51所述的方法,其中所述疾病是自身免疫疾病。
59.根据权利要求51-58中任一项所述的方法,还包括对所述受试者施用治疗方案。
60.根据权利要求59所述的方法,其中所述治疗方案是手术。
61.根据权利要求59所述的方法,其中所述治疗方案是放射。
62.根据权利要求59所述的方法,其中所述治疗方案是药物。
63.根据权利要求51所述的方法,还包括施用佐剂。
64.根据权利要求51所述的方法,其中所述纳米结构与靶向分子结合。
65.根据权利要求51的方法,其中所述纳米结构通过选自口服、鼻、舌下、静脉内、皮下、粘膜、呼吸、直接注射、灌肠和皮肤的途径递送。
66.一种用于治疗疾病的组合物,其包含权利要求1-49中任一项的酸性纳米结构。
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US20220257512A1 (en) | 2022-08-18 |
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