CN101932707B - 作为免疫刺激剂/佐剂的式(I)(NuGlXmGnNv)a的核酸及其衍生物 - Google Patents
作为免疫刺激剂/佐剂的式(I)(NuGlXmGnNv)a的核酸及其衍生物 Download PDFInfo
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Abstract
本发明涉及作为免疫刺激剂/佐剂的通式(I)的核酸:(NuGlXmGnNv)a及其衍生物,以及包含其的组合物,所述组合物任选地包含另外的佐剂。本发明还涉及各自包含作为免疫刺激剂的上述式(I)的核酸和/或其衍生物,和任选地包含至少一种另外的药用活性成分,例如抗原剂的药物组合物或疫苗。本发明同样涉及药物组合物或疫苗用于治疗癌症疾病,感染性疾病,变应性和自体免疫疾病等的应用。同样地,本发明包括通式(I)的核酸:(NuGlXmGnNv)a和/或其衍生物用于制备药物组合物的应用,所述药物组合物用于治疗所述疾病。
Description
本发明涉及作为免疫刺激剂/佐剂的通式(I):(NuGlXmGnNv)a的核酸及其衍生物并且涉及包含其的组合物,所述组合物任选地还包含另外的佐剂。本发明另外涉及药物组合物或疫苗,每一种包含上述式(I)的核酸和/或其衍生物作为免疫刺激剂,和任选地包括至少一种另外的药用活性成分,例如,抗原试剂。本发明同样涉及药物组合物或疫苗用于治疗癌症疾病,感染性疾病,变应性疾病和自体免疫疾病等的应用。同样地,本发明包括式(I):(NuGlXmGnNv)a的核酸和/或其衍生物用于制备治疗所述疾病的药物组合物的应用。
在常规和遗传疫苗中,频繁出现这样的问题,即在被治疗或接种的生物体中仅发生较少并因此频繁的不充分的免疫应答。为此原因,经常将所谓的佐剂加入疫苗或药用活性成分中,即将能够以靶向方式增加和/或影响免疫应答的物质或组合物,加入例如抗原中。例如,已知一些可注射的医用活性成分的有效性可以通过组合活性成分以及能够影响活性成分释放到宿主细胞系统中以及任选地其吸收到宿主细胞中的佐剂组合而明显提高。以该方式,可以获得这样的作用,其与以常规间隔周期性地施用许多小剂量相当。术语“佐剂”在该背景下一般指充当免疫原和/或其它药用活性化合物的载体或辅助物质的化合物或组合物。典型地,术语“佐剂”以广义解释并且指广谱物质或stratagerm,其能够增加结合到目的佐剂或与目的佐剂共同施用的抗原的免疫原性。佐剂可以进一步分为,而不限于,免疫强化剂,抗原递送系统或甚至其组合。
已经将许多化合物和组合物提议作为本领域的佐剂,例如弗氏佐剂,金属氧化物(氢氧化铝等),明矾,无机螯合物或其盐,各种石蜡样油,合成树脂,藻酸盐,类黏蛋白,多糖化合物,酪蛋白酸盐,以及分离自血液和/或血凝块的化合物,如例如纤维蛋白衍生物等。然而,在大多数情况下,所述佐剂产生不理想的副作用,例如皮肤刺激和在施用位点的炎症。在某些病例中还观察到毒性副作用,特别是组织坏死。不幸的是,在大多数情形中,这些已知的佐剂仅带来对细胞免疫应答的不充分的刺激,因为仅B细胞被激活。
分离自动物的化合物,如例如明胶通常不适合作为用于免疫刺激目的的佐剂。尽管所述化合物通常不显示对于目的宿主生物或宿主细胞的负面作用,它们典型地以太快的速度从注射位点迁移到宿主生物或到宿主细胞中,从而几乎不能获得通常对于佐剂是理想的性质,如,例如,任选地与佐剂等一起注射的活性成分的延迟的释放。在某些情形中,所述快速分布可以被单宁或其它(无机)化合物抵消。然而尚不能充分解释所述另外的化合物的代谢和它们在体内的所在。因此,还是在该情形中,假定这些化合物在碎片中聚集并因此明显地干扰过滤机制,例如肾细胞,肝细胞和/或脾细胞是合理的。此外,明胶的当肠胃外施用时溶胀的性质可在体内条件下导致令人不愉快的副作用,如,例如,特别是在施用位点的溶胀,并且导致疾病的感觉。
在分离自血液和/或血凝块的化合物的情形中,如例如,纤维蛋白衍生物等,已经典型地证实了免疫刺激作用。然而,大多数这些化合物,当作为佐剂施用时,不适合用于该目的,因为它们对免疫系统具有副作用(这与需要的免疫原性质平行发生)。例如,许多这样的化合物被分类为变应原性的,并且在某些情形中,导致免疫系统的过度反应,其远远超过需要的程度。因此,出于上述原因,这些化合物同样地不适合作为佐剂来用于免疫刺激。
因此,本发明的第一个目的是提供免疫刺激剂,其作用为佐剂并刺激先天免疫系统,优选地,如果与其它生物活性化合物组合施用,特别是如果与免疫调节化合物组合施用,更优选地与特异性刺激适应性免疫系统的化合物,如抗原组合施用。
在该背景下,已知还可以通过直接使用引发非特异性(即,先天)免疫应答的核酸,例如用细菌CpG-DNA序列(其不仅用作遗传信息)来产生(非特异性)免疫刺激作用。例如,已知DNA在非特异性免疫应答的产生中具有关键作用。例如,已知细菌DNA作为“危险”信号来警告免疫细胞,如巨噬细胞和树突细胞并促进保护性的Th1极化T细胞免疫应答。免疫刺激作用似乎由未甲基化的CG(核酸)基序的存在导致,并且因此像这样这样的CpG-DNA被提议作为免疫刺激剂(见例如US 5,663,153)。CpG-DNA直接导致先天免疫系统的成员的激活,产生了共刺激分子和促炎性细胞因子的上调。还可以通过DNA寡核苷酸来实现DNA的免疫刺激性质,所述DNA寡核苷酸通过硫代磷酸酯修饰而被稳定(见例如US 6,239,116)。所述免疫刺激DNA还可以与另外的免疫刺激化合物组合。例如,US专利6,406,705公开这样的免疫刺激组合物,其包含CpG寡脱氧核糖核苷酸和非核酸化合物的协同组合以发挥对于先天免疫系统的刺激作用。
然而,有一些观点认为使用DNA来刺激非特异性免疫应答是不太有利的。DNA在体内仅仅相对缓慢地分解,从而当使用免疫刺激(外源)DNA时,可能发生抗-DNA抗体的形成,这已经在鼠的动物模型中得到证实(Gilkeson等,J.Clin.Invest.(临床研究杂志)1995,95:1398-1402)。因此,(外源)DNA在生物体中的持久性可以导致免疫系统的过度激活,这已知在鼠中会导致脾肿大(Montheith等,Anticancer Drug Res(抗癌药物研究).1997,12(5):421-432)。此外,(外源)DNA可以与宿主基因组相互作用并且导致突变,特别是通过整合到宿主基因组中来进行。例如,将引入的(外源)DNA掺入完整的基因中可以发生,其代表了可能阻碍或甚至完全消除内源基因功能的突变。作为所述整合事件的结果,可以摧毁对于细胞至关重要的酶系统。然而,还存在这样的风险,即这样改变的细胞将转化为退化态。这样的转化可以发生,例如如果通过(外源)DNA的整合,改变了对于细胞生长的调节是关键的基因。因此,在迄今已知的方法中,当使用(外源)DNA作为免疫刺激剂时,不能排除形成癌症的可能风险。
因此,通常使用特异性RNA分子作为激发先天免疫系统的(非特异性)应答的化合物是更加有利的。在这种背景下,作为免疫系统的部分的先天免疫系统在大多数生物中是占优势的宿主防御系统,并且包括屏障如体液和化学屏障,例如炎症,补体系统,和细胞屏障。另外,先天免疫系统基于少量受体,即模式识别受体或病原体相关分子模式受体(PAMP-受体),如Toll样受体(TLR)家族的成员(见例如Trinchieri和Sher,Nature reviews,Immunology(自然综述,免疫学),卷7,2007年3月)。所述TLRs是识别细胞外环境或内体腔的配体的跨膜蛋白。在配体结合后,它们通过细胞质衔接头蛋白转换信号,所述细胞质衔接头蛋白导致宿主-防御反应的引发,并伴随着抗菌肽,促炎性趋化因子和细胞因子,抗病毒细胞因子等的产生(见例如Meylan,E.,J.Tschopp,等(2006).“Intracellular pattern recognitionreceptors in the host response(在宿主反应中的细胞内模式识别受体).”Nature(自然)442(7098):39-44)。
到目前为止,已经在人中鉴定了Toll-样受体(TLRs)的至少10个成员并且在小鼠中鉴定了13个成员,其部分地关于它们的作用模式而被鉴定。在人中,那些Toll样受体(TLRs)包括TLR1-TLR2(已知配体:三酰基脂肽),TLR1-TLR6(已知配体:二酰基脂肽),TLR2(已知配体:肽聚糖),TLR3(已知配体:dsRNA),TLR4(已知配体:革兰氏阴性细菌的LPS(脂多糖))),TLR5(已知配体:细菌鞭毛蛋白),TLR7/8(已知配体:咪唑并喹啉,鸟苷(鸟嘌呤)类似物和ssRNA),TLR9(已知配体:细菌,病毒和原生动物的CpGDNA,以及疟原虫色素(malaria pigment hemozoin)(血红蛋白消化的产物)和TLR10。在识别微生物病原体后,这些TLRs典型地引发细胞内信号传导途径,其导致炎性细胞因子(例如TNF-α,IL-6,IL-1-β和IL-12),I型干扰素(IFN-β和多种IFN-α)和趋化因子的诱导(Kawai,T.和S.Akira(2006).″TLR signalling(TLR信号传导).″Cell Death Differ(细胞、死亡与分化)13(5):816-25)。
在该背景下,RNAs出于几种原因是有利的。例如,如目前已知和上述的,ssRNA能够结合于TLR-7/-8受体并且dsRNA能够结合于TLR受体由此挥发免疫刺激作用。此外,作为免疫刺激剂的RNA典型地具有明显比DNA更短的体内半衰期,由此避免了DNA的上述缺陷。然而,已知作为免疫刺激剂的那些特异性RNA分子在本领域中的应用也具有一些局限性。例如,在本领域中迄今公开的特异性RNA序列仅显示有限的体内免疫刺激能力。这可能需要增加量的RNA用于免疫刺激,其不管由于待施用的RNA的增加的量造成的增加的费用,包括前文通常所述的常见的不需要的副作用的风险,例如在施用部位的刺激和炎症,即使对于有限的时间范围内可能是这样的。此外。当施用大量的免疫刺激剂时,不能排除毒性副作用。
另外的限制是通过已知的免疫刺激RNA分子对I型干扰素(例如IFNα和IFNβ)的较低诱导,所述免疫刺激RNA分子是淋巴细胞、天然杀伤细胞和巨噬细胞中的抗病毒和抗增殖活性以及细胞溶解活性的重要诱导物。
已知的免疫刺激dsRNA分子例如是聚A:U和聚I:C。然而,这些免疫刺激dsRNA分子的不利之处在于它们未明确的长度,其可能导致不可预期的分子结构并由此导致聚集物。所述聚集物还可能导致不理想的副作用如血管的阻塞或在注射位点的过度免疫刺激。另外,所述不可预期的分子结构表现出了在日常实验室和生产程序上的问题,因为由于可变的产物参数,可能不能进行足够的质量控制。在此,优选地将显示限定的长度和结构并且适合作为佐剂的限定的核酸分子用于药物应用。
尽管到目前为止用RNA取得了成功,仍旧存在对于可通过它们本身产生患者的先天免疫系统的免疫应答的改进的免疫刺激剂的持续需要以及相当的兴趣。因此,本发明的第二个目的是提供通过激活患者的先天免疫系统来产生非特异性免疫应答的免疫刺激剂。
本发明的两个目的都通过提供下面通式(I)的核酸分子而得以解决。这些创造性的核酸分子激活先天免疫系统,因此激发非特异性免疫应答。作为佐剂(例如,作为疫苗的成分),它们可以另外支持特异性激活适应性免疫系统的第二化合物的免疫刺激活性。
本发明提供式(I)的核酸(分子):
(NuGlXmGnNv)a,
其中:
G 是鸟苷(鸟嘌呤),尿苷(尿嘧啶)或鸟苷(鸟嘌呤)或尿苷(尿嘧啶)的类似物,优选地鸟苷(鸟嘌呤)或其类似物;
X 是鸟苷(鸟嘌呤),尿苷(尿嘧啶),腺苷(腺嘌呤),胸苷(胸腺嘧啶),胞苷(胞嘧啶),或这些核苷酸(核苷)的类似物,优选地尿苷(尿嘧啶)或其类似物;
N 是具有长度为约4-50,优选地约4-40,更优选地约4-30或约4-20个核酸的核酸序列,每个N独立地选自鸟苷(鸟嘌呤),尿苷(尿嘧啶),腺苷(腺嘌呤),胸苷(胸腺嘧啶),胞苷(胞嘧啶)或这些核苷酸(核苷)的类似物;
a 是1-20,优选地1-15,最优选地1-10的整数;
l 是1-40的整数,
其中当l=1时,G是鸟苷(鸟嘌呤)或其类似物,
当l>1时,这些核苷酸(核苷)的至少50%是鸟苷(鸟嘌呤)或其类似物;
m 是整数并且至少是3;
其中当m=3时,X是尿苷(尿嘧啶)或其类似物,并且
当m>3时,存在至少3个连续的尿苷(尿嘧啶)或尿苷(尿嘧啶)的类似物;
n 是1-40的整数,
其中当n=1时,G是鸟苷(鸟嘌呤)或其类似物,
当n>1时,这些核苷酸(核苷)的至少50%是鸟苷(鸟嘌呤)或其类似物;
u,v 可以彼此独立地是0-50的整数,
优选地,其中当u=0时,v≥1,或
当v=0时,u≥1;
其中根据本发明的式(I)的核酸分子具有至少50个核苷酸的长度,优选地至少100个核苷酸的长度,更优选地至少150个核苷酸的长度,甚至更优选地至少200个核苷酸的长度和最优选地至少250个核苷酸的长度。
根据本发明的式(I)的分子(NuGlXmGnNv)a典型地是核酸,其可以任何DNA或RNA的形式存在,所述DNA或RNA优选地,但是不限于,是环状或线性DNA或RNA,单链或双链DNA或RNA(由于两条单链DNA或RNA的非共价缔合,其也可以被视为一条DNA或RNA)或部分双链DNA或RNA(其典型地由更长和至少一个更短的单链DNA或RNA分子或由至少两个长度大约相同的单链DNA或RNA-分子形成,其中一个或多个单链DNA或RNA分子部分与一个或多个其它单链DNA或RNA分子互补,并因此在该区域中形成双链RNA),例如(部分地)单链DNA或RNA,其与(部分)双链DNA或RNA的区域混合。优选地,根据本发明的式(I)的核酸分子可以以单链或双链DNA或RNA的形式,更优选地部分双链DNA或RNA的形式存在。还优选的是,根据本发明的式(I)的核酸分子以单链核酸和双链DNA或RNA的混合物的形式存在。
如果根据本发明的式(I)的本发明的核酸(NuGlXmGnNv)a是部分双链核酸分子,这是特别有利的,因为所述根据式(I)(或如下文定义的式(Ia),(II)(IIa),(IIb),(IIIa)和/或(IIIb))的(部分双链)本发明核酸分子可以通过定向单链RNA的PAMP-(病原体相关分子模式)受体(TLR-7和TLR-8),以及双链RNA的PAMP-受体(TLR-3,RIG-I和MDA-5)而正向刺激待治疗的患者中的先天免疫应答。受体TLR-3,TLR-7和TLR-8位于内体中并且由被内体摄取的RNA激活。与此相反,RIG-I和MDA-5是细胞质受体,其由RNA激活,被直接摄取到细胞质中或已经从内体中释放(内体的释放或内体的逃逸)。因此式(I)的任何部分双链的本发明核酸(NuGlXmGnNv)a(或根据式(I)(和如下文定义的(Ia),(II)(IIa),(IIb),(IIIa)和(IIIb)的(部分双链)的本发明的核酸分子)能够激活免疫刺激的不同信号级联并因此导致先天免疫应答或显著增强这样的应答。
根据本发明的式(I)的结构(NuGlXmGnNv)a包括元件GlXmGn作为核心结构,以及另外的边界元件Nu和/或Nv,其中完整的元件NuGlXmGnNv可以重复出现,即至少一次,如通过整数a所确定的。在该背景下,本发明人惊奇地发现,根据本发明的式(I)的分子,即具有如上定义的结构(NuGlXmGnNv)a,导致当与施用像这样的核心结构GlXmGn比较时患者中增加的先天免疫应答,其特别由IFNα释放的增加而指示。此外,当其边界是如在式(I)中定义的重复元件Nu和/或Nv时,包含上述核心结构GlXmGn的分子可以在细菌生物中以明显更好的产率扩增。当通过使用体外转录方法来取代本领域已知的固相合成方法(其典型地受限于核酸的具体大小)而制备根据如上定义的式(I)的结构(NuGlXmGnNv)a的分子时,这种分子设计是特别有利的。
根据本发明的式(I)的核心结构GlXmGn在下文中更精确地定义:
在根据本发明的式(I)的核酸分子中的G是核苷酸或脱氧核苷酸或包括核苷,其中所述核苷酸(核苷)是鸟苷(鸟嘌呤)或尿苷(尿嘧啶)或其类似物,更优选地鸟苷(鸟嘌呤)或其类似物。在该情形中,鸟苷(鸟嘌呤)或尿苷(尿嘧啶)核苷酸(核苷)类似物如天然存在的核苷酸(核苷)鸟苷(鸟嘌呤)和尿苷(尿嘧啶)的非天然存在的变体定义。因此,鸟苷(鸟嘌呤)或尿苷(尿嘧啶)类似物典型地是具有非天然存在的官能团或成分的化学衍生的核苷酸(核苷),所述官能团或成分被优选地加入,被修饰,或从天然存在的鸟苷(鸟嘌呤)或尿苷(尿嘧啶)核苷酸中去除,或其取代天然存在的鸟苷(鸟嘌呤)或尿苷(尿嘧啶)核苷酸的天然存在的官能团或成分。因此,天然存在的鸟苷(鸟嘌呤)或尿苷(尿嘧啶)核苷酸的每个官能团或成分可以被修饰或从其中去除,即碱基成分,糖(核糖)成分,任何天然存在的功能侧基和/或形成寡核苷酸主链的磷酸酯成分。磷酸酯部分可以由例如氨基磷酸酯,硫代磷酸酯,肽核苷酸,甲基膦酸酯等取代,然而,在本发明的背景中,天然存在的磷酸二酯主链仍旧是优选的。另外,糖(核糖)成分选自脱氧核糖,特别地所述核酸是如上定义的RNA,其中糖(核糖)成分选自脱氧核糖。
因此,鸟苷(鸟嘌呤)或尿苷(尿嘧啶)的类似物,包括但不限于,已经通过乙酰化,甲基化,羟基化等化学改变的任何天然存在或非天然存在的鸟苷(鸟嘌呤)或尿苷(尿嘧啶),包括例如1-甲基-鸟苷(鸟嘌呤),2-甲基-鸟苷(鸟嘌呤),2,2-二甲基-鸟苷(鸟嘌呤),7-甲基-鸟苷(鸟嘌呤),二氢-尿苷(尿嘧啶),4-硫代-尿苷(尿嘧啶),5-羧甲基氨基甲基-2-硫代-尿苷(尿嘧啶),5-(羧基-羟甲基)-尿苷(尿嘧啶),5-氟-尿苷(尿嘧啶),5-溴-尿苷(尿嘧啶),5-羧甲基氨基甲基-尿苷(尿嘧啶),5-甲基-2-硫代-尿苷(尿嘧啶),N-尿苷(尿嘧啶)-5-氧乙酸甲酯,5-甲基氨基甲基-尿苷(尿嘧啶),5-甲氧基氨基甲基-2-硫代-尿苷(尿嘧啶),5′-甲氧基羰基甲基-尿苷(尿嘧啶),5-甲氧基-尿苷(尿嘧啶),尿苷(尿嘧啶)-5-氧乙酸甲酯,尿苷(尿嘧啶)-5-氧乙酸(v)。所述类似物的制备是本领域技术人员已知的,例如从美国专利4,373,071,US 4,401,796,US4,415,732,US 4,458,066,US 4,500,707,US 4,668,777,US 4,973,679,US5,047,524,US 5,132,418,US 5,153,319,US 5,262,530和5,700,642中已知,将其全部公开内容通过引用结合在本文中。在如上述的类似物的情形中,根据本发明尤其优选那些类似物,其增加根据本发明的式(I)的核酸分子的免疫原性和/或不干扰已经被引入的另外的修饰。至少一种鸟苷(鸟嘌呤)或尿苷(尿嘧啶)或其类似物可以存在于核心结构元件Gl和/或Gn中,任选地,核心结构元件Gl和/或Gn中的核苷酸的至少10%,20%,30%,40%,50%,60%,70%,80%90%或甚至100%是天然存在的鸟苷(鸟嘌呤),天然存在的尿苷(尿嘧啶),和/或其类似物,和/或显示如本文定义的其类似物的性质。优选地,所述核心结构元件Gl和/或Gn包含天然存在的鸟苷(鸟嘌呤)和/或天然存在的尿苷(尿嘧啶)的至少一种类似物。最优选地,这些核心结构元件Gl和/或Gn的所有的核苷酸(核苷)是类似物,其可以-最优选地-是关于相同类型的核苷酸(例如,将所有的鸟苷(鸟嘌呤)核苷酸提供为1-甲基-鸟苷(鸟嘌呤))的相同类似物,或它们可以是独特的(例如至少两个不同的鸟嘌呤类似物取代天然存在的鸟嘌呤核苷酸)。
在根据本发明的式(I)的核酸分子中的核心结构元件G(Gl和/或Gn)的核苷酸(核苷)的数目由l和n确定。l和n,彼此独立地分别是整数1-100,1-90,1-80,1-70,1-60,优选地1-50,更优选地1-40,和甚至更优选地1-30,其中该范围的下限可以是1,但是备选地也可以是2,3,4,5,6,7,8,9,10,11,12,13,14,15,16,17,18,19,20,21,22,23,24,25,26,27,28,29,30,或甚至更多。优选地,对于每个整数,当l和/或n=1时,G是鸟苷(鸟嘌呤)或其类似物,并且当l或n>1时,核心结构元件G(Gl和/或Gn)的至少50%,更优选地至少50%,60%,70%,80%,90%或甚至100%的核苷酸(核苷)是鸟苷(鸟嘌呤)或其类似物。例如,但不限于,当l或n=4时,Gl和/或Gn可以是例如,GUGU,GGUU,UGUG,UUGG,GUUG,GGGU,GGUG,GUGG,UGGG或GGGG,等.;当l或n=5时,Gl和/或Gn可以是例如,GGGUU,GGUGU,GUGGU,UGGGU,UGGUG,UGUGG,UUGGG,GUGUG,GGGGU,GGGUG,GGUGG,GUGGG,UGGGG,或GGGGG,等;等。在根据本发明的式(I)的核酸分子中,直接邻近于Xm的核心结构元件Gl和/或Gn的核苷酸(核苷)优选地不是尿苷(尿嘧啶)或其类似物。更优选地,在根据本发明的式(I)的核酸分子中,直接邻近于Xm的核心结构元件Gl和/或Gn的核苷酸(核苷)是至少一个(鸟嘌呤)或其类似物,更优选地至少2,3,4,5,6,7,8,9,10,11,12,13,14,15,16,17,18,19或甚至20或更多鸟苷(鸟嘌呤)或其类似物的片段。另外,在根据本发明的式(I)的核酸分子中的直接邻近于N,例如Nu,和/或Nv(或如下文定义的Nw1或Nw2)的核心结构元件Gl和/或Gn的核苷酸优选地不是尿苷(尿嘧啶)或其类似物。更优选地,在根据本发明的式(I)的核酸分子中直接邻近于N,例如Nu,和/或Nv(或如下文定义的Nw1或Nw2)的核心结构元件Gl和/或Gn的核苷酸优选地是至少一个鸟苷(鸟嘌呤)或其类似物,更优选地至少2,3,4,5,6,7,8,9,10,11,12,13,14,15,16,17,18,19或甚至20个或更多个鸟苷(鸟嘌呤)或其类似物的片段。
在本申请中,术语“同一性”意为序列相对于参照序列进行比较,并且百分比同一性通过比较它们而确定。例如为了确定两个核酸序列的百分比同一性,所述序列可以首先相对于彼此排列(排比)从而可以进行序列的随后的比较。为此目的,例如,可以将缺口引入第一核酸序列的序列中并且所述核苷酸可以与第二核酸序列的相应位置比较。当在第一核酸序列中的位置被与第二序列中的位置相同的核苷酸占据时,那么两个序列在该位置是相同的。两个序列之间的百分比同一性是相同位置的数目除以序列的函数。如果,例如,关于与具有限定长度的参照核酸比较的特定核酸而设定具体的序列同一性,那么相对于参照核酸相对地指出该百分比同一性。因此,例如从与具有100个核苷酸的长度的参照核酸序列具有50%序列同一性的核酸序列起始,核酸序列可以代表具有50个核苷酸的长度的核酸序列,其与具有长度为50个核苷酸的参照核酸序列的部分完全相同。然而,其还可以代表具有50%同一性的具有长度为100个核苷酸的核酸序列,即在该情形中,在其完整长度上与参照核酸序列50%相同的核酸。备选地,该核酸序列可以是具有长度为200核苷酸的核酸序列,其在具有100个核苷酸长度的核酸序列部分中,与具有长度为100个核苷酸的参照核酸序列完全相同。其它核酸序列自然同等满足这些标准。
确定两个序列的百分比同一性可以通过数学算法来进行。可以用于比较两个序列的数学算法的优选但非限制性的实例是Karlin等(1993),PNAS USA,90:5873-5877的算法。将所述算法整合到NBLAST程序中,使用所述程序可鉴定与本发明的序列具有需要的同一性的序列。为了获得上述缺口排比(gapped alignment),可以使用“缺口BLAST”程序,如在Altschul等(1997),Nucleics Acids Res(核酸研究),25:3389-3402中所述。当使用BLAST和缺口BLAST程序时,可以使用特定程序(例如NBLAST)的默认值参数。还可以使用版本9的来自″Genetic Computing Group(基因计算组)″的GAP(global alignment program(缺口排比程序))进一步排比序列,其中使用默认值(BLOSUM62)矩阵(-4-+11),其具有-12的缺口开放罚分(对于缺口的第一个0)和-4的缺口延伸罚分(对于缺口中的每个另外的连续的0)。在排比后,通过将对应的数目表示为要求保护的序列的核酸的百分比来计算百分比同一性。还可以使用适合的程序,来将用于确定两个核酸序列的百分比同一性的所述方法相应地应用于氨基酸序列。
同样优选地,对于式(I),当l或n>1时,核心结构元件Gl和/或Gn的至少60%,70%,80%,90%或甚至100%的核苷酸(核苷)是鸟苷(鸟嘌呤)或其类似物,如上定义。在核心结构元件Gl和/或Gn中的剩余到100%的核苷酸(核苷)(当鸟苷(鸟嘌呤)组成少于100%的这些核苷酸(核苷)时),可以是尿苷(尿嘧啶)或其类似物,如前文定义。
在根据本发明的式(I)的核酸分子中的X,特别是Xm,也是核心结构元件并且是核苷酸或脱氧核苷酸或包括核苷,其中所述核苷酸(核苷)典型地选自鸟苷(鸟嘌呤),尿苷(尿嘧啶),腺苷(腺嘌呤),胸苷(胸腺嘧啶),胞苷(胞嘧啶)或其类似物,优选地尿苷(尿嘧啶)或其类似物。在该情形中,核苷酸(核苷)类似物如天然存在的核苷酸(核苷)的非天然存在的变体定义。因此,类似物是用非天然存在的官能团化学衍生的核苷酸(核苷),其优选地加入或从天然存在的核苷酸(核苷)中去除或其取代核苷酸(核苷)的天然存在的官能团。因此,可以对天然存在的核苷酸的每种成分进行修饰,即碱基成分,糖(核糖或脱氧核糖)成分和/或形成寡核苷酸主链的磷酸酯成分。磷酸酯成分可以被例如,氨基磷酸酯,硫代磷酸酯,肽核苷酸,甲基膦酸酯等取代,然而其中天然存在的磷酸二酯主链仍旧是优选的。如果本发明的核酸包含至少一种类似物,优选地至少10%,更优选地至少20%,更优选地至少30%,更优选地至少50%,更优选地至少70%和甚至更优选地至少90%的所有“X”核苷酸可以显示如本文定义的类似物的性质。取代在核心结构元件“Xm”中的特定核苷酸类型的类似物可以是相同的,例如在核心结构元件“Xm”中存在的所有胞苷(胞嘧啶)核苷酸(核苷)由特定胞苷(胞嘧啶)类似物(例如2-硫代-胞苷(胞嘧啶))形成,或它们对于特定核苷酸(核苷)可以是独特的,例如至少两个独特的胞苷(胞嘧啶)类似物被包含在核心结构元件“Xm”中。
鸟苷(鸟嘌呤),尿苷(尿嘧啶),腺苷(腺嘌呤),胸苷(胸腺嘧啶),胞苷(胞嘧啶)的类似物包括,但不限于,任何天然存在或非天然存在的鸟苷(鸟嘌呤),尿苷(尿嘧啶),腺苷(腺嘌呤),胸苷(胸腺嘧啶)或胞苷(胞嘧啶),其已经通过化学方式,例如通过乙酰化,甲基化,羟基化等改变,包括1-甲基-腺苷(腺嘌呤),2-甲基-腺苷(腺嘌呤),2-甲硫基-N6-异戊烯基-腺苷(腺嘌呤),N6-甲基-腺苷(腺嘌呤),N6-异戊烯基-腺苷(腺嘌呤),2-硫代-胞苷(胞嘧啶),3-甲基-胞苷(胞嘧啶),4-乙酰基-胞苷(胞嘧啶),2,6-二甲基氨基嘌呤,1-甲基-鸟苷(鸟嘌呤),2-甲基-鸟苷(鸟嘌呤),2,2-二甲基-鸟苷(鸟嘌呤),7-甲基-鸟苷(鸟嘌呤),肌苷,1-甲基-肌苷,二氢-尿苷(尿嘧啶),4-硫代-尿苷(尿嘧啶),5-羧甲基氨基甲基-2-硫代-尿苷(尿嘧啶),5-(羧基羟甲基)-尿苷(尿嘧啶),5-氟-尿苷(尿嘧啶),5-溴-尿苷(尿嘧啶),5-羧甲基氨基甲基-尿苷(尿嘧啶),5-甲基-2-硫代-尿苷(尿嘧啶),N-尿苷(尿嘧啶)-5-氧乙酸甲酯,5-甲基氨基甲基-尿苷(尿嘧啶),5-甲氧基氨基甲基-2-硫代-尿苷(尿嘧啶),5′-甲氧基羰基甲基-尿苷(尿嘧啶),5-甲氧基-尿苷(尿嘧啶),尿苷(尿嘧啶)-5-氧乙酸甲酯,尿苷(尿嘧啶)-5-氧乙酸(v),queosine,β-D-甘露糖基-queosine,wybutoxosine,和肌苷。所述类似物的制备是本领域技术人员已知的,例如从US 4,373,071,US 4,401,796,US 4,415,732,US 4,458,066,US 4,500,707,US 4,668,777,US4,973,679,US 5,047,524,US 5,132,418,US 5,153,319,US 5,262,530和US5,700,642中已知。在如上述的类似物的情形中,根据本发明尤其优选那些核苷酸(核苷)类似物,其增加根据本发明的式(I)的核酸分子的免疫原性和/或不干扰已经被引入的另外的修饰。
在根据本发明的式(I)的核酸分子中的核心结构元件X的数目由m确定。m是整数并且典型地是至少3,4,5,6,7,8,9,10,11,12,13,14,15,16,17,18,19,20,20-30,30-40,40-50,50-60,60-70,70-80,80-90,90-100,100-150,150-200,或甚至更多,其中当m=3时,X是尿苷(尿嘧啶)或其类似物,并且当m>3时,至少3或更多个直接连续的尿苷(尿嘧啶)或其类似物在上述式(I)的元件X中存在。这样的至少3个或更多个直接连续的尿苷(尿嘧啶)的序列在本申请中被称为“单调的尿苷(尿嘧啶)序列”。单调的尿苷(尿嘧啶)序列典型地具有至少3,4,5,6,7,8,9或10,11,12,13,14,15,16,17,18,19,20,20-30,30-40,40-50,50-60,60-70,70-80,80-90,90-100,100-150,150-200个如上定义的尿苷(尿嘧啶)或任选地尿苷(尿嘧啶)的类似物的长度。所述单调的尿苷(尿嘧啶)序列在根据本发明的式(I)的核酸分子的核心结构元件X中出现至少一次。因此,对于具有至少3个或更多个尿苷(尿嘧啶)或其类似物的1,2,3,4,5或更多个单调的尿苷(尿嘧啶)序列,这是可以发生的,所述单调的尿苷(尿嘧啶)序列可以在核心结构元件X中被至少一个,优选地2,3,4,5或更多个鸟苷(鸟嘌呤),腺苷(腺嘌呤),胸苷(胸腺嘧啶),胞苷(胞嘧啶)或其类似物中断。例如,当m=3时,Xm是UUU。当m=4时,Xm可以是,例如,但没有任何限制,UUUA,UUUG,UUUC,UUUU,AUUU,GUUU或CUUU,等。当n=10时,Xm可以是,例如,但没有任何限制,UUUAAUUUUC,UUUUGUUUUA,UUUGUUUGUU,UUGUUUUGUU,UUUUUUUUUU,等。邻近根据本发明的式(I)的核酸分子的Gl或Gn的Xm的核苷酸优选地包含尿苷(尿嘧啶)或其类似物。当m>3时,典型地Xm的至少50%,优选地至少60%,70%,80%,90%或甚至100%的核苷酸是如上定义的尿苷(尿嘧啶)或其类似物。Xm的剩余到100%的核苷酸(其中在序列Xm中存在少于100%的尿苷(尿嘧啶))是如上定义的鸟苷(鸟嘌呤),尿苷(尿嘧啶),腺苷(腺嘌呤),胸苷(胸腺嘧啶),胞苷(胞嘧啶)或其类似物。
上述本发明的根据式(I)的核酸包含边界元件N。边界元件N典型地是具有长度为约4-50,优选地约4-40,更优选地约4-30个核苷酸(核苷),甚至更优选地约4-20个核苷酸(核苷)的核酸序列,其中这些范围的下限备选地也可以是5,6,7,8,9,10,或更多。优选地,每个N的核苷酸(核苷)独立地选自鸟苷(鸟嘌呤),尿苷(尿嘧啶),腺苷(腺嘌呤),胸苷(胸腺嘧啶),胞苷(胞嘧啶)和/或其类似物。换言之,在根据本发明的式(I)的核酸分子中的边界元件N可以是这样的序列,其可以由本领域可知的任何(随机)序列组成,每个N独立地选自鸟苷(鸟嘌呤),尿苷(尿嘧啶),腺苷(腺嘌呤),胸苷(胸腺嘧啶),胞苷(胞嘧啶)和/或这些核苷酸的类似物,或选自这些核苷酸(核苷)的均聚物,在每种情形中,假定所述序列具有约4-50,优选地约4-40,更优选地约4-30长度核苷酸(核苷)和甚至更优选地约4-30或4-20长度的根据上述的定义的核苷酸(核苷)。
根据具体实施方案,N可以是在上述定义中的核酸序列,其中所述序列典型地在直接相邻的位置包含不超过2个相同的如上定义的核苷酸(核苷),即,所述序列典型地不包含超过两个相同的选自腺苷(腺嘌呤),胞苷(胞嘧啶),尿苷(尿嘧啶)和/或鸟苷(鸟嘌呤),和/或其类似物的核苷酸(核苷)的片段(即,“aa”,“cc”,“uu”,“gg”和/或其类似物的片段),更优选地不包含这样的片段,即在直接相邻的位置不包含相同的如上定义的核苷酸(核苷)。另外或备选地,N可以是在上述定义中的核酸序列,其中所述序列典型地包含优选地约0-50%,5-45%,或10-40%,更优选地约15-35%,甚至更优选地约20-30%,和最优选地约25%的腺苷(腺嘌呤)或其类似物的含量;优选地约0-50%,5-45%,或10-40%,更优选地约15-35%,甚至更优选地约20-30%,和最优选地约25%的尿苷(尿嘧啶)或其类似物的含量;优选地约0-50%,5-45%,或10-40%,更优选地约15-35%,甚至更优选地约20-30%,和最优选地约25%的胞苷(胞嘧啶)或其类似物含量;优选地约0-50%,5-45%,或10-40%,更优选地约15-35%,甚至更优选地约20-30%,和最优选地约25%的鸟苷(鸟嘌呤)或其类似物的含量。最优选地,N可以是在上述定义中的核酸序列,其中所述序列典型地包含含量各为约25%的腺苷(腺嘌呤),鸟苷(鸟嘌呤),胞苷(胞嘧啶)和尿苷(尿嘧啶)。所述N的序列的实例包括例如agcu,aguc,augc,acgu,gcua,gcau,gacu,guca,cuag,caug,cagu,cgau,uagc,uacg,ucga,ucag,agcugcua,gcaucaug,caguucga,等。
在根据本发明的式(I)的核酸分子中的边界元件N的数目,即,其重复,由整数u和/或v确定。因此,在根据本发明的式(I)的核酸分子中的N可以作为(重复)边界元件Nu和/或Nv存在,其中u和/或v可以彼此独立地选自0或1到100的整数,更优选地选自0或1-50的整数,甚至更优选地选自0或1-40的整数,和最优选地选自0或1-30的整数,例如0或1-5,10,20,25,或30;选自5-10,10-15,15-20,20-25或25-30。更优选地,在式(I)中可以存在至少一个(重复的)边界元件Nu和/或Nv,即u或v不是0,更优选地存在两个(重复的)边界元件Nu和/或Nv,甚至更优选地在上述定义中。
另外,核心结构元件和边界元件与元件NuGlXmGnNv的组合可以作为根据如上定义的本发明的式(I)的分子的重复元件,(NuGlXmGnNv)a存在,其中根据式(I)的组合元件,(NuGlXmGnNv)a的重复的数目由整数a确定。优选地,a是来自约1-100,1-50,1-20的整数,更优选地是约1-15的整数,最优选地是约1-10的整数。在该情形中,重复元件NuGlXmGnNv可以是彼此相同或彼此不同的。
根据特别优选的实施方案,如上定义的本发明的式(I)的核酸分子(NuGlXmGnNv)a包括核心结构GlXmGn,优选地选自下列SEQ ID NOs:1-80序列的至少一个:
-GGUUUUUUUUUUUUUUUGGG(SEQ ID NO:1);
-GGGGGUUUUUUUUUUGGGGG(SEQ ID NO:2);
-GGGGGUUUUUUUUUUUUUUUUUUUUUUUUUUUUUUGGGGG(SEQ ID NO:3);
-GUGUGUGUGUGUUUUUUUUUUUUUUUUGUGUGUGUGUGU(SEQ ID NO:4);
-GGUUGGUUGGUUUUUUUUUUUUUUUUUGGUUGGUUGGUU(SEQ ID NO:5);
-GGGGGGGGGUUUGGGGGGGG(SEQ ID NO:6);
-GGGGGGGGUUUUGGGGGGGG(SEQ ID NO:7);
-GGGGGGGUUUUUUGGGGGGG(SEQ ID NO:8);
-GGGGGGGUUUUUUUGGGGGG(SEQ ID NO:9);
-GGGGGGUUUUUUUUGGGGGG(SEQ ID NO:10);
-GGGGGGUUUUUUUUUGGGGG(SEQ ID NO:11);
-GGGGGGUUUUUUUUUUGGGG(SEQ ID NO:12);
-GGGGGUUUUUUUUUUUGGGG(SEQ ID NO:13);
-GGGGGUUUUUUUUUUUUGGG(SEQ ID NO:14);
-GGGGUUUUUUUUUUUUUGGG(SEQ ID NO:15);
-GGGGUUUUUUUUUUUUUUGG(SEQ ID NO:16);
-GGUUUUUUUUUUUUUUUUGG(SEQ ID NO:17);
-GUUUUUUUUUUUUUUUUUUG(SEQ ID NO:18);
-GGGGGGGGGGUUUGGGGGGGGG(SEQ ID NO:19);
-GGGGGGGGGUUUUGGGGGGGGG(SEQ ID NO:20);
-GGGGGGGGUUUUUUGGGGGGGG(SEQ ID NO:21);
-GGGGGGGGUUUUUUUGGGGGGG(SEQ ID NO:22);
-GGGGGGGUUUUUUUUGGGGGGG(SEQ ID NO:23);
-GGGGGGGUUUUUUUUUGGGGGG(SEQ ID NO:24);
-GGGGGGGUUUUUUUUUUGGGGG(SEQ ID NO:25);
-GGGGGGUUUUUUUUUUUGGGGG(SEQ ID NO:26);
-GGGGGGUUUUUUUUUUUUGGGG(SEQ ID NO:27);
-GGGGGUUUUUUUUUUUUUGGGG(SEQ ID NO:28);
-GGGGGUUUUUUUUUUUUUUGGG(SEQ ID NO:29);
-GGGUUUUUUUUUUUUUUUUGGG(SEQ ID NO:30);
-GGUUUUUUUUUUUUUUUUUUGG(SEQ ID NO:31);
-GGGGGGGGGGGUUUGGGGGGGGGG(SEQ ID NO:32);
-GGGGGGGGGGUUUUGGGGGGGGGG(SEQ ID NO:33);
-GGGGGGGGGUUUUUUGGGGGGGGG(SEQ ID NO:34);
-GGGGGGGGGUUUUUUUGGGGGGGG(SEQ ID NO:35);
-GGGGGGGGUUUUUUUUGGGGGGGG(SEQ ID NO:36);
-GGGGGGGGUUUUUUUUUGGGGGGG(SEQ ID NO:37);
-GGGGGGGGUUUUUUUUUUGGGGGG(SEQ ID NO:38);
-GGGGGGGUUUUUUUUUUUGGGGGG(SEQ ID NO:39);
-GGGGGGGUUUUUUUUUUUUGGGGG(SEQ ID NO:40);
-GGGGGGUUUUUUUUUUUUUGGGGG(SEQ ID NO:41);
-GGGGGGUUUUUUUUUUUUUUGGGG(SEQ ID NO:42);
-GGGGUUUUUUUUUUUUUUUUGGGG(SEQ ID NO:43);
-GGGUUUUUUUUUUUUUUUUUUGGG(SEQ ID NO:44);
-GUUUUUUUUUUUUUUUUUUUUUUUUUUUUUUG(SEQ ID NO:45);
-GGUUUUUUUUUUUUUUUUUUUUUUUUUUUUUUGG(SEQ ID NO:46);
-GGGUUUUUUUUUUUUUUUUUUUUUUUUUUUUUUGGG(SEQ IDNO:47);
-GGGGUUUUUUUUUUUUUUUUUUUUUUUUUUUUUUGGGSEQID NO:48);
-GGGGGUUUUUUUUUUUUUUUUUUUUUUUUUUUUUUGGGG(SEQ ID NO:49);
-GGGGGGUUUUUUUUUUUUUUUUUUUUUUUUUUUUUUGGGGG(SEQ ID NO:50);
-GGGGGGGUUUUUUUUUUUUUUUUUUUUUUUUUUUUUUGGGGGG(SEQ ID NO:51);
-GGGGGGGGUUUUUUUUUUUUUUUUUUUUUUUUUUUUUUGGGGGGG(SEQ ID NO:52);
-GGGGGGGGGUUUUUUUUUUUUUUUUUUUUUUUUUUUUUUGGGGGGGG(SEQ ID NO:53);
-GGUUUGG(SEQ ID NO:54);
-GGUUUUGG(SEQ ID NO:55);
-GGUUUUUGG(SEQ ID NO:56);
-GGUUUUUUGG(SEQ ID NO:57);
-GGUUUUUUUGG(SEQ ID NO:58);
-GGUUUUUUUUGG(SEQ ID NO:59);
-GGUUUUUUUUUGG(SEQ ID NO:60);
-GGUUUUUUUUUUGG(SEQ ID NO:61);
-GGUUUUUUUUUUUGG(SEQ ID NO:62);
-GGUUUUUUUUUUUUGG(SEQ ID NO:63);
-GGUUUUUUUUUUUUUGG(SEQ ID NO:64);
-GGUUUUUUUUUUUUUUGG(SEQ ID NO:65);
-GGUUUUUUUUUUUUUUUGG(SEQ ID NO:66);
-GGGUUUGGG(SEQ ID NO:67);
-GGGUUUUGGG(SEQ ID NO:68);
-GGGUUUUUGGG(SEQ ID NO:69);
-GGGUUUUUUGGG(SEQ ID NO:70);
-GGGUUUUUUUGGG(SEQ ID NO:71);
-GGGUUUUUUUUGGG(SEQ ID NO:72);
-GGGUUUUUUUUUGGG(SEQ ID NO:73);
-GGGUUUUUUUUUUGGG(SEQ ID NO:74);
-GGGUUUUUUUUUUUGGG(SEQ ID NO:75);
-GGGUUUUUUUUUUUUGGG(SEQ ID NO:76);
-GGGUUUUUUUUUUUUUGGG(SEQ ID NO:77);
-GGGUUUUUUUUUUUUUUUGGGUUUUUUUUUUUUUUUGGGUUUUUUUUUUUUUUUGGG(SEQ ID NO:78);
-GGGUUUUUUUUUUUUUUUGGGGGGUUUUUUUUUUUUUUUGGG(SEQ ID NO:79);
-GGGUUUGGGUUUGGGUUUGGGUUUGGGUUUGGGUUUGGGUUUGGGUUUGGG(SEQ ID NO:80);
根据另一个特别优选的实施方案,本发明待解决的问题可以通过根据式(Ia)的备选的核酸分子而解决,
(NuClXmCnNv)a
其中:
C 是胞苷(胞嘧啶),尿苷(尿嘧啶)或胞苷(胞嘧啶)或尿苷(尿嘧啶)的类似物,优选地胞苷(胞嘧啶)或其类似物;
X 是鸟苷(鸟嘌呤),尿苷(尿嘧啶),腺苷(腺嘌呤),胸苷(胸腺嘧啶),胞苷(胞嘧啶)或上述核苷酸(核苷)的类似物,优选地尿苷(尿嘧啶)或其类似物;
N 分别是这样的核酸序列,其彼此独立地具有约4-50,优选地约4-40,更优选地约4-30或4-20个核酸的长度,每个N独立地选自鸟苷(鸟嘌呤),尿苷(尿嘧啶),腺苷(腺嘌呤),胸苷(胸腺嘧啶),胞苷(胞嘧啶)或这些核苷酸(核苷)的类似物;
a 是1-20的整数,优选地1-15的整数,最优选地1-10的整数;
l 是1-40的整数,
其中当l=1时,C是胞苷(胞嘧啶)或其类似物,
当l>1时,这些核苷酸(核苷)的至少50%是胞苷(胞嘧啶)或其类似物;
m 是整数并且至少是3;
其中,当m=3时,X是尿苷(尿嘧啶)或其类似物,
当m>3,存在至少3个连续尿苷(尿嘧啶)或尿苷(尿嘧啶)的类似物;
n 是1-40的整数,
其中,当n=1时,C是胞苷(胞嘧啶)或其类似物,
当n>1时,这些核苷酸(核苷)的至少50%是胞苷(胞嘧啶)或其类似物。
u,v 可以彼此独立地是0-50的整数,
优选地其中当u=0,v≥1,或
当v=0,u≥1时;
其中根据本发明的式(Ia)的核酸分子具有至少50个核苷酸的长度,优选地至少100个核苷酸的长度,更优选地至少150个核苷酸的长度,甚至更优选地至少200个核苷酸的长度和最优选地至少250个核苷酸的长度。
对于式(Ia),任何上述关于元件N(即Nu和Nv)和X(Xm),特别是关于如上定义的核心结构,以及关于整数a,l,m,n,u和v所给出的定义类似地相应应用于式(Ia)的元件,其中在式(Ia)中,核心结构由ClXmCn所限定。边界元件Nu和Nv的定义与上述关于Nu和Nv的定义相同。
更具体地,在根据本发明的式(Ia)的核酸分子中的C是核苷酸或脱氧核苷酸或包括核苷,其中所述核苷酸(核苷)典型地是胞苷(胞嘧啶)或尿苷(尿嘧啶)或其类似物。在该情形中,胞苷(胞嘧啶)或尿苷(尿嘧啶)核苷酸类似物如天然存在的胞苷(胞嘧啶)或尿苷(尿嘧啶)核苷酸的非天然存在的变体所定义。因此,胞苷(胞嘧啶)或尿苷(尿嘧啶)类似物是用非天然存在的官能团化学衍生的核苷酸(核苷),所述官能团被优选地加入,或从天然存在的胞苷(胞嘧啶)或尿苷(尿嘧啶)核苷酸(核苷)中去除或其取代胞苷(胞嘧啶)或尿苷(尿嘧啶)核苷酸(核苷)的天然存在的官能团。因此,天然存在的胞苷(胞嘧啶)或尿苷(尿嘧啶)核苷酸的每种成分可以被修饰,即碱基成分,糖(核糖成分)和/或形成寡核苷酸主链的磷酸酯成分。磷酸酯部分可以被例如氨基磷酸酯,硫代磷酸酯,肽核苷酸,甲基膦酸酯等取代,其中仍旧优选天然存在的磷酸二酯主链。
因此,胞苷(胞嘧啶)或尿苷(尿嘧啶)的类似物包括,但不限于,任何天然存在或非天然存在的胞苷(胞嘧啶)或尿苷(尿嘧啶),其已经通过化学方式,例如通过乙酰化,甲基化,羟基化等改变,包括,例如,2-硫代-胞苷(胞嘧啶),3-甲基-胞苷(胞嘧啶),4-乙酰基-胞苷(胞嘧啶),二氢-尿苷(尿嘧啶),4-硫代-尿苷(尿嘧啶),5-羧甲基氨基甲基-2-硫代-尿苷(尿嘧啶),5-(羧基-羟甲基)-尿苷(尿嘧啶),5-氟-尿苷(尿嘧啶),5-溴-尿苷(尿嘧啶),5-羧甲基氨基甲基-尿苷(尿嘧啶),5-甲基-2-硫代-尿苷(尿嘧啶),N-尿苷(尿嘧啶)-5-氧乙酸甲酯,5-甲基氨基甲基-尿苷(尿嘧啶),5-甲氧基氨基甲基-2-硫代-尿苷(尿嘧啶),5′-甲氧基羰基甲基-尿苷(尿嘧啶),5-甲氧基-尿苷(尿嘧啶),尿苷(尿嘧啶)-5-氧乙酸甲酯,尿苷(尿嘧啶)-5-氧乙酸(v)。所述类似物的制备是本领域技术人员已知的,例如从US 4,373,071,US 4,401,796,US 4,415,732,US 4,458,066,US 4,500,707,US 4,668,777,US 4,973,679,US 5,047,524,US5,132,418,US 5,153,319,US 5,262,530和US 5,700,642中了解,将其全部公开内容通过引用结合在本文中。在如上述的核苷酸(核苷)类似物的情形中,根据本发明尤其优选那些类似物,其增加根据本发明的式(Ia)的核酸分子的免疫原性和/或不干扰已经被引入的另外的修饰。至少一种胞苷(胞嘧啶)或尿苷(尿嘧啶)或其类似物可以存在于核心结构元件Cl和/或Cn中,任选地,核心结构元件Cl和/或Cn中的核苷酸(核苷)的至少10%,20%,30%,40%,50%,60%,70%,80%90%或甚至100%是天然存在的胞苷(胞嘧啶),天然存在的尿苷(尿嘧啶),和/或其类似物,和/或显示如本文定义的其类似物的性质。优选地,所述核心结构元件Cl和/或Cn包含天然存在的胞苷(胞嘧啶)和/或天然存在的尿苷(尿嘧啶)的至少一种类似物。最优选地,这些核心结构元件Cl和/或Cn的所有的核苷酸(核苷)是类似物,其可以-最优选地-是关于相同类型的核苷酸(核苷)(例如,将所有的胞苷(胞嘧啶)核苷酸提供为2-硫代-胞苷(胞嘧啶))的相同类似物,或它们可以是独特的(例如至少两个不同的胞苷(胞嘧啶)类似物取代天然存在的胞苷(胞嘧啶)核苷酸)。
在根据本发明的式(Ia)的核酸分子中的核心结构元件C(Cl和/或Cn)的核苷酸(核苷)的数目由l和n确定。l和n,彼此独立地分别是1-90,1-80,1-70,1-60,优选地1-50,更优选地1-40,和甚至更优选地1-30的整数,其中该范围的下限可以是1,但是备选地也可以是2,3,4,5,6,7,8,9,10,11,12,13,14,15,16,17,18,19,20,21,22,23,24,25,26,27,28,29,30,或甚至更多。优选地,对于每个整数,当l和/或n=1时,C是胞苷(胞嘧啶)或其类似物,并且当l或n>1时,核心结构元件C(Cl和/或Cn)的至少50%,更优选地至少50%,60%,70%,80%,90%或甚至100%的核苷酸(核苷)是胞苷(胞嘧啶)或其类似物。例如,但不限于,当l或n=4时,Cl和/或Cn可以是例如,CUCU,CCUU,UCUC,UUCC,CUUC,CCCU,CCUC,CUCC,UCCC或CCCC,等.;当l或n=5时,Cl和/或Cn可以是例如,CCCUU,CCUCU,CUCCU,UCCCU,UCCUC,UCUCC,UUCCC,CUCUC,CCCCU,CCCUC,CCUCC,CUCCC,UCCCC,或CCCCC,等;等。在根据本发明的式(Ia)的核酸分子中,直接邻近于Xm的核心结构元件Cl和/或Cn的核苷酸(核苷)优选地不是尿苷(尿嘧啶)或其类似物。更优选地,在根据本发明的式(Ia)的核酸分子中,直接邻近于Xm的核心结构元件Cl和/或Cn的核苷酸(核苷)是至少一个胞苷(胞嘧啶)或其类似物,更优选地至少2,3,4,5,6,7,8,9,10,11,12,13,14,15,16,17,18,19或甚至20或更多胞苷(胞嘧啶)或其类似物的片段。另外,在根据本发明的式(Ia)的核酸分子中的直接邻近于N,例如Nu,和/或Nv(或如下文定义的Nw1或Nw2)的核心结构元件Cl和/或Cn的核苷酸(核苷)优选地不是尿苷(尿嘧啶)或其类似物。更优选地,在根据本发明的式(Ia)的核酸分子中直接邻近于N,例如Nu,和/或Nv(或如下文定义的Nw1或Nw2)的核心结构元件Cl和/或Cn的核苷酸(核苷)是至少一个胞苷(胞嘧啶)或其类似物,更优选地至少2,3,4,5,6,7,8,9,10,11,12,13,14,15,16,17,18,19或甚至20个或更多个胞苷(胞嘧啶)或其类似物的片段。同样优选地,对于式(Ia),当l或n>1时,核心结构元件Cl和/或Cn的至少60%,70%,80%,90%或甚至100%的核苷酸是胞苷(胞嘧啶)或其类似物,如上定义。在核心结构元件Cl和/或Cn中的剩余到100%的核苷酸(核苷)(当胞苷(胞嘧啶)组成少于100%的这些核苷酸(核苷)时),可以是尿苷(尿嘧啶)或其类似物,如前文定义。
X,特别是Xm,作为在本发明的根据式(Ia)的核酸分子中的另外的核心结构元件,优选地如关于式(I)所定义。在根据本发明的式(Ia)的核酸分子中的核心结构元件X的数目由m确定。m是整数并且典型地是至少3,4,5,6,7,8,9,10,11,12,13,14,15,16,17,18,19,20,20-30,30-40,40-50,50-60,60-70,70-80,80-90,90-100,100-150,150-200,或甚至更多,其中当m=3时,X是尿苷(尿嘧啶)或其类似物,并且当m>3时,至少3或更多个直接连续的尿苷(尿嘧啶)或其类似物在上述式(Ia)的元件X中存在。这样的至少3个或更多个直接连续的尿苷(尿嘧啶)的序列在本申请中被称为“单调的尿苷(尿嘧啶)序列”。单调的尿苷(尿嘧啶)序列典型地具有至少3,4,5,6,7,8,9或10,11,12,13,14,15,16,17,18,19,20,20-30,30-40,40-50,50-60,60-70,70-80,80-90,90-100,100-150,150-200个如上定义的尿苷(尿嘧啶)或任选地尿苷(尿嘧啶)的类似物的长度。所述单调的尿苷(尿嘧啶)序列在根据本发明的式(Ia)的核酸分子的核心结构元件X中出现至少一次。因此,对于具有至少3个或更多个尿苷(尿嘧啶)或其类似物的1,2,3,4,5或更多个单调的尿苷(尿嘧啶)序列,这是可以发生的,所述单调的尿苷(尿嘧啶)序列可以在核心结构元件X中被至少一个,优选地2,3,4,5或更多个鸟苷(鸟嘌呤),腺苷(腺嘌呤),胸苷(胸腺嘧啶),胞苷(胞嘧啶)或其类似物中断。例如,当m=3时,Xm是UUU。当m=4时,Xm可以是,例如,但没有任何限制,UUUA,UUUG,UUUC,UUUU,AUUU,GUUU或CUUU,等。当n=10时,Xm可以是,例如,但没有任何限制,UUUAAUUUUC,UUUUGUUUUA,UUUGUUUGUU,UUGUUUUGUU,UUUUUUUUUU,等。邻近根据本发明的式(Ia)的核酸分子的Cl或Cn的Xm的核苷酸(核苷)优选地包含尿苷(尿嘧啶)或其类似物。当m>3时,典型地Xm的至少50%,优选地至少60%,70%,80%,90%或甚至100%的核苷酸是如上定义的尿苷(尿嘧啶)或其类似物。Xm剩余到100%的核苷酸(核苷)(其中在序列Xm中存在少于100%的尿苷(尿嘧啶))是如上定义的鸟苷(鸟嘌呤),尿苷(尿嘧啶),腺苷(腺嘌呤),胸苷(胸腺嘧啶),胞苷(胞嘧啶)或其类似物。
同样地,上述本发明的根据式(Ia)的核酸包含边界元件N,特别是Nu和/或Nv,其中边界元件N,特别是Nu和/或Nv,以及整数x和y如上定义。
元件NuClXmCnNv可以作为根据如上定义的本发明的式(Ia)的核酸分子的重复元件,(NuClXmCnNv)a存在,其中根据式(Ia)的元件,(NuGlXmGnNv)a的重复的数目由整数a确定。优选地,a是来自约1-100,1-50,1-20的整数,更优选地是约1-15的整数,最优选地是约1-10的整数。在该情形中,重复元件NuClXmCnNv可以是彼此相同或彼此不同的。
根据特别优选的实施方案,如上定义的本发明的式(Ia)的核酸分子(NuClXmCnNv)a包括核心结构ClXmCn,优选地选自下列SEQ ID NOs:81-83的序列的至少一个:
-CCCUUUUUUUUUUUUUUUCCCUUUUUUUUUUUUUUUCCCUUUUUUUUUUUUUUUCCC(SEQ ID NO:81)
-CCCUUUCCCUUUCCCUUUCCCUUUCCCUUUCCCUUUCCCUUUCCCUUUCCC(SEQ ID NO:82)
-CCCUUUUUUUUUUUUUUUCCCCCCUUUUUUUUUUUUUUUCCC(SEQ ID NO:83)
本发明根据式(I)(或(Ia))的核酸分子,特别是其每个单重复元件NuGlXmGnNv(或NuClXmCnNv),可以是通常如关于式(I)所定义的单链,双链或部分双链。
如果本发明的根据式(I)(或(Ia))的核酸分子是单链核酸分子,所述序列典型地在其整个长度上是单链的。
同样地,如果本发明的根据式(I)(或(Ia))的核酸分子是双链核酸分子,所述序列在其整个长度上典型地是双链的。
如果本发明的根据式(I)(或(Ia))的核酸分子是部分双链核酸分子,那么式(I)(或(Ia))的核酸分子的核酸序列在核心结构GlXmGn(或ClXmCn)之外的区域内可以是单链的,并且在所述核心结构区域内是双链的,所述核心结构GlXmGn(或ClXmCn)优选地选自上述定义的SEQ ID NOs:1-83序列的至少一个。甚至更优选地,式(I)(或(Ia))的核心结构GlXmGn(或ClXmCn)在核心结构的所述区域内可以是双链的,其中最优选地在整个尿苷(尿嘧啶)片段或至少其60%,70%,80%,90%,95%,98%或99%存在尿苷(尿嘧啶)片段。
备选地或另外地,如果本发明的根据式(I)或(Ia)的核酸分子是部分双链核酸分子,根据如上定义的式(I)或(Ia)的本发明的核酸分子的其它部分(非核心结构GlXmGn)可以是双链的。例如,式(I)或(Ia)的核酸分子的核酸序列在核心结构GlXmGn(或ClXmCn)之外的区域(例如在边界元件Nu和/或Nv中)可以是双链的,并且在所述核心结构的区域中是单链的,所述核心结构GlXmGn(或ClXmCn)优选地选自上述SEQ ID NOs:1-83的限定序列的至少一个。例如,边界元件Nv和/或Nv的至少一个可以是双链的,而式(I)或(Ia)的其它元件,例如核心结构GlXmGn和/或其它元件可以仍然为单链的。
备选地或另外地,本发明的根据式(I)的核酸分子可以选自优选地以约1∶10-10∶1的比率,更优选地以1∶3-3∶1的比率存在的根据式(I)或(Ia)的单链核酸分子和根据式(I)(或(Ia))的(部分)双链核酸分子的混合物。
根据特别优选的实施方案,本发明的根据式(I)的核酸分子可以选自例如下列序列的任一个:
来自SEQ ID NO:84:
UAGCGAAGCU CUUGGACCUA GG UUUUU UUUUU UUUUU GGG
UGCGUUCCUA GAAGUACACG
或来自SEQ ID NO:85:
UAGCGAAGCU CUUGGACCUA GG UUUUU UUUUU UUUUU GGG
UGCGUUCCUA GAAGUACACG
AUCGCUUCGA GAACCUGGAU CC AAAAA AAAAA AAAAA CCC
ACGCAAGGAU CUUCAUGUGC
或来自SEQ ID NO:114(R820:(N100)2)
GGGAGAAAGCUCAAGCUUGGAGCAAUGCCCGCACAUUGAGGAA
ACCGAGUUGCAUAUCUCAGAGUAUUGGCCCCCGUGUAGGUUAU
UCUUGACAGACAGUGGAGCUUAUUCACUCCCAGGAUCCGAGUC
GCAUACUACGGUACUGGUGACAGACCUAGGUCGUCAGUUGACC
AGUCCGCCACUAGACGUGAGUCCGUCAAAGCAGUUAGAUGUUA
CACUCUAUUAGAUC
或来自SEQ ID NO:115(R719:(N100)5)
GGGAGAAAGCUCAAGCUUGGAGCAAUGCCCGCACAUUGAGGAA
ACCGAGUUGCAUAUCUCAGAGUAUUGGCCCCCGUGUAGGUUAU
UCUUGACAGACAGUGGAGCUUAUUCACUCCCAGGAUCCGAGUC
GCAUACUACGGUACUGGUGACAGACCUAGGUCGUCAGUUGACC
AGUCCGCCACUAGACGUGAGUCCGUCAAAGCAGUUAGAUGUUA
CACUCUAUUAGAUCUCGGAUUACAGCUGGAAGGAGCAGGAGU
AGUGUUCUUGCUCUAAGUACCGAGUGUGCCCAAUACCCGAUCA
GCUUAUUAACGAACGGCUCCUCCUCUUAGACUGCAGCGUAAGU
GCGGAAUCUGGGGAUCAAAUUACUGACUGCCUGGAUUACCCUC
GGACAUAUAACCUUGUAGCACGCUGUUGCUGUAUAGGUGACCA
ACGCCCACUCGAGUAGACCAGCUCUCUUAGUCCGGACAAUGAU
AGGAGGCGCGGUCAAUCUACUUCUGGCUAGUUAAGAAUAGGC
UGCACCGACCUCUAUAAGUAGCGUGUCCUCUAG
或来自SEQ ID NO:116(R720:(N100)10)
GGGAGAAAGCUCAAGCUUGGAGCAAUGCCCGCACAUUGAGGAA
ACCGAGUUGCAUAUCUCAGAGUAUUGGCCCCCGUGUAGGUUAU
UCUUGACAGACAGUGGAGCUUAUUCACUCCCAGGAUCCGAGUC
GCAUACUACGGUACUGGUGACAGACCUAGGUCGUCAGUUGACC
AGUCCGCCACUAGACGUGAGUCCGUCAAAGCAGUUAGAUGUUA
CACUCUAUUAGAUCUCGGAUUACAGCUGGAAGGAGCAGGAGU
AGUGUUCUUGCUCUAAGUACCGAGUGUGCCCAAUACCCGAUCA
GCUUAUUAACGAACGGCUCCUCCUCUUAGACUGCAGCGUAAGU
GCGGAAUCUGGGGAUCAAAUUACUGACUGCCUGGAUUACCCUC
GGACAUAUAACCUUGUAGCACGCUGUUGCUGUAUAGGUGACCA
ACGCCCACUCGAGUAGACCAGCUCUCUUAGUCCGGACAAUGAU
AGGAGGCGCGGUCAAUCUACUUCUGGCUAGUUAAGAAUAGGC
UGCACCGACCUCUAUAAGUAGCGUGUCCUCUAGAGCUACGCAG
GUUCGCAAUAAAAGCGUUGAUUAGUGUGCAUAGAACAGACCU
CUUAUUCGGUGAAACGCCAGAAUGCUAAAUUCCAAUAACUCUU
CCCAAAACGCGUACGGCCGAAGACGCGCGCUUAUCUUGUGUAC
GUUCUCGCACAUGGAAGAAUCAGCGGGCAUGGUGGUAGGGCA
AUAGGGGAGCUGGGUAGCAGCGAAAAAGGGCCCCUGCGCACGU
AGCUUCGCUGUUCGUCUGAAACAACCCGGCAUCCGUUGUAGCG
AUCCCGUUAUCAGUGUUAUUCUUGUGCGCACUAAGAUUCAUGG
UGUAGUCGACAAUAACAGCGUCUUGGCAGAUUCUGGUCACGUG
CCCUAUGCCCGGGCUUGUGCCUCUCAGGUGCACAGCGAUACUU
AAAGCCUUCAAGGUACUCGACGUGGGUACCGAUUCGUGACACU
UCCUAAGAUUAUUCCACUGUGUUAGCCCCGCACCGCCGACCUA
AACUGGUCCAAUGUAUACGCAUUCGCUGAGCGGAUCGAUAAUA
AAAGCUUGAAUU
或来自SEQ ID NO:117(R821:(N40U20N40)2)
GGGAGAAAGCUCAAGCUUAUCCAAGUAGGCUGGUCACCUGUAC
AACGUAGCCGGUAUUUUUUUUUUUUUUUUUUUUUUGACCGUC
UCAAGGUCCAAGUUAGUCUGCCUAUAAAGGUGCGGAUCCACAG
CUGAUGAAAGACUUGUGCGGUACGGUUAAUCUCCCCUUUUUUU
UUUUUUUUUUUUUUAGUAAAUGCGUCUACUGAAUCCAGCGAU
GAUGCUGGCCCAGAUC
或来自SEQ ID NO:118(Seq.R722:(N40U20N40)5)
GGGAGAAAGCUCAAGCUUAUCCAAGUAGGCUGGUCACCUGUAC
AACGUAGCCGGUAUUUUUUUUUUUUUUUUUUUUUUGACCGUC
UCAAGGUCCAAGUUAGUCUGCCUAUAAAGGUGCGGAUCCACAG
CUGAUGAAAGACUUGUGCGGUACGGUUAAUCUCCCCUUUUUUU
UUUUUUUUUUUUUUAGUAAAUGCGUCUACUGAAUCCAGCGAU
GAUGCUGGCCCAGAUCUUCGACCACAAGUGCAUAUAGUAGUCA
UCGAGGGUCGCCUUUUUUUUUUUUUUUUUUUUUUUGGCCCAG
UUCUGAGACUUCGCUAGAGACUACAGUUACAGCUGCAGUAGUA
ACCACUGCGGCUAUUGCAGGAAAUCCCGUUCAGGUUUUUUUUU
UUUUUUUUUUUUCCGCUCACUAUGAUUAAGAACCAGGUGGAG
UGUCACUGCUCUCGAGGUCUCACGAGAGCGCUCGAUACAGUCC
UUGGAAGAAUCUUUUUUUUUUUUUUUUUUUUUUGUGCGACGA
UCACAGAGAACUUCUAUUCAUGCAGGUCUGCUCUA
或来自SEQ ID NO:119(R723:(N40U20N40)10):
GGGAGAAAGCUCAAGCUUAUCCAAGUAGGCUGGUCACCUGUAC
AACGUAGCCGGUAUUUUUUUUUUUUUUUUUUUUUUGACCGUC
UCAAGGUCCAAGUUAGUCUGCCUAUAAAGGUGCGGAUCCACAG
CUGAUGAAAGACUUGUGCGGUACGGUUAAUCUCCCCUUUUUUU
UUUUUUUUUUUUUUAGUAAAUGCGUCUACUGAAUCCAGCGAU
GAUGCUGGCCCAGAUCUUCGACCACAAGUGCAUAUAGUAGUCA
UCGAGGGUCGCCUUUUUUUUUUUUUUUUUUUUUUUGGCCCAG
UUCUGAGACUUCGCUAGAGACUACAGUUACAGCUGCAGUAGUA
ACCACUGCGGCUAUUGCAGGAAAUCCCGUUCAGGUUUUUUUUU
UUUUUUUUUUUUCCGCUCACUAUGAUUAAGAACCAGGUGGAG
UGUCACUGCUCUCGAGGUCUCACGAGAGCGCUCGAUACAGUCC
UUGGAAGAAUCUUUUUUUUUUUUUUUUUUUUUUGUGCGACGA
UCACAGAGAACUUCUAUUCAUGCAGGUCUGCUCUAGAACGAAC
UGACCUGACGCCUGAACUUAUGAGCGUGCGUAUUUUUUUUUU
UUUUUUUUUUUUUCCUCCCAACAAAUGUCGAUCAAUAGCUGGG
CUGUUGGAGACGCGUCAGCAAAUGCCGUGGCUCCAUAGGACGU
GUAGACUUCUAUUUUUUUUUUUUUUUUUUUUUCCCGGGACCA
CAAAUAAUAUUCUUGCUUGGUUGGGCGCAAGGGCCCCGUAUCA
GGUCAUAAACGGGUACAUGUUGCACAGGCUCCUUUUUUUUUU
UUUUUUUUUUUUUCGCUGAGUUAUUCCGGUCUCAAAAGACGG
CAGACGUCAGUCGACAACACGGUCUAAAGCAGUGCUACAAUCU
GCCGUGUUCGUGUUUUUUUUUUUUUUUUUUUUGUGAACCUAC
ACGGCGUGCACUGUAGUUCGCAAUUCAUAGGGUACCGGCUCAG
AGUUAUGCCUUGGUUGAAAACUGCCCAGCAUACUUUUUUUUU
UUUUUUUUUUUCAUAUUCCCAUGCUAAGCAAGGGAUGCCGCGA
GUCAUGUUAAGCUUGAAUU
根据另外的特别优选的实施方案,本发明的根据式(Ia)的核酸分子可以选自例如下列序列中的任一个:
UAGCGAAGCU CUUGGACCUA CC UUUUU UUUUU UUUUU CCC
UGCGUUCCUA GAAGUACACG
(SEQ ID NO:86)
或
UAGCGAAGCU CUUGGACCUA CC UUUUU UUUUU UUUUU CCC
UGCGUUCCUA GAAGUACACG
AUCGCUUCGA GAACCUGGAU GG AAAAA AAAAA AAAAA GGG
ACGCAAGGAU CUUCAUGUGC
(SEQ ID NO:87)
根据一个优选的实施方案,本发明的根据如上定义的式(I)(或(Ia))的核酸分子可以用聚(X)序列(修饰元件)修饰。本发明的核酸分子可以包含例如根据式(II)的核酸分子:
聚(X)s(NuGlXmGnNv)a聚(X)t,
其中根据本发明的式(II)的核酸分子同样具有至少50个核苷酸的长度,优选地至少100个核苷酸的长度,更优选地至少150个核苷酸的长度,甚至更优选地至少200个核苷酸和最优选地至少250个核苷酸的长度。
在根据本发明的式(II)的核酸分子中,元件G,X和N,特别是核心结构GlXmGn,和元件Nu和Nv,以及整数a,l,m,n,u和v如上关于式(I)定义。在本发明的情形中,根据式(II)的本发明的核酸分子的修饰元件聚(X),特别是聚(X)s和/或聚(X)t典型地是单链,双链或部分双链核酸序列,例如通常如上定义的DNA或RNA序列。优选地修饰元件聚(X),特别是聚(X)s和/或聚(X)t,是核酸的同聚片段,其中X可以是任何核苷酸或脱氧核苷酸或包含这样的核苷,其如上关于本发明的根据式(I)或(Ia)的核酸分子定义。优选地,X可以独立地关于聚(X),特别是聚(X)s和/或聚(X)t的每个,选自核苷酸或脱氧核苷酸或包括核苷,其中所述核苷酸(核苷)选自鸟苷(鸟嘌呤),尿苷(尿嘧啶),腺苷(腺嘌呤),胸苷(胸腺嘧啶),胞苷(胞嘧啶),肌苷或这些核苷酸的类似物,例如选自胞苷(胞嘧啶)(聚(C))的单链片段,鸟苷(鸟嘌呤)(聚(G))的单链片段,腺苷(腺嘌呤)(聚(A))的单链片段,尿苷(尿嘧啶)(聚(U))的单链片段,肌苷(聚(I))的单链片段等,或选自肌苷和胞苷(胞嘧啶)(聚(I:C))的同聚双链片段,腺苷(腺嘌呤)和尿苷(尿嘧啶)(聚(A:U))的同聚双链片段等,其中所述同聚序列,特别是聚(I:C)和/或聚(A:U)可以通过其链的任一条(例如使用聚-C,聚-I,聚-A或聚-U序列)偶联于根据式(II)的核酸分子的序列(NuGlXmGnNv)a。本发明的式(II)的核酸分子的修饰元件聚(X),特别是聚(X)s和/或聚(X)t的长度由整数s和/或t确定,其中s和/或t,彼此独立地可以是约5-100的整数,优选地约5-70,更优选地约5-50,甚至更优选地约5-30和最优选地约5-20的整数。
根据特别优选的实施方案,根据如上定义的式(II)的核酸分子,可以具体的包含例如根据式(IIa)的核酸分子,
聚(X)(NuGlXmGnNv)a,
或根据式(IIb)的核酸分子,
聚(X)(NuGlXmGnNv)a聚(X),
其中,根据本发明的式(IIa)或(IIb)的这些核酸分子的任一个同样地具有至少50个核苷酸的长度,优选地至少100个核苷酸,更优选地至少150个核苷酸,甚至更优选地至少200个核苷酸和最优选地至少250个核苷酸的长度。类似地,所有其它定义如上述式(II)或(I)所述。同样地,所述式(II),(IIa)和(IIb)可以基于根据式(Ib)的式定义,即引入核心结构ClXmCn。
更优选地,在本发明的根据式(II),(IIa)和/或(IIb)任一的核酸分子可以选自如上定义的聚(X),更优选地选自聚(I:C)和/或选自聚(A:U)。这些修饰元件聚(X),特别是聚(I:C)和/或聚(A:U),可以通过其任一条链,例如使用聚-C,聚-G,聚-I,聚-A或聚-U序列偶联于根据式(II),(IIa)和/或(IIb)的序列。
类似地,如上关于式(I)或(Ia)定义,本发明的根据式(II),(IIa)和/或(IIb)任一的核酸分子可以是如上定义的单链,双链或部分双链核酸分子。
如果本发明的根据式(II),(IIa)和/或(IIb)任一的核酸分子是单链核酸分子,所述序列典型地在其整个长度上是单链的。
同样地,如果本发明的根据式(II),(IIa)和/或(IIb)任一的核酸分子是双链核酸分子,所述序列在其整个长度上典型地是双链的
如果本发明的根据式(II),(IIa)和/或(IIb)任一的核酸分子是部分双链核酸分子,那么式(II),(IIa)和/或(IIb)任一的核酸分子的核酸序列在核心结构GlXmGn之外的区域内可以是单链的,并且在所述核心结构区域内是双链的,所述核心结构GlXmGn优选地选自上述定义的SEQ ID NOs:1-80或SEQID NOs:81-83序列的至少一个。甚至更优选地,式(I)(或(Ia))的核心结构GlXmGn(或ClXmCn)在核心结构的所述区域内可以是双链的,其中最优选地在整个尿苷(尿嘧啶)片段或至少其60%,70%,80%,90%,95%,98%或99%中存在尿苷(尿嘧啶)片段。
备选地或另外地,如果本发明的根据式(II),(IIa)和/或(IIb)任一的核酸分子是部分双链核酸分子,根据如上定义的式(II),(IIa)和/或(IIb)任一的本发明的核酸分子的其它部分(非核心结构GlXmGn)可以是双链的。例如,式(II),(IIa)和/或(IIb)的核酸分子的核酸序列在核心结构GlXmGn之外的区域(例如在边界元件Nu和/或Nv中,和/或在修饰元件聚(X),例如聚(X)s和或聚(X)t(如例如聚(I:C)或聚(A:U)序列中))可以是双链的,并且例如在所述核心结构的区域中是单链的,所述核心结构GlXmGn优选地选自上述SEQID NOs:1-83的限定序列的至少一个。例如,边界元件Nv和/或Nv的至少一个和/或修饰元件聚(X),例如聚(X)s和或聚(X)t中的至少一个可以是双链的,而式(II),(IIa)和/或(IIb)的其它元件,例如核心结构GlXmGn和/或其它元件可以仍然为单链的。
备选地或另外地,根据式(II),(IIa)和/或(IIb)任一的单链核酸分子,和根据式(II),(IIa)和/或(IIb)任一的(部分)双链核酸分子的混合物,优选地以约1∶10-10∶1的比率,更优选地以1∶3-3∶1的比率存在。
根据特别优选的实施方案,本发明的根据式(II),(IIa)和/或(IIb)任一的核酸分子可以选自例如下列序列的任一个:
-CCCCCCCCCC CCCCCCCCCC GG UUUUU UUUUU UUUUU GGG (SEQ ID NO:88)
-CCCCCCCCCC CCCCCCCCCC GG UUUUU UUUUU UUUUU GGG (SEQ ID NO:89)
IIIIIIIIII IIIIIIIIII
-CCCCCCCCCC CCCCCCCCCC GG UUUUU UUUUU UUUUU GGG (SEQ ID NO:90)
AAAAA AAAAA AAAAA
-CCCCCCCCCC CCCCCCCCCC GG UUUUU UUUUU UUUUU GGG (SEQ ID NO:91)
GGGGGGGGGG GGGGGGGGGG CC AAAAA AAAAA AAAAA CCC
-CCCCCCCCCC CCCCCCCCCC UAGCGAAGCU CUUGGACCUA GG UUUUU UUUUU UUUUU
GGG UGCGUUCCUA GAAGUACACG
(SEQ ID NO:92)
-CCCCCCCCCC CCCCCCCCCC GG UUUUU UUUUU UUUUU GGG UGCGUUCCUA
GAAGUACACG
GGGGGGGGGG GGGGGGGGGG CC AAAAA AAAAA AAAAA CCC ACGCAAGGAU
CUUCAUGUGC
UAGCGAAGCU CUUGGACCUA (SEQ ID NO:93)
AUCGCUUCGA GAACCUGGAU
-CCCCCCCCCC CCCCCCCCCC GG UUUUU UUUUU UUUUU GGG UGCGUUCCUA
GAAGUACACG
CC AAAAA AAAAA AAAAA CCC ACGCAAGGAU CUUCAUGUGC
UAGCGAAGCU CUUGGACCUA (SEQ ID NO:94)
AUCGCUUCGA GAACCUGGAU
根据另一个优选的实施方案,本发明的根据如上定义的式(I)(或(Ia))的核酸分子可以通过插入茎或茎环来进行修饰,例如得到根据式(IIIa)的核酸分子,
(Nu茎1GlXmGn茎2Nv)a,
或根据式(IIIb)的核酸分子,
(NuGlXmGnNv)a茎1Nw1茎2Nw2,
其中根据本发明的式(IIIa)和/或(IIIb)的核酸分子具有至少100个核苷酸,更优选地至少150个核苷酸,甚至更优选地至少200个核苷酸和最优选地至少250个核苷酸的长度。同样地,所述式(IIIa)和(IIIb)可以基于根据式(Ib)的式定义,即引入核心结构ClXmCn。
特别地,本发明的式(IIIa)和/或(IIIb)的核酸代表如上定义的式(I)的变体。在根据式(IIIa)和/或(IIIb)的任一个的核酸中,接近核心结构GlXmGn的边界元件N,即Nu和/或Nv,由至少一个茎或茎环结构进一步扩充,所述茎环结构优选地由单一茎环元件茎1和茎2组成。在本发明的根据如上定义的式(IIIa)和/或(IIIb)的任一个的核酸中,元件G,X和N,特别地,核心结构GlXmGn,和整数a,l,m,n,u和v如上定义。更优选地整数a=1。任选地u和/或v可以是0。另外地,邻近于茎环元件茎1和茎2的元件Nw1和Nw2代表另外的边界元件,其如上述关于边界元件Nu和/或Nv所定义。特别地,边界元件N通常如上述关于式(I)中的N所述,并且整数w1和w2彼此独立地选择并且如上述在式(I)中的整数u和/或v所定义。
在该背景下,茎或茎环结构是在单链DNA或更常见地在RNA中存在的分子内碱基配对。该结构还已知为发夹或发夹环。当相同分子的两个区域,例如茎环元件茎1和茎2,通常地核酸序列的回文序列元件彼此形成碱基对时,发生这样的现象,导致形成(双螺旋,其终止于)未配对的环。未配对的环由此典型地代表核酸区域,其显示与茎1或茎2的序列没有同源性,或几乎没有同源性,并且因此不能够与这些茎环元件的任一个碱基配对。得到的巨头噬菌体形状结构是许多RNA次级结构的关键构件。茎-环结构的形成因此取决于得到的螺旋和环区域的稳定性,其中第一先决条件典型地是本身可以折叠回以形成配对的双螺旋的存在。配对的茎环元件的稳定性由长度,其包含的错配或凸出部分的数目(少量的错配典型地是可忍受的,尤其在长螺旋中),以及配对区域的碱基组成确定。例如,在鸟苷(鸟嘌呤)和胞苷(胞嘧啶)之间的配对在这样的序列中可以是更优选的,因为它们具有三个氢键并且与仅具有两个氢键的腺苷(腺嘌呤)-尿苷(尿嘧啶)配对相比更稳定。在RNA中,特征是两个氢键的鸟苷(鸟嘌呤)-尿苷(尿嘧啶)配对因此可以是有利的。环的稳定性还影响茎-环结构的形成。少于三个碱基长度的″环″(即,仅不包含茎环元件茎1和茎2的环)在空间排列上是较不优选的。然而,还可以包含这样的茎,即在茎1和茎2之间不显示(限定的)环,而仅显示未配对的区域的形成。在本发明的背景中,任选的环的长度倾向于是约4-100个碱基,更优选地4-50个碱基或甚至4-30个碱基或甚至4-20个碱基的长度。
因此,在根据式(IIIa)和/或(IIIb)任一个的核酸分子的情形中,茎环元件茎1和茎2典型地代表一个茎或茎环结构的部分,其中所述茎或茎环结构可以由茎环元件茎1和茎2形成,并且环可以由位于这些茎环元件之间的序列形成。所述茎或茎环可以在碱基配对区域中具有螺旋形式。每个茎环元件茎1和茎2优选地是如上定义的核酸,更优选地是RNA,并且最优选地是单链RNA,其中如上关于核心结构元件X定义的核苷酸(核苷)或类似物的任一种可以用作茎1和/或茎2的核苷酸(核苷)。另外地,茎环元件茎1表示茎环元件茎2的回文序列。因此,两个序列优选地能够与彼此碱基配对,并因此在一起形成茎或茎环的基础。
因此,茎环元件茎1或茎2可以成对地选自任何核酸序列,条件是茎环元件茎1或茎2是彼此回文的,即一个序列等价于回读的其它(互补序列)或当回读时,显示该序列与其它序列至少90%,更优选地至少95%,和最优选地至少99%的同源性。所述回文序列茎1和茎2分别可以由具有约5-50,更优选地约5-40和最优选地约5-30个核酸的长度的核酸序列形成,所述核酸选自腺苷(腺嘌呤),鸟苷(鸟嘌呤),胞苷(胞嘧啶),尿苷(尿嘧啶),胸苷(胸腺嘧啶),或其如本文定义的类似物。
a) 对于茎1:
UAGCGAAGCUCUUGGACCUA(SEQ ID NO:95)
对于茎2:
UAGGUCCAAGAGCUUCGCUA(SEQ ID NO:96)
b) 对于茎1:
UAGGUCCAAGAGCUUCGCUA(SEQ ID NO:96)
对于茎2:
UAGCGAAGCUCUUGGACCUA(SEQ ID NO:95)
c) 对于茎1:
GCCGCGGGCCG(SEQ ID NO:97)
对于茎2:
CGGCCCGCGGC(SEQ ID NO:98)
d) 对于茎1:
CGGCCCGCGGC(SEQ ID NO:98)
对于茎2:
GCCGCGGGCCG(SEQ ID NO:97)
e) 对于茎1:
GACACGGUGC(SEQ ID NO:99)
对于茎2:
GCACCGUGCA(SEQ ID NO:100)
f) 对于茎1:
GCACCGUGCA(SEQ ID NO:100)
对于茎2:
GACACGGUGC(SEQ ID NO:99)
g) 对于茎1:
ACCUAGGU(SEQ ID NO:101)
对于茎2:
ACCUAGGU(SEQ ID NO:101)
h) 对于茎1:
UGGAUCCA(SEQ ID NO:102)
对于茎2:
UGGAUCCA(SEQ ID NO:102)
i) 对于茎1:
CCUGC(SEQ ID NO:103)
对于茎2:
GCAGG(SEQ ID NO:104)
j) 对于茎1:
GCAGG(SEQ ID NO:105)
对于茎2:
CCUGC(SEQ ID NO:106)等。
根据一个第一备选方案,所述核心结构GlXmGn可以位于茎环结构内,即,所述核心结构GlXmGn可以位于茎环元件茎1和茎2之间,由此优选地形成环。这样的核酸分子与式(IIIa)类似,其具有如上定义的组成(Nu茎1GlXmGn茎2Nv)a。当u和/或v=0,且a=1时,式(IIIa)可以形成特定的核酸分子“茎1GlXmGn茎2“,其也可以结合在本发明中。
根据另一个备选方案,所述核心结构GlXmGn可以位于所述茎环结构的外部,其中同样地,茎环元件茎1和茎2可以彼此通过一定序列(优选地,边界元件N,例如Nw1或Nw2)分离,其接着可以在茎环元件茎1和茎2的碱基配对后形成环结构。另外,邻近于核心结构GlXmGn的茎环元件1和/或1,可以通过其它的边界元件,例如Nw1或Nw2与核心结构GlXmGn分离。根据本发明,这样的核酸与式(IIIb)类似,其具有如上定义的组成(NuGlXmGnNv)a茎1Nw1茎2Nw2。
本发明的根据式(IIIa)和/或(IIIb)的核酸分子可以是单链的,或部分双链的。
如果本发明的根据式(IIIa)和/或(IIIb)的核酸分子是单链核酸分子,那么所述序列典型地在其整个长度上是单链的。
如果本发明的根据式(IIIa)和/或(IIIb)的核酸分子是部分双链核酸分子,那么式(IIIa)和/或(IIIb)的核酸分子优选地在茎环元件茎1和茎2的区域中并且在由核心结构GlXmGn或任何其它元件(例如Nw1或Nw2)形成的区域中可以是单链的。那么位于茎环元件茎1和茎2外部和在由核心结构GlXmGn或由任何其它元件(例如Nw1或Nw2)形成的环的区域中的元件,可以彼此独立地是单链或双链。
备选地或另外地,优选地以约1∶10-10∶1的比率,更优选地以1∶3-3∶1的比率存在的根据式(IIIa)和/或(IIIb)的单链或部分双链核酸分子,和根据式(IIIa)或(IIIb)的(部分)双链核酸分子的混合物。
根据特别优选的实施方案,本发明的根据式(IIIa)和/或(IIIb)的核酸分子可以选自例如下列序列的任一个:
-UAGCGAAGCU CUUGGACCUAUGCGUUCCUAGAAGUACACG GCCGCGGGCCG UGCGUUCCUA GAAGUACACG CGGCCCGCGGCUGCGUUCCUA GAAGUACACG(SEQ ID NO:108)
(茎1和茎2以下划线表示,核心结构GlXmGn以粗体表示)
如上定义的根据本发明的式(I),(Ia),(II),(IIa),(IIb),(IIIa)和/或(IIIb)的核酸分子可以使用本领域已知的任何方法进行制备,所述方法包括合成方法如例如固相合成,以及体外方法如体外转录反应。优选地,体外转录用于本发明的核酸分子的制备。发明人惊奇地发现,当与通过合成方法制备的根据本发明的式(I),(Ia),(II),(IIa),(IIb),(IIIa)和/或(IIIb)的核酸分子比较时,当通过基于其5’-磷酸酯的体外转录制备时,如上定义的根据本发明的式(I),(Ia),(II),(IIa),(IIb),(IIIa)和/或(IIIb)的核酸分子显示甚至更好的对先天免疫系统的刺激。所述对先天免疫系统的刺激,有利于(但不限于此)对受体RIG-1的激活。因此如上定义的根据本发明的式(I),(Ia),(II),(IIa),(IIb),(IIIa)和/或(IIIb)的核酸分子是特别优选的,当通过体外转录反应制备时。
将如上定义的根据本发明的式(I),(Ia),(II),(IIa),(IIb),(IIIa)和/或(IIIb)的核酸分子典型地作为“稳定的寡核苷酸”提供,即作为对体内降解(例如通过核酸外切酶或核酸内切酶)具有抗性的寡核糖核苷酸或寡脱氧核糖核苷酸提供。这样的稳定可以例如通过如上定义的根据本发明的式(I),(Ia),(II),(IIa),(IIb),(IIIa)和/或(IIIb)的核酸分子的修饰的磷酸酯主链来实现的。优选用于该情形的核苷酸包含硫代硫酸酯-修饰的磷酸酯主链,优选地至少一个包含在磷酸酯主链中被硫原子取代的磷酸酯氧。其它稳定的寡核苷酸包括:非离子类似物,如例如,烷基膦酸酯和芳基膦酸酯,其中带电的膦酸酯氧被烷基基团或芳基基团,或磷酸二酯和烷基磷酸三酯取代,其中带电的氧残基以烷基化形式存在。然而,天然存在的磷酸二酯主链仍旧是优选的。
如上定义的根据本发明的式(I),(Ia),(II),(IIa),(IIb),(IIIa)和/或(IIIb)的核酸分子可以同样地被稳定。如上提及的,任何核酸,例如DNA或RNA,可以原则上用于如上定义的根据本发明的式(I),(Ia),(II),(IIa),(IIb),(IIIa)和/或(IIIb)的核酸分子。然而,从安全性观点,优选RNA用于这样的核酸分子的应用。具体地,RNA不涉及被稳定地整合到转染细胞的基因组中的风险。此外,RNA明显更容易地在体内降解。同样地,迄今尚未检测到抗-RNA的抗体,这可能是由于与DNA相比,RNA在体内相对较短的半衰期。与DNA相比,RNA相对在溶液中更不稳定,这特别是由于RNA降解酶,所谓的RNA酶(核糖核酸酶)造成的。甚至最少量的核糖核酸酶污染也足以在溶液中完全降解RNA。这样的RNA酶污染通常可以仅通过特殊的处理,具体地用焦碳酸二乙酯(DEPC)处理来去除。因此,在细胞的细胞质中对mRNA的天然降解是受到非常精细调节的。在现有技术中关于此已经了解许多机制。因此,末端结构典型地对于体内mRNA是至关重要的。在天然存在的mRNAs的5′末端,通常存在所谓的“帽结构”(修饰的鸟苷(鸟嘌呤)核苷酸)并且在3′端存在多到200腺苷(腺嘌呤)核苷酸(所谓的聚A尾)的序列。
如上定义的根据本发明的式(I),(Ia),(II),(IIa),(IIb),(IIIa)和/或(IIIb)任一的核酸分子,特别是如果作为(m)RNA提供,可以因此通过加入所谓的″5′帽″结构来对抗RNA酶的降解而得以稳定。在这方面,特别优选m7G(5′)ppp(5′(A,G(5′)ppp(5′)A或G(5′)PPP(5′)G作为5′帽″结构。然而,这样的修饰仅是如果修饰,例如脂质修饰尚未被引入如上定义的根据本发明的式(I),(Ia),(II),(IIa),(IIb),(IIIa)和/或(IIIb)任一的核酸分子的5′端或如果所述修饰不干扰如上定义的根据本发明的式(I),(Ia),(II),(IIa),(IIb),(IIIa)和/或(IIIb)任一的(未修饰的或化学修饰的)核酸分子的免疫原性,才会被引入。
备选地,如上定义的根据本发明的式(I),(Ia),(II),(IIa),(IIb),(IIIa)和/或(IIIb)任一的核酸分子的3′端,特别如果作为RNA提供,可以被至少50个腺苷核糖核苷酸,优选地至少70个腺苷核糖核苷酸,更优选地至少100个腺苷核糖核苷酸,特别优选地至少200个腺苷(腺嘌呤)核糖核苷酸(所谓的″聚A尾″)的序列修饰。特别地,尤其是如果RNA以(m)RNA的形式存在,如上定义的根据本发明的式(I),(Ia),(II),(IIa),(IIb),(IIIa)和/或(IIIb)任一的核酸分子可以在3′末端,包含典型地约10-200个腺苷核苷酸,优选地约10-100个腺苷核苷酸,更优选地约20-100个腺苷核苷酸或甚至更优选地约40-80个腺苷核苷酸的聚腺苷酸尾。
此外,如上定义的根据本发明的式(I),(Ia),(II),(IIa),(IIb),(IIIa)和/或(IIIb)任一的核酸分子的3′端,特别地如果作为RNA提供,可以被至少50个胞苷核糖核苷酸,优选地至少70胞苷核糖核苷酸,更优选地至少100个胞苷核糖核苷酸,特别优选地至少200个胞苷核糖核苷酸的序列(所谓的″聚-C尾″)修饰。特别地,尤其是如果RNA以(m)RNA的形式存在,如上定义的根据本发明的式(I),(Ia),(II),(IIa),(IIb),(IIIa)和/或(IIIb)任一的核酸分子可以在3′末端包含典型地约10-200个胞苷核苷酸,优选地约10-100个胞苷核苷酸,更优选地约20-70个胞苷核苷酸或甚至更优选地约20-60个或甚至10-40个胞苷核苷酸的聚-C尾。
类似地,在该情形中,这样的(“聚腺苷酸”和/或“聚-C尾”-)修饰仅在如果修饰,例如脂质修饰尚未被引入如上定义的根据本发明的式(I),(Ia),(II),(IIa),(IIb),(IIIa)和/或(IIIb)任一的核酸分子的3′端或如果所述修饰不干扰如上定义的根据本发明的式(I),(Ia),(II),(IIa),(IIb),(IIIa)和/或(IIIb)任一的(未修饰的或化学修饰的)核酸分子的免疫原性时,才会被引入。
上述修饰,即将″5′帽″结构或″聚腺苷酸″和/或“聚-C尾”插入3′端,防止了如上定义的根据本发明的式(I),(Ia),(II),(IIa),(IIb),(IIIa)和/或(IIIb)任一的核酸分子的体内过早降解,并且因此在体内稳定如上定义的根据本发明的式(I),(Ia),(II),(IIa),(IIb),(IIIa)和/或(IIIb)任一的核酸分子。
根据特定的实施方案,如上定义的根据本发明的式(I),(Ia),(II),(IIa),(IIb),(IIIa)和/或(IIIb)任一的核酸分子可以包含脂质修饰。所述根据本发明的脂质-修饰的核酸分子典型地包含如上定义的根据本发明的式(I),(Ia),(II),(IIa),(IIb),(IIIa)和/或(IIIb)任一的核酸分子,至少一种与根据本发明的核酸分子共价连接的接头,和至少一种与各个接头共价连接的脂质。备选地,根据本发明的脂质-修饰的核酸分子包含(至少一种)如上定义的根据本发明的式(I),(Ia),(II),(IIa),(IIb),(IIIa)和/或(IIIb)任一的核酸分子和至少一种与根据本发明的核酸分子共价连接(无接头)的(双官能)脂质。根据第三个备选方案,根据本发明的脂质-修饰的核酸分子包含如上定义的根据本发明的式(I),(Ia),(II),(IIa),(IIb),(IIIa)和/或(IIIb)任一的核酸分子,至少一种与根据本发明的核酸分子共价连接的接头,和至少一种与各个接头共价连接的脂质,以及至少一种与根据本发明的核酸分子共价连接(无接头)的(双官能)脂质。
在根据本发明的脂质-修饰的核酸分子中包含的脂质典型地是优选地其本身具有生物活性的脂质或亲脂残基。所述脂质优选地包括天然物质或化合物,如例如维生素,例如α-生育酚(维生素E),包括RRR-α-生育酚(以前的D-α-生育酚),L-α-生育酚,外消旋物D,L-α-生育酚,维生素E琥珀酸酯(VES),或维生素A及其衍生物,例如视黄酸,视黄醇,维生素D及其衍生物,例如维生素D及其麦角固醇前体,维生素E及其衍生物,维生素K及其衍生物,例如维生素K和相关的醌或植醇化合物,或类固醇,如胆汁酸,例如胆酸,脱氧胆酸,去氢胆酸,可的松(cortisone),地高辛(digoxygenin),睾酮(testosterone),胆固醇或硫代胆固醇。在本发明范围内的另外的脂质或亲脂残基包括,但不限于,聚亚烷基二醇(Oberhauser等,Nucl.Acids Res.(核酸研究),1992,20,533),脂族基团如,例如,C1-C20-烷,C1-C20-烯或C1-C20-链烷醇化合物,等,如,例如,十二烷二醇,十六醇或十一烷基残基(Saison-Behmoaras等,EMBO J,1991,10,111;Kabanov等,FEBS Lett.(FEBS通讯),1990,259,327;Svinarchuk等,Biochimie,1993,75,49),磷脂如,例如,磷脂酰甘油,二酰基磷脂酰甘油,磷脂酰胆碱,二棕榈酰磷脂酰胆碱,二硬脂酰磷脂酰胆碱,磷脂酰丝氨酸,磷脂酰乙醇胺,双-十六烷基-外消旋-甘油,鞘脂,脑苷脂,神经节苷酯,或1,2-二-O-十六烷基-外消旋-甘油-3-H-磷酸三乙铵(Manoharan等,Tetrahedron Lett.(四面体通讯),1995,36,3651;Shea等,Nucl.Acids Res.(核酸研究),1990,18,3777),多胺或聚(亚烷基)二醇,如例如,聚乙二醇(PEG)(Manoharan等,Nucleosides & Nucleotides(核苷 & 核苷酸),1995,14,969),六甘醇(HEG),棕榈酸甘油酯或棕榈基残基(Mishra等,Biochim.Biophys.Acta(生物化学生物物理学报),1995,1264,229),十八胺或己基氨基-羰基-氧基胆固醇残基(Crooke等,J.Pharmacol.Exp.Ther.,1996,277,923),以及蜡,萜,脂族烃,饱和的和单或多不饱和脂肪酸残基等。
在脂质和如上定义的根据本发明的式(I),(Ia),(II),(IIa),(IIb),(IIIa)和/或(IIIb)任一的核酸分子之间的连接原则上可以发生在本发明核酸的任何核苷酸、任何核苷酸的碱基或糖成分上,发生在如上定义的根据本发明的式(I),(Ia),(II),(IIa),(IIb),(IIIa)和/或(IIIb)任一的核酸分子的3′和/或5′端,和/或在磷酸酯主链上。根据本发明,特别优选根据本发明的核酸分子在其3′和/或5′端的末端脂质修饰。与序列内的修饰相比,末端修饰具有许多优势。另一方面,在序列内的修饰可以影响杂交行为,其可以在空间需求的残基方面具有不利的作用。在其它方面,在仅在末端修饰的脂质-修饰的根据本发明的核酸分子的合成制备中,如上定义的根据本发明的式(I),(Ia),(II),(IIa),(IIb),(IIIa)和/或(IIIb)任一的核酸分子的合成可以用可大量获得的商购单体进行,并且可以使用现有技术中已知的合成方案。
根据第一个优选的实施方案,在根据本发明的核酸分子和所用的至少一种脂质之间的连接通过接头(与如上定义的根据本发明的式(I),(Ia),(II),(IIa),(IIb),(IIIa)和/或(IIIb)任一的核酸分子的共价连接)实现。在本发明范围内的接头典型地具有至少两个,和任选地3,4,5,6,7,8,9,10,10-20,20-30或更多个反应基,所述反应基选自例如羟基、氨基、烷氧基等。一个反应基优选地用于结合上述如上定义的根据本发明的式(I),(Ia),(II),(IIa),(IIb),(IIIa)和/或(IIIb)任一的核酸分子,例如RNA寡核苷酸。该反应基可以以保护的形式存在,例如作为DMT基团(二甲氧基三苯甲基氯),作为Fmoc基团,作为MMT(单甲氧基三苯甲基)基团,作为TFA(三氟乙酸)基团,等。此外,硫基团可以通过二硫化物进行保护,所述二硫化物例如烷基硫醇,如例如,3-硫代丙醇,或通过激活成分如2-硫代吡啶保护。一个或多个另外的反应基根据本发明用于一个或多个脂质的共价结合。因此,根据第一个实施方案,如上定义的根据本发明的式(I),(Ia),(II),(IIa),(IIb),(IIIa)和/或(IIIb)任一的核酸分子可以通过共价结合的接头优选地结合至少一种脂质,例如每个如上定义的根据本发明的式(I),(Ia),(II),(IIa),(IIb),(IIIa)和/或(IIIb)任一的核酸分子结合1,2,3,4,5,5-10,10-20,20-30或更多脂质(s),特别地优选地至少3-8或更多个脂质。由此,结合的脂质可以彼此独立地在如上定义的根据本发明的式(I),(Ia),(II),(IIa),(IIb),(IIIa)和/或(IIIb)任一的核酸分子的不同位置结合,或它们以在如上定义的根据本发明的式(I),(Ia),(II),(IIa),(IIb),(IIIa)和/或(IIIb)任一的核酸分子的一个或多个位置的复合物的形式存在。接头的另外的反应基可以用于直接或间接(可裂解的)结合载体物质,例如固相。根据本发明优选的接头,例如是乙二醇,甘油和甘油衍生物,2-氨基丁基-1,3-丙二醇和2-氨基丁基-1,3-丙二醇衍生物/骨架,吡咯烷接头或包含吡咯烷的有机分子(具体地用于在3′端的修饰)等。甘油或甘油衍生物(C3锚)或2-氨基丁基-1,3-丙二醇衍生物/骨架(C7锚)是根据本发明特别优选使用的接头。当脂质修饰可以通过醚键引入时,作为接头的甘油衍生物(C3锚)是特别优选的。如果脂质修饰通过酰胺或氨基甲酸酯键引入,例如优选2-氨基丁基-1,3-丙二醇骨架(C7锚)。在该情形中,在接头和如上定义的根据本发明的式(I),(Ia),(II),(IIa),(IIb),(IIIa)和/或(IIIb)任一的核酸分子之间形成的键的性质优选地是这样的从而使其与amidite化学的条件和化学品是相容的,即,其优选地不是酸不稳定的也不是碱不稳定的。特别优选容易通过合成获得的碱并且其不通过核酸合成工艺的氨性裂解方法被水解。适合的键原则上是所有相应的适合的键,优选地酯键,酰胺键,氨基甲酸酯键和醚键。除了原材料的良好可及性(很少的合成步骤)之外,特别优选醚键,这是因为其针对酶促水解的相对较高的生物学稳定性。
根据第二个优选的实施方案,(至少一种)如上定义的根据本发明的式(I),(Ia),(II),(IIa),(IIb),(IIIa)和/或(IIIb)任一的核酸分子直接与如上所述的至少一种(双官能)脂质直接连接,即不使用如上所述的接头。在该情形中,根据本发明使用的(双官能)脂质优选地包含至少两个反应基或任选地3,4,5,6,7,8,9,10或更多个反应基,第一反应基用于直接或间接结合本文所述的载体物质并且至少一种另外的反应基用于结合如上定义的根据本发明的式(I),(Ia),(II),(IIa),(IIb),(IIIa)和/或(IIIb)任一的核酸分子。根据第二个实施方案,如上定义的根据本发明的式(I),(Ia),(II),(IIa),(IIb),(IIIa)和/或(IIIb)任一的核酸分子可以优选地结合至少一种脂质(直接地而无需接头),例如每个如上定义的根据本发明的式(I),(Ia),(II),(IIa),(IIb),(IIIa)和/或(IIIb)任一的核酸分子结合1,2,3,4,5,5-10,10-20,20-30或更多脂质,特别优选地至少3-8或更多个脂质。结合的脂质可以彼此独立地在如上定义的根据本发明的式(I),(Ia),(II),(IIa),(IIb),(IIIa)和/或(IIIb)任一的核酸分子的不同位置结合,或它们可以以复合物的形式存在于如上定义的根据本发明的式(I),(Ia),(II),(IIa),(IIb),(IIIa)和/或(IIIb)任一的核酸分子的一个或多个位置上。备选地,至少一种如上定义的根据本发明的式(I),(Ia),(II),(IIa),(IIb),(IIIa)和/或(IIIb)任一的核酸分子,例如,任选地如上定义的根据本发明的式(I),(Ia),(II),(IIa),(IIb),(IIIa)和/或(IIIb)任一的3,4,5,6,7,8,9,10,10-20,20-30或更多个核酸通过其反应基根据第二个实施方案结合于如上所述的脂质。可以用于该第二个实施方案的脂质特别优选地包括那些(双官能)脂质,其容许偶联(优选地,在其末端或任选地分子内地),如例如聚乙二醇(PEG)及其衍生物,六乙二醇(HEG)及其衍生物,烷二醇,氨基烷,硫代烷醇等。在(双官能)脂质和上述如上定义的根据本发明的式(I),(Ia),(II),(IIa),(IIb),(IIIa)和/或(IIIb)的核酸分子之间的键的性质优选地如第一个优选实施方案所述。
根据第三个实施方案,在如上定义的根据本发明的式(I),(Ia),(II),(IIa),(IIb),(IIIa)和/或(IIIb)任一的核酸分子和至少一种如上所述的脂质之间的连接可以通过两种上述实施方案同时发生。例如,如上定义的根据本发明的式(I),(Ia),(II),(IIa),(IIb),(IIIa)和/或(IIIb)任一的核酸分子可以在核酸的一个位置与至少一种脂质通过接头连接(类似于第一个实施方案)和在如上定义的根据本发明的式(I),(Ia),(II),(IIa),(IIb),(IIIa)和/或(IIIb)任一的核酸分子的不同位置直接与至少一种脂质不使用接头连接(类似于第二个实施方案)。例如,在如上定义的根据本发明的式(I),(Ia),(II),(IIa),(IIb),(IIIa)和/或(IIIb)任一的核酸分子的3′端,至少一种如上所述的脂质可以与核酸通过接头共价连接,并且在根据本发明的核酸分子的5′端,如上所述的脂质可以与核酸不经过接头共价连接。备选地,在如上定义的根据本发明的式(I),(Ia),(II),(IIa),(IIb),(IIIa)和/或(IIIb)任一的核酸分子的5′端,至少一种如上所述的脂质可以与核酸分子通过接头共价连接,并且在如上定义的根据本发明的式(I),(Ia),(II),(IIa),(IIb),(IIIa)和/或(IIIb)任一的核酸分子的3′端,如上所述的脂质可以与核酸分子,不经过接头而共价连接。同样地,共价连接可以不仅在如上定义的根据本发明的式(I),(Ia),(II),(IIa),(IIb),(IIIa)和/或(IIIb)任一的核酸分子的末端发生,还可以在分子内发生,如上所述,例如在3′端和分子内,在5′端和分子内,在3′和5′端和分子内,仅分子内等。
脂质-修饰的如上定义的根据本发明的式(I),(Ia),(II),(IIa),(IIb),(IIIa)和/或(IIIb)任一的核酸分子可以优选地通过各种方法获得。脂质修饰可以原则上-如上定义-被引入如上定义的根据本发明的式(I),(Ia),(II),(IIa),(IIb),(IIIa)和/或(IIIb)任一的核酸分子的任何位置,例如在如上定义的根据本发明的式(I),(Ia),(II),(IIa),(IIb),(IIIa)和/或(IIIb)任一的核酸分子的3′和/或5′端或在磷酸酯主链上,和/或在如上定义的根据本发明的式(I),(Ia),(II),(IIa),(IIb),(IIIa)和/或(IIIb)任一的核酸分子的任何核苷酸的任何碱基或糖上。根据本发明,优选在如上定义的根据本发明的式(I),(Ia),(II),(IIa),(IIb),(IIIa)和/或(IIIb)任一的核酸的3′和/或5′端的末端脂质修饰。通过所述末端化学修饰的方式,可以根据本发明获得大量的不同衍生的核酸。用于制备如上定义的根据本发明的式(I),(Ia),(II),(IIa),(IIb),(IIIa)和/或(IIIb)任一的所述脂质-修饰的核酸优选地基于脂质修饰的位置选择。
如果,脂质修饰例如发生在如上定义的根据本发明的式(I),(Ia),(II),(IIa),(IIb),(IIIa)和/或(IIIb)任一的核酸分子的3′端,那么脂质修饰典型地在制备如上定义的根据本发明的式(I),(Ia),(II),(IIa),(IIb),(IIIa)和/或(IIIb)任一的核酸分子之前或之后进行。如上定义的根据本发明的式(I),(Ia),(II),(IIa),(IIb),(IIIa)和/或(IIIb)的核酸分子的制备可以通过直接合成核酸或任选地通过加入快速合成的核酸或来自分离自其它来源的样品的核酸来进行。
根据第一个备选方案,如上定义的根据本发明的式(I),(Ia),(II),(IIa),(IIb),(IIIa)和/或(IIIb)的核酸分子在引入脂质前直接合成,其典型地通过现有技术合成核酸已知的方法进行。为此目的,起始核苷酸(核苷)优选地结合于固相,例如通过偶联分子,例如琥珀酰残基,例如通过amidite化学方法合成了如上定义的根据本发明的式(I),(Ia),(II),(IIa),(IIb),(IIIa)和/或(IIIb)任一的核酸分子。接着,优选地通过所述接头的第一反应基,将前文所述的接头与如上定义的根据本发明的式(I),(Ia),(II),(IIa),(IIb),(IIIa)和/或(IIIb)任一的核酸分子的3′端结合。接着,可以将如前文所述的脂质与接头通过接头的第二反应基共价连接。备选地,接头可以在其结合于如上定义的根据本发明的式(I),(Ia),(II),(IIa),(IIb),(IIIa)和/或(IIIb)任一的核酸分子的3′端之前,与脂质共价连接。在该情形中,仅接头的第一反应基与如上定义的根据本发明的式(I),(Ia),(II),(IIa),(IIb),(IIIa)和/或(IIIb)任一的核酸分子的3′端的结合是必需的。在合成如上定义的根据本发明的式(I),(Ia),(II),(IIa),(IIb),(IIIa)和/或(IIIb)任一的核酸分子后,或在脂质的结合后,如上定义的根据本发明的式(I),(Ia),(II),(IIa),(IIb),(IIIa)和/或(IIIb)任一的核酸分子可以从固相分离,并且被去保护。如果合成已经在溶液中进行,用于去除未反应的反应物以及溶剂和不合需要的次级产物的洗涤和纯化步骤可以在合成脂质-修饰的根据本发明的核酸分子进行(并且任选地,在从载体物质分离之前进行)。
根据另一个备选方案,如上定义的3′-脂质-修饰的如上定义的根据本发明的式(I),(Ia),(II),(IIa),(IIb),(IIIa)和/或(IIIb)任一的核酸分子在将脂质引入接头的反应基后或结合于接头的反应基后,作为快速合成的如上定义的根据本发明的式(I),(Ia),(II),(IIa),(IIb),(IIIa)和/或(IIIb)任一的核酸分子合成。为此目的,例如,如上所述的接头的第一反应基可以与如前所述的脂质反应。接着,优选地在第二个步骤中,给所述接头的第二反应基提供酸稳定性的保护基,例如DMT,Fmoc,等,从而容许随后将如上定义的根据本发明的式(I),(Ia),(II),(IIa),(IIb),(IIIa)和/或(IIIb)任一的核酸分子结合于该反应基。接着,所述接头可以直接或间接通过接头的第三反应基结合于固相。间接结合是可能的,例如通过(偶联)分子,其可以共价结合于接头和固相。所述(偶联)分子例如是如前文所述的琥珀酰残基等。接着通常发生在接头的第三反应基的保护基的去除和在目前可及的反应基结合或合成如上定义的根据本发明的式(I),(Ia),(II),(IIa),(IIb),(IIIa)和/或(IIIb)任一的核酸分子。最后,脂质-修饰的根据本发明的核酸分子典型地从载体物质上裂解下来(并且在核酸上的保护基任选地被去除)。然而,其它的脂质也可以任选地偶联于偶联的式(I),(Ia),(II),(IIa),(IIb),(IIIa)和/或(IIIb)任一的根据本发明的核酸分子,其优选地根据前述的一个步骤进行。
根据该前述备选方案的变体,如上所述的接头可以直接或间接地通过第一反应基连接于固相。接着,将酸稳定的保护基首先结合于接头的第二反应基。在将保护基结合于第二反应基后,如上所述的脂质可以首先结合于所述接头的第三反应基。接着,同样地优选地进行在接头的第三反应基的保护基的去除,如上定义的根据本发明的式(I),(Ia),(II),(IIa),(IIb),(IIIa)和/或(IIIb)任一的核酸分子在目前可及的反应基的结合或合成,以及脂质-修饰的根据本发明的核酸分子从所述载体物质的裂解(并且任选地,在所述核酸去除保护基)。
根据如上定义的根据本发明的式(I),(Ia),(II),(IIa),(IIb),(IIIa)和/或(IIIb)任一的核酸分子的3′-脂质修饰的特别优选的实施方案,所述脂质-修饰的根据本发明的核酸分子可以通过具有三个基于甘油基本物质(C3锚)的反应基(三官能锚定化合物)和具有单官能脂质的接头合成,所述脂质如例如,棕榈基残基,胆固醇或生育酚。作为合成接头的起始物质,可以使用例如α,β-异亚丙基-甘油(包含缩酮保护基的甘油),其优选地首先用氢氧化钠转化为醇化物并且与十六烷基溴和脂质在威廉逊合成法中反应以形成相应的醚。备选地,醚键可以在第一个步骤中通过不同的方法连接,例如通过形成α,β-异亚丙基-甘油的甲苯磺酸酯,并且使甲苯磺酸酯与脂质的反应基(例如酸性质子)反应,以形成相应的醚。在第二个阶段中,可以用酸(例如乙酸、稀释的盐酸等)去除缩酮保护基,接着可以选择性地通过二甲氧基三苯甲基氯(DMT-Cl)来保护二醇的伯羟基。在最后的阶段中,优选地进行在前一个步骤中获得的产物与琥珀酸酐的反应从而形成琥珀酸酯,其中用DMAP作为催化剂。所述接头特别适合于例如结合作为脂质的棕榈基残基或生育酚。
根据另一个备选方案,如上定义的根据本发明的式(I),(Ia),(II),(IIa),(IIb),(IIIa)和/或(IIIb)任一的核酸分子的3′-脂质修饰使用(双官能)脂质,如,例如,聚乙二醇(PEG)或六乙二醇(HEG),而不使用如上所述的接头来实现。所述双官能脂质典型地具有如上所述的两个官能团,其中双官能脂质的一端可以优选地通过偶联分子,例如如本文所述的碱不稳定的琥珀酰基锚等而结合于载体物质,并且如上定义的根据本发明的式(I),(Ia),(II),(IIa),(IIb),(IIIa)和/或(IIIb)任一的核酸分子可以在双官能脂质的其它端合成(E.Bayer,M.Maier,K.Bleicher,H.-J.Gaus Z.Naturforsch.50b(1995)671)。通过分别省略如前文使用的第三次官能化和接头,简化了这样的脂质-修饰的根据本发明的核酸分子的合成。对于制备,根据本发明使用的双官能脂质,例如聚乙二醇典型地首先用保护基(例如DMT)单取代。在第二个阶段,通常用琥珀酸酐,用DMAP催化,进行在反应基保护的脂质的酯化,从而形成琥珀酸酯。随后,在第三个阶段中,在如上定义的根据本发明的式(I),(Ia),(II),(IIa),(IIb),(IIIa)和/或(IIIb)任一的核酸分子的合成根据如前所述的方法发生在第四个步骤中后,所述双官能脂质与载体物质偶联并进行去保护。接着任选地进行合成的如上定义的根据本发明的式(I),(Ia),(II),(IIa),(IIb),(IIIa)和/或(IIIb)任一的核酸分子的去保护和脂质-修饰的核酸从载体物质上的裂解。
根据另一个优选的实施方案,如上定义的根据本发明的式(I),(Ia),(II),(IIa),(IIb),(IIIa)和/或(IIIb)任一的核酸分子的脂质修饰发生在核酸的5′端。由此,脂质修饰典型地在提供或在合成如上定义的根据本发明的式(I),(Ia),(II),(IIa),(IIb),(IIIa)和/或(IIIb)任一的核酸分子后进行。如上定义的根据本发明的式(I),(Ia),(II),(IIa),(IIb),(IIIa)和/或(IIIb)任一的核酸分子的提供可以如上定义,通过如上定义的根据本发明的式(I),(Ia),(II),(IIa),(IIb),(IIIa)和/或(IIIb)任一的核酸分子的直接合成或通过加入快速合成的如上定义的根据本发明的式(I),(Ia),(II),(IIa),(IIb),(IIIa)和/或(IIIb)任一的核酸分子来进行。如上定义的根据本发明的式(I),(Ia),(II),(IIa),(IIb),(IIIa)和/或(IIIb)任一的核酸分子的合成优选地类似于上述方法,根据现有技术已知的核酸合成的方法,更优选地根据亚磷酰胺方法发生。
根据特别优选的实施方案,在用于合成核酸的亚磷酰胺方法后,如上定义的根据本发明的式(I),(Ia),(II),(IIa),(IIb),(IIIa)和/或(IIIb)任一的核酸分子的脂质修饰通过特定修饰的亚磷酰胺发生在根据本发明的核酸分子的5′端。可通过合成相当简单的获得的这些amidites作为最后的单体常规偶联于商购的或快速合成的核酸。这些反应由相当快速的反应动力学和非常高的偶联收率区分。修饰的amidites的合成优选地通过亚磷酰胺,例如β-氰基乙基-单氯亚磷酰胺(磷酸单-(2-氰基乙酯)-二异丙基-酰胺氯)与如上定义的脂质的醇(溶解在适合的溶剂中,例如在无水二氯甲烷中),例如生育酚、胆固醇、十六烷醇、DMT-PEG等的脂质醇反应而进行。同样优选地,将DIPEA作为酸性受体加入反应溶液中。
用于合成5′-脂质-修饰的根据本发明的核酸的这些亚磷酰胺对于水解具有相对的抗性,并且可以(在合成前)通过硅胶的方式通过色谱法纯化。为此目的,将少量的弱碱,如例如三乙胺,典型地加入洗脱液中从而避免amidite的分解。该碱从产物中再次彻底去除从而避免较差的偶联产率是重要的。例如,这可以这样进行,例如通过在真空中的简单干燥,但是优选地通过使用戊烷将亚磷酰胺从叔丁基甲醚中沉淀出来而纯化。如果所用的脂质-修饰的amidites具有非常高的粘性,例如以粘性油的形式存在,还可以进行(快速)柱色谱法,其使用三乙胺作为碱进行分配成为可能。然而,这样的纯化典型地不在PEG-修饰的amidites的情形中进行,因为它们包含酸不稳定的DMT保护基。
对于脂质-修饰的亚磷酰胺与如上定义的根据本发明的式(I),(Ia),(II),(IIa),(IIb),(IIIa)和/或(IIIb)的核酸分子的5′端的偶联反应,优选地使用那些溶剂,其中所用的amidites是充分可溶的。例如,由于根据本发明使用的amidites的高亲油性,它们在乙腈中的溶解性可以受到限制。除了典型使用的作为溶剂的乙腈之外,优选地将氯化烃的溶液用于偶联反应,例如在(无水)二氯甲烷中的0.1M溶液。然而,二氯甲烷的应用需要合成循环的标准方案的一些变化。例如,为了避免amidite沉淀在自动合成装置的管道中以及在载体物质上,在实际偶联步骤和吹干之前和之后,将与amidite接触的所有阀门和管道用(无水)二氯甲烷冲洗。
当使用脂质-修饰的amidites时,典型地获得高偶联收率,其与常规用于现有技术中的amidites的偶联产率相当。脂质-修饰的amidites的反应动力学通常更缓慢地进行。为此原因,与标准方案比较时,当使用脂质-修饰的amidites时,偶联时间优选地(明显地)被增长。所述偶联时间可以容易地由本领域技术人员确定。因为,可以省略在偶联后的加帽步骤,如果需要同样可以用相同的脂质-修饰的amidite进行的另外的合成循环从而增加反应的总收率。在该情形中,通常不进行去三苯甲基化步骤,例如在DMT-修饰的脂质如DMT-PEG的情形中。
在根据本发明的5′-脂质-修饰的核酸分子的合成中,可以将亚磷酸三酯通过硫化剂进行氧化,通过所述亚磷酸三酯脂质结合于如上定义的根据本发明的式(I),(Ia),(II),(IIa),(IIb),(IIIa)和/或(IIIb)任一的核酸分子。为此目的,优选地,使用硫化剂,其尽可能彻底地实现磷酸三酯的氧化。另外,硫化反应,例如出于空间原因,可以进行地这样不彻底,以至于在MON的氨性裂解和去保护后获得仅少量的产物或根本没有获得产物。这种现象取决于修饰的类型,所用的硫化剂和硫化条件。因此,优选地用碘进行氧化。结果,尽管引入了磷酸二酯键,由于脂质残基的接近,不预期键作为底物被核酸酶识别。
在脂质修饰中,包含在如上定义的根据本发明的式(I),(Ia),(II),(IIa),(IIb),(IIIa)和/或(IIIb)任一的核酸分子中的接头或(双官能)脂质或任选地如上定义的根据本发明的式(I),(Ia),(II),(IIa),(IIb),(IIIa)和/或(IIIb)任一的核酸分子本身可以如前文所述,直接地或间接地偶联于载体物质。直接偶联优选地直接地与载体物质进行,而间接偶联于载体物质典型地通过另外的(偶联)分子进行。通过偶联于载体物质形成的结合优选地显示与接头或双官能脂质的(可裂解)共价结合和/或与固相的(可裂解)共价结合。适合作为(偶联)分子的化合物例如是二羧酸,例如琥珀酰残基(=琥珀酰锚),草酰残基(=草酰锚)等。如上定义的根据本发明的式(I),(Ia),(II),(IIa),(IIb),(IIIa)和/或(IIIb)任一的接头,(双官能)脂质或任选地核酸,例如氨基烷基残基(例如,氨基丙基或氨基己基残基),携带游离的氨基官能团,所述接头,(双官能)脂质或任选地核酸可以通过苯邻二甲酰亚胺接头结合于载体物质。如上定义的根据本发明的式(I),(Ia),(II),(IIa),(IIb),(IIIa)和/或(IIIb)的包含巯基的接头,(双官能)脂质或任选地核酸可以以二硫化物的形式结合于载体物质。在本发明的该情形中的适合的载体物质特别是固相如CPG,Tentagel,氨基-官能化的PS-PEG(TentagelS NH2),等,优选地Tentagel或氨基-官能化的PS-PEG(TentagelS NH2)。根据特定的实施方案,对于偶联于载体物质,可以将例如根据本发明使用的所述接头或双官能脂质的琥珀酸酯,与氨基-官能化的PS-PEG(TentagelS NH2)进行偶联,其中优选地用TBTU/NMM(1H-苯并三唑-1-基-1,1,3,3-四甲基尿鎓四氟硼酸酯/N-甲基吗啉)作为偶联剂。在常规使用的1μmol等级的PS-PEG载体物质的情形中,用50-100μmol/g的负荷典型地获得最佳的结果(E.Bayer,K.Bleicher,M.Maier Z.Naturforsch.50b(1995)1096)。然而,如果在根据本发明的大规模等级上合成核苷酸,载体物质的负荷优选地是尽可能高的(≥100μmol)。根据本发明,这样的方法同样导致良好的偶联收率(M.Gerster,M.Maier,N.Clausen,J.Schewitz,E.Bayer Z.Naturforsch.52b(1997)110)。例如,可以使用载体物质如,例如具有多到138μmol/g或任选地更高负荷的树脂,其获得了良好的合成收率。因为用上述接头或双官能脂质获得的偶联收率是约100%,可以通过这些化合物的化学计量相对精确地调整所述载体物质的负荷。所述负荷优选地通过裂解的DMT保护基的分光光度法量化来监测(见实验部分)。仍旧存在于载体物质上的残余的氨基官能团可以用乙酸酐进行加帽。这种加帽在通常情形下,在加载载体物质后进行,但是也可以直接地在核酸合成中发生,例如在DNA合成仪中发生。对于在衍生化的PS-PEG载体物质上的脂质-修饰的核酸的合成,优选地使用特别关于Tentagel开发的合成循环,其考虑了所述物质的特征性性质(E.Bayer,M.Maier,K.Bleicher,H.-J.Gaus Z.Naturforsch.50b(1995)671,E.Bayer,K.Bleicher,M.Maier Z.Naturforsch.50b(1995)1096.)。与标准方案相当的优选的变化包括:
·在偶联、加帽和氧化步骤中的反应时间增长;
·去三苯甲基化步骤数量增加;
·在每个步骤后的洗涤步骤加长;
·在氧化步骤后使用包含抗坏血酸的洗涤溶液(0.1M二噁烷/水=9∶1),(其通常在amidite方法中是必需的(用于亚磷酸三酯的氧化)),以去除痕量的碘。
应该注意,修饰的性质可以对合成循环的每个步骤具有影响。例如,在PEG1500-衍生的载体物质的情形中,观察到相当缓慢的反应动力学,这需要再次加长去三苯甲基化步骤,以及另外延长偶联时间。所述变化和改进在本领域技术人员的正常能力范围内,并且可以在本发明公开内容中的任何时间进行。使用这些这样改进的反应循环,可以合成脂质-修饰的磷酸二酯和硫代磷酸酯。在根据本发明使用的接头或双官能脂质上的amidites的偶联收率没有被脂质残基损害,而是对应于常规值(97-99%)。当使用所述3′修饰时,仍旧保留5′衍生化和引入另外的修饰(例如碱、糖或磷酸酯主链)的可能性。
如上定义的根据本发明的式(I),(Ia),(II),(IIa),(IIb),(IIIa)和/或(IIIb)任一的核酸分子,如化学未修饰的核酸或(化学)修饰的核酸,例如脂质修饰的如上定义的根据本发明的式(I),(Ia),(II),(IIa),(IIb),(IIIa)和/或(IIIb)任一的核酸分子,可以同样地通过使如上定义的根据本发明的式(I),(Ia),(II),(IIa),(IIb),(IIIa)和/或(IIIb)任一的核酸分子与,例如但不限于阳离子聚合物,阳离子肽或多肽,优选地与聚阳离子聚合物如聚赖氨酸或聚精氨酸,或备选地与阳离子脂质或lipofectants,与组蛋白,核仁蛋白,鱼精蛋白,寡核苷酸转染(oligofectamine),精胺或亚精胺,和阳离子多糖,特别是脱乙酰壳多糖,TDM,MDP,胞壁酰二肽,泊洛沙姆,和/或其衍生物之一等形成复合物而得以稳定。组蛋白和鱼精蛋白是天然包装DNA的阳离子蛋白质。因此,它们在体内负责未翻译的DNA和某些病毒的DNA的缩合。作为可以用于本发明与如上定义的根据本发明的式(I),(Ia),(II),(IIa),(IIb),(IIIa)和/或(IIIb)任一的核酸分子形成复合物的组蛋白,可以更特别提及组蛋白H1,H2a,H3和H4。然而,鱼精蛋白(鱼精蛋白P1或P2)或鱼精蛋白的阳离子部分序列是特别优选的。在本发明的情形中,化合物可以有利地由从鱼精蛋白P1或P2衍生的肽序列,更精确地对应于(阳离子)序列(SRSRYYRQRQRSRRRRRR(SEQ ID NO:109)或RRRLHRIHRRQHRSCRRRKRR(SEQ ID NO:110)的肽序列表示。适合于与如上定义的根据本发明的式(I),(Ia),(II),(IIa),(IIb),(IIIa)和/或(IIIb)任一的根据本发明的核酸分子形成复合物的其它化合物可以选自如本文所述的佐剂化合物,但不限于此。
在该情形中,“形成复合物”应该意味着如上定义的根据本发明的式(I),(Ia),(II),(IIa),(IIb),(IIIa)和/或(IIIb)任一的核酸分子与如上定义的稳定化合物,例如阳离子聚合物,阳离子肽或多肽,等,通过在核酸和稳定化合物之间形成非共价复合物而结合。在本文中,“非共价”意味着核酸和稳定化合物之间的可逆缔合通过这些分子的非共价相互作用而形成,其中所述分子通过一些类型的电子相互作用,而非共价键,例如通过范德瓦尔斯-键缔合,所述范德瓦尔斯-键即由两种分子的非特异性吸引力导致的弱静电吸引。如上定义的根据本发明的式(I),(Ia),(II),(IIa),(IIb),(IIIa)和/或(IIIb)任一的核酸分子和稳定化合物之间的缔合与该复合物的解离平衡。不限于任何理论,预期所述平衡在细胞内向解离的如上定义的根据本发明的式(I),(Ia),(II),(IIa),(IIb),(IIIa)和/或(IIIb)任一的核酸分子和稳定化合物偏向。
根据一个实施方案,如果不和任何其它药用活性成分一起施用,如上定义的根据本发明的式(I),(Ia),(II),(IIa),(IIb),(IIIa)和/或(IIIb)任一的核酸分子可以是免疫刺激剂,或如果和药用活性成分一起施用,其可以用作佐剂,,例如作为包含药用活性成分和佐剂组分的组合物(例如包含特异性抗原和作为佐剂的如上定义的根据本发明的(I),(Ia),(II),(IIa),(IIb),(IIIa)和/或(IIIb)任一的核酸分子的疫苗组合物)。
如上定义的作为″免疫刺激剂″的根据本发明的式(I),(Ia),(II),(IIa),(IIb),(IIIa)和/或(IIIb)任一的核酸分子优选地能够促发非抗原特异性免疫反应(如先天免疫系统提供),优选以免疫刺激的方式进行。免疫反应可以以多种方式发生。对于合适的免疫应答的一个重要因素是不同T细胞亚群的刺激。T淋巴细胞典型地分化成两种亚群,T-辅助1(Th1)细胞和T-辅助2(Th2)细胞,免疫系统使用所述T-辅助1(Th1)细胞和T-辅助2(Th2)细胞能够破坏细胞内(Th1)和细胞外(Th2)病原体(例如抗原)。两种Th细胞群区别在于由它们产生的效应蛋白(细胞因子)的模式。因而,Th1细胞通过巨噬细胞和细胞毒性T-细胞的激活帮助细胞免疫应答。相反,Th2细胞,通过刺激B-细胞转变成浆细胞和通过抗体(例如针对抗原)的形成来促进体液免疫应答。所以Th1/Th2比率在免疫应答中非常重要。在本发明的背景中,优选地将免疫应答的Th1/Th2比率用免疫刺激剂来替代,即针对细胞反应的方向上如上定义的根据本发明的式(I),(Ia),(II),(IIa),(IIb),(IIIa)和/或(IIIb)任一的核酸分子,也就是说Th1应答,并且主要的细胞免疫应答由此诱导。如上定义,本发明的核酸其自身产生非特异性免疫应答,这使得该核酸象这样(不用添加其它药用活性成分)被用作免疫刺激剂。如果与其它药用活性成分一起施用,优选特异性免疫刺激组分,本发明的核酸充当佐剂,其支持由其它药用活性成分诱发的特异性免疫应答。
本发明还涉及药物组合物,其包含至少一种创造性的如上定义的根据本发明的式(I),(Ia),(II),(IIa),(IIb),(IIIa)和/或(IIIb)任一的核酸分子和任选地(相容的)药用载体和/或其它辅助物质和添加剂和/或佐剂(本发明组合物的第一种实施方案)。另外,本发明涉及药物组合物,其包含至少一种如上定义的根据本发明的式(I),(Ia),(II),(IIa),(IIb),(IIIa)和/或(IIIb)任一的核酸分子,例如一种,两种,三种,四种,六种,七种,或其更多核酸分子,药用活性成分和任选地药用载体和/或其它辅助物质和添加剂和/或佐剂(本发明组合物的第二种实施方案)。
根据本发明的药物组合物典型地包含安全和有效量的至少一种如上定义的根据本发明的式(I),(Ia),(II),(IIa),(IIb),(IIIa)和/或(IIIb)任一的核酸分子,或一种,两种,三种,四种,六种,七种,或其更多核酸分子。本文所用的″安全和有效量″意指在组合物中如上定义的根据本发明式(I),(Ia),(II),(IIa),(IIb),(IIIa)和/或(IIIb)任一的每一种或全部核酸的量,其足以显著诱导待治疗疾病的阳性改善,所述疾病例如肿瘤,自体免疫疾病,变应性疾病或感染性疾病,等等。同时,不过,″安全和有效量″是足够小以避免严重的副作用,也就是说允许介于益处和危险之间的敏感关系。这些限制的确定一般存在于敏感医学判断的范围内。关于如上定义的根据本发明的式(I),(Ia),(II),(IIa),(IIb),(IIIa)和/或(IIIb)任一的核酸分子,″安全和有效量″的表达方式优选地意指适合刺激免疫系统的量,这种刺激是以不获得过量或有害的免疫反应的方式进行的,但也优选没有低于可测量水平的这种免疫反应。如上定义的根据本发明的式(I),(Ia),(II),(IIa),(IIb),(IIIa)和/或(IIIb)任一的核酸分子的″安全和有效量″,将根据待治疗的特定疾病有所变化,也取决于待治疗患者的年龄和身体状况,病症的严重性,治疗的持续时间,伴随性治疗的性质,所用的特定药用载体,和类似的因素,在相关医生的知识和经验范围内。根据本发明的药物组合物可以根据本发明用于人,并且也可以用于兽医疗目的。
根据第一个实施方案,上述如上定义的根据本发明的式(I),(Ia),(II),(IIa),(IIb),(IIIa)和/或(IIIb)任一的核酸分子,其自身可以是免疫刺激剂(不用添加任何其它药用活性成分)。如果如上定义的根据本发明的式(I),(Ia),(II),(IIa),(IIb),(IIIa)和/或(IIIb)任一的核酸分子包含脂质修饰的话,这特别适用。脂质可以进一步增强本发明的核酸的免疫刺激特性或者可以良好地形成治疗活性的分子,如,例如,维生素,或类固醇,如上所述,例如α-生育酚(维生素E),D-α-生育酚,L-α-生育酚,D,L-α-生育酚,维生素E琥珀酸酯(VES),维生素A及其衍生物,维生素D及其衍生物,维生素K及其衍生物,等等。
根据本发明的第二个实施方案的药物组合物可以包含(除了如上定义的根据本发明的式(I),(Ia),(II),(IIa),(IIb),(IIIa)和/或(IIIb)任一的核酸分子的至少一种之外)至少一种另外的药用活性成分。在此背景中药用活性成分是具有针对特定适应症的治疗作用的化合物,所述适应症优选地是癌症疾病,自体免疫疾病,变应性或感染性疾病。所述化合物包括,但不限于,肽,蛋白质,核酸,(治疗活性的)低分子量有机或无机化合物(小于5000的分子量,优选地小于1000),糖,抗原或抗体,现有技术中已知的治疗剂,抗原性细胞,抗原性细胞片段,细胞级分;经修饰的,减毒的或失活的(例如通过化学手段或通过刺激)病原体(病毒,细菌等)等。
根据(根据本发明的组合物)第二个实施方案的第一种备选,包含在药物组合物中的药用活性成分是免疫调节组分,优选是免疫刺激性组分。最优选地所述药用活性成分是抗原或免疫原。″抗原″和″免疫原″应理解为是任何能够带来抗体形成和/或细胞免疫应答的激活的任何结构,所述免疫应答即特异性(并且不是辅助)免疫应答。所以,根据本发明,术语″抗原″和″免疫原″被同义使用。抗原的实例是肽,多肽,即蛋白质,细胞,细胞提取物,多糖,多糖缀合物,脂质,糖脂和碳水化合物。作为抗原,可以考虑例如,肿瘤抗原,动物,草药,病毒,细菌,真菌和原生动物抗原,自身免疫抗原或变应原。优选肿瘤细胞的表面抗原和病毒,细菌,真菌和原生动物病原体的表面抗原,特别是分泌型形式的。当然,所述抗原可以存在于,例如根据本发明的疫苗中,还可以作为偶联到合适载体上的半抗原。还可以使用其它抗原性组分,例如失活的或减毒的病原体(如上所述)。
抗原性(多)肽包括所有已知的抗原性肽,例如肿瘤抗原,等。肿瘤抗原的具体实例特别是肿瘤特异性表面抗原(TSSAs),例如5T4,707-AP,9D7,AFP,AlbZIP HPG1,α-5-β-1-整联蛋白,α-5-β-6-整联蛋白,α-辅肌动蛋白-4/m,α-甲基酰基-辅酶A消旋酶,ART-4,ARTC1/m,B7H4,BAGE-1,BCL-2,bcr/abl,β-连环蛋白/m,BING-4,BRCA1/m,BRCA2/m,CA 15-3/CA 27-29,CA 19-9,CA72-4,CA125,钙网织蛋白,CAMEL,CASP-8/m,组织蛋白酶B,组织蛋白酶L,CD19,CD20,CD22,CD25,CDE30,CD33,CD4,CD52,CD55,CD56,CD80,CDC27/m,CDK4/m,CDKN2A/m,CEA,CLCA2,CML28,CML66,COA-1/m,毛状蛋白(coactosin)-样蛋白,collage XXIII,COX-2,CT-9/BRD6,Cten,细胞周期蛋白B1,细胞周期蛋白D1,cyp-B,CYPB1,DAM-10,DAM-6,DEK-CAN,EFTUD2/m,EGFR,ELF2/m,EMMPRIN,EpCam,EphA2,EphA3,ErbB3,ETV6-AML1,EZH2,FGF-5,FN,Frau-1,G250,GAGE-1,GAGE-2,GAGE-3,GAGE-4,GAGE-5,GAGE-6,GAGE7b,GAGE-8,GDEP,GnT-V,gp100,GPC3,GPNMB/m,HAGE,HAST-2,hepsin(一种丝氨酸蛋白酶),Her2/neu,HERV-K-MEL,HLA-A*0201-R17I,HLA-A11/m,HLA-A2/m,HNE,同源框NKX3.1,HOM-TES-14/SCP-1,HOM-TES-85,HPV-E6,HPV-E7,HSP70-2M,HST-2,hTERT,iCE,IGF-1R,IL-13Ra2,IL-2R,IL-5,未成熟层粘连蛋白受体,激肽释放酶-2,激肽释放酶-4,Ki67,KIAA0205,KIAA0205/m,KK-LC-1,K-Ras/m,LAGE-A1,LDLR-FUT,MAGE-A1,MAGE-A2,MAGE-A3,MAGE-A4,MAGE-A6,MAGE-A9,MAGE-A10,MAGE-A12,MAGE-B1,MAGE-B2,MAGE-B3,MAGE-B4,MAGE-B5,MAGE-B6,MAGE-B10,MAGE-B16,MAGE-B17,MAGE-C1,MAGE-C2,MAGE-C3,MAGE-D1,MAGE-D2,MAGE-D4,MAGE-E1,MAGE-E2,MAGE-F1,MAGE-H1,MAGEL2,乳腺珠蛋白(mammaglobin)A,MART-1/melan-A,MART-2,MART-2/m,基质蛋白22,MC1R,M-CSF,ME1/m,间皮素(mesothelin),MG50/PXDN,MMP11,MN/CA IX-抗原,MRP-3,MUC-1,MUC-2,MUM-1/m,MUM-2/m,MUM-3/m,I类肌球蛋白/m,NA88-A,N-乙酰基葡糖胺基转移酶-V,Neo-PAP,Neo-PAP/m,NFYC/m,NGEP,NMP22,NPM/ALK,N-Ras/m,NSE,NY-ESO-1,NY-ESO-B,OA1,OFA-iLRP,OGT,OGT/m,OS-9,OS-9/m,鲑鱼降钙素注射剂,骨桥蛋白,p15,p190较小bcr-abl,p53,p53/m,PAGE-4,PAI-1,PAI-2,PART-1,PATE,PDEF,Pim-1-激酶,Pin-1,Pml/PARα,POTE,PRAME,PRDX5/m,前列腺癌相关抗原(prostein),蛋白酶-3,PSA,PSCA,PSGR,PSM,PSMA,PTPRK/m,RAGE-1,RBAF600/m,RHAMM/CD168,RU1,RU2,S-100,SAGE,SART-1,SART-2,SART-3,SCC,SIRT2/m,Sp17,SSX-1,SSX-2/HOM-MEL-40,SSX-4,STAMP-1,STEAP,存活素,存活素-2B,SYT-SSX-1,SYT-SSX-2,TA-90,TAG-72,TARP,TEL-AML1,TGFβ,TGFβRII,TGM-4,TPI/m,TRAG-3,TRG,TRP-1,TRP-2/6b,TRP/INT2,TRP-p8,酪氨酸酶,UPA,VEGF,VEGFR-2/FLK-1,和WT1。任何类别的肿瘤抗原都适于本发明的目的,例如已知涉及新血管生成,涉及影响细胞外基质结构等的肿瘤抗原。肿瘤抗原可以在药物组合物中作为蛋白质或肽抗原或作为编码肿瘤抗原或其表位的mRNA或DNA而被提供,优选以上肿瘤抗原。
通过第二个实施方案(关于包含本发明的核酸(作为佐剂)和另外的药用活性成分的根据本发明的组合物)的第二个备选,所述药用活性成分是抗体。在该情形中,可以使用任何在治疗上适合的抗体。根据本发明特别优选针对在癌症疾病或感染性疾病中发挥重要作用的抗原,蛋白质或核酸的抗体,例如细胞表面蛋白,肿瘤抑制基因或其抑制剂,生长因子和延长因子,凋亡相关蛋白,肿瘤抗原,或如前文所述抗原,等等。
根据第二个实施方案的第三个备选,根据本发明的药物组合物中包含的药用活性成分是核酸。这种核酸可以是单链或双链并且可以是同型或异型双链体的形式并且还是线状或环状形式。作为药用活性成分包含在药物组合物中的核酸在其长度方面并不限制并且可以包含任何天然存在的核酸序列或其互补体或其片段。同样地,在该情形中所用的核酸可以是部分或完全合成的性质。例如,该核酸可以包括编码(治疗上相关的)蛋白和/或能够带来免疫反应的核酸,例如抗原或编码抗原的核酸。在此抗原优选如前文所述的抗原。
优选地作为药用活性成分包含在根据本发明的药物组合物中的核酸是mRNA。可以将这种mRNA以其裸露形式加入到根据本发明的药物组合物中,或以稳定化的形式存在,这种形式减弱或甚至阻止核酸在体内降解,例如,通过核酸外切酶和/或核酸内切酶阻止。
例如,作为药用活性成分包含在根据本发明的药物组合物中的mRNA可以通过以上定义的5′帽加以稳定化,备选地或另外地通过3′端的聚腺苷酸尾和/或聚C尾加以稳定化,其至少是50个核苷酸,优选地至少70个核苷酸,更优选地至少100个核苷酸,特别地优选地至少200个核苷酸。正如已经提到的,末端结构在体内非常重要。通过这些结构RNA被识别为mRNA并且降解得以被调节。此外,然而,存在稳定RNA或使RNA去稳定的另外的方法。这些方法中的许多仍旧是未知的,但是在RNA和蛋白质之间的相互作用通常因此是决定性的。例如最近已经描述了“mRNA监督系统”(Hellerin和Parker,Ann.Rev.Genet.1999,33:229-260),其中不完全或无义mRNA由细胞溶质中的特定反馈蛋白相互作用识别,并且易于降解,这些方法的大部分由核酸外切酶进行。
包含在根据本发明的药物组合物中,作为药用活性成分的mRNA的稳定可以同样地通过使mRNA与阳离子化合物,特别的聚阳离子化合物,例如,(聚)阳离子肽或蛋白缔合或复合,或将其结合于所述聚阳离子化合物来进行。具体地,将鱼精蛋白,核仁蛋白,精胺或亚精胺用作聚阳离子(核酸结合)蛋白是特别有效的。另外,其它阳离子肽或蛋白质,如聚-L-赖氨酸或组蛋白同样是可以的。在EP-A-1083232中描述了用于稳定mRNA的这种方法,将其公开内容全文结合在本发明中作为参考。可以用于稳定作为药用活性成分存在的mRNA的另外的优选的阳离子物质包括本文关于佐剂公开的阳离子化合物,其适合于本发明核酸的贮存和递送,例如阳离子多糖,例如脱乙酰壳多糖,1,5-二甲基-1,5-二氮十一亚甲基聚甲溴化物,聚乙烯亚胺(PEI)或聚-L-赖氨酸(PLL),等。除了以佐剂形式存在的脂质-修饰的式(I),(Ia),(II),(IIa),(IIb),(IIIa)和/或(IIIb)任一的核酸分子在提高细胞渗透性方面的作用(这已经是有利的)之外,mRNA与阳离子化合物,例如阳离子蛋白质或阳离子脂质,例如作为基于脂质的复合剂的寡核苷酸转染优选地增加作为药用活性成分存在的mRNA向待治疗的细胞或向待治疗的生物中的转移。关于本发明核酸分子通过复合的稳定作用也参见本文的披露内容,所述复合作用也带来mRNA的稳定等。
在根据本发明的药物组合物中将mRNA作为药用活性成分加以稳定的其它方法是通过除去或改变所谓的去稳定序列元件(DSEs)进行mRNA的序列的靶向改变。信号蛋白能够结合到这些去稳定序列元件(DSEs)上,其特别存在于真核mRNA中,并调节体内mRNA的酶降解。所以,为了进一步稳定作为药用活性成分存在的mRNA,优选与野生型mRNA的相应区域相比进行一个或多个变化,从而不存在去稳定序列元件。当然,根据本发明同样优选从mRNA上消除DSEs,所述DSEs任选地存在于非翻译区(3′-和/或5′-UTR)。以上DSEs的实例是富含AU序列(″AURES″),其存在于多种不稳定mRNAs的3′-UTR部分(Caput等,Proc.Natl.Acad.Sci.USA(美国国家科学院学报)1986,83:1670-1674)。所以用作药用活性成分的mRNA优选地是与野生型mRNA相比经修饰的,所述修饰是以这样的方式进行的,即它不包含任何这种去稳定序列。对于被可能的核酸内切酶识别的那些序列基序也是正确的,所述基序例如序列GAACAAG,其包含在编码运铁蛋白受体的基因的3′-UTR片段中(Binder等,EMBO J.1994,13:1969-1980)。还优选从脂质修饰的根据本发明的核酸分子中消除这样的序列基序。
在根据本发明的药物组合物中作为药用活性成分的mRNA可以进一步加以修饰,例如为了进行所需的有效翻译,其方式是核糖体有效结合到核糖体结合位点(Kozak序列:GCCGCCACCAUGG(SEQ ID NO:111),AUG形成起始密码子)。已经注意到在此背景下提高这一位置周围的A/U含量允许核糖体更有效地结合到mRNA上。
另外,有可能将一个或多个所谓的IRES(内部核糖体进入位点)(序列)引入到用作药用活性成分的mRNA中。因而IRES可以充当唯一的核糖体结合位点,但是它还可以作用来提供编码多种肽或多肽的mRNA,所述肽或多肽由核糖体彼此独立翻译(″多顺反子mRNA″)。根据本发明可以使用的IRES序列的实例是来自小RNA病毒(例如FMDV),瘟疫病毒(CFFV),脊髓灰质炎病毒(PV),脑心肌炎病毒(ECMV),口蹄疫病毒(FMDV),丙型肝炎病毒(HCV),常规猪霍乱病毒(CSFV),猪白血病病毒(MLV),猿猴免疫缺陷病毒(SIV)或蟋蟀麻痹病毒(CrPV)的序列。
同样地在根据本发明的药物组合物中任选地用作药用活性成分的mRNA可以在其5′-和/或3′-非翻译区中包含稳定序列,所述稳定序列能够提高mRNA在细胞溶质中的半衰期。这些稳定序列可以显示与存在于病毒、细菌和真核生物中的天然存在序列100%的序列同源性,但是它们还可以是部分或全部合成性质的。作为可以用在本发明中的稳定序列的实例可以提及β-珠蛋白基因的非翻译序列(UTR),例如人(Homo sapiens)或非洲爪蛙(Xenopus laevis)的序列。稳定序列的另一个实例具有通式(C/U)CCANxCCC(U/A)PyxUC(C/U)CC(SEQ ID NO:112),其包含在编码α-珠蛋白,α-(I)-胶原,15-脂肪加氧酶或酪氨酸-羟化酶的非常稳定的mRNA的3′-UTR中(见Holclik等,Proc.Natl.Acad.Sci.USA 1997,94:2410-2414)。当然,这种稳定序列可以个别使用或结合另一种使用以及结合本领域技术人员已知的其它稳定序列使用。
为了进一步增强最终所需的翻译,作为药用活性成分使用的mRNA与相应野生型mRNA相比能够显示下列修饰,该修饰可以作为备选物存在或彼此结合存在。一方面,编码肽或多肽的修饰的mRNA区域的G/C含量可以比编码肽或多肽的野生型mRNA的编码区的G/C含量更高,与野生型相比氨基酸序列编码未修饰。这种修饰是基于这种事实,即对于mRNA的有效翻译来说,mRNA的这种稳定性是关键的。各种核苷酸的组分和序列由此发挥很大作用。特别地,具有增加的G(鸟苷(鸟嘌呤))/C(胞苷(胞嘧啶))含量的序列比具有增加的A(腺苷(腺嘌呤))/U(尿苷(尿嘧啶))含量的序列更加稳定。所以,根据本发明,尽管保留翻译的氨基酸序列,但密码子与野生型mRNA相比是变化的,所述变化是以它们包含更多G/C核苷酸的方式进行的。因为几种密码子编码相同的氨基酸(遗传密码子的简并性)可以确定有益于稳定性的密码子(选择性密码子的用法)。取决于mRNA所编码的氨基酸,与野生型序列相比mRNA序列修饰的不同可能性是可以的。对于由只包含G或C核苷酸的密码子所编码的氨基酸的情形,没有密码子的修饰是必需的。因此,Pro(CCC或CCG),Arg(CGC或CGG),Ala(GCC或GCG)和Gly(GGC或GGG)的密码子并不需要任何变化,因为并不存在A或U。在下列情形中,通过取代编码相同氨基酸但不包含A和/或U的不同密码子来改变包含A和/或U核苷酸的密码子。实例是:Pro的密码子可以由CCU或CCA改变至CCC或CCG;Arg的密码子可以由CGU或CGA或AGA或AGG改变为CGC或CGG;Ala的密码子可以由GCU或GCA改变至GCC或GCG;Gly的密码子可以由GGU或GGA改变至GGC或GGG。在其它情形中,尽管A和U核苷酸不能从密码子中消除,但有可能通过使用包含较少A和/或U核苷酸的密码子来减少A和U含量。例如:Phe的密码子可以由UUU改变至UUC;Leu的密码子可以由UUA,CUU或CUA改变至CUC或CUG;Ser的密码子可以由UCU或UCA或AGU改变至UCC,UCG或AGC;Tyr的密码子可以由UAU改变至UAC;终止密码子UAA可以改变至UAG或UGA;Cys的密码子可以由UGU改变至UGC;His的密码子可以由CAU改变至CAC;Gln的密码子可以由CAA改变至CAG;Ile的密码子可以由AUU或AUA改变至AUC;Thr的密码子可以由ACU或ACA改变至ACC或ACG;Asn的密码子可以由AAU改变至AAC;Lys的密码子可以由AAA改变至AAG;Val的密码子可以由GUU或GUA改变至GUC或GUG;Asp的密码子可以由GAU改变至GAC;Glu的密码子可以由GAA改变至GAG。另一方面,对于Met(AUG)和Trp(UGG)的密码子的情形,没有序列修饰的可能性。以上列出的取代当然可能个别使用,但也可以进行所有可能的组合来与原始序列相比提高修饰mRNA的G/C含量。因而,例如,所有存在于原始(野生型)序列中的Thr的密码子都可以改变至ACC(或ACG)。不过,优选地,使用以上取代可能性的组合,例如:在原始序列中编码Thr的所有密码子取代为ACC(或ACG)和原始编码Ser的所有密码子都取代为UCC(或UCG或AGC);在原始序列中编码Ile的所有密码子取代为AUC和原始编码Lys的所有密码子都取代为AAG和原始编码Tyr的所有密码子都取代为UAC;在原始序列中编码Val的所有密码子取代为GUC(或GUG)和原始编码Glu的所有密码子都取代为GAG和原始编码Ala的所有密码子都取代为GCC(或GCG)和原始编码Arg的所有密码子都取代为CGC(或CGG);在原始序列中编码Val的所有密码子取代为GUC(或GUG)和原始编码Glu的所有密码子都取代为GAG和原始编码Ala的所有密码子都取代为GCC(或GCG)和原始编码Gly的所有密码子都取代为GGC(或GGG)和原始编码Asn的所有密码子都取代为AAC;在原始序列中编码Val的所有密码子取代为GUC(或GUG)和原始编码Phe的所有密码子都取代为UUC和原始编码Cys的所有密码子都取代为UGC和原始编码Leu的所有密码子都取代为CUG(或CUC)和原始编码Gln的所有密码子都取代为CAG和原始编码Pro的所有密码子都取代为CCC(或CCG);等。与编码相应肽或多肽的野生型mRNA的编码区的G/C含量相比,优选地编码肽或多肽的mRNA的区域(或任选地存在的每一个其它片段)的G/C含量提高了至少7%个点,更优选地提高了至少15%个点,特别地优选地提高了至少20%个点,并且优选地至少50%,更优选地至少70%和最优选地至少90%。在此背景下特别优选与野生型序列相比将如此修饰的mRNA的G/C含量提高至最大可能的程度。
在药物组合物中用作药用活性成分的mRNA的另外优选的修饰基于这样的发现,即翻译效率也通过tRNAs在细胞中存在的不同频率来确定。因此,如果所谓的“稀有”密码子以增加的数量存在于RNA序列中,那么在其中存在编码相对“频繁的”tRNAs的密码子的情形中,相应的mRNA显著更差地进行翻译。因此,根据本发明,与野生型mRNA的相应区域比较,用作药用活性成分的mRNA中的编码区以这样的方式进行修饰,即在所述细胞中编码相对稀有tRNA的野生型序列的至少一种密码子由在细胞中编码相对频繁的tRNA的密码子取代,其携带与相对稀有的tRNA相同的氨基酸。通过这种修饰,所述RNA序列被这样修饰以致于将密码子引入,对此其可获得频繁存在的tRNAs。在细胞中相对频繁地存在的并且通过比较是相对稀有的tRNAs是本领域技术人员已知的;见例如Akashi,Curr.Opin.Genet.Dev.2001,11(6):660-666。通过这种修饰,可以根据本发明用编码细胞中相对频繁的tRNA的密码子取代细胞中编码相对稀有的tRNA的野生型序列的所有密码子,其携带与相对稀有的tRNA相同的氨基酸。特别优选将如上所述的mRNA中的增加的,特别是最大的连续G/C含量与“频繁的”密码子组合,而不会改变由mRNA的编码区编码的抗原肽或多肽(一种或多种)的氨基酸序列。如上列出可以由G/C富集的/优化的mRNA编码的优选抗原。
根据第二个实施方案(对于本发明的组合物)的第四个备选,包含在根据本发明的药物组合物中作为药用活性成分的核酸是dsRNA,优选地siRNA。关于RNA干扰现象,dsRNA,或siRNA特别令人感兴趣。在免疫学研究过程中,RNA干扰的现象引起了关注。近年来,已经发现了基于RNA的防御机制,其存在于真菌王国和植物和动物王国中,并且作为“基因组的免疫系统”起作用。在可以将所述方法的潜在机制鉴定为相同的之前,所述系统最初在各个物种中彼此独立地描述,首先在秀丽线虫(C.elegans)中描述:在植物中的RNA介导的病毒抗性,在植物中的PTGS(翻译后基因沉默),和在真核生物中的RNA干扰相应地基于共同的程序。RNA干扰(RNAi)的体外技术基于双链RNA分子(dsRNA),其引发序列特异性的对基因表达的抑制(Zamore(2001)Nat.Struct.Biol.(自然结构生物学)9:746-750;Sharp(2001)Genes Dev.(基因递送)5:485-490:Hannon(2002)Nature(自然)41:244-251)。在用长dsRNA转染哺乳动物细胞中,蛋白激酶R和RnaseL的激活导致非特异性的作用,如例如干扰素反应(Stark等(1998)Annu.Rev.Biochem.(生物化学年评)67:227-264;He和Katze(2002)Viral Immunol.(病毒免疫学)15:95-119)。当使用更短的,例如21-23 mer的所谓siRNA(小干扰RNA),可以避免这些非特异性的作用,因为短于30bp的siRNA不能引发非特异性作用(Elbashir等(2001)Nature(自然)411:494-498)。最近,已将dsRNA分子体内应用(McCaffrey等(2002),Nature(自然)418:38-39;Xia等(2002),Nature Biotech.(自然生物技术)20:1006-1010;Brummelkamp等(2002),Cancer Cell(癌症细胞)2:243-247)。
因此,最终在根据本发明的药物组合物中用作药用活性成分的双链RNA(dsRNA)优选地包含具有一般结构5′-(N17-29)-3′的序列,其中N是任何碱基并且代表核苷酸。一般结构由具有核糖核苷酸组成的大分子的双链RNA,包含戊糖(核糖或脱氧核糖)的核糖核苷酸,有机碱和磷酸酯(盐)组成。在本文的RNA中的有机碱包含嘌呤碱腺苷(腺嘌呤)(A)和鸟苷(鸟嘌呤)(G)和嘧啶碱胞苷(胞嘧啶)(C)和尿苷(尿嘧啶)(U)。在根据本发明的药物组合物中最终用作药用活性成分的dsRNA包含具有定向结构的这样的核苷酸或核苷酸类似物。用作根据本发明的药用活性成分的dsRNAs优选地具有一般结构5′-(N19-25)-3′,更优选地5′-(N19-24)-3′,更优选地5′-(N21-23)-3′,其中N是任何碱基。优选地至少90%,更优选地95%和尤其优选地100%的用作药用活性成分的dsRNA核苷酸与前文所述的(治疗相关)蛋白或抗原(作为药用活性成分)的(m)RNA序列的部分互补。90%互补意为对于例如长度为20个核苷酸的根据本发明使用的dsRNA,其包含不超过2个这样的核苷酸,所述核苷酸与(m)RNA的相应部分没有相应的互补性。然而,任选地用于根据本发明的药物组合物的双链RNA的序列,优选地在其一般结构中完全互补于如前所述的作为药用活性成分的蛋白或抗原的(m)RNA的部分。
原则上,存在于(m)RNA编码区中所有的长度为17-29,优选地19-25个碱基对部分可以作为dsRNA的靶序列,所述dsRNA最终将用作根据本发明的药物组合物中的药用活性成分。同样地,还可以将用作药用活性成分的dsRNAs针对前文所述的(治疗相关)蛋白或抗原(作为药用活性成分)的核苷酸序列,其不位于(m)RNA的编码区内,特别是在5′非编码区内,例如因此针对具有调节功能的(m)RNA的非编码区。因此,用作前文所述的蛋白或抗原的药用活性成分的dsRNA的靶序列可以位于(m)RNA的翻译区和非翻译区和/或在控制元件的区域中。用作根据本发明的药物组合物中的药用活性成分的dsRNA的靶序列也可以位于非翻译序列和翻译序列的重叠区域中;特别地,所述靶序列可以包含位于(m)RNA的编码区的起始三联体上游的至少一种核苷酸。
修饰的核苷酸可以优选地存在于最终用作根据本发明的药物组合物中的药用活性成分的dsRNA中。表述“修饰的核苷酸”根据本发明意为目的核苷酸已经经过化学修饰。通过表述“化学修饰”,本领域技术人员理解与天然存在的核苷酸相比,通过取代、添加或去除一个或多个原子或原子基团,修饰的核苷酸已经被改变。在根据本发明使用的dsRNA中的至少一种修饰的核苷酸一方面是为了稳定性,而另一方面是为了防止解离。优选地,已经修饰在根据本发明使用的dsRNA中的2-10个,和更优选地2-5个核苷酸。有利地,在双链结构中的dsRNA的核苷酸的至少一个2′-羟基基团已经被化学基团(优选2′-氨基或2′-甲基)所取代。在所述双链结构的至少一条链中的至少一个核苷酸也可以是具有糖环的所谓的“锁定核苷酸”,所述糖环已经经过化学修饰,优选地通过2′-O,4′-C-亚甲基桥进行。根据本发明使用的dsRNA的一些核苷酸有利的是锁定的核苷酸。而且,通过修饰根据本发明的dsRNA的主链,可以防止其过早的降解。在该情形下,特别优选已经以硫代硫酸酯,2′-O-甲基-RNA,LNA,LNA/DNA gapmers等形式进行修饰并因此具有更长的体内半衰期的dsRNA。
在根据本发明的药物组合物中用作药用活性成分的双链RNA(dsRNA)的末端可以优选地进行修饰从而消除细胞中的降解或解离成单链,特别是为了避免由核酸酶造成的过早降解。特别当使用其低浓度或短链长度时,发生dsRNA各个链的正常情况不合乎需要的解离。为了特别有效的抑制解离,由根据本发明使用的dsRNA的双链结构的核苷酸对所实现的内聚力可以由至少一个,优选地超过一个化学键增加。在根据本发明的药物组合物中用作药用活性成分的dsRNA(其解离已经被减少)具有针对在细胞或在生物(体内)或离体中的酶促和化学降解的更高的稳定性并因此具有更长的半衰期。防止根据本发明使用的dsRNA在细胞中过早解离的另外的可能性存在于在所述链的每一端形成发夹环。在特定实施方案中,在根据本发明的药物组合物中所用的dsRNA因此具有发夹结构从而减缓解离动力学。在这样的结构中,环结构优选地在5′和/或3′端形成。所述环结构不具有氢桥接,并典型地因此在核苷酸碱基之间不存在互补性。典型地,这样的环具有至少5个,优选地至少7个核苷酸的环,并且以该方式连接根据本发明使用的dsRNA的两条互补的个体链。为了防止链的解离,根据本发明使用的dsRNA的两条链的核苷酸可以同样优选地这样修饰从而获得氢桥键的加强,例如通过任选地修饰的核苷酸增加在碱基之间的氢桥键合能力。作为结果,增加了在所述链之间的相互作用的稳定性,并且dsRNA被保护免于RNA酶的攻击。
根据特别优选的实施方案,在根据本发明的药物组合物中用作药用活性成分的dsRNA针对如前文所述的蛋白或抗原的(m)RNA。所用的dsRNA由此优选地抑制细胞中的上述蛋白或抗原的翻译达至少50%,更优选地60%,更优选地70%和最优选地至少90%的程度,即所述细胞优选地包含不超过天然存在的(没有用根据本发明使用的dsRNA处理)的上述蛋白或抗原的细胞浓度的一半。在加入根据本发明使用的dsRNA分子后,对细胞中这些蛋白或抗原的翻译的抑制是基于由所述分子造成的RNA干扰的现象。根据本发明使用的dsRNA是这样的siRNA,其引发RNA干扰的现象,并且可以结合上述蛋白或抗原的(m)RNA。测量或显示细胞中由根据本发明使用的dsRNA引发的翻译抑制可以通过RNA印迹、定量实时PCR或在蛋白水平,用针对上述蛋白或抗原的特异性抗体进行。最终在根据本发明的药物组合物中用作药用活性成分的dsRNA,和相应的siRNA可以通过本领域技术人员已知的方法进行制备。
根据本发明的药物组合物(根据第一或第二个实施方案)典型地包含(相容性的)药用载体。用于本文时,表述“(相容的)药用载体”优选地包括所述组合物的液体或非液体基础。用于本文时,术语“相容的”意为药物组合物的成分能够与药用活性成分,与象这样作为免疫刺激剂或作为佐剂的本发明的核酸,和与一种另外的成分以这样的方式混合,即不存在这样的相互作用,所述相互作用会在正常使用条件下,减少组合物的药物有效性。当然,药用载体必需具有足够高的纯度和足够低的毒性从而使它们适合施用于待治疗的人。
如果所述组合物以液体形式提供,所述药用载体将典型地包含一种或多种(相容)药用液体载体。所述组合物可以包含例如无热原的水;等渗盐水或缓冲(水性)溶液,例如磷酸盐,柠檬酸盐等缓冲溶液,植物油,如例如,花生油,棉子油,芝麻油,橄榄油,玉米油和来自梧桐科植物(theobroma)的油;多元醇如,例如聚丙二醇,甘油,山梨糖醇,甘露醇和聚乙二醇;海藻酸等作为(相容性)药用液体载体。特别地,对于本发明的药物组合物的注射,可以使用缓冲液,优选水性缓冲液,所述缓冲液包含钠盐,优选地至少50mM的钠盐,钙盐,优选地至少0,01mM钙盐,和任选地钾盐,优选地至少3mM钾盐。根据优选的实施方案,所述钠盐,钙盐和任选地,钾盐可以以它们的卤化物(例如氯化物,碘化物或溴化物)的形式存在,以它们的氢氧化物,碳酸盐,碳酸氢盐或硫酸盐等形式存在。不限于此,钠盐的实例包括例如NaCl,NaI,NaBr,Na2CO3,NaHCO3,Na2SO4,任选的钾盐的实例包括例如KCl,KI,KBr,K2CO3,KHCO3,K2SO4,并且钙盐的实例包括例如CaCl2,CaI2,CaBr2,CaCO3,CaSO4,Ca(OH)2。另外,前述阳离子的有机阴离子可以包含在缓冲液中。根据更优选的实施方案,适合用于如上定义的注射目的的缓冲液可以包含选自氯化钠(NaCl),氯化钙(CaCl2)和任选地氯化钾(KCl)的盐,其中除了氯化物之外,可以存在另外的阴离子。典型地,在注射缓冲液中的盐以至少50mM氯化钠(NaCl),至少3mM氯化钾(KCl)和至少0,01mM氯化钙(CaCl2)的浓度存在。所述注射缓冲液可以是参照具体参照介质高渗、等渗或低渗的,即参照特定的参照介质所述缓冲液可以具有更高,相同或更低的盐含量,其中优选地,可以使用前述盐的所述浓度,所述浓度不会由于渗透性或其它浓度作用导致对细胞的损伤。参照介质在“体内”方法中,例如是存在的液体如血液,淋巴,细胞溶质液体,或其它体液,或例如这样的液体,其可以在“体外”方法中,用作参照介质,如常规缓冲液或液体。所述常见的缓冲液或液体是本领域技术人员已知的。特别优选将林格氏-乳酸溶液作为液体基础。
如果所述组合物以固体形式提供,所述药用载体典型地包含一种或多种(相容)药用固体载体。所述组合物还可以包含例如一种或多种相容的固体或液体填充剂或稀释剂作为(相容的)药用固体载体,或还可以使用包封化合物,其适合于施用于人。所述(相容)药用固体载体的一些实例例如是糖,如例如,乳糖,葡萄糖和蔗糖;淀粉如例如,玉米淀粉或马铃薯淀粉;纤维素及其衍生物,如例如,羧甲基纤维素钠,乙基纤维素,醋酸纤维素;粉末状的黄蓍树胶;麦芽;明胶;牛油;固体助流剂,如,例如,硬脂酸,硬脂酸镁;硫酸钙,等。
对(相容性)药用载体的选择主要由施用根据本发明的药物组合物的方式确定。根据本发明的药物组合物例如以系统内的方式进行。用于施用的路径包括,例如口服、皮下、静脉内、肌内、关节内、滑液内、胸骨内、鞘内、肝内、病灶内、颅内、经皮、皮内、肺内、腹膜内、心内、动脉内和舌下局部和/或鼻内途径。待用的药物组合物的适合的量可以通过用动物模型进行的常规实验确定。所述模型包括,但不限于,兔、羊、小鼠、大鼠、狗和非人灵长类动物模型。用于注射的优选单位剂型包括无菌水溶液,生理盐水或其混合物。应该将所述溶液的pH调节为约7.4。用于注射的适合的载体包括水凝胶、用于控制和延迟释放的装置、聚乳酸和胶原蛋白基质。用于局部应用的适合的药用载体包括那些,其适合用于洗剂、膏剂、凝胶等。如果化合物将通过口服施用,片剂、胶囊等是优选的单位剂型。可以用于口服施用的制备单位剂型的药用载体是现有技术中已知的。对其的选择将取决于次要考虑,如味道、费用和贮存性,这对于本发明的目的不是关键的,并且这对于本领域技术人员而言没有难度。
为了进一步增加免疫原性,根据本发明的药物组合物可以另外包含一种或多种辅助物质。如上定义的根据本发明的式(I),(Ia),(II),(IIa),(IIb),(IIIa)和/或(IIIb)任一的核酸分子和任选地另外包含在如上所述的药物组合物(和最后,药用活性成分)中的辅助物质的协同作用优选地这样获得。取决于各种类型的辅助物质,在这方面可以考虑各种机制。例如,容许树突细胞(DCs)成熟的化合物,例如,脂多糖、TNF-α或CD40配体,形成第一类适合的辅助物质。一般地,可以使用以“危险信号”(LPS,GP96,等)或细胞因子,如GM-CFS的方式影响免疫系统的任何试剂作为辅助物质,其使根据本发明的免疫刺激佐剂产生的免疫应答以靶向方式得以增强和/或被影响。特别优选的辅助物质是细胞因子,如单核因子,淋巴因子,白介素或趋化因子,其促进免疫应答,如IL-1,IL-2,IL-3,IL-4,IL-5,IL-6,IL-7,IL-8,IL-9,IL-10,IL-12,IL-13,IL-14,IL-15,IL-16,IL-17,IL-18,IL-19,IL-20,IL-21,IL-22,IL-23,IL-24,IL-25,IL-26,IL-27,IL-28,IL-29,IL-30,IL-31,IL-32,IL-33,INF-α,IFN-β,INF-γ,GM-CSF,G-CSF,M-CSF,LT-β或TNF-α,生长因子,如hGH。
根据本发明的药物组合物(第一(无药用活性成分)和第二(用药用活性成分)实施方案)还可以另外包含佐剂。因此,作为免疫刺激剂或作为佐剂(对于本发明药物组合物的第二个实施方案)的如上定义的根据本发明的式(I),(Ia),(II),(IIa),(IIb),(IIIa)和/或(IIIb)任一的核酸分子,可以与另外的免疫刺激剂/佐剂组合。在本发明范围内,用于这些目的的适合对于试剂/佐剂特别是那些化合物,其增强(通过一种或多种机制)根据本发明的式(I),(Ia),(II),(IIa),(IIb),(IIIa)和/或(IIIb)任一的(修饰的或未修饰的)核酸分子的生物学一种或多种性质,也就是说,特别是有利于根据本发明的式(I),(Ia),(II),(IIa),(IIb),(IIIa)和/或(IIIb)任一的核酸分子的免疫刺激作用的物质。可以根据本发明使用的试剂/佐剂的实例包括,但不限于如上所述的稳定的阳离子肽或多肽,其包括鱼精蛋白,核仁蛋白,精胺或亚精胺,和阳离子多糖,特别是脱乙酰壳多糖,TDM,MDP,胞壁酰二肽,泊洛沙姆,明矾溶液,氢氧化铝,ADJUMERTM(聚磷腈);磷酸铝凝胶;来自海藻的葡聚糖;algammulin;氢氧化铝凝胶(明矾);高蛋白吸附性氢氧化铝凝胶;低粘性氢氧化铝凝胶;AF或SPT(角鲨烷的乳状液(5%),吐温80(0.2%),泊洛沙姆L121(1.25%),磷酸盐缓冲盐水,pH 7.4);AVRIDINETM(丙二胺);BAYR1005TM((N-(2-脱氧-2-L-亮氨酰氨基-b-D-吡喃葡萄糖基)-N-十八烷基十二烷酰-酰胺氢化乙酸盐(hydroacetate);CALCITRIOLTM(1-,25-二甲基羟基-维生素D3);磷酸钙凝胶;CAPTM(磷酸钙纳米颗粒);霍乱全毒素,霍乱-毒素-Al-蛋白-A-D-片段融合蛋白,霍乱毒素的B亚基;CRL 1005(嵌段共聚物P1205);包含细胞因子的脂质体;DDA(二甲基二(十八烷基)溴化铵);DHEA(脱氢表雄酮);DMPC(二肉豆蔻酰磷脂酰胆碱);DMPG(二肉豆蔻酰磷脂酰甘油);DOC/明矾复合物(脱氧胆酸钠盐);弗氏完全佐剂;弗氏不完全佐剂;γ菊粉;Gerbu佐剂((i)N-乙酰基葡糖胺基-(P1-4)-N-乙酰基胞壁酰-L-丙氨酰-D-谷氨酰胺(GMDP),ii)二甲基二(十八烷基)氯化铵(DDA),iii)锌-L-脯氨酸盐复合物(ZnPro-8)的混合物);GM-CSF);GMDP(N-乙酰基葡糖胺基-(b1-4)-N-乙酰基胞壁酰-L-丙氨酰-D-异谷氨酰胺);咪喹莫特(1-(2-甲基丙基)-1H-咪唑并[4,5-c]喹啉-4-胺);ImmTherTM(N-乙酰基葡糖胺基-N-乙酰基胞壁酰-L-Ala-D-isoGlu-L-Ala-甘油二棕榈酸酯);DRVs(制备自脱水-再水合的囊泡的免疫脂质体);γ-干扰素;白介素-1β;白介素-2;白介素-7;白介素-12;ISCOMSTM(″免疫刺激复合物″);ISCOPREP 7.0.3. TM;脂质体;LOXORIBINETM(7-烯丙基-8-氧代鸟苷(鸟嘌呤));LT口服佐剂(大肠杆菌(E.coli)不稳定的肠毒素-原毒素);任何组合物的微球体和微粒;MF59TM;(角鲨烯-水乳状液);MONTANIDE ISA 51TM(纯化的不完全弗氏佐剂);MONTANIDE ISA 720TM(可代谢的油性佐剂);MPLTM(3-Q-脱酰基-4′-单磷酰基脂质A);MTP-PE和MTP-PE脂质体((N-乙酰基-L-丙氨酰-D-异谷氨酰基-L-丙氨酸-2-(1,2-二棕榈酰-sn-甘油-3-(羟基磷酰氧基))乙基酰胺,单钠盐);MURAMETIDETM(Nac-Mur-L-Ala-D-Gln-OCH3);MURAPALMITINETM和D-MURAPALMITINETM(Nac-Mur-L-Thr-D-异GIn-sn-甘油二棕榈酰);NAGO(神经氨酸酶-半乳糖氧化酶);任何组合物的纳米球体或纳米颗粒;NISVs(非离子表面活性剂囊泡);PLEURANTM(β-葡聚糖);PLGA,PGA和PLA(乳酸和羟基乙酸的均聚物和共聚物;微球体/纳米球体);泊洛沙姆L121TM;PMMA(聚甲基甲基丙烯酸酯);PODDSTM(类蛋白微球体);聚乙烯氨基甲酸酯衍生物;聚-rA:聚-rU(聚腺苷酸-聚尿苷酸复合物);聚山梨酸酯80(吐温80);蛋白脂质卷(cochleates)(AvantiPolar Lipids,Inc.,Alabaster,AL);STIMULONTM(QS-21);Quil-A(Quil-A皂苷);S-28463(4-氨基-otec-二甲基-2-乙氧基甲基-1H-咪唑并[4,5-c]喹啉-1-乙醇);SAF-1TM(″兴泰克(Syntex)佐剂制剂″);仙台脂蛋白体和包含仙台的脂质基质;司盘-85(三油酸山梨坦);Specol(Marcol 52,司盘85和吐温85的乳状液);角鲨烯或Robane(2,6,10,15,19,23-六甲基二十四烷和2,6,10,15,19,23-六甲基-2,6,10,14,18,22-二十四碳己烷);硬脂酰酪氨酸(十八烷基酪氨酸盐酸盐);Theramid(N-乙酰基葡糖胺基-N-乙酰基胞壁酰-L-Ala-D-异Glu-L-Ala-二棕榈氧基丙酰胺);苏氨酰(Theronyl)-MDP(TermurtideTM或[thr 1]-MDP;N-乙酰基胞壁酰-L-苏氨酰-D-异谷氨酰胺);Ty颗粒(Ty-VLPs或病毒样颗粒);Walter-Reed脂质体(包含吸附在氢氧化铝上的脂质A的脂质体)等。脂肽,如Pam3Cys,同样特别适合与本发明如上定义的根据本发明的式(I),(Ia),(II),(IIa),(IIb),(IIIa)和/或(IIIb)的核酸分子组合,其以免疫刺激佐剂的形式存在(见Deres等,Nature(自然)1989,342:561-564)。
如上定义的佐剂可以归为数类,包括适合于贮库和递送,用于共刺激的佐剂,适合作为拮抗剂的佐剂等。优选的适合贮存和递送的佐剂可以包括例如,铝盐,如Adju-phos,铝胶,吸附氢氧化铝凝胶,等;乳状液,如CFA,SAF,IFA,MF59,Provax,TiterMax,Montanide,Vaxfectin,等;共聚物,如Optivax(CRL1005),L121,泊洛沙姆4010),等;脂质体,如Stealth,等,脂质卷(cochleates),如BIORAL,等;植物衍生的佐剂,如QS21,Quil A,Iscomatrix,ISCOM,等;适合于共刺激的优选的佐剂可以包括例如番茄素,生物聚合物,如PLG,PMM,菊粉,等;微生物衍生的佐剂,如罗莫肽,DETOX,MPL,CWS,甘露糖,CPG7909,ISS-1018,IC31,咪唑并喹啉,聚肌胞,Ribi529,IMOxine,IRIVs,VLPs,霍乱毒素,热不稳定的毒素,Pam3Cys,鞭毛蛋白,GPI锚,LNFPIII/LewisX,抗菌肽,UC-1 V150,RSV融合蛋白,cdiGMP,等;适合作为拮抗剂的优选佐剂可以例如包括CGRP神经肽等。
适合贮库和递送的特别优选的佐剂是阳离子或聚阳离子化合物,包括鱼精蛋白,核仁蛋白,精胺或亚精胺,或其它阳离子肽或蛋白质,如聚-L-赖氨酸(PLL),聚-精氨酸,碱性多肽,细胞渗透肽(CPPs),包括HIV结合肽,Tat,HIV-1 Tat(HIV),Tat衍生的肽,穿膜肽(Penetratin),VP22衍生的或类似的肽,HSV VP22(单纯疱疹),MAP,KALA或蛋白转导结构域(PTDs,PpT620,富含脯氨酸的肽,富含精氨酸的肽,富含赖氨酸的肽,一种或多种MPG-肽,Pep-1,L-寡聚体,一种或多种降钙素肽,触角足衍生肽(特别地来自果蝇(Drosophila)触角足),pAntp,pIsl,FGF,乳铁蛋白,Transportan,Buforin-2,Bac715-24,SynB,SynB(1),pVEC,hCT-衍生的肽,SAP,鱼精蛋白,精胺,亚精胺,或组蛋白。另外地,优选的阳离子或聚阳离子蛋白质或肽可以是选自具有下列总式的下列蛋白或肽:(Arg)l;(Lys)m;(His)n;(Orn)o;(Xaa)x,其中l+m+n+o+x=8-15,并且l,m,n或o彼此独立地可以是选自0,1,2,3,4,5,6,7,8,9,10,11,12,13,14或15的任何数字,条件是Arg,Lys,His和Orn的总含量代表寡肽的所有氨基酸的至少50%;并且Xaa可以是选自除Arg,Lys,His或Orn之外的天然(=天然存在)或非天然氨基酸的任何氨基酸;并且x可以是选自0,1,2,3或4的任何数字,条件是Xaa的总含量不超过寡肽的所有氨基酸的50%。在该情形中特别优选的寡精氨酸例如是Arg7,Arg8,Arg9,Arg7,H3R9,R9H3,H3R9H3,YSSR9SSY,(RKH)4,Y(RKH)2R,等。可以用作佐剂的另外的优选的阳离子或聚阳离子化合物可以包括阳离子多糖,例如脱乙酰壳多糖,1,5-二甲基-1,5-二氮十一亚甲基聚甲溴化物,阳离子聚合物,例如聚乙烯亚胺(PEI),阳离子脂质,包括DOTMA:[1-(2,3-二油酰氧基(sioleyloxy)丙基)]-N,N,N-三甲基氯化铵,DMRIE,二-C14-脒,DOTIM,SAINT,DC-Chol,BGTC,CTAP,DOPC,DODAP,DOPE:二油基磷脂酰乙醇-胺,DOSPA,DODAB,DOIC,DMEPC,DOGS:二(十八烷基)氨基甘氨酰(glicyl)精胺,DIMRI:二肉豆蔻酸-氧基丙基二甲基羟基乙基溴化铵,DOTAP:二油酰氧基-3-(三甲基氨溶)丙烷,DC-6-14:O,O-二(十四烷酰)-N-(α-三甲基氨溶乙酰基)二乙醇胺氯化物,CLIP1:外消旋-[(2,3-二(十八烷基)氧基丙基)(2-羟基乙基)]-二甲基氯化铵,CLIP6:外消旋-[2(2,3-二(十六烷基)氧基丙基-氧基甲氧基)乙基]三甲基铵,CLIP9:外消旋-[2(2,3-二(十六烷基)氧基丙基-氧基琥珀酰氧基)乙基]-三甲基铵,寡核苷酸转染(oligofetamine),或阳离子或聚阳离子聚合物,包括修饰的聚氨基酸,包括β-氨基酸-聚合物或逆聚酰胺,修饰的聚乙烯,如PVP(聚(N-乙基-4-乙烯基溴化吡啶鎓))等,修饰的丙烯酸酯,包括pDMAEMA(聚(二甲基氨基乙基甲基丙烯酸酯)),修饰的酰胺胺包括pAMAM(聚(酰胺胺))等,修饰的聚β氨基酯(PBAE),如二胺端修饰的1,4丁二醇二丙烯酸酯-共-5-氨基-1-戊醇聚合物等,树状聚体,如聚丙基胺树状聚体或基于pAMAM的树状聚体,多种聚亚胺,如PEI:聚(乙烯亚胺),聚(丙烯亚胺),聚烯丙基胺,基于糖主链的聚合物,如基于环糊精的聚合物,基于葡聚糖的聚合物,脱乙酰壳多糖等,,基于硅烷主链的聚合物,如PMOXA-PDMS共聚物等,由一个或多个阳离子嵌段(包含如上所述的选择的阳离子聚合物)和一个或多个亲水性或疏水性嵌段(例如聚乙烯乙二醇)的组合组成的嵌段聚合物等。本发明如上定义的根据本发明的式(I),(Ia),(II),(IIa),(IIb),(IIIa)和/或(IIIb)任一的核酸分子与阳离子或聚阳离子化合物的缔合或复合优选地给核酸提供佐剂性质并将稳定作用通过复合赋予核酸。用于稳定本发明核酸的方法通常描述在EP-A-1083232中,将所述公开内容的全部通过引用结合在本文中。特别地,优选的阳离子或聚阳离子化合物是选自由下列各项组成的组的化合物:如上定义的鱼精蛋白,核仁蛋白,精胺,亚精胺,寡精氨酸,如Arg7,Arg8,Arg9,Arg7,H3R9,R9H3,H3R9H3,YSSR9SSY,(RKH)4,Y(RKH)2R,等。
可以具有共刺激作用的佐剂包括式(IV):GlXmGn的核酸,其中:G是鸟苷(鸟嘌呤),尿苷(尿嘧啶)或鸟苷(鸟嘌呤),尿苷(尿嘧啶)的类似物;X是鸟苷(鸟嘌呤),尿苷(尿嘧啶),腺苷(腺嘌呤),胸苷(胸腺嘧啶),胞苷(胞嘧啶)或上述核苷酸的类似物;l是1-40的整数,其中当l=1时,G是鸟苷(鸟嘌呤)或其类似物,当l>1时,至少50%的核苷酸是鸟苷(鸟嘌呤)或其类似物;m是整数并且至少是3;其中当m=3时,X是尿苷(尿嘧啶)或其类似物,当m>3时,至少3个连续的尿苷(尿嘧啶)或尿苷(尿嘧啶)的类似物存在;n是1-40的整数,其中当n=1时,G是鸟苷(鸟嘌呤)或其类似物,当n>1时,至少50%的核苷酸是鸟苷(鸟嘌呤)或其类似物;
或式(V):ClXmCn的核酸,其中:C是胞苷(胞嘧啶),尿苷(尿嘧啶)或胞苷(胞嘧啶)或尿苷(尿嘧啶)的类似物;X是鸟苷(鸟嘌呤),尿苷(尿嘧啶),腺苷(腺嘌呤),胸苷(胸腺嘧啶),胞苷(胞嘧啶)或上述核苷酸的类似物;l是1-40的整数,其中当l=1时,C是胞苷(胞嘧啶)或其类似物,当l>1时,至少50%的核苷酸是核苷或其类似物;m是整数并且至少是3;其中当m=3时,X是尿苷(尿嘧啶)或其类似物,当m>3时,至少3个连续的尿苷(尿嘧啶)或尿苷(尿嘧啶)的类似物存在;n是1-40的整数,其中当n=1时,C是胞苷(胞嘧啶)或其类似物,当n>1时,至少50%的核苷酸是胞苷(胞嘧啶)或其类似物。
已知由于其与Toll样受体:TLR1,TLR2,TLR3,TLR4,TLR5,TLR6,TLR7,TLR8,TLR9,TLR10,TLR11,TLR12或TLR13的结合亲和性(作为配体)而具有免疫刺激性的任何化合物可以适当地用作另外的成分从而进一步刺激由本发明的药物组合物中的本发明的核酸诱导的免疫应答。
可以加入本发明的药物组合物中的另一类化合物是CpG核酸,特别是CpG-RNA或CpG-DNA。CpG-RNA或CpG-DNA可以是单链CpG-DNA(ss CpG-DNA),双链CpG-DNA(dsDNA),单链CpG-RNA(ss CpG-RNA)或双链CpG-RNA(ds CpG-RNA)。所述CpG核酸优选地以CpG-RNA形式,更优选地以单链CpG-RNA(ss CpG-RNA)的形式存在。所述CpG核酸优选地包含至少一个或多个(促有丝分裂)的胞苷(胞嘧啶)/鸟嘌呤二核苷酸序列(s)(CpG基序)。根据第一个优选的备选,包含在这些序列中的至少一种CpG基序,即CpG基序的C(胞苷(胞嘧啶))和G(鸟嘌呤)是未甲基化的。任选地包含在这些序列中的所有其它胞苷(胞嘧啶)或鸟嘌呤可以是甲基化或未甲基化的。然而,根据另外的优选备选,CpG基序的C(胞苷(胞嘧啶))和G(鸟嘌呤)也可以以甲基化形式存在。
根据特别优选的实施方案,还可以将根据本发明的药物组合物作为疫苗提供。根据本发明的疫苗典型地包含(对应于)根据本发明的药物组合物。根据本发明的所述疫苗的组成特征在于结合到疫苗组合物中的药用活性成分的具体种类。典型地,药用活性化合物是免疫刺激性物质,其激发针对某些抗原的特异性(适应性)免疫应答。激发的特异性(适应性)免疫应答使受试者开发针对例如具体病原体或具体肿瘤的免疫应答(通过主动或被动模式激发)。
本发明的药物组合物,和具体地本发明的疫苗具体地特征在于施用其的方式。典型地,本发明的药物组合物,特别是疫苗,优选系统地进行施用。用于施用所述本发明的药物组合物/疫苗的路径典型地包括口服、皮下、静脉内、肌内、关节内、滑液内、胸骨内、鞘内、肝内、病灶内、颅内、经皮、皮内、肺内、腹膜内、心内、动脉内和舌下局部和/或鼻内途径。备选地,本发明的疫苗或药物组合物可以通过皮内、皮下、肌内途径进行施用。因此,优选地将组合物/疫苗以如上通常关于药物组合物定义的液体或固体形式进行配制。另外的辅助物质(如上定义)可以进一步增加特别是疫苗的免疫原性,其可以优选地结合在根据本发明的疫苗中。有利地,选择如前文定义的一种或多种所述辅助物质,这取决于在根据本发明的疫苗中的药用活性成分的免疫原性和其它性质。
根据本发明的另一个优选目的,根据本发明的药物组合物,特别优选的本发明的疫苗,用于通过如下实施例的方式治疗提及的适应症。用根据本发明的药物组合物,特别优选地用本发明的疫苗,可以治疗在治疗情形中的与例如与各种病理学上缺乏的免疫应答相关或需要免疫应答,优选地增加的免疫应答的疾病或病症,例如肿瘤特异性或病原体特异性疾病,感染性疾病,等或可以通过将(过量)免疫应答转变为TH1主导的免疫应答和/或通过使遭受过量免疫应答折磨的患者脱敏的疾病,如例如在变应性或自体免疫疾病中。由根据本发明的药物组合物产生这样的免疫应答,或已经存在但任选地不充分的免疫应答的增加明显基于其引发非抗原-特异性免疫反应的能力。对于适合的免疫应答的重要因素是对不同T细胞亚群的刺激。T-淋巴细胞典型地分化为两个亚群,T-辅助1(Th1)细胞和T-辅助2(Th2)细胞,使用所述细胞免疫系统能够破坏细胞内(Th1)和细胞外(Th2)病原体(例如抗原)。两个Th细胞群在由它们产生的效应蛋白(细胞因子)的模式上不同。因此,Th1细胞通过激活巨噬细胞和细胞毒性T-细胞来辅助细胞免疫应答。在另一方面,Th2细胞通过刺激B细胞转化为浆细胞和通过形成抗体(例如针对抗原)促进体液免疫应答。因此,Th1/Th2比率在免疫应答中是非常重要的。关于本发明,免疫应答的Th1/Th2比率优选地由根据本发明的药物组合物以朝向细胞应答的方向替换,所述药物组合物包含至少一种如上定义的根据本发明的式(I),(Ia),(II),(IIa),(IIb),(IIIa)和/或(IIIb)任一的核酸分子,例如其1种,2种,3种,4种,6种,7种或更多的核酸,即由此诱导Th1应答和主要地细胞免疫应答。仅通过这种替换和优先,或甚至排他的发生TH1免疫应答,有效治疗上述适应症是可以的。因此,优选地,本发明的药物组合物或根据本发明的疫苗用于引发肿瘤特异性或病原体特异性免疫应答。所述药物组合物或根据本发明的疫苗可以特别优选地用于增加抗原呈递细胞(APCs)的免疫应答。同样地,特别优选地,根据本发明的药物组合物或疫苗可以用于治疗癌症或肿瘤疾病,所述疾病优选地选自结肠癌,黑素瘤,肾癌,淋巴瘤,急性髓性白血病(AML),急性淋巴细胞白血病(ALL),慢性髓性白血病(CML),慢性淋巴细胞白血病(CLL),胃肠肿瘤,肺癌,神经胶质瘤,甲状腺肿瘤,乳癌,前列腺肿瘤,肝癌,各种病毒诱导的肿瘤如,例如,乳头状瘤病毒诱导的癌症(例如宫颈癌),腺癌,疱疹病毒诱导的肿瘤(例如伯基特淋巴瘤,EBV-诱导的B-细胞淋巴瘤),乙型肝炎病毒诱导的肿瘤(肝细胞癌),HTLV-1-和HTLV-2-诱导的淋巴瘤,听神经瘤/神经鞘瘤,宫颈癌,肺癌,咽癌,肛门癌,胶质母细胞瘤,淋巴瘤,直肠癌,星形细胞瘤,脑肿瘤,胃癌,视网膜母细胞瘤,基底细胞癌,脑转移,髓母细胞瘤,阴道癌,胰腺癌,睾丸癌,黑素瘤,甲状腺癌,膀胱癌,霍奇金综合征,脑膜瘤,Schneeberger病,支气管癌,垂体肿瘤,蕈样肉芽肿病,食管癌,乳腺癌,类癌,神经鞘瘤,spinaliomas,伯基特淋巴瘤,喉癌,肾癌,胸腺瘤,子宫体癌,骨癌,非霍奇金淋巴瘤,尿道癌,CUP综合征,头/颈肿瘤,少突神经胶质瘤,外阴癌,小肠癌,结肠癌,食管癌,疣累及,小肠肿瘤,颅咽管瘤,卵巢癌,软组织肿瘤/肉瘤,卵巢癌,肝癌,胰腺癌,宫颈癌,子宫内膜癌,肝转移,阴茎癌,舌癌,胆囊癌,白血病,浆细胞瘤,子宫癌,睑肿瘤和前列腺癌等。如果用在脂质-修饰的核酸中或作为组合物中的药用活性成分的脂质是α-生育酚(维生素E),D-α-生育酚,L-α-生育酚,D,L-α-生育酚或维生素E琥珀酸酯VES),这是特别优选的。α-生育酚(维生素E)不是非常毒性的并且显示有效的抗肿瘤活性(A.Bendich,L.J.Machlin Am.J.Clin.Nutr.48(1988)612),这使其似乎在癌症治疗中非常有前景。作为抑制肿瘤细胞增殖或其细胞毒性活性的解释,已知两种机制:在一方面,维生素E是有效的抗氧化剂和良好的原子团受体(C.Borek Ann.NY Acad.Sci.570(1990)417);另一方面,其通过刺激免疫应答,能够防止肿瘤生长(G.Shklar,J.Schwartz,D.P.Trickler,S.Reid J.Oral Pathol.Med.19(1990)60)。在最近的工作中,已经进一步发现在肿瘤细胞(口腔鳞状细胞癌)的肿瘤抑制基因p53的表达与用维生素E琥珀酸酯(VES)进行的治疗之间的关联(J.Schwartz,G.Shklar,D.Trickler Oral Oncol.Europ.J.Cancer 29B(1993)313)。由此可以观察到对作用为肿瘤抑制子的野生型p53的生产的刺激,和发展致癌活性的突变的p53的减少。有趣的是,VES对这些肿瘤细胞的生物学活性在两个方面是剂量依赖性的:以生理剂量(0.001-50μmol/l),观察到增加的细胞生长;以药理学剂量(100-154μmol/l),抑制了细胞生长。这已经显示在细胞培养物中(T.M.A.Elattar,A.S.Virji Anticancer Res(抗癌研究).19(1999)365)。还可以通过用VES治疗来诱导各种乳腺癌细胞系中的凋亡(W.Yu,K.Israel,Q.Y.Liao,C.M.Aldaz,B.G.Sanders,K.Kline Cancer Res(癌症研究).59(1999)953)。诱导的凋亡通过Fas配体和Fas受体之间的相互作用起始。这是被特别强调的,因为迄今尚不可以在相应的细胞系中观察到这样的机制。存在维生素E的各种异构体,其在芳香环的甲基的数量和位置上不同。在所述的工作中,使用天然存在的维生素E,α-生育酚的生物学最具活性的形式。这又发生在各种立体异构体中,因为所述分子包含三种光学活性中心。维生素E的天然形式是RRR-α-生育酚(以前的D-α-生育酚),而目前主要使用外消旋物(D,L-α-生育酚)。作为脂质的维生素E的所有上述形式同样地被包括在本发明的范围内。
同样特别优选地,至少一种如上定义的根据本发明的式(I),(Ia),(II),(IIa),(IIb),(IIIa)和/或(IIIb)任一的核酸分子,或根据本发明的药物组合物用于治疗感染性疾病。没有任何限制,所述感染性疾病优选地选自流感,疟疾,SARS,黄热病,AIDS,莱姆疏螺旋体病,利什曼病,炭疽,脑膜炎,病毒传染性疾病如AIDS,尖锐湿疣,空心疣(hollow warts),登革热,三日热,埃博拉病毒,感冒,早夏脑膜脑炎(early summermeningoencephalitis)(FSME),流行性感冒,带状疱疹,肝炎,I型单纯疱疹,II型单纯疱疹,带状疱疹,流感,日本脑炎,拉沙热,马尔堡病毒,麻疹,口蹄疫,单核细胞增多症,流行性腮腺炎,诺瓦克病毒感染,传染性单核细胞增多症,天花,脊髓灰质炎(儿童跛行),假格鲁布,传染性红斑,狂犬病,疣,西尼罗热,水痘,巨细胞症病毒(CMV),选自细菌感染性疾病,如流产(前列腺炎症),炭疽,阑尾炎,疏螺旋体病,肉毒中毒,弯曲菌属(Camphylobacter),沙眼衣原体(Chlamydia trachomatis)(尿道炎症,结膜炎),霍乱,白喉,杜诺凡菌病,会厌炎,斑疹伤寒,气性坏疽,淋病,兔热病,幽门螺杆菌(Heliobacter pylori),百日咳,腹股沟淋巴肉芽肿,骨髓炎,军团病,麻风病,利斯特菌病,肺炎,脑膜炎,细菌性脑膜炎,炭疽,中耳炎,人支原体,新生儿脓毒症(绒毛膜羊膜炎),坏疽性口炎,副伤寒(paratyphus),鼠疫,莱特尔综合征,洛矶山斑疹热,副伤寒沙门氏菌(Salmonella paratyphus),伤寒沙门氏菌(Salmonella typhus),猩红热,梅毒,破伤风,淋病(tripper),恙虫病,结核病,斑疹伤寒,鞘炎(阴道炎),软下疳,和选自由寄生虫、原生动物或真菌引起的感染性疾病,如阿米巴病,血吸虫病,美洲锥虫病,足癣,酵母菌斑,疥疮,疟疾,盘尾丝虫病(河盲),或真菌病,弓形体病,滴虫病,锥虫病(昏睡病),内脏利什曼病,尿布/尿布皮炎,血吸虫病,鱼肉中毒(雪卡毒素),念珠菌病,皮肤利什曼病,兰氏鞭毛虫病(贾第虫病),或昏睡病,或选自由棘球绦虫、阔节裂头绦虫、狐绦虫、犬绦虫、虱、牛肉绦虫、猪肉绦虫和微小绦虫引起的感染性疾病。
因此,如上定义的根据本发明的式(I),(Ia),(II),(IIa),(IIb),(IIIa)和/或(IIIb)任一的本发明至少一种核酸,或本发明的药物组合物可以用于制备药物,所述药物用于治疗变应性疾病或病症。变应性是一种涉及某些外源抗原或变应原的异常、需要的的免疫学超敏反应。变应性在正常情况下导致针对这些抗原或变应原的局部或系统炎性反应,并在体内导致针对这些变应原的免疫性。在此背景下的变应原包括例如草、花粉、霉菌、药物或许多环境触发物等。不限于理论,设想一些不同的疾病机制涉及变应性的发展。根据P.gell和R.Coombs的分类方案,术语“变应性”限于I型超敏反应,其由经典IgE机制所导致。I型超敏反应特征在于由IgE过量激活肥大细胞和嗜碱细胞,导致系统炎性反应,所述炎性反应可以导致良性症状如鼻漏(runny nose),到威胁生命的过敏性休克和死亡。熟知的变应性类型包括,但不限于,变应性哮喘(导致鼻粘膜的肿胀),变应性结膜炎(导致结膜的发红和发痒),变应性鼻炎(″花粉热″),过敏反应,血管性水肿(angiodema),特异性皮炎(湿疹),荨麻疹(假膜性喉头炎),嗜酸粒细胞增多,对于昆虫叮咬的呼吸系统变应性,皮肤变应性(导致并包括各种皮疹,如湿疹,假膜性喉头炎(荨麻疹),和(接触性)皮炎),食物变应性,和对于药物的变应性。关于本发明,提供例如本发明的药物组合物或疫苗,所述药物组合物或疫苗包含作为蛋白,编码该蛋白变应原的mRNA(或DNA)的变应原(例如,来自猫变应原,粉尘变应原,螨虫变应原,植物抗原(例如桦抗原)等),以及如上定义的根据本发明的式(I),(Ia),(II),(IIa),(IIb),(IIIa)和/或(IIIb)任一的核酸分子。本发明的药物组合物可以将(过量的)免疫应答转向更强的TH1应答,由此抑制或减弱不需要的IgE应答。
同样地,至少一种如上定义的根据本发明的式(I),(Ia),(II),(IIa),(IIb),(IIIa)和/或(IIIb)任一的本发明核酸或本发明的药物活性组合物可以用于制备药物,所述药物用于治疗自体免疫疾病。根据每种疾病主要的临床-病理学特征,可以将自体免疫疾病在广泛意义上分成系统和器官特异性或局部的自体免疫疾病。自体免疫疾病可以分为系统综合征的种类,包括SLE,斯耶格伦综合征,硬皮病,类风湿性关节炎和多肌炎或可以是内分泌性的局部综合征(I型DM,桥本甲状腺炎,艾迪生病等),皮肤性的局部综合征(寻常型天疱疮),血液性的局部综合征(自身免疫溶血性贫血),神经性局部综合征(多发性硬化)或可以实际上包括体组织的任何局限肿块。待治疗的自体免疫疾病可以选自由下列各项组成的组:I型自体免疫疾病或II型自体免疫疾病或III型自体免疫疾病或IV型自体免疫疾病,如,例如,多发性硬化(MS),类风湿性关节炎,糖尿病,I型糖尿病(糖尿病),系统性红斑狼疮(SLE),慢性多关节炎,巴塞多氏病,慢性肝炎的自体免疫形式,溃疡性结肠炎,I型变应性疾病,II型变应性疾病,III型变应性疾病,IV型变应性疾病,纤维肌痛,脱发,别赫捷列夫氏病,克罗恩氏病,重症肌无力,神经性皮炎,风湿性多肌痛,进行性系统性硬化病(PSS),银屑病,莱特尔综合征,风湿性关节炎,银屑病,脉管炎,等,或II型糖尿病。尽管尚未阐释为什么免疫系统诱导针对自体抗原的免疫反应的精确模式,存在关于该病因学的数种发现。因此,自体反应可以是由于T-细胞旁路引起的。正常的免疫系统需要由T-细胞激活B-细胞,之后前者可以大量产生抗体。在少数情况下,对T细胞的需要可以被绕过,如由产生超抗原的生物的感染,其能够通过以非特异性方式直接结合T-细胞受体的一个亚基而起始对B-细胞,或甚至T细胞的多克隆激活。另一种解释从分子拟态推导出自体免疫疾病。外源抗原可以与某些宿主抗原享有结构类似性;因此,针对该抗原(其模拟自体抗原)产生的任何抗体可以在理论上结合宿主抗原并且放大免疫应答。在组Aβ-溶血性链球菌(streptococci)中观察到分子拟态的最引人注目的形式,其与人心肌共享抗原,并且是风湿热的心脏表现的原因。因此,本发明可以提供包含自体抗原(如蛋白,编码自体抗原蛋白的mRNA或DNA)和典型地允许免疫系统脱敏的本发明的核酸的药物组合物。
本发明涉及将至少一种本发明的如上定义的根据本发明的式(I),(Ia),(II),(IIa),(IIb),(IIIa)和/或(IIIb)任一的核酸分子用于制备根据本发明的药物组合物或根据本发明的疫苗的应用,所述药物组合物或疫苗用于治疗前文所述的适应症,例如用于治疗提及的肿瘤,自体免疫疾病,变应性和感染性疾病。备选地,本发明包括至少一种如上定义的根据本发明的式(I),(Ia),(II),(IIa),(IIb),(IIIa)和/或(IIIb)任一的核酸分子用于治疗如前文所述的肿瘤或感染性疾病的(治疗)应用。
同样地,本发明包括试剂盒,例如多部件试剂盒,(每个部件)包含至少一种根据本发明的式(I),(Ia),(II),(IIa),(IIb),(IIIa)和/或(IIIb)任一的核酸分子和/或根据本发明的药物组合物,和/或根据本发明的疫苗以及,任选地用于利用关于至少一种根据本发明的式(I),(Ia),(II),(IIa),(IIb),(IIIa)和/或(IIIb)任一的核酸分子和/或根据本发明的药物组合物,和/或根据本发明的疫苗的施用和剂量的信息的技术说明书。
治疗选自由癌症疾病,感染性疾病,自体免疫疾病和变应性的组的疾病或病症的方法,其通过给需要其的患者施用药用有效量的根据本发明的核酸分子进行。
图
下图意欲进一步举例说明本发明。它们并不意欲限制本发明的主题。
图1:显示根据式(I)的DOTAP配制的RNA的TNFα诱导能力。将PBMCs以2*105/孔/200μl的培养基的密度接种并用以DOTAP(12μg/ml)配制的RNA(4μg/ml)刺激20小时。接着用无细胞的上清液进行TNFα-ELISA。如可以在图1中观察到的,TNFα的分泌显著地由本发明的根据式(I)的核酸诱导,特别由如上定义的根据式(I)的本发明核酸根据SEQ ID NOs:114-119的mRNA序列显著诱导,即根据SEQ ID NOs:114-119(SEQ ID NO:114(R820/(N100)2),SEQ ID NO:115(R719/(N100)5),SEQ ID NO:116(R720/(N100)10),SEQ ID NO:117(R821/(N40T20N40)2),SEQ ID NO:118(R722/(N40T20N40)5),和SEQ ID NO:119(R723/(N40T20N40)10))的mRNA序列和对照G2U20G20(GGUUUUUUUUUUUUUUUUUUUUGG),Seq.U21:UUUUUUUUUUUUUUUUUUUUU(磷酸二酯)和聚(U)(Sigma,800-1000kDa)。
图2:显示根据式(I)的DOTAP配制的RNA的IFNα诱导能力。将PBMCs以2*105/孔/200μl的培养基的密度接种并用以DOTAP(12μg/ml)配制的RNA(2μg/ml)刺激20小时。接着用无细胞的上清液进行IFNα-ELISA。如可以在图2中观察到的,IFNα的分泌显著地由本发明的根据式(I)的核酸诱导,特别由如上定义的根据式(I)的本发明核酸根据SEQ ID NOs:114-119的mRNA序列显著诱导,即,根据SEQ ID NOs:114-119(SEQ ID NO:114(R820/(N100)2),SEQ ID NO:115(R719/(N100)5),SEQ ID NO:116(R720/(N100)10),SEQ ID NO:117(R821/(N40T20N40)2),SEQ ID NO:118(R722/(N40T20N40)5),和SEQ ID NO:119(R723/(N40T20N40)10))的mRNA序列和对照G2U20G20(GGUUUUUUUUUUUUUUUUUUUUGG),Seq.U21:UUUUUUUUUUUUUUUUUUUUU(磷酸二酯)和聚(U)(Sigma,800-1000kDa)。
实施例:
下面的实施例意欲进一步举例说明本发明。它们并不意欲限制本发明的主题。
1.合成根据本发明的式(I),(Ia),(II),(IIa),(IIb),(IIIa)和/或(IIIb)任一的示
例性核酸
RNA寡核苷酸,作为根据本发明的通式(I),(Ia),(II),(IIa),(IIb),(IIIa)和/或(IIIb)的核酸的实例通过亚磷酰胺化学的方式通过自动固相合成(包括根据SEQ ID NOs:84-85(式(I)),SEQ ID NOs:86-87(式(Ia)),SEQ IDNOs:88-94(式(II),(IIa)和(IIb)),和SEQ ID NOs:107-108(式(IIIa)和(IIIb))的序列)制备。在每种情形中,将核苷酸的RNA-特异性2′-羟基用TBDMS保护基保护。在硫代磷酸酯的合成中,使用Beaucage试剂进行氧化。用甲胺进行载体物质和碱不稳定的保护基的裂解,并且用三乙胺氟化氢进行TBDMS保护基的裂解。
将粗制产物通过离子对色谱法,通过离子交换色谱法或通过两种方法的组合,通过HPLC进行纯化,脱盐和干燥。通过质谱法检查产物的纯度和正确的碱基组成。
根据备选方法,通过基于携带本发明的序列的DNA载体或寡核苷酸序列的体外翻译制备上述序列。
2.根据本发明的式(I),(Ia),(II),(IIa),(IIb),(IIIa)和/或(IIIb)任一的示例性
核酸的体外免疫刺激
a)对于刺激小鼠BDMCs(骨髓来源的树突细胞),将3μl的oligofectamine与30μl的无FCS IMDM培养基(BioWhittaker,批号.BE12-722F)混合,并在室温温育5分钟。将6μg的RNA形式的根据SEQID NOs:84-94和107-108的核酸(每种类型的核酸形成单一实验),分别与60μl的无FCS-IMDM混合,并与oligofectamine/IMDM混合,在室温温育20分钟。接着,将33μl的这种混合物置于96孔微量培养板的孔中培养过夜,在所述微量培养板的每个孔中,在200μl的无FCS IMDM培养基中包含200,000小鼠BDMCs。4小时后,加入100μl包含20% FCS的IMDM,并且在16小时的共温育后,去除上清液,并且通过细胞因子ELISA测试白介素-6(IL-6)和白介素-12(IL-12)。使用与鱼精蛋白复合的β-半乳糖苷酶(lacZ)的免疫刺激的未加帽野生型mRNA,以类似于上述序列的方式进行比较测试。
以RNA形式存在的根据本发明式(I),(Ia),(II),(IIa),(IIb),(IIIa)和/或(IIIb)的核酸,特别是根据SEQ ID NOs:84-94和107-108的本发明的序列具有刺激先天免疫应答的良好的免疫刺激性质。(b)通过菲可密度梯度和在X-VIVO-15培养基(BioWhittaker,批号BE04-418Q)中在存在10μg/ml的以RNA形式存在的根据本发明的式(I),(Ia),(II),(IIa),(IIb),(IIIa)和/或(IIIb)任一的核酸,特别是SEQ ID NOs:84-94和107-108的根据本发明的序列(每种类型的核酸形成单一实验)情况下,培养过夜来获得人PBMCs,所述培养基包含1%谷氨酰胺和1%青霉素。
对于刺激,将3μl的oligofectamine与30μl的X-VIVO-15培养基(BioWhittaker,批号BE04-418Q)混合,并将其在室温温育5分钟。将6μg的以RNA形式存在的根据本发明的式(I),(Ia),(II),(IIa),(IIb),(IIIa)和/或(IIIb)任一的核酸,特别是根据本发明SEQ ID NOs:84-94和107-108的序列(对每种类型的核酸进行一个实验)分别与60μl X-VIVO-15培养基(BioWhittaker,catalogue no.BE04-418Q)混合,并且与oligofectamine/X-VIVO培养基混合,在室温温育20分钟。接着,将33μl的这种混合物置于96孔微量培养板的每个孔中进行培养过夜,在所述每个孔中,在200μl的X-VIVO-15培养基(BioWhittaker,catalogue no.BE04-418Q)中包含200,000 PBMCs。在共培育16小时后,去除上清液并通过细胞因子-ELISA的方式测试白介素-6(IL-6)和白介素-12(IL-12)和TNFα。用免疫刺激性寡RNA40(5′-GCCCGUCUGUUGUGUGACUC-3′,SEQ ID NO:113),以类似于根据本发明序列(见上)的方式进行比较测试。
可以显示以RNA形式存在的本发明的核酸,特别是具有如上定义的根据本发明的式(I),(Ia),(II),(IIa),(IIb),(IIIa)和/或(IIIb)任一的本发明序列的本发明核酸具有良好的免疫刺激性质。
3.用根据本发明的式(I),(Ia),(II),(IIa),(IIb),(IIIa)和/或(IIIb)任一的示例 性核酸进行的体内免疫刺激-用作佐剂
将BALB/c小鼠(每组5只)用β-半乳糖苷酶蛋白和用佐剂(如本文定义)在第0天和第10天进行注射。将小鼠在第20天处死,并通过ELISA,将血清用于针对β-半乳糖苷酶蛋白的抗体测试,并以类似于上述体外培养的方式确定IL-6,IL-12和TNF-α值。
4.用以式(I),(Ia),(II),(IIa),(IIb),(IIIa)和/或(IIIb)任一的核酸分子的形
式存在的根据本发明的佐剂刺激人细胞
a)为了确定以佐剂形式存在的如上定义的根据本发明的式(I),(Ia),(II),(IIa),(IIb),(IIIa)和/或(IIIb)任一的核酸的免疫原活性,特别地包含根据SEQ ID NOs:84-94和107-108序列的核酸的免疫原活性(每种类型的核酸再次形成单一实验)与人细胞共温育。为此目的,将人PBMC细胞,例如,在X-VIVO-15培养基(BioWhittaker,批号BE04-418Q)中共温育16小时,将所述培养基用2mM L-谷氨酰胺(BioWhittaker),10U/ml青霉素(BioWhittaker)和10μg/ml链霉素,用编码β-半乳糖苷酶的RNA(mRNA),和任选地用10μg/ml鱼精蛋白富集。去除上清液,并通过ELISA的方式分析IL-6和TNFα的释放。
b)在另外的实验中,在用根据本发明的式(I),(Ia),(II),(IIa),(IIb),(IIIa)和/或(IIIb)任一的本发明核酸(SEQ ID NOs:84-94和107-108,每种类型的核酸在单一实验中进行,见上)和根据本发明使用的佐剂刺激后确定人PBMC细胞释放的TNF-α。
为此目的,将人PBMC细胞与10μg/ml的所述本发明核酸在X-VIVO15培养基(BioWhittaker)中共温育16小时,所述培养基用2mM L-谷氨酰胺(BioWhittaker),10U/ml青霉素(BioWhittaker)和10μg/ml链霉素富集。去除上清液,并通过ELISA的方式进行分析。
5.在人PBMCs中分泌TNFα和IFN-α
对于该实验,用DOTAP(Roche)配制如上定义的数种根据式(I)的本发明核酸,即根据SEQ ID NOs:114-119的mRNA序列。
在所述实验中使用的本发明的核酸序列是
SEQ ID NO:114(R820/(N100)2);
SEQ ID NO:115(R719/(N100)5);
SEQ ID NO:116(R720/(N100)10);
SEQ ID NO:117(R821/(N40T20N40)2);
SEQ ID NO:118(R722/(N40T20N40)5);和
SEQ ID NO:119(R723/(N40T20N40)10).
接着,将人PBMCs用浓度为8μg/ml和12μg/ml DOTAP的配制的RNA刺激20小时。接着,使用匹配-配对的ELISA研究上清液的TNFa和IFN-a分泌。
对于所述实验,通过菲可密度梯度和在X-VIVO-15培养基(BioWhittaker,批号BE04-418Q)中在存在2或4μg/ml的上述核酸的情况下培养20小时来获得人PBMCs分别用于IFNα和TNFα刺激,所述培养基包含1%谷氨酰胺和1%青霉素。对于配制和刺激,将3或6μg在HBS缓冲液中的RNA转移到在HBS缓冲液中包含18μg N-[1-(2,3-二甲基油酰氧基)丙基]-N,N,N三甲基甲基硫酸铵(DOTAP)(Roche Diagnostics,批号11811 177 001)的瓶中,并通过轻柔吹吸混合物数次来仔细混合。将转染的混合物在15-25℃温育15分钟。接着,将1体积的DOTAP/核酸混合物用7.3体积的X-Vivo培养基轻轻稀释。接着,将100μl的这种混合物在96孔微量培养板的孔中培养过夜,所述培养板的每孔在100μl的X-VIVO-15培养基(BioWhittaker,catalogue no.BE04-418Q)中包含2*105 PBMCs。在共温育20小时后,去除上清液,并通过细胞因子-ELISA的方式测试IFNα和TNFα。用免疫刺激寡G2U20G2(硫代硫酸酯-修饰的),聚(U)(Sigma,Taufkirchen,德国)和寡U21(磷酸二酯),以类似于根据本发明的序列(见上)的方式进行比较测试。
将结果显示在图1和2中。图1显示DOTAP配制的RNAs的TNFα诱导能力。将PBMCs以2*105/孔/200μl培养基的密度接种,并用以DOTAP(12μg/ml)配制的RNA(4μg/ml)刺激20小时。接着用无细胞的上清液进行TNFα-ELISA。图2显示DOTAP配制的RNAs的IFNα诱导能力。将PBMCs以2*105/孔/200μl培养基的密度接种,并用以DOTAP(12μg/ml)配制的RNA(2μg/ml)刺激20小时。接着,用无细胞的上清液进行IFNα-ELISA。
如可以在图1和图2中观察到的,TNFα和IFNα的分泌由根据式(I)的本发明的核酸,特别由如上定义的根据式(I)的根据SEQ ID NOs:114-119本发明核酸的mRNA序列显著诱导,即,根据SEQ ID NOs:114-119(SEQ ID NO:114(R820/(N100)2),SEQ ID NO:115(R719/(N100)5),SEQ IDNO:116(R720/(N100)10),SEQ ID NO:117(R821/(N40T20N40)2),SEQ IDNO:118(R722/(N40T20N40)5),和SEQ ID NO:119(R723/(N40T20N40)10))的mRNA序列对比对照序列G2U20G2(硫代硫酸酯修饰的),聚(U)(Sigma,Taufkirchen,Germany)和寡U21(磷酸二酯)。
本发明的益处:
根据本发明的通式(I),(Ia),(II),(IIa),(IIb),(IIIa)和/或(IIIb)的核酸可以用作象这样的免疫刺激剂,其刺激待治疗的患者的先天免疫系统。这种免疫刺激性质可以通过加入本领域已知的其它化合物来主动刺激针对本发明核酸的先天免疫应答(例如通过脂质修饰或通过加入另外的佐剂)从而充分地增强。如上定义的本发明核酸,特别是包含结构(NuGlXmGnNv)a,或其衍生物的根据式(I)的那些,显示在细菌(例如大肠杆菌)中明显更好的扩增。如果本发明式(I)的核酸(NvGlXmGnNu)a,或其衍生物,是部分双链核酸分子或单链和双链核酸分子的混合物,这是另外特别有利的,因为根据式(I)(或式(Ia),(II)(IIa),(IIb),(IIIa)和/或(IIIb))的(部分双链)本发明的核酸分子可以通过定向关于单链RNA的PAMP-(病原体相关分子模式模式)受体(TLR-7和TLR-8)以及关于双链RNA的PAMP-受体(TLR-3,RIG-I和MDA-5)来正向刺激待治疗的患者中的先天免疫应答。受体TLR-3,TLR-7和TLR-8位于内体内,并且被由内体摄取的RNA激活。与此相反,RIG-I和MDA-5是细胞质受体,其由直接被摄取到细胞质中或已经由内体释放(内体释放或内体逃逸)的RNA激活。因此,式(I)的部分双链本发明的核酸(NuGlXmGnNv)a(或其衍生物,例如如上定义的根据式(Ia),(II)(IIa),(IIb),(IIIa)和(IIIb)的(部分双链)本发明核酸分子)能够激活不同的免疫刺激信号级联并由此导致增加的先天免疫应答或显著增强这样的反应。本发明的另外的益处是优选用于刺激先天免疫系统的抗病毒细胞因子IFNα的高度诱导。对通常公认的免疫刺激核酸(例如聚A:U和聚I:C)的一般估计不足的限制是它们未明确的结构,这导致调节受限。
Claims (9)
1.核酸分子,其序列为SEQ ID NO:117,118或119所示的序列。
2.根据权利要求1的核酸在制备药物中的应用。
3.权利要求2的应用,其中所述药物是免疫刺激剂。
4.药物组合物,其包含:根据权利要求1的核酸,和药用载体。
5.权利要求4的药物组合物,其还包含另外的辅助物质、添加剂和/或佐剂。
6.根据权利要求4的药物组合物,其另外地包含至少一种药用活性成分。
7.根据权利要求4的药物组合物,其特征在于所述组合物包含至少一种另外的佐剂,其是免疫刺激剂,其中所述佐剂是微生物衍生的佐剂。
8.根据权利要求4-7中任一项的药物组合物,其特征在于所述药物组合物是疫苗。
9.试剂盒,其包含根据权利要求1的核酸或根据权利要求4-8中任一项的药物组合物,以及另外任选地包含用于利用关于所述核酸或所述药物组合物的施用和剂量的信息的技术说明书。
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Families Citing this family (217)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US9393315B2 (en) | 2011-06-08 | 2016-07-19 | Nitto Denko Corporation | Compounds for targeting drug delivery and enhancing siRNA activity |
DK2056845T3 (da) | 2006-08-08 | 2017-11-27 | Rheinische Friedrich-Wilhelms-Universität Bonn | Struktur og anvendelse af 5'-phosphat-oligonukleotider |
WO2008039969A2 (en) | 2006-09-28 | 2008-04-03 | Cedars-Sinai Medical Center | Cancer vaccines and vaccination methods |
WO2009030254A1 (en) | 2007-09-04 | 2009-03-12 | Curevac Gmbh | Complexes of rna and cationic peptides for transfection and for immunostimulation |
EP3346005A1 (en) * | 2008-01-31 | 2018-07-11 | CureVac AG | Nucleic acids of formula (i) (nuglxmgnnv)a and derivatives thereof as an immunostimulating agent/adjuvant |
US9107815B2 (en) * | 2008-02-22 | 2015-08-18 | Allergan, Inc. | Sustained release poloxamer containing pharmaceutical compositions |
JP5689413B2 (ja) | 2008-05-21 | 2015-03-25 | ライニッシュ フリードリッヒ−ウィルヘルムズ−ユニバーシタット ボン | 平滑末端を有する5’三リン酸オリゴヌクレオチドおよびその使用 |
US20100160368A1 (en) | 2008-08-18 | 2010-06-24 | Gregory Jefferson J | Methods of Treating Dermatological Disorders and Inducing Interferon Biosynthesis With Shorter Durations of Imiquimod Therapy |
WO2010037408A1 (en) | 2008-09-30 | 2010-04-08 | Curevac Gmbh | Composition comprising a complexed (m)rna and a naked mrna for providing or enhancing an immunostimulatory response in a mammal and uses thereof |
EA201100984A1 (ru) | 2008-12-19 | 2012-01-30 | Грэйсуэй Фармасьютикалс, Ллс | Композиции с более низким содержанием имиквимода и короткие режимы дозирования для лечения актинического кератоза |
MX336923B (es) | 2009-07-13 | 2016-02-05 | Medicis Pharmaceutical Corp | Formulaciones de imiquimod de concentracion de dosificacion inferior y regimenes de dosificacion cortos para tratar verrugas genitales y perianales. |
US20110053829A1 (en) | 2009-09-03 | 2011-03-03 | Curevac Gmbh | Disulfide-linked polyethyleneglycol/peptide conjugates for the transfection of nucleic acids |
WO2011069529A1 (en) | 2009-12-09 | 2011-06-16 | Curevac Gmbh | Mannose-containing solution for lyophilization, transfection and/or injection of nucleic acids |
CA2801523C (en) | 2010-07-30 | 2021-08-03 | Curevac Gmbh | Complexation of nucleic acids with disulfide-crosslinked cationic components for transfection and immunostimulation |
EP3578205A1 (en) | 2010-08-06 | 2019-12-11 | ModernaTX, Inc. | A pharmaceutical formulation comprising engineered nucleic acids and medical use thereof |
WO2012019630A1 (en) | 2010-08-13 | 2012-02-16 | Curevac Gmbh | Nucleic acid comprising or coding for a histone stem-loop and a poly(a) sequence or a polyadenylation signal for increasing the expression of an encoded protein |
EP2609931B1 (en) * | 2010-08-26 | 2020-09-16 | Toray Industries, Inc. | Immunogenic composition |
HUE058896T2 (hu) | 2010-10-01 | 2022-09-28 | Modernatx Inc | N1-metil-pszeudo-uracilt tartalmazó ribonukleinsavak és azok felhasználásai |
WO2012089225A1 (en) | 2010-12-29 | 2012-07-05 | Curevac Gmbh | Combination of vaccination and inhibition of mhc class i restricted antigen presentation |
WO2012116715A1 (en) | 2011-03-02 | 2012-09-07 | Curevac Gmbh | Vaccination in newborns and infants |
WO2012113413A1 (en) | 2011-02-21 | 2012-08-30 | Curevac Gmbh | Vaccine composition comprising complexed immunostimulatory nucleic acids and antigens packaged with disulfide-linked polyethyleneglycol/peptide conjugates |
WO2012116714A1 (en) | 2011-03-02 | 2012-09-07 | Curevac Gmbh | Vaccination in elderly patients |
JP2014511687A (ja) | 2011-03-31 | 2014-05-19 | モデルナ セラピューティクス インコーポレイテッド | 工学操作された核酸の送達および製剤 |
US10196637B2 (en) | 2011-06-08 | 2019-02-05 | Nitto Denko Corporation | Retinoid-lipid drug carrier |
US9844592B2 (en) * | 2011-07-18 | 2017-12-19 | Icahn School Of Medicine At Mount Sinai | Bacterial RNAs as vaccine adjuvants |
US9464124B2 (en) | 2011-09-12 | 2016-10-11 | Moderna Therapeutics, Inc. | Engineered nucleic acids and methods of use thereof |
WO2013040552A2 (en) * | 2011-09-16 | 2013-03-21 | Georgia Health Sciences University | Methods of promoting immune tolerance |
RU2648950C2 (ru) | 2011-10-03 | 2018-04-02 | Модерна Терапьютикс, Инк. | Модифицированные нуклеозиды, нуклеотиды и нуклеиновые кислоты и их применение |
EP2773760B2 (en) | 2011-10-31 | 2020-11-04 | RiboxX GmbH | Double-stranded rna for immunostimulation |
AU2012340887A1 (en) * | 2011-11-22 | 2014-07-03 | Trustees Of Tufts College | Small molecule enhancer for dendritic cell cancer vaccines |
EP2791160B1 (en) | 2011-12-16 | 2022-03-02 | ModernaTX, Inc. | Modified mrna compositions |
WO2013110030A2 (en) | 2012-01-19 | 2013-07-25 | Duke University | Vaccines against antigens involved in therapy resistance and methods of using same |
WO2013113326A1 (en) * | 2012-01-31 | 2013-08-08 | Curevac Gmbh | Pharmaceutical composition comprising a polymeric carrier cargo complex and at least one protein or peptide antigen |
WO2013120499A1 (en) | 2012-02-15 | 2013-08-22 | Curevac Gmbh | Nucleic acid comprising or coding for a histone stem-loop and a poly (a) sequence or a polyadenylation signal for increasing the expression of an encoded pathogenic antigen |
WO2013120500A1 (en) | 2012-02-15 | 2013-08-22 | Curevac Gmbh | Nucleic acid comprising or coding for a histone stem-loop and a poly(a) sequence or a polyadenylation signal for increasing the expression of an encoded tumour antigen |
WO2013120497A1 (en) | 2012-02-15 | 2013-08-22 | Curevac Gmbh | Nucleic acid comprising or coding for a histone stem-loop and a poly(a) sequence or a polyadenylation signal for increasing the expression of an encoded therapeutic protein |
WO2013120498A1 (en) | 2012-02-15 | 2013-08-22 | Curevac Gmbh | Nucleic acid comprising or coding for a histone stem-loop and a poly(a) sequence or a polyadenylation signal for increasing the expression of an encoded allergenic antigen or an autoimmune self-antigen |
BR112014023898A2 (pt) | 2012-03-27 | 2017-07-11 | Curevac Gmbh | moléculas de ácido nucleico artificiais compreendendo 5''utr top |
KR102186497B1 (ko) | 2012-03-27 | 2020-12-04 | 큐어백 아게 | 인공 핵산 분자 |
AU2013242404B2 (en) | 2012-03-27 | 2018-08-30 | CureVac SE | Artificial nucleic acid molecules for improved protein or peptide expression |
US9572897B2 (en) | 2012-04-02 | 2017-02-21 | Modernatx, Inc. | Modified polynucleotides for the production of cytoplasmic and cytoskeletal proteins |
AU2013243951A1 (en) | 2012-04-02 | 2014-10-30 | Moderna Therapeutics, Inc. | Modified polynucleotides for the production of secreted proteins |
US9254311B2 (en) | 2012-04-02 | 2016-02-09 | Moderna Therapeutics, Inc. | Modified polynucleotides for the production of proteins |
US9283287B2 (en) | 2012-04-02 | 2016-03-15 | Moderna Therapeutics, Inc. | Modified polynucleotides for the production of nuclear proteins |
CN102854276B (zh) * | 2012-08-09 | 2014-07-16 | 深圳万乐药业有限公司 | 米伐木肽的高效液相色谱分析方法 |
CN102813921B (zh) * | 2012-08-16 | 2014-04-16 | 中国农业科学院兰州兽医研究所 | 一种口蹄疫疫苗新型复合氢氧化铝佐剂以及制备疫苗方法 |
EP2712870A1 (en) | 2012-09-27 | 2014-04-02 | Rheinische Friedrich-Wilhelms-Universität Bonn | Novel RIG-I ligands and methods for producing them |
EP2922554B1 (en) | 2012-11-26 | 2022-02-23 | ModernaTX, Inc. | Terminally modified rna |
WO2014127296A1 (en) | 2013-02-14 | 2014-08-21 | Immunocellular Therapeutics, Ltd | Cancer vaccines and vaccination methods |
WO2014127276A1 (en) * | 2013-02-14 | 2014-08-21 | Immunocellular Therapeutics, Ltd. | Ovarian cancer vaccines and vaccination methods |
US9974845B2 (en) | 2013-02-22 | 2018-05-22 | Curevac Ag | Combination of vaccination and inhibition of the PD-1 pathway |
EP2983804A4 (en) | 2013-03-15 | 2017-03-01 | Moderna Therapeutics, Inc. | Ion exchange purification of mrna |
WO2014152030A1 (en) | 2013-03-15 | 2014-09-25 | Moderna Therapeutics, Inc. | Removal of dna fragments in mrna production process |
EP3578663A1 (en) | 2013-03-15 | 2019-12-11 | ModernaTX, Inc. | Manufacturing methods for production of rna transcripts |
US8980864B2 (en) | 2013-03-15 | 2015-03-17 | Moderna Therapeutics, Inc. | Compositions and methods of altering cholesterol levels |
EP2971161B1 (en) | 2013-03-15 | 2018-12-26 | ModernaTX, Inc. | Ribonucleic acid purification |
KR101501583B1 (ko) * | 2013-03-29 | 2015-03-12 | 주식회사 차백신연구소 | 리포펩티드 및 폴리(i:c)를 포함하는 아쥬반트 및 이를 이용한 개선된 제형의 백신 조성물 |
US20160136197A1 (en) * | 2013-06-14 | 2016-05-19 | Intervet International B.V. | Pharmaceutical Compositions Comprising a GPG Oligodeoxynucleotide and Cyclic Di-GMP |
US9775894B2 (en) | 2013-07-09 | 2017-10-03 | University Of Washington Through Its Center For Commercialization | Methods and compositions for activation of innate immune responses through RIG-I like receptor signaling |
EP3971287A1 (en) | 2013-07-11 | 2022-03-23 | ModernaTX, Inc. | Compositions comprising synthetic polynucleotides encoding crispr related proteins and synthetic sgrnas and methods of use |
CA2915730A1 (en) | 2013-08-21 | 2015-02-26 | Karl-Josef Kallen | A combination rsv/influenza a vaccine |
SG11201510746WA (en) | 2013-08-21 | 2016-03-30 | Curevac Ag | Respiratory syncytial virus (rsv) vaccine |
SG11201510747RA (en) | 2013-08-21 | 2016-03-30 | Curevac Ag | Method for increasing expression of rna-encoded proteins |
CN105517569A (zh) | 2013-08-21 | 2016-04-20 | 库瑞瓦格股份公司 | 狂犬病疫苗 |
WO2015048744A2 (en) | 2013-09-30 | 2015-04-02 | Moderna Therapeutics, Inc. | Polynucleotides encoding immune modulating polypeptides |
US10385088B2 (en) | 2013-10-02 | 2019-08-20 | Modernatx, Inc. | Polynucleotide molecules and uses thereof |
EA201690675A1 (ru) | 2013-10-03 | 2016-08-31 | Модерна Терапьютикс, Инк. | Полинуклеотиды, кодирующие рецептор липопротеинов низкой плотности |
CA2925021A1 (en) | 2013-11-01 | 2015-05-07 | Curevac Ag | Modified rna with decreased immunostimulatory properties |
CA2927254C (en) | 2013-12-30 | 2023-10-24 | Curevac Ag | Artificial nucleic acid molecules |
BR112016014462A2 (pt) | 2013-12-30 | 2017-10-24 | Curevac Ag | moléculas de ácido nucleico artificiais |
US11254951B2 (en) | 2014-12-30 | 2022-02-22 | Curevac Ag | Artificial nucleic acid molecules |
WO2015101416A1 (en) | 2013-12-30 | 2015-07-09 | Curevac Gmbh | Methods for rna analysis |
ES2754239T3 (es) | 2014-03-12 | 2020-04-16 | Curevac Ag | Combinación de vacunación y agonistas de OX40 |
WO2015144714A1 (en) * | 2014-03-24 | 2015-10-01 | INSERM (Institut National de la Santé et de la Recherche Médicale) | Methods and pharmaceutical compositions for the treatment of allergic contact dermatitis |
CA2936286A1 (en) | 2014-04-01 | 2015-10-08 | Curevac Ag | Polymeric carrier cargo complex for use as an immunostimulating agent or as an adjuvant |
PT3134131T (pt) | 2014-04-23 | 2022-03-24 | Modernatx Inc | Vacinas de ácidos nucleicos |
JP6748579B2 (ja) | 2014-06-10 | 2020-09-02 | キュアバック リアル エステート ゲゼルシャフト ミット ベシュレンクテル ハフツング | Rna生成を強化する方法及び手段 |
US10286086B2 (en) | 2014-06-19 | 2019-05-14 | Modernatx, Inc. | Alternative nucleic acid molecules and uses thereof |
CN106795096B (zh) | 2014-06-25 | 2020-05-29 | 爱康泰生治疗公司 | 用于递送核酸的新型脂质和脂质纳米颗粒制剂 |
US20170196952A1 (en) | 2014-07-07 | 2017-07-13 | Duke University | Vaccines against an oncogenic isoform of esr1 and methods of using the same |
US20170196953A1 (en) | 2014-07-07 | 2017-07-13 | Duke University | VACCINES AGAINST AN ONCOGENIC ISOFORM OF HER2 (ErbB2) AND METHODS OF USING THE SAME |
WO2016011222A2 (en) | 2014-07-16 | 2016-01-21 | Moderna Therapeutics, Inc. | Circular polynucleotides |
EP4241784A3 (en) | 2014-12-12 | 2023-11-15 | CureVac SE | Artificial nucleic acid molecules for improved protein expression |
US9682100B2 (en) | 2015-01-26 | 2017-06-20 | International Business Machines Corporation | Cationic polyamines for treatment of viruses |
WO2016165825A1 (en) | 2015-04-13 | 2016-10-20 | Curevac Ag | Method for producing rna compositions |
EP3283125B1 (en) | 2015-04-17 | 2021-12-29 | CureVac Real Estate GmbH | Lyophilization of rna |
MX2017013321A (es) * | 2015-04-22 | 2018-07-06 | Curevac Ag | Composicion que contiene arn para tratamiento de enfermedades tumorales. |
EP3289101B1 (en) | 2015-04-30 | 2021-06-23 | CureVac AG | Immobilized poly(n)polymerase |
EP3294885B1 (en) | 2015-05-08 | 2020-07-01 | CureVac Real Estate GmbH | Method for producing rna |
US11559570B2 (en) | 2015-05-15 | 2023-01-24 | CureVac SE | Prime-boost regimens involving administration of at least one mRNA construct |
CN107530448A (zh) | 2015-05-20 | 2018-01-02 | 库瑞瓦格股份公司 | 包含长链rna的干粉组合物 |
US10517827B2 (en) | 2015-05-20 | 2019-12-31 | Curevac Ag | Dry powder composition comprising long-chain RNA |
WO2016193226A1 (en) | 2015-05-29 | 2016-12-08 | Curevac Ag | Method for adding cap structures to rna using immobilized enzymes |
EP3744843A1 (en) | 2015-05-29 | 2020-12-02 | CureVac Real Estate GmbH | A method for producing and purifying rna, comprising at least one step of tangential flow filtration |
DK3313829T3 (da) | 2015-06-29 | 2024-06-17 | Acuitas Therapeutics Inc | Lipider og lipide nanopartikelformuleringer til levering af nukleinsyrer |
US10501768B2 (en) | 2015-07-13 | 2019-12-10 | Curevac Ag | Method of producing RNA from circular DNA and corresponding template DNA |
US11364292B2 (en) | 2015-07-21 | 2022-06-21 | Modernatx, Inc. | CHIKV RNA vaccines |
WO2017015463A2 (en) | 2015-07-21 | 2017-01-26 | Modernatx, Inc. | Infectious disease vaccines |
WO2017036889A1 (en) | 2015-08-28 | 2017-03-09 | Biontech Rna Pharmaceuticals Gmbh | Method for reducing immunogenicity of rna |
US11434486B2 (en) | 2015-09-17 | 2022-09-06 | Modernatx, Inc. | Polynucleotides containing a morpholino linker |
LT3350157T (lt) | 2015-09-17 | 2022-02-25 | Modernatx, Inc. | Junginiai ir kompozicijos terapinei medžiagai teikti intraceliuliniu būdu |
US11225682B2 (en) | 2015-10-12 | 2022-01-18 | Curevac Ag | Automated method for isolation, selection and/or detection of microorganisms or cells comprised in a solution |
WO2017066797A1 (en) | 2015-10-16 | 2017-04-20 | Modernatx, Inc. | Trinucleotide mrna cap analogs |
CA3001014A1 (en) | 2015-10-16 | 2017-04-20 | Modernatx, Inc. | Mrna cap analogs and methods of mrna capping |
EP3362461B1 (en) | 2015-10-16 | 2022-03-16 | Modernatx, Inc. | Mrna cap analogs with modified phosphate linkage |
WO2017066791A1 (en) | 2015-10-16 | 2017-04-20 | Modernatx, Inc. | Sugar substituted mrna cap analogs |
WO2017066782A1 (en) | 2015-10-16 | 2017-04-20 | Modernatx, Inc. | Hydrophobic mrna cap analogs |
WO2017066789A1 (en) | 2015-10-16 | 2017-04-20 | Modernatx, Inc. | Mrna cap analogs with modified sugar |
US10646576B2 (en) * | 2015-10-21 | 2020-05-12 | Sprna Gmbh | Immunostimulating-toxic RNA in alkaline earth metal formulation |
EP3364950A4 (en) | 2015-10-22 | 2019-10-23 | ModernaTX, Inc. | VACCINES AGAINST TROPICAL DISEASES |
WO2017070613A1 (en) | 2015-10-22 | 2017-04-27 | Modernatx, Inc. | Human cytomegalovirus vaccine |
HUE059127T2 (hu) | 2015-10-22 | 2022-10-28 | Modernatx Inc | Légúti vírusok elleni vakcinák |
CA3201644A1 (en) | 2015-10-28 | 2017-05-04 | Acuitas Therapeutics, Inc. | Lipids and lipid nanoparticle formulations for delivery of nucleic acids |
EP3373965A1 (en) | 2015-11-09 | 2018-09-19 | CureVac AG | Rotavirus vaccines |
AU2016377681B2 (en) | 2015-12-22 | 2021-05-13 | Modernatx, Inc. | Compounds and compositions for intracellular delivery of agents |
AU2016375021B2 (en) | 2015-12-22 | 2022-02-03 | CureVac SE | Method for producing RNA molecule compositions |
US11248223B2 (en) | 2015-12-23 | 2022-02-15 | Curevac Ag | Method of RNA in vitro transcription using a buffer containing a dicarboxylic acid or tricarboxylic acid or a salt thereof |
US11253580B2 (en) | 2016-01-07 | 2022-02-22 | Duke University | Cancer vaccines and methods of delivery |
WO2017121494A1 (en) * | 2016-01-15 | 2017-07-20 | Riboxx Gmbh | 5'-triphosphated short immunostimulatory nucleotides, oligonucleotides and polynucleotides |
SG11201806340YA (en) | 2016-02-17 | 2018-09-27 | Curevac Ag | Zika virus vaccine |
CN107149671B (zh) * | 2016-03-03 | 2021-02-05 | 郭文江 | 一种药物组合物及其应用 |
EP3423595A1 (en) | 2016-03-03 | 2019-01-09 | CureVac AG | Rna analysis by total hydrolysis |
US20190343942A1 (en) | 2016-04-22 | 2019-11-14 | Curevac Ag | Rna encoding a tumor antigen |
US11596699B2 (en) | 2016-04-29 | 2023-03-07 | CureVac SE | RNA encoding an antibody |
WO2017191274A2 (en) | 2016-05-04 | 2017-11-09 | Curevac Ag | Rna encoding a therapeutic protein |
EP3452493A1 (en) | 2016-05-04 | 2019-03-13 | CureVac AG | Nucleic acid molecules and uses thereof |
KR20190029576A (ko) | 2016-06-09 | 2019-03-20 | 큐어백 아게 | 핵산 카고용 하이브리드 담체 |
JP2019525901A (ja) | 2016-06-14 | 2019-09-12 | モデルナティエックス インコーポレイテッドModernaTX,Inc. | 脂質ナノ粒子の安定化製剤 |
AU2017280943B2 (en) * | 2016-06-20 | 2023-05-18 | Emory University | Circular RNAs and their use in immunomodulation |
EP3500295A2 (en) * | 2016-08-19 | 2019-06-26 | CureVac AG | Rna for cancer therapy |
WO2018041921A1 (en) | 2016-08-31 | 2018-03-08 | Curevac Ag | Mixing device for the production of a liquid nucleic acid composition |
CA3035473A1 (en) | 2016-09-13 | 2018-03-22 | Allergan, Inc. | Non-protein clostridial toxin compositions |
US10487143B2 (en) | 2016-10-05 | 2019-11-26 | Duke University | Vaccines against HER3 antigens and methods of using the same |
US11224665B2 (en) | 2016-10-05 | 2022-01-18 | Duke University | Mitochondrial antiviral signaling (MAVS) protein compositions and methods of using the same |
WO2018075980A1 (en) | 2016-10-21 | 2018-04-26 | Modernatx, Inc. | Human cytomegalovirus vaccine |
EP3532094A1 (en) | 2016-10-26 | 2019-09-04 | CureVac AG | Lipid nanoparticle mrna vaccines |
WO2018089540A1 (en) | 2016-11-08 | 2018-05-17 | Modernatx, Inc. | Stabilized formulations of lipid nanoparticles |
WO2018096179A1 (en) | 2016-11-28 | 2018-05-31 | Curevac Ag | Method for purifying rna |
CN110177544A (zh) | 2016-11-29 | 2019-08-27 | 普尔泰克健康有限公司 | 用于递送治疗剂的外泌体 |
CN106496589B (zh) * | 2016-11-30 | 2019-05-17 | 南方医科大学 | 一种两性羧酸三维金属配位聚合物及其制备方法和应用 |
MA50335A (fr) | 2016-12-08 | 2020-08-19 | Modernatx Inc | Vaccins à acide nucléique contre des virus respiratoires |
WO2018104540A1 (en) | 2016-12-08 | 2018-06-14 | Curevac Ag | Rnas for wound healing |
CN110582304A (zh) | 2016-12-08 | 2019-12-17 | 库尔维科公司 | 用于治疗或预防肝脏疾病的rna |
WO2018115527A2 (en) | 2016-12-23 | 2018-06-28 | Curevac Ag | Mers coronavirus vaccine |
EP3558354A1 (en) | 2016-12-23 | 2019-10-30 | CureVac AG | Lassa virus vaccine |
EP3558355A2 (en) | 2016-12-23 | 2019-10-30 | CureVac AG | Henipavirus vaccine |
WO2018141371A1 (en) | 2017-01-31 | 2018-08-09 | Curevac Ag | Purification and/or formulation of rna |
EP3582790A4 (en) | 2017-02-16 | 2020-11-25 | ModernaTX, Inc. | VERY POWERFUL IMMUNOGENIC COMPOSITIONS |
PE20200735A1 (es) | 2017-02-28 | 2020-07-23 | Sanofi Sa | Arn terapeutico |
CA3055653A1 (en) | 2017-03-15 | 2018-09-20 | Modernatx, Inc. | Lipid nanoparticle formulation |
RS63953B1 (sr) | 2017-03-15 | 2023-02-28 | Modernatx Inc | Jedinjenje i kompozicije za intracelularnu isporuku terapeutskih sredstava |
US20200030432A1 (en) | 2017-03-17 | 2020-01-30 | Modernatx, Inc. | Zoonotic disease rna vaccines |
EP3601576A1 (en) | 2017-03-24 | 2020-02-05 | CureVac AG | Nucleic acids encoding crispr-associated proteins and uses thereof |
WO2018191657A1 (en) | 2017-04-13 | 2018-10-18 | Acuitas Therapeutics, Inc. | Lipids for delivery of active agents |
US11660332B2 (en) | 2017-04-27 | 2023-05-30 | The Trustees Of The University Of Pennsylvania | Nucleoside-modified mRNA-lipid nanoparticle lineage vaccine for hepatitis C virus |
AU2018256877B2 (en) | 2017-04-28 | 2022-06-02 | Acuitas Therapeutics, Inc. | Novel carbonyl lipids and lipid nanoparticle formulations for delivery of nucleic acids |
US20210198200A1 (en) | 2017-06-14 | 2021-07-01 | Modernatx, Inc. | Compounds and compositions for intracellular delivery of agents |
US11786607B2 (en) | 2017-06-15 | 2023-10-17 | Modernatx, Inc. | RNA formulations |
WO2018232217A1 (en) | 2017-06-16 | 2018-12-20 | William Marsh Rice University | Hydrogel delivery of sting immunotherapy for treatment of cancer |
CN111328287A (zh) | 2017-07-04 | 2020-06-23 | 库瑞瓦格股份公司 | 新型核酸分子 |
WO2019036008A1 (en) | 2017-08-16 | 2019-02-21 | Acuitas Therapeutics, Inc. | LIPIDS FOR USE IN LIPID NANOPARTICULAR FORMULATIONS |
US11542225B2 (en) | 2017-08-17 | 2023-01-03 | Acuitas Therapeutics, Inc. | Lipids for use in lipid nanoparticle formulations |
US11524932B2 (en) | 2017-08-17 | 2022-12-13 | Acuitas Therapeutics, Inc. | Lipids for use in lipid nanoparticle formulations |
US20200362382A1 (en) | 2017-08-18 | 2020-11-19 | Modernatx, Inc. | Methods of preparing modified rna |
EP3673069A1 (en) | 2017-08-22 | 2020-07-01 | CureVac AG | Bunyavirales vaccine |
AU2018326799A1 (en) | 2017-08-31 | 2020-02-27 | Modernatx, Inc. | Methods of making lipid nanoparticles |
WO2019051642A1 (zh) * | 2017-09-12 | 2019-03-21 | 广州中科蓝华生物科技有限公司 | 一种转染细胞内寄生虫的试剂盒及其应用 |
US10653767B2 (en) | 2017-09-14 | 2020-05-19 | Modernatx, Inc. | Zika virus MRNA vaccines |
WO2019077001A1 (en) | 2017-10-19 | 2019-04-25 | Curevac Ag | NEW ARTIFICIAL NUCLEIC ACID MOLECULES |
WO2019092153A1 (en) | 2017-11-08 | 2019-05-16 | Curevac Ag | Rna sequence adaptation |
EP3723796A1 (en) | 2017-12-13 | 2020-10-21 | CureVac AG | Flavivirus vaccine |
WO2019122371A1 (en) | 2017-12-21 | 2019-06-27 | Curevac Ag | Linear double stranded dna coupled to a single support or a tag and methods for producing said linear double stranded dna |
WO2019204743A1 (en) | 2018-04-19 | 2019-10-24 | Checkmate Pharmaceuticals, Inc. | Synthetic rig-i-like receptor agonists |
WO2020002598A1 (en) | 2018-06-28 | 2020-01-02 | Curevac Ag | Bioreactor for rna in vitro transcription |
JP7410135B2 (ja) | 2018-09-19 | 2024-01-09 | モデルナティエックス インコーポレイテッド | 治療薬の細胞内送達のための化合物及び組成物 |
US20210378980A1 (en) | 2018-09-20 | 2021-12-09 | Modernatx, Inc. | Preparation of lipid nanoparticles and methods of administration thereof |
WO2020160430A1 (en) | 2019-01-31 | 2020-08-06 | Modernatx, Inc. | Vortex mixers and associated methods, systems, and apparatuses thereof |
CN113939282A (zh) | 2019-01-31 | 2022-01-14 | 摩登纳特斯有限公司 | 制备脂质纳米颗粒的方法 |
US11351242B1 (en) | 2019-02-12 | 2022-06-07 | Modernatx, Inc. | HMPV/hPIV3 mRNA vaccine composition |
KR102264536B1 (ko) * | 2019-06-07 | 2021-06-15 | 가톨릭대학교 산학협력단 | 안정화된 핵산 면역증강제를 함유하는 약학 조성물 |
CN110483706B (zh) * | 2019-07-11 | 2021-10-12 | 江苏大学 | 一种基于寡核苷酸双亲性温敏性嵌段聚合物双功能荧光探针的制备方法及应用 |
CA3144902A1 (en) * | 2019-08-14 | 2022-01-19 | Andreas Thess | Rna combinations and compositions with decreased immunostimulatory properties |
AU2020407285A1 (en) | 2019-12-20 | 2022-08-11 | CureVac SE | Lipid nanoparticles for delivery of nucleic acids |
US11576966B2 (en) | 2020-02-04 | 2023-02-14 | CureVac SE | Coronavirus vaccine |
US11241493B2 (en) | 2020-02-04 | 2022-02-08 | Curevac Ag | Coronavirus vaccine |
CA3178455A1 (en) | 2020-04-09 | 2021-10-14 | Suzhou Abogen Biosciences Co., Ltd. | Lipid nanoparticle composition |
WO2021204179A1 (en) | 2020-04-09 | 2021-10-14 | Suzhou Abogen Biosciences Co., Ltd. | Nucleic acid vaccines for coronavirus |
WO2022002040A1 (en) | 2020-06-30 | 2022-01-06 | Suzhou Abogen Biosciences Co., Ltd. | Lipid compounds and lipid nanoparticle compositions |
EP4182297A1 (en) | 2020-07-16 | 2023-05-24 | Acuitas Therapeutics, Inc. | Cationic lipids for use in lipid nanoparticles |
CN111920946B (zh) * | 2020-08-07 | 2021-05-28 | 合肥诺为尔基因科技服务有限公司 | 环二核苷酸修饰铝纳米粒疫苗佐剂-传递系统及基于其的SARS-CoV-2亚单位疫苗 |
JP2023537887A (ja) | 2020-08-20 | 2023-09-06 | スージョウ・アボジェン・バイオサイエンシズ・カンパニー・リミテッド | 脂質化合物及び脂質ナノ粒子組成物 |
US11406703B2 (en) | 2020-08-25 | 2022-08-09 | Modernatx, Inc. | Human cytomegalovirus vaccine |
EP4208286A1 (en) | 2020-09-01 | 2023-07-12 | CureVac RNA Printer GmbH | Manufacturing device for a pharmaceutical product |
KR20230121791A (ko) * | 2020-12-17 | 2023-08-21 | 새미-사빈사 그룹 리미티드 | 섬유아세포-유사 활막세포 매개된 류마티스 관절염의효과적인 관리를 위한 조성물 |
CA3205569A1 (en) | 2020-12-22 | 2022-06-30 | CureVac SE | Rna vaccine against sars-cov-2 variants |
WO2022152141A2 (en) | 2021-01-14 | 2022-07-21 | Suzhou Abogen Biosciences Co., Ltd. | Polymer conjugated lipid compounds and lipid nanoparticle compositions |
WO2022152109A2 (en) | 2021-01-14 | 2022-07-21 | Suzhou Abogen Biosciences Co., Ltd. | Lipid compounds and lipid nanoparticle compositions |
WO2022207862A2 (en) | 2021-03-31 | 2022-10-06 | Curevac Ag | Syringes containing pharmaceutical compositions comprising rna |
EP4334446A1 (en) | 2021-05-03 | 2024-03-13 | CureVac SE | Improved nucleic acid sequence for cell type specific expression |
KR20240013087A (ko) | 2021-05-24 | 2024-01-30 | 쑤저우 아보젠 바이오사이언시스 컴퍼니 리미티드 | 지질 화합물 및 지질 나노입자 조성물 |
EP4362984A1 (en) | 2021-07-02 | 2024-05-08 | Yale University | Compositions and methods for treating cancers |
WO2023034864A1 (en) | 2021-08-31 | 2023-03-09 | Yale University | Compositions and methods for treating cancers |
IL309505A (en) | 2021-09-03 | 2024-02-01 | CureVac SE | Lipid nanoparticles for nucleic acid delivery |
AU2022336664A1 (en) | 2021-09-03 | 2024-01-18 | CureVac SE | Novel lipid nanoparticles for delivery of nucleic acids comprising phosphatidylserine |
WO2023044343A1 (en) | 2021-09-14 | 2023-03-23 | Renagade Therapeutics Management Inc. | Acyclic lipids and methods of use thereof |
CA3232386A1 (en) | 2021-09-14 | 2023-03-23 | Renagade Therapeutics Management Inc. | Cyclic lipids and methods of use thereof |
AU2022358824A1 (en) | 2021-10-08 | 2024-04-11 | Suzhou Abogen Biosciences Co., Ltd. | Lipid compounds and lipid nanoparticle compositions |
AR127312A1 (es) | 2021-10-08 | 2024-01-10 | Suzhou Abogen Biosciences Co Ltd | Compuestos lipídicos ycomposiciones de nanopartículas lipídicas |
CN116064598B (zh) | 2021-10-08 | 2024-03-12 | 苏州艾博生物科技有限公司 | 冠状病毒的核酸疫苗 |
WO2023116804A1 (zh) | 2021-12-23 | 2023-06-29 | 苏州艾博生物科技有限公司 | 脂质化合物和脂质纳米颗粒组合物 |
WO2023122752A1 (en) | 2021-12-23 | 2023-06-29 | Renagade Therapeutics Management Inc. | Constrained lipids and methods of use thereof |
CN114344278B (zh) * | 2022-01-19 | 2023-06-06 | 南京吉迈生物技术有限公司 | 核酸递送载体及其应用 |
WO2023168352A1 (en) | 2022-03-03 | 2023-09-07 | Yale University | Humanized 3e10 antibodies, variants, and antigen binding fragments thereof |
WO2023196931A1 (en) | 2022-04-07 | 2023-10-12 | Renagade Therapeutics Management Inc. | Cyclic lipids and lipid nanoparticles (lnp) for the delivery of nucleic acids or peptides for use in vaccinating against infectious agents |
WO2024011033A1 (en) | 2022-07-07 | 2024-01-11 | The United States Of America, As Represented By The Secretary, Department Of Health And Human Services | Immunogens and methods for inducing an immune response |
WO2024037578A1 (en) | 2022-08-18 | 2024-02-22 | Suzhou Abogen Biosciences Co., Ltd. | Composition of lipid nanoparticles |
CN116478410B (zh) * | 2023-06-20 | 2023-09-12 | 觅投克(北京)生物医学技术有限公司 | 一种菊糖修饰的聚乙烯亚胺衍生物及其制备方法和应用 |
Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN1235609A (zh) * | 1996-10-30 | 1999-11-17 | 艾奥华大学研究基金会 | 免疫刺激性核酸分子 |
WO2005042018A2 (en) * | 2003-10-30 | 2005-05-12 | Coley Pharmaceutical Gmbh | C-class oligonucleotide analogs with enhanced immunostimulatory potency |
WO2005097993A2 (en) * | 2004-02-19 | 2005-10-20 | Coley Pharmaceutical Group, Inc. | Immunostimulatory viral rna oligonucleotides |
Family Cites Families (96)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US3906092A (en) | 1971-11-26 | 1975-09-16 | Merck & Co Inc | Stimulation of antibody response |
US4500707A (en) | 1980-02-29 | 1985-02-19 | University Patents, Inc. | Nucleosides useful in the preparation of polynucleotides |
US5132418A (en) | 1980-02-29 | 1992-07-21 | University Patents, Inc. | Process for preparing polynucleotides |
US4458066A (en) | 1980-02-29 | 1984-07-03 | University Patents, Inc. | Process for preparing polynucleotides |
US4668777A (en) | 1981-03-27 | 1987-05-26 | University Patents, Inc. | Phosphoramidite nucleoside compounds |
US4415732A (en) | 1981-03-27 | 1983-11-15 | University Patents, Inc. | Phosphoramidite compounds and processes |
US4973679A (en) | 1981-03-27 | 1990-11-27 | University Patents, Inc. | Process for oligonucleo tide synthesis using phosphormidite intermediates |
US4373071A (en) | 1981-04-30 | 1983-02-08 | City Of Hope Research Institute | Solid-phase synthesis of polynucleotides |
US4401796A (en) | 1981-04-30 | 1983-08-30 | City Of Hope Research Institute | Solid-phase synthesis of polynucleotides |
DE3314999A1 (de) | 1983-04-26 | 1985-03-14 | Behringwerke Ag, 3550 Marburg | Verwendung des diterpen-derivates forskolin zur immunstimulation |
US5153319A (en) | 1986-03-31 | 1992-10-06 | University Patents, Inc. | Process for preparing polynucleotides |
US5663163A (en) | 1987-09-07 | 1997-09-02 | Fujisawa Pharmaceutical Co., Ltd. | Cephem compounds and processes for preparation thereof |
CA1320446C (en) | 1988-06-20 | 1993-07-20 | William A. Carter | Modulation of lymphokine-resistant cellular states by dsrnas |
US5262530A (en) | 1988-12-21 | 1993-11-16 | Applied Biosystems, Inc. | Automated system for polynucleotide synthesis and purification |
US5047524A (en) | 1988-12-21 | 1991-09-10 | Applied Biosystems, Inc. | Automated system for polynucleotide synthesis and purification |
ATE147630T1 (de) | 1989-10-11 | 1997-02-15 | Hem Pharma Corp | Schutz gegen schock infolge einer schädigung durch doppelsträngige rna's |
JPH08508714A (ja) | 1993-01-25 | 1996-09-17 | ハイブライドン インコーポレイテッド | オリゴヌクレオチド・アルキルホスホネートおよびアルキルホスホノチオエート |
CA2153243A1 (en) | 1993-01-27 | 1994-08-18 | Harold E. Selick | Compositions and methods for transdermal drug delivery |
US5516652A (en) | 1993-10-06 | 1996-05-14 | Merck Frosst Canada Inc. | DNA encoding prostaglandin receptor IP |
JP3482209B2 (ja) | 1994-03-18 | 2003-12-22 | ジェロン・コーポレーション | オリゴヌクレオチドn3’→p5’ホスホルアミデート:合成および化合物;ハイブリダイゼーションおよびヌクレアーゼ耐性特性 |
WO1995026204A1 (en) | 1994-03-25 | 1995-10-05 | Isis Pharmaceuticals, Inc. | Immune stimulation by phosphorothioate oligonucleotide analogs |
US5874560A (en) | 1994-04-22 | 1999-02-23 | The United States Of America As Represented By The Department Of Health And Human Services | Melanoma antigens and their use in diagnostic and therapeutic methods |
US6239116B1 (en) | 1994-07-15 | 2001-05-29 | University Of Iowa Research Foundation | Immunostimulatory nucleic acid molecules |
EP1167379A3 (en) | 1994-07-15 | 2004-09-08 | University Of Iowa Research Foundation | Immunomodulatory oligonucleotides |
US5700642A (en) | 1995-05-22 | 1997-12-23 | Sri International | Oligonucleotide sizing using immobilized cleavable primers |
US6689757B1 (en) | 1996-02-12 | 2004-02-10 | M.L. Laboratories Plc | Methods for vaccination and vaccines therefor |
US6090391A (en) | 1996-02-23 | 2000-07-18 | Aviron | Recombinant tryptophan mutants of influenza |
EP1537877A3 (en) | 1996-10-11 | 2005-08-03 | The Regents Of The University Of California | Immunostimulatory polynucleotide/immunomodulatory molecule conjugates |
EP0839912A1 (en) | 1996-10-30 | 1998-05-06 | Instituut Voor Dierhouderij En Diergezondheid (Id-Dlo) | Infectious clones of RNA viruses and vaccines and diagnostic assays derived thereof |
EP0855184A1 (en) | 1997-01-23 | 1998-07-29 | Grayson B. Dr. Lipford | Pharmaceutical composition comprising a polynucleotide and an antigen especially for vaccination |
US6406705B1 (en) | 1997-03-10 | 2002-06-18 | University Of Iowa Research Foundation | Use of nucleic acids containing unmethylated CpG dinucleotide as an adjuvant |
EP1374894A3 (en) | 1997-06-06 | 2004-09-22 | Dynavax Technologies Corporation | Immunostimulatory oligonucleotides, compositions thereof and methods of use thereof |
US20040006034A1 (en) | 1998-06-05 | 2004-01-08 | Eyal Raz | Immunostimulatory oligonucleotides, compositions thereof and methods of use thereof |
US6589940B1 (en) | 1997-06-06 | 2003-07-08 | Dynavax Technologies Corporation | Immunostimulatory oligonucleotides, compositions thereof and methods of use thereof |
EP1872786A1 (en) | 1997-09-05 | 2008-01-02 | The Regents of the University of California | Use of immunostimulatory oligonucleotides for preventing or reducing antigen-stimulated, granulocyte-mediated inflammation |
US6096307A (en) | 1997-12-11 | 2000-08-01 | A. Glenn Braswell | Compositions for immunostimulation containing Echinacea angustofolia, bromelain, and lysozyme |
ATE356630T1 (de) | 1998-04-03 | 2007-04-15 | Univ Iowa Res Found | Verfahren und produkte zur stimulierung des immunsystems mittels immunotherapeutischer oligonukleotide und zytokine |
AU3758199A (en) | 1998-04-23 | 1999-11-08 | Regents Of The University Of Michigan, The | Peptides for efficient gene transfer |
GB9912432D0 (en) * | 1999-05-27 | 1999-07-28 | Angeletti P Ist Richerche Bio | Novel gbv sequence |
WO2000075304A1 (fr) | 1999-06-08 | 2000-12-14 | Aventis Pasteur | Oligonucleotide immunostimulant |
US6514948B1 (en) | 1999-07-02 | 2003-02-04 | The Regents Of The University Of California | Method for enhancing an immune response |
AU6097100A (en) | 1999-07-13 | 2001-01-30 | Regents Of The University Of Michigan, The | Crosslinked dna condensate compositions and gene delivery methods |
AU6389000A (en) * | 1999-07-28 | 2001-02-19 | Valentis, Inc. | Sonoporation of tumors |
ATE289630T1 (de) | 1999-09-09 | 2005-03-15 | Curevac Gmbh | Transfer von mrnas unter verwendung von polykationischen verbindungen |
US6552006B2 (en) | 2000-01-31 | 2003-04-22 | The Regents Of The University Of California | Immunomodulatory polynucleotides in treatment of an infection by an intracellular pathogen |
EP2345742B1 (en) | 2000-03-30 | 2014-06-11 | The Whitehead Institute for Biomedical Research | RNA sequence-specific mediators of RNA interference |
WO2001093902A2 (en) | 2000-06-07 | 2001-12-13 | Biosynexus Incorporated | Immunostimulatory rna/dna hybrid molecules |
AU7013401A (en) | 2000-06-22 | 2002-01-02 | Univ Iowa Res Found | Methods for enhancing antibody-induced cell lysis and treating cancer |
CN1298738C (zh) | 2000-06-23 | 2007-02-07 | 惠氏控股有限公司 | 修饰的麻疹病毒v蛋白 |
US6376704B1 (en) | 2000-06-28 | 2002-04-23 | 3M Innovative Properties Company | Naphthyoxyalkyl(meth)acrylates with high refractive indices and low glass transition temperatures |
US6716434B1 (en) | 2000-09-19 | 2004-04-06 | Daniel R. Ansley | Composition and method for immunostimulation in non- mammalian vertebrates |
GB0025577D0 (en) | 2000-10-18 | 2000-12-06 | Smithkline Beecham Biolog | Vaccine |
AU2002303214A1 (en) | 2001-04-02 | 2002-10-15 | University Of South Florida | Lps-responsive chs1/beige-like anchor gene and therapeutic applications thereof |
EP1800697B1 (de) | 2001-06-05 | 2010-04-14 | CureVac GmbH | Stabilisierte mRNA mit erhöhtem G/C-Gehalt für die Gentherapie |
US7785610B2 (en) | 2001-06-21 | 2010-08-31 | Dynavax Technologies Corporation | Chimeric immunomodulatory compounds and methods of using the same—III |
AR045702A1 (es) | 2001-10-03 | 2005-11-09 | Chiron Corp | Composiciones de adyuvantes. |
DE10148886A1 (de) | 2001-10-04 | 2003-04-30 | Avontec Gmbh | Inhibition von STAT-1 |
US7276489B2 (en) | 2002-10-24 | 2007-10-02 | Idera Pharmaceuticals, Inc. | Modulation of immunostimulatory properties of oligonucleotide-based compounds by optimal presentation of 5′ ends |
WO2003035836A2 (en) | 2001-10-24 | 2003-05-01 | Hybridon Inc. | Modulation of immunostimulatory properties of oligonucleotide-based compounds by optimal presentation of 5' ends |
DE10162480A1 (de) | 2001-12-19 | 2003-08-07 | Ingmar Hoerr | Die Applikation von mRNA für den Einsatz als Therapeutikum gegen Tumorerkrankungen |
WO2003059381A2 (en) | 2002-01-18 | 2003-07-24 | Curevac Gmbh | Immunogenic preparations and vaccines on the basis of mrna |
AU2003203079B8 (en) | 2002-02-04 | 2009-01-15 | Oncothyreon Inc. | Immunostimulatory, covalently lipidated oligonucleotides |
DK1487493T3 (da) | 2002-03-01 | 2010-05-25 | Univ Tulane | Konjugater af cytotoksiske midler og biologisk aktive peptider |
NZ535952A (en) | 2002-04-04 | 2009-01-31 | Coley Pharm Gmbh | Immunostimulatory G,U-containing oligoribonucleotides |
DE10229872A1 (de) | 2002-07-03 | 2004-01-29 | Curevac Gmbh | Immunstimulation durch chemisch modifizierte RNA |
EP1393745A1 (en) | 2002-07-29 | 2004-03-03 | Hybridon, Inc. | Modulation of immunostimulatory properties of oligonucleotide-based compounds by optimal presentation of 5'ends |
EP1625140A4 (en) | 2002-12-23 | 2008-06-18 | Dynavax Tech Corp | BRANCHED IMMUNOMODULAR COMPOUNDS AND METHOD OF USE THEREOF |
CA2512484A1 (en) | 2003-01-16 | 2004-05-08 | Hybridon, Inc. | Modulation of immunostimulatory properties of oligonucleotide-based compounds by utilizing modified immunostimulatory dinucleotides |
CA2522213A1 (en) | 2003-04-08 | 2004-10-28 | Dante J. Marciani | Semi-synthetic saponin analogs with carrier and immune stimulatory activities for dna and rna vaccines |
CA2521662A1 (en) | 2003-04-10 | 2005-01-06 | 3M Innovative Properties Company | Methods and compositions for enhancing immune response |
EP1641820B1 (en) | 2003-06-30 | 2008-05-28 | Université de Lausanne | Rasgap derived peptide for selectively killing cancer cells |
WO2005030800A2 (en) | 2003-08-05 | 2005-04-07 | Avi Biopharma, Inc. | Oligonucleotide analog and method for treating flavivirus infections |
JP4989225B2 (ja) | 2003-09-25 | 2012-08-01 | コーリー ファーマシューティカル グループ,インコーポレイテッド | 核酸親油性接合体 |
RU2006116569A (ru) * | 2003-10-16 | 2007-11-27 | Дзе Юниверсити Корт Оф Дзе Юниверсити Оф Эдинбург(Gb) | Улучшенный контроль самоподдержания линейной спецификации es-клеток и их среды |
CA2549173A1 (en) | 2003-12-08 | 2005-07-07 | Hybridon, Inc. | Modulation of immunostimulatory properties by small oligonucleotide-based compounds |
CA2572439A1 (en) | 2004-07-02 | 2006-01-12 | Protiva Biotherapeutics, Inc. | Immunostimulatory sirna molecules and uses therefor |
DE102004042546A1 (de) | 2004-09-02 | 2006-03-09 | Curevac Gmbh | Kombinationstherapie zur Immunstimulation |
WO2006029223A2 (en) | 2004-09-08 | 2006-03-16 | Children's Medical Center Corporation | Method for stimulating the immune response of newborns |
US20060241076A1 (en) * | 2005-04-26 | 2006-10-26 | Coley Pharmaceutical Gmbh | Modified oligoribonucleotide analogs with enhanced immunostimulatory activity |
US8076068B2 (en) | 2005-09-14 | 2011-12-13 | Gunther Hartmann | Method for determining immunostimulatory activity of RNA oligonucleotides |
CN101321868A (zh) | 2005-09-16 | 2008-12-10 | 科利制药公司 | 通过核苷酸修饰调节短干扰核糖核酸(siRNA)的免疫刺激特性 |
KR20080065656A (ko) * | 2005-10-12 | 2008-07-14 | 캔써 리서치 테크놀로지 리미티드 | 면역질환을 치료하기 위한 방법 및 조성물 |
CA2628300C (en) * | 2005-11-02 | 2018-04-17 | Protiva Biotherapeutics, Inc. | Modified sirna molecules and uses thereof |
US7470674B2 (en) | 2005-11-07 | 2008-12-30 | Idera Pharmaceuticals, Inc. | Immunostimulatory properties of oligonucleotide-based compounds comprising modified immunostimulatory dinucleotides |
US7662949B2 (en) * | 2005-11-25 | 2010-02-16 | Coley Pharmaceutical Gmbh | Immunostimulatory oligoribonucleotides |
DE102006007433A1 (de) | 2006-02-17 | 2007-08-23 | Curevac Gmbh | Adjuvanz in Form einer Lipid-modifizierten Nukleinsäure |
WO2007124755A1 (en) | 2006-05-02 | 2007-11-08 | The Antibody Project Aps | Method for immunizing an avian species |
AU2007280690C1 (en) * | 2006-07-31 | 2012-08-23 | Curevac Gmbh | Nucleic acid of formula (I): GIXmGn, or (II): CIXmCn, in particular as an immune-stimulating agent/adjuvant |
DE102006035618A1 (de) | 2006-07-31 | 2008-02-07 | Curevac Gmbh | Nukleinsäure der Formel (I): GlXmGn, insbesondere als immunstimulierendes Adjuvanz |
KR20090058584A (ko) * | 2006-10-26 | 2009-06-09 | 콜리 파마슈티칼 게엠베하 | 올리고리보뉴클레오티드 및 그의 용도 |
WO2009030254A1 (en) | 2007-09-04 | 2009-03-12 | Curevac Gmbh | Complexes of rna and cationic peptides for transfection and for immunostimulation |
WO2009053700A1 (en) | 2007-10-23 | 2009-04-30 | Cancer Research Technology Limited | Modification of nucleic acid-containing biological entities |
EP2247308A4 (en) | 2008-01-10 | 2012-04-18 | Nventa Biopharmaceuticals Corp | ADJUVANT COMPOSITIONS COMPRISING POLY-IC AND CATIONIC POLYMER |
EP3346005A1 (en) * | 2008-01-31 | 2018-07-11 | CureVac AG | Nucleic acids of formula (i) (nuglxmgnnv)a and derivatives thereof as an immunostimulating agent/adjuvant |
WO2010037408A1 (en) * | 2008-09-30 | 2010-04-08 | Curevac Gmbh | Composition comprising a complexed (m)rna and a naked mrna for providing or enhancing an immunostimulatory response in a mammal and uses thereof |
WO2012113413A1 (en) * | 2011-02-21 | 2012-08-30 | Curevac Gmbh | Vaccine composition comprising complexed immunostimulatory nucleic acids and antigens packaged with disulfide-linked polyethyleneglycol/peptide conjugates |
-
2009
- 2009-01-28 EP EP17205028.8A patent/EP3346005A1/en not_active Withdrawn
- 2009-01-28 JP JP2010544630A patent/JP5721441B2/ja active Active
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- 2009-01-28 RU RU2010135630/10A patent/RU2545701C2/ru active
- 2009-01-28 EP EP12004156.1A patent/EP2548960B1/en active Active
- 2009-01-28 HU HUE09705604A patent/HUE025027T2/en unknown
- 2009-01-28 DK DK09705604.8T patent/DK2176408T5/en active
- 2009-01-28 PT PT97056048T patent/PT2176408E/pt unknown
- 2009-01-28 CN CN2009801037284A patent/CN101932707B/zh not_active Expired - Fee Related
- 2009-01-28 WO PCT/EP2009/000546 patent/WO2009095226A2/en active Application Filing
- 2009-01-28 BR BRPI0907087-7A patent/BRPI0907087B1/pt not_active IP Right Cessation
- 2009-01-28 AU AU2009210266A patent/AU2009210266B2/en not_active Ceased
- 2009-01-28 MX MX2010008468A patent/MX2010008468A/es active IP Right Grant
- 2009-01-28 KR KR1020107017901A patent/KR101483715B1/ko active IP Right Grant
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- 2009-01-28 ES ES09705604.8T patent/ES2537703T3/es active Active
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- 2009-01-28 US US12/672,442 patent/US9226959B2/en active Active
- 2009-01-28 EP EP09705604.8A patent/EP2176408B9/en active Active
-
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- 2015-05-18 HR HRP20150528T patent/HRP20150528T2/hr unknown
- 2015-11-30 US US14/954,363 patent/US20160250321A1/en not_active Abandoned
-
2019
- 2019-08-15 US US16/541,376 patent/US20200085942A1/en not_active Abandoned
-
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- 2022-06-29 US US17/809,680 patent/US20220401555A1/en active Pending
Patent Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN1235609A (zh) * | 1996-10-30 | 1999-11-17 | 艾奥华大学研究基金会 | 免疫刺激性核酸分子 |
WO2005042018A2 (en) * | 2003-10-30 | 2005-05-12 | Coley Pharmaceutical Gmbh | C-class oligonucleotide analogs with enhanced immunostimulatory potency |
WO2005097993A2 (en) * | 2004-02-19 | 2005-10-20 | Coley Pharmaceutical Group, Inc. | Immunostimulatory viral rna oligonucleotides |
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