CN102123733A - 用于提供或增强哺乳动物中免疫刺激应答的包含复合(m)RNA和裸(m)RNA的组合物及其应用 - Google Patents
用于提供或增强哺乳动物中免疫刺激应答的包含复合(m)RNA和裸(m)RNA的组合物及其应用 Download PDFInfo
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Abstract
本发明涉及免疫刺激组合物,其包含a)佐剂成分,其包括或由至少一种(m)RNA组成,所述(m)RNA与阳离子或聚阳离子化合物复合,和b)至少一种游离mRNA,其编码至少一种治疗活性蛋白,抗原,过敏原和/或抗体,其中所述免疫刺激组合物能够引起或增强哺乳动物中的先天性和任选地适应性免疫应答。本发明的免疫刺激组合物可以是药物组合物或疫苗。本发明还涉及制备本发明的免疫刺激组合物的方法。本发明还涉及本发明的免疫刺激组合物或其成分用于治疗多种疾病(用于制备用于治疗多种疾病的药物组合物或疫苗)的用途。最后,本发明还涉及包含本发明的免疫刺激组合物,其成分和/或所述药物组合物或疫苗的试剂盒。
Description
本发明涉及免疫刺激组合物,其包含a)佐剂成分,其包括或由至少一种(m)RNA组成,所述(m)RNA与阳离子或聚阳离子化合物复合,和b)至少一种游离mRNA,其编码至少一种治疗活性蛋白、抗原、过敏原和/或抗体,其中所述免疫刺激组合物能够引起或增强哺乳动物中的先天性和任选地适应性免疫应答。本发明的免疫刺激组合物可以是药物组合或疫苗。本发明进一步涉及制备本发明的免疫刺激组合物的方法。本发明还涉及本发明的免疫刺激组合物或其成分用于治疗多种疾病(用于制备用于治疗多种疾病的药物组合或疫苗)的应用。最后,本发明涉及含有本发明的免疫刺激组合物、其成分和/或所述药物组合物或疫苗的试剂盒。
先天性和/或适应性免疫系统的免疫应答的诱导和/或增强在治疗和预防多种疾病中起重要作用。为了该目的,典型通过例如施用免疫刺激剂或佐剂来调节免疫系统。然而,脊椎动物诸如人的免疫系统非常复杂且受到精细调节。其由许多类型的蛋白、细胞、器官和组织组成,它们在精细和动态网络中相互作用。免疫系统典型地使用特异性逐渐增加的分层防御来保护这些生物体免受感染。一层防御包括物理或化学屏障并容许至少一些病原体和抗原的推测的(priori)消除。另一层防御包括先天性和适应性免疫系统。
先天性免疫系统,作为免疫系统的一部分,是大多数生物体中主要的宿主防御系统并包括屏障诸如体液屏障和化学屏障包括,例如,发炎、补体系统和细胞屏障。先天性免疫系统典型地基于少量受体,称为模式识别受体。它们识别保守的分子模式,所述分子模式将外源生物体,如病毒、细菌、真菌和寄生虫与它们的宿主的细胞相区分。这样的病原体相关分子模式包括病毒核酸、细菌和真菌壁成分、鞭毛蛋白,以及更多。
详尽研究的模式识别受体的第一家族是Toll样受体(TLR)家族。TLR是跨膜蛋白,其识别胞外环境的配体或内体腔的配体。在配体结合后,它们通过胞质衔接蛋白转导信号,这导致触发宿主防御应答和引起抗微生物肽、促炎趋化因子和细胞因子、抗病毒细胞因子等的产生(参见例如Meylan,E.,J.Tschopp,等(2006).“Intracellular pattern recognition receptors in the host response(宿主应答中的胞内模式识别受体).”Nature(自然)442(7098):39-44)。迄今为止,已经在人中识别了至少10种Toll样受体成员(TLRs 1-10)并在小鼠中识别了13种(TLRs 1-13)。人中的那些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,鸟苷类似物和ssRNA),TLR9(已知配体:细菌、病毒和原生动物的CpG DNA和疟褐素(血红蛋白的消化产物))和TLR10。在识别微生物病原体后,这些TLR典型地触发胞内信号传导途径,所述途径导致诱导炎性细胞因子(例如,TNF-α,IL-6,IL-1-β和IL-12)、I型干扰素(IFN-β和多IFN-α)和趋化因子(Kawai,T.和S.Akira(2006).″TLR signaling(TLR信号传导).″Cell Death Differ(细胞死亡和分化)13(5):816-25)。
作为更复杂的脊椎动物免疫应答的一部分,免疫系统随时间适应于更有效地识别特定病原体或抗原。这些适应过程创建免疫记忆并在将来遭遇这些病原体的过程中容许甚至更有效的保护。该适应性或后天免疫性的过程形成疫苗接种策略的基础。与如上所述的先天性免疫系统相反,适应性免疫系统是抗原-特异性的且要求在称为抗原呈递过程中识别特异性“自身”或“非自身”抗原。此外,与以种属方式识别和应答病原体的先天性免疫系统的细胞不同,适应性免疫系统对宿主赋予持久的或保护性免疫并由此容许针对特异性病原体、病原体感染细胞或抗原的更特定应答。建立这些特定应答的能力通过所谓的“记忆细胞”保持在体内。如果抗原或病原体进入/感染身体超过一次,则这些特异性记忆细胞用于快速消除它们。适应性免疫系统由此容许更强的免疫应答以及免疫记忆,其中有利于特定疾病可能有不同的免疫应答。例如,在感染的情形中,各种病原体通过标志(signature)抗原来“记忆”,而在癌症情形中,肿瘤抗原或自身抗原可以通过适应性免疫系统来识别和中和。
脊椎动物中的适应性免疫系统的主要成分在细胞水平上主要包括淋巴细胞且在分子水平上主要包括抗体。作为适应性免疫系统的细胞成分的淋巴细胞包括源自骨髓中造血干细胞的B细胞和T细胞。B细胞参与体液应答,而T细胞参与细胞介导的免疫应答。B细胞和T细胞均携带识别特异性靶标的受体分子。T细胞仅在抗原(例如病原体的小片段)已经在与称为主要组织相容性复合物(MHC)分子的“自身”受体结合的条件下加工和呈递后,识别“非自身”靶标,诸如病原体靶标结构。相反,B细胞抗原特异性受体是B细胞表面上的抗体分子,并在其表面上的抗体结合特异性外源抗原时照此识别病原体。这种抗原/抗体复合物被B细胞吸收并通过蛋白水解加工为肽。B细胞然后在其表面MHC II型分子上展示这些抗原肽。这种MHC和抗原的组合吸引匹配的辅助性T细胞,这释放淋巴因子并激活B细胞。当活化的B细胞再开始分裂时,其后代分泌数百万识别该抗原的抗体拷贝。这些抗体在血浆和淋巴中循环,结合病原体或表达抗原的肿瘤细胞并对其进行标记从而通过补体活化来破坏或通过吞噬细胞来吸收和破坏。作为适应性免疫系统的细胞成分,细胞毒性T细胞(CD8+)也可以形成CTL应答。细胞毒性T细胞(CD8+)可以识别来自内源病原体和通过MHC I型分子结合的自身抗原的肽。CD8+-T细胞通过在细胞中释放细胞毒性蛋白执行其杀伤功能。
免疫系统的两种基础机制,即先天性免疫系统以及适应性免疫系统,均可以由此形成药物治疗和预防多种疾病的靶标。本领域中目前已知的合适方法利用佐剂引起先天性免疫应答或利用抗原、病原体或免疫原来引起适应性免疫应答,或在一些罕见的情形中,二者。
具体地,适应性免疫应答可以通过对细胞或宿主生物体施用如上所述采用肽或蛋白抗原形式的特异性外源抗原来引起,或抗原可以由核酸,例如cDNA或信使RNA来编码。为了引起有效的适应性免疫应答,先天性免疫系统的另外的非特异性刺激是有利的,例如当与抗原特异性信号平行地提供非特异性刺激时。平行的非特异性刺激将免疫系统转变为活化状态,这提高适应性免疫应答。能够提供这样的非特异性免疫应答的化合物典型地称为“佐剂”。现有技术中已经将许多化合物和组合物提议为佐剂,例如Freund佐剂,金属氧化物,例如明矾(氢氧化铝),无机螯合物或其盐,多种石蜡样油,合成树脂,藻酸盐,类粘蛋白,多糖化合物,酪蛋白酸盐,以及由血液和/或血块分离的化合物,诸如,例如,血纤蛋白衍生物,等。这些佐剂典型地可以与其他化合物,诸如例如蛋白,肽,DNA-或RNA-分子或其他治疗活性化合物组合使用,这取决于待获得的结果。
然而,可以编码特异性抗原或任何其他治疗活性蛋白的游离信使RNA(mRNA)分子,cDNAs或核酸一般适合于特异性治疗,典型地不表现出显著或甚至无免疫刺激性质。然而,当与肽或蛋白,诸如鱼精蛋白或核酸结合蛋白复合时,这样的免疫刺激性质可以赋予给mRNA分子、cDNA或核酸。在该上下文中,mRNA分子或核酸可以这样配制,以使得mRNA分子或核酸与肽或蛋白之间形成复合物,其中在mRNA分子或核酸与肽或蛋白之间可以形成不同的复合物。特别强的(佐剂)复合物可以在通常在中性pH下带负电的核酸与阳离子或聚阳离子肽或蛋白结合时发生
然而,当在疫苗接种方法中使用mRNA或核酸分子时,mRNA或核酸分子体内翻译保持最重要且最基本的诱导适应性免疫应答或表达通常编码蛋白的因素,例如在治疗活性蛋白或肽的情形中。因此,复合的mRNA或核酸分子将必须由与(阳离子)肽或蛋白的复合物释放,这发生在将该复合物转染到细胞中以容许mRNA的有效翻译之后。不幸地,这在大多数情形中不发生。更典型地,mRNA分子或核酸与阳离子或聚阳离子化合物复合甚至可以防止核酸翻译或至少显著地减小体内翻译速度,这归因于聚阳离子化合物与通常mRNA分子、cDNA或核酸分子的强结合。因此,使用这些化合物很难获得该组合物关于先天性免疫系统的良好免疫刺激性质,且当使用这样制剂很难平行地确保mRNA分子、cDNA或核酸分子的有效翻译。
避开以上问题的一种可能性可以是以分开的制剂施用佐剂和mRNA。然而,这致使施药更加复杂得多。还优选的是,佐剂和抗原编码mRNA进入同一细胞,以获得最佳免疫应答。此外,佐剂有益地支持适应性免疫应答的诱导,条件是该佐剂在其中由编码mRNA表达抗原的同一细胞中诱导先天性免疫应答。
避开以上问题的另一种可能性可以是排他的施用裸mRNA,cDNA或核酸。这样的方法虽然有利于mRNA,cDNA或核酸体内有效翻译的目的,但是免除由如上所述的佐剂引起的先天性免疫系统的有利活化。
因此,这些方法中没有一种是实际上令人信服的并且也不导致与施用的mRNA,cDNA或核酸的良好翻译平行的先天性免疫应答。因此,本领域中仍存在对提供容许引起先天性和任选地适应性免疫应答的有效免疫刺激组合物或方法的需要,其中施用不受mRNA无效翻译的削弱,mRNA无效翻译归因于与复合配偶体形成复合物,这赋予mRNA免疫刺激性质。换言之,本发明的目的是提供容许在哺乳动物中引起或增强先天性和任选地适应性免疫刺激应答的方法和免疫刺激组合物,由此确保有效佐剂(免疫刺激)性质和待施用的mRNA的有效翻译。
该目的通过本发明的主题,优选通过所附权利要求来解决。具体地,本发明通过免疫刺激组合物来解决以上目的,所述免疫刺激组合物包括:a)佐剂成分,其包括或由至少一种(m)RNA组成,所述(m)RNA与阳离子或聚阳离子化合物复合,和b)至少一种游离mRNA,其编码至少一种治疗活性蛋白、抗原、过敏原和/或抗体,其中所述免疫刺激组合物能够引起或增强哺乳动物中的先天性和任选地适应性免疫应答。
在本发明的上下文中,哺乳动物可以选自任何哺乳动物,优选选自包括但不仅限于,例如山羊、牛、猪、狗、猫、驴、猴、猿、啮齿动物诸如小鼠、仓鼠、兔、和特别地,人的组的哺乳动物。
本发明免疫刺激组合物的主要优点是在哺乳动物中有效引起先天性和任选地适应性免疫应答,其中至少一种编码至少一种治疗活性蛋白的游离mRNA的翻译不被佐剂成分,特别地,所述至少一种(m)RNA与阳离子或聚阳离子化合物的复合而削弱。这具体归因于这样的事实,即佐剂成分通过使用用于复合的阳离子或聚阳离子化合物形成,这典型地导致RNA和阳离子化合物之间的强复合,该阳离子化合物几乎不释放与其复合的RNA。因此,游离mRNA不再受阳离子化合物的影响,尽管在一种制剂中共同施用佐剂成分和游离mRNA也导致游离mRNA的体内转染和表达显著提高。根据本发明的溶液利用本发明的发明人的惊人发现,即免疫刺激组合物的两种性质,即有效免疫刺激性质和RNA的有效翻译,可以在同一个制剂中获得,条件是该制剂本身以两个分离的步骤制备。该溶液甚至是更令人信服的,因为它容许佐剂成分与任何游离mRNA在不通过与佐剂成分的阳离子化合物复合而失去游离mRNA的条件下混合。该溶液甚至可以在不导致复合的RNA和游离mRNA之间的平衡反应的条件下保存相当长时间。换言之,不存在形成的佐剂成分的分解,所述分解可以导致游离mRNA与佐剂成分的阳离子化合物结合并导致结合的RNA从复合物中释放。
作为第一成分,本发明的免疫刺激组合物包括所谓的“佐剂成分”,其包括或由至少一种(m)RNA组成,所述(m)RNA与阳离子或聚阳离子化合物复合。
所谓的“佐剂成分”根据第一步骤制备,所述第一步骤是通过使佐剂成分的至少一种(m)RNA与阳离子或聚阳离子化合物以特定比率复合形成稳定的复合物。在该上下文中,重要的是,在与(m)RNA复合后,无游离阳离子或聚阳离子化合物或仅可忽视的小量保持在佐剂成分中。因此,佐剂成分中(m)RNA和阳离子或聚阳离子化合物的比率典型地在这样的范围中选择,即(m)RNA完全复合和无游离阳离子或聚阳离子化合物或仅可忽视的小量保持在组合物中。优选地,佐剂成分的比率,即(m)RNA与阳离子或聚阳离子化合物的比率选自约6∶1(w/w)-约0.25∶1(w/w),更优选约5∶1(w/w)-约0.5∶1(w/w),甚至更优选约4∶1(w/w)-约1∶1(w/w)或约3∶1(w/w)-约1∶1(w/w),和最优选约3∶1(w/w)-约2∶1(w/w)的比率的范围。
此外,佐剂成分中(m)RNA与阳离子或聚阳离子化合物的比率,也可以基于整个RNA复合物的氮/磷比(N/P-比)计算。例如,1μg RNA典型地包含约3nmol磷酸残基,条件是RNA表现出统计学碱基分布。另外,1μg肽典型地包含约x nmol氮残基,这取决于碱性氨基酸的分子量和数量。当示范性计算(Arg)9(分子量1424g/mol,9个氮原子)时,1μg(Arg)9包含约700pmol(Arg)9且因此700x 9=6300pmol碱性氨基酸=6.3nmol氮原子。对于约1∶1的RNA/(Arg)9质量比,可以计算出约2的N/P比。当示范性地计算具有约2∶1质量比、具有2μg RNA的鱼精蛋白(分子量约4250g/mol,21个氮原子,当使用来自鲑鱼的鱼精蛋白时)时,关于RNA计算出6nmol磷酸;1μg鱼精蛋白包含约235pmol鱼精蛋白分子并且因此235x 21=4935pmol碱性氮原子=4.9nmol氮原子。对于约2∶1的RNA/鱼精蛋白质量比,可以计算出约0.81的N/P比。对于约8∶1的RNA/鱼精蛋白质量比,可以计算出约0.2的N/P比。在本发明的上下文中,关于该复合物中的RNA∶肽比,N/P-比优选在约0.1-10的范围内,优选在约0.3-4的范围内和最优选在约0.5-2或0.7-2的范围内,和最优选在约0.7-1.5的范围内。
在本发明的上下文中,阳离子或聚阳离子化合物优选选自任何适合于复合并由此稳定核酸,特别地至少一种(m)RNA的阳离子或聚阳离子化合物,所述稳定作为是例如通过使所述至少一种(m)RNA与阳离子或聚阳离子化合物的缔合实现的。这样的阳离子或聚阳离子化合物本身不需要展示任何佐剂性质,因为佐剂性质,特别是诱导先天性免疫应答的能力优选在至少一种(m)RNA与阳离子或聚阳离子化合物复合时产生。当至少一种(m)RNA与阳离子或聚阳离子化合物复合时。形成佐剂成分。特别优选地,阳离子或聚阳离子肽或蛋白作为成分P2可以选自鱼精蛋白,核仁蛋白,精胺或亚精胺,聚-L-赖氨酸(PLL),碱性多肽,聚-精氨酸,细胞渗透肽(CPPs),嵌合CPPs,诸如Transportan,或MPG肽,HIV结合肽,Tat,HIV-1Tat(HIV),Tat衍生的肽,寡精氨酸,穿膜肽(penetratin)家族成员,例如穿膜肽,触角足衍生肽(特别地来自果蝇触角足),pAntp,pIsl,等,抗微生物衍生的CPPs例如Buforin-2,Bac715-24,SynB,SynB(1),pVEC,hCT-衍生的肽,SAP,MAP,KALA,PpTG20,富含脯氨酸的肽,L-寡聚体,富含精氨酸的肽,降钙素肽,FGF,乳铁蛋白,聚-L-赖氨酸,聚精氨酸,组蛋白,VP22衍生肽或类似物肽,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,Pep-1,一种或多种降钙素肽等。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0,1,2,3,4,5,6,7或8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。可以用于复合以上佐剂成分的至少一种(m)RNA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:二十八烷基酰氨基甘氨酰精胺(Dioctadecylamidoglicylspermin),DIMRI:二肉豆蔻酸(myristo)-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,oligofectamine,或阳离子或聚阳离子聚合物,例如修饰的聚氨基酸,如β-氨基酸-聚合物或逆聚酰胺类,等,修饰的聚乙烯类,如PVP(聚(N-乙基-4-乙烯基溴化吡啶鎓))等,修饰的丙烯酸酯类,如pDMAEMA(聚(二甲基氨基乙基甲基丙烯酸酯)),等,修饰的酰胺胺类(amidoamines)如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,树型化合物(dendrimers),如聚丙基胺树型化合物或基于pAMAM的树型化合物,等,聚亚胺类,如PEI:聚(乙烯亚胺),聚(丙烯亚胺),等,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(例如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(例如聚乙二醇(polyethyleneglycole))的组合组成的嵌段聚合物等。本发明免疫刺激组合物的修饰的(m)RNA与阳离子或聚阳离子化合物的缔合或复合优选地为该(m)RNA提供佐剂性质并将稳定作用通过复合赋予佐剂成分的(m)RNA。用于稳定修饰的(m)RNA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。
在本发明的上下文中,本发明的免疫刺激组合物的“佐剂成分”的至少一种(m)RNA可以是任何RNA,优选,但不仅限于,短RNA寡核苷酸,编码RNA,免疫刺激性RNA,siRNA,反义RNA,或核开关(riboswitches),核酶或适体。此外,佐剂成分的至少一个(m)RNA可以是单链或双链RNA(其也可以被认为是RNA(分子),这归因于两个单链RNA(分子)的非共价结合)或至少部分自身互补的部分双链或部分单链RNA(这些部分双链或部分单链RNA分子均典型地由较长和较短的单链RNA分子或由2个基本等长的单链RNA分子形成,其中一个单链RNA分子与另一个单链RNA分子部分互补且二者由此在该区域内形成双链RNA分子,即部分双链或部分单链RNA)。优选地,“佐剂成分”的至少一种(m)RNA可以是单链RNA。此外,“佐剂成分”的至少一种(m)RNA可以是环形或线性RNA,优选是线性RNA。更优选地,“佐剂成分”的至少一种(m)RNA可以是(线性)单链RNA。“佐剂成分”的至少一种(m)RNA可以是核糖体RNA(rRNA),转运RNA(tRNA),信使RNA(mRNA),或病毒RNA(vRNA),更优选是mRNA。本发明容许全部这些RNA单独地或组合地成为本发明的组合物的“佐剂成分”的一部分。在本发明的上下文中,mRNA典型地是这样的RNA,其由若干结构部件组成,例如任选的5’-UTR区,即位于上游的核糖体结合位点及随后的编码区,任选的3’-UTR区,所述3’-UTR区后可以是聚-A尾部(和/或聚-C-尾部)。mRNA可以作为单、双或甚至多顺反子RNA,即携带1个、2个或更多蛋白质或肽的编码序列的RNA存在。二或甚至多顺反子mRNA中的这种编码序列可以由至少一个IRES序列分开,例如如上定义地。
优选地,本发明的免疫刺激组合物的佐剂成分的至少一种(m)RNA包括约5至约20,000,或100至约20,000个核苷酸,优选约250至约20,000个核苷酸,更优选约500至约10,000,甚至更优选约500至约5,000的长度,最优选约100-10,000个核苷酸的长度或约100-5,000个核苷酸的长度。
根据第一个实施方案,本发明的免疫刺激组合物的佐剂成分的至少一种(m)RNA可以是短RNA寡核苷酸。本发明上下文中的短RNA寡核苷酸可以包括任何如上定义的RNA。优选地,所述短RNA寡核苷酸可以是单链或双链RNA寡核苷酸,更优选是单链RNA寡核苷酸。甚至更优选地,所述短RNA寡核苷酸可以是线性单链RNA寡核苷酸。还优选地,如本文中使用的短RNA寡核苷酸可以包括如上通常关于RNA分子定义的长度,更优选5-100,5-50,或5-30个核苷酸的长度,和甚至更优选,20-100,20-80,或20-60个核苷酸的长度。
按照第二个实施方案,本发明的免疫刺激组合物的佐剂成分的至少一种(m)RNA可以是免疫刺激性RNA,即源自免疫刺激性RNA的RNA,其触发或增加(先天性)免疫应答。优选地,本发明的免疫刺激组合物的佐剂成分的至少一种(m)RNA可以是单链、双链或部分双链或部分单链RNA,更优选单链RNA,和/或环状或线性RNA,更优选线性RNA。更优选地,所述佐剂成分的至少一种(m)RNA可以是(线性)单链RNA。甚至更优选地,所述佐剂成分的至少一种(m)RNA可以是((线性)单链)信使RNA(mRNA)。本发明的免疫刺激组合物的佐剂成分的至少一种(m)RNA还可以作为如上定义的短RNA寡核苷酸存在。本发明的免疫刺激组合物的佐剂成分的至少一种(m)RNA还可以选自天然发现或合成制备的任何RNA分子类型,并且其可以诱导先天性免疫应答。在该上下文中,优选的是,本发明的免疫刺激组合物的佐剂成分典型地引起先天性免疫应答,而本发明的免疫刺激组合物的游离mRNA可以引起适应性免疫应答,特别是如果游离mRNA编码如本文中所述的抗原或过敏原或能够引起适应性免疫应答的任何其他分子。特别地,可以诱导先天性免疫应答的那些类型的RNA分子可以选自Toll样受体(TLRs)的配体。本发明的免疫刺激组合物的佐剂成分的至少一种免疫刺激性RNA可以因此包括已知为免疫刺激性的任何RNA序列,包括但不仅限于,表示和/或编码TLRs的配体的RNA序列,所述TLRs优选选自人家族成员TLR1-TLR10或鼠科家族成员TLR1-TLR13,更优选选自TLR7和TLR8,关于RNA胞内受体的配体(诸如RIG-I或MDA-5,等.)(参见例如Meylan,E.,Tschopp,J.(2006)Toll-like receptors and RNA helicases:two parallel ways to trigger antiviral responses(Toll样受体和RNA螺旋:两种用于触发抗病毒应答的平行方式).Mol.Cell(分子细胞)22,561-569),或任何其他免疫刺激性RNA序列。
典型地,作为本发明的免疫刺激组合物的佐剂成分的至少一种(m)RNA使用的免疫刺激性RNA可以包括如上关于本发明的免疫刺激组合物的佐剂成分的RNA的RNA分子普遍定义的长度。优选地,该RNA可以具有1000-5000,500-5000,5-5000,或5-1000,5-500,5-250,5-100,5-50或5-30个核苷酸的长度。
这样的免疫刺激性序列可以包括例如式(I)的核酸:
GlXmGn
其中:
G是鸟苷、尿嘧啶或鸟苷或尿嘧啶的类似物;
X是鸟苷、尿嘧啶、腺苷、胸苷、胞嘧啶或上述核苷酸的类似物;
l是由1到40的整数,
其中当l=1时,G是鸟苷或其类似物,
当l>1时,至少50%的核苷酸是鸟苷或其类似物;
m是整数且至少是3;
其中当m=3时,X是尿嘧啶或其类似物,
当m>3时,存在至少3个连续的尿嘧啶或尿嘧啶类似物;
n是由1到40的整数,
其中当n=1时,G是鸟苷或其类似物,
当n>1时,至少50%的核苷酸是鸟苷或其类似物。
这样的免疫刺激性序列还可以包括例如式(II)的核酸:
ClXmCn
其中:
C是胞嘧啶、尿嘧啶或胞嘧啶或尿嘧啶类似物;
X是鸟苷、尿嘧啶、腺苷、胸苷、胞嘧啶或上述核苷酸的类似物;
l是由1到40的整数,
其中当l=1时,C是胞嘧啶或其类似物,
当l>1时,至少50%的核苷酸是胞嘧啶或其类似物;
m是整数且至少是3;
其中当m=3时,X是尿嘧啶或其类似物,
当m>3时,存在至少3个连续的尿嘧啶或尿嘧啶类似物;
n是由1到40的整数,
其中当n=1时,C是胞嘧啶或其类似物,
当n>1时,至少50%的核苷酸是胞嘧啶或其类似物。
式(I)或(II)的核酸,其可以用于本发明的免疫刺激组合物的佐剂成分的至少一种(m)RNA,典型地是相对短的核酸分子且典型地具有约5-100(但对于特定实施方案也可以比100个核苷酸更长,例如最长至200个核苷酸),5-90或5-80个核苷酸的长度,优选约5-70的长度,更优选约8-60的长度和,更优选约15-60个核苷酸,更优选20-60,最优选30-60个核苷酸的长度。如果本发明的核酸具有例如100个核苷酸的最大长度,则m应该典型地<=98。式(I)核酸中的核苷酸G的数量由l或n确定。l和n,彼此独立,分别是由1到40的整数,其中当l或n=1时,G是鸟苷或其类似物,且当l或n>1时,至少50%的核苷酸是鸟苷或其类似物。例如,在不暗示任何限制的条件下,当l或n=4时,Gl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)的核酸中与Xm相邻的核苷酸优选不是尿嘧啶。类似地,根据本发明的式(II)的核酸中的核苷酸C的数量由l或n确定。l和n,彼此独立,分别是由1到40的整数,其中当l或n=1时,C是胞嘧啶或其类似物,且当l或n>1时,至少50%的核苷酸是胞嘧啶或其类似物。例如,在不暗示任何限制的条件下,当l或n=4时,Cl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(II)的核酸中与Xm相邻的核苷酸优选不是尿嘧啶。优选地,关于式(I),当l或n>1时,至少60%,70%,80%,90%或甚至100%的核苷酸是鸟苷或其类似物,如上定义。旁侧序列Gl和/或Gn中剩余核苷酸至100%(当鸟苷构成少于100%的核苷酸时)的是尿嘧啶或其类似物,如此前定义地。还优选,l和n,彼此独立,分别是由2到30的整数,更优选是2到20的整数和还更优选2到15的整数。l或n的下限,如果需要,可以变化并且是至少1,优选至少2,更优选至少3,4,5,6,7,8,9或10。该定义对应地应用于式(II)。
根据特别优选的实施方案,根据以上式(I)或(II)的核酸,其可以用于本发明的免疫刺激组合物的佐剂成分的至少一种(m)RNA,可以选自由任意以下序列组成或包括任意以下序列的序列:
-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 ID NO:47);
-GGGGUUUUUUUUUUUUUUUUUUUUUUUUUUUUUUGGG(SEQ ID 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);
或
-CCCUUUUUUUUUUUUUUUCCCUUUUUUUUUUUUUUUCCCUUUUUUUUUUUUUUUCCC(SEQ ID NO:81)
-CCCUUUCCCUUUCCCUUUCCCUUUCCCUUUCCCUUUCCCUUUCCCUUUCCC(SEQ ID NO:82)
-CCCUUUUUUUUUUUUUUUCCCCCCUUUUUUUUUUUUUUUCCC(SEQ ID NO:83)
或选自与这些序列中任一种具有至少60%,70%,80%,90%,或甚至95%序列同一性的序列。
在该上下文中,本申请中的术语“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,关于与具有确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的数值),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。
另外,这样的免疫刺激序列还可以包括例如式(III)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;
其中根据式(III)的免疫刺激序列具有至少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(III)的结构(NuGlXmGnNv)a包括优选如上定义的元件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。如由本发明人意外发现地,根据式(III)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(III)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(III)的结构(NuGlXmGnNv)a的分子时,这种分子设计是特别有利的。
式(III)的核心结构GlXmGn在下文中更精确地定义:
在式(III)(和式(I)和(II))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)类似物被定义为天然存在的核苷酸(核苷)鸟苷(鸟嘌呤)和尿苷(尿嘧啶)的非天然存在的变体。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(phosphoramidates),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,已经例如通过乙酰化,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,US 4,415,732,US 4,458,066,US 4,500,707,US 4,668,777,US 4,973,679,US 5,047,524,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,尤其优选那些类似物,其增加式(III)(和式(I)和(II))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全然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(核苷)(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)。
在式(III)(和式(I)和(II))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。在式(III)(和式(I)和(II))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,在式(III)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,在式(III)(和式(I)和(II))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,在式(III)(和式(I)和(II))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(核苷)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。
同样优选地,对于式(III)(和式(I)和(II)),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。然后在核心结构元件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。
在式(III)(和式(I)和(II))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)类似物被定义为天然存在的核苷酸(核苷)的非天然存在的变体。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。如果免疫刺激序列全然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,US 4,973,679,US 5,047,524,US 5,132,418,US 5,153,319,US 5,262,530和US 5,700,642中已知。在如上述的类似物的情形中,尤其优选那些核苷酸(核苷)类似物,其增加式(III)(和式(I)和(II))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。
在式(III)(和式(I)和(II))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(III)(和式(I)和(II))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)序列在式(III)(和式(I)和(II))的核酸分子的核心结构元件X中出现至少一次。因此,例如对于具有至少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,UUUUUUUUU,等。邻近式(III)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。然后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。
上述根据式(III)的免疫刺激序列包含边界元件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(III)的核酸分子中的边界元件N可以是这样的序列,其可以由本领域可获得的任何(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。
在式(III)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,在式(III)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可以彼此独立地是0或1到100的整数,更优选地是0或1-50的整数,甚至更优选地是0或1-40的整数,和最优选地是0或1-30的整数,例如0或1-5,10,20,25,或30;或是5-10,10-15,15-20,20-25或25-30的整数。更优选地,在式(III)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式(III)的免疫刺激序列的重复元件,(NuGlXmGnNv)a存在,其中根据式(III)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,如上定义的式(III)的免疫刺激序列(NuGlXmGnNv)a包括核心结构GlXmGn,优选地选自下列如上定义的SEQ ID NOs:1-80序列的至少一个:
此外,如本文中定义的免疫刺激序列还可以包括例如式(IIIa)的核酸(分子)
(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;
其中式(IIIa)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(IIIa),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(IIIa)的元件,其中在式(IIIa)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,在式(IIIa)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)核苷酸类似物被定义为天然存在的胞苷(胞嘧啶)或尿苷(尿嘧啶)核苷酸的非天然存在的变体。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,US 5,132,418,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,尤其优选那些类似物,其增加式(IIIa)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全然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)。
在式(IIIa)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。在式(IIIa)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,在式(IIIa)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,在式(IIIa)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,在式(IIIa)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(IIIa),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。然后在核心结构元件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,作为在根据式(IIIa)的免疫刺激序列中的另外的核心结构元件,优选地如上关于式(III)所定义。在式(IIIa)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(IIIa)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)序列在式(IIIa)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。邻近式(IIIa)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。然后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,上述根据式(IIIa)的免疫刺激序列包含边界元件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式(IIIa)的免疫刺激序列的重复元件,(NuClXmCnNv)a存在,其中根据式(IIIa)的元件,(NuClXmCnNv)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,如上定义的式(IIIa)的免疫刺激序列(NuClXmCnNv)a包括核心结构ClXmCn,优选地选自下列如上定义的SEQ ID NOs:81-83的序列的至少一个:
根据式(III)(或(IIIIa))的免疫刺激序列,特别是其每个单重复元件NuGlXmGnNv(或NuClXmCnNv),可以是通常如关于式(III)所定义的单链,双链或部分双链,等。
如果根据式(III)(或(IIIIa))的免疫刺激序列是单链核酸分子,所述序列典型地在其整个长度上是单链的。
同样地,如果根据式(III)(或(IIIIa))的免疫刺激序列是双链核酸分子,所述序列在其整个长度上典型地是双链的。
如果根据式(III)(或(IIIIa))的免疫刺激序列是部分双链核酸分子,那么式(III)(或(IIIa))的核酸分子的核酸序列可以在核心结构GlXmGn(或ClXmCn)之外的区域内是单链的,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(III)(或(IIIa))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,如果根据式(III)(或(IIIa))的免疫刺激序列是部分双链核酸分子,根据如上定义的式(III)(或(IIIa))的免疫刺激序列的其它部分(非核心结构GlXmGn)可以是双链的。例如,式(III)或(IIIa)的核酸分子的核酸序列可以在核心结构GlXmGn(或ClXmCn)之外的区域(例如在边界元件Nu和/或Nv中)是双链的,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(III)或(IIIa)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(III)的免疫刺激序列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(III)或(IIIa)的单链核酸分子和根据式(III)(或(IIIa))的(部分)双链核酸分子的混合物。
根据特别优选的实施方案,根据式(III)的免疫刺激序列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)
GGGAGAAAGCUCAAGCUUGGAGCAAUGCCCGCACAUUGAGGAAACCGAGUUGCAUAUCUCAGAGUAUUG
GCCCCCGUGUAGGUUAUUCUUGACAGACAGUGGAGCUUAUUCACUCCCAGGAUCCGAGUCGCAUACUAC
GGUACUGGUGACAGACCUAGGUCGUCAGUUGACCAGUCCGCCACUAGACGUGAGUCCGUCAAAGCAGUU
AGAUGUUACACUCUAUUAGAUC
或来自SEQ ID NO:115(R719:(N100)5)
GGGAGAAAGCUCAAGCUUGGAGCAAUGCCCGCACAUUGAGGAAACCGAGUUGCAUAUCUCAGAGUAUUG
GCCCCCGUGUAGGUUAUUCUUGACAGACAGUGGAGCUUAUUCACUCCCAGGAUCCGAGUCGCAUACUAC
GGUACUGGUGACAGACCUAGGUCGUCAGUUGACCAGUCCGCCACUAGACGUGAGUCCGUCAAAGCAGUU
AGAUGUUACACUCUAUUAGAUCUCGGAUUACAGCUGGAAGGAGCAGGAGUAGUGUUCUUGCUCUAAGUA
CCGAGUGUGCCCAAUACCCGAUCAGCUUAUUAACGAACGGCUCCUCCUCUUAGACUGCAGCGUAAGUGC
GGAAUCUGGGGAUCAAAUUACUGACUGCCUGGAUUACCCUCGGACAUAUAACCUUGUAGCACGCUGUUG
CUGUAUAGGUGACCAACGCCCACUCGAGUAGACCAGCUCUCUUAGUCCGGACAAUGAUAGGAGGCGCGG
UCAAUCUACUUCUGGCUAGUUAAGAAUAGGCUGCACCGACCUCUAUAAGUAGCGUGUCCUCUAG
或来自SEQ ID NO:116(R720:(N100)10)
GGGAGAAAGCUCAAGCUUGGAGCAAUGCCCGCACAUUGAGGAAACCGAGUUGCAUAUCUCAGAGUAUUG
GCCCCCGUGUAGGUUAUUCUUGACAGACAGUGGAGCUUAUUCACUCCCAGGAUCCGAGUCGCAUACUAC
GGUACUGGUGACAGACCUAGGUCGUCAGUUGACCAGUCCGCCACUAGACGUGAGUCCGUCAAAGCAGUU
AGAUGUUACACUCUAUUAGAUCUCGGAUUACAGCUGGAAGGAGCAGGAGUAGUGUUCUUGCUCUAAGUA
CCGAGUGUGCCCAAUACCCGAUCAGCUUAUUAACGAACGGCUCCUCCUCUUAGACUGCAGCGUAAGUGC
GGAAUCUGGGGAUCAAAUUACUGACUGCCUGGAUUACCCUCGGACAUAUAACCUUGUAGCACGCUGUUG
CUGUAUAGGUGACCAACGCCCACUCGAGUAGACCAGCUCUCUUAGUCCGGACAAUGAUAGGAGGCGCGG
UCAAUCUACUUCUGGCUAGUUAAGAAUAGGCUGCACCGACCUCUAUAAGUAGCGUGUCCUCUAGAGCUA
CGCAGGUUCGCAAUAAAAGCGUUGAUUAGUGUGCAUAGAACAGACCUCUUAUUCGGUGAAACGCCAGAA
UGCUAAAUUCCAAUAACUCUUCCCAAAACGCGUACGGCCGAAGACGCGCGCUUAUCUUGUGUACGUUCU
CGCACAUGGAAGAAUCAGCGGGCAUGGUGGUAGGGCAAUAGGGGAGCUGGGUAGCAGCGAAAAAGGGCC
CCUGCGCACGUAGCUUCGCUGUUCGUCUGAAACAACCCGGCAUCCGUUGUAGCGAUCCCGUUAUCAGUG
UUAUUCUUGUGCGCACUAAGAUUCAUGGUGUAGUCGACAAUAACAGCGUCUUGGCAGAUUCUGGUCACG
UGCCCUAUGCCCGGGCUUGUGCCUCUCAGGUGCACAGCGAUACUUAAAGCCUUCAAGGUACUCGACGUG
GGUACCGAUUCGUGACACUUCCUAAGAUUAUUCCACUGUGUUAGCCCCGCACCGCCGACCUAAACUGGU
CCAAUGUAUACGCAUUCGCUGAGCGGAUCGAUAAUAAAAGCUUGAAUU
或来自SEQ ID NO:117(R821:(N40U20N40)2)
GGGAGAAAGCUCAAGCUUAUCCAAGUAGGCUGGUCACCUGUACAACGUAGCCGGUAUUUUUUUUUUUUU
UUUUUUUUUGACCGUCUCAAGGUCCAAGUUAGUCUGCCUAUAAAGGUGCGGAUCCACAGCUGAUGAAAG
ACUUGUGCGGUACGGUUAAUCUCCCCUUUUUUUUUUUUUUUUUUUUUAGUAAAUGCGUCUACUGAAUCC
AGCGAUGAUGCUGGCCCAGAUC
或来自SEQ ID NO:118(Seq.R722:(N40U20N40)5)
GGGAGAAAGCUCAAGCUUAUCCAAGUAGGCUGGUCACCUGUACAACGUAGCCGGUAUUUUUUUUUUUUU
UUUUUUUUUGACCGUCUCAAGGUCCAAGUUAGUCUGCCUAUAAAGGUGCGGAUCCACAGCUGAUGAAAG
ACUUGUGCGGUACGGUUAAUCUCCCCUUUUUUUUUUUUUUUUUUUUUAGUAAAUGCGUCUACUGAAUCC
AGCGAUGAUGCUGGCCCAGAUCUUCGACCACAAGUGCAUAUAGUAGUCAUCGAGGGUCGCCUUUUUUUU
UUUUUUUUUUUUUUUGGCCCAGUUCUGAGACUUCGCUAGAGACUACAGUUACAGCUGCAGUAGUAACCA
CUGCGGCUAUUGCAGGAAAUCCCGUUCAGGUUUUUUUUUUUUUUUUUUUUUCCGCUCACUAUGAUUAAG
AACCAGGUGGAGUGUCACUGCUCUCGAGGUCUCACGAGAGCGCUCGAUACAGUCCUUGGAAGAAUCUUU
UUUUUUUUUUUUUUUUUUUGUGCGACGAUCACAGAGAACUUCUAUUCAUGCAGGUCUGCUCUA
或来自SEQ ID NO:119(R723:(N40U20N40)10):
GGGAGAAAGCUCAAGCUUAUCCAAGUAGGCUGGUCACCUGUACAACGUAGCCGGUAUUUUUUUUUUUUU
UUUUUUUUUGACCGUCUCAAGGUCCAAGUUAGUCUGCCUAUAAAGGUGCGGAUCCACAGCUGAUGAAAG
ACUUGUGCGGUACGGUUAAUCUCCCCUUUUUUUUUUUUUUUUUUUUUAGUAAAUGCGUCUACUGAAUCC
AGCGAUGAUGCUGGCCCAGAUCUUCGACCACAAGUGCAUAUAGUAGUCAUCGAGGGUCGCCUUUUUUUU
UUUUUUUUUUUUUUUGGCCCAGUUCUGAGACUUCGCUAGAGACUACAGUUACAGCUGCAGUAGUAACCA
CUGCGGCUAUUGCAGGAAAUCCCGUUCAGGUUUUUUUUUUUUUUUUUUUUUCCGCUCACUAUGAUUAAG
AACCAGGUGGAGUGUCACUGCUCUCGAGGUCUCACGAGAGCGCUCGAUACAGUCCUUGGAAGAAUCUUU
UUUUUUUUUUUUUUUUUUUGUGCGACGAUCACAGAGAACUUCUAUUCAUGCAGGUCUGCUCUAGAACGA
ACUGACCUGACGCCUGAACUUAUGAGCGUGCGUAUUUUUUUUUUUUUUUUUUUUUUUCCUCCCAACAAA
UGUCGAUCAAUAGCUGGGCUGUUGGAGACGCGUCAGCAAAUGCCGUGGCUCCAUAGGACGUGUAGACUU
CUAUUUUUUUUUUUUUUUUUUUUUCCCGGGACCACAAAUAAUAUUCUUGCUUGGUUGGGCGCAAGGGCC
CCGUAUCAGGUCAUAAACGGGUACAUGUUGCACAGGCUCCUUUUUUUUUUUUUUUUUUUUUUUCGCUGA
GUUAUUCCGGUCUCAAAAGACGGCAGACGUCAGUCGACAACACGGUCUAAAGCAGUGCUACAAUCUGCC
GUGUUCGUGUUUUUUUUUUUUUUUUUUUUGUGAACCUACACGGCGUGCACUGUAGUUCGCAAUUCAUAG
GGUACCGGCUCAGAGUUAUGCCUUGGUUGAAAACUGCCCAGCAUACUUUUUUUUUUUUUUUUUUUUCAU
AUUCCCAUGCUAAGCAAGGGAUGCCGCGAGUCAUGUUAAGCUUGAAUU
根据另外的特别优选的实施方案,根据式(IIIa)的免疫刺激序列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,根据如上定义的式(III)(或(IIIa))的免疫刺激序列可以用聚(X)序列(修饰元件)修饰。所述免疫刺激序列可以包含例如根据式(IV)的核酸分子:
聚(IV)s(Nu GlXmGn Nv)a聚(IV)t,
其中式(IV)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。
在根据式(IV)的免疫刺激序列中,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(III)定义。在本发明的情形中,根据式(IV)的免疫刺激序列的修饰元件聚(IV),特别是聚(IV)s和/或聚(IV)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(IV),特别是聚(IV)s和/或聚(IV)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,其如上关于根据式(III)或(IIIa)的免疫刺激序列的X所定义。优选地,X可以独立地关于聚(IV),特别是聚(IV)s和/或聚(IV)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(III))的单链片段等,或选自肌苷和胞苷(胞嘧啶)(聚(III: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(III: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(IV)的核酸分子的序列(Nu GlXmGn Nv)a。式(IV)的免疫刺激序列的修饰元件聚(IV),特别是聚(IV)s和/或聚(IV)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(IV)的核酸分子,可以具体的包含例如根据式(IVa)的核酸分子,
聚(X)(Nu GlXmGn Nv)a,
或根据式(IVb)的核酸分子,
聚(X)(Nu GlXmGn Nv)a聚(X),
其中,式(IVa)或(IVb)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(IV)或(III)所述。同样地,所述式(IV),(IVa)和(IVb)可以基于根据式(IIIb)的式定义,即引入核心结构ClXmCn。
更优选地,根据式(IV),(IVa)和/或(IVb)任一的免疫刺激序列可以选自如上定义的聚(IV),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(IV),(IVa)和/或(IVb)的序列。
类似地,如上关于式(III)或(IIIa)定义,根据式(IV),(IVa)和/或(IVb)任一的免疫刺激序列可以是如上定义的单链,双链或部分双链核酸分子。
如果根据式(IV),(IVa)和/或(IVb)的免疫刺激序列是单链核酸分子,所述序列典型地在其整个长度上典型地是单链的。
同样地,如果根据式(IV),(IVa)和/或(IVb)任一的免疫刺激序列是双链核酸分子,所述序列在其整个长度上典型地是双链的
如果根据式(IV),(IVa)和/或(IVb)任一的免疫刺激序列是部分双链核酸分子,那么式(IV),(IVa)和/或(IVb)任一的核酸分子的核酸序列可以在核心结构GlXmGn之外的区域内是单链的,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SEQ ID NOs:81-83序列的至少一个。甚至更优选地,式(III)(或(IIIa))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,如果根据式(IV),(IVa)和/或(IVb)任一的免疫刺激序列是部分双链核酸分子,根据如上定义的式(IV),(IVa)和/或(IVb)任一的免疫刺激序列的其它部分(非核心结构GlXmGn)可以是双链的。例如,式(IV),(IVa)和/或(IVb)任一的核酸分子的核酸序列可以在核心结构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))是双链的,和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SEQ ID NOs:1-83的限定序列的至少一个。例如,边界元件Nu和/或Nv的至少一个和/或修饰元件聚(IV),例如聚(IV)s和或聚(IV)t中的至少一个可以是双链的,而式(IV),(IVa)和/或(IVb)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(IV),(IVa)和/(IVb)任一的单链核酸分子,和根据式(IV),(IVa)和/(IVb)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,根据式(IV),(IVa)和/或(IVb)任一的免疫刺激序列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
根据如上定义的式(III)(或(IIIa))的免疫刺激序列还可以通过插入茎或茎环来进行修饰,例如得到根据式(Va)的核酸分子,
(Nu茎1GlXmGn茎2Nv)a,
或根据式(Vb)的核酸分子,
(NuGlXmGnNv)a茎1Nw1茎2Nw2,
其中根据式(Va)和/或(Vb)任一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(Va)和(Vb)可以基于式(IIIb),即通过引入核心结构ClXmCn定义。
特别地,式(Va)和/或(Vb)任一的免疫刺激序列代表如上定义的式(III)的变体。在根据式(Va)和/或(Vb)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,优选地由单一茎环元件茎1和茎2组成,进一步扩充。在根据如上定义的式(Va)和/或(Vb)的任一个的免疫刺激序列中,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(III)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(III)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的序列没有同一性或同源性,或几乎没有同一性或同源性,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序列的存在。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(Va)和/或式(Vb)任一个的免疫刺激序列的情形中,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%的同一性或同源性。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。
茎环元件茎1和茎2的示范性序列可以包括例如:
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(SEO 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(SEO 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(Va)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(Va)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(Vb)类似,其具有如上定义的组成NuGlXmGnNv)a茎1Nw1茎2Nw2。
根据式(Va)和/或(Vb)任一的免疫刺激序列可以是单链的,或部分双链的。如果根据式(Va)和/或(Vb)任一的免疫刺激序列是单链核酸分子,那么所述序列典型地在其整个长度上是单链的。如果根据式(Va)和/或(Vb)任一的免疫刺激序列是部分双链核酸分子,那么式(Va)和/或(Vb)任一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)形成的环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(Va)或(Vb)的单链或部分双链核酸分子,和根据式(Va)或(Vb)的(部分)双链核酸分子的混合物。
根据特别优选的实施方案,分别根据式(Va)和/或(Vb)任一的免疫刺激序列可以选自例如下列序列的任一个:
(SEQ ID NO:107)
GCCGCGGGCCGUGCGUUCCUA GAAGUACACGCGGCCCGCGGCUGCGUUCCUA 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)
如上定义的式(I),(II),(III),(IIIa),(IV),(IVa),(IVb),(Va)和/或(Vb)的免疫刺激序列典型地是核酸,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,如上定义的式(I),(II),(III),(IIIa),(IV),(IVa),(IVb),(Va)和/或(Vb)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,如上定义的式(I),(II),(III),(IIIa),(IV),(IVa),(IVb),(Va)和/或(Vb)的免疫刺激序列以单链核酸和双链DNA或RNA的混合物的形式存在。
如果如上定义的式(I),(II),(III),(IIIa),(IV),(IVa),(IVb),(Va)和/或(Vb)的免疫刺激序列是部分双链核酸分子,这是特别有利的,因为所述根据如上定义的式(I),(II),(III),(IIIa),(IV),(IVa),(IVb),(Va)和/或(Vb)的(部分双链)免疫刺激序列可以通过定向单链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)。因此如上定义的式(I),(II),(III),(IIIa),(IV),(IVa),(IVb),(Va)和/或(Vb)的任何部分双链的免疫刺激序列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。
如上定义的式(I),(II),(III),(IIIa),(IV),(IVa),(IVb),(Va)和/或(Vb)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,体外转录用于免疫刺激序列的制备。本发明的发明人惊奇地发现,当与通过合成方法制备的如上定义的式(I),(II),(III),(IIIa),(IV),(IVa),(IVb),(Va)和/或(Vb)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,如上定义的式(I),(II),(III),(IIIa),(IV),(IVa),(IVb),(Va)和/或(Vb)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。因此如上定义的式(I),(II),(III),(IIIa),(IV),(IVa),(IVb),(Va)和/或(Vb)的核酸分子是特别优选的,当通过体外转录反应制备时。
此外,可以用于本发明的免疫刺激组合物的佐剂成分的至少一种(m)RNA的RNA分子(类型)可以包括能够引起免疫应答的任何其他RNA。不局限于此,这样的免疫刺激性RNA可以包括核糖体RNA(rRNA),转移RNA(tRNA),信使RNA(mRNA),和病毒RNA(vRNA)。
根据第三种实施方案,本发明的免疫刺激组合物的佐剂成分的至少一种(m)RNA可以是siRNA。siRNA是与RNA干扰现象有关特别感兴趣的。在免疫学研究期间,注意力集中在RNA干扰的现象。近年来,发现了基于RNA的防卫机制,其在真菌界中和植物和动物界中均存在并起“基因组免疫系统”的作用。该系统最初描述于多种彼此独立的物种中,首先在线虫(C.elegans)中描述,这先于可能确定以下相同过程的基础机制:植物中的RNA-介导的病毒抗性,植物中的PTGS(转录后基因沉默),和真核生物中的RNA干扰因此基于常用程序。RNA干扰(RNAi)的体外技术基于双链RNA分子(dsRNA),其触发基因表达的序列特异性抑制(Zamore(2001)Nat.Struct.Biol.(自然结构生物学)9:746-750;Sharp(2001)Genes Dev.(基因发展)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的活化导致非特异性作用,诸如,例如,干扰素反应(Stark等(1998)Annu.Rev.Biochem.(生物化学年度综述)67:227-264;He和Katze(2002)Viral Immunol.(病毒免疫学)15:95-119)。近期,dsRNA分子也已经在体内使用(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(癌细胞)2:243-247)。因此,用于本发明的免疫刺激组合物的佐剂成分的至少一种(m)RNA的siRNA可以是免疫刺激性RNA,并典型地包括(单-或)双链的、优选双链的且具有约8-30个核苷酸,优选17-25个核苷酸,甚至更优选20-25和最优选21-23个核苷酸的RNA序列。原则上,所有具有如上提及的RNA序列的编码区中存在的17-29,优选19-25,最优选21-23对碱基对的长度的部分起所述siRNA的靶序列作用。同等地,siRNA还可以针对阴性调节(先天性或适应性)免疫应答的诱导的蛋白,特别是调节蛋白的不位于编码区中特别地RNA的5’非编码区中的核苷酸序列,例如,因此,针对具有调节功能的RNA的非编码区。作为本发明的免疫刺激组合物的佐剂成分的至少一种(m)RNA使用的siRNA的靶序列因此可以位于如上定义的蛋白的核苷酸序列的翻译和/或不翻译区中和/或在其控制元件区中。如上定义的siRNA的靶序列还可以位于不翻译和翻译的序列的重叠区域内;特别地,靶序列可以包括RNA编码区起始三联体上游的至少一个核苷酸。
根据第四种实施方案,本发明的免疫刺激组合物的佐剂成分的至少一种(m)RNA可以是反义RNA。在本发明的上下文中,反义RNA优选是由DNA编码链,而非DNA模板链转录的(单链)RNA分子,因此(优选地)(完整)反义mRNA序列与有义(信使)RNA互补。在本文中定义的反义RNA典型地在有义和反义RNA分子之间形成双链体,并因此能够阻断编码链的转录。作为本发明的免疫刺激组合物的佐剂成分的至少一种(m)RNA使用的反义RNA可以针对编码蛋白或肽的核苷酸序列,例如(天然存在的)mRNA或基因组序列,所述蛋白或肽可以选自适合于该目的的任何蛋白或肽序列。优选地,作为本发明的免疫刺激组合物的佐剂成分的至少一种(m)RNA使用的反义RNA包括如上关于RNA分子普遍定义的长度,更优选1000-5000或,500-5000,5-5000,或5-1000,5-500或5-250,5-100,5-50或5-30个核苷酸的长度。
根据第五个实施方案,本发明的免疫刺激组合物的佐剂成分的至少一种(m)RNA是编码RNA。所述编码RNA可以是如上定义的任何RNA。优选地,所述编码RNA可以是单链或双链RNA,更优选是单链RNA,和/或环形或线性RNA,更优选是线性RNA。甚至更优选地,所述编码RNA可以是(线性)单链RNA。最优选地,所述编码RNA可以是((线性)单链)信使RNA(mRNA)。作为本发明的免疫刺激组合物的佐剂成分的至少一种(m)RNA使用的编码RNA还可以编码蛋白质或肽,其可以选自,不仅限于,例如选自治疗活性蛋白或肽,选自抗原,例如肿瘤抗原,致病性抗原(例如选自如上定义的致病性蛋白或选自动物抗原、病毒抗原、原生动物抗原、细菌抗原、过敏抗原),自体免疫抗原,或其他抗原,选自过敏原,选自抗体,选自免疫刺激蛋白或肽,选自抗原特异性T细胞受体,或任何其他适合于特异性(治疗)应用的蛋白或肽,其中可以将作为本发明的免疫刺激组合物的佐剂成分的至少一种(m)RNA使用的编码RNA运送到细胞、组织或生物体中并可以随后在该细胞、组织或生物体内表达该蛋白。
a)治疗活性蛋白
在该上下文中,由所述免疫刺激组合物的佐剂成分的至少一种(m)RNA编码的治疗活性蛋白可以选自现有技术的技术人员已知的任何天然存在的重组的或分离的蛋白。不受限于此,治疗活性蛋白可以包括能够刺激或抑制细胞内信号转导的蛋白,例如细胞因子、抗体等。治疗活性蛋白由此可以包括细胞因子家族I类细胞因子,其具有4个位置保守的半胱氨酸残基(CCCC)并包括保守序列基序Trp-Ser-X-Trp-Ser(WSXWS),其中X是非保守氨基酸。细胞因子家族I类细胞因子包括GM-CSF亚家族,例如IL-3,IL-5,GM-CSF,IL-6-亚家族,例如IL-6,IL-11,IL-12,或IL-2-亚家族,例如IL-2,IL-4,IL-7,IL-9,IL-15,等,或细胞因子IL-1α,IL-1β,IL-10等。治疗活性蛋白还可以包括细胞因子家族II类细胞因子,其也包括4个位置保守的半胱氨酸残基(CCCC),但无保守序列基序Trp-Ser-X-Trp-Ser(WSXWS)。细胞因子家族II类细胞因子包括例如IFN-α,IFN-β,IFN-γ,等。治疗活性蛋白可以另外包括肿瘤坏死因子家族的细胞因子,例如TNF-α,TNF-β,等,或趋化因子家族的细胞因子,其包括7个跨膜螺旋并与G-蛋白相互作用,例如IL-8,MIP-1,RANTES,CCR5,CXR4,等,或细胞因子特异性受体,诸如TNF-RI,TNF-RII,CD40,OX40(CD134),Fas。
由免疫刺激组合物的佐剂成分的至少一种(m)RNA编码的治疗活性蛋白也可以选自以下给出的任何蛋白:0ATL3,0FC3,0PA3,0PD2,4-1BBL,5T4,6Ckine,707-AP,9D7,A2M,AA,AAAS,AACT,AASS,ABAT,ABCA1,ABCA4,ABCB1,ABCB11,ABCB2,ABCB4,ABCB7,ABCC2,ABCC6,ABCC8,ABCD1,ABCD3,ABCG5,ABCG8,ABL1,ABO,ABR ACAA1,ACACA,ACADL,ACADM,ACADS,ACADVL,ACAT1,ACCPN,ACE,ACHE,ACHM3,ACHM1,ACLS,ACPI,ACTA1,ACTC,ACTN4,ACVRL1,AD2,ADA,ADAMTS13,ADAMTS2,ADFN,ADH1B,ADH1C,ADLDH3A2,ADRB2,ADRB3,ADSL,AEZ,AFA,AFD1,AFP,AGA,AGL,AGMX2,AGPS,AGS1,AGT,AGTR1,AGXT,AH02,AHCY,AHDS,AHHR,AHSG,AIC,AIED,AIH2,AIH3,AIM-2,AIPL1,AIRE,AK1,ALAD,ALAS2,ALB,HPG1,ALDH2,ALDH3A2,ALDH4A1,ALDH5A1,ALDH1A1,ALDOA,ALDOB,ALMS1,ALPL,ALPP,ALS2,ALX4,AMACR,AMBP,AMCD,AMCD1,AMCN,AMELX,AMELY,AMGL,AMH,AMHR2,AMPD3,AMPD1,AMT,ANC,ANCR,ANK1,ANOP1,AOM,AP0A4,AP0C2,AP0C3,AP3B1,APC,aPKC,APOA2,APOA1,APOB,APOC3,APOC2,APOE,APOH,APP,APRT,APS1,AQP2,AR,ARAF1,ARG1,ARHGEF12,ARMET,ARSA,ARSB,ARSC2,ARSE,ART-4,ARTC1/m,ARTS,ARVD1,ARX,AS,ASAH,ASAT,ASD1,ASL,ASMD,ASMT,ASNS,ASPA,ASS,ASSP2,ASSP5,ASSP6,AT3,ATD,ATHS,ATM,ATP2A1,ATP2A2,ATP2C1,ATP6B1,ATP7A,ATP7B,ATP8B1,ATPSK2,ATRX,ATXN1,ATXN2,ATXN3,AUTS1,AVMD,AVP,AVPR2,AVSD1,AXIN1,AXIN2,AZF2,B2M,B4GALT7,B7H4,BAGE,BAGE-1,BAX,BBS2,BBS3,BBS4,BCA225,BCAA,BCH,BCHE,BCKDHA,BCKDHB,BCL10,BCL2,BCL3,BCL5,BCL6,BCPM,BCR,BCR/ABL,BDC,BDE,BDMF,BDMR,BEST1,beta-Catenin/m,BF,BFHD,BFIC,BFLS,BFSP2,BGLAP,BGN,BHD,BHR1,BING-4,BIRC5,BJS,BLM,BLMH,BLNK,BMPR2,BPGM,BRAF,BRCA1,BRCA1/m,BRCA2,BRCA2/m,BRCD2,BRCD1,BRDT,BSCL,BSCL2,BTAA,BTD,BTK,BUB1,BWS,BZX,C0L2A1,C0L6A1,C1NH,C1QA,C1QB,C1QG,C1S,C2,C3,C4A,C4B,C5,C6,C7,C7orf2,C8A,C8B,C9,CA125,CA15-3/CA 27-29,CA195,CA19-9,CA72-4,CA2,CA242,CA50,CABYR,CACD,CACNA2D1,CACNA1A,CACNA1F,CACNA1S,CACNB2,CACNB4,CAGE,CA1,CALB3,CALCA,CALCR,CALM,CALR,CAM43,CAMEL,CAP-1,CAPN3,CARD15,CASP-5/m,CASP-8,CASP-8/m,CASR,CAT,CATM,CAV3,CB1,CBBM,CBS,CCA1,CCAL2,CCAL1,CCAT,CCL-1,CCL-11,CCL-12,CCL-13,CCL-14,CCL-15,CCL-16,CCL-17,CCL-18,CCL-19,CCL-2,CCL-20,CCL-21,CCL-22,CCL-23,CCL-24,CCL-25,CCL-27,CCL-3,CCL-4,CCL-5,CCL-7,CCL-8,CCM1,CCNB1,CCND1,CCO,CCR2,CCR5,CCT,CCV,CCZS,CD1,CD19,CD20,CD22,CD25,CD27,CD27L,cD3,CD30,CD30,CD30L,CD33,CD36,CD3E,CD3G,CD3Z,CD4,CD40,CD40L,CD44,CD44v,CD44v6,CD52,CD55,CD56,CD59,CD80,CD86,CDAN1,CDAN2,CDAN3,CDC27,CDC27/m,CDC2L1,CDH1,CDK4,CDK4/m,CDKN1C,CDKN2A,CDKN2A/m,CDKN1A,CDKN1C,CDL1,CDPD1,CDR1,CEA,CEACAM1,CEACAM5,CECR,CECR9,CEPA,CETP,CFNS,CFTR,CGF1,CHAC,CHED2,CHED1,CHEK2,CHM,CHML,CHR39C,CHRNA4,CHRNA1,CHRNB1,CHRNE,CHS,CHS1,CHST6,CHX10,CIAS1,CIDX,CKN1,CLA2,CLA3,CLA1,CLCA2,CLCN1,CLCN5,CLCNKB,CLDN16,CLP,CLN2,CLN3,CLN4,CLN5,CLN6,CLN8,C1QA,C1QB,C1QG,C1R,CLS,CMCWTD,CMDJ,CMD1A,CMD1B,CMH2,MH3,CMH6,CMKBR2,CMKBR5,CML28,CML66,CMM,CMT2B,CMT2D,CMT4A,CMT1A,CMTX2,CMTX3,C-MYC,CNA1,CND,CNGA3,CNGA1,CNGB3,CNSN,CNTF,COA-1/m,COCH,COD2,COD1,COH1,COL10A,COL2A2,COL11A2,COL17A1,COL1A1,COL1A2,COL2A1,COL3A1,COL4A3,COL4A4,COL4A5,COL4A6,COL5A1,COL5A2,COL6A1,COL6A2,COL6A3,COL7A1,COL8A2,COL9A2,COL9A3,COL11A1,COL1A2,COL23A1,COL1A1,COLQ,COMP,COMT,CORD5,CORD1,COX10,COX-2,CP,CPB2,CPO,CPP,CPS1,CPT2,CPT1A,CPX,CRAT,CRB1,CRBM,CREBBP,CRH,CRHBP,CRS,CRV,CRX,CRYAB,CRYBA1,CRYBB2,CRYGA,CRYGC,CRYGD,CSA,CSE,CSF1R,CSF2RA,CSF2RB,CSF3R,CSF1R,CST3,CSTB,CT,CT7,CT-9/BRD6,CTAA1,CTACK,CTEN,CTH,CTHM,CTLA4,CTM,CTNNB1,CTNS,CTPA,CTSB,CTSC,CTSK,CTSL,CTS1,CUBN,CVD1,CX3CL1,CXCL1,CXCL10,CXCL11,CXCL12,CXCL13,CXCL16,CXCL2,CXCL3,CXCL4,CXCL5,CXCL6,CXCL7,CXCL8,CXCL9,CYB5,CYBA,CYBB,CYBB5,,CYFRA 21-1,CYLD,CYLD1,CYMD,CYP11B1,CYP11B2,CYP17,CYP17A1,CYP19,CYP19A1,CYP1A2,CYP1B1,CYP21A2,CYP27A1,CYP27B1,CYP2A6,CYP2C,CYP2C19,CYP2C9,CYP2D,CYP2D6,CYP2D7P1,CYP3A4,CYP7B1,CYPB1,CYP11B1,CYP1A1,CYP1B1,CYRAA,D40,DADI,DAM,DAM-10/MAGE-B1,DAM-6/MAGE-B2,DAX1,DAZ,DBA,DBH,DBI,DBT,DCC,DC-CK1,DCK,DCR,DCX,DDB1,DDB2,DDIT3,DDU,DECR1,DEK-CAN,DEM,DES,DF,DFN2,DFN4,DFN6,DFNA4,DFNA5,DFNB5,DGCR,DHCR7,DHFR,DHOF,DHS,DIA1,DIAPH2,DIAPH1,DIH1,DIO1,DISCI,DKC1,DLAT,DLD,DLL3,DLX3,DMBT1,DMD,DM1,DMPK,DMWD,DNAI1,DNASE1,DNMT3B,DPEP1,DPYD,DPYS,DRD2,DRD4,DRPLA,DSCR1,DSG1,DSP,DSPP,DSS,DTDP2,DTR,DURS1,DWS,DYS,DYSF,DYT2,DYT3,DYT4,DYT2,DYT1,DYX1,EBAF,EBM,EBNA,EBP,EBR3,EBS1,ECA1,ECB2,ECE1,ECGF1,ECT,ED2,ED4,EDA,EDAR,ECA1,EDN3,EDNRB,EEC1,EEF1A1L14,EEGV1,EFEMP1,EFTUD2/m,EGFR,EGFR/Her1,EGI,EGR2,EIF2AK3,eIF4G,EKV,EI IS,ELA2,ELF2,ELF2M,ELK1,ELN,ELONG,EMD,EML1,EMMPRIN,EMX2,ENA-78,ENAM,END3,ENG,ENO1,ENPP1,ENUR2,ENUR1,EOS,EP300,EPB41,EPB42,EPCAM,EPD,EPhA1,EphA2,EphA3,肝配蛋白A2,肝配蛋白A3,EPHX1,EPM2A,EPO,EPOR,EPX,ERBB2,ERCC2ERCC3,ERCC4,ERCC5,ERCC6,ERVR,ESR1,ETFA,ETFB,ETFDH,ETM1,ETV6-AML1,ETV1,EVC,EVR2,EVR1,EWSR1,EXT2,EXT3,EXT1,EYA1,EYCL2,EYCL3,EYCL1,EZH2,F10,F11,F12,F13A1,F13B,F2,F5,F5F8D,F7,F8,F8C,F9,FABP2,FACL6,FAH,FANCA,FANCB,FANCC,FANCD2,FANCF,FasL,FBN2,FBN1,FBP1,FCG3RA,FCGR2A,FCGR2B,FCGR3A,FCHL,FCMD,FCP1,FDPSL5,FECH,FEO,FEOM1,FES,FGA,FGB,FGD1,FGF2,FGF23,FGF5,FGFR2,FGFR3,FGFR1,FGG,FGS1,FH,FIC1,FIH,F2,FKBP6,FLNA,FLT4,FMO3,FMO4,FMR2,FMR1,FN,FN1/m,FOXC1,FOXE1,FOXL2,FOXO1A,FPDMM,FPF,Fra-1,FRAXF,FRDA,FSHB,FSHMD1A,FSHR,FTH1,FTHL17,FTL,FTZF1,FUCA1,FUT2,FUT6,FUT1,FY,G250,G250/CAIX,G6PC,G6PD,G6PT1,G6PT2,GAA,GABRA3,GAGE-1,GAGE-2,GAGE-3,GAGE-4,GAGE-5,GAGE-6,GAGE-7b,GAGE-8,GALC,GALE,GALK1,GALNS,GALT,GAMT,GAN,GAST,GASTRIN17,GATA3,GATA,GBA,GBE,GC,GCDH,GCGR,GCH1,GCK,GCP-2,GCS1,G-CSF,GCSH,GCSL,GCY,GDEP,GDF5,GDI1,GDNF,GDXY,GFAP,GFND,GGCX,GGT1,GH2,GH1,GHR,GH RHR,GHS,GIF,GINGF,GIP,GJA3,GJA8,GJB2,GJB3,GJB6,GJB1,GK,GLA,GLB,GLB1,GLC3B,GLC1B,GLC1C,GLDC,GLI3,GLP1,GLRA1,GLUD1,GM1(fuc-GM1),GM2A,GM-CSF,GMPR,GNAI2,GNAS,GNAT1,GNB3,GNE,GNPTA,GNRH,GNRH1,GNRHR,GNS,GnT-V,gp100,GP1BA,GP1BB,GP9,GPC3,GPD2,GPDS1,GPI,GP1BA,GPN1LW,GPNMB/m,GPSC,GPX1,GRHPR,GRK1,GROα,GROβ,GROγ,GRPR,GSE,GSM1,GSN,GSR,GSS,GTD,GTS,GUCA1A,GUCY2D,GULOP,GUSB,GUSM,GUST,GYPA,GYPC,GYS1,GYS2,H0KPP2,H0MG2,HADHA,HADHB,HAGE,HAGH,HAL,HAST-2,HB1,HBA2,HBA1,HBB,HBBP1,HBD,HBE1,HBG2,HBG1,HBHR,HBP1,HBQ1,HBZ,HBZP,HCA,HCC-1,HCC-4,HCF2,HCG,HCL2,HCL1,HCR,HCVS,HD,HPN,HER2,HER2/NEU,HER3,HERV-K-MEL,HESX1,HEXA,HEXB,HF1,HFE,HF1,HGD,HHC2,HHC3,HHG,HK1 HLA-A,HLA-A*0201-R170I,HLA-A11/m,HLA-A2/m,HLA-DPB1 HLA-DRA,HLCS,HLXB9,HMBS,HMGA2,HMGCL,HMI,HMN2,HMOX1,HMS1 HMW-MAA,HND,HNE,HNF4A,HOAC,HOMEOBOX NKX 3.1,HOM-TES-14/SCP-1,HOM-TES-85,HOXA1 HOXD13,HP,HPC1,HPD,HPE2,HPE1,HPFH,HPFH2,HPRT1,HPS1,HPT,HPV-E6,HPV-E7,HR,HRAS,HRD,HRG,HRPT2,HRPT1,HRX,HSD11B2,HSD17B3,HSD17B4,HSD3B2,HSD3B3,HSN1,HSP70-2M,HSPG2,HST-2,HTC2,HTC1,hTERT,HTN3,HTR2C,HVBS6,HVBS1,HVEC,HV1S,HYAL1,HYR,I-309,IAB,IBGC1,IBM2,ICAM1,ICAM3,iCE,ICHQ,ICR5,ICR1,ICS 1,IDDM2,IDDM1,IDS,IDUA,IF,IFNa/b,IFNGR1,IGAD1,IGER,IGF-1R,IGF2R,IGF1,IGH,IGHC,IGHG2,IGHG1,IGHM,IGHR,IGKC,IHG1,IHH,IKBKG,IL1,IL-1RA,IL10,IL-11,IL12,IL12RB1,IL13,IL-13Rα2,IL-15,IL-16,IL-17,IL18,IL-1a,IL-1α,IL-1b,IL-1β,IL1RAPL1,IL2,IL24,IL-2R,IL2RA,IL2RG,IL3,IL3RA,IL4,IL4R,IL4R,IL-5,IL6,IL-7,IL7R,IL-8,IL-9,未成熟层粘连蛋白受体,IMMP2L,INDX,INFGR1,INFGR2,INFα,IFN,INFγ,INS,INSR,INVS,IP-10,IP2,IPF1,IP1,IRF6,IRS1,ISCW,ITGA2,ITGA2B,ITGA6,ITGA7,ITGB2,ITGB3,ITGB4,ITIH1,ITM2B,IV,IVD,JAG1,JAK3,JBS,JBTS1,JMS,JPD,KAL1,KAL2,KALI,KLK2,KLK4,KCNA1,KCNE2,KCNE1,KCNH2,KCNJ1,KCNJ2,KCNJ1,KCNQ2,KCNQ3,KCNQ4,KCNQ1,KCS,KERA,KFM,KFS,KFSD,KHK,ki-67,KIAA0020,KIAA0205,KIAA0205/m,KIF1B,KIT,KK-LC-1,KLK3,KLKB1,KM-HN-1,KMS,KNG,KNO,K-RAS/m,KRAS2,KREV1,KRT1,KRT10,KRT12,KRT13,KRT14,KRT14L1,KRT14L2,KRT14L3,KRT16,KRT16L1,KRT16L2,KRT17,KRT18,KRT2A,KRT3,KRT4,KRT5,KRT6A,KRT6B,KRT9,KRTHB1,KRTHB6,KRT1,KSA,KSS,KWE,KYNU,L0H19CR1,L1CAM,LAGE,LAGE-1,LALL,LAMA2,LAMA3,LAMB3,LAMB1,LAMC2,LAMP2,LAP,LCA5,LCAT,LCCS,LCCS 1,LCFS2,LCS1,LCT,LDHA,LDHB,LDHC,LDLR,LDLR/FUT,LEP,LEWISY,LGCR,LGGF-PBP,LGI1,LGMD2H,LGMD1A,LGMD1B,LHB,LHCGR,LHON,LHRH,LHX3,LIF,LIG1,LIMM,LIMP2,LIPA,LIPA,LIPB,LIPC,LIVIN,L1CAM,LMAN1,LMNA,LMX1B,LOLR,LOR,LOX,LPA,LPL,LPP,LQT4,LRP5,LRS 1,LSFC,LT-β,LTBP2,LTC4S,LYL1,XCL1,LYZ,M344,MA50,MAA,MADH4,MAFD2,MAFD1,MAGE,MAGE-A1,MAGE-A10,MAGE-A12,MAGE-A2,MAGE-A3,MAGE-A4,MAGE-A6,MAGE-A9,MAGEB1,MAGE-B10,MAGE-B16,MAGE-B17,MAGE-B2,MAGE-B3,MAGE-B4,MAGE-B5,MAGE-B6,MAGE-C1,MAGE-C2,MAGE-C3,MAGE-D1,MAGE-D2,MAGE-D4,MAGE-E1,MAGE-E2,MAGE-F1,MAGE-H1,MAGEL2,MGB1,MGB2,MAN2A1,MAN2B1,MANBA,MANBB,MAOA,MAOB,MAPK8IP1,MAPT,MART-1,MART-2,MART2/m,MAT1A,MBL2,MBP,MBS1,MC1R,MC2R,MC4R,MCC,MCCC2,MCCC1,MCDR1,MCF2,MCKD,MCL1,MC1R,MCOLN1,MCOP,MCOR,MCP-1,MCP-2,MCP-3,MCP-4,MCPH2,MCPH1,MCS,M-CSF,MDB,MDCR,MDM2,MDRV,MDS 1,ME1,ME1/m,ME2,ME20,ME3,MEAX,MEB,MEC CCL-28,MECP2,MEFV,MELANA,MELAS,MEN1 MSLN,MET,MF4,MG50,MG50/PXDN,MGAT2,MGAT5,MGC1 MGCR,MGCT,MGI,MGP,MHC2TA,MHS2,MHS4,MIC2,MIC5,MIDI,MIF,MIP,MIP-5/HCC-2,MITF,MJD,MKI67,MKKS,MKS1,MLH1,MLL,MLLT2,MLLT3,MLLT7,MLLT1,MLS,MLYCD,MMA1a,MMP 11,MMVP1,MN/CA IX-Antigen,MNG1,MN1,MOC31,MOCS2,MOCS1,MOG,MORC,MOS,MOV18,MPD1,MPE,MPFD,MPI,MPIF-1,MPL,MPO,MPS3C,MPZ,MRE11A,MROS,MRP1,MRP2,MRP3,MRSD,MRX14,MRX2,MRX20,MRX3,MRX40,MRXA,MRX1,MS,MS4A2,MSD,MSH2,MSH3,MSH6,MSS,MSSE,MSX2,MSX1,MTATP6,MTC03,MTCO1,MTCYB,MTHFR,MTM1,MTMR2,MTND2,MTND4,MTND5,MTND6,MTND1,MTP,MTR,MTRNR2,MTRNR1,MTRR,MTTE,MTTG,MTTI,MTTK,MTTL2,MTTL1,MTTN,MTTP,MTTS1,MUC1,MUC2,MUC4,MUC5AC,MUM-1,MUM-1/m,MUM-2,MUM-2/m,MUM-3,MUM-3/m,MUT,突变体p21 ras,MUTYH,MVK,MX2,MXI1,MY05A,MYB,MYBPC3,MYC,MYCL2,MYH6,MYH7,MYL2,MYL3,MYMY,MYO15A,MYO1G,MYO5A,MYO7A,MYOC,肌球蛋白/m,MYP2,MYP1,NA88-A,N-
乙酰葡糖氨基转移酶-V,NAGA,NAGLU,NAMSD,NAPB,NAT2,NAT,NBIA1,NBS1,NCAM,NCF2,NCF1,NDN,NDP,NDUFS4,NDUFS7,NDUFS8,NDUFV1,NDUFV2,NEB,NEFH,NEM1,Neo-PAP,neo-PAP/m,NEU1,NEUROD1,NF2,NF1,NFYC/m,NGEP,NHS,NKS1,NKX2E,NM,NME1,NMP22,NMTC,NODAL,NOG,NOS3,NOTCH3,NOTCH1,NP,NPC2,NPC1,NPHL2,NPHP1,NPHS2,NPHS1,NPM/ALK,NPPA,NQO1,NR2E3,NR3C1,NR3C2,NRAS,NRAS/m,NRL,NROB1,NRTN,NSE,NSX,NTRK1,NUMA1,NXF2,NY-CO1,NY-ESO1,NY-ESO-B,NY-LU-12,ALDOA,NYS2,NYS4,NY-SAR-35,NYS1,NYX,OA3,OA1,OAP,OASD,OAT,OCA1,OCA2,OCD1,OCRL,OCRL1,OCT,ODDD,ODT1,OFC1,OFD1,OGDH,OGT,OGT/m,OPA2,OPA1,OPD1,OPEM,OPG,OPN,OPN1LW,OPN1MW,OPN1SW,OPPG,OPTB1,TTD,ORM1,ORP1,OS-9,OS-9/m,OSM LIF,OTC,OTOF,OTSC1,OXCT1,OYTES1,P15,P190 MINOR BCR-ABL,P2RY12,P3,P16,P40,P4HB,P-501,P53,P53/m,P97,PABPN1,PAFAH1B1,PAFAH1P1,PAGE-4,PAGE-5,PAH,PAI-1,PAI-2,PAK3,PAP,PAPPA,PARK2,PART-1,PATE,PAX2,PAX3,PAX6,PAX7,PAX8,PAX9,PBCA,PBCRA1,PBT,PBX1,PBXP1,PC,PCBD,PCCA,PCCB,PCK2,PCK1,PCLD,PCOS1,PCSK1,PDB1,PDCN,PDE6A,PDE6B,PDEF,PDGFB,PDGFR,PDGFRL,PDHA1,PDR,PDX1,PECAM1,PEE1,PEO1,PEPD,PEX10,PEX12,PEX13,PEX3,PEX5,PEX6,PEX7,PEX1,PF4,PFBI,PFC,PFKFB1,PFKM,PGAM2,PGD,PGK1,PGK1P1,PGL2,PGR,PGS,PHA2A,PHB,PHEX,PHGDH,PHKA2,PHKA1,PHKB,PHKG2,PHP,PHYH,PI,PI3,PIGA,PIM1-KINASE,PIN1,PIP5K1B,PITX2,PITX3,PKD2,PKD3,PKD1,PKDTS,PKHD1,PKLR,PKP1,PKU1,PLA2G2A,PLA2G7,PLAT,PLEC1,PLG,PLI,PLOD,PLP1,PMEL17,PML,PML/RARα,PMM2,PMP22,PMS2,PMS1,PNKD,PNLIP,POF1,POLA,POLH,POMC,PON2,PON1,PORC,POTE,POU1F1,POU3F4,POU4F3,POU1F1,PPAC,PPARG,PPCD,PPGB,PPH1,PPKB,PPMX,PPOX,PPP1R3A,PPP2R2B,PPT1,PRAME,PRB,PRB3,PRCA1,PRCC,PRD,PRDX5/m,PRF1,PRG4,PRKAR1A,PRKCA,PRKDC,PRKWNK4,PRNP,PROC,PRODH,PROM1,PROP1,PROS1,PRST,PRP8,PRPF31,PRPF8,PRPH2,PRPS2,PRPS1,PRS,PRSS7,PRSS1,PRTN3,PRX,PSA,PSAP,PSCA,PSEN2,PSEN1,PSG1,PSGR,PSM,PSMA,PSORS1,PTC,PTCH,PTCH1,PTCH2,PTEN,PTGS1,PTH,PTHR1,PTLAH,PTOS1,PTPN12,PTPNI I,PTPRK,PTPRK/m,PTS,PUJO,PVR,PVRL1,PWCR,PXE,PXMP3,PXR1,PYGL,PYGM,QDPR,RAB27A,RAD54B,RAD54L,RAG2,RAGE,RAGE-1,RAG1,RAP1,RARA,RASA1,RBAF600/m,RB1,RBP4,RBP4,RBS,RCA1,RCAS1,RCCP2,RCD1,RCV1,RDH5,RDPA,RDS,RECQL2,RECQL3,RECQL4,REG1A,REHOBE,REN,RENBP,RENS1,RET,RFX5,RFXANK,RFXAP,RGR,RHAG,RHAMM/CD168,RHD,RHO,Rip-1,RLBP1,RLN2,RLN1,RLS,RMD1,RMRP,ROM1,ROR2,RP,RP1,RP14,RP17,RP2,RP6,RP9,RPD1,RPE65,RPGR,RPGRIP1,RP1,RP10,RPS19,RPS2,RPS4X,RPS4Y,RPS6KA3,RRAS2,RS1,RSN,RSS,RU1,RU2,RUNX2,RUNXI,RWS,RYR1,S-100,SAA1,SACS,SAG,SAGE,SALL1,SARDH,SART1,SART2,SART3,SAS,SAX1,SCA2,SCA4,SCA5,SCA7,SCA8,SCA1,SCC,SCCD,SCF,SCLC1,SCN1A,SCN1B,SCN4A,SCN5A,SCNN1A,SCNN1B,SCNN1G,SCO2,SCP1,SCZD2,SCZD3,SCZD4,SCZD6,SCZD1,SDF-1α/β,SDHA,SDHD,SDYS,SEDL,SERPENA7,SERPINA3,SERPINA6,SERPINA1,SERPINC1,SERPIND1,SERPINE1,SERPINF2,SERPING1,SERPINI1,SFTPA1,SFTPB,SFTPC,SFTPD,SGCA,SGCB,SGCD,SGCE,SGM1,SGSH,SGY-1,SH2D1A,SHBG,SHFM2,SHFM3,SHFM1,SHH,SHOX,SI,SIAL,SIALYL LEWISX,SIASD,S11,SIM1,SIRT2/m,SIX3,SJS1,SKP2,SLC10A2,SLC12A1,SLC12A3,SLC17A5,SLC19A2,SLC22A1L,SLC22A5,SLC25A13,SLC25A15,SLC25A20,SLC25A4,SLC25A5,SLC25A6,SLC26A2,SLC26A3,SLC26A4,SLC2A1,SLC2A2,SLC2A4,SLC3A1,SLC4A1,SLC4A4,SLC5A1,SLC5A5,SLC6A2,SLC6A3,SLC6A4,SLC7A7,SLC7A9,SLC11A1,SLOS,SMA,SMAD1,SMAL,SMARCB1,SMAX2,SMCR,SMCY,SM1,SMN2,SMN1,SMPD1,SNCA,SNRPN,SOD2,SOD3,SOD1,SOS1,SOST,SOX9,SOX10,Sp17,SPANXC,SPG23,SPG3A,SPG4,SPG5A,SPG5B,SPG6,SPG7,SPINK1,SPINK5,SPPK,SPPM,SPSMA,SPTA1,SPTB,SPTLC1,SRC,SRD5A2,SRPX,SRS,SRY,βhCG,SSTR2,SSX1,SSX2(HOM-MEL-40/SSX2),SSX4,ST8,STAMP-1,STAR,STARP1,STATH,STEAP,STK2,STK11,STn/KLH,STO,STOM,STS,SUOX,SURF1,SURVIVIN-2B,SYCP1,SYM1,SYN1,SYNS1,SYP,SYT/SSX,SYT-SSX-1,SYT-SSX-2,TA-90,TAAL6,TACSTD1,TACSTD2,TAG72,TAF7L,TAF1,TAGE,TAG-72,TALI,TAM,TAP2,TAP1,TAPVR1,TARC,TARP,TAT,TAZ,TBP,TBX22,TBX3,TBX5,TBXA2R,TBXAS1,TCAP,TCF2,TCF1,TCIRG1,TCL2,TCL4,TCL1A,TCN2,TCOF1,TCR,TCRA,TDD,TDFA,TDRD1,TECK,TECTA,TEK,TEL/AML1,TELAB1,TEX15,TF,TFAP2B,TFE3,TFR2,TG,TGFA,TGF-β,TGFBI,TGFB1,TGFBR2,TGFBRE,TGFβ,TGFβRII,TGIF,TGM-4,TGM1,TH,THAS,THBD,THC,THC2,THM,THPO,THRA,THRB,TIMM8A,TIMP2,TIMP3,TIMP1,TITF1,TKCR,TKT,TLP,TLR1,TLR10,TLR2,TLR3,TLR4,TLR4,TLR5,TLR6,TLR7,TLR8,TLR9,TLX1,TM4SF1,TM4SF2,TMC1,TMD,TMIP,TNDM,TNF,TNFRSF11A,TNFRSF1A,TNFRSF6,TNFSF5,TNFSF6,TNFα,TNFβ,TNNI3,TNNT2,TOC,TOP2A,TOP1,TP53,TP63,TPA,TPBG,TPI,TPI/m,TPI1,TPM3,TPM1,TPMT,TPO,TPS,TPTA,TRA,TRAG3,TRAPPC2,TRC8,TREH,TRG,TRH,TRIM32,TRIM37,TRP1,TRP2,TRP-2/6b,TRP-2/INT2,Trp-p8,TRPS1,TS,TSC2,TSC3,TSC1,TSG101,TSHB,TSHR,TSP-180,TST,TTGA2B,TTN,TTPA,TTR,TU M2-PK,TULP1,TWIST,TYH,TYR,TYROBP,TYROBP,TYRP1,TYS,UBE2A,UBE3A,UBE1,UCHL1,UFS,UGT1A,ULR,UMPK,UMPS,UOX,UPA,UQCRC1,URO5,UROD,UPK1B,UROS,USH2A,USH3A,USH1A,USH1C,USP9Y,UV24,VBCH,VCF,VDI,VDR,VEGF,VEGFR-2,VEGFR-1,VEGFR-2/FLK-1,VHL,VIM,VMD2,VMD1,VMGLOM,VNEZ,VNF,VP,VRNI,VWF,VWS,WAS,WBS2,WFS2,WFS1,WHCR,WHN,WISP3,WMS,WRN,WS2A,WS2B,WSN,WSS,WT2,WT3,WT1,WTS,WWS,XAGE,XDH,XIC,XIST,XK,XM,XPA,XPC,XRCC9,XS,ZAP70,ZFHX1B,ZFX,ZFY,ZIC2,ZIC3,ZNF145,ZNF261,ZNF35,ZNF41,ZNF6,ZNF198,ZWS1.
治疗活性蛋白还可以选自细胞凋亡因子或细胞凋亡相关蛋白包括AIF,Apaf例如Apaf-1,Apaf-2,Apaf-3,oder APO-2(L),APO-3(L),凋亡酶,Bad,Bak,Bax,Bcl-2,Bcl-xL,Bcl-xS,bik,CAD,钙激活中性蛋白酶,胱天蛋白酶例如胱天蛋白酶-1,胱天蛋白酶-2,胱天蛋白酶-3,胱天蛋白酶-4,胱天蛋白酶-5,胱天蛋白酶-6,胱天蛋白酶-7,胱天蛋白酶-8,胱天蛋白酶-9,胱天蛋白酶-10,胱天蛋白酶-11,ced-3,ced-9,c-Jun,c-Myc,crm A,细胞色素C,CdR1,DcR1,DD,DED,DISC,DNA-PKCS,DR3,DR4,DR5,FADD/MORT-1,FAK,Fas(Fas-配体CD95/fas(受体)),FLICE/MACH,FLIP,胞衬蛋白,fos,G-肌动蛋白,Gas-2,凝溶胶蛋白,粒酶A/B,ICAD,ICE,JNK,核纤层蛋白A/B,MAP,MCL-1,Mdm-2,MEKK-1,MORT-1,NEDD,NF-κB,NuMa,p53,PAK-2,PARP,穿孔蛋白,PITSLRE,PKCδ,pRb,早老蛋白,prICE,RAIDD,Ras,RIP,鞘磷脂酶,来自单纯疱疹的胸苷激酶,TRADD,TRAF2,TRAIL-R1,TRAIL-R2,TRAIL-R3,转谷氨酰胺酶,等。
可以由本发明的免疫刺激组合物的佐剂成分的至少一种(m)RNA编码的治疗活性蛋白还可以是佐剂蛋白。在上下文中,佐剂蛋白优选被理解为能够引起如本文中定义的先天免疫应答的任何蛋白。优选地,所述先天免疫应答包括模式识别受体,诸如例如选自Toll-样受体(TLR)家族的受体,包括例如选自人TLR1-TLR10或选自鼠Toll样受体TLR1-TLR13的Toll样受体的活化。优选地,先天免疫应答在如上定义的哺乳动物中被激发。更优选地,所述佐剂蛋白选自人佐剂蛋白或选自致病性佐剂蛋白,特别选自细菌佐剂蛋白。另外,也可以使用编码参与佐剂作用的人蛋白的mRNA。
可以由本发明的免疫刺激组合物的佐剂成分的至少一种(m)RNA编码的人佐剂蛋白典型地包括任何人蛋白,其能够引起先天免疫反应(在哺乳动物中),例如作为外源TLR配体与TLR结合反应。更优选地,由本发明的免疫刺激组合物的至少一种修饰的(m)RNA编码的人佐剂蛋白选自由,但不仅限于以下各项组成的组:诱导或增强先天免疫反应的细胞因子,包括IL-2,IL-12,IL-15,IL-18,IL-21CCL21,GM-CSF和TNF-α;由巨噬细胞释放的细胞因子,包括IL-1,IL-6,IL-8,IL-12和TNF-α;选自补体系统的成分,包括C1q,MBL,C1r,C1s,C2b,Bb,D,MASP-1,MASP-2,C4b,C3b,C5a,C3a,C4a,C5b,C6,C7,C8,C9,CR1,CR2,CR3,CR4,C1qR,C1INH,C4bp,MCP,DAF,H,I,P和CD59;选自作为图式识别受体的信号传导网络成分的蛋白包括TLR和IL-1R1,而所述成分是图式识别受体的配体包括IL-1α,IL-1β,β-防卫素,热激蛋白,诸如HSP10,HSP60,HSP65,HSP70,HSP75和HSP90,gp96,血纤蛋白原,纤连蛋白的TypIII重复额外结构域A;受体,包括IL-1RI,TLR1,TLR2,TLR3,TLR4,TLR5,TLR6,TLR7,TLR8,TLR9,TLR10,TLR11;信号转导物包括小GTP酶信号传导的成分(RhoA,Ras,Rac1,Cdc42等),PIP信号传导的成分(PI3K,Src-激酶,等),MyD88-依赖性信号传导的成分(MyD88,IRAK1,IRAK2,等),MyD88-不依赖性信号传导的成分(TICAM1,TICAM2等);活化的转录因子包括例如NF-κB,c-Fos,c-Jun,c-Myc;和诱导的靶基因包括例如IL-1α,IL-1β,β-防卫素,IL-6,IFNγ,IFNα和IFNβ;选自共刺激分子,包括CD28或CD40-配体或PD1;蛋白结构域,包括LAMP;细胞表面蛋白;或人佐剂蛋白包括CD80,CD81,CD86,trif,flt-3配体,胸腺五肽,Gp96或纤连蛋白,等,或任意以上人佐剂蛋白的任意物种同系物。
可以由本发明的免疫刺激组合物的佐剂成分的至少一种(m)RNA编码的致病性佐剂蛋白典型地包括任何能够引起先天免疫反应(在哺乳动物中)的致病性(佐剂)蛋白,更优选选自源自细菌、原生动物、病毒或真菌、动物,等的致病性(佐剂)蛋白,和甚至更优选地来自选自由,但不仅限于,细菌蛋白、原生生物蛋白(例如刚地弓形虫(Toxoplasma gondii)的抑制蛋白样蛋白),病毒蛋白,或真菌蛋白,动物蛋白,等组成的组的致病性佐剂蛋白。
在该上下文中,可以由本发明的免疫刺激组合物的佐剂成分的至少一种(m)RNA编码的细菌(佐剂)蛋白可以包括任何能够引起先天免疫应答(优选在哺乳动物中)或显示佐剂特征的细菌蛋白。更优选地,所述细菌(佐剂)蛋白选自由以下组成的组:细菌热激蛋白或蛋白伴侣,包括Hsp60,Hsp70,Hsp90,Hsp100;来自革兰士阴性菌的OmpA(外膜蛋白);细菌孔蛋白,包括OmpF;细菌毒素,包括来自百日咳博德特氏菌(Bordetella pertussis)的百日咳毒素(PT),来自百日咳博德特氏菌的百日咳腺苷酸环化酶毒素CyaA和CyaC,来自百日咳毒素的PT-9K/129G突变体,来自百日咳博德特氏菌的百日咳腺苷酸环化酶毒素CyaA和CyaC,破伤风毒素,霍乱毒素(CT),霍乱毒素B-亚单元,来自霍乱毒素的CTK63突变体,来自CT的CTE112K突变体,大肠埃希氏菌热-不稳定性肠毒素(LT),来自减毒热-不稳定性肠毒素(LTB)大肠埃希氏菌(Escherichia coli)热-不稳定性肠毒素变体的B亚单元,包括LTK63,LTR72;可溶于苯酚的modulin;来自幽门螺杆菌(Helicobacter pylor)的嗜中性白细胞活化蛋白(HP-NAP);表面活性剂蛋白D;来自布氏疏螺旋体(Borrelia burgdorferi)的外表面蛋白A脂蛋白,来自结核分枝杆菌(Mycobacterium tuberculosis)的Ag38(38kDa抗原);来自细菌菌毛的蛋白;霍乱弧菌(Vibrio cholerae)的肠毒素CT,来自革兰士阴性菌的菌毛的菌毛蛋白,和表面活性剂蛋白A;等,或任意以上细菌(佐剂)蛋白的任何物种同系物。
可以由本发明的免疫刺激组合物的佐剂成分的至少一种(m)RNA编码的细菌(佐剂)蛋白还可以选自细菌佐剂蛋白,甚至更优选选自由以下组成的组,但不仅限于:细菌鞭毛蛋白,包括来自以下生物的鞭毛蛋白:土壤杆菌属(Agrobacterium),产液菌属(Aquifex),固氮螺菌属(Azospirillum),芽孢杆菌属(Bacillus),巴尔通氏体属(Bartonella),博德特氏菌属(Bordetella),疏螺旋体属(Borrelia),伯克霍尔德氏菌属(Burkholderia),弯曲杆菌属(Campylobacter),柄杆菌属(Caulobacte),梭菌属(Clostridium),埃希氏菌属(Escherichia),螺杆菌属(Helicobacter),Lachnospiraceae,军团菌属(Legionella),利斯特氏菌属(Listeria),变形菌属(Proteus),假单胞菌属(Pseudomonas),根瘤菌属(Rhizobium),红细菌属(Rhodobacter),Roseburia,沙门氏菌属(Salmonella),小蛇菌属(Serpulina),沙雷氏菌属(Serratia),志贺氏菌属(Shigella),密螺旋体属(Treponema),弧菌属(Vibrio),沃林氏菌属(Wolinella),耶尔森氏菌属(Yersinia),更优选来自下述物种的鞭毛蛋白,所述物种不仅限于,根癌土壤杆菌(Agrobacterium tumefaciens),嗜火产液菌(Aquifex pyrophilus),巴西固氮螺菌(Azospirillum brasilense),枯草芽孢杆菌(Bacillus subtilis),苏云金芽孢杆菌(Bacillus thuringiensis),杆状巴尔通氏体(Bartonella bacilliformis),支气管炎博德特氏菌(Bordetella bronchiseptica),布氏疏螺旋体(Borrelia burgdorferi),洋葱伯克霍尔德氏菌(Burkholderia cepacia),空肠弯曲杆菌空肠亚种(Campylobacter jejuni),新月柄杆菌(Caulobacter crescentus),肉毒梭菌(Clostridium botulinum)菌株Bennett克隆1,大肠埃希氏菌(Escherichia coli),幽门螺杆菌(Helicobacter pylori),Lachnospiraceae bacterium,侵肺军团菌(Legionella pneumophila),单核细胞增生利斯特氏菌(Listeria monocytogenes),奇异变形菌(Proteus mirabilis),Pseudomonas aeroguinosa,丁香假单胞菌(Pseudomonas syringae),苜蓿中华根瘤菌(Rhizobium meliloti),类球红细菌(Rhodobacter sphaeroides),Roseburia cecicola,Roseburis hominis,鼠伤寒沙门氏菌(Salmonella typhimurium),邦戈尔沙门氏菌(Salmonella bongori),伤寒沙门氏菌(Salmonella typhi),Salmonella enteritidis,猪痢疾小蛇菌(Serpulina hyodysenteriae),粘质沙雷氏菌(Serratia marcescens),鲍氏志贺氏菌(Shigella boydii),溃蚀密螺旋体(Treponema phagedenis),解藻朊酸弧菌(Vibrio alginolyticus),霍乱弧菌(Vibrio cholerae),副溶血弧菌(Vibrio parahaemolyticus),产琥珀酸沃林氏(Wolinella succinogenes)和小肠结肠炎耶尔森氏菌(Yersinia enterocolitica)。
可以由本发明的免疫刺激组合物的佐剂成分的至少一种(m)RNA编码的细菌鞭毛蛋白甚至更优选地包括选自这样的组中的序列,所述组包括任意以下参考其编号的序列:
还可以由本发明的免疫刺激组合物的佐剂成分的至少一种(m)RNA编码的原生动物蛋白可以选自任何表现出佐剂特征的原生动物蛋白,更优选地,选自由,不仅限于,以下各项组成的组:来自美洲锥虫(Trypanosoma cruzi)的Tc52,来自刚地锥虫(Trypanosoma gondii)的PFTG,原生动物热激蛋白,来自利什曼虫属物种(Leishmania spp.)的LeIF,来自刚地弓形虫的抑制蛋白样蛋白,等。
可以由本发明的免疫刺激组合物的佐剂成分的至少一种(m)RNA编码的病毒蛋白可以选自任何表现出佐剂特征的病毒蛋白,更优选地,选自由,不仅限于,以下各项组成的组:呼吸道合胞体病毒融合糖蛋白(F-蛋白),来自MMT病毒的包膜蛋白,小鼠白血病病毒蛋白,野生型麻疹病毒的血凝素蛋白,等。
可以由本发明的免疫刺激组合物的佐剂成分的至少一种(m)RNA编码的真菌蛋白可以选自任何表现出佐剂特征的真菌蛋白,更优选地,选自由,不仅限于,真菌免疫调节蛋白(FIP;LZ-8),等组成的组。
最后,可以由本发明的免疫刺激组合物的佐剂成分的至少一种(m)RNA编码的致病性佐剂蛋白可以最终选自任何表现出佐剂特征的其他致病性蛋白,更优选地,选自由,不仅限于,匙孔血蓝蛋白(KLH),OspA,等组成的组。
b)抗原
所述免疫刺激组合物的佐剂成分的至少一种(m)RNA可以备选地编码抗原。根据本发明,术语“抗原”指由免疫系统识别并能够,例如通过形成抗体作为适应性免疫应答或抗原特异性T-细胞的一部分来触发抗原特异性免疫反应的物质。在该上下文中,适应性免疫应答的第一步是由抗原呈递细胞激活幼稚抗原特异性T细胞。这发生在幼稚T细胞经常通过的淋巴组织和器官中。可以起抗原呈递细胞作用的三种细胞类型是树突细胞、巨噬细胞、和B细胞。这些细胞中的每种在引起免疫应答中具有不同功能。组织树突细胞通过吞噬作用和大胞饮吸收抗原并受感染刺激移动到局部淋巴组织,它们在该处分化为成熟树突细胞。巨噬细胞摄取微粒抗原诸如细菌并受传染原诱导表达MHC II类分子。B细胞经由其受体结合并内在化可溶性蛋白抗原的独特能力对于诱导T细胞可能是重要的。通过在MHC分子上呈递抗原,导致T细胞的活化,这诱导其增殖和分化为武装效应T细胞。效应T细胞的最重要功能是通过CD8细胞毒性T细胞杀死被感染的细胞和通过TH1细胞激活巨噬细胞,它们共同组成细胞介导的免疫性,和通过TH2和TH1细胞二者激活B细胞以产生不同类型的抗体,由此驱动体液免疫应答。T细胞通过其T细胞受体识别抗原,所述T细胞受体不直接识别和结合抗原,而是识别与其他细胞表面上的MHC分子结合的例如病原体蛋白抗原的短肽片段。
T细胞属于两种具有不同效应子功能的主要类型。这两类通过细胞表面蛋白CD4和CD8的表达来区分。这两种T细胞类型的不同之处在于它们识别的MHC分子类型。存在两种MHC分子类型—MHC I类和MHC II类—其区别在于它们的结构和身体组织上的表达模式。CD4 T细胞结合MHC II类分子且CD8 T细胞结合MHC I类分子。MHC I类和MHC II类在细胞之间具有不同的分布,这反映识别它们的T细胞的不同效应子功能。MHC I类分子将来自病原体,常见地,病毒的肽呈递到CD8T细胞,其分化为细胞毒性T细胞,所述细胞毒性T细胞特化为杀死它们特异性识别的任何细胞。几乎所有细胞表达MHC I类分子,尽管组成型表达的水平从一种细胞类型到下一种变化。但是不仅来自病毒的致病性肽由MHC I类分子呈递,而且自身-抗原样肿瘤抗原也由它们呈递。MHC I类分子结合来自在细胞溶胶中降解和在内质网中运输的蛋白的肽。由此,受病毒或其他胞质病原体感染的细胞表面上的MHC I类分子展示来自这些病原体的肽。识别MHC I类:肽复合物的CD8 T细胞被特化为杀死展示外源肽的任何细胞并因此除去受病毒和其他胞质病原体感染的细胞体。识别MHC II类分子的CD4 T细胞(CD4辅助性T细胞)的主要功能是激活免疫系统的其他效应细胞。因此MHC II类分子通常存在于参与免疫应答的B淋巴细胞,树突细胞,和巨噬细胞上,而不在其他组织细胞上。激活例如巨噬细胞,从而杀死它们包埋的小泡内病原体,并且激活B细胞,从而分泌针对外源分子的免疫球蛋白。抑制MHC II类分子与内质网中的肽结合,并且因此MHC II类分子结合来自在内体中降解的蛋白的肽。它们可以捕获来自已经进入巨噬细胞小泡系统的病原体的肽,或来自通过未成熟树突细胞或B细胞免疫球蛋白受体内在化的抗原的肽。在巨噬细胞和树突细胞小泡内部大量积聚的病原体倾向于刺激TH1细胞的分化,而胞外抗原倾向于刺激TH2细胞生成。TH1细胞激活巨噬细胞的杀微生物性质并诱导B细胞产生IgG抗体,所述IgG抗体非常有效地调理胞外病原体,从而被吞噬细胞摄取,而TH2细胞通过激活幼稚B细胞分泌IgM而起始体液应答,并诱导弱调理抗体诸如IgG1和IgG3(小鼠)和IgG2和IgG4(人)以及IgA和IgE(小鼠和人)的生成。
在本发明的上下文中,由本发明的免疫刺激组合物的佐剂成分的至少一种(m)RNA编码的抗原典型地包括被归入以上定义的任何抗原,更优选蛋白和肽抗原,例如肿瘤抗原,过敏反应抗原,自体免疫自身-抗原,致病性抗原,等。根据本发明,由本发明的免疫刺激组合物的佐剂成分的至少一种(m)RNA编码的抗原可以是细胞外部产生的抗原,更典型地,不源自宿主生物体(例如人)自身(即非-自身抗原)而源自宿主生物体外部的宿主细胞的抗原,例如病毒抗原,细菌抗原,真菌抗原,原生动物抗原,动物抗原(优选选自如本文中公开的动物或生物体),过敏反应抗原,等。过敏反应抗原典型地是在人中导致过敏反应并可以源自人或其他来源的抗原。由本发明的免疫刺激组合物的佐剂成分的至少一种(m)RNA编码的抗原还可以是在细胞、组织或身体内,例如通过蛋白的分泌,其降解、代谢等产生的抗原。这样的抗原包括源自宿主生物体(例如人)自身的抗原,例如肿瘤抗原,自身-抗原或自体-抗原,诸如自体免疫自身-抗原,等,还包括如上定义的(非-自身)抗原,其最初源自宿主生物体外部的宿主细胞,但在身体、组织或细胞内部,例如通过(蛋白酶)降解、代谢等断裂或降解。致病性抗原特别包括例如来自流行性感冒的抗原,包括血凝素(HA),神经酰胺酶(NA),基质蛋白1(M1),离子通道蛋白M2(M2),核蛋白(NP),等;或例如来自呼吸道合胞病毒(RSV)的抗原,包括F-蛋白,G-蛋白,等。
由本发明的免疫刺激组合物的佐剂成分的至少一种(m)RNA编码的抗原还可以包括本文中提及的所述抗原的片段,特别是蛋白或肽抗原。本发明上下文中的所述抗原的片段可以包括优选具有约6-约20或甚至更多氨基酸长度的片段,例如由MHC I类分子加工和呈递的片段,其优选具有约8-约10个氨基酸,例如8,9,或10,(或甚至11,或12个氨基酸)的长度,或由MHC II类分子加工和呈递的片段,其优选具有约13或更多氨基酸,例如13,14,15,16,17,18,19,20或甚至更多氨基酸的长度,其中这些片段可以选自所述氨基酸的任何部分。这些片段典型地采用由肽片段和MHC分子组成的复合物形式被T细胞识别,即该片段典型地在处于其幼稚形式时不被识别。
如本文中定义的抗原的片段还可以包括那些抗原的表位。表位(也称为“抗原决定簇”)典型地是位于如本文中定义的(幼稚)蛋白或肽抗原的外表面上的片段,其优选具有5-15个氨基酸,更优选具有5-12个氨基酸,,甚至更优选具有6-9个氨基酸,其可以被抗体,即以其幼稚形式被识别。
一类由本发明的免疫刺激组合物的佐剂成分的至少一种(m)RNA编码的抗原包括肿瘤抗原。“肿瘤抗原”优选位于(肿瘤)细胞表面上。肿瘤抗原还可以选自与正常细胞相比在肿瘤细胞中过表达的蛋白。此外,肿瘤抗原还包括在自身(或最初自身)不退化但与假定的肿瘤有关的细胞中表达的抗原。与肿瘤供给管或其(再)形成相关的抗原,特别地与新血管形成相关的那些抗原,例如生长因子,诸如VEGF,bFGF等,也包括在本文中。与肿瘤有关的抗原还包括来自细胞或组织,典型地包埋肿瘤的细胞或组织的抗原。此外,一些物质(通常是蛋白或肽)表达在患有(已知或未知)癌症疾病的患者中,并且它们以增高的浓度存在于所述患者的体液中。这些物质也称为“肿瘤抗原”,然而在免疫应答诱导物质的严格意义上它们不是抗原。该类肿瘤抗原可以进一步分为肿瘤特异性抗原(TSAs)和肿瘤相关抗原(TAAs)。TSAs仅可以由肿瘤细胞且从不由正常“健康”细胞呈递。它们典型地由肿瘤特异性突变引起。TAAs,其更常见,通常由肿瘤和健康细胞二者呈递。这些抗原被识别并且抗原呈递细胞可以被细胞毒性T细胞破坏。另外,肿瘤抗原还可以以例如突变受体的形式存在于肿瘤表面上。在该情形中,它们可以被抗体识别。
由本发明的免疫刺激组合物的佐剂成分的至少一种(m)RNA编码的肿瘤抗原的实例显示在下表1和2中。这些表关于与其相关的癌症疾病举例说明特异性(蛋白)抗原(即“肿瘤抗原”)。根据本发明,术语“癌症疾病”和“肿瘤疾病”在本文中同义使用。
表1:癌症疾病中表达的抗原
表2:癌症疾病中表达的突变抗原
在按照本发明的优选实施方案中,可以由本发明的免疫刺激组合物的佐剂成分的至少一种(m)RNA编码的肿瘤抗原选自由以下各项组成的组: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-联蛋白/m,BING-4,BRCA1/m,BRCA2/m,CA15-3/CA 27-29,CA 19-9,CA72-4,CA125,钙网蛋白,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,coactosin-样蛋白,胶原蛋白(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,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,mammaglobin A,MART-1/melan-A,MART-2,MART-2/m,基质蛋白22,MC1R,M-CSF,ME1/m,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(Myosin class I/m),NA88-A,N-乙酰葡糖胺转移酶-V,新-PAP,新-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,骨钙蛋白,骨桥蛋白,p15,p190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,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,存活蛋白,存活蛋白-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。
在特别优选实施方案中,可以由本发明的免疫刺激组合物的佐剂成分的至少一种(m)RNA编码的肿瘤抗原选自由以下各项组成的组:MAGE-A1(例如根据编号M77481的MAGE-A1),MAGE-A2,MAGE-A3,MAGE-A6(例如根据编号NM_005363的MAGE-A6),MAGE-C1,MAGE-C2,melan-A(例如根据编号NM_005511的melan-A),GP100(例如根据编号M77348的GP100),酪氨酸酶(例如根据编号NM_000372的酪氨酸酶),存活蛋白(例如根据编号AF077350的存活蛋白),CEA(例如根据编号NM_004363的CEA),Her-2/neu(例如根据编号M11730的Her-2/neu),WT1(例如根据编号NM_000378的WT1),PRAME(例如根据编号NM_006115的PRAME),EGFRI(表皮生长因子受体1)(例如根据编号AF288738的EGFRI(表皮生长因子受体1)),MUC1,黏蛋白-1(例如根据编号NM_002456的黏蛋白-1),SEC61G(例如根据编号NM_014302的SEC61G),hTERT(例如根据编号NM_198253的hTERT),5T4(例如根据编号NM_006670的5T4),NY-Eso-1(例如根据编号NM_001327的NY-Eso1),TRP-2(例如根据编号NM_001922的TRP-2),STEAP,PCA,PSA,PSMA,等。
根据进一步特别优选的实施方案,由本发明的免疫刺激组合物的佐剂成分的至少一种(m)RNA编码的肿瘤抗原可以形成,例如处于活性(免疫刺激)组合物中的抗原混合物或多部分的试剂盒(其中优选地,各种抗原容纳在试剂盒的一部分中),优选用于引起用于治疗前列腺癌(PCa),优选肿瘤辅助和/或激素-不应前列腺癌,和与其相关的疾病或病症的(适应性)免疫应答。为了该目的,本发明的免疫刺激组合物的佐剂成分的至少一种(m)RNA优选是至少一种RNA,更优选至少一种mRNA,其可以编码以下抗原组中的至少1种,优选2,3或甚至4种(优选不同的)抗原:
●PSA(前列腺-特异性抗原)=KLK3(激肽释放酶-3),
●PSMA(前列腺-特异性膜抗原),
●PSCA(前列腺干细胞抗原),
●STEAP(前列腺的六次跨膜上皮抗原(Six Transmembrane Epithelial Antigen of the Prostate)。
根据另一个特别优选的实施方案,由本发明的免疫刺激组合物的佐剂成分的至少一种(m)RNA编码的肿瘤抗原可以形成抗原混合物,例如处于活性(免疫刺激)组合物中的抗原混合物或多部分的试剂盒(其中优选地,各种抗原容纳在试剂盒的一部分中),优选用于引起用于治疗非小细胞肺癌(NSCLC),优选选自三种主要亚型鳞状细胞肺癌(squamous cell lung carcinoma),腺癌(adenocarcinoma)和大细胞肺癌(large cell lung carcinoma),或与其相关病症的(适应性)免疫应答。为了该目的,本发明的免疫刺激组合物的佐剂成分的至少一种(m)RNA优选是至少一种mRNA,其可以编码以下抗原组中的至少1种,优选2、3、4、5、6、7、8、9、10、11或12种(优选不同的)抗原:
●hTERT,
●WT1,
●MAGE-A2,
●5T4,
●MAGE-A3,
●MUC1,
●Her-2/neu,
●NY-ESO-1,
●CEA,
●存活蛋白,
●MAGE-C1,和/或
●MAGE-C2,
其中这些抗原的任意组合是可能的。
根据进一步特别优选的实施方案,由本发明的免疫刺激组合物的佐剂成分的至少一种(m)RNA编码的肿瘤抗原可以形成,例如处于活性(免疫刺激)组合物中的抗原混合物或多部分的试剂盒(其中优选地,各种抗原容纳在试剂盒的一部分中),优选用于引起用于治疗非小细胞肺癌(NSCLC),优选选自三种主要亚型鳞状细胞肺癌,腺癌和大细胞肺癌,或与其相关病症的(适应性)免疫应答。为了该目的,本发明的免疫刺激组合物的佐剂成分的至少一种(m)RNA优选是至少一种RNA,更优选至少一种mRNA,其可以编码至少2种(优选不同的)抗原。
a)其中这至少2种抗原中的至少1种,优选至少2,3,4,5,或甚至6种选自:
●5T4
●NY-ESO-1,
●MAGE-A2,
●MAGE-A3,
●MAGE-C1,和/或
●MAGE-C2,和
b)其中另一种抗原选自如本文中所定义的至少一种抗原,优选处于本文中提及的任何抗原组合、组或亚组中,例如所述另一种抗原选自,例如:
●hTERT,
●WT1,
●MAGE-A2,
●5T4,
●MAGE-A3,
●MUC1,
●Her-2/neu,
●NY-ESO-1,
●CEA,
●存活蛋白,
●MAGE-C1,和/或
●MAGE-C2。
在以上实施方案中,以上定义的蛋白中的每一种,例如如本文中定义的治疗活性蛋白、抗体、抗原、等可以由一种(单顺反子)RNA,优选一种(单顺反子)mRNA编码。换言之,本发明的免疫刺激组合物的佐剂成分的至少一种(m)RNA可以包括至少2种(单顺反子)RNAs,优选mRNAs,其中这至少2种(单顺反子)RNA中每一种,优选mRNAs,可以编码,例如仅一种(优选不同的)蛋白,例如抗原,优选选自以上提及的抗原组合之一。
根据另一个特别优选的实施方案,本发明的免疫刺激组合物的佐剂成分的至少一种(m)RNA可以包括(至少)一种双-或甚至多顺反子RNA,优选mRNA,即(至少)一种携带,例如至少2种(优选不同)蛋白,例如抗原,优选选自以上提及的抗原组合之一抗原的2个或甚至更多编码序列的RNA。所述编码序列,例如所述(至少)一种双-或甚至多顺反子RNA的至少2种(优选不同)蛋白,例如抗原的编码序列,可以通过至少一个IRES(内部核糖体进入位点)序列分开,如下定义。因此,术语“编码至少2种(优选不同)蛋白”可以意指,不仅限于,所述(至少)一种(双-或甚至多顺反子)RNA,优选mRNA,可以编码例如至少2、3、4、5、6、7、8、9、10、11或12种以上(优选不同的)蛋白,例如以上提及的抗原组的抗原,或其片段或变体,治疗活性蛋白,抗体,佐剂蛋白,等。更优选地,不仅限于,所述(至少)一种(双-或甚至多顺反子)RNA,优选mRNA,可以编码例如至少2,3,4,5,或6种以上(优选不同的)蛋白,例如以上提及的抗原亚组的抗原,或其在以上定义范围内的片段或变体。在该上下文中,如本文中定义的所谓IRES(内部核糖体进入位点)序列可以起单独核糖体结合位点功能,但是它还可以起提供如本文中定义的编码若干待由核糖体彼此独立翻译的蛋白的双-或甚至多顺反子RNA的作用。可以按照本发明使用的IRES序列的实例是来自小RNA病毒(例如FMDV),鼠疫病毒(pestiviruses)(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),经典猪瘟病毒(CSFV),鼠白血病病毒(mouse leukoma virus,MLV),猿猴免疫缺陷病毒(SIV)或蟋蟀麻痹病毒(CrPV)的那些。
根据进一步特别优选的实施方案,本发明的免疫刺激组合物的佐剂成分的至少一种(m)RNA可以包括至少一种如本文中定义的单顺反子RNA,优选mRNA和至少一种如本文中定义的双-或甚至多顺反子RNA,优选mRNA的混合物。所述至少一种单顺反子RNA和/或所述至少一种双-或甚至多顺反子RNA优选编码不同的蛋白,例如抗原,或其片段或变体,所述抗原优选选自以上提及的抗原组或亚组之一,更优选以上提及的组合之一。然而,所述至少一种单顺反子RNA和所述至少一种双-或甚至多顺反子RNA还可以优选编码(部分)相同的蛋白,如本文中定义的,例如选自以上提及的抗原组或亚组之一,优选以上提及的组合之一的抗原,条件是本发明的免疫刺激组合物的佐剂成分的至少一种(m)RNA作为整体提供至少两种(优选不同的)蛋白,例如抗原,如本文中定义的。这样的实施方案可以有利于例如将本发明的免疫刺激组合物的佐剂成分的至少一种(m)RNA的一种或多种例如作为药物组合交错的,例如时间依赖性施用给有此需要的患者。本发明的这种药物组合物的成分,特别是编码至少两种(优选不同的)蛋白的不同复合RNA,可以例如包含在多部分组合物试剂盒(的不同部分)中或可以例如根据本发明作为不同药物组合成分分别施用。
由本发明的免疫刺激组合物的佐剂成分的至少一种(m)RNA编码的另一类抗原包括过敏反应抗原。所述过敏反应抗原可以选自源自不同来源,例如来自动物、植物、真菌、细菌等的抗原。在该上下文中的过敏原包括例如草、花粉、霉菌、药物或许多环境触发物等。过敏反应抗原典型地属于不同的化合物类型,诸如核酸及其片段、蛋白或肽及其片段、碳水化合物、多糖、糖、脂质、磷脂等。在本发明上下文中特别感兴趣的是由本发明的免疫刺激组合物的佐剂成分的至少一种(m)RNA编码的抗原,即蛋白或肽抗原及其片段或表位,或核酸及其片段,特别是编码所述蛋白或肽抗原及其片段或表位的核酸及其片段。
特别优选地,由本发明的免疫刺激组合物的佐剂成分的至少一种(m)RNA编码的源自动物的抗原可以包括源自,但不仅限于以下物种的抗原:昆虫类,诸如螨(例如屋尘螨),蚊子,蜂(例如蜜蜂,大黄蜂),蟑螂,虱,蛾(例如蚕蛾),蠓,臭虫,跳蚤,胡蜂,毛虫,果蝇,飞蝗,蚱蜢,蚁蚜虫(ant aphide),源自甲壳纲动物,诸如虾,蟹,磷虾,龙虾,对虾,小龙虾,挪威海蛰虾,源自鸟类,诸如鸭,鹅,海鸥,火鸡,鸵鸟,鸡,源自鱼类,诸如鳗鱼,鲱鱼,鲤鱼,鲷鱼,鳕鱼,大比目鱼,鲶鱼,白鲸,鲑鱼,比目鱼,鲭鱼,墨鱼,河鲈,源自软体动物,诸如扇贝,章鱼,鲍鱼,蜗牛,蛾螺,鱿鱼,蛤,贻贝,源自蜘蛛,源自哺乳动物,诸如牛,兔,绵羊,狮子,美洲虎,豹,大鼠,猪,水牛,狗,懒猴,仓鼠,豚鼠,猪,鹿,马,猫,小鼠,豹猫,薮猫,源自节肢动物,诸如蜘蛛,或银鱼,源自蠕虫类,诸如线虫,源自旋毛虫物种,或蛔虫,源自两栖动物,诸如青蛙,或源自海鞘,等。
由本发明的免疫刺激组合物的佐剂成分的至少一种(m)RNA编码的源自植物的抗原可以包括源自,但不仅限于以下物种的抗原:水果,诸如猕猴桃,菠萝,木菠萝,木瓜,柠檬,橙,柑橘,瓜,柿子,草莓,荔枝,苹果,cherry paradise apple,芒果,西番莲果,李子,杏,油桃,梨,西番莲果,覆盆子,葡萄,源自蔬菜,诸如蒜,洋葱,韭,大豆,芹菜,花椰菜,芜菁,红辣椒,鹰嘴豆,茴香,绿皮西葫芦,黄瓜,胡萝卜,山药,豆,豌豆,橄榄,蕃茄,马铃薯,小扁豆,生菜,鳄梨,欧芹,辣根,番荔枝,甜菜,南瓜,菠菜,源自香料,诸如芥末,芫荽,藏红花,胡椒,八角,源自农作物,诸如燕麦,荞麦,大麦,稻米,小麦,玉米,油菜籽,芝麻,源自坚果类,诸如腰果,胡桃,灰胡桃,阿月浑子,杏仁,榛子,花生,巴西坚果,山核桃,栗子,源自树木,诸如桤木,角树,雪松,桦树,榛木,山毛榉,白蜡树,水蜡树,橡树,悬铃叔(plane tree),柏树,棕榈,源自花,诸如豚草,康乃馨,连翘,向日葵,羽扇豆,甘菊,丁香,西番莲,源自草,诸如庸医草(quack grass),common bent,雀麦草,狗牙根(Bermuda grass),黄花草(sweet vernal grass),黑麦草,或源自其他植物,诸如罂粟,墙草属植物,长叶车前草(ribwort),烟草,芦笋,艾蒿(mugwort),水芹,等。
由本发明的免疫刺激组合物的佐剂成分的至少一种(m)RNA编码的源自真菌的抗原可以包括源自,但不仅限于以下物种的抗原,例如链格孢属(Alternia sp.),曲霉属(Aspergillus sp.),白僵菌属(Beauveria sp.),念珠菌属(Candida sp.),支孢属(Cladosporium sp.),内座壳属(Endothia sp.),Curcularia sp.,Embellisia sp.,附球菌属(Epicoccum sp.),镰孢属(Fusarium sp.),马拉色氏菌属(Malassezia sp.),青霉属(Penicillum sp.),格孢腔菌属(Pleospora sp.),酵母属(Saccharomyces sp.),等。
由本发明的免疫刺激组合物的佐剂成分的至少一种(m)RNA编码的源自细菌的抗原可以包括源自,但不仅限于以下物种的抗原,例如破伤风芽孢杆菌(Bacillus tetani),金黄色葡萄球菌(Staphylococcus aureus),灰色链霉菌(Streptomyces griseus),等。
c)抗体
根据另一个实施方案,本发明的免疫刺激组合物的佐剂成分的至少一种(m)RNA可以编码抗体。根据本发明,所述抗体可以选自本领域中已知的任何抗体,例如任何重组产生或天然存在的抗体,具体地,适合于治疗、诊断或科学目的的抗体,或已经关于特定癌症疾病鉴别的抗体。在本文中,术语“抗体”以其最广泛的含义使用并具体地涵盖单克隆和多克隆抗体(包括激动剂、拮抗剂、和阻断或中和抗体)和具有多表位特异性的抗体种类。根据本发明,“抗体”典型地包括本领域中已知的任何抗体(例如IgM,IgD,IgG,IgA和IgE抗体),诸如天然存在的抗体,在宿主生物体中通过免疫生成的抗体,由天然存在的抗体或在宿主生物体通过免疫生成和通过本领域中已知的生物分子方法重组产生的抗体分离和鉴别的抗体,以及嵌合抗体,人抗体,人源化抗体,双特异性抗体,胞内抗体,即在细胞中表达的和任选位于特定细胞区室内的抗体,和前述抗体的片段和变体。通常,抗体由均具有可变结构域和恒定结构域的轻链和重链组成。轻链由N端可变结构域,VL,和C端恒定结构域,CL组成。相反,IgG抗体的重链,例如,包括N端可变结构域,VH,和三个恒定结构域,CH1,CH2和CH3。另外单链抗体可以由本发明的修饰的(m)RNA的RNA,优选由单链RNA,更优选由mRNA编码。
按照第一个备选方案,本发明的免疫刺激组合物的佐剂成分的至少一种(m)RNA可以编码多克隆抗体。在该上下文中,术语“多克隆抗体”典型地意指针对特异性抗原或免疫原或由宿主生物体诸如哺乳动物例如包括山羊、牛、猪、狗、猫、驴、猴、猿、啮齿类动物诸如小鼠、仓鼠和兔的免疫生成的蛋白表位的抗体的混合物。多克隆抗体一般不相同,且因此通常识别来自相同抗原的不同表位或区域。因此,在这样的情形中,典型地,将不同RNA的混合物(组合物)用作本发明的免疫刺激组合物的佐剂成分的至少一种(m)RNA,每种RNA分别编码针对特异性抗原或免疫原或蛋白表位的特异性(单克隆)抗体。
按照另一个备选方案,本发明的免疫刺激组合物的佐剂成分的至少一种(m)RNA可以编码单克隆抗体。术语“单克隆抗体”在本文中典型地指获自实质同质抗体群体的抗体,即组成该群的各种抗体除可能可以少量存在的天然存在的突变以外均相同。单克隆抗体是高度特异性的,其针对单一抗原性位点。此外,与典型地包括针对不同决定簇(表位)的不同抗体的常规(多克隆)抗体制剂相反,每种单克隆抗体针对抗原中的单一决定簇。例如,如上定义的单克隆抗体可以通过由Kohler和Milstein,Nature(自然),256:495(1975)首先描述的杂交瘤方法制备,或可以通过重组DNA方法制备,例如,如U.S.Pat.No.4,816,567中所述。“单克隆抗体”还可以分离自利用例如McCafferty等,Nature(自然),348:552-554(1990)中所述的技术生成的噬菌体文库。根据Kohler和Milstein,将目的免疫原(抗原)注射到宿主,诸如小鼠中,并在一段时间后收获对免疫原反应产生的B细胞淋巴细胞。B细胞与获自小鼠的骨髓瘤细胞组合并引入到容许B细胞与骨髓瘤细胞融合的培养基中,以生成杂交瘤。然后将这些融合细胞(杂交瘤)置于微滴定板的分开的孔中,并生长以生成单克隆抗体。测试单克隆抗体,以确定它们中的哪些适合于检测目的抗原。选择后,单克隆抗体可以在细胞培养物中或通过注射杂交瘤进入小鼠中而生长。然而,为了本发明的目的,已经测序这些单克隆抗体的肽序列且编码这些抗体的RNA序列可以用作本发明的免疫刺激组合物的佐剂成分的至少一种(m)RNA,其可以按照本领域中熟知的程序制备。
为了在人中的治疗目的,非人单克隆或多克隆抗体,诸如鼠抗体也可以由本发明的免疫刺激组合物的佐剂成分的至少一种(m)RNA编码。然而,这样的抗体典型地仅有有限的用途,因为它们通常在人体中,通过生成针对所述非人抗体的人抗体而诱导免疫反应。因此,具体的非人抗体仅能对人施用一次。为了解决这个问题,嵌合的、人源化的非人和人抗体可以设想为由本发明的免疫刺激组合物的佐剂成分的至少一种(m)RNA编码。可以由本发明的免疫刺激组合物的佐剂成分的至少一种(m)RNA编码的“嵌合”抗体优选是这样的抗体,其中上述抗体的恒定结构域被来自其他生物体的抗体序列,优选人序列替代。也可以由本发明的免疫刺激组合物的佐剂成分的至少一种(m)RNA编码的“人源化”(非人)抗体是这样的抗体,其中抗体的上述恒定结构域和可变结构域(除超可变结构域以外)被人序列替代。根据另一个备选方案,本发明的免疫刺激组合物的佐剂成分的至少一种(m)RNA可以编码人抗体,即仅具有人序列的抗体。这样的人抗体可由人组织或由关于人IgG基因基因座转基因的免疫化非人宿主生物体分离,并且RNA序列可以按照本领域中公知的程序制备。另外,人抗体可以通过使用噬菌体展示提供。
另外,本发明的免疫刺激组合物的佐剂成分的至少一种(m)RNA可以编码双特异性抗体。本发明上下文中的“双特异性”抗体优选是通过两个不同的Fa/b-结构域在效应子和各种靶标之间起衔接子作用的抗体,例如,为了募集效应子分子诸如毒素、药物、细胞因子等,靶向效应子细胞诸如CTL、NK细胞、巨噬细胞、粒细胞,等(参见综述:Kontermann R.E.,Acta Pharmacol.Sin,2005,26(1):1-9)。如本文中所述的双特异性抗体通常被设定为通过两个不同的Fa/b-结构域识别,例如2种不同的抗原、免疫原、表位、药物、细胞(或细胞上的受体)、或如上所述的其他分子(或结构)。双特异性因此意指抗体的抗原结合区特异于2种不同的表位。因此,不同的抗原、免疫原或表位等可以集合在一起,这任选地容许这2种成分的直接相互作用。例如,不同的细胞诸如效应子细胞和靶细胞可以通过双特异性抗体连接。本发明包括,但不仅限于,一方面结合如本文中所述的可溶性抗原且另一方面结合肿瘤细胞表面上的抗原或受体的抗体或其片段。
根据本发明,本发明的免疫刺激组合物的佐剂成分的至少一种(m)RNA还可以编码胞内抗体,其中这些胞内抗体可以是如上定义的抗体。因为这些抗体是胞内表达的抗体,即由位于细胞特定区域中核酸编码并也在那里表达的抗体,所以所述抗体可以称为胞内抗体。
如由本发明的免疫刺激组合物的佐剂成分的至少一种(m)RNA编码的抗体可以优选包括全长抗体,即由完整重链和完整轻链组成的抗体,如上所述。然而,抗体的衍生物诸如抗体片段、变体或加合物也可以由本发明的免疫刺激组合物的佐剂成分的至少一种(m)RNA编码。
本发明的免疫刺激组合物的佐剂成分的至少一种(m)RNA还可以编码抗体片段,其选自前述(全长)抗体的Fab,Fab’,F(ab’)2,Fc,Facb,pFc’,Fd和Fv片段。通常,抗体片段是本领域中已知的。例如,Fab(“片段,抗原结合”)片段由重链和轻链的各一个恒定结构域和一个可变结构域组成。这两个可变结构域结合特异性抗原上的表位。这两个链通过二硫键相连。scFv(“单链可变片段”)片段,例如,典型地由轻链和重链的可变结构域组成。所述结构域通过人工键,通常多肽键诸如由15-25个甘氨酸、脯氨酸和/或丝氨酸残基组成的肽相连。
作为第二成分,本发明的免疫刺激组合物包括至少一种游离的mRNA,其编码至少一种如本文中定义的治疗活性蛋白或肽,至少一种如本文中定义的抗原,例如肿瘤抗原,致病性抗原(例如选自如上定义的致病性蛋白或选自动物抗原,病毒抗原,原生动物抗原,细菌抗原,过敏性抗原),自体免疫抗原,或其他抗原,至少一种如本文中定义的过敏原,至少一种如本文中定义的抗体,至少一种如本文中定义的抗原特异性T细胞受体,或至少一种适合于如本文中定义的特定(治疗)应用的其他蛋白或肽。(根据制备本发明的免疫刺激组合物的第二步骤)添加该第二成分到以上制备的“佐剂成分”中,以形成本发明的免疫刺激组合物。在添加前,不复合至少一种游离mRNA并应该优选在添加佐剂成分时,不经历任何可检测的或显著的复合反应。这归因于阳离子或聚阳离子化合物与佐剂成分中的上述至少一种(m)RNA的强结合。换言之,当所述至少一种编码治疗活性蛋白的游离mRNA加入“佐剂成分”时,优选不存在游离或基本不存在游离阳离子或聚阳离子化合物,其可以与所述至少一种游离mRNA形成复合物。因此,本发明的组合物的至少一种游离mRNA的有效翻译在体内是可能的。
所述至少一种游离mRNA,其是本发明的免疫刺激组合物的第二成分,是信使RNA,其编码至少一种如本文中定义的治疗活性蛋白或肽,至少一种如本文中定义的抗原,例如肿瘤抗原,致病性抗原(例如选自如上定义的致病性蛋白或选自动物抗原,病毒抗原,原生动物抗原,细菌抗原,过敏性抗原),自体免疫抗原,或其他抗原,至少一种如本文中定义的过敏原,至少一种如本文中定义的抗体,至少一种如本文中定义的抗原特异性T细胞受体,或至少一种适合于如本文中定义的特定(治疗)应用的其他蛋白或肽。在该上下文中,mRNA通常如上关于佐剂成分定义为这样的RNA,其由若干结构部件组成,例如任选的5’-UTR区,位于上游的核糖体结合位点及随后的编码区,任选的3’-UTR区,所述3’-UTR区后可以是聚-A尾部(和/或聚-C-尾部)。所述至少一种游离mRNA可以作用单、双或甚至多顺反子RNA,即携带1个、2个或更多蛋白的编码序列的RNA存在。二或甚至多顺反子mRNA中的这种编码序列可以由至少一个IRES序列分开,例如如上定义地。
所述至少一种游离mRNA,其作为本发明的免疫刺激组合物的第二成分提供,可以编码至少一种治疗活性蛋白。在本发明的上下文中,所述治疗活性蛋白优选可以是任何适合于治疗目的的蛋白或肽,更优选可以选自现有技术的技术人员已知的任何重组的或分离的蛋白,且甚至更优选可以选自任何如上关于本发明的免疫刺激组合物的佐剂成分定义的治疗活性蛋白。所述如上定义的治疗活性蛋白包括,但不仅限于,例如能够刺激或抑制细胞内信号转导的蛋白,例如细胞因子,抗体,等,细胞凋亡因子或细胞凋亡相关蛋白,佐剂蛋白,例如选自人佐剂蛋白或选自致病性佐剂蛋白,特别选自细菌佐剂蛋白,等。
所述至少一种游离mRNA,其作为本发明的免疫刺激组合物的第二成分提供,还可以编码至少一种抗体或抗体片段。在该上下文中,所述至少一种游离mRNA,其作为本发明的免疫刺激组合物的第二成分提供,可以编码如上关于本发明的免疫刺激组合物的佐剂成分定义的任何抗体或抗体片段。
最后,所述至少一种游离mRNA,其作为本发明的免疫刺激组合物的第二成分提供,还可以编码至少一种如上定义的抗原。在该上下文中,(肿瘤)抗原或一般地,术语“抗原”如上所述关于本发明的免疫刺激组合物的佐剂成分定义并典型地意指由免疫系统识别并能够例如通过形成作为适应性免疫应答一部分的抗体来触发抗原特异性免疫应答的物质。根据优选的实施方案,所述至少一种游离mRNA,其作为本发明的免疫刺激组合物的第二成分提供,可以编码任何如上关于本发明的免疫刺激组合物的佐剂成分定义的抗原。根据甚至更优选的实施方案,所述抗原可以选自如上关于本发明的免疫刺激组合物的佐剂成分定义的肿瘤抗原,例如如上定义的肿瘤特异性抗原(TSAs)和肿瘤相关抗原(TAAs),等。
所述至少一种游离mRNA,其作为本发明的免疫刺激组合物的第二成分提供,可以与本发明的免疫刺激组合物的佐剂成分的至少一种(m)RNA相同或不同,这取决于特定的治疗需要。甚至更优选地,所述至少一种游离mRNA,其作为本发明的免疫刺激组合物的第二成分提供,与本发明的免疫刺激组合物的佐剂成分的至少一种(m)RNA相同。
所述第一成分(即包括与阳离子或聚阳离子化合物复合的至少一种(m)RNA或由其组成的佐剂成分)和所述第二成分(即所述至少一种游离mRNA)的比在本发明的免疫刺激组合物中可以根据具体治疗,例如癌症治疗的特定需要等来选择。典型地,选择本发明的免疫刺激组合物的佐剂成分和至少一种游离mRNA的比(佐剂成分∶游离mRNA),以使得由于佐剂成分引起先天性免疫系统的显著刺激。平行地,该比例这样选择,以使得可以体内提供显著量的至少一种游离mRNA,从而导致体内表达的蛋白,例如,如上定义的至少一种抗体、抗原和/或治疗活性蛋白等的有效翻译和浓缩。优选地,本发明的免疫刺激组合物中的佐剂成分∶游离mRNA的比选自约5∶1(w/w)至约1∶10(w/w)的范围,更优选选自约4∶1(w/w)至约1∶8(w/w)的范围,甚至更优选选自约3∶1(w/w)至约1∶5(w/w)或1∶3(w/w)的范围,且最优选地,本发明的免疫刺激组合物的佐剂成分∶游离mRNA的比选自约1∶1(w/w)的范围。
另外地或备选地,所述第一成分(即包括与阳离子或聚阳离子化合物复合的至少一种(m)RNA或由其组成的佐剂成分)和所述第二成分(即所述至少一种游离mRNA)的比可以基于整个RNA复合物的氮/磷比(N/P-比)计算。在本发明的上下文中,N/P-比优选在约0.1-10的范围内,优选在约0.3-4的范围内和最优选在约0.5-2的范围内或关于该复合物中RNA∶肽的比在0.7-2的范围内,和最优选在约0.7-1.5的范围内。
另外地或备选地,所述第一成分(即包括与阳离子或聚阳离子化合物复合的至少一种(m)RNA或由其组成的佐剂成分)和所述第二成分(即所述至少一种游离mRNA)的比也可以在本发明的免疫刺激组合物中,基于两种RNA,即佐剂成分的(m)RNA(其与阳离子或聚阳离子化合物复合)和第二成分的至少一种游离mRNA彼此间的摩尔比来选择。典型地,佐剂成分的(m)RNA与第二成分的至少一种游离mRNA的摩尔比可以这样选择,以使得该摩尔比满足以上(w/w)和/或N/P-定义。更优选地,佐剂成分的(m)RNA与第二成分的至少一种游离mRNA的摩尔比可以选自例如约0.001∶1,0.01∶1,0.1∶1,0.2∶1,0.3∶1,0.4∶1,0.5∶1,0.6∶1,0.7∶1,0.8∶1,0.9∶1,1∶1,1∶0.9,1∶0.8,1∶0.7,1∶0.6,1∶0.5,1∶0.4,1∶0.3,1∶0.2,1∶0.1,1∶0.01,1∶0.001,等的摩尔比或选自由以上任意两个数值形成的任何范围,例如选自约0.001∶1-1∶0.001的范围,包括约0.01∶1-1∶0.001,0.1∶1-1∶0.001,0.2∶1-1∶0.001,0.3∶1-1∶0.001,0.4∶1-1∶0.001,0.5∶1-1∶0.001,0.6∶1-1∶0.001,0.7∶1-1∶0.001,0.8∶1-1∶0.001,0.9∶1-1∶0.001,1∶1-1∶0.001,1∶0.9-1∶0.001,1∶0.8-1∶0.001,1∶0.7-1∶0.001,1∶0.6-1∶0.001,1∶0.5-1∶0.001,1∶0.4-1∶0.001,1∶0.3-1∶0.001,1∶0.2-1∶0.001,1∶0.1-1∶0.001,1∶0.01-1∶0.001的范围,或约0.01∶1-1∶0.01,0.1∶1-1∶0.01,0.2∶1-1∶0.01,0.3∶1-1∶0.01,0.4∶1-1∶0.01,0.5∶1-1∶0.01,0.6∶1-1∶0.01,0.7∶1-1∶0.01,0.8∶1-1∶0.01,0.9∶1-1∶0.01,1∶1-1∶0.01,1∶0.9-1∶0.01,1∶0.8-1∶0.01,1∶0.7-1∶0.01,1∶0.6-1∶0.01,1∶0.5-1∶0.01,1∶0.4-1∶0.01,1∶0.3-1∶0.01,1∶0.2-1∶0.01,1∶0.1-1∶0.01,1∶0.01-1∶0.01的范围,或包括约0.001∶1-1∶0.01,0.001∶1-1∶0.1,0.001∶1-1∶0.2,0.001∶1-1∶0.3,0.001∶1-1∶0.4,0.001∶1-1∶0.5,0.001∶1-1∶0.6,0.001∶1-1∶0.7,0.001∶1-1∶0.8,0.001∶1-1∶0.9,0.001∶1-1∶1,0.001-0.9∶1,0.001-0.8∶1,0.001-0.7∶1,0.001-0.6∶1,0.001-0.5∶1,0.001-0.4∶1,0.001-0.3∶1,0.001-0.2∶1,0.001-0.1∶1的范围,或约0.01∶1-1∶0.01,0.01∶1-1∶0.1,0.01∶1-1∶0.2,0.01∶1-1∶0.3,0.01∶1-1∶0.4,0.01∶1-1∶0.5,0.01∶1-1∶0.6,0.01∶1-1∶0.7,0.01∶1-1∶0.8,0.01∶1-1∶0.9,0.01∶1-1∶1,0.001-0.9∶1,0.001-0.8∶1,0.001-0.7∶1,0.001-0.6∶1,0.001-0.5∶1,0.001-0.4∶1,0.001-0.3∶1,0.001-0.2∶1,0.001-0.1∶1的范围,等。
甚至更优选地,佐剂成分的(m)RNA与第二成分的至少一种游离mRNA的摩尔比可以选自例如约0.01∶1-1∶0.01的范围。最优选地,佐剂成分的(m)RNA与第二成分的至少一种游离mRNA的摩尔比可以选自约1∶1的摩尔比。任何以上关于(w/w)和/或N/P比的定义也均适用。
根据本发明,如上定义的佐剂成分的至少一种(m)RNA和/或本发明的免疫刺激组合物的至少一种游离mRNA,其编码蛋白,例如治疗活性蛋白,抗体和/或抗原,还可以编码上述蛋白的片段和/或变体,其中所述片段和/或变体可以在编码这些蛋白的(编码)核酸序列全长上,与上述蛋白之一具有至少5%,10%,20%,30%,40%,50%,60%,70%,80%或85%,优选至少90%,更优选至少95%和最优选至少99%的序列同一性。在本发明的上下文中,所述蛋白的片段被理解为其平截蛋白,即氨基酸序列,其与原始(天然)蛋白的氨基酸序列相比是在N端、在C端和/或在内部序列平截的。特别优选包括抗原表位的片段。在该上下文中,片段和表位优选如上明确地关于抗原定义。
“变体”在本发明的上下文中指如上定义的蛋白,例如如上定义的治疗活性蛋白,佐剂蛋白,抗原或抗体(或其编码mRNA或(m)RNA序列),其中本发明的免疫刺激组合物的佐剂成分的至少一种(m)RNA的核酸或本发明的免疫刺激组合物的至少一种游离mRNA的核酸,其编码例如治疗活性蛋白,抗体和/或抗原,等,可以交换。由此,生成治疗活性蛋白,佐剂蛋白,抗原或抗体,其具有与原始序列相差一个或多个突变,诸如一个或多个置换、插入和/或缺失的氨基酸的氨基酸序列。优选地,所述片段和/或变体与全长天然蛋白,例如治疗活性蛋白,抗原或抗体相比,具有相同生物学功能或特异性活性。所述“生物学功能”包括例如(例如特定抗原的)特异性结合能力,这些蛋白,例如治疗活性蛋白的催化活性,等。在该上下文中,本文中所述的抗体的“生物学功能”还包括抗原的中和,补体活化或调理。因此,抗体典型地识别细胞表面上的天然表位或自由抗原。如上定义的抗体可以与细胞呈递抗原相互作用并起始不同的防卫机制。在一方面,抗体可以在靶细胞内起始信号传导机制,其导致细胞的自我-破坏作用(凋亡)。在另一方面,它可以以这样的方式标记细胞,从而可以识别和攻击身体免疫系统的其他成分或效应子细胞。攻击机制称为抗体依赖性补体介导的细胞毒性(CMC)和抗体依赖性细胞毒性作用(ADCC)。ADCC涉及由参与抗体标记细胞的免疫细胞识别抗体,并通过它们的直接作用,或通过募集其他细胞类型,导致标记的细胞死亡。CMC是这样的过程,其中不同补体蛋白的级联变为活化的,通常在若干抗体彼此接近时,其导致细胞溶解或吸引其他免疫细胞到该位置,以获得效应子细胞功能。在抗原的中和中,抗体可以结合抗原并对其进行中和。所述中和反应随即通常导致抗体的封闭。因此,抗体仅能结合一种抗原,或,在双特异性抗体的情形中,仅能结合2种抗原。特别地,scFv抗体片段有效用于中和反应,因为在于它们不包含抗体恒定结构域的功能。在补体活化中,补体蛋白的复杂系统可以通过结合独立于抗体的Fc部分的抗体来活化。补体级联的最终产物导致细胞的溶解和炎性环境的产生。在调理中,将病原体或其他非细胞颗粒制成通过结合抗体的恒定结构域而易受吞噬细胞的影响。备选地,被识别为外源的细胞可以通过抗体依赖性细胞介导细胞毒性(ADCC)溶解。特别地,NK细胞可以通过激活Fc受体展示出溶胞功能。
为了确定2种序列相同的百分比,特别是本发明的免疫刺激组合物的佐剂成分的至少一种(m)RNA和/或本发明的免疫刺激组合物的至少一种游离mRNA,可以比对序列,从而随后彼此比较。因此,作为实例,例如可以将裂隙插入到第一序列(例如(m)RNA或mRNA)的序列中并可以比较位于第二序列(例如(m)RNA或mRNA)相应位置处的组成。如果第一序列(例如(m)RNA或mRNA)序列中的位置被与第二序列(例如(m)RNA或mRNA)中该位置的情形相同的组成占据,则这两个序列在该位置相同。两个(m)RNA(或mRNA)序列相同的百分比是相同的位置数量除以位置总数的函数。当然这也因此同样适用于DNA序列或编码的氨基酸序列。
两序列,诸如本发明的免疫刺激组合物的佐剂成分的至少一种(m)RNA和/或本发明的免疫刺激组合物的至少一种游离mRNA,或其编码的氨基酸序列相同的百分比可以利用数学运算法则来确定。可以使用的数学运算法则的优选但非局限性实例是Karlin等(1993),PNAS USA,90:5873-5877或Altschul等(1997),Nucleic Acids Res(核酸研究),25:3389-3402的运算法则。这样的运算法则可以整合到BLAST或NBLAST程序中。与本发明的免疫刺激组合物的佐剂成分的至少一种(m)RNA或本发明的免疫刺激组合物的至少一种游离mRNA的序列(或与其编码区)相同到一定程度的序列可以通过这些程序识别。
对应于佐剂成分的至少一种(m)RNA或本发明的免疫刺激组合物的至少一种游离mRNA、编码与生理学,即天然且非修饰的序列相比具有保守置换的氨基酸序列的RNA序列被特别归入术语“变体”。其中源自相同类型的被编码氨基酸彼此交换的置换称为保守置换。具体地,这些是编码的氨基酸,编码的脂肪族侧链,带正电荷或带负电荷的侧链,侧链中的芳香族基团或编码的氨基酸,其侧链可以成为氢键的一部分,例如具有羟基功能的侧链。这意味着例如具有极性侧链的氨基酸被另一个也具有极性侧链的氨基酸替换,或例如,特征为疏水性侧链的氨基酸被另一个也具有疏水性侧链的氨基酸置换(例如丝氨酸(苏氨酸)被苏氨酸(丝氨酸)置换或亮氨酸(异亮氨酸)被异亮氨酸(亮氨酸)置换)。插入和置换,特别地在那些不导致三维结构变化或不影响结合区域或催化结构域的序列位置处是可能的。由插入或缺失引起的三维结构变化可以容易地例如利用CD谱(圆二色谱)来确定(Urry,1985,Absorption,Circular Dichroism and ORD of Polypeptides,(多肽的吸收,圆二色性和ORD),在:Modern Physical Methods in Biochemistry(现代生物化学中的物理方法),Neuberger等(编),Elsevier,阿姆斯特丹)。
对应于本发明的免疫刺激组合物的佐剂成分的至少一种(m)RNA或对应于本发明的免疫刺激组合物的至少一种游离mRNA的那些RNA序列,其编码如上定义的的氨基酸序列,可以作为单、双或甚至多顺反子RNA,即携带1个、2个或更多如上定义的蛋白,例如如上定义的治疗活性蛋白,佐剂蛋白,(蛋白)抗原或抗体的编码序列的RNA存在。如果对应于以上定义范围内的佐剂成分的至少一种(m)RNA和/或本发明的免疫刺激组合物的至少一种游离mRNA的RNA序列编码如上定义的至少一种蛋白,例如,两、三或更多如上定义的治疗活性蛋白,佐剂蛋白,抗原或抗体,则这些蛋白中的每一种均可以选自如上定义的的相同或(优选)不同蛋白。在任何情形中,对应于本发明的免疫刺激组合物的佐剂成分的至少一种(m)RNA和/或本发明的免疫刺激组合物的至少一种游离mRNA的RNA序列编码的各种蛋白均可以独立选择。
根据另一个特别优选的实施方案,本发明的免疫刺激组合物可以包括作为至少一种游离mRNA或作为佐剂成分的至少一种(m)RNA的至少一种如上定义的双-或甚至多顺反子RNA序列。这些如上定义的双-或甚至多顺反子RNA序列中各编码序列可以由至少一个所谓的IRES(内部核糖体进入位点)序列分开。在该上下文中,IRES序列可以起单独核糖体结合位点功能,但是它还可以起提供如本文中定义的编码若干待由核糖体彼此独立翻译的蛋白的双-或甚至多顺反子RNA序列的作用。可以按照本发明使用的IRES序列的实例是来自小RNA病毒(例如FMDV),鼠疫病毒(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),经典猪瘟病毒(CSFV),鼠白血病病毒(MLV),猿猴免疫缺陷病毒(SIV)或蟋蟀麻痹病毒(CrPV)的那些
根据特别优选的实施方案,本发明的免疫刺激组合物还可以包括作为佐剂成分的至少一种(m)RNA和/或至少一种游离mRNA的不同RNA序列的混合物,其中该混合物包括例如编码如上定义的蛋白的至少一种单顺反子mRNA,和/或编码如上定义的相同或不同蛋白,例如如上定义的治疗活性蛋白,佐剂蛋白,抗原和/或抗体的至少一种双-或甚至多顺反子mRNA。
根据另一个具体实施方案,本发明的免疫刺激组合物的佐剂成分的至少一种(m)RNA和/或本发明的免疫刺激组合物的至少一种游离mRNA可以作为“稳定化RNA”,优选稳定化mRNA,即作为基本对抗由不同方法(例如通过外切-或内切-核酸酶)引起的体内降解的RNA来提供。在本领域中已知,通常mRNA或RNA体内的不稳定性和(快速)降解可以代表应用基于RNA的组合物中的严重问题。这种RNA的不稳定性典型地归因于RNA降解酶,即“RNA酶”(核糖核酸酶),其中被该核糖核酸酶污染有时可以完全降解溶液中的RNA。因此,细胞胞质中RNA的天然降解受到非常精细地调节,且RNA酶污染通常可以通过在使用所述组合物前的特殊处理,特别是用焦碳酸二乙酯(DEPC)处理来去除。在现有技术中关于这一点已知许多天然降解机制,这些机制也可以被使用。例如,末端结构典型地对于体内mRNA是至关重要的。作为实例,在天然存在的mRNAs的5′末端,通常存在所谓的“帽结构”(修饰的鸟苷核苷酸)并且在3′端典型地存在多到200腺苷核苷酸(所谓的聚A尾)的序列。
根据特别优选的实施方案,本发明的免疫刺激组合物的佐剂成分的至少一种(m)RNA和/或本发明的免疫刺激组合物的至少一种游离mRNA,特别是如果作为mRNA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,这样的修饰仅在如果修饰,特别如上定义地,尚未被引入如上定义的至少一种(m)RNA和/或mRNA的5′端或如果所述修饰不干扰如上定义的至少一种(m)RNA和/或mRNA的免疫原性时,才会被引入。
根据另一个特别优选的实施方案,本发明的免疫刺激组合物的佐剂成分的至少一种(m)RNA和/或本发明的免疫刺激组合物的至少一种游离mRNA,可以在其3’端包含,特别是如果RNA采用mRNA的形式,典型地约10-200个腺苷核苷酸,优选约10-100个腺苷核苷酸,更优选约20-100个腺苷核苷酸或甚至更优选约40-80个腺苷核苷酸的聚A尾部。
根据另一个特别优选的实施方案,本发明的免疫刺激组合物的佐剂成分的至少一种(m)RNA和/或本发明的免疫刺激组合物的至少一种游离mRNA,可以在其3’端包含,特别是如果RNA采用mRNA的形式,典型地约10-200个胞嘧啶核苷酸,优选约10-100个胞嘧啶核苷酸,更优选约20-70个胞嘧啶核苷酸或甚至更优选约20-60或甚至10-40个胞嘧啶核苷酸的聚C尾部。
根据另一个实施方案,本发明的免疫刺激组合物的佐剂成分的至少一种(m)RNA和/或本发明的免疫刺激组合物的至少一种游离mRNA还可以是GC-修饰的或以其他形式修饰的。一些RNA修饰,取决于RNA类型,可以一般更适合于RNA,或,例如在GC-修饰的(m)RNA或mRNA序列的情形中,更适合于编码RNA,优选如上定义的(m)RNA和/或mRNA。如上定义的的所述其他修饰优选导致如上定义的稳定化(m)RNA和/或mRNA。
根据一个具体实施方案,所述稳定化RNA可以通过修饰本文中提及的RNA序列,例如对应于佐剂成分的至少一种(m)RNA和/或对应于本发明的免疫刺激组合物的至少一种游离mRNA的RNA序列的编码区的G/C含量而制备。
在本发明的特别优选的实施方案中,佐剂成分的至少一种(m)RNA和/或本发明的免疫刺激组合物的至少一种游离mRNA的编码区的G/C含量与相对应的非修饰的RNA(在以下“天然RNA”)的编码区的G/C含量相比变化,优选增加。在该上下文中,这种与佐剂成分的至少一种(m)RNA或本发明的免疫刺激组合物的至少一种游离mRNA相对应的G/C增加的RNA序列的编码氨基酸序列与相对应的天然RNA相比,优选不变化。这种GC序列的变化可以根据以下GC稳定性来表示。
本发明的免疫刺激组合物的佐剂成分的至少一种(m)RNA和/或本发明的免疫刺激组合物的至少一种游离mRNA的这种GC稳定性基于这样的事实,即待翻译的任何RNA区域的序列对于该RNA有效翻译非常重要。因此,不同核苷酸的序列是重要的。具体地,具有增加的G(鸟苷)/C(胞嘧啶)含量的序列比具有增加的A(腺苷)/U(尿嘧啶)含量的序列更稳定。根据本发明,本发明的免疫刺激组合物的佐剂成分的至少一种(m)RNA或本发明的免疫刺激组合物的至少一种游离mRNA的密码子因此与其天然RNA序列相比变化,但保持翻译的氨基酸序列,以使其包括增加量的G/C核苷酸。关于这样的事实,即若干密码子编码一种且相同的氨基酸(所谓的遗传密码简并),可以确定关于稳定性最有利的密码子(所谓的备选密码子的使用)。
根据由本发明的免疫刺激组合物的佐剂成分的至少一种(m)RNA和/或本发明的免疫刺激组合物的至少一种游离mRNA编码的氨基酸,与其天然序列相比,存在RNA序列G/C修饰的多种可能性。在由排他地包含G或C核苷酸的密码子编码的氨基酸的情形中,不需要密码子的G/C修饰。因此,关于Pro(CCC或CCG),Arg(CGC或CGG),Ala(GCC或GCG)和Gly(GGC或GGG)的密码子不需要G/C修饰,因为不存在A或U。
相反,包含A和/或U核苷酸的密码子可以通过置换编码相同氨基酸但不包含A和/或U的其他密码子来G/C修饰。这些的实例是:
关于Pro的密码子可以从CCU或CCA被G/C修饰为CCC或CCG;
关于Arg的密码子可以从CGU或CGA或AGA或AGG被G/C修饰为CGC或CGG;
关于Ala的密码子可以从GCU或GCA被G/C修饰为GCC或GCG;
关于Gly的密码子可以从GGU或GGA被G/C修饰为GGC或GGG。
在其他情形中,尽管A或U核苷酸不能从密码子中消除,然而可能通过使用包含较低A和/或U核苷酸含量的密码子减少A和U的含量。这些的实例是:
关于Phe的密码子可以从UUU被G/C修饰为UUC;
关于Leu的密码子可以从UUA,UUG,CUU或CUA被G/C修饰为CUC或CUG;
关于Ser的密码子可以从UCU或UCA或AGU被G/C修饰为UCC,UCG或AGC;
关于Tyr的密码子可以从UAU被G/C修饰为UAC;
关于Cys的密码子可以从UGU被G/C修饰为UGC;
关于His的密码子可以从CAU被G/C修饰为CAC;
关于Gln的密码子可以从CAA被G/C修饰为CAG;
关于Ile的密码子可以从AUU或AUA被G/C修饰为AUC;
关于Thr的密码子可以从ACU或ACA被G/C修饰为ACC或ACG;
关于Asn的密码子可以从AAU被G/C修饰为AAC;
关于Lys的密码子可以从AAA被G/C修饰为AAG;
关于Val的密码子可以从GUU或GUA被G/C修饰为GUC或GUG;
关于Asp的密码子可以从GAU被G/C修饰为GAC;
关于Glu的密码子可以从GAA被G/C修饰为GAG;
终止密码子UAA可以被G/C修饰为UAG或UGA。
在关于Met(AUG)和Trp(UGG)的密码子的情形中,在另一方面,不存在序列修饰的可能性。
以上列出的置换可以分别或以所有可能的组合使用,以与其具体的天然RNA(即非修饰序列)相比,增加本发明的免疫刺激组合物的佐剂成分的至少一种(m)RNA和/或本发明的免疫刺激组合物的至少一种游离mRNA的G/C含量。因此,例如,天然序列中存在的所有关于Thr密码子可以被G/C修饰为ACC(或ACG)。然而,优选地,例如,使用以上置换可能性的组合:
非修饰序列(天然RNA)中所有编码Thr的密码子向ACC(或ACG)的置换和
所有最初编码Ser的密码子向UCC(或UCG或AGC)的置换;
原始序列中所有编码Ile的密码子向AUC的置换和
所有最初编码Lys的密码子向AAG的置换和
所有最初编码Tyr的密码子向UAC的置换;
原始序列中所有编码Val的密码子向GUC(或GUG)的置换和
所有最初编码Glu的密码子向GAG的置换和
所有最初编码Ala的密码子向GCC(或GCG)的置换和
所有最初编码Arg的密码子向CGC(或CGG)的置换;
原始序列中所有编码Val的密码子向GUC(或GUG)的置换和
所有最初编码Glu的密码子向GAG的置换和
所有最初编码Ala的密码子向GCC(或GCG)的置换和
所有最初编码Gly的密码子向GGC(或GGG)的置换和
所有最初编码Asn的密码子向AAC的置换;
原始序列中所有编码Val的密码子向GUC(或GUG)的置换和
所有最初编码Phe的密码子向UUC的置换和
所有最初编码Cys的密码子向UGC的置换和
所有最初编码Leu的密码子向CUG(或CUC)的置换和
所有最初编码Gln的密码子向CAG的置换和
所有最初编码Pro的密码子向CCC(或CCG)的置换;等。
优选地,对应于佐剂成分的至少一种(m)RNA和/或本发明的免疫刺激组合物的至少一种游离mRNA的RNA序列的编码区的G/C含量与编码蛋白的天然RNA的编码区的G/C含量相比,增加至少7%,更优选至少15%,特别优选至少20%。根据具体的实施方案,置换编码蛋白的区域或天然RNA序列的完整序列中可置换的密码子的至少60%,更优选至少70%,甚至更优选至少80%和最优选至少90%,95%或甚至100%,由此增加所述序列的G/C含量。
在该上下文中,特别优选增加本发明的免疫刺激组合物的佐剂成分的至少一种(m)RNA和/或本发明的免疫刺激组合物的至少一种游离mRNA的天然RNA,特别在编码蛋白的区域内的G/C含量到最大值(即天然RNA的100%的可置换的密码子)。
按照本发明,本发明的免疫刺激组合物的佐剂成分的至少一种(m)RNA和/或本发明的免疫刺激组合物的至少一种游离mRNA的另一种优选修饰基于这样的发现,即翻译效率也通过细胞中tRNA出现的不同频率确定。因此,如果天然RNA序列中存在所谓的“罕用密码子”达到增多的范围,则相应G/C稳定化的或天然的RNA序列可以被翻译至比其中存在编码相对“频繁”tRNA的密码子的情形显著更差的程度。
按照本发明,在本发明的免疫刺激组合物的佐剂成分的至少一种(m)RNA和/或本发明的免疫刺激组合物的至少一种游离mRNA中,编码蛋白的区域与各自天然RNA的相应区域相比优选是GC稳定化的,因此编码细胞中相对稀有的tRNA的天然序列的至少一个密码子换成编码细胞中相对频繁的tRNA的密码子并携带与相对稀有tRNA相同的氨基酸。通过该修饰,天然RNA序列被G/C稳定化,从而插入可以获得频繁出现的tRNA的密码子。换言之,按照本发明,在各种情形中,通过该修饰,天然序列的编码细胞中相对稀有的tRNA的所有密码子可以换成编码细胞中相对频繁的tRNA的密码子,并且其,在各种情形中,携带与相对稀有tRNA相同的氨基酸。
哪些tRNA在细胞中相对频繁出现和相反地哪些相对罕见出现是本领域中技术人员已知的,cf.例如Akashi,Curr.Opin.Genet.Dev.(当前遗传发育观点)2001,11(6):660-666。特别优选对于特定氨基酸,使用最频繁出现的tRNA的密码子,例如Gly密码子,其使用在(人)细胞中最频繁出现的tRNA。
按照本发明,特别优选的是将佐剂成分的至少一种(m)RNA和/或本发明的免疫刺激组合物的至少一种游离mRNA的G/C稳定化的RNA序列中增加的特别是最大化的序列G/C含量与不改变由天然RNA编码区编码的蛋白的氨基酸序列的“频繁”密码子相联系。这个优选的实施方案容许提供本发明的免疫刺激组合物的佐剂成分的至少一种(m)RNA和/或本发明的免疫刺激组合物的至少一种游离mRNA的特别有效翻译和GC稳定化的RNA序列。
如上所述地,本发明的免疫刺激组合物的佐剂成分的至少一种(m)RNA和/或本发明的免疫刺激组合物的至少一种游离mRNA的必要(和/或可能)GC修饰(增加的G/C含量;交换tRNA)的确定可以利用如WO02/098443中解释的计算机程序进行——其公开内容全文包括在本发明的范围内。利用该计算机程序,如上定义的任何所需的编码RNA的核苷酸序列可以借助于遗传密码或其简并性质来GC稳定化,由此获得最大G/C含量。与使用编码细胞中尽可能频繁出现的tRNA的密码子相结合,由佐剂成分的至少一种(m)RNA和/或本发明的免疫刺激组合物的至少一种游离mRNA的GC稳定化RNA序列编码的氨基酸序列与其天然RNA序列相比,优选不被进一步修饰。备选地,与原始序列相比,还可能仅改变G/C含量或仅改变密码子的使用。Visual Basic(视觉基础)6.0(使用的开发环境:具有Servicepack3的Microsoft Visual Studio Enterprise6.0)中的源码也记述在WO 02/098443中。
根据另一个具体实施方案,本发明的免疫刺激组合物的佐剂成分的至少一种(m)RNA和/或本发明的免疫刺激组合物的至少一种游离mRNA,可以作为稳定化RNA来提供,即基本对抗由修饰如本文中定义的这种(这些)RNA序列的磷酸主链(例如由外切-或内切-核酸酶)引起的体内降解。可以优选关于这一点使用的核苷酸包含硫代磷酸酯-修饰的磷酸主链,优选地至少一个包含在磷酸主链中被硫原子取代的磷酸酯氧。如本文中定义的稳定的RNA序列还可以包括,例如,非离子磷酸酯类似物,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。更具体地,磷酸酯结构部分可以优选被,例如,氨基磷酸酯、硫代磷酸酯、肽核苷酸、甲基膦酸酯等取代。
根据另一个实施方案,如本文中定义的RNA序列,优选本发明的免疫刺激组合物的佐剂成分的至少一种(m)RNA和/或本发明的免疫刺激组合物的至少一种游离mRNA,可以同样地通过将包含其核糖或碱基结构部分的修饰的修饰的核苷酸引入至RNA序列而修饰。一般地,如本文中定义的RNA序列,优选本发明的免疫刺激组合物的佐剂成分的至少一种(m)RNA和/或本发明的免疫刺激组合物的至少一种游离mRNA,可以包含任何天然(=天然存在的)核苷酸,例如鸟苷,尿嘧啶,腺苷,胸苷和/或胞嘧啶或其类似物。就此而论,核苷酸类似物被定义为天然存在的核苷酸的非天然存在的变体。因此,类似物是具有非天然存在的官能团的化学衍生的核苷酸,所述官能团优选添加到天然存在的核苷酸或由其缺失,或取代核苷酸的天然存在的官能团。因此,天然存在的核苷酸的各种成分可以被修饰,即形成RNA序列主链的碱基成分、糖(核糖)成分和/或磷酸酯成分被修饰。鸟苷,尿嘧啶,腺苷,和胞嘧啶的类似物包括,但不仅限于,已经例如通过乙酰化、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,尿嘧啶,腺苷,胸苷或胞嘧啶,包括1-甲基-腺苷,1-甲基-鸟苷,1-甲基-肌苷,2,2-二甲基-鸟苷,2,6-二氨基嘌呤,2′-氨基-2′-脱氧腺苷,2′-氨基-2′-脱氧胞苷,2′-氨基-2′-脱氧鸟苷,2′-氨基-2′-脱氧尿苷,2-氨基-6-氯嘌呤核糖核苷,2-氨基嘌呤-核糖核苷,2′-阿糖腺苷(Araadenosine),2′-阿糖胞苷(Aracytidine),2′-阿糖尿苷(Arauridine),2′-叠氮-2′-脱氧腺苷,2′-叠氮-2′-脱氧胞苷,2′-叠氮-2′-脱氧鸟苷,2′-叠氮-2′-脱氧尿苷,2-氯腺苷,2′-氟-2′-脱氧腺苷,2′-氟-2′-脱氧胞苷,2′-氟-2′-脱氧鸟苷,2′-氟-2′-脱氧尿苷,2′-氟胸苷,2-甲基-腺苷,2-甲基-鸟苷,2-甲基-硫代-N6-异戊烯基(isopenenyl)-腺苷,2′-O-甲基-2-氨基腺苷,2′-O-甲基-2′-脱氧腺苷,2′-O-甲基-2′-脱氧胞苷,2′-O-甲基-2′-脱氧鸟苷,2′-O-甲基-2′-脱氧尿苷,2′-O-甲基-5-甲基尿苷,2′-O-甲基肌苷,2′-O-甲基假尿苷,2-硫代胞苷,2-硫代-胞嘧啶,3-甲基-胞嘧啶,4-乙酰基-胞嘧啶,4-硫代尿苷,5-(羧基羟基甲基)-尿嘧啶,5,6-二氢尿苷,5-氨基烯丙基胞苷,5-氨基烯丙基-脱氧-尿苷,5-溴尿苷,5-羧基甲基氨基甲基-2-硫代-尿嘧啶,5-羧基甲基amono甲基-尿嘧啶,5-氯-阿糖-胞嘧啶,5-氟-尿苷,5-碘尿苷,5-甲氧基羰基甲基-尿苷,5-甲氧基-尿苷,5-甲基-2-硫代-尿苷,6-氮胞苷,6-氮尿苷,6-氯-7-脱氮-鸟苷,6-氯嘌呤核糖核苷,6-巯基-鸟苷,6-甲基-巯基嘌呤-核糖核苷,7-脱氮-2′-脱氧-鸟苷,7-脱氮腺苷,7-甲基-鸟苷,8-氮杂腺苷,8-溴-腺苷,8-溴-鸟苷,8-巯基-鸟苷,8-氧代鸟苷,苯并咪唑-核糖核苷,β-D-甘露糖基-辫苷(β-D-mannosyl-queosine),二氢-尿嘧啶,肌苷,N1-甲基腺苷,N6-([6-氨基己基]氨基甲酰基甲基)-腺苷,N6-异戊烯基-腺苷,N6-甲基-腺苷,N7-甲基-黄苷,N-尿嘧啶-5-氧乙酸甲酯,嘌呤霉素,辫苷(Queosine),尿嘧啶-5-氧乙酸,尿嘧啶-5-氧乙酸甲酯,Wybutoxosine,黄苷,和木糖-腺苷(xylo-adenosine)。所述类似物的制备是本领域中技术人员已知的,例如,来自美国专利4,373,071,US 4,401,796,US 4,415,732,US 4,458,066,US4,500,707,US 4,668,777,US 4,973,679,US 5,047,524,US 5,132,418,US5,153,319,US 5,262,530和5,700,642。在如上所述的类似物的情形中,按照本发明特别优选是那样的类似物,所述类似物增加如本文中定义的RNA序列,优选本发明的免疫刺激组合物的佐剂成分的至少一种(m)RNA和/或本发明的免疫刺激组合物的至少一种游离mRNA的免疫原性和/或不干扰已经引入的RNA的其他修饰。
如本文中定义的本发明的免疫刺激组合物的RNA序列,优选佐剂成分的至少一种(m)RNA和/或本发明的免疫刺激组合物的至少一种游离mRNA可以包含主链修饰。与本发明有关的主链修饰是这样的修饰,其中RNA中包含的核苷酸主链的磷酸被化学修饰。所述主链修饰典型地包括,但不意味着限于,来自由甲基膦酸酯,氨基磷酸酯和硫代磷酸[酯](例如胞苷-5′-O-(1-硫代磷酸))组成的组的修饰。
如本文中定义的本发明的免疫刺激组合物的RNA序列,优选佐剂成分的至少一种(m)RNA和/或本发明的免疫刺激组合物的至少一种游离mRNA可以另外地或备选地还包含糖修饰。与本发明有关的糖修饰是存在的核苷酸的糖的化学修饰,并且典型地包括,但不意味着任何限制,选自由以下各项组成的组中的糖修饰:2′-脱氧-2′-氟-寡核糖核苷酸(2′-氟-2′-脱氧胞苷-5′-三磷酸,2′-氟-2′-脱氧尿苷-5′-三磷酸),2′-脱氧-2′-脱氨基寡核糖核苷酸(2′-氨基-2′-脱氧胞苷-5′-三磷酸,2′-氨基-2′-脱氧尿苷-5′-三磷酸),2′-O-烷基寡核糖核苷酸,2′-脱氧-2′-C-烷基寡核糖核苷酸(2′-O-甲基胞苷-5′-三磷酸,2′-甲基尿苷-5′-三磷酸),2′-C-烷基寡核糖核苷酸,及其异构体(2′-阿糖胞苷-5′-三磷酸,2′-阿糖尿苷-5′-三磷酸),或叠氮三磷酸(2′-叠氮-2′-脱氧胞苷-5′-三磷酸,2′-叠氮-2′-脱氧尿苷-5′-三磷酸)。
如本文中定义的本发明的免疫刺激组合物的RNA序列,优选佐剂成分的至少一种(m)RNA和/或本发明的免疫刺激组合物的至少一种游离mRNA可以另外地或备选地还包含至少一个碱基修饰,其优选适合于与未改变的即天然(natural)(=天然(native))RNA序列相比,显著增加由所述RNA序列,优选所述佐剂成分的至少一种(m)RNA编码的蛋白的表达。在该情形中“显著的”意指与天然RNA序列的表达相比该蛋白的表达增加至少20%,优选至少30%,40%,50%或60%,更优选至少70%,80%,90%或甚至100%和最优选至少150%,200%或甚至300%。与本发明有关地,具有碱基修饰的核苷酸优选选自由以下各项组成的碱基修饰的核苷酸组:2-氨基-6-氯嘌呤核糖核苷-5′-三磷酸,2-氨基腺苷-5′-三磷酸,2-硫代胞苷-5′-三磷酸,2-硫代尿苷-5′-三磷酸,4-硫代尿苷-5′-三磷酸,5-氨基烯丙基胞苷-5′-三磷酸,5-氨基烯丙基尿苷-5′-三磷酸,5-溴胞苷-5′-三磷酸,5-溴尿苷-5′-三磷酸,5-碘胞苷-5′-三磷酸,5-碘尿苷-5′-三磷酸,5-甲基胞苷-5′-三磷酸,5-甲基尿苷-5′-三磷酸,6-氮杂胞苷-5′-三磷酸,6-氮杂尿苷-5′-三磷酸,6-氯嘌呤核糖核苷-5′-三磷酸,7-脱氮腺苷-5′-三磷酸,7-脱氮鸟苷-5′-三磷酸,8-氮杂腺苷-5′-三磷酸,8-叠氮腺苷-5′-三磷酸,苯并咪唑-核糖核苷-5′-三磷酸,N1-甲基腺苷-5′-三磷酸,N1-甲基鸟苷-5′-三磷酸,N6-甲基腺苷-5′-三磷酸,O6-甲基鸟苷-5′-三磷酸,假尿苷-5′-三磷酸,或嘌呤霉素-5′-三磷酸,黄苷-5′-三磷酸。对核苷酸特别优选的是选自由以下各项组成的碱基修饰的核苷酸组的碱基修饰:5-甲基胞苷-5′-三磷酸,7-脱氮鸟苷-5′-三磷酸,5-溴胞苷-5′-三磷酸,和假尿苷-5′-三磷酸。
根据特别具体的实施方案,如本文中定义的RNA序列,优选本发明的免疫刺激组合物的佐剂成分的至少一种(m)RNA和/或本发明的免疫刺激组合物的至少一种游离mRNA包括0.1%-100%(修饰的)核苷酸,其选自如上关于非修饰的,即天然RNA序列定义的(修饰的)核苷酸,其中优选本发明的免疫刺激组合物的佐剂成分的至少一种(m)RNA和/或本发明的免疫刺激组合物的至少一种游离mRNA,或其相对应的DNA-模板的如上定义的RNA序列的优选0.1%-100%各种天然存在的非修饰的ATP,GTP,CTP,UTP(和/或TTP)核苷酸,可以利用如上定义的的相应修饰的核苷酸来修饰,更优选地,所述非修饰的RNA的0,1%-20%,10%-30%,20%-40%,30%-50%,40%-60%,50%-70%,60%-80%,70%-90%,或80%-100%或至少10%,更优选至少30%,更优选至少40%,更优选至少60%,更优选至少70%,更优选至少80%和更优选至少90%和最优选100%的各种天然存在的非修饰的ATP,GTP CTP,UTP(和/或TTP)核苷酸。
在本发明的进一步优选实施方案中,如本文中定义的(任选已经GC稳定化的)RNA序列,优选本发明的免疫刺激组合物的佐剂成分的至少一种(m)RNA和/或本发明的免疫刺激组合物的至少一种游离mRNA的核糖体结合位点的环境中的A/U含量与其特定天然RNA序列的核糖体结合位点的环境中的A/U含量相比增加。这种变化(在核糖体结合位点周围增加的A/U含量)增加核糖体结合RNA序列的效率。核糖体与核糖体结合位点(Kozak序列:GCCGCCACCAUGG(SEQ ID NO:122),AUG形成起始密码子)的有效结合随之具有有效翻译如本文中定义的RNA序列的作用。
根据本发明的另一个实施方案,如本文中定义的RNA序列,优选本发明的免疫刺激组合物的佐剂成分的至少一种(m)RNA和/或本发明的免疫刺激组合物的至少一种游离mRNA可以进一步关于潜在促降解序列元件来修饰。具体地,如本文中定义的RNA序列的编码区和/或5’和/或3’不翻译区与特定天然RNA序列相比可以被进一步修饰,从而不包含促降解序列元件,如本文中定义的RNA序列的编码氨基酸序列与其特定天然RNA相比优选不被修饰。已知,例如,在真核生物的RNA序列中存在促降解序列元件(DSE),信号蛋白与其结合并在体内调节RNA的酶降解。为了进一步稳定如本文中定义的RNA序列,任选地在编码蛋白的区域内,可以因此进行与天然RNA的相应区域相比的一种或多种这样的进一步修饰,从而使其中不含有或基本不含有促降解序列元件。按照本发明,也可以通过所述进一步修饰,从如本文中定义的RNA序列,优选从本发明的免疫刺激组合物的佐剂成分的至少一种(m)RNA和/或从本发明的免疫刺激组合物的至少一种游离mRNA中除去不翻译区(3′-和/或5′-UTR)中存在的DSE。
所述促降解序列是例如富含AU的序列(AURES),其存在于许多不稳定RNA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)。因此如本文中定义的RNA序列,优选本发明的免疫刺激组合物的佐剂成分的至少一种(m)RNA和/或本发明的免疫刺激组合物的至少一种游离mRNA与天然RNA相比,优选被(进一步)修饰使得修饰的RNA不含有所述促降解序列。这还应用于那些由可能的核酸内切酶识别的序列基序,例如序列GAACAAG,其包含在编码转铁蛋白受体的基因的3′-UTR片段中(Binder等,EMBO J.(EMBO杂志)1994,13:1969-1980)。这些序列基序也可以优选根据本发明从如本文中定义的RNA序列,优选本发明的免疫刺激组合物的佐剂成分的至少一种(m)RNA和/或本发明的免疫刺激组合物的至少一种游离mRNA中除去。
还优选根据本发明,如本文中定义的RNA序列,优选本发明的免疫刺激组合物的佐剂成分的至少一种(m)RNA和/或本发明的免疫刺激组合物的至少一种游离mRNA,在进一步修饰的形式中,具有至少一个如上定义的IRES和/或至少一个5′和/或3′稳定序列,例如从而增强核糖体结合或容许表达如上定义位于如本文中定义的至少一种(双-或甚至多顺反子)RNA上的不同编码蛋白,例如,抗体,治疗活性蛋白或抗原。
按照本发明,如本文中定义的RNA序列,优选本发明的免疫刺激组合物的佐剂成分的至少一种(m)RNA和/或本发明的免疫刺激组合物的至少一种游离mRNA更优选还可以具有至少一个5′和/或3′稳定序列。5′和/或3′不翻译区中的这些稳定序列具有增长如本文中定义的RNA在细胞溶胶中半衰期的作用。这些稳定序列可以与在病毒、细菌和真核生物中存在的天然存在序列具有100%序列同源性,但也可以是部分或完全合成的。例如来自智人(Homo sapiens)或非洲爪蟾(Xenopus laevis)的珠蛋白基因的不翻译序列(UTR)可以作为可以在本发明中用于进一步稳定的如本文中定义的RNA,优选进一步稳定的本发明的免疫刺激组合物的佐剂成分的至少一种(m)RNA和/或进一步稳定的本发明的免疫刺激组合物的至少一种游离mRNA使用的稳定序列的实例提及。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:123),其包含在编码珠蛋白,(I)-胶原蛋白,15-脂加氧酶或编码酪氨酸羟化酶的非常稳定的RNA的3’UTR中(cf.Holcik等,Proc.Natl.Acad.Sci.USA(美国国家科学院学报)1997,94:2410-2414)。所述稳定序列当然可以单独或彼此组合使用和还与本领域中技术人员已知的其他稳定序列组合使用。如本文中定义的RNA序列,优选本发明的免疫刺激组合物的佐剂成分的至少一种(m)RNA和/或本发明的免疫刺激组合物的至少一种游离mRNA因此优选表示为球蛋白UTR(不翻译区)-稳定的RNA。
任意以上修饰可以应用于如本文中定义的RNA序列,优选本发明的免疫刺激组合物的佐剂成分的至少一种(m)RNA和/或本发明的免疫刺激组合物的至少一种游离mRNA,并进一步应用于如本发明上下文中使用的任何RNA并且,如果需要或必要,可以以任何组合相互组合,条件是这些修饰的组合在各自修饰的RNA中不相互干扰。本领域中技术人员应该能够相应地进行选择。
根据本发明,如本文中定义的RNA序列,优选本发明的免疫刺激组合物的佐剂成分的至少一种(m)RNA和/或本发明的免疫刺激组合物的至少一种游离mRNA,可以利用本领域中可获得的任何天然或合成的DNA或RNA序列作为模板,即任何合适的(脱氧)核糖核酸来制备。所述天然或合成的DNA或RNA序列可以获自技术人员可以获得的任何合成的或天然存在的来源,例如可以源自蛋白或肽文库或可以由核酸文库,诸如cDNA文库转录,或可以获自任何活的或死的组织,来自获自例如人、动物或细菌来源的样品。备选地,如本文中定义的RNA序列,优选本发明的免疫刺激组合物的佐剂成分的至少一种(m)RNA和/或本发明的免疫刺激组合物的至少一种游离mRNA,可以通过本领域中技术人员已知的方法,例如通过固相合成或任何其他适合于制备核酸序列,特别是RNA序列的方法来合成制备。此外,这些序列中的核苷酸或碱基置换、添加或删除优选利用用于制备如本文中定义的RNA的DNA基质或通过公知的位点定向诱变技术或使用寡核苷酸连接策略进行(参见例如Maniatis等,Molecular Cloning:A Laboratory Manual(分子克隆:实验室手册),Cold Spring Harbor Laboratory Press(冷泉港实验室出版社),第3版,Cold Spring Harbor(冷泉港),NT,2001)。如本文中定义的RNA序列,优选本发明的免疫刺激组合物的佐剂成分的至少一种(m)RNA和/或本发明的免疫刺激组合物的至少一种游离mRNA的修饰还可以通过本领域中技术人员已知的其他方法引入RNA。合适的方法是,例如,利用(自动或半自动)寡核苷酸合成装置的合成法,生物化学方法,诸如,例如,体外转录法,等。就此而论,利用(自动或半自动)寡核苷酸合成装置的合成法以及体外转录法可以优选用在长度一般不超过50-100个核苷酸的(相对短的)序列的情形中。在(相对长的)序列,例如长度大于50-100个核苷酸的序列的情形中,生物化学方法是优选适合的,诸如,例如,体外转录法。然而,甚至更长的碱基修饰RNA分子可以通过共价偶联多种合成片段来通过合成的方法来合成。
如上定义地,本发明的免疫刺激组合物包括a)佐剂成分和b)至少一种游离mRNA。根据另一个实施方案,本发明的免疫刺激组合物可以包含另外的佐剂,即除以上定义的佐剂成分以外包含在本发明的免疫刺激组合物中的佐剂。在该上下文中,佐剂可以被理解为适合于支持根据本发明施用和任选递送本发明的免疫刺激组合物的任何化合物。此外,所述佐剂在不与其结合的条件下,可以起始或增加先天性免疫系统的免疫应答,即非特异性免疫应答。换言之,在施用时,本发明的免疫刺激组合物典型地引起先天性免疫应答,这归因于所述佐剂成分,其包括如上定义的与阳离子或聚阳离子化合物复合的至少一种(m)RNA或由其组成。然而,所述先天性免疫应答可以通过添加另外的佐剂来增加,如下定义。所述另外的佐剂可以选自技术人员已知并且适合于本情形,即支持在哺乳动物中诱导先天性免疫应答的任何佐剂,但除去如上定义的阳离子或聚阳离子化合物以防止所述至少一种游离mRNA的复合。优选地,所述佐剂可以选自由以下各项组成,但不仅限于此的组,包括壳多糖,TDM,MDP,胞壁酰二肽,普流罗尼克(pluronics),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%),普流罗尼克L121(1.25%),磷酸盐缓冲盐水,pH 7.4);AVRIDINETM(丙二胺);BAY R1005TM((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(酯)(hydroacetate);CALCITRIOLTM(1-α,25-二羟基-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-A1-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(imiquimod)(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;ISCOPREP 7.0.3.TM;脂质体;LOXORIBINETM(7-烯丙基-8-氧代鸟苷);LT口服佐剂(大肠杆菌(E.coli)不稳定的肠毒素-原毒素);任何组成的微球体和微粒;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Gln-sn-甘油二棕榈酰);NAGO(神经氨酸酶-半乳糖氧化酶);任何组成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);普流罗尼克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)(Avanti Polar 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已烷);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),和脂肽,包括Pam3Cys,具体地铝盐,如Adju-phos,铝胶(Alhydrogel),吸附氢氧化铝凝胶(Rehydragel);乳状液,包括CFA,SAF,IFA,MF59,Provax,TiterMax,Montanide,Vaxfectin;共聚物,包括Optivax(CRL1005),L121,Poloaxmer4010),等;脂质体,包括Stealth,脂质卷(cochleates),包括BIORAL;植物衍生的佐剂,包括QS21,Quil A,Iscomatrix,ISCOM;适合于共刺激的佐剂包括番茄素,生物聚合物,包括PLG,PMM,菊粉,;微生物衍生的佐剂,包括罗莫肽,DETOX,MPL,CWS,甘露糖,CpG核酸序列,CpG7909,人TLR 1-10的配体,鼠TLR 1-13的配体,ISS-1018,IC31,咪唑并喹啉,阿普林津(Ampligen),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-1V150,RSV融合蛋白,cdiGMP;和适合作为拮抗剂的佐剂,包括CGRP神经肽。适合的佐剂还可以选自脂质修饰的核酸或选自如上定义的式(I),(II),(III),(IIIa),(IV),(IVa),(IVb),(Va)和/或(Vb)的任何免疫刺激序列。
根据另一个实施方案,本发明还提供药物组合物,其包括如上定义的本发明的免疫刺激组合物和任选地药用载体和/或媒介物。
作为第一成分,本发明的药物组合物包括如上定义的本发明的免疫刺激组合物,即a)佐剂成分,其包括至少一种(m)RNA或由其组成,所述至少一种(m)RNA与阳离子或聚阳离子化合物复合,和b)至少一种游离mRNA,其编码至少一种治疗活性蛋白,抗原和/或抗体,其中所述免疫刺激组合物能够在哺乳动物中引起或增强先天性和任选地适应性免疫应答。因此,本发明的药物组合物典型地支持待治疗患者的免疫系统的先天性免疫应答和任选地适应性免疫应答。
此外,本发明药物组合物可以包括药用载体和/或媒介物。在本发明的上下文中,药用载体典型地包括液体或非液体基的本发明的药物组合物。如果本发明的药物组合物以液体形式提供,则载体应该典型的是无热原的水;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。特别地,对于本发明的药物组合物的注射,可以使用水或优选缓冲液,更优选水性缓冲液,其包含钠盐,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。CaCl2也可以由另一种盐如KCl来代替。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而高渗、等渗或低渗的,即参照具体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。参照介质是例如“体内”方法中存在的液体,如血液,淋巴,细胞溶质液体,或其它体液,或可以在“体外”方法中用作参照介质的液体,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。特别优选将林格氏或林格氏-乳酸盐溶液作为液体基础。
然而,一种或多种相容性固体或液体填充剂,或稀释剂或包封化合物也可以用于本发明的药物组合物,其适合于对待治疗的患者施用。术语“相容性”用于本文中时,意指本发明药物组合物的这些成分能够以这样的方式与如本文中定义的RNA序列,优选本发明的免疫刺激组合物的佐剂成分的与阳离子或聚阳离子化合物复合的至少一种(m)RNA,和本发明的免疫刺激组合物的至少一种游离mRNA混合,以使得不发生将在通常使用条件下实质上减小本发明药物组合物的药物效力的相互作用。药用载体、填充剂和稀释剂当然必须具有足够高的纯度和足够低的毒性以使得它们适合于对待治疗的人进行施药。可以用作药用载体、填充剂或其成分的化合物的一些实例是糖,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;植物油,诸如,例如,花生油,棉籽油,芝麻油,橄榄油,玉米油和可可油(oil from Theobroma);多元醇,诸如,例如,聚丙二醇,甘油,山梨醇,甘露醇和聚乙二醇;褐藻酸。
本发明的药物组合物可以口服、肠胃外、通过吸入喷雾、局部、直肠、鼻腔、口腔、阴道或经由植入型药盒(implanted reservoir)施用。术语肠胃外用于本文中时包括皮下、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、动脉内和舌下注射或灌输技术。
优选地,本发明的药物组合物通过肠胃外注射,更优选通过皮下、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、动脉内和舌下注射或经由灌输技术施用。本发明的药物组合物的无菌可注射形式可以是水性或油质混悬液。这些混悬液可以根据本领域中已知的技术,使用适合的分散剂或湿润剂和悬浮剂来配制。所述无菌可注射制剂还可以是处于无毒可肠胃外用稀释剂或溶剂中的无菌可注射溶液或混悬液,例如如处于1,3-丁二醇中的溶液。可以使用的可用载体和溶剂包括水、林格氏溶液和等渗氯化钠溶液。另外,无菌不挥发性油常规用作溶剂或悬浮介质。为了该目的,可以使用任何温和的不挥发性油,包括合成的单甘油酯或双甘油酯。脂肪酸,诸如油酸及其甘油酯衍生物有效用于制备注射剂,天然的药用油,诸如橄榄油或蓖麻油,特别是处于其聚氧乙烯化形式时也有效用于制备注射剂。这些油溶液或混悬液还可以包含长链醇稀释剂或分散剂,诸如羧甲基纤维素或常规用于配制药用剂型包括乳剂和混悬液的类似分散剂。其他常用的表面活性剂,诸如Tweens,Spans和常规用于制备药用固体、液体、或其剂型的其他乳化剂或生物适用性增强剂也可以用于配制本发明的药物组合物的目的。
如上定义的本发明的药物组合物还可以以任何口服可接受的剂型,包括但不仅限于,胶囊剂、片剂、水性混悬液或溶液口服施用。在用于口服使用的片剂的情形中,常用的载体包括乳糖和玉米淀粉。还典型地添加润滑剂,诸如硬脂酸镁。为了以胶囊剂形式口服施用,有效的稀释剂包括乳糖和干玉米淀粉。当需要水性混悬液来口服使用时,活性成分,即形成如上定义的本发明的药物组合物的一部分的本发明的免疫刺激组合物的佐剂成分的至少一种(m)RNA和/或本发明的免疫刺激组合物的至少一种游离mRNA与乳化剂和混悬剂组合。如果需要,还可以添加某些甜味剂、调味剂或着色剂。
本发明的药物组合物还可以局部施用,特别是当治疗标本包括容易通过局部施用接近的区域或器官,例如包括皮肤或任何其他可接近的上皮组织的疾病时。合适的局部制剂对于这些区域或器官的每一个容易地制备。为了局部施用,本发明的药物组合物可以以合适的膏剂来配制,所述膏剂包含本发明的免疫刺激组合物,特别是其如上定义的成分,所述膏剂悬浮或溶解在一种或多种载体中。用于局部施用的载体包括,但不仅限于,矿物油,液体石蜡、白软石蜡、丙二醇、聚氧乙烯、聚氧丙烯化合物、乳化蜡和水。备选地,本发明的药物组合物可以以合适的洗剂或膏剂来配制。在本发明的上下文中,合适的载体包括,但不仅限于,矿物油、脱水山梨醇单硬脂酸酯、聚山梨醇酯60、十六烷基酯蜡、鲸蜡硬脂醇、2-辛基十二醇、苯甲醇和水。
本发明的药物组合物典型地包含“安全且有效量”的本发明的药物组合物的成分,特别是本发明的免疫刺激组合物的佐剂成分的与阳离子或聚阳离子化合物复合的至少一种(m)RNA,和/或本发明的免疫刺激组合物的至少一种游离mRNA。用于本文中时,“安全且有效量”意指足以显著诱导如本文中定义的疾病或病症的正向改善的本发明的免疫刺激组合物的佐剂成分的与阳离子或聚阳离子化合物复合的至少一种(m)RNA,和/或本发明的免疫刺激组合物的至少一种游离mRNA的量。然而,同时,“安全且有效量”足够小到避免严重的副作用,即允许合理的优势和风险之间的关系。这些限制的决定典型地属于合理的医学判断范围之内。本发明的药物组合物的成分,特别是本发明的免疫刺激组合物的佐剂成分的与阳离子或聚阳离子化合物复合的至少一种(m)RNA,和/或本发明的免疫刺激组合物的至少一种游离mRNA的“安全且有效量”,在本文中还应该关于具体的待治疗病症以及还有待治疗患者的年龄和身体状态、体重、一般健康、性别、饮食、施药时间、排泄速度、药物组合、所述的如本文中定义的特定(m)RNA或mRNA的活性、病症的严重性、治疗的持续时间、附随治疗的天性、所用的具体药用载体、和类似因素,在陪同医生的知识和经验范围内而变化。本发明的药物组合物可以用于人类医学并还可以用于兽医目的,优选用于人类医学目的,其作为一般的药物组合物或作为疫苗。
根据具体实施方案,本发明的药物组合物可以作为疫苗提供。所述的本发明疫苗典型地包括如本发明的药物组合物和优选至少支持待治疗患者的免疫系统的先天性免疫应答。因此,本发明的疫苗此外还可以引起适应性免疫应答,优选地,如果(本发明的免疫刺激组合物的佐剂成分的与阳离子或聚阳离子化合物复合的至少一种(m)RNA,和/或优选)本发明的免疫刺激组合物的至少一种游离mRNA编码任何上述引起适应性免疫应答的抗原(或抗体)。
本发明的疫苗还可以包括如上关于本发明的药物组合物定义的药用载体、佐剂、和/或媒介物。在本发明的疫苗的特定上下文中,药用载体的选择原则上通过在其中施用本发明的疫苗的方式来确定。本发明的疫苗可以,例如,系统或局部施用。用于系统施用的途径一般包括,例如,经皮、口、肠胃外途径,包括皮下、静脉内、肌内、动脉内、皮内和腹膜内注射和/或鼻内施用途径。用于局部施用的途径一般不仅包括,例如,局部施用途径,而且包括皮内,经皮,皮下,或肌内注射或病灶内,颅内,肺内,心内,和舌下注射。更优选地,疫苗可以通过皮内,皮下,或肌内途径施用。本发明的疫苗因此优选以液体(或有时以固体)形式配制。待施用的本发明的疫苗的合适量可以通过关于动物模型的常规实验来确定。所述模型包括,但不仅限于,兔、绵羊、小鼠、大鼠、狗和非人灵长类动物模型。优选的用于注射的单位剂型包括无菌水溶液、生理盐水或其混合物。所述溶液的pH应该调节为约7.4。用于注射的合适载体包括水凝胶、用于受控或延迟释放的装置、聚乳酸和胶原蛋白基质。用于局部施用的合适药用载体包括适合于用在洗剂、霜剂、凝胶剂等中的那些。如果本发明的疫苗要经口施用,则片剂、胶囊等是优选的单位剂型。对于制备可以应用于口服施药的单位剂型的药用载体是现有技术中公知的。其选择取决于次要的考虑,诸如味道、成本和储存稳定性,这些对本发明的目的不是关键的且可以由本领域中技术人员毫不费力地执行。
本发明的疫苗还可以包含一种或多种辅助物质,从而进一步增加其免疫原性。如上定义的本发明的免疫刺激组合物的佐剂成分的与阳离子或聚阳离子化合物复合的至少一种(m)RNA、和/或本发明的免疫刺激组合物的至少一种游离mRNA、和如上所述可以任选包含在本发明的疫苗中的辅助物质的协同作用优选由此获得。根据辅助物质的不同类型,就此可以考虑多种机制。例如,允许树突细胞(DCs)成熟的化合物,例如脂多糖,TNF-α或CD40配体,形成第一类合适的辅助物质。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,诸如单核因子,淋巴因子,白介素或趋化因子,其进一步促进先天性免疫应答,诸如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,诸如hGH。
本发明的疫苗还可以另外包含任何其他化合物,所述化合物已知由于其与人Toll样受体TLR1,TLR2,TLR3,TLR4,TLR5,TLR6,TLR7,TLR8,TLR9,TLR10的结合亲和性(作为配体),或由于其与鼠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。
可以加入该上下文中的本发明疫苗的另一类化合物可以是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)的胞嘧啶/鸟嘌呤二核苷酸序列(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(胞嘧啶)和G(鸟嘌呤)也可以以甲基化形式存在。
根据本发明的进一步优选的目的,本发明的免疫刺激组合物,优选本发明的免疫刺激组合物的成分,即本发明的免疫刺激组合物的佐剂成分的与阳离子或聚阳离子化合物复合的至少一种(m)RNA,以及本发明的免疫刺激组合物的至少一种游离mRNA可以用于制备药物组合物或疫苗,所述药物组合物或疫苗优选全部如本文中定义,用于预防、治疗和/或改善如本文中定义的任何疾病和病症。
因此,本发明的免疫刺激组合物,本发明的药物组合物或本发明的疫苗,或本发明的免疫刺激组合物的佐剂成分的与阳离子或聚阳离子化合物复合的至少一种(m)RNA,连同本发明的免疫刺激组合物的至少一种游离mRNA可以用于预防、治疗和/或改善例如癌症或肿瘤疾病(的药物的制备),所述癌症或肿瘤疾病优选选自黑素瘤,恶性黑素瘤,结肠癌,淋巴瘤,肉瘤,胚细胞瘤,肾癌,胃肠瘤,神经胶质瘤,前列腺肿瘤,膀胱癌,直肠瘤,胃癌,食管癌,胰腺癌,肝癌,乳腺癌(mammary carcinomas=breast cancer)),子宫癌,宫颈癌,急性髓细胞样白血病(AML),急性淋巴样白血病(ALL),慢性髓细胞样白血病(CML),慢性淋巴细胞白血病(CLL),肝细胞瘤,多种病毒诱导的肿瘤,诸如例如乳头瘤病毒诱导的癌(例如宫颈癌(cervical carcinoma=cervical cancer),腺癌,疱疹病毒诱导的肿瘤(例如伯基特淋巴瘤,EB病毒诱导的B细胞淋巴瘤),乙型肝炎诱导的肿瘤(肝细胞癌),HTLV-1-和HTLV-2-诱导的淋巴瘤,听觉神经瘤(acoustic neuroma),肺癌(lung carcinomas=lung cancer=支气管癌),小细胞肺癌,喉癌,肛门癌,成胶质细胞瘤,直肠癌,星形细胞瘤,脑瘤,成视网膜细胞瘤,基底细胞癌,脑转移,成神经管细胞瘤,阴道癌,胰腺癌,睾丸癌,霍奇金综合征,脑膜瘤,Schneeberger病,垂体瘤,蕈样霉菌病,类癌瘤,神经鞘瘤,spinalioma,伯基特淋巴瘤,喉癌,肾癌,胸腺瘤,体癌(corpus carcinoma),骨癌,非霍奇金细胞淋巴瘤,尿道癌,CUP综合征,头/颈肿瘤,少突神经胶质瘤,外阴癌,肠癌,结肠癌,食管癌(oesophageal carcinoma=oesophageal cancer),疣累及(wart involvement),小肠瘤,颅咽管瘤,卵巢癌,软组织瘤,卵巢癌(ovarian cancer=ovarian carcinoma),胰腺癌(pancreatic carcinoma=pancreatic cancer ),子宫内膜癌,肝转移,阴茎癌,舌癌,胆囊癌,白血病,浆细胞瘤,眼睑瘤,前列腺癌(=前列腺肿瘤)等。
此外,本发明的免疫刺激组合物,本发明的药物组合物或本发明的疫苗,或本发明的免疫刺激组合物的佐剂成分的与阳离子或聚阳离子化合物复合的至少一种(m)RNA,连同本发明的免疫刺激组合物的至少一种游离mRNA可以用于预防、治疗和/或改善例如传染病,优选(病毒、细菌或原生动物)传染病(的药物的制备)。所述传染病,优选(病毒、细菌或原生动物)传染病典型地选自流感,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 summer meningoencephalitis)(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),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,棘球绦虫,阔节裂头绦虫,鱼肉中毒(雪卡毒素),狐绦虫,足癣,犬绦虫,念珠菌病,酵母菌斑,疥疮,皮肤利什曼病,兰氏鞭毛虫病(贾第虫病),虱,疟疾,显微镜,盘尾丝虫病(河盲),真菌病,牛肉绦虫,血吸虫病,猪肉绦虫,弓形体病,滴虫病,锥虫病(昏睡病),内脏利什曼病,尿布/尿布皮炎或微小绦虫引起的传染病。
同样地,本发明的免疫刺激组合物,本发明的药物组合物或本发明的疫苗,或本发明的免疫刺激组合物的佐剂成分的与阳离子或聚阳离子化合物复合的至少一种(m)RNA,连同本发明的免疫刺激组合物的至少一种游离mRNA可以用于预防、治疗和/或改善例如自身免疫疾病(的药物的制备)。自身免疫性疾病可以广泛地分为系统性和器官特异性或局部化自身免疫病症,这取决于各种疾病的主要临床病理学特征。自身免疫疾病可以分为系统性综合征类型,包括系统性红斑狼疮(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型糖尿病(糖尿病1型),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1型),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型过敏性疾病,II型过敏性疾病,III型过敏性疾病,IV型过敏性疾病,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),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β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A β-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。
另外,本发明的免疫刺激组合物,本发明的药物组合物或本发明的疫苗,或本发明的免疫刺激组合物的佐剂成分的与阳离子或聚阳离子化合物复合的至少一种(m)RNA,连同本发明的免疫刺激组合物的至少一种游离mRNA可以用于预防、治疗和/或改善过敏症或过敏性疾病,即涉及过敏症的疾病(的药物的制备)。过敏症是这样的病症,其典型地涉及对某些外源抗原或过敏原,诸如如上定义的过敏反应抗原的异常的获得性免疫超敏性。所述过敏反应抗原或过敏原可以选自如上定义的过敏反应抗原,源自不同来源,例如源自动物、植物、真菌、细菌等的抗原。在该上下文中,过敏原包括例如草、花粉、霉菌、药物或许多环境触发物等。过敏性在正常情况下导致针对这些抗原或过敏原的局部或系统炎性应答,并在体内导致针对这些过敏原的免疫性。不限于理论,设想一些不同的疾病机制涉及过敏症的发展。根据P.Gell和R.Coombs的分类方案,术语“过敏症”限于I型超敏性,其由经典IgE机制引起。I型超敏性的特征是由IgE引起的肥大细胞和嗜碱性粒细胞过度活化,从而导致系统性炎性反应,所述系统性炎性反应能够引起与流鼻涕一样良性的症状到危及生命的过敏性休克和死亡。公知的过敏症类型包括,但不仅限于,过敏性哮喘(导致鼻粘膜肿胀),过敏性结膜炎(导致结膜红痒),过敏性鼻炎(″枯草热″),过敏反应,血管性水肿(angiodema),特应性皮炎(湿疹),荨麻疹(urticaria)(荨麻疹(hives)),嗜酸粒细胞增多,呼吸,对昆虫叮咬过敏,皮肤过敏(导致并包括多种皮疹,诸如湿疹,荨麻疹(hives和urticaria)和(接触性)皮炎),食物过敏,药物过敏,等。关于本发明,本发明的免疫刺激组合物,本发明的药物组合物或本发明的疫苗,或本发明的免疫刺激组合物的佐剂成分的与阳离子或聚阳离子化合物复合的至少一种(m)RNA,连同本发明的免疫刺激组合物的至少一种游离mRNA可以用于优选通过使触发特异性免疫应答的免疫反应脱敏来治疗所述过敏性病症或疾病。所述脱敏可以通过施用有效量的由本发明的免疫刺激组合物的RNA,优选至少一种游离mRNA编码的过敏原或过敏性抗原来进行,从而诱导轻微的免疫反应。然后,过敏原或过敏性抗原的量可以在随后的施用中逐步升高,直至待治疗的患者的免疫系统耐受特定量的过敏原或过敏性抗原。
在以上上下文中,本发明此外还涉及本发明的免疫刺激组合物,本发明的药物组合物或本发明的疫苗,或本发明的免疫刺激组合物的佐剂成分的与阳离子或聚阳离子化合物复合的至少一种(m)RNA,连同本发明的免疫刺激组合物的至少一种游离mRNA用于预防、治疗和/或改善如本文中提及的疾病或病症的用途。还具体包括本发明的免疫刺激组合物,本发明的药物组合物或本发明的疫苗,或本发明的免疫刺激组合物的佐剂成分的与阳离子或聚阳离子化合物复合的至少一种(m)RNA,连同本发明的免疫刺激组合物的至少一种游离mRNA用于接种的用途或这些成分作为接种体的用途。根据本发明的一个特别优选的实施方案,所述用于预防、治疗、和/或改善上述疾病或病症的方法,或用预防上述疾病的接种方法,典型地包括将所述药物组合物,优选以如以上关于本发明药物组合物所述的“安全且有效量”和以上剂型之一,施用于有此需要(例如,患有任何以上疾病或表现出其症状)的患者,具体地施用于人。施药模式也可以如以上关于本发明药物组合物或疫苗所述。
本发明还涉及用于制备如上定义的与阳离子或聚阳离子化合物复合的至少一种(m)RNA,或如上定义的至少一种游离mRNA,分别编码至少一种治疗活性蛋白,抗原和/或抗体,的体外转录方法,所述方法包括以下步骤:
a)提供/供应作为用于本发明如上所述与阳离子或聚阳离子化合物复合的至少一种(m)RNA,或如上所述至少一种游离mRNA,分别编码至少一种治疗活性蛋白,抗原和/或抗体,的模板的(脱氧)核糖核酸;
b)将所述(脱氧)核糖核酸添加至体外转录培养基,所述转录培养基包含RNA聚合酶,合适的缓冲液,核苷酸混合物,和任选地RNA酶抑制剂,所述核苷酸混合物任选地包含一种或多种核苷酸,所述核苷酸用化学修饰的核苷替换(部分或全部)天然存在的核苷A,G,U和/或C中的一种或多种,和如果天然存在的核苷A,G,U和/或C不全部被替换,则替换任选地,一个或多个天然存在的核苷A,G,U和/或C,所述化学修饰的核苷选自如上定义的化学修饰的核苷;
c)在体外转录培养基中温育所述(脱氧)核糖核酸和体外转录所述(脱氧)核糖核酸;和
d)任选地,从所述体外转录培养基中纯化和去除未结合的核苷酸。
如本发明的体外转录方法的步骤a)中所述的(脱氧)核糖核酸可以是如上所述可以用作制备与阳离子或聚阳离子化合物复合的至少一种(m)RNA,和/或如上定义的至少一种游离mRNA,分别编码至少一种治疗活性蛋白,抗原和/或抗体,的模板的任意核酸。为了该目的,典型地使用DNA序列,例如基因组DNA或其片段,或质粒,或RNA序列(与其相对应),例如mRNA序列,优选采用线性化形式。体外转录反应通常可以通过利用具有RNA聚合酶结合位点的载体来进行。为了该目的,可以使用本领域中已知的任何载体,例如可商购的载体(见上)。优选例如,在克隆位点上游和/或下游具有SP6或T7或T3结合位点的那些载体。因此,如果需要,所用(脱氧)核糖核酸序列可以稍后转录,这取决于所选择的RNA聚合酶。用于体外转录和编码如上定义的蛋白,例如治疗活性蛋白、抗原或抗体的(脱氧)核糖核酸序列典型地,例如经由所用载体的多克隆位点克隆到载体中。在转录前,典型地使用合适的限制酶,在这样的位点处用限制酶裂解质粒,如上定义的佐剂成分的至少一种(m)RNA或如上定义的至少一种游离mRNA的将来的3’末端位于所述位点处,并纯化该片段。这防止将来的如上定义的佐剂成分的至少一种(m)RNA或如上定义的至少一种游离mRNA包含载体序列,并且可以获得确定的长度。
备选地,还可能通过聚合酶链反应(PCR)制备(脱氧)核糖核酸作为转录模板。为了该目的,用于PCR的引物之一典型地包含RNA聚合酶结合位点序列。进一步优选的是,引物的5’末端具有约10-50个更多的核苷酸,更优选15-30个更多的核苷酸和最优选约20核苷酸的长度。
在体外转录反应前,(脱氧)核糖核酸,例如特定的DNA或RNA模板,典型地被纯化并不含RNA酶,从而确保高产率。纯化可以通过现有技术中已知的任何方法,例如利用氯化铯梯度或离子交换法进行。
根据本发明体外转录方法的方法步骤b)将(脱氧)核糖核酸添加至体外转录培养基。合适的体外转录培养基首先含有如根据步骤a)制备的(脱氧)核糖核酸,例如约0.1-约10μg,优选约1-约5μg,更优选约2.5μg和最优选约1μg所述核酸。合适的体外转录培养基还任选地包含还原剂,例如DTT,更优选约1-约20μl的约50mM DTT,还更优选约5μl的约50mM DTT。体外转录培养基还包含核苷酸(AMP,GMP,UMP和/或CMP),例如核苷酸混合物。在本发明的情形中,核苷酸优选包括如上定义的化学修饰的核苷。所述(化学修饰的)核苷酸可以起替换天然存在的核苷酸AMP,GMP,UMP和/或CMP中的一种或多种,和如果天然存在的核苷酸AMP,GMP,UMP和/或CMP不全部被替换,则任选地替换一个或多个天然存在的核苷酸AMP,GMP,UMP和/或CMP的作用。核苷酸AMP,GMP,UMP和/或CMP典型地存在于所述核苷酸混合物中,其浓度典型地是约0.1-10mM/核苷酸,优选0.1-1mM/核苷酸,优选总共约4mM。如上所述(化学)修饰的核苷酸(约1mM/核苷酸,优选总共约4mM)典型地,以这样的量加入,以使得天然核苷酸全部被包含如上定义的化学修饰的核苷的(修饰的)核苷酸替换。然而,还可能使用一种或多种如上定义的修饰的核苷酸和一种或多种天然存在的核苷酸而非特定核苷酸的混合物,即一种或多种如上所述的化学修饰的核苷酸可以作为天然存在的核苷酸AMP,GMP,UMP和/或CMP的一种或多种的替换,和如果天然存在的核苷酸AMP,GMP,UMP和/或CMP不全部被替换,则任选地另外地作为一个或多个天然存在的核苷酸AMP,GMP,UMP和/或CMP的替换而存在。通过将所需碱基选择性添加至体外转录培养基,可以因此控制所需核苷酸修饰在转录的本发明的与阳离子或聚阳离子化合物复合的至少一种(m)RNA或至少一种游离mRNA,其编码至少一种治疗活性蛋白,抗原和/或抗体,中的含量,即发生率和量。合适的体外转录培养基同样含有RNA聚合酶,例如T7-RNA聚合酶(例如T7-Opti mRNA试剂盒,CureVac,Tübingen,德国),T3-RNA聚合酶或SP6,典型地约10-500U,优选约25-250U,更优选约50-150U,和最优选约100U RNA聚合酶。体外转录培养基还优选保持无RNA酶,从而避免降解转录的(m)RNA。合适的体外转录培养基因此任选地另外包含RNA酶抑制剂。
在本发明的体外转录方法的步骤c)中,将步骤b)的(脱氧)核糖核酸在体外转录培养基中,约30-45℃,优选37-42℃,温育和转录典型地约30-120分钟,优选约40-90分钟和最优选约60分钟。温育温度由所用RNA聚合酶决定,例如在T7 RNA聚合酶的情形中,温育温度为约37℃。通过转录获得的核酸优选是与阳离子或聚阳离子化合物复合的至少一种(m)RNA或至少一种游离mRNA,分别编码至少一种治疗活性蛋白,抗原和/或抗体,二者均如上定义。
在根据以上方法步骤c)温育后,在根据本发明的体外转录方法的步骤d)中任选地进行反应的纯化。为了该目的,可以使用本领域中已知的任何合适方法,例如色谱纯化法,例如亲合层析法,凝胶过滤等。通过纯化,非结合的,即过量的核苷酸可以从体外转录培养基中除去。现有技术中已知的任何合适方法,例如色谱纯化法,例如亲合层析法,凝胶过滤等,可以用于此。通过纯化,可以获得如本文中定义的RNA序列,例如与阳离子或聚阳离子化合物复合的至少一种(m)RNA或至少一种游离的mRNA,分别编码至少一种治疗活性蛋白,抗原和/或抗体,的干净的转录的RNA。例如,转录后,含有转录的RNA的反应混合物可以典型地用DNA酶消化,从而去除反应混合物中仍然含有的DNA模板。转录的RNA可以随后或备选地用LiCl沉淀。然后转录的RNA的纯化可以通过离子对反相(IP RP)-HPLC进行。这使得较长和较短片段彼此特别有效的分离成为可能。优选地,在该上下文中,纯化可以通过用于根据制备级纯化RNA的方法来进行,其区别在于如上定义的RNA,具体地与阳离子或聚阳离子化合物复合的至少一种(m)RNA或至少一种游离mRNA,分别编码至少一种治疗活性蛋白,抗原和/或抗体,通过利用多孔反相作为固定相(PURE信使)的HPLC方式来纯化。例如,为了本发明体外转录方法的步骤d)中的纯化,反相可以用作HPLC纯化的固定相。对于使用反相的层析法,非极性化合物典型地起固定相的作用,且极性溶剂,诸如通常采用缓冲液形式使用的水和乙腈和/或甲醇的混合物,起用于洗脱的流动相的作用。优选地,多孔反相具有颗粒尺寸8.0±2μm,优选±1μm,更优选+/-0.5μm。反相材料可以采用珠的形式。纯化可以以多孔反相的特别有利的方式进行,所述多孔反相具有该颗粒尺寸,任选采用珠形式,获得特别良好的分离结果。使用的反相优选是多孔的,因为使用非多孔固定反相,诸如例如由Azarani A.and Hecker K.H.所述的,逐渐形成太高的压力,由此使得如上定义的RNA,具体地与阳离子或聚阳离子化合物复合的至少一种(m)RNA或至少一种游离mRNA,分别编码至少一种治疗活性蛋白,抗原和/或抗体,的制备级纯化是可能的,但是具有很大难度。反相优选具有孔尺寸特别地孔尺寸对于反相特别优选的孔尺寸是 和使用具有这些孔尺寸的反相,关于方法步骤d)中如上定义的RNA的纯化,可以获得特别良好的结果。关于反相的材料优选是聚苯乙烯-二乙烯基苯,且具体可以使用非烷基化的聚苯乙烯-二乙烯基苯。具有聚苯乙烯-二乙烯基苯的固定相本身已知。为了方法步骤d)中的纯化,可以使用本身已知并已经用于HPLC方法且可商购的聚苯乙烯-二乙烯基苯。非烷基化的多孔聚苯乙烯-二乙烯基苯,其具体具有颗粒尺寸8.0±0.5μm和孔尺寸 或非常特别优选地用于方法步骤d)中的纯化。以上所述的优势可以以特别有利的方式,使用该反相材料获得。HPLC纯化可以通过离子对方法进行,将具有正电荷的离子加入到流动相中作为带负电荷的RNA的平衡离子。具有亲脂性特征的离子对,其通过反相系统的非极性固定相减慢,以该方式形成。实践中,关于离子对方法的精确条件必须通过经验对每个具体分离问题作出。平衡离子的尺寸,其浓度和溶液的pH对分离结果作出巨大贡献。以有利的方式,将烷基铵盐,诸如乙酸三乙基铵和/或四烷基铵化合物,诸如四丁基铵加入到流动相中。优选地,加入0.1M乙酸三乙基铵并将pH调节到约7。流动相的选择取决于所需分离的性质。这意味着关于特定分离发现的流动相,诸如可以例如由现有技术已知的,不能容易地转化为另一个具足够成功前景的分离问题。理想的洗脱条件,具体地所用的流动相,必须通过经验实验,对每个分离问题确定。水性溶剂和有机溶剂的混合物可以用作通过HPLC法洗脱如上定义的RNA,具体地与阳离子或聚阳离子化合物复合的至少一种(m)RNA或至少一种游离mRNA,分别编码至少一种治疗活性蛋白,抗原和/或抗体,的流动相。在该上下文中,如果具有,具体地约7,例如6.5-7.5,例如7.0的pH的缓冲液用作水性溶剂,则是有利的,优选地,使用缓冲液乙酸三乙基铵,特别优选如上所述也在离子对方法中起如上定义的RNA的平衡离子作用的0.1M乙酸三乙基铵缓冲液。流动相中使用的有机溶剂可以是乙腈,甲醇或这二者的混合物,非常特别优选是乙腈。利用所述HPLC法在方法步骤d)中纯化本文定义的RNA,特别是纯化与阳离子或聚阳离子化合物复合的至少一种(m)RNA或至少一种游离mRNA,分别编码至少一种治疗活性蛋白,抗原和/或抗体,,以使用这些有机溶剂的特别有利的方式进行。流动相特别优选是0.1M乙酸三乙基铵(pH 7)和乙腈的混合物。发现同样特别有利的是如果流动相包含基于流动相的5.0vol.%-20.0vol.%的有机溶剂,且补足100%的剩余部分是水性溶剂。对按照本发明的方法非常特别有利的是,如果流动相包含基于流动相的9.5vol.%-14.5vol.%的有机溶剂,则补足100%的剩余部分是水性溶剂。如本文定义的RNA,具体地与阳离子或聚阳离子化合物复合的至少一种(m)RNA或至少一种游离mRNA,分别编码至少一种治疗活性蛋白,抗原和/或抗体,的洗脱可以随后等度地或通过梯度分离的方式进行。在等度分离的情形中,如本文定义的RNA的洗脱使用保持恒定的单一洗脱剂或若干洗脱剂的混合物进行,以上详细描述的溶剂作为洗脱剂使用是可能的。
本发明还提供转染和任选施用如上定义的本发明的免疫刺激组合物或其成分、如上定义的本发明的药物组合物或本发明的疫苗的方法,所述方法包括以下步骤:
(a)收集血细胞,专职抗原呈递细胞(APCs),特别是树突细胞(DCs),和
(b)用本发明的免疫刺激组合物或其成分,本发明的药物组合物或本发明的疫苗体外转染所述血细胞,专职抗原呈递细胞(APCs),特别是树突细胞(DCs)。
在本发明的上下文中,“血细胞”优选根据本发明理解为意指来自全血、血清或另一种来源例如来自脾或淋巴结的红细胞、粒细胞、单核细胞(PBMCs)和/或血小板的混合物或富含到充分纯的群体,仅存在小比例的专职APC。优选地,本发明中的血细胞典型地特征在于,它们含有小比例的充分分化的专职抗原呈递细胞(APCs),特别是树突细胞(DCs)。按照本发明使用的血细胞优选是新鲜血细胞,即血细胞收集(具体地抽血)和转染之间的期间仅非常短,例如小于12h,优选小于6h,特别优选小于2h和非常特别优选小于1h。然而,按照本发明使用的血细胞还可以是在需要例如如本文中定义的操作或处理前抽血时获得并随后保存直至使用的血细胞。
血细胞可以通过例如标准方法,由动物或人患者中收集。因此,全血可以通过刺破合适的血管容易地获得。血清以已知的方式通过凝固固体血液成分来获得。PBMC可以作为血细胞的富集部分群体的实例提及。这些通过首先由描述的方法常规分离(Nature(自然)204,793-794,1964;Scan.J.Lab.Clin.Invest.Suppl.(斯堪的纳维亚临床和实验室研究杂志增刊)97,1967)。这通常通过从个体抽血和将其加入至例如常规包含Ficoll和泛影酸钠的密度1.077g/ml(25℃)的溶液,以用于密度梯度离心来进行。在室温下小心离心过程中,PBMC在Ficoll/血液的界面处收集,而红细胞和剩余白细胞沉积。回收与PBMC的界面并用合适的缓冲液,例如无菌PBS常规洗涤。PBMC优选经历使用例如氯化铵水溶液的短等渗处理。最后,用缓冲液诸如PBS(无菌)再洗涤PBMC一次或多次。然后,获得的细胞任选地在合适条件下,常规在-70℃保存,直至进一步使用。
根据一个优选的实施方案,血细胞在即将转染前是新鲜血细胞,即步骤(a)中收集血细胞(具体地抽血)和根据步骤(b)转染之间的期间仅非常短,例如小于12h,优选小于6h,特别优选小于2h和非常特别优选小于1h。
在本发明的上下文中,树突细胞(DCs),用于上述本发明的转染和任选施用方法中时,典型地是有效的抗原呈递细胞(APCs),其典型地具有刺激幼稚T细胞的能力。它们包括广泛分布于所有组织,尤其在提供环境界面的那些组织中的白细胞系统。DCs具有异源造血谱系,因为来自不同组织的子集已经显示出具有不同的形态学、表型和功能。刺激幼稚T细胞增殖的能力似乎在这些不同DC子集中共享。已经提示所谓的骨髓和淋巴来源的DC子集分别执行特异性刺激或耐受原功能。DC源自骨髓先祖并且在移动至外周组织前,在血液中作为不成熟的前体循环。在不同组织中,DC分化并变为具有吸收和加工抗原的活性,并且它们在细胞表面上的随后的呈递与主要组织相容性(MHC)分子相关。在适当刺激时,DC经历进一步熟化并移动至第二淋巴组织,在那里它们将抗原呈递至T细胞并诱导免疫应答。DC受到逐渐增长的科学和临床兴趣,这归因于它们在抗癌宿主应答中的关键作用和作为肿瘤疫苗中生物佐剂的潜在用途,以及它们在耐受性和自身免疫的免疫生物学中的参与。然而,树突细胞(DC)还可以用于本发明的上下文中,条件是不需要或设想免疫应答或需要或设想较低的免疫应答。所述树突细胞(DC),如上定义,可以由如上提及的不同组织或由血液,特别由如上所述的血样中分离。
优选地,用于本发明的转染和任选施用根据本发明的药物组合物或疫苗的方法的血细胞,专职抗原呈递细胞(APC),特别是树突细胞(DC)源自将使用本发明的药物组合物处理的真实患者(自体细胞)。根据本发明的药物组合物或疫苗因此优选含有自体血细胞,专职抗原呈递细胞(APC),特别是树突细胞(DC)。
血细胞,专职抗原呈递细胞(APC),特别是树突细胞(DC)的转染,同样通过常用方法,例如通过电穿孔或化学方法,尤其脂转染,优选仅通过施用本发明的组合物而不需要其他转染试剂来进行。
根据步骤(b)用于体外转染的如上定义的RNA,具体地与阳离子或聚阳离子化合物复合的至少一种(m)RNA和至少一种游离mRNA,分别编码至少一种治疗活性蛋白,抗原和/或抗体,通过本领域中技术人员已知的方法,尤其通过化学合成或特别优选通过已经在上文中提及的分子生物学方法来制备。
如上定义,可能需要用如本文中定义的RNA,具体本发明的免疫刺激组合物或其成分,或本发明的药物组合物或疫苗来转染用于本发明的转染和任选施用方法的血细胞,专职抗原呈递细胞(APC),特别是树突细胞(DC)。此外,还可以设想将所述转染的细胞施用于患者,体内施用于活组织和/或生物体,特别是在自体细胞的情形中再植入宿主生物体内,并可以将其作为上述方法的任选步骤c)来执行。在该上下文中,生物体(或生物)典型地意指哺乳动物,其选自但不仅限于,包括人,和动物包括猪、山羊、牛、猪、狗、猫、驴、猴、猿或啮齿类动物,包括小鼠、仓鼠和兔的组。此外,如上所述的活组织优选源自这些生物体。将转染的细胞施用于那些活组织和/或生物体可以经由任何合适的施药途径,例如系统性,并包括例如如上定义的皮内或经皮,口服,肠胃外,包括皮下,肌内或静脉内注射,局部和/或鼻内途径发生。
根据另一个实施方案,本发明还提供用于制备本发明的免疫刺激组合物的方法,所述方法包括以下步骤:
a)制备包括与如上定义的阳离子或聚阳离子化合物复合的如上定义的至少一种(m)RNA或由其组成的“佐剂成分”,其优选通过将如上定义的至少一种(m)RNA以特定比例与如上定义的阳离子或聚阳离子化合物混合实现;和
b)通过以如上定义的特定比例,将如上定义的至少一种游离mRNA加入至根据步骤a)制备的佐剂成分制备本发明的免疫刺激组合物,其中如上定义的至少一种游离mRNA编码如上定义的至少一种治疗活性蛋白,抗原和/或抗体。
所谓的“佐剂成分”根据本发明的制备方法的步骤a),通过使佐剂成分的至少一种(m)RNA与阳离子或聚阳离子化合物,优选以特定比例复合形成稳定复合物来制备。如上定义,重要的是,在复合(m)RNA后,佐剂成分中无游离阳离子或聚阳离子化合物剩余或仅剩余可忽视的小量。因此,佐剂成分中(m)RNA与阳离子或聚阳离子化合物的比典型地这样选择,以使得(m)RNA完全复合并且无游离阳离子或聚阳离子化合物或仅可忽视的小量剩余在组合物中。优选地,佐剂成分的比,即(m)RNA与阳离子或聚阳离子化合物的比在约6∶1(w/w)-约0,25∶1(w/w),更优选约5∶1(w/w)-约0,5∶1(w/w),甚至更优选约4∶1(w/w)-约1∶1(w/w)或约3∶1(w/w)-约1∶1(w/w),和最优选约3∶1(w/w)-约2∶1(w/w)的比的范围内选择。
另外地或备选地,所述第一成分(即包括与阳离子或聚阳离子化合物复合的至少一种(m)RNA或由其组成的佐剂成分)和所述第二成分(即所述至少一种游离mRNA)的比可以基于整个RNA复合物的氮/磷比(N/P-比)计算。在本发明的上下文中,N/P-比优选在约0.1-10的范围内,优选在约0.3-4的范围内和最优选在约0.5-2的范围内或关于该复合物中RNA∶肽的比在0.7-2的范围内,和最优选在约0.7-1.5的范围内。
另外地或备选地,所述第一成分(即包括与阳离子或聚阳离子化合物复合的至少一种(m)RNA或由其组成的佐剂成分)和所述第二成分(即所述至少一种游离mRNA)的比也可以在本发明的免疫刺激组合物中,基于两种RNA,即佐剂成分的(m)RNA(其与阳离子或聚阳离子化合物复合)和第二成分的至少一种游离mRNA彼此间的摩尔比来选择。典型地,佐剂成分的(m)RNA与第二成分的至少一种游离mRNA的摩尔比可以这样选择,以使得该摩尔比满足以上(w/w)和/或N/P-定义。更优选地,佐剂成分的(m)RNA与第二成分的至少一种游离mRNA的摩尔比可以选自例如如上定义的摩尔比,例如约0.001∶1,0.01∶1,0.1∶1,0.2∶1,0.3∶1,0.4∶1,0.5∶1,0.6∶1,0.7∶1,0.8∶1,0.9∶1,1∶1,1∶0.9,1∶0.8,1∶0.7,1∶0.6,1∶0.5,1∶0.4,1∶0.3,1∶0.2,1∶0.1,1∶0.01,1∶0.001,等或选自由以上任意两个数值形成的任何范围,例如选自约0.001∶1-1∶0.001,0.01∶1-1∶0.001,0.1∶1-1∶0.001,1∶1-1∶0.001,0.001∶1-1∶0.01,0.001∶1-1∶0.1,0.001∶1-1∶1,0.01∶1-1∶0.01,0.1∶1-1∶0.1,1∶1,等的范围。
甚至更优选地,佐剂成分的(m)RNA与第二成分的至少一种游离mRNA的摩尔比可以选自例如约0.01∶1-1∶0.01的范围。最优选地,佐剂成分的(m)RNA与第二成分的至少一种游离mRNA的摩尔比可以选自例如约1∶1的摩尔比。在该具体的实施方案中,任何以上关于(w/w)和/或N/P比的定义也均适用。
在本发明方法的上下文中,阳离子或聚阳离子化合物优选选自如上定义的阳离子或聚阳离子化合物,其例如通过使核酸与阳离子或聚阳离子化合物缔合而适合于复合并由此稳定核酸,具体地(m)RNA。本发明的免疫刺激组合物的修饰的(m)RNA与如上定义的阳离子或聚阳离子化合物的缔合或复合优选为该(m)RNA提供佐剂性质并将稳定作用通过复合赋予佐剂成分的(m)RNA。用于稳定修饰的(m)RNA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,但也可以通过本领域中已知的任何合适方法来进行。
根据如上描述的本发明制备方法的步骤b),本发明的免疫刺激组合物通过以特定比例,将如上定义的至少一种游离mRNA加入至根据步骤a)制备的佐剂成分获得,其中如上定义的至少一种游离mRNA编码如上定义的至少一种治疗活性蛋白,抗原和/或抗体。如上进一步所述,本发明的免疫刺激组合物中佐剂成分(包含与阳离子或聚阳离子化合物复合的至少一种(m)RNA)和第二成分(至少一种游离mRNA)的比可以根据具体治疗,例如癌症或抗肿瘤治疗、基因治疗、抗过敏治疗(脱敏)、预防性或治疗性疫苗接种等的特殊要求来选择。典型地,本发明的免疫刺激组合物的佐剂成分和第二成分的比这样选择,以使得由于佐剂成分引起先天性免疫系统的显著刺激。平行地,该比例这样选择,以使得可以在体内提供显著量的至少一种游离mRNA,由此导致有效翻译体内表达的蛋白。优选地,本发明的免疫刺激组合物中佐剂成分∶游离mRNA的比选自如上定义的范围,例如约5∶1(w/w)-约1∶10(w/w)的范围,更优选约4∶1(w/w)-约1∶8(w/w)的范围,甚至更优选约3∶1(w/w)-约1∶5(w/w)或1∶3(w/w)的范围,和最优选本发明的免疫刺激组合物中佐剂成分∶游离mRNA的比选自约1∶1(w/w)的比。
任选地,在一个或更多另外的步骤中,可以向本发明的免疫刺激组合物加入如上定义的其他成分。
根据最后的实施方案,本发明还提供试剂盒,具体地多部分的试剂盒,其包括,作为成分,单独地或组合地,本发明的免疫刺激组合物或其成分,即与阳离子或聚阳离子化合物复合的至少一种(m)RNA,和至少一种游离mRNA,分别编码至少一种治疗活性蛋白,抗原和/或抗体,和/或本发明的药物组合物或疫苗,和任选地,关于这些成分的施用和剂量的信息的技术说明书。所述试剂盒,优选多部分的试剂盒,可以应用于,例如,任何以上提及的应用或用途。
附图
以下附图意欲进一步图示本发明。它们不意欲将本发明的主题限制于此。
图1:描述体内皮内注射编码荧光素酶的mRNA后荧光素酶表达的结果,其中制备包含10μg与鱼精蛋白(2∶1和1∶1)复合、结合或不结合LacZ-mRNA(wt LacZ)的编码荧光素酶(Pp Luc)的游离mRNA的组合物,并将其皮内注射到耳廓中。如可见,分别以1∶1或2∶1的比例配制的LacZ-mRNA∶鱼精蛋白复合物对荧光素酶表达不具有负面影响,即无游离鱼精蛋白或仅非常少量游离鱼精蛋白存在于溶液中,这也不对翻译具有负面影响。因此,鱼精蛋白和ppLuc mRNA之间不可能形成复合物,这表示已经形成的LacZ-mRNA∶鱼精蛋白复合物的稳定性。
图2:显示用于治疗目的的E.G7-OVA-模型中疫苗接种反应的结果。为了该实验,在C57 BL/6小鼠中植入300,000个E.G7-OVA肿瘤细胞,并在2周内用本发明的免疫刺激组合物对小鼠接种8次,所述本发明的免疫刺激组合物包含20μg编码原鸡(Gallus gallus)卵清蛋白的富含GC的mRNA。在第一个实验中,使用以3∶1的比例与鱼精蛋白完全复合的RNA,或其中复合的RNA与游离RNA以1∶1,1∶4和1∶8(w/w)的比例混合的RNA。如图2中可见,游离RNA以及鱼精蛋白单独地,与缓冲液对照(林格氏-乳酸盐溶液)相比,不表现出对肿瘤生长的任何影响。令人意外地,用以3∶1(RNA∶鱼精蛋白)的比例与RNA复合的鱼精蛋白接种显著减小肿瘤生长。添加游离RNA甚至进一步增强肿瘤应答,其中已经证明大于1∶8(复合的RNA∶游离RNA),例如1∶4或甚至1∶1的比例是特别有利的。
图3:描述用于与图2的实验中类似的治疗目的的E.G7-OVA-模型中疫苗接种反应的结果。为了这第二个实验,使用以3∶1的比例与鱼精蛋白完全复合的RNA,或根据改良方案的RNA,其中复合的RNA与游离RNA以RNA∶鱼精蛋白3∶1+游离RNA(1∶1)的比例混合。如在图3中可见,复合的RNA和游离RNA,具体地以所述比例的组合,导致改善的肿瘤防御。
图4:显示根据图3的实验的统计学(数学)分析。图4具体显示组间差异是显著的。该统计学(数学)分析使用GraphPad Prism软件执行,并利用Mann Whitney检验确定p值。该分析强调图3中所示的结果。
图5:描述检测免疫刺激性质和用mRNA(CAP-GgOva(GC)-muag-A70-C30)刺激hPBMC的结果。为了该实验,将2x105个hPBMCs接种到96孔板中的200μl培养基/孔中,并且加入50μl本发明的组合物,其包含10μg编码原鸡卵清蛋白的mRNA,以在37℃过夜刺激细胞因子释放。使用包含复合的和游离RNA的组合物的hPBMC中的细胞因子(TNFα和IL6)的分泌在ELISA检测中显示出显著升高,这说明良好的免疫刺激性质。
图6:描述体内诱导体液免疫应答的结果,其中C57BL/6小鼠用各16μg编码原鸡卵清蛋白的富含GC的mRNA(CAP-GgOva(GC)-muag-A70-C30)或“无关”对照RNA(pB-Luc RNA)接种8次。如图6中可见,复合的RNA与游离RNA,具体地以(1∶1)的比例的结合导致与用完全复合的RNA接种相比升高的体液免疫应答。
图7:显示根据SEQ ID NO:120的mRNA序列,其表现出1365个核苷酸的长度并称为“CAP-GgOva(GC)-muag-A70-C30”。mRNA序列CAP-GgOva(GC)-muag-A70-C30含有以下序列元件:
用于更佳密码子应用和稳定性的GC-最优化序列
muag(突变的α-球蛋白-3’-UTR)
处于3’-末端的70×腺苷(聚-A-尾部),
处于3’-末端的30×胞嘧啶(聚-C-尾部)。
ORF以斜体字母表示,muag(突变的α-球蛋白-3’-UTR)用虚线表示,聚-A-尾部下划单线,且聚-C-尾部下划双线。
图8:描述根据SEQ ID NO:121的mRNA序列,其表现出1816个核苷酸的长度并称为“T7TS-Ppluc(wt)-A70”。完整mRNA序列的编码序列(CDS)以斜体字母表示,聚-A-尾部下划单线。
图9:显示Balb/c小鼠中荧光素酶表达的统计学分析。该统计学分析使用GraphPad Prism软件执行,并利用Mann Whitney检验确定p值。图9中的结果显示根据本发明复合的RNA(2∶1(50%)+游离(50%))在与裸RNA和以4∶1的比例与鱼精蛋白复合的RNA相比时,表现出相同的表达。如可见,相关组之间的差别不显著(ns)。因此,使用本发明的复合的RNA可以有效提供免疫刺激,其中与裸RNA和以4∶1的比例与鱼精蛋白复合的RNA相比保持表达水平(也参见图10)。
图10:描述Balb/c小鼠中诱导IL-12的统计学分析。该统计学分析使用GraphPad Prism软件执行,并利用Mann Whitney检验确定p值。该结果显示本发明的复合的RNA(2∶1(50%+游离(50%))和包含等量RNA和鱼精蛋白的组4∶1(100%)之间的差别是显著的。因此,使用本发明的复合的RNA可以有效提供免疫刺激,其中与裸RNA和以4∶1的比例与鱼精蛋白复合的RNA相比保持表达水平(也参见图9)。
图11:显示针对流感抗原血凝素(HA)的IgG2a抗体的诱导。因此,小鼠用20μg编码裸血凝素(HA)或如所示与鱼精蛋白盐酸盐(Prot.Val)或鱼精蛋白硫酸盐(Prot.Leo)一起配制的血凝素(HA)的富含GC的mRNA接种2次。如图11中可见,复合的RNA与游离RNA的结合导致与用完全复合的RNA接种相比升高的体液免疫应答。与裸RNA相比,复合的RNA导致更高的IgG2a抗体效价,即Th1驱动的应答的指示剂。RNA与鱼精蛋白盐酸盐(鱼精蛋白Valeant)的复合具有比与鱼精蛋白硫酸盐复合更强的作用。
图12:图示免疫后超过15周,针对流感抗原HA的IgG2a特异性抗体的诱导。因此,小鼠用20μg编码裸血凝素(HA)或与鱼精蛋白复合的血凝素(HA)(RNA∶鱼精蛋白2∶1+游离RNA(1∶1)(w/w))的富含GC的mRNA接种2次,并在所示时间点测量IgG2a抗体。来自免疫后不同时间点的血清通过ELISA分析。IgG2a亚型的血凝素特异性抗体效价关于用缓冲液(80%RiLa)、裸HAmRNA或复合的HAmRNA处理的组作图。
图13:通过HAI测定描述针对流感抗原HA的抗体的诱导。因此,小鼠用20μg编码裸血凝素(HA)或与鱼精蛋白一起配制的血凝素(HA)(RNA∶鱼精蛋白2∶1+游离RNA(1∶1)(w/w))的富含GC的mRNA接种2次,并在所示时间点进行HAI测定。
图14:显示编码来自流感病毒的致病性抗原血凝素(HA)的mRNA序列。
实施例:
以下实施例意欲进一步举例说明本发明。它们不意欲将本发明的主题限制于此。
实施例1-制备编码Pp荧光素酶(萤火虫(Photinus pyralis))的mRNA构建体
为了以下实验,制备编码Pp荧光素酶(萤火虫)并对应于编码如本文中使用的Pp荧光素酶序列的各自mRNA的DNA序列,并将其用于随后的转染和疫苗接种实验中。由此,与编码天然Pp荧光素酶的mRNA相对应的DNA序列用聚-A-标记物(A70)来修饰,从而导致SEQ ID NO:121(参见图8)。最终构建体具有1816个核苷酸的长度并称为“T7TS-Ppluc(wt)-A70”。
实施例2-制备编码原鸡卵清蛋白的mRNA构建体
为了以下实验,制备编码原鸡卵清蛋白并对应于各自mRNA序列的另一种DNA序列,并将其用于随后的转染和疫苗接种实验中。由此,与编码天然原鸡卵清蛋白的mRNA相对应的DNA序列是为了更好的密码子应用和稳定性而GC-优化的。然后,将与编码原鸡卵清蛋白的mRNA序列相对应的DNA序列转移至RNActive构建体中,其已经用聚-A-标记物和聚-C-标记物(A70-C30)修饰。最终的构建体具有1365个核苷酸的长度并称为“CAP-GgOva(GC)-muag-A70-C30”。其包含以下序列元件:
用于更佳密码子应用和稳定性的GC-最优化序列
muag(突变的α-球蛋白-3’-UTR)
处于3’-末端的70×腺苷(聚-A-尾部),
处于3’-末端的30×胞嘧啶(聚-C-尾部)。
相对应的mRNA序列显示在图7中(参见SEQ ID NO:120)。
实施例3-体外转录实验
线性化重组质粒DNA,并随后利用T7 RNA聚合酶体外转录。然后DNA模板由DNA酶I消化来降解。通过LiCl沉淀回收RNA并通过HPLC提取(PUREMessenger,CureVac GmbH,Tübingen,德国)来进一步净化。
实施例4-制备本发明组合物:
以下实验中使用的mRNA与鱼精蛋白复合,其通过将鱼精蛋白以所示比例(1∶1-1∶4)(w/w)加入至mRNA实现。温育10分钟后,加入游离RNA。
实施例5-皮内注射编码荧光素酶的mRNA后的体内荧光素酶表达
在该实验中,研究包含容易制备的mRNA∶鱼精蛋白复合物和/或游离mRNA的组合物对翻译的影响。因此,制备包含10μg与鱼精蛋白(2∶1和1∶1)复合、结合或不结合LacZ-mRNA的编码荧光素酶(Pp Luc)的游离mRNA的组合物并将其皮内注射到耳廓中。
编码Pp荧光素酶的mRNA如上所述制备。待施用的组合物不含其他复合的RNA,浓度为2∶1的lacZ-mRNA∶鱼精蛋白或浓度为1∶1的lacZ-mRNA∶鱼精蛋白。作为对照,施用不含编码Pp荧光素酶(萤火虫)的mRNA的组合物。鱼精蛋白用作对照。为了制备这些组合物,lacZ-mRNA在第一步中与不同量和比例(2∶1和1∶1(w/w))的鱼精蛋白一起配制,并作为第一成分加入。然后,10分钟后向该组合物加入游离Pp Luc mRNA。
24h后,去除耳廓并在液氮中冷冻。为了匀浆,将样品置于处于30s-1的TissueLyser中3分钟。然后加入800μl溶胞-缓冲液(25mM Tris-HCl pH(7.5-7.8);2mM EDTA;10%(w/v)甘油;1%(w/v)Triton-X-100;2mMDTT;1mM PMSF),并再次将样品置于处于30s-1的TissueLyser中6分钟。样品在13500rpm和4℃离心10分钟。移出上清并保存在-80℃直至荧光素酶测量。上清与荧光素缓冲液(25mM甘氨酰甘氨酸,15mM MgSO4,5mM ATP,62.5μM荧光素)混合并用光度计(Lumat LB 9507;Berthold Technologies,Bad Wildbad,德国)测量发光。
结果(参见图1),分别以1∶1或2∶1的比例配制的LacZ-mRNA∶鱼精蛋白复合物对荧光素酶的表达没有负面影响,即无游离鱼精蛋白或仅非常少量游离鱼精蛋白存在于溶液中,这对翻译没有负面影响。因此,在鱼精蛋白和ppLuc mRNA之间不可能形成复合物,这说明已经形成的LacZ-mRNA∶鱼精蛋白复合物的稳定性。
实施例6-用于治疗目的的E.G7-OVA-模型中的疫苗接种
一般方法:
将300000个E.G7-OVA肿瘤细胞植入C57 BL/6小鼠。在随后的3周中,小鼠在3周内用本发明的组合物接种8次,所述本发明的组合物包含20μg编码原鸡卵清蛋白的富含GC的mRNA。肿瘤尺寸在植入肿瘤细胞后18天时测量。
A)第一个实验
将300000个E.G7-OVA肿瘤细胞植入C57 BL/6小鼠。在随后的2周内,各用20μg编码原鸡卵清蛋白的富含GC的mRNA接种小鼠8次。为了该实验,使用以3∶1的比例与鱼精蛋白完全复合的RNA,或其中复合的RNA与游离RNA以1∶1,1∶4和1∶8(w/w)的比例混合的RNA。
结果显示在图2中。如图2中可见,游离RNA以及鱼精蛋白单独地,与缓冲液对照(林格氏-乳酸盐溶液)相比,不表现出对肿瘤生长的任何微小影响。令人意外地,用以3∶1(RNA∶鱼精蛋白)的比例与RNA复合的鱼精蛋白接种显著减小肿瘤生长。添加游离RNA甚至进一步增强肿瘤应答,其中已经证明大于1∶8(复合的RNA∶游离RNA),例如1∶4或甚至1∶1的比例是特别有利的。
B)第二个实验
将300000个E.G7-OVA肿瘤细胞植入C57 BL/6小鼠。在随后的3周内,各用20μg编码原鸡卵清蛋白的富含GC的mRNA接种小鼠8次。为了该实验,使用以3∶1的比例与鱼精蛋白完全复合的RNA,或根据改良方案的RNA,其中复合的RNA与游离RNA以RNA∶鱼精蛋白3∶1+游离RNA(1∶1)的比例混合。
该实验的结果描述在图3中。如在图3中可见,复合的RNA和游离RNA的组合,具体地以所述比例的组合,导致改善的肿瘤防御。
统计学(数学)分析使用GraphPad Prism软件执行,并利用Mann Whitney检验确定p值(参见图4)。
实施例7-检测免疫刺激性质和用mRNA刺激hPBMC
为了该实验,hPBMC通过在Ficoll(20min,2000rpm)上离心来分离,并随后在PBS中洗涤2次。然后将hPBMC以5x107/ml的密度重新悬浮在FCS,10%DMSO中。将1ml等分试样冷冻保存在-80℃。
在该实验前,hPBMC通过重新悬浮在PBS中来融化,随后在PBS中洗涤2次。然后将hPBMC以1x106/ml的密度悬浮在X-Vivo 15,1%谷氨酰胺,1%Pen/Strep中。在96孔板中以2x105/孔接种hPBMC后,加入50μl本发明的组合物,其包含8μg编码原鸡卵清蛋白的mRNA,从而在37℃过夜刺激细胞因子释放。
因此,人PBMCs与编码原鸡卵清蛋白(OVA)、与鱼精蛋白(3∶1)复合RNA+50%游离RNA(如下配制:RNA∶鱼精蛋白3∶1+游离RNA(1∶1)(w/w))一起温育20小时。利用标准ELISA测量和检测上清中的细胞因子(TNFα和IL6)的分泌。
为了TNFα和IL6的量化(ELISA),用捕获抗体(1μg/ml)包被Maxisorb板过夜(4℃),并随后用1%BSA在室温(RT)下封闭1小时。在用0.05%吐温洗涤3次后,将用15-100μl封闭缓冲液调节过的50μl(TNFα)或50μl(IL-6)hPBMC上清加入至孔中。容许结合进行2小时(RT)。然后洗涤该板,并加入100μl链霉抗生物素-缀合的辣根过氧化物酶。温育30分钟和洗涤后,加入比色物质(TMB,Perbio Science)。利用Tecan ELISA板读数器,在450nm测量光密度。全部温育在室温下进行,并且洗涤步骤包括使用PBS/吐温20(0.05%v/v)的至少3步。
加入100μl/孔Strept-HRP(1/1000稀释的)和生物素化的检测抗体(0,5μg/ml)的混合物。在RT温育1小时后,用0.05%吐温洗涤3次。最后,加入100μl/孔Amplex Red HRP物质(50μM),0.014%H2O2。在Spectramax Gemini板读数器中测量荧光性(Ex 540nm,Em 590nm,截取值590nm)。
结果显示在图5中。如图5中可见,包含复合的和游离RNA的组合物表现出免疫刺激性质,这通过hPBMC中显著的TNFα和IL6分泌反映。
实施例8-诱导体液免疫应答
C57 BL/6小鼠用各16μg编码原鸡卵清蛋白的富含GC的mRNA或“无关”对照RNA(pB-Luc RNA)接种8次。由此,RNA以2∶1的比例完全与鱼精蛋白一起配制,或该比例根据改良方案RNA∶鱼精蛋白2∶1+游离RNA(1∶1)(w/w)))。最后疫苗接种后2周时,收集血样并确定卵清蛋白特异性抗体的表达。
为了检测抗原特异性抗体,用抗原(卵清蛋白,重组蛋白)包被MaxiSorb板(Nalgene Nunc International)。用1×PBS,0,05%吐温和1%BSA封闭后,用小鼠血清,在室温下温育该板4小时。随后,加入生物素-偶联的第二抗体。洗涤后,用辣根过氧化物酶温育该板,并通过测量底物(2,2’-连氮基-双(3-乙基-苯并噻唑啉-6-磺酸)(OD 450nm)的转化来确定酶活性。利用Tecan ELISA板读数器,在450nm测量光密度。
结果显示在图6中。如图6中可见,复合的RNA与游离RNA的结合导致与用完全复合的RNA接种相比升高的体液免疫应答。
实施例9-Balb/c小鼠中荧光素酶表达的统计学分析
在该实验中,研究关于鱼精蛋白的不同配制策略对荧光素酶翻译的影响。在每组中,2只小鼠在4个不同位点皮内注射以下各项:
(1)包含与50%游离RNA结合的50%鱼精蛋白-复合的(2∶1)Luc-RNA的组合物,
(2)包含以4∶1的比例与鱼精蛋白复合的Luc-RNA的组合物,
(3)100%游离Luc-RNA,或
(4)林格氏-乳酸盐缓冲液作为对照。
各样品包含处于50μl林格氏-乳酸盐缓冲液中的10μg编码荧光素酶的mRNA(Luc-RNA,即上述根据SEQ ID NO:121的构建体“T7TS-Ppluc(wt)-A70”)。第一组和第二组也包含相同量的鱼精蛋白,但是它们不同配制。组(1)的免疫刺激组合物根据本发明制备。
结果显示在图9中。图9显示Balb/c小鼠中荧光素酶表达的统计学分析。该统计学分析使用GraphPad Prism软件执行,并利用Mann Whitney检验确定p值。图9中的结果显示根据本发明复合的RNA(2∶1(50%)+游离(50%),组(1))在与裸RNA和以4∶1的比例与鱼精蛋白复合的RNA(组(2)和(3))相比时,表现出相同的表达。如可见,相关组之间的差别不显著(ns)。因此,使用本发明的免疫刺激组合物可以有效提供免疫刺激,其中与裸RNA和以4∶1的比例与鱼精蛋白复合的RNA相比保持表达水平(也参见图10)。
实施例10-Balb/c小鼠中诱导IL-12的统计学分析:
为了该实验,将处于以下组合物中的40μg编码荧光素酶的mRNA(Luc-RNA,即上述根据SEQ ID NO:121的构建体“T7TS-Ppluc(wt)-A70”)静脉内注射到Balb/c小鼠的尾静脉中(4只小鼠/组):
(1)2∶1(50%)+游离(50%),其包含20μg Luc-RNA,其与鱼精蛋白复合(2∶1)(w/w)和20μg游离Luc-RNA(即本发明的免疫刺激组合物),
(2)4∶1(100%),其包含40μg Luc-RNA,其与鱼精蛋白复合(4∶1)(w/w),
(3)40μg游离Luc-RNA,
(4)10μg鱼精蛋白,和
(5)800μl RiLa(全部样品溶解在林格氏-乳酸盐缓冲液中达到最终体积800μl)。
4小时后,通过刺穿眼球后静脉采血并将血清用于细胞因子(IL-12)ELISA。ELISA如实施例7所述进行。
结果显示在图10中。图10描述根据实施例10,Balb/c小鼠中诱导IL-12的统计学分析。该统计学分析使用GraphPad Prism软件执行,并利用Mann Whitney检验确定p值。该结果显示本发明的免疫刺激组合物(2∶1(50%+游离(50%))和包含等量RNA和鱼精蛋白的组4∶1(100%)之间的差别实际上是显著的。因此,使用本发明的免疫刺激组合物可以有效提供免疫刺激,其中与裸RNA和以4∶1的比例与鱼精蛋白复合的RNA相比保持表达水平(也参见图9)。
实施例11-诱导针对病毒抗原的体液免疫应答
疫苗接种:
Balb/c小鼠用20μg编码Influenza A/Puerto Rico/8/34(PR8)的血凝素(HA)的富含GC的mRNA或注射缓冲液(80%林格氏-乳酸盐)接种2次。由此,RNA以2∶1的比例完全与鱼精蛋白一起配制,或该比例是根据本发明的是RNA∶鱼精蛋白2∶1+游离RNA(1∶1)(w/w)。为了配制,测试两种不同的鱼精蛋白,即鱼精蛋白盐酸盐(protamine hydrochloride)(鱼精蛋白Valeant)或鱼精蛋白硫酸盐(protamine sulphate)(鱼精蛋白LEO)。
检测特异性抗体:
在最后疫苗接种后不同时间点收集血样,并通过ELISA(图11和12)或血凝抑制测定(HAI)(图13)确定血凝素特异性抗体的表达。
通过ELISA检测抗原特异性抗体:
为了通过ELISA检测抗原特异性抗体,用抗原(灭活的PR8)包被MaxiSorb板(Nalgene Nunc International)。用1×PBS,0,05%吐温和1%BSA封闭后,用小鼠血清,在室温下温育该板4小时。随后,加入生物素-偶联的第二抗体。洗涤后,用辣根过氧化物酶温育该板,并通过测量底物(2,2’-连氮基-双(3-乙基-苯并噻唑啉-6-磺酸)(OD 405nm)的转化来确定酶活性。利用Tecan ELISA板读数器,在405nm测量光密度。免疫后2周获得的血清的分析结果显示在图11中。如图11中可见,复合的RNA与游离RNA的结合导致与用完全复合的RNA接种相比升高的体液免疫应答。与裸RNA相比,复合的RNA导致更高的IgG2a抗体效价,即Th1驱动的应答的指示剂。RNA与鱼精蛋白盐酸盐(鱼精蛋白Valeant)的复合具有比与鱼精蛋白硫酸盐复合更强的作用。
在图12中,来自免疫后不同时间点的血清通过ELISA分析。IgG2a亚型的血凝素特异性抗体效价关于用缓冲液(80%RiLa)、裸HA mRNA或复合的HAmRNA处理的组作图。复合遵从改良方案RNA∶鱼精蛋白2∶1+游离RNA(1∶1)(w/w),与鱼精蛋白Valeant进行。
通过HAI测定检测抗原特异性抗体:
还通过HAI测定分析免疫小鼠的血清。在HAI测定中,检测通过阻断宿主细胞上病毒血凝素和唾液酸的相互作用而中和病毒的抗体。
血清在56℃灭活10分钟,以破坏补体和HAI抑制剂。血清进一步与高岭土一起温育20分钟并预吸附于鸡红细胞30分钟,以去除影响血凝的非特异性因子。将预处理的血清样品以连续稀释和一式二份的方式,加入至96孔U底板中。然后加入25μl在PBS中含有4个血凝单位的失活PR8和50μl 0.5%鸡红细胞,并在室温下温育45分钟。终点HAI效价定义为完全抑制红细胞血凝的最高血清稀释度的倒数。来自免疫后不同时间点的血清的效价关于用缓冲液(80%RiLa)、裸HA mRNA或复合的HA mRNA处理的组作图。复合与鱼精蛋白Valeant和改良方案RNA∶鱼精蛋白2∶1+游离RNA(1∶1)(w/w)进行。假定效价40在流感感染的情形中具有保护性。用复合的HARNA免疫的小鼠表现出大于40的持久HAI效价,而裸HA mRNA导致平均低于保护性效价40的效价。
Claims (17)
1.免疫刺激组合物,其包含
a)佐剂成分,其包括至少一种(m)RNA或由其组成,所述(m)RNA与阳离子或聚阳离子化合物复合,和
b)至少一种游离mRNA,其编码至少一种治疗活性蛋白,抗原和/或抗体,
其中所述免疫刺激组合物能够引起或增强哺乳动物中的先天性和任选地适应性免疫应答。
2.根据权利要求1的免疫刺激组合物,其中所述佐剂成分的至少一种(m)RNA选自短RNA寡核苷酸,编码RNA,包括mRNA,免疫刺激性RNA,siRNA,反义RNA,或核开关,核酶或适体。
3.根据权利要求1或2的免疫刺激组合物,其中所述佐剂成分的至少一种(m)RNA是mRNA。
4.根据权利要求1-3中任一项的免疫刺激组合物,其中所述至少一种游离mRNA和所述佐剂成分的至少一种(m)RNA彼此相同。
5.根据权利要求1-3中任一项的免疫刺激组合物,其中所述至少一种游离mRNA和所述佐剂成分的至少一种(m)RNA彼此不同。
6.根据权利要求1-5中任一项的免疫刺激组合物,其中所述佐剂成分中m(RNA)与阳离子或聚阳离子化合物的N/P比在约0.1-10的范围,包括约0.3-4,约0.5-2,约0.7-2和约0.7-1.5的范围内。
7.根据权利要求1-7中任一项的免疫刺激组合物,其中所述佐剂成分的(m)RNA与第二成分b)的至少一种游离mRNA的摩尔比可以选自约0.001∶1-约1∶0.001的摩尔比,包括约1∶1的比。
8.根据权利要求1-7中任一项的免疫刺激组合物,其中所述至少一种游离mRNA和/或所述佐剂成分的至少一种(m)RNA是GC-稳定化的。
9.根据权利要求8的免疫刺激组合物,其中GC-稳定化的RNA编码区的G/C含量与天然RNA编码区的G/C含量相比增加,GC-稳定化的修饰(m)RNA的编码氨基酸序列与天然修饰(m)RNA的编码氨基酸序列相比不改变。
10.根据权利要求1-9中任一项的免疫刺激组合物,其中所述阳离子或聚阳离子化合物选自鱼精蛋白,核仁蛋白,精胺或亚精胺,聚-L-赖氨酸(PLL),碱性多肽,聚-精氨酸,细胞渗透肽(CPPs),嵌合CPPs,包括Transportan,或MPG肽,HIV结合肽,Tat,HIV-1Tat(HIV),Tat衍生的肽,寡精氨酸,穿膜肽家族成员,包括穿膜肽,触角足衍生肽(来自果蝇触角足),pAntp,pIsl,抗微生物衍生的CPPs包括Buforin-2,Bac715-24,SynB,SynB(1),pVEC,hCT-衍生的肽,SAP,MAP,KALA,PpTG20,富含脯氨酸的肽,L-寡聚体,富含精氨酸的肽,降钙素肽,FGF,乳铁蛋白,聚-L-赖氨酸,聚精氨酸,组蛋白,VP22衍生肽或类似物肽,HSV,VP22(单纯疱疹),MAP,KALA或蛋白转导结构域包括PTDs,PpT620,富含脯氨酸的肽,富含精氨酸的肽,富含赖氨酸的肽,Pep-1,和一种或多种降钙素肽,或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0,1,2,3,4,5,6,7或8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%,
或选自寡精氨酸,包括Arg7,Arg8,Arg9,Arg7,H3R9,R9H3,H3R9H3,YSSR9SSY,(RKH)4,Y(RKH)2R,
或选自阳离子多糖,包括脱乙酰壳多糖,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,聚乙烯亚胺(PEI),阳离子脂质,DOTMA:[1-(2,3-二油氧基丙基)]-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)酰氨基甘氨酰精胺),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,oligofectamine,或选自阳离子或聚阳离子聚合物,包括修饰的聚氨基酸类,包括如β-氨基酸-聚合物或逆聚酰胺类,改性的聚乙烯类,包括PVP(聚(N-乙基-4-乙烯基溴化吡啶鎓)),修饰的丙烯酸酯类,包括pDMAEMA(聚(二甲基氨基乙基甲基丙烯酸酯)),修饰的酰胺胺类包括pAMAM(聚(酰胺胺)),修饰的聚β氨基酯(PBAE),包括二胺端修饰的1,4丁二醇二丙烯酸酯-共-5-氨基-1-戊醇聚合物,树型化合物,包括聚丙基胺树型化合物或基于pAMAM的树型化合物,聚亚胺(类),包括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,包括基于环糊精的聚合物,基于葡聚糖的聚合物,脱乙酰壳多糖,基于硅烷主链的聚合物,包括PMOXA-PDMS共聚物,由一个或多个阳离子嵌段(选自如上所述的阳离子聚合物)和一个或多个亲水性或疏水性嵌段(包括聚乙二醇)的组合组成的嵌段聚合物。
11.根据权利要求1-10中任一项的免疫刺激组合物,其中所述至少一种游离mRNA编码抗原,所述抗原选自肿瘤抗原,包括5T4,707-AP,9D7,AFP,AlbZIP HPG1,α5β1-整联蛋白,α5β6-整联蛋白,α-甲基酰基-辅酶A消旋酶,ART-4,B7H4,BAGE-1,BCL-2,BING-4,CA 15-3/CA 27-29,CA 19-9,CA 72-4,CA125,钙网蛋白,CAMEL,CASP-8,组织蛋白酶B,组织蛋白酶L,CD19,CD20,CD22,CD25,CD30,CD33,CD4,CD52,CD55,CD56,CD80,CEA,CLCA2,CML28,Coactosin-样蛋白,胶原蛋白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/MAGE-B1,DAM-6/MAGE-B2,EGFR/Her1,EMMPRIN,EpCam,EphA2,EphA3,ErbB3,EZH2,FGF-5,FN,Fra-1,G250/CAIX,GAGE-1,GAGE-2,GAGE-3,GAGE-4,GAGE-5,GAGE-6,GAGE-7b,GAGE-8,GDEP,GnT-V,gp100,GPC3,HAGE,HAST-2,hepsin,Her2/neu/ErbB2,HERV-K-MEL,HNE,同源框NKX 3.1,HOM-TES-14/SCP-1,HOM-TES-85,HPV-E6,HPV-E7,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,KK-LC-1,KM-HN-1,LAGE-1,Livin,MAGE-A1,MAGE-A10,MAGE-A12,MAGE-A2,MAGE-A3,MAGE-A4,MAGE-A6,MAGE-A9,MAGE-B1,MAGE-B10,MAGE-B16,MAGE-B17,MAGE-B2,MAGE-B3,MAGE-B4,MAGE-B5,MAGE-B6,MAGE-C1,MAGE-C2,MAGE-C3,MAGE-D1,MAGE-D2,MAGE-D4,MAGE-E1,MAGE-E2,MAGE-F1,MAGE-H1,MAGEL2,mammaglobin A,MART-1/Melan-A,MART-2,基质蛋白22,MC1R,M-CSF,Mesothelin,MG50/PXDN,MMP 11,MN/CA IX-抗原,MRP-3,MUC1,MUC2,NA88-A,N-乙酰葡糖胺转移酶-V,新-PAP,NGEP,NMP22,NPM/ALK,NSE,NY-ESO-1,NY-ESO-B,OA1,OFA-iLRP,OGT,OS-9,骨钙蛋白,骨桥蛋白,p15,p15,p190小bcr-abl,p53,PAGE-4,PAI-1,PAI-2,PAP,PART-1,PATE,PDEF,Pim-1-激酶,Pin1,POTE,PRAME,prostein,蛋白酶-3,PSA,PSCA,PSGR,PSM,PSMA,RAGE-1,RHAMM/CD168,RU1,RU2,S-100,SAGE,SART-1,SART-2,SART-3,SCC,Sp17,SSX-1,SSX-2/HOM-MEL-40,SSX-4,STAMP-1,STEAP,存活蛋白,存活蛋白-2B,TA-90,TAG-72,TARP,TGFb,TGFbRII,TGM-4,TRAG-3,TRG,TRP-1,TRP-2/6b,TRP-2/INT2,Trp-p8,酪氨酸酶,UPA,VEGF,VEGFR-2/FLK-1,WT1;或选自癌症疾病中表达的突变抗原,包括α-辅肌动蛋白-4/m,ARTC1/m,bcr/abl,β-联蛋白/m,BRCA1/m,BRCA2/m,CASP-5/m,CASP-8/m,CDC27/m,CDK4/m,CDKN2A/m,CML66,COA-1/m,DEK-CAN,EFTUD2/m,ELF2/m,ETV6-AML1,FN1/m,GPNMB/m,HLA-A*0201-R170I,HLA-A11/m,HLA-A2/m,HSP70-2M,KIAA0205/m,K-Ras/m,LDLR-FUT,MART2/m,ME1/m,MUM-1/m,MUM-2/m,MUM-3/m,I类肌球蛋白/m,新-PAP/m,NFYC/m,N-Ras/m,OGT/m,OS-9/m,p53/m,Pml/RARa,PRDX5/m,PTPRK/m,RBAF600/m,SIRT2/m,SYT-SSX-1,SYT-SSX-2,TEL-AML1,TGFbRII,TPI/m。
12.根据权利要求1-11中任一项的免疫刺激组合物,其中所述至少一种游离mRNA编码:
a)以下抗原组中的至少1、2、3或4种(不同的)抗原:
●PSA(前列腺-特异性抗原)=KLK3(激肽释放酶-3),
●PSMA(前列腺-特异性膜抗原),
●PSCA(前列腺干细胞抗原),
●STEAP(前列腺的六次跨膜上皮抗原),
或
b)以下抗原组中的至少1、2、3、4、5、6、7、8、9、10、11或12种(不同的)抗原:
●hTERT,
●WT1,
●MAGE-A2,
●5T4,
●MAGE-A3,
●MUC1,
●Her-2/neu,
●NY-ESO-1,
●CEA,
●存活蛋白,
●MAGE-C1,和/或
●MAGE-C2,
其中这些抗原的任意组合是可能的。
13.药物组合物,其包含根据权利要求1-12中任一项的免疫刺激组合物和任选地药用载体、佐剂、和/或媒介物。
14.根据权利要求13的药物组合物,其中所述药物组合物是疫苗。
15.用于制备如根据权利要求1-12中任一项定义的免疫刺激组合物的方法,所述方法包括以下步骤:
a)制备包括与阳离子或聚阳离子化合物复合的至少一种(m)RNA或由其组成的佐剂成分,其通过以特定比例混合如根据权利要求1-12中任一项定义的至少一种(m)RNA和阳离子或聚阳离子化合物实现;和
b)通过以特定比例,将如根据权利要求1-12中任一项定义的至少一种游离mRNA加入至根据步骤a)制备的佐剂成分来制备本发明的免疫刺激组合物,其中如根据权利要求1-12中任一项定义的所述至少一种游离mRNA编码至少一种治疗活性蛋白,抗原和/或抗体。
16.根据权利要求1-15中任一项的免疫刺激组合物,或如根据权利要求1-12中任一项定义的包括与阳离子或聚阳离子化合物复合的至少一种(m)RNA或由其组成的佐剂成分和编码至少一种治疗活性蛋白,抗原和/或抗体的至少一种游离mRNA用于制备预防、治疗、和/或改善选自癌症或肿瘤疾病,自身免疫疾病,传染病,包括病毒、细菌或原生动物传染病或过敏症或过敏性疾病的任何疾病和病症的药物组合物的用途。
17.试剂盒,其包括根据权利要求1-12中任一项的免疫刺激组合物,和/或根据权利要求13-14中任一项的药物组合物,和任选地关于所述免疫刺激组合物和/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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