CN101796191B - 用于转染和用于免疫刺激的rna和阳离子肽的复合物 - Google Patents
用于转染和用于免疫刺激的rna和阳离子肽的复合物 Download PDFInfo
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- CN101796191B CN101796191B CN200880105611.5A CN200880105611A CN101796191B CN 101796191 B CN101796191 B CN 101796191B CN 200880105611 A CN200880105611 A CN 200880105611A CN 101796191 B CN101796191 B CN 101796191B
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Abstract
本发明涉及复合的RNA,其包含至少一个与一种或多种寡肽复合的RNA,其中所述寡肽具有穿透细胞的肽(CPP)的功能,具有8-15个氨基酸的长度并具有主要残基选自Arg,Lys,His,Orn的实验式(Arg)1;(;Lys)m;(His)n;(Orn)o;(Xaa)x。本发明还涉及用于转染细胞或生物体的方法,从而应用本发明的复合RNA。另外,本文中公开了包含本发明复合RNA的药物组合物和试剂盒,以及本发明复合RNA用于转染细胞,组织或生物体和/或用于调节,优选诱导或增强免疫反应的用途。
Description
本发明涉及复合的RNA,其包括至少一种与一种或多种寡肽复合的RNA(分子),其中所述寡肽具有8-15个氨基酸的长度并具有通式(Arg)l(Lys)m(His)n(Orn)o(Xaa)x。本发明还涉及用于转染细胞或生物体的方法,从而应用本发明的复合RNA。另外,本文中公开了包含本发明的复合RNA的药物组合物和试剂盒,以及本发明的复合RNA用于转染细胞、组织或生物体和/或用于调节,优选诱导或增强免疫反应的用途。
通过基因转移的方法将核酸转染到患者的细胞或组织中是重要的分子医学方法并且在治疗和预防许多疾病中起关键作用。用于转染核酸的方法可以导致组织或生物体的免疫刺激。备选地或另外地,核酸转染后可以加工由引入的核酸编码的信息,即所需多肽或蛋白质的翻译。DNA或RNA作为核酸形成基因治疗的备选方法。核酸的转染还可以导致基因表达的调节例如抑制或增强,这取决于转染的核酸的类型。这些核酸的转染典型地通过使用基因转移的方法进行。
在过去的几十年中集中研究了将基因转移到细胞或组织中的方法,然而,仅在某种程度上具有有限的成功。公知的方法包括物理或物理化学方法,诸如(直接)注射(裸)核酸或生物射弹基因转移。生物射弹基因转移(也称为生物射弹粒子轰击)是在康奈尔大学(CornellUniversity)开发的方法,其容许将遗传物质引入到组织或培养的细胞中。生物射弹基因转移典型地通过表面包被金属粒子,诸如金或银粒子,和通过使用基因枪将这些包含吸附的DNA的金属粒子发射到细胞中来完成。然而,生物射弹基因转移方法尚未表现出对RNA起作用,这可能归因于它的快速降解。此外,这些方法不适合于体内应用,即代表严重实践局限性的问题。
备选的物理或物理化学方法包括体外电穿孔方法。体外电穿孔基于使用高压电流使细胞膜可渗透以容许将新的DNA或RNA引入细胞。因此,在转染前,典型地通过使用化学品或通过小心的冷冻以使其成为“电感受态”(″electrocompetent″)的过程来弱化细胞壁。如果电感受态细菌或细胞(例如真核细胞)和DNA(或RNA)混合在一起,则可以通过使用放电将质粒转移到细胞中,从而通过穿过反应室的火光将DNA(或RNA)运送到细胞中。
另一种备选的物理或物理化学方法包括使用纳米复合物(nanoplexes)(纳米颗粒系统)、脂质体复合物(lipoplexes)(脂质体系统),或使用多聚复合物(polyplexes)或阳离子聚合物。所述纳米复合物(纳米颗粒系统)包括使用聚丙烯酸酯、聚酰胺、聚苯乙烯、氰基丙烯酸酯、聚乳酸酯(PLA)、聚(乳酸-共-乙醇酸)(PLGA)、聚乙基等,作为用于运输核酸进入细胞或组织的载体系统。脂质体复合物或脂质体系统典型地包括使用阳离子脂质,其能够模拟细胞膜。由此,脂质的带正电荷部分与核酸的带负电荷部分相互反应,由此容许与细胞膜的融合。脂质体复合物或脂质体系统包括例如DOTMA,DOPE,DOSPA,DOTAP,DC-Chol,EDMPC等。多聚复合物(阳离子聚合物)典型地与带负电的核酸形成复合物,从而导致核酸的缩合并防止这些核酸降解。利用多聚复合物(阳离子聚合物)向细胞内运输典型地通过受体介导的胞吞作用实现。由此,DNA通过例如与表面受体结合并触发胞吞作用的多聚复合物聚-L-赖氨酸(PLL)与不同的分子诸如转铁蛋白偶联。多聚复合物(阳离子聚合物)包括例如聚-L-赖氨酸(PLL)、脱乙酰壳多糖、聚氮丙啶(PEI)、聚二甲基氨基乙基甲基丙烯酸酯(PD-MAEMA)、聚酰胺型胺(PAMAM)。
其他公知的将基因转移到细胞或生物体内的物理或物理化学方法包括这样的方法,诸如基于病毒的转染法。作为具体的实例,DNA病毒可以用作DNA载体。因为它们的感染特性,这样的病毒具有非常高的转染率。典型使用的病毒以这样的方式遗传修饰,即在转染的细胞中不形成功能性感染颗粒。然而,尽管该安全性预警,例如由于可能的重组事件,不能排除引入的治疗活性基因和病毒基因不受控增殖的风险。
在本文中更有利的是所谓的易位蛋白或蛋白转导结构域(PTDs)用于将大分子运输到细胞或组织中的应用。易位蛋白被认为是一组能够影响细胞间大分子运输的肽(易位蛋白),诸如HIVtat(HIV),触角(果蝇触角(Drosophilaantennapedia)),HSVVP22(单纯疱疹),FGF或乳铁蛋白,等。相反,蛋白转导结构域(PTDs)被认为是一组能够指导与这些序列共价结合的蛋白和肽通过细胞膜进入细胞的肽(Leifert和Whitton:Translocatoryproteinsandproteintransductiondomains:acriticalanalysisoftheirbiologicaleffectsandtheunderlyingmechanisms(易位蛋白和蛋白转导结构域:它们的生物学作用和基础机制的重要分析).MolecularTherapy(分子治疗)Vol.8,No.1,2003)。与易位蛋白以及与PTDs共同的是一个碱性区域,其被认为主要负责融合肽的运输,因为其能够结合聚阴离子诸如核酸。不与其结合,PTDs可以利用受体依赖性不可饱和的吸附胞吞作用起与阳离子转染试剂类似的作用。PTDs典型地与蛋白质或肽偶联,从而在施用基于肽的疫苗时,实现或增强CTL反应(参见综述:Melikov和Chernomordik,Arginine-richcellpenetratingpeptides:fromendosomaluptaketonucleardelivery(富含精氨酸的细胞穿透肽:由内体吸收到细胞核递送),Cell.Mol.LifeSci.(细胞分子生命科学)2005)。
蛋白转导结构域(PTDs)有时也称为“细胞穿透肽”(CPPs),这归因于其穿透细胞膜并由此影响(大)分子运输进入细胞的能力。CPPs是小肽并且典型地包括高含量的碱性氨基酸并展示出7-30个氨基酸的长度。表现出通过CPPs运输进入细胞的大分子包括肽以及DNA、siRNA或PNAs(肽核酸),其中CPPs典型地通过共价键与这些大分子结合并转染到细胞中。尽管细胞穿透肽(CPPs)已经成功用于在体外和体内介导广泛多种的药理学目的分子的胞内递送,但是发生细胞摄入的机制仍不清楚。CPPs组是高度多样的,并由下述组成:两性分子,螺旋肽诸如转运蛋白(transportan),穿透蛋白(penetratin),疏水性肽诸如MTS,VP22,MAP,KALA,PpTG20,富含prolin的肽,MPG-肽,Pep-1,L-低聚物,降钙素-肽,或富含精氨酸的阳离子亲水性肽,包括富含精氨酸的CPPs,其通过与细胞的蛋白聚糖,诸如HIV-1Tat蛋白的转导结构域结合介导(共价)缀合的分子的细胞摄入(综述:Deshayes等Cell-penetratingpeptides:toolsforintracellulardeliveryoftherapeutics(细胞穿透肽:用于胞内递送治疗剂的工具).Cell.Mol.LifeSci.(细胞分子生命科学)2005)。具体地,富含精氨酸的CPPs被描述为蛋白质或DNA,例如质粒DNA等进入细胞的载体。聚-精氨酸还可以用于运输(大)分子进入细胞,其典型地包括至少60-80个氨基酸(具体地,精氨酸),更典型地1000-15000个氨基酸的长度,并由此代表高分子量化合物。即使CPPs的细胞摄入机制总体上不清楚,但是胞吞作用被暗示为聚-精氨酸的摄入机制。胞吞作用是这样的分子过程,通过该分子过程大分子可以在不穿透细胞膜的条件下进入细胞,其中已经提示了三种不同的胞吞机制(网格蛋白(chlathrin)-依赖性胞吞作用,窖蛋白-依赖性胞吞作用和/或F肌动蛋白-依赖性胞吞作用,参见例如综述:Melikov和Chernomordik,Arginine-richcellpenetratingpeptides:fromendosomaluptaketonucleardelivery(富含精氨酸的细胞穿透肽:由内体吸收到细胞核递送),Cell.Mol.LifeSci.(细胞分子生命科学)2005)。不受任何理论束缚,在胞吞作用过程中,CPP-复合的大分子首先结合带负电的细胞表面糖胺聚糖(GAGs),包括类肝素(HS)。然后,CPP结合的大分子通过网格蛋白(chlathrin)-依赖性胞吞作用,窖蛋白-依赖性胞吞作用和/或F肌动蛋白-依赖性胞吞作用,例如通过细胞外CPP结合的大分子周围的膜的折叠,进入细胞。这导致将CPP结合的大分子引入其中的囊状小泡的形成。CPP结合的大分子经由晚期内体和/或高尔基体和/或内质网(ER)的运输将CPP结合的大分子递送到胞质中,其中这个阶段可能包括CPP诱导的脂质双分子层中瞬间孔的打开。备选地,CPP复合的大分子可以被运输到细胞中的其他位置,例如内体中,这取决于特定目的所需的作用模式。作为一个实例,TLR-7和TLR-8受体位于内体中。因此,用免疫刺激性RNA转染细胞可以导致向内体运输和(取决于特异性相互作用和相互作用配偶体)例如通过RNA配体的免疫刺激,所述免疫刺激性RNA可以是例如Toll样受体(TLRs),其选自TLR1-TLR13的配体(Toll样受体:TLR1,TLR2,TLR3,TLR4,TLR5,TLR6,TLR7,TLR8,TLR9,TLR10,TLR11,TLR12或TLR13)。
如上定义的细胞穿透肽(CPPs)是本领域中公知并广泛讨论的。然而,针对肽、蛋白质和DNA作为货物(cargo)的转运确定这些CPPs(作为载体)的应用,其中CPPs典型地以共价方式与货物分子相连。相反,仅针对非常有限数量的情形,具体地针对短RNA序列,例如双链siRNA序列,显示了利用CPPs的RNA细胞运输。
通过举例,Futaki等(TheJournalofBiologicalChemistry(生物化学杂志),Vol.276,No.8,第5836-5840页,2001)公开了具有4-16个氨基酸长度的载体寡肽(Arg)n用于体外转移货物肽的应用,其中载体肽与货物肽共价连接。分别关于具有6或8个精氨酸的(Arg)n证明了易位最适性。
通过CPPs跨膜运输肽或拟肽(peptidomimetics)也由Deshayes等(2005,见上)显示。Deshayes等(2005,见上)公开了寡肽Arg7和Arg9用于体外转移货物肽和体内转移货物蛋白诸如环孢菌素或过氧化氢酶的应用。
为了用大分子,诸如DNA,肽或蛋白质转染细胞,根据本领域的技术,使用高分子量多肽诸如聚-L-精氨酸(例如,典型具有约5000Da-15kDa的MW)或聚-L-赖氨酸(例如典型具有约54kDa的MW)以及高分子量PEI(聚乙烯亚胺)(例如,典型具有约25kDa的MW)(还参见Bettinger等,NucleicAcidsResearch(核酸研究),Vol.29,No.18,(2001))。然而,高分子量聚-L-赖氨酸和PEI作为载体分子似乎是无效的。此外,当使用高浓度的高分子量聚-L-精氨酸时,观察到导致补体系统活化的毒性作用。因此,付出了开发低分子量转染试剂,诸如,例如低分子量聚-精氨酸的努力。然而,所述低分子量聚-精氨酸典型地展示出载体-货物-复合物,即由作为载体的聚-精氨酸和作为货物的DNA分子形成的复合物的低稳定性。因此,McKenzie等(McKenzie等Apotentnewclassofreductivelyactivatedpeptidegenedeliveryagents(有效的新型还原活化肽基因递送试剂);TheJournalofBiologicalChemistry(生物化学杂志),Vol.274,No.14,2000)试图通过使这些肽通过戊二醛与DNA交联提高肽-DNA-复合物的稳定性,由此形成希夫氏碱(Schiff’sbase)。然而,所述交联导致该复合物在细胞中极端缓慢的解离并且,因此,编码蛋白的表达随着时间的过去非常低。为了避开这个问题,McKenzie等(2000,见上)将半胱氨酸残基引入到CPP载体中,这通过在CPP和DNA之间形成二硫键稳定该复合物。在转染时,由于细胞内的还原条件,这些二硫键在细胞中裂开,由此导致编码肽增加的表达。然而,所述交联是费力的且可能导致另外不需要的DNA修饰。
此外,低分子量PEI(例如,典型地具有约2000Da的MW)和低分子量聚-L-赖氨酸(例如,典型地具有约3400Da的MW)可以用于转染如上提及的大分子。然而,即使在这些实验中关于低分子量PEI或聚-L-赖氨酸观察到改善的转染,但是表达是不可检测的,这归因于这些载体分子与DNA形成极端稳定的复合物。结果,这些载体分子似乎不展示出它们复合的DNA的解离,这是翻译和表达编码蛋白的必要步骤(参见Bettinger等,(2001),见上文)。
通过CPPs运输DNA进一步由Niidome等(TheJournalofBiologicalChemistry(生物化学杂志),Vol.272,No.24,第15307-15312页,1997)。显示。Niidome等(1997,见上文)公开了CPPs,特别地分别具有25%确定的精氨酸含量和12或24个氨基酸长度的阳离子α-螺旋肽用于运输作为货物部分的质粒DNA的应用。结果,发现长和/或疏水性肽可以与DNA强力结合并影响DNA向细胞内的运输。而且,Niidome等(BioconjugateChem(生物缀合化学).1999,10,773-780)显示具有16-17个氨基酸长度的肽对于运输质粒DNA最有效。然而,当使用小肽(例如约12个氨基酸)作为CPPs时,DNA进入细胞的转染效率变为显著降低。
为了提高短精氨酸分子的细胞转染效率,Futaki等(BioconjugateChem(生物缀合化学).2001,12,1005-1011)使用具有4-16个氨基酸长度的硬脂酰化(stearylated)寡肽(Arg)n。这些寡肽在转染实验中与具有4-16个氨基酸长度的非硬脂酰化寡肽(Arg)n和聚-精氨酸(MW5000-15000)对比,用于体外转移编码荧光素酶的质粒DNA。因此,用于转染的载体肽与质粒DNA混合并形成载体/货物复合物。关于具有8个精氨酸长度的硬脂酰化(Arg)n证明了易位最适性,而具有6-7和9-15个精氨酸长度的精氨酸显示出显著降低的细胞运输活性。此外,非硬脂酰化精氨酸和聚-精氨酸的运输活性展示出不良结果,这说明当使用这些载体肽时损失运输活性。由Futaki等(2001,见上文)所示的关于硬脂酰化和非硬脂酰化载体肽观察到的转染效率差异因此归因于脂质部分的存在,这显著改变这些实验中使用的CPPs的化学特性。
根据Kim等(Kim等,Basicpeptidesystemforefficientdeliveryofforeigngenes(用于有效递送外源基因的碱性肽系统),BiochimicaetBiophysicaActa1640(2003)129-136),短精氨酸载体肽诸如(Arg)9-(Arg)15可以用于编码绿色荧光蛋白PEGFP-N3的DNA的复合和细胞转染。当使用精氨酸(Arg)9-(Arg)15时,使用(Arg)15获得最佳结果,这显示由(Arg)9到(Arg)15增加细胞转染效率。这些结果说明关于用DNA转染细胞的最佳运输特性可以使用(Arg)n载体肽完成,其中n远超过15。然而,短精氨酸肽用于转染目的的适用性由Kim等针对作为货物部分的DNA分子专门记录(2003,见上文)。
细胞还可以通过使用CPPs与RNA的结合来转染。然而,对于RNA的细胞运输仅进行了少量工作实例,这可能归因于其在复合物中的快速降解和低稳定性。因此,使用CPPs转染RNA似乎局限于更稳定的双链RNA,诸如siRNA。通过举例,等(RNA(2006),12:1431-1438)使用硬脂酰化的八-精氨酸(Arg)8体外转移双链短siRNA进入神经元海马细胞,其中硬脂酰化的八-精氨酸(Arg)8与siRNA形成复合物。基于等(2006,见上)的结果,载体肽的硬脂酰成分似乎是运输siRNA或运输其他RNA分子不可缺少的(indispensible)。
Veldhoen等(2006)还公开处于非共价复合物中的特定CPPs用于双链短siRNA序列的细胞转染的应用(Veldhoen等,CellulardeliveryofsmallinterferingRNAbyanon-covalentlyattachedcellpenetratingpeptide:quantitativeanalysisofuptakeandbiologicaleffect(通过非共价附着的细胞穿透肽细胞递送小干扰RNA:吸收和生物学作用的定量分析).NucleicAcidsResearch(核酸研究)2006)。由Veldhoen等(2006)使用的肽是MPGα(Ac-GALFLAFLAAALSLMGLWSQPKKKRKV-Cya)和MPGα-mNLS(Ac-GALFLAFLAAALSLMGLWSQPKSKRKV-Cya)。这些特定的肽另外在N端用乙酰基部分(Ac)和在C端用半光酰胺(cysteamide)部分修饰。Veldhoen等(2006)能够显示通过使用前述载体肽将具有约18-40个核苷酸长度的双链siRNA转移到细胞中。
综上所述,主要针对肽和针对DNA分子展示CPPs或其他载体肽用于大分子的细胞运输的应用。少数非常具体的出版物公开了双链siRNA的细胞穿透特性。
RNA转移代表现代分子医学中的重要工具并表现出超越DNA细胞转染的出众特性,因为DNA分子可能导致严重的问题。例如,DNA分子的应用具有DNA整合到宿主基因组中的风险。外源DNA整合到宿主基因组中可以对宿主基因的表达具有影响并可能触发致癌基因的表达或破坏肿瘤抑制基因。对于宿主必要的基因-和因此的基因产物也可以由外源DNA向该基因的编码区内的整合而失活。如果DNA整合发生在参与细胞生长调节的基因内,则存在特别的危险。在这种情形中,宿主细胞可能进入退化状态并导致癌症或肿瘤形成。所述不希望的向DNA内的整合甚至可能引起更多问题,条件是转染到细胞内的DNA包括有效的启动子,诸如病毒CMV启动子。所述启动子整合到受处理的细胞的基因组中可以导致细胞中基因表达调节的不理想变化。另外的缺点是DNA分子长期保持在细胞核中,其作为游离基因或,如上提及地,整合到宿主基因组中。这种现象导致不受限制的或不能及时受到限制的转基因蛋白的生成和针对该转基因蛋白的相关耐受性危险。此外,抗DNA抗体的开发(Gilkeson等,JClinInvest(临床研究杂志)95,1398-1402(1995))和自体免疫疾病的诱导可以通过注射DNA触发。所有这些列出的风险均与应用DNA有关。相反,如果使用RNA,特别是mRNA代替DNA,则它们不发生。例如,mRNA不整合到宿主基因组中,有效转录等不需要病毒序列,诸如启动子等。由使用RNA引起的缺点可以归因于其与DNA相比的不稳定性(RNA降解酶,具体地,所谓的RNA酶(核糖核酸酶),但还有许多其他去稳定化RNA的过程是造成RNA不稳定的原因)。然而,其间,用于稳定RNA的方法已经公开在本领域中,诸如,例如,在WO03/051401,WO02/098443,WO99/14346,EP-A-1083232,US5,580,859和US6,214,804中。还开发了关于保护RNA免受核糖核酸酶降解的方法,其利用脂质体(Martinon等,EurJImmunol(欧洲免疫学杂志)23,1719-1722(1993))或使用弹道装置(基因枪)胞质内体内施用核酸(Vassilev等,Vaccine(疫苗)19,2012-2019(2001))。
因为RNA分子同样提供超越如上讨论的DNA的有利特性,本发明的目的是提供用于运输RNA进入细胞内的合适有效载体。因此,本发明提供容许RNA以有效方式转染细胞的方案。
本发明的这个目的通过如由权利要求表征的本发明的实施方案实现。具体地,以上目的通过复合的RNA(分子)解决,所述复合的RNA(分子)包括至少一种RNA(分子),优选地mRNA,其与一种或多种寡肽复合,其中所述至少一种寡肽具有8-15个氨基酸的长度,且其中所述至少一种寡肽含有1个Arg残基,m个Lys残基,n个His残基,o个Orn残基和x个Xaa残基,其以任何顺序位于具有以下实验式的至少一种寡肽中:
(Arg)l;(Lys)m;(His)n;(Orn)o;(Xaa)x(通式I)
其中
·l+m+n+o+x=8-15,且
l,m,n或o彼此独立,可以是选自0,1,2,3,4,5,6,7,8,9,10,11,12,13,14或15的任一数值,条件是Arg,Lys,His和Orn的总含量代表该寡肽所有氨基酸的至少50%,例如至少60%或70%;且
·Xaa可以是选自除Arg,Lys,His或Orn以外的天然(=天然存在的)或非天然氨基酸中的任一氨基酸;且
·X可以是选自0,1,2,3,4,5,6,7或8的任一数值,条件是Xaa的总含量不超过该寡肽所有氨基酸的50%,例如不超过40%或30%。
在本发明的上下文中,复合的RNA被理解为如本文中定义的RNA(分子),优选地mRNA,其与按照实验式(Arg)l;(Lys)m;(His)n;(Orn)o;(Xaa)x的一种或多种寡肽通过在RNA和寡肽之间形成非共价复合物来复合。在本文中,“非共价”意指RNA和寡肽的可逆结合通过这些分子的非共价相互作用形成,其中所述分子通过除共价键以外的任何类型的电子相互作用,例如通过范德瓦尔斯键,即由复合分子的非特异性吸引力产生的弱静电吸引结合在一起。RNA与至少一种寡肽的结合与该复合物的解离平衡。在胞内,不受任何理论束缚,该平衡似乎朝向解离的RNA和寡肽移动。
按照本发明的复合RNA的至少一种寡肽具有8-15个氨基酸的长度,优选8-14,8-13,8-12或9-12或9-11个氨基酸,和更优选8-10,9-11,10-12,11-13,12-14或13-15个氨基酸的长度,或甚至更优选可以选自具有8,9,10,11,12,13,14或15个氨基酸长度的上述通式的肽。
按照本发明的复合RNA的寡肽具有实验式(Arg)l;(Lys)m;(His)n;(Orn)o;(Xaa)x,如上定义地,其中l+m+n+o+x=8-15,且l,m,n或o彼此独立,可以是选自0,1,2,3,4,5,6,7,8,9,10,11,12,13,14或15的任一数值,或由这些数值中的两个形成的任何范围,条件是(碱性氨基酸)Arg,Lys,His和/或Orn的总含量代表按照本发明的复合RNA的寡肽的所有氨基酸的至少50%(例如至少51%,52%,53%,54%,55%,56%,57%,58%,或59%),至少60%(例如至少61%,62%,63%,64%,65%,66%,67%,68%,或69%),至少70%(例如至少71%,72%,73%,74%,75%,76%,77%,78%,或79%),至少80%(例如至少81%,82%,83%,84%,85%,86%,87%,88%,或89%),至少90%(例如至少91%,92%,93%,94%,95%,96%,97%,98%,或99%),或甚至100%。氨基酸Arg,Lys,His和Orn(三字母密码)被分别理解为氨基酸精氨酸、赖氨酸、组氨酸和鸟氨酸。在该上下文中,鸟氨酸是这样的氨基酸,其结构是NH2-CH2-CH2-CH2-CHNH2-COOH。鸟氨酸被人工引入为第21种氨基酸并不属于“天然存在的”20种氨基酸,即鸟氨酸不是由DNA编码的氨基酸,且,因此,不参与主要的蛋白质合成。然而,鸟氨酸由从L-精氨酸开始的酶反应提供。不认为其是遗传密码的一部分,因为含有无保护的鸟氨酸的多肽经历自发的内酰胺化作用。认为鸟氨酸是碱性氨基酸,因为它是酶精氨酸酶针对L-精氨酸反应,形成尿素的产物之一。
根据另外的优选实施方案,本发明复合RNA的具有如上所示实验式(Arg)l;(Lys)m;(His)n;(Orn)o;(Xaa)x(通式I)的寡肽的(单)氨基酸可以以如上定义的任何频率存在于该实验式中,即每种碱性氨基酸(以及Xaa)可以在以上定义的数值或范围内存在于以上定义的实验式中,其中任何范围可以由通过如上定义的数值中的2个形成。然而,特别优选地,如果以上实验式中碱性氨基酸Arg的含量是关于整个实验式的至少10%,更优选至少20%,甚至更优选至少30%,40%或甚至50%,甚至更优选至少60%,70%,80%90%或甚至100%。根据另一个特别优选的实施方案,以上实验式中碱性氨基酸Lys的含量是关于整个实验式的至少10%,更优选至少20%,甚至更优选至少30%,40%或甚至50%,甚至更优选至少60%,70%,80%90%或甚至100%。根据另一个特别优选的实施方案,上述实验式中碱性氨基酸His的含量是关于整个实验式的至少10%,更优选至少20%,甚至更优选至少30%,40%或甚至50%,甚至更优选至少60%,70%,80%90%或甚至100%。根据一个其他特别优选的实施方案,上述实验式中碱性氨基酸Orn的含量是关于整个实验式的至少10%,更优选至少20%,甚至更优选至少30%,40%或甚至50%,甚至更优选至少60%,70%,80%90%或甚至100%。任何以上定义的如上定义的碱性氨基酸Arg,Lys,His和/或Orn的含量、数值或范围还可以彼此组合,优选地导致本发明复合RNA的寡肽的全部碱性氨基酸的总含量是至少50%(至少51%,52%,53%,54%,55%,56%,57%,58%,或59%),至少60%(至少61%,62%,63%,64%,65%,66%,67%,68%,或69%),至少70%(至少71%,72%,73%,74%,75%,76%,77%,78%,或79%),至少80%(至少81%,82%,83%,84%,85%,86%,87%,88%,或89%)至少90%(至少91%,92%,93%,94%,95%,96%,97%,98%,或99%),或甚至100%,如最初定义地。
此外,上述通式(Arg)l;(Lys)m;(His)n;(Orn)o;(Xaa)x中的氨基酸,即Arg,Lys,His和/或Orn可以选自天然(=天然存在的)氨基酸Arg,Lys,His和Orn或选自由这些氨基酸衍生的非天然(=不天然存在的)氨基酸。作为由氨基酸Arg,Lys,His和Orn衍生的非天然(=不天然存在的)氨基酸,可以使用这些氨基酸的任何已知的经化学修饰的衍生物,条件是这些衍生物在与以上寡肽一起提供时,对细胞或生物体无毒(所述氨基酸衍生物由不同的公司分销;参见例如SigmaAldrich(西格玛奥德里奇)(参见http://www.sigmaaldrich.com))。
此外,按照本发明的复合RNA的寡肽可以包含以上实验式(Arg)l;(Lys)m;(His)n;(Orn)o;(Xaa)x中的氨基酸Xaa,其可以是选自除Arg,Lys,His或Orn以外的天然(=天然存在的)或非天然(=不天然存在的)氨基酸中的任何氨基酸。优选地,Xaa可以选自,但不仅限于,天然存在的中性(和疏水性)氨基酸,即具有中性(和疏水性)侧链的氨基酸,诸如丙氨酸(Ala)、缬氨酸(Val)、亮氨酸(Leu)、异亮氨酸(Ile)、脯氨酸(Pro)、色氨酸(Trp)、苯丙氨酸(Phe)、或甲硫氨酸(Met),和/或选自天然存在的中性(和极性)氨基酸,即具有中性(和极性)侧链的氨基酸,诸如甘氨酸(Gly)、丝氨酸(ser)、苏氨酸(Thr)、酪氨酸(Tyr)、半胱氨酸(Cys)、天冬酰胺(Asn)、或谷氨酰胺(Glu),和/或选自天然存在的酸性氨基酸,即具有酸性侧链的氨基酸,诸如天冬氨酸(Asp)或谷氨酸(Glu)。优选地,按照本发明的复合RNA的寡肽可以包含上述实验式(Arg)l;(Lys)m;(His)n;(Orn)o;(Xaa)x中的氨基酸Xaa,其选自不具有酸性侧链的氨基酸。甚至更优选地,实验式(Arg)l;(Lys)m;(His)n;(Orn)o;(Xaa)x中的Xaa选自具有中性侧链的氨基酸,即选自具有中性(和疏水性)侧链的氨基酸和/或选自具有中性(和极性)侧链的氨基酸,如上定义。另外,氨基酸的任何已知衍生物可以用于以上实验式(Arg)l;(Lys)m;(His)n;(Orn)o;(Xaa)x中的Xaa,即已被化学修饰的氨基酸,条件是这些衍生物在与以上寡肽一起提供时,对细胞或生物体无毒。(所述氨基酸衍生物由不同的公司分销;参见例如SigmaAldrich(西格玛奥德里奇)(参见http://www.sigmaaldrich.com))。Xaa典型地以整个寡肽序列所有氨基酸的0-30%,0-40%或0-50%的含量存在于以上通式中,即Xaa的总含量不可以超过整个寡肽序列的全部氨基酸的30%,40%或50%,优选地,其不可以超过整个寡肽序列的全部氨基酸的20%,甚至更优选不超过10%,和最优选不超过5%。因此,如上所示的实验式(Arg)l;(Lys)m;(His)n;(Orn)o;(Xaa)x中的x可以是选自0,1,2,3,4,5,6,7或8的任一数值,条件是Xaa的含量不超过复合RNA的寡肽全部完整氨基酸的以上指定数值即30%(或更少),40%或50%。
典型地,按照本发明复合RNA的具有如上指定的实验式(Arg)l;(Lys)m;(His)n;(Orn)o;(Xaa)x的寡肽的氨基酸Arg,Lys,His,Orn和Xaa可以位于寡肽序列的任何位置。因此,实验式(I)不确定氨基酸的任何特定顺序,而是意欲反映氨基酸的类型及其在该肽中出现的频率,其表明该肽链含有1个Arg残基,m个Lys残基,n个His残基,o个Orn残基和x个Xaa残基,其不指定这些残基在肽链中任何顺序。
然而,优选地,以上寡肽在一端或优选两末端包含氨基酸,其不包含酸性侧链。更优选地,以上寡肽序列在一端或优选两末端均包含中性或碱性氨基酸,甚至更优选地,在一端或两末端均包含碱性氨基酸。在另一个优选的实施方案中,按照以上给定通式的寡肽在每个末端包含至少2,更优选至少3,至少4或甚至至少5个末端碱性残基,特别地Arg,Orn或Lys。根据正好另一个优选的实施方案,按照以上给定通式的寡肽优选在一端或优选两末端均不包含阳离子氨基酸(即无Arg,Orn或Lys),甚至更优选在两末端均不包含阳离子氨基酸(即无Arg,Orn或Lys)。换言之,按照以上给定通式的寡肽的一端或更优选两末端可以包含如本文中定义的任何非阳离子氨基酸,条件是所述非阳离子氨基酸选自除Arg,Orn或Lys或这些阳离子氨基酸的任何变体或衍生物以外的氨基酸。末端可以从具体序列的N-和/或C-末端开始包含例如1,个至少2个,至少3个,至少4个,至少5个或甚至更多如上定义的碱性非阳离子残基。
根据另一个优选的实施方案,按照本发明的复合RNA的寡肽的一端或两末端可以在其一或两末端处包含至少一个组氨酸残基,例如按照本发明的复合RNA的寡肽可以在一或两末端处包含1个,2个,3个或更多处于连续顺序的组氨酸残基,条件是该寡肽的总长度限于如上定义的8-15个氨基酸。
另外,按照本发明的复合RNA的寡肽的Xaa残基典型地通过至少一个Arg,Lys,His或Orn彼此分开。Xaa残基的这种分开优选避免寡肽中的非碱性氨基酸聚簇,因为这样的非碱性聚簇可能减少该寡肽作为按照本发
然而,按照以上给定通式的复合RNA的寡肽的碱性氨基酸残基选自如上定义的Arg,Lys,His或Orn并典型地存在于至少2个,优选至少3个,4个,5个,或甚至6个或更多如上定义的碱性氨基酸的聚簇中。根据特别优选的实施方案,所述聚簇还可以包含6个,7个,8个,9个,10个,11个,12个,13个,14个或甚至15个氨基酸。这样的碱性氨基酸聚簇,优选至少3个,4个,5个,或甚至6个或更多碱性氨基酸的聚簇优选在寡肽内形成碱性表面或结合区,这为该寡肽提供作为按照本发明的复合RNA的载体肽的有利特性。
根据另外的优选实施方案,本发明的复合RNA的寡肽,其具有如上所示实验式(Arg)l;(Lys)m;(His)n;(Orn)o;(Xaa)x(通式I),可以,不仅限于,选自以下通式子集:
Arg8,Arg9,Arg10,Arg11,Arg12,Arg13,Arg14,Arg15,(SEQIDNOs:1-8);
Lys8,Lys9,Lys10,Lys11,Lys12,Lys13,Lys14,Lys15,(SEQIDNOs:9-16);
His8,His9,His10,His11,His12,His13,His14,His15,(SEQIDNOs:17-24);
Orn8,Orn9,Orn10,Orn11,Orn12,Orn13,Orn14,Orn15,(SEQIDNOs:25-32);
根据另一个优选实施方案,本发明的复合RNA的寡肽,其具有如上所示实验式(Arg)l;(Lys)m;(His)n;(Orn)o;(Xaa)x(通式I),可以,不仅限于,选自以下子集。该子集示范性定义具体的本发明寡肽,其被归入如上定义的实验式I,其中以下通式(如具有实验式(I))不指定任何氨基酸顺序,但意欲通过专门指定作为各种肽的成分的氨基酸(的数量)来反映实验式。因此,实验式Arg(7-14)Lys1意指被归入该通式的肽含有处于任意顺序的7-14个Arg残基和1个Lys残基。如果该肽含有7个Arg残基和1个Lys残基,则包括所有具有7个Arg残基和1个Lys残基的变体。Lys残基因此可以位于例如由7个Arg和1个Lys残基组成的8个氨基酸长的序列中的任意位置。所述子集优选包括:
Arg(7-14)Lys1,Arg(7-14)His1,Arg(7-14)Orn1,Lys(7-14)His1,Lys(7-14)Orn1,His(7-14)Orn1,;
Arg(6-13)Lys2,Arg(6-13)His2,Arg(6-13)Orn2,Lys(6-13)His2,Lys(6-13)Orn2,His(6-13)Orn2,;
Arg(5-12)Lys3,Arg(5-12)His3,Arg(5-12)Orn3,Lys(5-12)His3,Lys(5-12)Orn3,His(5-12)Orn3,;
Arg(4-11)Lys4,Arg(4-11)His4,Arg(4-11)Orn4,Lys(4-11)His4,Lys(4-11)Orn4,His(4-11)Orn4,;
Arg(3-10)Lys5,Arg(3-10)His5,Arg(3-10)Orn5,Lys(3-10)His5,Lys(3-10)Orn5,His(3-10)Orn5,;
Arg(2-9)Lys6,Arg(2-9)His6,Arg(2-9)Orn6,Lys(2-9)His6,Lys(2-9)Orn6,His(2-9)Orn6,;
Arg(1-8)Lys7,Arg(1-8)His7,Arg(1-8)Orn7,Lys(7-8)His7,Lys(1-8)Orn7,His(1-8)Orn7,;
Arg(6-13)Lys1His1,Arg(6-13)Lys1Orn1,Arg(6-13)His1Orn1,Arg1Lys(6-13)His1,Arg1Lys(6-13)Orn1,Lys(6- 13)His1Orn1,Arg1Lys1His(6-13),Arg1His(6-13)Orn1,Lys1His(6-13)Orn1;
Arg(5-12)Lys2His1,Arg(5-12)Lys1His2,Arg(5-12)Lys2Orn1,Arg(5-12)Lys1Orn2,Arg(5-12)His2Orn1,Arg(5- 12)His1Orn2,Arg2Lys(5-12)His1,Arg1Lys(5-12)His2,Arg2Lys(5-12)Orn1,Arg1Lys(5-12)Orn2,Lys(5- 12)His2Orn1,Lys(5-12)His1Orn2,Arg2Lys1His(5-12),Arg1Lys2His(5-12),Arg2His(5-12)Orn1,Arg1His(5- 12)Orn2,Lys2His(5-12)Orn1,Lys1His(5-12)Orn2;
Arg(4-11)Lys3His1,Arg(4-11)Lys2His2,Arg(4-11)Lys1His3,Arg(4-11)Lys3Orn1,Arg(4-11)Lys2Orn2,Arg(4- 11)Lys1Orn3,Arg(4-11)His3Orn1,Arg(4-11)His2Orn2,Arg(4-11)His1Orn3,Arg3Lys(4-11)His1,Arg2Lys(4- 11)His2,Arg1Lys(4-11)His3,Arg3Lys(4-11)Orn1,Arg2Lys(4-11)Orn2,Arg1Lys(4-11)Orn3,Lys(4-11)His3Orn1,Lys(4-11)His2Orn2,Lys(4-11)His1Orn3,Arg3Lys1His(4-11),Arg2Lys2His(4-11),Arg1Lys3His(4-11),Arg3His(4-11)Orn1,Arg2His(4-11)Orn2,Arg1His(4-11)Orn3,Lys3His(4-11)Orn1,Lys2His(4-11)Orn2,Lys1His(4-11)Orn3;
Arg(3-10)Lys4His1,Arg(3-10)Lys3His2,Arg(3-10)Lys2His3,Arg(3-10)Lys1His4,Arg(3-10)Lys4Orn1,Arg(3- 10)Lys3Orn2,Arg(3-10)Lys2Orn3,Arg(3-10)Lys1Orn4,Arg(3-10)His4Orn1,Arg(3-10)His3Orn2,Arg(3- 10)His2Orn3,Arg(3-10)His1Orn4,Arg4Lys(3-10)His1,Arg3Lys(3-10)His2,Arg2Lys(3-10)His3,Arg1Lys(3- 10)His4,Arg4Lys(3-10)Orn1,Arg3Lys(3-10)Orn2,Arg2Lys(3-10)Orn3,Arg1Lys(3-10)Orn4,Lys(3-10)His4Orn1,Lys(3-10)His3Orn2,Lys(3-10)His2Orn3,Lys(3-10)His1Orn4,Arg4Lys1His(3-10),Arg3Lys2His(3-10),Arg2Lys3His(3-10),Arg1Lys4His(3-10),Arg4His(3-10)Orn1,Arg3His(3-10)Orn2,Arg2His(3-10)Orn3,Arg1His(3-10)Orn4,Lys4His(3-10)Orn1,Lys3His(3-10)Orn2,Lys2His(3-10)Orn3,Lys1His(3-10)Orn4;
Arg(2-9)Lys5His1,Arg(2-9)Lys4His2,Arg(2-9)Lys3His3,Arg(2-9)Lys2His4,Arg(2-9)Lys1His5,Arg(2- 9)Lys5Orn1,Arg(2-9)Lys4Orn2,Arg(2-9)Lys3Orn3,Arg(2-9)Lys2Orn4,Arg(2-9)Lys1Orn5,Arg(2-9)His5Orn1,Arg(2-9)His4Orn2,Arg(2-9)His3Orn3,Arg(2-9)His2Orn4,Arg(2-9)His1Orn5,Arg5Lys(2-9)His1,Arg4Lys(2- 9)His2,Arg3Lys(2-9)His3,Arg2Lys(2-9)His4,Arg1Lys(2-9)His5,Arg5Lys(2-9)Orn1,Arg4Lys(2-9)Orn2,Arg3Lys(2-9)Orn3,Arg2Lys(2-9)Orn4,Arg1Lys(2-9)Orn5,Lys(2-9)His5Orn1,Lys(2-9)His4Orn2,Lys(2- 9)His3Orn3,Lys(2-9)His2Orn4,Lys(2-9)His1Orn5,Arg5Lys1His(2-9),Arg4Lys2His(2-9),Arg3Lys3His(2-9),Arg2Lys4His(2-9),Arg1Lys5His(2-9),Arg5His(2-9)Orn1,Arg4His(2-9)Orn2,Arg3His(2-9)Orn3,Arg2His(2- 9)Orn4,Arg1His(2-9)Orn5,Lys5His(2-9)Orn1,Lys4His(2-9)Orn2,Lys3His(2-9)Orn3,Lys2His(2-9)Orn4,Lys1His(2-9)Orn5;
Arg(1-8)Lys6His1,Arg(1-8)Lys5His2,Arg(1-8)Lys4His3,Arg(1-8)Lys3His4,Arg(1-8)Lys2His5,Arg(1- 8)Lys1His6,Arg(1-8)Lys6Orn1,Arg(1-8)Lys5Orn2,Arg(1-8)Lys4Orn3,Arg(1-8)Lys3Orn4,Arg(1-8)Lys2Orn5,Arg(1-8)Lys1Orn6,Arg(1-8)His6Orn1,Arg(1-8)His5Orn2,Arg(1-8)His4Orn3,Arg(1-8)His3Orn4,Arg(1- 8)His2Orn5,Arg(1-8)His1Orn6,Arg6Lys(1-8)His1,Arg5Lys(1-8)His2,Arg4Lys(1-8)His3,Arg3Lys(1-8)His4,Arg2Lys(1-8)His5,Arg1Lys(1-8)His6,Arg6Lys(1-8)Orn1,Arg5Lys(1-8)Orn2,Arg4Lys(1-8)Orn3,Arg3Lys(1- 8)Orn4,Arg2Lys(1-8)Orn5,Arg1Lys(1-8)Orn6,Lys(1-8)His6Orn1,Lys(1-8)His5Orn2,Lys(1-8)His4Orn3,Lys(1-8)His3Orn4,Lys(1-8)His2Orn5,Lys(1-8)His1Orn6,Arg6Lys1His(1-8),Arg5Lys2His(1-8),Arg4Lys3His(1-8),Arg3Lys4His(1-8),Arg2Lys5His(1-8),Arg1Lys6His(1-8),Arg6His(1-8)Orn1,Arg5His(1- 8)Orn2,Arg4His(1-8)Orn3,Arg3His(1-8)Orn4,Arg2His(1-8)Orn5,Arg1His(1-8)Org6,Lys6His(1-8)Orn1,Lys5His(1-8)Orn2,Lys4His(1-8)Orn3,Lys3His(1-8)Orn4,Lys2His(1-8)Orn5,Lys1His(1-8)Orn6;
Arg(5-12)Lys1His1Orn1,Arg1Lys(5-12)His1Orn1,Arg1Lys1His(5-12)Orn1,Arg1Lys1His1Orn(5-12);
Arg(4-11)Lys2His1Orn1,Arg(4-11)Lys1His2Orn1,Arg(4-11)Lys1His1Orn2,Arg2Lys(4-11)His1Orn1,Arg1Lys(4-11)His2Orn1,Arg1Lys(4-11)His1Orn2,Arg2Lys1His(4-11)Orn1,Arg1Lys2His(4-11)Orn1,Arg1Lys1His(4-11)Orn2,Arg2Lys1His1Orn(4-11),Arg1Lys2His1Orn(4-11),Arg1Lys1His2Orn(4-11);
Arg(3-10)Lys3His1Orn1,Arg(3-10)Lys2His2Orn1,Arg(3-10)Lys2His1Orn2,Arg(3-10)Lys1His2Orn2,Arg(3- 10)Lys1His1Orn3,Arg3Lys(3-10)His1Orn1,Arg2Lys(3-10)His2Orn1,Arg2Lys(3-10)His1Orn2,Arg1Lys(3- 10)His2Orn2,Arg1Lys(3-10)His1Orn3,Arg3Lys1His(3-10)Orn1,Arg2Lys2His(3-10)Orn1,Arg2Lys1His(3- 10)Orn2,Arg1Lys2His(3-10)Orn2,Arg1Lys1His(3-10)Orn3,Arg3Lys1His1Orn(3-10),Arg2Lys2His1Orn(3-10),Arg2Lys1His2Orn(3-10),Arg1Lys2His2Orn(3-10),Arg1Lys1His3Orn(3-10);
Arg(2-9)Lys4His1Orn1,Arg(2-9)Lys1His4Orn1,Arg(2-9)Lys1His1Orn4,Arg(2-9)Lys3His2Orn1,Arg(2- 9)Lys3His1Orn2,Arg(2-9)Lys2His3Orn1,Arg(2-9)Lys2His1Orn3,Arg(2-9)Lys1His2Orn3,Arg(2- 9)Lys1His3Orn2,Arg(2-9)Lys2His2Orn2,Arg4Lys(2-9)His1Orn1,Arg1Lys(2-9)His4Orn1,Arg1Lys(2- 9)His1Orn4,Arg3Lys(2-9)His2Orn1,Arg3Lys(2-9)His1Orn2,Arg2Lys(2-9)His3Orn1,Arg2Lys(2- 9)His1Orn3,Arg1Lys(2-9)His2Orn3,Arg1Lys(2-9)His3Orn2,Arg2Lys(2-9)His2Orn2,Arg4Lys1His(2- 9)Orn1,Arg1Lys4His(2-9)Orn1,Arg1Lys1His(2-9)Orn4,Arg3Lys2His(2-9)Orn1,Arg3Lys1His(2-9)Orn2,Arg2Lys3His(2-9)Orn1,Arg2Lys1His(2-9)Orn3,Arg1Lys2His(2-9)Orn3,Arg1Lys3His(2-9)Orn2,Arg2Lys2His(2-9)Orn2,Arg4Lys1His1Orn(2-9),Arg1Lys4His1Orn(2-9),Arg1Lys1His4Orn(2-9),Arg3Lys2His1Orn(2-9),Arg3Lys1His2Orn(2-9),Arg2Lys3His1Orn(2-9),Arg2Lys1His3Orn(2-9),Arg1Lys2His3Orn(2-9),Arg1Lys3His2Orn(2-9),Arg2Lys2His2Orn(2-9);
Arg(1-8)Lys5His1Orn1,Arg(1-8)Lys1His5Orn1,Arg(1-8)Lys1His1Orn5,Arg(1-8)Lys4His2Orn1,Arg(1- 8)Lys2His4Orn1,Arg(1-8)Lys2His1Orn4,Arg(1-8)Lys1His2Orn4,Arg(1-8)Lys1His4Orn2,Arg(1- 8)Lys4His1Orn2,Arg(1-8)Lys3His3Orn1,Arg(1-8)Lys3His1Orn3,Arg(1-8)Lys1His3Orn3,Arg5Lys(1- 8)His1Orn1,Arg1Lys(1-8)His5Orn1,Arg1Lys(1-8)His1Orn5,Arg4Lys(1-8)His2Orn1,Arg2Lys(1- 8)His4Orn1,Arg2Lys(1-8)His1Orn4,Arg1Lys(1-8)His2Orn4,Arg1Lys(1-8)His4Orn2,Arg4Lys(1- 8)His1Orn2,Arg3Lys(1-8)His3Orn1,Arg3Lys(1-8)His1Orn3,Arg1Lys(1-8)His3Orn3,Arg5Lys1His(1- 8)Orn1,Arg1Lys5His(1-8)Orn1,Arg1Lys1His(1-8)Orn5,Arg4Lys2His(1-8)Orn1,Arg2Lys4His(1-8)Orn1,Arg2Lys1His(1-8)Orn4,Arg1Lys2His(1-8)Orn4,Arg1Lys4His(1-8)Orn2,Arg4Lys1His(1-8)Orn2,Arg3Lys3His(1-8)Orn1,Arg3Lys1His(1-8)Orn3,Arg1Lys3His(1-8)Orn3,Arg5Lys1His1Orn(1-8),Arg1Lys5His1Orn(1-8),Arg1Lys1His5Orn(1-8),Arg4Lys2His1Orn(1-8),Arg2Lys4His1Orn(1-8),Arg2Lys1His4Orn(1-8),Arg1Lys2His4Orn(1-8),Arg1Lys4His2Orn(1-8),Arg4Lys1His2Orn(1-8),Arg3Lys3His1Orn(1-8),Arg3Lys1His3Orn(1-8),Arg1Lys3His3Orn(1-8);
根据一个优选的实施方案,本发明复合RNA的寡肽,其具有如上所示实验式(Arg)l;(Lys)m;(His)n;(Orn)o;(Xaa)x,选自由Arg8,Arg9,Arg10,Arg11,Arg12,Arg13,Arg14,Arg15,(SEQIDNOs:1-8);Lys8,Lys9,Lys10,Lys11,Lys12,Lys13,Lys14,Lys15,(SEQIDNOs:9-16);His8,His9,His10,His11,His12,His13,His14,His15,(SEQIDNOs:17-24);或Orn8,Orn9,Orn10,Orn11,Orn12,Orn13,Orn14,Orn15,(SEQIDNOs:25-32)组成的子集。
根据另一个优选的实施方案,本发明复合RNA的寡肽,其具有如上所示实验式(Arg)l;(Lys)m;(His)n;(Orn)o;(Xaa)x,选自由通式Arg9(也称为R9),Arg9His3(也称为R9H3),His3Arg9His3(也称为H3R9H3),TyrSerSerArg9SerSerTyr(也称为YSSR9SSY),His3Arg9SerSerTyr(也称为H3R9SSY),(ArgLysHis)4(也称为(RKH)4),Tyr(ArgLysHis)2Arg(也称为Y(RKH)2R)组成的子集。甚至更优选,这些通式定义如下:
Arg9:Arg-Arg-Arg-Arg-Arg-Arg-Arg-Arg-Arg(SEQIDNO:2)
Arg9His3:Arg-Arg-Arg-Arg-Arg-Arg-Arg-Arg-Arg-His-His-His
(SEQIDNO:39)
His3Arg9His3:His-His-His-Arg-Arg-Arg-Arg-Arg-Arg-Arg-Arg-Arg-His-His-His
(SEQIDNO:40)
TyrSerSerArg9SerSerTyr:Tyr-Ser-Ser-Arg-Arg-Arg-Arg-Arg-Arg-Arg-Arg-Arg-Ser-Ser-Tyr
(SEQIDNO:41)
His3Arg9SerSerTyr:His-His-His-Arg-Arg-Arg-Arg-Arg-Arg-Arg-Arg-Arg-Ser-Ser-Tyr
(SEQIDNO:42)
(ArgLysHis)4:Arg-Lys-His-Arg-Lys-His-Arg-Lys-His-Arg-Lys-His
(SEQIDNO:43)
Tyr(ArgLysHis)2Arg:Tyr-Arg-Lys-His-Arg-Lys-His-Arg(SEQIDNO:44)
本发明复合RNA(分子)的至少一种寡肽,其具有如上所示实验式(Arg)l;(Lys)m;(His)n;(Orn)o;(Xaa)x,可以被另外修饰。修饰在本发明的上下文中典型地包括适合于肽的任何修饰,条件是这些修饰不干扰由此生成的复合RNA的转染能力。
典型的修饰可以因此包括例如使用如上定义的修饰的氨基酸。此外,具有如上所示实验式(Arg)l;(Lys)m;(His)n;(Orn)o;(Xaa)x、具有其羧基(C-端)和其氨基(N-端)基团(以及羧基或酰胺氨基酸侧链基团,见上)的寡肽的末端氨基酸残基可以利用合适的氨基或羧基保护基团以其受保护(例如由酰胺基团保护的C端)和/或不受保护的形式存在。而且,可以使用具有如上所示实验式(Arg)l;(Lys)m;(His)n;(Orn)o;(Xaa)x的寡肽的酸式加成盐。常见的酸式加成盐是氢卤酸盐,即HBr,HI,或更优选地,HCl。
具有如上所示实验式(Arg)l;(Lys)m;(His)n;(Orn)o;(Xaa)x的寡肽中存在的赖氨酸的末端或侧链羧基基团或ε-氨基基团的PEG化赋予针对团聚和血清降解的抗性,且也属于本发明的范围。
此外,本发明复合RNA(分子)的至少一种寡肽,其具有如上所示实验式(Arg)l;(Lys)m;(His)n;(Orn)o;(Xaa)x,可以被修饰为结合或偶联至少一种特异性配体,其中所述至少一种特异性配体可以与所述至少一种寡肽的一个或两个末端结合或偶联。与所述寡肽的一个或两个末端结合或偶联的至少一种特异性配体可以是相同或不同的且可以选自任一化合物,其能够结合于或相互作用于例如细胞表面上的受体或蛋白或蛋白/受体复合物,例如,不限于,RGD-肽,转铁蛋白或甘露糖等。
引起具有如上所示实验式(Arg)l;(Lys)m;(His)n;(Orn)o;(Xaa)x的寡肽的衍生物的其他优选修饰基于可以与该寡肽共价偶联的碳水化合物和/或脂质。使碳水化合物和/或脂质与丝氨酸,苏氨酸,天冬酰胺,谷氨酰胺或酪氨酸或谷氨酸或天冬氨酸通过其反应性侧链部分偶联是优选的。备选地,碳水化合物和/或脂质还可以与如上定义的寡肽的末端部分连接。此外,该寡肽可以与功能不同的肽或蛋白部分偶联,所述肽或蛋白部分还可以稳定该寡肽和/或可以起改善寡肽在体液,特别是血液中的运输特性的作用。合适的肽或蛋白可以例如选自清蛋白、转铁蛋白等,其可以与具有如上所示实验式(Arg)l;(Lys)m;(His)n;(Orn)o;(Xaa)x的寡肽直接偶联,或通过肽或有机连接体序列偶联。优选地,这些肽或蛋白与该寡肽的末端之一连接。
在该上下文中,应该注意到用脂质修饰具有如上所示实验式(Arg)l;(Lys)m;(His)n;(Orn)o;(Xaa)x的寡肽典型地不包括使用(饱和或不饱和)脂肪酸,特别是不使用长链(饱和或不饱和)脂肪酸(具体地具有>C12,>C14或>C16的链长)。因此,在本发明的上下文中,用脂肪酸修饰具有如上所示实验式(Arg)l;(Lys)m;(His)n;(Orn)o;(Xaa)x的寡肽不形成本发明的组成部分。然而,如果脂肪酸完全用于修饰载体肽,则可以选自,不限于,包括下述物质的组:例如丁酸脂肪酸(butanoicfattyacid或butyricfattyacid),戊酸脂肪酸(pentanoicfattyacid或valericfattyacid),己酸脂肪酸(hexanoicfattyacid或caproicfattyacid),辛酸脂肪酸(octanoicfattyacid或caprylicfattyacid),壬酸脂肪酸(nonanoicfattyacid或pelargonicfattyacid),癸酸脂肪酸(decanoicfattyacid或capricfattyacid),十二烷酸脂肪酸(月桂酸脂肪酸),十四烷酸脂肪酸(肉豆蔻酸脂肪酸),十六烷酸脂肪酸(棕榈酸脂肪酸),十七烷酸脂肪酸(margaric(daturic)fattyacid),十八烷酸脂肪酸(硬脂酸脂肪酸),二十烷酸脂肪酸(花生酸脂肪酸),二十二烷酸脂肪酸(山萮酸脂肪酸),二十四烷酸脂肪酸(tetracosanoicfattyacid或lignocericfattyacid)),二十六烷酸脂肪酸(蜡酸脂肪酸),二十七烷酸脂肪酸(heptacosanoicfattyacid或carbocericfattyacid),二十八烷酸脂肪酸(褐煤酸脂肪酸),三十烷酸脂肪酸(蜂花酸脂肪酸),三十二烷酸脂肪酸(紫胶蜡酸脂肪酸),三十三烷酸脂肪酸(蜡蜜酸(叶酸)脂肪酸),三十四烷酸脂肪酸(tetratriacontanoicfattyacid或geddicfattyacid),三十五烷酸脂肪酸(蜡塑酸脂肪酸),等,或它们的不饱和类似物。作为具体的实例,本发明典型地不包括十八烷酸脂肪酸(硬脂酸脂肪酸)或其不饱和类似物用于修饰通式I的载体肽的应用,即典型地在本文中不可以使用硬脂酰化的通式I寡肽来与本发明复合物的RNA成分复合。
为了避开具有如上所示实验式(Arg)l;(Lys)m;(His)n;(Orn)o;(Xaa)x的寡肽降解的问题,根据本发明的另一个实施方案,可以使用以上由D氨基酸组成或至少部分由D氨基酸组成的寡肽的逆-反异构体(retro-inversoisomer)。术语″逆-反异构体″指线性肽的异构体,其中序列方向颠倒且每个氨基酸残基的手性倒转(参见,例如,Jameson等,Nature(自然),368,744-746(1994);Brady等,Nature(自然),368,692-693(1994))。关于母体肽,逆-反肽由方向相反的氨基酸装配,典型地具有F-moc氨基酸衍生物。典型地,粗肽可以由反相HPLC纯化。
其他可以引入具有如上所示实验式(Arg)l;(Lys)m;(His)n;(Orn)o;(Xaa)x的寡肽的修饰涉及肽主链的修饰。优选地,修饰的寡肽是支架模拟物。它们的主链与自然存在的主链不同,而它们的侧链结构与寡肽或其片段、变体或衍生物相同。通常,支架模拟物表现出一个或多个主链成员(NH,CH,CO)作为置换(优选)或作为插入的修饰。置换是例如(I)-O-,-S-,或-CH2-代替-NH-;(II)-N-,C-烷基-,或-BH-代替-CHR-和(III)-CS-,-CH2-,-SOn-,-P=O(OH)-,或-B(OH)-代替-CO-。具有如本文定义的实验式(Arg)l;(Lys)m;(His)n;(Orn)o;(Xaa)x的寡肽的肽模拟物可以是这些修饰中每一种的组合。特别地,每种修饰可以组合以组I,II和III。在肽模拟物中,每个主链成员可以是修饰的,或备选地,仅一些数量的链成员可以被换为非天然存在的部分。优选地,具有如本文定义的实验式(Arg)l;(Lys)m;(His)n;(Orn)o;(Xaa)x的寡肽的所有主链成员,-NH-,-CHR-或CO被换为另一种非天然存在的基团。在置换寡肽主链的酰胺键(-NH-CO-)(在完整分子中或至少在一个单一位置中)的情形中,优选的置换部分是生物同配的,例如逆-反酰胺键(-CO-NH-),羟基乙烯(-CH(OH)-CH2-),烯烃(CH2=CH-),carba(CH2-CH2-)和/或-P=O(OH)-CH2-)。备选地,由插入引起的主链延长可以发生在具有如本文定义的实验式(Arg)l;(Lys)m;(His)n;(Orn)o;(Xaa)x的寡肽的支架模拟物中,例如通过侧邻C-α原子的部分。在C-α原子的任一侧,可以插入例如-O-,-S-,-CH-,-NH-。
特别优选的是具有如本文定义的实验式(Arg)l;(Lys)m;(His)n;(Orn)o;(Xaa)x的寡肽的寡氨基甲酸酯肽主链结构。因此酰胺键可以被氨基甲酸酯部分替换。单体N-保护的氨基氨基甲酸烷基酯易通过相应的氨基酸或氨基醇得到。将它们通过利用F-moc部分转变为活性酯,例如对-硝基苯酯或通过固相合成转变为光敏感nitroatryloxy羰基基团。
本发明的复合RNA还包括至少一个适合于转染目的的RNA(分子),其中所述至少一个RNA(分子)与一种或多种如上使用实验式I((Arg)l;(Lys)m;(His)n;(Orn)o;(Xaa)x)公开的寡肽复合。
本发明的复合RNA的至少一个RNA(分子)可以具有任意长度(优选取决于待作为按照本发明的复合RNA应用的RNA的类型)。不受其局限,所述至少一种RNA(分子)可以具有5-20000个核苷酸的长度,更优选5-10000或300-10000个核苷酸的长度,甚至更优选5-5000个核苷酸的长度,和最优选20-5000,50-5000,100-5000或300-10000个核苷酸的长度,这取决于待转染的RNA的类型(参见以下公开内容)。
本发明的复合RNA的至少一个RNA(分子)可以是任意RNA,优选但不仅限于,短RNA寡核苷酸(优选5-80或,更优选20-80个核苷酸的长度),编码RNA,免疫刺激性RNA,siRNA,反义RNA,或riboswitches,核酶或适体。此外,本发明的复合RNA的至少一个RNA(分子)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)或部分双链RNA(其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)。优选地,本发明的复合RNA的至少一个RNA(分子)可以是单链RNA。本发明的复合RNA的至少一个RNA(分子)还可以是环形或线性RNA,优选是线性RNA。更优选地,本发明的复合RNA的至少一个RNA(分子)可以是(线性)单链RNA。本发明的复合RNA的至少一个RNA(分子)可以是核糖体RNA(rRNA),转运RNA(tRNA),信使RNA(mRNA),或病毒RNA(vRNA),优选是mRNA。本发明容许全部这些RNA转染到细胞中。在该上下文中,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,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可以作用单、双或甚至多顺反子RNA,即携带1个、2个或更多蛋白质的编码序列的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。
短RNA寡核苷酸
在第一个实施方案中,本发明的复合RNA的至少一个RNA(分子)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。
优选地,如本文中使用的短RNA寡核苷酸包括如上通常关于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,或,备选地,20-100,20-80,或,甚至更优选地,20-60个核苷酸的长度。短RNA寡核苷酸可以用于多种目的,例如用于(非特异性)免疫刺激,或减少/抑制基因的转录/翻译。
编码RNA
在第二个实施方案中,本发明的复合RNA的至少一个RNA(分子)可以编码RNA。本发明的复合RNA的编码RNA可以是如上定义的任意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)。
所述编码RNA还可以编码蛋白质或肽,其可以选自,不仅限于,例如治疗活性蛋白或肽,肿瘤抗原,抗体,免疫刺激蛋白或肽,等,或任何其他适合于特异性(治疗)应用的蛋白或肽,其中需要将至少一个编码所述蛋白的RNA(分子)运送到细胞、组织或生物体中并需要随后在该细胞、组织或生物体内表达该蛋白。
在该上下文中,治疗活性蛋白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。不受限于此,由如本文中定义的复合RNA的至少一个RNA(分子)编码的治疗活性蛋白可以选自凋亡因子或凋亡相关蛋白包括AIF,Apaf例如Apaf-1,Apaf-2,Apaf-3,oderAPO-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,crmA,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。
由如本文中定义的复合RNA的至少一个RNA(分子)编码的治疗活性蛋白还可以选自重组蛋白,包括选自由以下各项组成的组中的蛋白:
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,ABRACAA1,ACACA,ACADL,ACADM,ACADS,ACADVL,ACAT1,ACCPN,ACE,ACHE,ACHM3,ACHM1,ACLS,ACP1,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,β-联蛋白/m,BF,BFHD,BFIC,BFLS,BFSP2,BGLAP,BGN,BHD,BHR1,BING-4,BIRC5,BIS,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/CA27-29,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,,CYFRA21-1,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,EIIS,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,GHRHR,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,GRO,GRO,GRO,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,HK1HLA-A,HLA-A*0201-R170I,HLA-A11/m,HLA-A2/m,HLA-DPB1HLA-DRA,HLCS,HLXB9,HMBS,HMGA2,HMGCL,HMI,HMN2,HMOX1,HMS1HMW-MAA,HND,HNE,HNF4A,HOAC,同源框NKX3.1,HOM-TES-14/SCP-1,HOM-TES-85,HOXA1HOXD13,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,ICS1,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,IFNβINFγ,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,LCCS1,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,LRS1,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,MDS1,ME1,ME1/m,ME2,ME20,ME3,MEAX,MEB,MECCCL-28,MECP2,MEFV,MELANA,MELAS,MEN1MSLN,MET,MF4,MG50,MG50/PXDN,MGAT2,MGAT5,MGC1MGCR,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,MMP11,MMVP1,MN/CAIX-抗原,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,变体p21ras,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-乙酰葡糖胺转移酶-V,NAGA,NAGLU,NAMSD,NAPB,NAT2,NAT,NBIA1,NBS1,NCAM,NCF2,NCF1,NDN,NDP,NDUFS4,NDUFS7,NDUFS8,NDUFV1,NDUFV2,NEB,NEFH,NEM1,新-PAP,新-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,OAR,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,OSMLIF,OTC,OTOF,OTSC1,OXCT1,OYTES1,P15,P190MINORBCR-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-激酶,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,PTPNII,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/βSDHA,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,SIALYLLEWISX,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,βhhCG,SSTR2,SSX1,SSX2(HOM-MEL-40/SSX2),SSX4,ST8,STAMP-1,STAR,STARP1,STATH,STEAP,STK2,STK11,STn/KLH,STO,STOM,STS,SUOX,SURF1,存活蛋白-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,TGFα,TGFβ,TGFβI,TGFβ1,TGFβR2,TGFβRE,TGFγ,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,TUM2-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,和ZWS1。
另外,由如本文中定义的复合RNA的至少一个RNA(分子)编码的治疗活性蛋白还可以选自生长激素或生长因子,例如为了促进在(转基因)生命体中的生长,诸如,例如,TGFα和IGFs(胰岛素样生长因子),影响代谢和/或造血作用的蛋白,诸如,例如,α-抗-胰蛋白酶,LDL受体,红细胞生成素(EPO),胰岛素,GATA-1,等,或蛋白诸如,例如,血液凝固系统的因子VIII和XI,等。所述蛋白还包括酶,诸如,例如,β-半乳糖苷酶(lacZ),DNA限制酶(例如EcoRI,HindIII,等),溶菌酶,等,或蛋白酶,诸如,例如,木瓜蛋白酶,菠萝蛋白酶,角蛋白酶,胰蛋白酶,胰凝乳蛋白酶,胃蛋白酶,肾素(凝乳酶),suizyme,nortase,等。这些蛋白可以由如本文中定义的复合RNA的至少一个RNA(分子)编码。因此本发明提供这样的技术,其容许置换待处理的生物体中缺陷的蛋白(例如,由于突变,由于缺陷性或缺失表达)并由此产生有效和增加的蛋白表达,所述蛋白在待处理生物体中不具功能,如例如在单遗传病症存在,优选不引起先天免疫反应。
备选地,由如本文中定义的复合RNA的至少一个RNA(分子)编码的治疗活性蛋白还可以选自容许治愈特定疾病的蛋白酶等,所述疾病归因于例如导致病症或疾病的机能障碍性或外源性蛋白的(过)表达。因此,本发明可以用于将所述复合RNA治疗性引入生物体,其攻击致病生物(病毒,细菌等)。例如编码治疗蛋白酶的RNA可以用于裂解对于病毒装配或病毒生成的其他必需步骤所必要的病毒蛋白。
由如本文中定义的复合RNA的至少一个RNA(分子)编码的治疗活性蛋白还可以选自通过例如信号传输调节(抑制或刺激)调节多种胞内途径的蛋白,所述信号传输调节可以影响关键的胞内过程如凋亡,细胞生长等,特别关于生物体的免疫系统。因此,免疫调节剂,例如细胞因子,淋巴因子,单核因子,干扰素等可以通过如本文中定义的复合的RNA有效表达。优选地,这些蛋白质因此还包括,例如,包含4个位置特异性保守半胱氨酸残基(CCCC)和保守序列基序Trp-Ser-X-Trp-Ser(WSXWS)的细胞因子家族的I类细胞因子,其中X代表不保守的氨基酸。细胞因子家族的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。通过类推,所述蛋白质还可以包括细胞因子家族(干扰素受体家族)的II类细胞因子,其同样包含4个位置特异性保守半胱氨酸残基(CCCC)但无保守序列基序Trp-Ser-X-Trp-Ser(WSXWS)。胞因子家族的II类细胞因子包括,例如,IFN-α,IFN-β,IFN-γ,等。按照本发明使用的(本发明免疫抑制组合物的)由至少一个修饰的(m)RNA编码的蛋白质还可以包括肿瘤坏死家族的细胞因子,例如TNF-α,TNF-β,TNF-RI,TNF-RII,CD40,Fas,等,或趋化因子家族的细胞因子,其包含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。所述蛋白还可以选自凋亡因子或与凋亡相关或连锁的蛋白,包括AIF,Apaf,例如Apaf-1,Apaf-2,Apaf-3,或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,crmA,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,TRAIL-R1,TRAIL-R2,TRAIL-R3,转谷氨酰胺酶,等。
另外,由如本文中定义的复合RNA的至少一个RNA(分子)编码的治疗活性蛋白还可以编码抗原特异性T细胞受体。T细胞受体或TCR是存在于通常负责识别与主要组织相容性复合体(MHC)分子结合的抗原的T淋巴细胞(或T细胞)表面上的分子。它在95%的T细胞中是由α和β链组成的杂二聚体,而5%的T细胞具有由γ和δ链组成的TCR。TCR与抗原和MHC接合通过一系列由相关酶、共受体和特定协同分子介导的生物化学事件导致其T淋巴细胞的活化。因此,这些蛋白质容许特异性靶向特异性抗原并可以由于其靶向特性支持免疫系统的功能性。因此,可以进行通过施用由如本文中定义的复合RNA的至少一个编码这些受体的RNA(分子)的体内细胞转染或,优选地,先体外后体内细胞转染方法(例如通过特异性转染某些免疫细胞)。引入的T细胞受体分子识别MHC分子上的特异性抗原并可以由此支持免疫系统知晓会被攻击的抗原。
可以由如本文中定义的复合RNA的至少一个RNA(分子)编码的治疗活性蛋白还可以包括佐剂蛋白。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反应的任何蛋白。优选地,所述先天免疫反应包括图式识别受体,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,先天免疫反应在哺乳动物中,更优选在人中引起。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。
可以由如本文中定义的复合RNA的至少一个RNA(分子)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,可以由本发明的复合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,或以上任意人佐剂蛋白的任意物种类似物。
可以由如本文中定义的复合RNA的至少一个RNA(分子)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(Toxoplasmagondii)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,可以由如本文中定义的复合RNA的至少一个RNA(分子)编码的细菌(佐剂)蛋白可以包括任何能够引起先天免疫反应(优选在哺乳动物中)的细菌蛋白。更优选地,可以由所述复合RNA编码的细菌(佐剂)蛋白可以包括这样的细菌佐剂蛋白,其选自由,但不仅限于,细菌鞭毛蛋白,包括来自生物体的鞭毛蛋白,所述生物体包括土壤杆菌属(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(Agrobacteriumtumefaciens),嗜火产液菌(Aqufexpyrophilus),巴西固氮螺菌(Azospirillumbrasilense),枯草芽孢杆菌(Bacillussubtilis),苏云金芽孢杆菌(Bacillusthuringiensis),杆状巴尔通氏体(Bartonellabacilliformis),支气管炎博德特氏菌(Bordetellabronchiseptica),布氏疏螺旋体(Borreliaburgdorferi),洋葱伯克霍尔德氏菌(Burkholderiacepacia),空肠弯曲杆菌空肠亚种(Campylobacterjejuni),新月柄杆菌(Caulobactercrescentus),肉毒梭菌(Clostridiumbotulinum)菌株Bennett克隆1,大肠埃希氏菌(Escherichiacoli),幽门螺杆菌(Helicobacterpylori),Lachnospiraceaebacterium,侵肺军团菌(Legionellapneumophila),单核细胞增生利斯特氏菌(Listeriamonocytogenes),奇异变形菌(Proteusmirabilis),Pseudomonasaeroguinosa,丁香假单胞菌(Pseudomonassyringae),苜蓿中华根瘤菌(Rhizobiummeliloti),类球红细菌(Rhodobactersphaeroides),Roseburiacecicola,Roseburishominis,鼠伤寒沙门氏菌(Salmonellatyphimurium),邦戈尔沙门氏菌(Salmonellabongori),伤寒沙门氏菌(Salmonellatyphi),Salmonellaenteritidis,猪痢疾小蛇菌(Serpulinahyodysenteriae),粘质沙雷氏菌(Serratiamarcescens),鲍氏志贺氏菌(Shigellaboydii),溃蚀密螺旋体(Treponemaphagedenis),解藻朊酸弧菌(Vibrioalginolyticus),霍乱弧菌(Vibriocholerae),副溶血弧菌(Vibrioparahaemolyticus),产琥珀酸沃林氏菌(Wolinellasuccinogenes)和小肠结肠炎耶尔森氏菌(Yersiniaenterocolitica)。
可以由如本文中定义的复合RNA的至少一个RNA(分子)编码的细菌鞭毛蛋白是特别优选的且可以选自任何表现出佐剂特征的细菌鞭毛蛋白,更优选选自这样的细菌鞭毛蛋白,其选自由下述物质组成的组: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(Bordetellapertussis)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变体,来自CT的CTE112K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;来自布氏疏螺旋体的外表面蛋白A脂蛋白,来自结核分枝杆菌(Mycobacteriumtuberculosis)的Ag38(38kDa抗原);来自细菌菌毛的蛋白;霍乱弧菌的肠毒素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)蛋白的任何物种类似物。
可以由如本文中定义的复合RNA的至少一个RNA(分子)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一个序列,所述组包括任意以下参考其编号的序列:
生物体 | 物种 | 基因名称 | 编号 | GI No |
土壤杆菌属 | 根癌土壤杆菌 | FlaD(flaD)FlhB(flhB)FliG(fliG)FliN(fliN)FliM(fliM)MotA(motA)FlgF(flgF)FliI(fliI)FlgB(flgB)FlgC(flgC)FliE(fliE)FlgG(flgG)FlgA(flgA)FlgI(flgI)FlgH(flgH)FliL(fliL)FliP(fliP)FlaA(flaA)FlaB(flaB) | U95165 | GI:14278870 |
FlaC(flaC) | ||||
产液菌属 | 嗜火产液菌 | U17575 | GI:596244 | |
固氮螺菌属 | 巴西固氮螺菌 | Laf1 | U26679 | GI:1173509 |
芽孢杆菌属 | 枯草芽孢杆菌 | hag | AB033501 | GI:14278870 |
芽孢杆菌属 | 苏云金芽孢杆菌 | flab | X67138 | GI:46019718 |
巴尔通氏体属 | 杆状巴尔通氏体 | L20677 | GI:304184 | |
博德特氏菌属 | 支气管炎博德特氏菌 | flaA | L13034 | GI:289453 |
疏螺旋体属 | 布氏疏螺旋体 | X16833 | GI:39356 | |
伯克霍尔德氏菌属 | 洋葱伯克霍尔德氏菌 | fliC | AF011370 | GI:2935154 |
弯曲杆菌属 | 空肠弯曲杆菌空肠亚种 | flaAflaB | J05635 | GI:144197 |
柄杆菌属 | 新月饼杆菌 | J01556 | GI:144239 | |
梭菌属 | 肉毒梭菌菌株Bennett克隆1 | FlaA | DQ845000 | GI:114054886 |
埃希氏菌属 | 大肠埃希氏菌 | hag | M14358 | GI:146311 |
AJ 884569(EMBL-SVA) | ||||
螺杆菌属 | 幽门螺杆菌 | flaA | X60746 | GI:43631 |
Lachnospiraceae | Lachnospiraceaebacterium | DQ789131 | GI:113911615 | |
军团菌属 | 侵肺军团菌 | flaA | X83232 | GI:602877 |
利斯特氏菌属 | 单核细胞增生利斯特氏菌 | flaA | X65624 | GI:44097 |
变形菌属 | 奇异变形菌 | FlaD(flaD)FlaA(flaA)FlaB(flaB) | AF221596 | GI:6959881 |
FliA(fliA)FliZ(fliZ) | ||||
假单胞菌属 | Pseudomonasaeroguinosa | flaA | M57501 | GI:151225 |
假单胞菌属 | 丁香假单胞菌 | fliC | EF544882 | GI:146335619 |
根瘤菌属 | 苜蓿中华根瘤菌 | flaAflaB | M24526 | GI:152220 |
红细菌属 | 类球红细菌 | fliC | AF274346 | GI:10716972 |
Roseburia | Roseburiacecicola | M20983 | GI:152535 | |
Roseburia | Roseburishominis | Fla2 | DQ789141 | GI:113911632 |
沙门氏菌属 | 鼠伤寒沙门氏菌 | D13689(NCBI ID) | GI:217062 | |
沙门氏菌属 | 邦戈尔沙门氏菌 | fliC | AY603412 | GI:51342390 |
沙门氏菌属 | 伤寒沙门氏菌 | flag | L21912 | GI:397810 |
沙门氏菌属 | Salmonellaenteritidis | fliC | M84980 | GI:154015 |
小蛇菌属 | 猪痢疾小蛇菌 | flaB2 | X63513 | GI:450669 |
沙雷氏菌属 | 粘质沙雷氏菌 | hag | M27219 | GI:152826 |
志贺氏菌属 | 鲍氏志贺氏菌 | fliC-SB | D26165 | GI:442485 |
密螺旋体属 | 溃蚀密螺旋体 | flaB2 | M94015 | GI:155060 |
弧菌属 | 解藻朊酸弧菌 | flaA | EF125175 | GI:119434395 |
弧菌属 | 副溶血弧菌 | AF069392 | GI:7327274 | |
沃林氏菌属 | 产琥珀酸沃林氏菌 | flag | M82917 | GI:155337 |
耶尔森氏菌属 | 小肠结肠炎耶尔森氏菌 | L33467 | GI:496295 |
可以由如本文中定义的复合RNA的至少一个RNA(分子)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(Trypanosomacruzi)的Tc52,来自刚地锥虫(Trypanosomagondii)的PFTG,原生动物热激蛋白,来自利什曼虫属物种(Leishmaniaspp.)的LeIF,来自刚地弓形虫的抑制蛋白样蛋白,等。
可以由如本文中定义的复合RNA的至少一个RNA(分子)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。
可以由如本文中定义的复合RNA的至少一个RNA(分子)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,可以由如本文中定义的复合RNA的至少一个RNA(分子)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。
本发明的复合RNA的至少一个RNA(分子)可以备选地编码抗原。按照本发明,术语“抗原”指由免疫系统识别并能够,例如通过形成抗体触发抗原特异性免疫反应的物质。抗原可以按照其来源分类。因此,存在两大类抗原:外源性抗原和内源性抗原。外源性抗原是例如通过吸入、摄取或注射等,由(细胞或身体)外进入细胞或身体的抗原。这些抗原通过抗原呈递细胞(“APCs”,诸如树突细胞或巨噬细胞)内在化并被加工为片段。APC然后通过使用其表面上的MHCII分子,将该片段呈递到T辅助细胞(例如CD4+)。T细胞识别这些抗原片段导致T细胞的活化和细胞因子的分泌。细胞因子是可以激活免疫细胞诸如细胞毒性T细胞、B细胞或巨噬细胞增殖的物质。相反,内源性抗原是在细胞内,例如作为正常细胞代谢的结果已经生成了的抗原。这些抗原的片段在APC表面上的MHCI分子上呈递。这些抗原由活化的抗原特异性细胞毒性CD8+T细胞识别。识别后,那些T细胞在不同毒素的分泌中反应,所述毒素导致抗原呈递细胞的溶解或凋亡。内源性抗原包括这样的抗原,例如由细胞内的外源核酸编码的蛋白或肽以及由细胞本身的遗传信息编码的蛋白或肽,或来自胞内存在病毒的抗原。一类内源性抗原类型是肿瘤抗原类型。那些抗原由肿瘤细胞表面上的MHCI分子呈递。该类型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。
可以由本发明的复合RNA的至少一个RNA(分子)编码的抗原可以包括例如蛋白、肽或其片段。优选地,抗原是蛋白和肽或其片段,诸如那些蛋白或肽的表位。表位(也称为“抗原决定簇”),典型地,是位于所述抗原性蛋白或肽结构外表面上的具有5-15,优选9-15个氨基酸的片段(B细胞表位和T细胞表位典型地在MHC分子上呈递,其中例如MHC-I典型地呈递具有约9个aa长度的表位且MHC-II典型地呈递具有约12-15个aa的长度的表位)。此外,由按照本发明的复合物的至少一个RNA(分子)编码的抗原还可以包括任何其他生物分子,例如,脂质,碳水化合物,等,其可以共价或非共价地附着于该RNA(分子)。
根据本发明,可以由本发明的复合RNA的至少一个RNA(分子)编码的抗原可以是外源性或内源性抗原。内源性抗原包括在细胞中,特别是在退化细胞诸如肿瘤细胞中生成的抗原。这些抗原也称为“肿瘤抗原”。优选地,不受限制于此,它们位于细胞表面上。此外,“肿瘤抗原”还意指自身(或最初不是由自身)不退化但与假定的肿瘤相关的细胞中表达的抗原。与肿瘤供给管(tumor-supplyingvessels)或其(再)形成相连的抗原,特别是与新血管形成有关的那些抗原,例如生长因子,诸如VEGF,bFGF等也包括在本文中。与肿瘤相连的抗原还包括来自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,例如与肿瘤细胞入侵和转移有关的蛋白。这些物质也称为“肿瘤抗原”,然而它们在严格意义上不是免疫反应诱导物质的抗原。其应用也包括在本发明的范围内。
可以由本发明的复合RNA的至少一个RNA(分子)编码的抗原可以示范性地选自,不局限于,例如任何适合于特定目的的抗原,例如选自与特定传染病诸如本文中定义的传染病有关(或是其原因)的抗原,选自癌症抗原诸如肿瘤特异性表面抗原,选自在癌症疾病中表达的抗原,选自在癌症疾病中表达的突变抗原,或选自参与其他疾病,例如自体免疫疾病,过敏症等病因学的蛋白抗原,例如这些抗原可以用于通过施用导致患者过敏或自体免疫状态的抗原来对患者进行脱敏。
由如本文中定义的复合RNA的至少一个RNA(分子)编码的优选示范性抗原性(多)肽包括所有已知的抗原性肽,例如,肿瘤抗原,等。肿瘤抗原的具体实例特别是肿瘤特异性表面抗原(TSSAs),例如5T4,α5β1-整联蛋白,707-AP,AFP,ART-4,B7H4,BAGE,Bcr-abl,MN/CIX抗原,CA125,CAMEL,CAP-1,CASP-8,β-联蛋白/m,CD4,CD19,CD20,CD22,CD25,CDC27/m,CD30,CD33,CD52,CD56,CD80,CDK4/m,CEA,CT,Cyp-B,DAM,EGFR,ErbB3,ELF2M,EMMPRIN,EpCam,ETV6-AML1,G250,GAGE,GnT-V,Gp100,HAGE,HER-2/new,HLA-A*0201-R170I,HPV-E7,HSP70-2M,HAST-2,hTERT(或hTRT),iCE,IGF-1R,IL-2R,IL-5,KIAA0205,LAGE,LDLR/FUT,MAGE,MART-1/melan-A,MART-2/Ski,MC1R,肌球蛋白/m,MUC1,MUM-1,-2,-3,NA88-A,PAP,蛋白酶-3,p190小bcr-abl,Pml/RARα,PRAME,PSA,PSM,PSMA,RAGE,RU1或RU2,SAGE,SART-1或SART-3,存活蛋白,TEL/AML1,TGFβ,TPI/m,TRP-1,TRP-2,TRP-2/INT2,VEGF和WT1,或来自序列诸如,例如,NY-Eso-1或NY-Eso-B。任何肿瘤抗原类型适合于本发明的目的,例如已知参与新血管形成,影响胞外基质结构等的肿瘤抗原。还包括以上抗原的片段和类似物。
可以由本发明的复合RNA的至少一个RNA(分子)编码的肿瘤抗原的实例示于下表1和2中。这些表举例说明关于与其相关的癌症疾病的特异性(蛋白)抗原(即“肿瘤抗原”)。按照本发明,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,可以由本发明的复合RNA的至少一个RNA(分子)编码的肿瘤抗原的实例选自由以下各项组成的组:5T4,707-AP,9D7,AFP,AlbZIPHPG1,51-整联蛋白,56-整联蛋白,-辅肌动蛋白-4/m,甲基酰基-辅酶A消旋酶,ART-4,ARTC1/m,B7H4,BAGE-1,BCL-2,bcr/abl,联蛋白/m,BING-4,BRCA1/m,BRCA2/m,CA15-3/CA27-29,CA19-9,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,mammaglobinA,MART-1/melan-A,MART-2,MART-2/m,基质蛋白22,MC1R,M-CSF,ME1/m,mesothelin,MG50/PXDN,MMP11,MN/CAIX-抗原,MRP-3,MUC-1,MUC-2,MUM-1/m,MUM-2/m,MUM-3/m,肌球蛋白I/m型,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。
在按照本发明的优选实施方案中,可以由本发明的复合RNA的至少一个RNA(分子)编码的肿瘤抗原的实例选自由以下各项组成的组:MAGE-A1[编号M77481],MAGE-A6[编号NM_005363],melan-A[编号NM_005511],GP100[编号M77348],酪氨酸酶[编号NM_000372],存活蛋白[编号AF077350],CEA[编号NM_004363],Her-2/neu[编号M11730],WT1[编号NM_000378],PRAME[编号NM_006115],EGFRI(表皮生长因子受体1)[编号AF288738],黏蛋白-1[编号NM_002456]和SEC61G[编号NM_014302]。
作为进一步的备选方案,本发明的复合RNA的至少一个RNA(分子)可以编码抗体。按照本发明,这样的抗体可以选自本领域中已知的任何抗体,例如任何重组生成或天然存在的抗体,具体地,适合于治疗、诊断或科学目的的抗体,或已被鉴定与特定癌症疾病有关的抗体。在本文中,术语“抗体”以其最广泛的含义使用并具体包括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”典型地包括任何本领域中已知的抗体(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。单链抗体可以由如本文中定义的复合RNA的至少一个RNA(分子),优选由单链RNA,更优选由mRNA编码。
按照第一个备选方案,本发明的复合RNA的至少一个RNA(分子)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,将应用如通过本发明要求的复合的不同RNA分子的混合物(组合物),其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,本发明的复合RNA的至少一个RNA(分子)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)置于微滴定板中的分开的孔中,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复合RNA的至少一个RNA(分子)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、人源化非人和人抗体可以由本发明的复合RNA的至少一个RNA(分子)编码。可以由本发明的复合RNA的至少一个RNA(分子)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。也可以由本发明的复合RNA的至少一个RNA(分子)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,本发明的复合RNA的至少一个RNA(分子)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,测序的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,本发明的复合RNA的至少一个RNA(分子)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:KontermannR.E.,ActaPharmacol.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个不同的表位。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。
总之,根据本发明,本发明的复合RNA的至少一个RNA(分子)还可以编码如上定义的抗体。因为这些抗体是胞内表达的抗体,即由位于细胞特定区室中核酸编码并也在那里表达的抗体,所以所述抗体也可以称为胞内抗体。
如由本发明的复合RNA的至少一个RNA(分子)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、变体或加合物可以由以上按照本发明的复合RNA的至少一个RNA编码。
本发明的复合RNA的至少一个RNA(分子)还可以编码抗体片段,其选自前述抗体的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。
根据本发明,本发明的复合RNA的至少一个RNA(分子)可以编码前述治疗活性蛋白、抗原或抗体的片段和/或变体,其中所述片段和/或变体可以具有与前述治疗活性蛋白、抗原或抗体相比,在编码这些治疗活性蛋白、抗原或抗体的编码核酸或氨基酸序列全长上的至少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。优选地,所述片段和/或变体具有与全长天然治疗活性蛋白、抗原或抗体相比相同的生物学功能或特异性活性,例如特异性结合能力(例如特定抗原的),催化活性(例如治疗活性蛋白的)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,抗体仅能结合一个抗原,或,在双特异性抗体的情形中,仅能结合2个抗原。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RNA序列(核酸或氨基酸)相同的百分比,可以比对序列,从而随后彼此比较。因此,例如可以将裂隙插入到第一序列的序列中并可以比较位于第二序列相应位置处的组成。如果第一序列中的位置被与第二序列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。
两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),PNASUSA,90:5873-5877或Altschul等(1997),NucleicAcidsRes(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程序中。与本发明的复合RNA的RNA序列相同到一定程度的序列可以通过该程序识别。
那些编码具有保守置换的氨基酸序列的(本发明的复合RNA的)至少一个RNA分子与被特别归入术语变体的生理学序列比较。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,CircularDichroismandORDofPolypeptides,(多肽的吸收,圆二色性和ORD),在:ModernPhysicalMethodsinBiochemistry(现代生物化学中的物理方法),Neuberger等(编),Elsevier,阿姆斯特丹)。
免疫刺激性RNA
按照第三个实施方案,本发明的复合RNA的至少一个RNA(分子)可以是免疫刺激性RNA。因此,免疫刺激性RNA在与具有如上定义的按照通式(I)的本发明寡肽的RNA复合前已经可以表现出免疫刺激性作用,或,更优选地,如本文中使用的RNA的免疫刺激性作用可以通过与具有如上定义的按照通式(I)的本发明寡肽的RNA复合而得到增强或甚至诱导。本发明的复合RNA的免疫刺激性RNA可以是任何RNA,例如编码RNA,如上定义。优选地,免疫刺激性RNA可以是单链、双链或部分双链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,免疫刺激性RNA可以是(线性)单链RNA。甚至更优选地,免疫刺激性RNA可以是((线性)单链)信使RNA(mRNA)。免疫刺激性RNA还可以作为如上定义的短RNA寡核苷酸存在。
免疫刺激性RNA,用于本文中时,还可以选自以天然发现的或合成制备的,并可以诱导免疫反应的任何RNA分子类型。在该上下文中,免疫反应可以以多种方式发生。对于合适的免疫反应的基本因素是不同T细胞亚群的刺激。T淋巴细胞典型地分为2个亚群,T辅助1(Th1)细胞和T辅助2(Th2)细胞,免疫系统利用它们能够破坏胞内(Th1)和胞外(Th2)病原体(例如抗原)。这两种Th细胞群在由它们产生的效应蛋白(细胞因子)的模式中不同。因此,Th1细胞通过活化巨噬细胞和细胞毒性T细胞协助细胞免疫反应。Th2细胞,在另一方面,通过刺激B细胞转变为浆细胞和通过形成(例如针对抗原的)抗体促进体液免疫反应。Th1/Th2比因此在免疫反应中非常重要。与本发明有关地,免疫反应的Th1/Th2比优选向着细胞反应(Th1反应)的方向移动并且由此诱导细胞免疫反应。根据一个实例,免疫系统可以由Toll样受体(TLRs)的配体激活。TLRs是高度保守模式识别受体(PRR)多肽的家族,其识别病原体相关分子模式(PAMPs)并在哺乳动物的先天免疫性中起关键作用。目前,已经确定了至少13个家族成员,命名为TLR1-TLR13(Toll-样受体:TLR1,TLR2,TLR3,TLR4,TLR5,TLR6,TLR7,TLR8,TLR9,TLR10,TLR11,TLR12或TLR13)。此外,已经确定了许多特异性TLR配体。例如发现,未甲基化的细菌DNA及其合成类似物(CpGDNA)是TLR9的配体(HemmiH等(2000)Nature(自然)408:740-5;BauerS等(2001)ProcNatlAcadSciUSA(美国国家科学院学报)98,9237-42)。此外,报告了某些TLR的配体包括某些核酸分子并且某些RNA类型以与序列无关或序列依赖性方式是免疫刺激性的,其中这些不同的免疫刺激性RNA可以例如刺激TLR3,TLR7,或TLR8,或胞内受体诸如RIG-I,MDA-5,等。例如,Lipford等确定了某些包含G,U的寡核糖核苷酸通过TLR7和TLR8作用具免疫刺激性(参见WO03/086280)。由Lipford等所述的免疫刺激性包含G,U的寡核糖核苷酸被认为可源自包括核糖体RNA、转运RNA、信使RNA、和病毒RNA的RNA来源。
按照本发明,发现与按照实验式(Arg)l;(Lys)m;(His)n;(Orn)o;(Xaa)x(通式I)的载体肽复合的如例如以上定义的任何RNA(分子)(不考虑其特定长度、链、修饰和/或核苷酸序列)可以具有免疫刺激性特性,即增强免疫反应。与按照实验式(Arg)l;(Lys)m;(His)n;(Orn)o;(Xaa)x(通式I)的载体肽复合的如上定义的RNA因此可以用于增强(非特异性)免疫刺激,如果对特定的治疗是适合的和需要的。因此,通过将任何RNA与按照通式(I)的肽复合提供免疫刺激性作用可以是本发明复合RNA的固有特性。
本发明的复合RNA的至少一个(免疫刺激性)RNA(分子)因此可以包括已知具有免疫刺激性的任何RNA序列,包括但不仅限于,代表和/或编码TLRs的配体的RNA序列,优选选自家族成员TLR1-TLR13,更优选选自TLR7和TLR8,RNA的胞内受体的配体(诸如RIG-I或MAD-5,等)(参见例如Meylan,E.,Tschopp,J.(2006).Toll-likereceptorsandRNAhelicases:twoparallelwaystotriggerantiviralresponses(Toll-样受体和RNA解旋酶:触发抗病毒反应的两种平行的方法).Mol.Cell(分子细胞)22,561-569),或任何其他免疫刺激性RNA序列。此外,可以用作免疫刺激性RNA的RNA分子(类型)可以包括能够引起免疫反应的任何其他RNA。不受限于此,所述免疫刺激性RNA可以包括核糖体RNA(rRNA)、转运RNA(tRNA)、信使RNA(mRNA)、和病毒RNA(vRNA)。
可以用作本发明复合RNA的至少一个(免疫刺激性)RNA(分子)的所述其他RNA分子(类型)可以包括,不仅限于,例如通式(IIa)的RNA分子:
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。
另外,可以用作本发明复合RNA的至少一个(免疫刺激性)RNA(分子)的所述其他RNA分子(类型)可以包括,不仅限于,例如通式(IIb)的RNA分子:
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1>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。
优选地,作为本发明的复合RNA的至少一个RNA(分子)在本文中使用的免疫刺激性RNA包括如上关于本发明的复合RNA的RNA分子普遍定义的长度,更优选5-5000,500-5000或,更优选地,1000-5000或,备选地,5-1000,5-500,5-250,5-100,5-50或,更优选地,5-30个核苷酸的长度。
作为本发明的复合RNA的至少一个RNA(分子)在本文中使用的至少一个免疫刺激性RNA可以进一步被修饰,优选“化学修饰”,以增强所述DNA的免疫刺激性特性。术语“化学修饰”意指作为按照本发明的免疫刺激性RNA使用的RNA,与天然存在的RNA种类相比,通过替换、插入或去除个别或若干原子或原子团而被修饰。
优选地,RNA的化学修饰包括天然存在的核苷酸的至少一个类似物。在绝非结论性的列表中,关于可以按照本发明使用的核苷酸类似物可以提及的实例是鸟苷、尿嘧啶、腺苷、胸苷、胞嘧啶的类似物。修饰可以指碱基、核糖部分和/或磷酸主链部分的修饰。在该上下文中,鸟苷、尿嘧啶、腺苷、和胞嘧啶的类似物在不暗示任何局限性的条件下,包括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,所述非天然存在的鸟苷、尿嘧啶、腺苷、胸苷或胞嘧啶已经被化学修饰,例如通过乙酰化作用、甲基化作用、羟基化作用,等,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,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,US4,401,796,US4,415,732,US4,458,066,US4,500,707,US4,668,777,US4,973,679,US5,047,524,US5,132,418,US5,153,319,US5,262,530和5,700,642。在如上所述的类似物的情形中,特别优选物按照本发明是那样的类似物,所述类似物增加作为本发明的复合RNA的至少一个RNA(分子)在本文中使用的免疫刺激性RNA序列的免疫原性和/或不干扰已经引入到所述免疫刺激性RNA中的其他修饰。
siRNA
在第四个实施方案中,本发明的复合RNA的至少一个RNA(分子)可以采用siRNA的形式。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)GenesDev.(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)ViralImmunol.(病毒免疫学)15:95-119)。当使用较短的,例如21-到23-mer,所谓的siRNA(小干扰RNA)时,避免这些非特异性作用,因为非特异性作用不由短于30bp的siRNA触发(Elbashir等(2001)Nature(自然)411:494-498)。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),NatureBiotech.(自然生物技术)20:1006-1010;Brummelkamp等(2002),CancerCell(癌细胞)2:243-247)。因此,用于按照本发明的复合RNA的siRNA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,例如(m)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siRNA的靶序列作用。同等地,siRNA还可以针对以上所述的(治疗相关)蛋白或抗原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。siRNA的靶序列因此可以位于RNA的翻译和/或不翻译区中和/或控制元件区中。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。
反义RNA
根据第五个实施方案,本发明的复合RNA的至少一个RNA(分子)可以是反义RNA。在本发明的上下文中,反义RNA优选是基于DNA编码链,而非DNA模板链转录的(单链)RNA分子,因此其与有义(信使)RNA互补。作为本发明的复合RNA的至少一个RNA(分子)在本文中使用的反义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mRNA的翻译。作为本发明的复合RNA的至少一个RNA(分子)在本文中使用的反义RNA可以针对(可以互补于)mRNA序列的任何部分,其可以编码(治疗相关)蛋白或抗原(例如如以上所述),条件是由此减少/抑制编码蛋白的翻译。因此,靶mRNA上的反义RNA的靶序列可以位于mRNA的翻译和/或不翻译区中,例如mRNA控制元件区中,特别地发挥调节功能的RNA的5’非编码区中。还可以构建靶mRNA上的反义RNA的靶序列,以使得反义RNA通过用其序列覆盖与靶mRNA的不翻译和翻译(编码)序列部分互补的区域而结合mRNA;特别地,反义RNA可以通过靶mRNA编码区起始三联体上游的至少一个核苷酸,与靶mRNA序列互补。优选地,作为本发明的复合RNA的至少一个RNA(分子)在本文中使用的反义RNA包括如上关于(本发明的复合RNA的)RNA分子普遍定义的长度。典型地,作为本发明的复合RNA的至少一个RNA(分子)在本文中使用的反义RNA应该是靶mRNA的片段。更具体地,反义RNA可以更优选地具有5-5000,500-5000,和,更优选地,1000-5000或,备选地,5-1000,5-500,5-250,5-100,5-50或5-30个核苷酸的长度,或,备选地,和甚至更优选地20-100,20-80,或20-60个核苷酸的长度。
RNA的修饰
根据一个实施方案,作为本发明的复合RNA的至少一个RNA(分子)在本文中使用的RNA(不考虑其例如特异性治疗潜力、长度和/或序列),特别地短RNA寡核苷酸、编码RNA、免疫刺激性RNA、siRNA、反义RNA、riboswitches、核膜或适体可以作为修饰的RNA提供,其中任何修饰,特别是以下公开的修饰可以引入(以任何组合或原样)到如上定义的RNA(分子)中。然而,某些修饰类型可能更适合于特定的RNA类型(例如更适合于编码RNA),而其他修饰可以应用于任何RNA分子,例如如本文中定义的RNA分子,而不仅限于特定的RNA类型。因此,可以引入RNA的修饰,以获得对于本发明主题的应用而言可能需要的特定或复合作用。因此,修饰可以被设计用于例如稳定RNA以避免降解,增强它们的转染功效,改善其翻译功效,增加它们的免疫原性潜力和/或提高它们的治疗潜力(例如提高它们的沉默或反义特性)。如果作为本发明复合RNA的组成的修饰的RNA容许组合至少一种,更优选至少两种功能特性的改善,例如稳定RNA和改善治疗或免疫原性潜力,则是特别优选的。
通常,主要目的是稳定作为本发明的复合RNA的至少一个RNA(分子)在本文中使用的RNA,其容许延长其体内半衰期。优选地,修饰的RNA在体内条件下的半衰期延长(与未修饰RNA相比)至少20%,更优选至少40%,更优选至少50%和甚至更优选至少70%,80%,90%,100%,150%或200%。与未修饰的RNA相比,通过修饰获得的稳定化可以延长修饰的mRNA的半衰期至少5分钟,10分钟,15分钟,30分钟或更优选至少60分钟。
根据一个实施方案,本发明的复合RNA的至少一个RNA(分子),优选地编码RNA,例如mRNA,可以通过改变例如RNA编码区的G/C含量来稳定化。在本发明特别优选的实施方案中,与其相应的野生型RNA,即未修饰RNA的编码区的G/C含量相比,(本发明的复合RNA的)RNA的编码区的G/C含量变化,特别地增加。修饰的RNA的被编码氨基酸序列,与由相应的野生型RNA编码的氨基酸序列相比,优选不改变。
作为本发明的复合RNA的至少一个RNA(分子)在本文中使用的RNA的这种修饰基于这样的事实,即任何待翻译的RNA的编码序列对于RNA的有效翻译很重要。特别地,具有增多的G(鸟苷)/C(胞嘧啶)含量的序列比具有增多的A(腺苷)/U(尿嘧啶)含量的序列更稳定。按照本发明,RNA的密码子因此与野生型RNA相比改变,而保持翻译的氨基酸序列,因此它们包括增加量的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)。
根据由作为本发明的复合RNA的至少一个RNA(分子)在本文中使用的RNA编码的氨基酸,与其野生型序列相比,存在RNA序列修饰的多种可能性。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的其他密码子来修饰。这些的实例是:
关于Pro的密码子可以从CCU或CCA变化为CCC或CCG;
关于Arg的密码子可以从CGU或CGA或AGA或AGG变化为CGC或CGG;
关于Ala的密码子可以从GCU或GCA变化为GCC或GCG;
关于Gly的密码子可以从GGU或GGA变化为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变化为UUC;
关于Leu的密码子可以从UUA,UUG,CUU或CUA变化为CUC或CUG;
关于Ser的密码子可以从UCU或UCA或AGU变化为UCC,UCG或AGC;
关于Tyr的密码子可以从UAU变化为UAC;
关于Cys的密码子可以从UGU变化为UGC;
关于His的密码子可以从CAU变化为CAC;
关于Gln的密码子可以从CAA变化为CAG;
关于Ile的密码子可以从AUU或AUA变化为AUC;
关于Thr的密码子可以从ACU或ACA变化为ACC或ACG;
关于Asn的密码子可以从AAU变化为AAC;
关于Lys的密码子可以从AAA变化为AAG;
关于Val的密码子可以从GUU或GUA变化为GUC或GUG;
关于Asp的密码子可以从GAU变化为GAC;
关于Glu的密码子可以从GAA变化为GAG;
终止密码子UAA可以变化为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,以与其具体的野生型RNA(即原始序列)相比,增加作为本发明的复合RNA的至少一个RNA(分子)在本文中使用的RNA的G/C含量。因此,例如,野生型序列中存在的所有关于Thr密码子可以被改变为ACC(或ACG)。然而,优选地,例如,使用以上置换可能性的组合:
原始序列(野生型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,作为本发明的复合RNA的至少一个RNA(分子)在本文中使用的RNA的编码区的G/C含量与编码蛋白的野生型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野生型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%,由此增加或甚至最大化所述序列的G/C含量。
在该上下文中,特别优选与野生型序列相比,增加作为本发明的复合RNA的至少一个RNA(分子)在本文中使用的RNA,特别在编码蛋白的区域内的G/C含量到最大值(即100%的可置换的密码子)。
按照本发明,作为本发明的复合RNA的至少一个RNA(分子)在本文中使用的RNA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RNA序列中存在所谓的“罕用密码子”达到增多的范围,则相应修饰的RNA序列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,在作为本发明的复合RNA的至少一个RNA(分子)在本文中使用的RNA中,编码蛋白的区域与野生型RNA的相应区域相比被改变,因此编码细胞中相对稀有的tRNA的野生型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。通过该变化,改变RNA序列,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,通过该变化,野生型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,特别优选的是将作为本发明的复合RNA的至少一个RNA(分子)在本文中使用的RNA中增加的特别是最大化的序列G/C含量与不改变由RNA编码区编码的蛋白的氨基酸序列的“频繁”密码子相连。这个优选的实施方案容许提供按照本发明的复合RNA的特别有效翻译和稳定(修饰)的RNA。
作为本发明的复合RNA的至少一个RNA(分子)在本文中使用的RNA的G/C含量(增加的G/C含量;交换tRNA)的确定可以利用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,任何所需的RNA的核苷酸序列可以借助于遗传密码或其简并性质来改变,由此最大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,导致由RNA(分子)编码的氨基酸序列与未改变的序列相比,优选不被改变。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。VisualBasic(视觉基础)6.0(使用的开发环境:具有Servicepack3的MicrosoftVisualStudioEnterprise6.0)中的源码也记述在WO02/098443中。
在本发明的另一个优选实施方案中,本发明的复合RNA的至少一个RNA(分子)的核糖体结合位点环境中的A/U含量与其特定野生型RNA的核糖体结合位点环境中A/U含量相比增加。该修饰(在核糖体结合位点周围增加的A/U含量)增加核糖体结合被修饰的RNA的效率。核糖体与核糖体结合位点(Kozak序列:GCCGCCACCAUGG(SEQIDNO:33),AUG形成起始密码子)的有效结合随之具有有效翻译修饰的RNA的作用。
按照本发明的另一个实施方案,本发明的复合RNA的至少一个RNA(分子)可以关于潜在地促降解序列元件而被修饰。具体地,该RNA的编码区和/或5’和/或3’不翻译区与特定野生型RNA相比可以被修饰,从而不包含促降解序列元件,RNA(分子)的编码氨基酸序列与其特定野生型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RNA(分子),任选地在编码蛋白的区域内,可以因此进行与野生型RNA的相应区域相比的一种或多种这样的修饰,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,也可以通过所述修饰,从本发明的复合RNA的至少一个RNA(分子)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)。因此按照本发明的复合RNA的RNA与野生型RNA相比,优选被修饰使得该RNA不含有促降解序列。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,EMBOJ.(EMBO杂志)1994,13:1969-1980)。这些序列基序也可以优选根据本发明从本发明的复合RNA的至少一个RNA(分子)除去。
按照本发明,本发明的复合RNA的至少一个RNA(分子)可以具有5’帽结构。按照本发明可以使用的帽结构的实例是m7G(5′)ppp,(5′(A,G(5′)ppp(5′)A和G(5′)ppp(5′)G。
另一种增强本发明的复合RNA的至少一个RNA(分子)的稳定性的修饰基于RNA的5’-或3’延长,典型地,10-200个核苷酸长度的同型核苷酸延长。这些延长可以在3’端包含,特别是如果RNA以mRNA提供,典型约10-200个腺苷核苷酸,优选约10-100个腺苷核苷酸,更优选约20-70个腺苷核苷酸或甚至更优选约20-60个腺苷核苷酸的多聚-A尾部。备选地或另外地,本发明的复合RNA的至少一个RNA(分子)可以在3’端包含,特别是如果RNA以mRNA提供,典型约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个胞嘧啶核苷酸的多聚-C尾部。
可以在本发明的复合RNA的至少一个RNA(分子)中存在的另一种修饰,特别是如果RNA以mRNA提供,优选指至少一个IRES和/或至少一个5′和/或3′稳定序列。按照本发明,可以将一个或多个所谓的IRES(内部核糖体进入位点)插入到RNA中。IRES可以因此起单独的核糖体结合位点作用,但是它还可以起提供编码若干待由核糖体彼此独立翻译的蛋白的RNA(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),小鼠角膜白斑病毒(mouseleukomavirus,MLV),猿猴免疫缺陷病毒(SIV)或蟋蟀麻痹病毒(CrPV)的那些。
按照本发明,本发明的复合RNA的至少一个RNA(分子)可以表现出由本领域已知的至少一个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(Homosapiens)或非洲爪蟾(Xenopuslaevis)的珠蛋白基因的不翻译序列(UTR)可以作为可以在本发明中关于稳定的RNA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(SEQIDNO:34),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。本发明的复合RNA的至少一个RNA(分子)因此优选表示为球蛋白UTR(不翻译区)-稳定的RNA,特别地表示为球蛋白UTR--稳定的RNA。
如果需要,本发明的复合RNA的至少一个RNA(分子)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。
本发明的复合RNA的至少一个RNA(分子)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)。
本发明的复合RNA的至少一个RNA(分子)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,显著增加由所述至少一个RNA(分子)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。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。
本发明的复合RNA的至少一个RNA(分子)可以另外地或备选地还包含所述至少一个RNA(分子)中包含的核苷酸的核苷的至少一个修饰,其起免疫抑制的作用,即在当施用于有此需要的患者时,优选适合于防止或减少免疫反应。所述至少一个修饰优选选自核苷修饰,所述核苷修饰选自:
a)胞苷和/或尿苷的核苷的嘧啶碱基的4-,5-或6-位置处的化学修饰;
b)腺苷,肌苷和/或鸟苷的核苷的嘌呤碱基的2-,6-,7-或8-位置处的化学修饰;和/或
c)腺苷,肌苷,鸟苷,胞苷和/或尿苷的核苷的糖的2’-位置处的化学修饰。
在该上下文中,(m)RNA是由许多典型选自以下各项的核苷酸形成的核酸链:腺苷-5’-一磷酸,鸟苷-5’-一磷酸,肌苷-5’-一磷酸,胞苷-5’-一磷酸和/或尿苷-5’-一磷酸。那些核苷酸彼此通过它们的一磷酸相连。核苷酸包括核苷和5’-一磷酸作为结构组成,其中核苷典型地由核碱基(nucleobase),即嘧啶(尿嘧啶或胞嘧啶)或嘌呤(腺嘌呤或鸟嘌呤)碱基,和糖形成。因此,本发明的复合RNA的至少一个RNA(分子)的核苷的修饰通常意指所述至少一个RNA(分子)的各个核苷酸的核苷结构中的修饰。
按照第一种修饰a),本发明的复合RNA的至少一个RNA(分子)的至少一个核苷可以在核苷胞苷和/或尿苷的嘧啶碱基的5-或6-位置处使用化学修饰来修饰。不局限于此,在核苷胞苷和/或尿苷的碱基嘧啶的4-,5-或6-位置处的所述化学修饰可以选自由以下各项组成的组:4-硫代,5-碘-/(5-I-),5-溴-/(5-Br-),5-氨基烯丙基-,5-氟-/(5-F-),5-羟基-,5-氢-/(5-H-),5-硝基-,5-丙炔基-/(5-(C≡C-CH3)-),5-甲基-,5-甲基-2-硫代-,5-甲酰基-,5-羟基甲基-,5-甲氧基-,5-氧乙酸甲酯-,5-氧乙酸-,5-羧基羟基甲基-,5-(羧基羟基甲基)嘧啶甲酯-,5-甲氧基羰基甲基-,5-甲氧基羰基甲基-2-硫代,5-氨基甲基-,5-氨基甲基-2-硫代-,5-氨基甲基-2-硒代-,5-甲基氨基甲基-,5-氨基甲酰基甲基-,5-羧基甲基氨基甲基-,5-羧基甲基氨基甲基-2-硫代-,5-羧基甲基-,5-甲基二氢-,5-牛磺酸甲基-(5-taurinomethyl-),5-牛磺酸甲基-2-硫代尿苷,5-异戊烯基氨基甲基-,5-异戊烯基氨基甲基-2-硫代-,5-氨基丙基-/(5-(C3H6NH3)-),5-甲氧基-乙氧基-甲基-/(5-(CH2-O-C2H4-O-CH3)-),或6-氮杂-。
按照第二种修饰b),本发明的复合RNA的至少一个RNA(分子)的至少一个核苷,其适合于在施用相应未修饰的至少一个RNA(分子)时,典型地表现出抑制和/或避免哺乳动物中(先天)免疫刺激性反应,可以备选地用核苷腺苷、肌苷和/或鸟苷的嘌呤碱基的2-,6-,7-或8-位置处的化学修饰来修饰。不局限于此,在核苷腺苷、肌苷和/或鸟苷的嘌呤碱基的2-,6-,7-或8-位置处的所述化学修饰可以选自由以下各项组成的组:2-氨基-,7-脱氮-,8-氮杂-,或8-叠氮-。
按照第三种修饰c),本发明的复合RNA的至少一个RNA(分子)的至少一个核苷,其适合于在施用相应未修饰的至少一个RNA(分子)时,典型地表现出抑制和/或避免哺乳动物中(先天)免疫刺激性反应,可以在引入RNA序列时,用核苷腺苷,肌苷,鸟苷,胞苷和/或尿苷的糖的2-位置处的至少一个化学修饰来修饰。不局限于此,在核苷腺苷、肌苷、鸟苷、胞苷和/或尿苷的糖的2-位置处的所述化学修饰可以选自由以下各项组成的组:2’-脱氧-,2’-氨基-2’-脱氧-,2’-氨基-,2’-氟-2’-脱氧-,2’-氟-,2’-O-甲基-2’-脱氧-或2’-O-甲基-。
按照特别优选的实施方案,本发明的复合RNA的至少一个RNA(分子)的至少一个核苷已经在核苷胞苷和/或尿苷的碱基嘧啶的4,-5-或6-位置处和在核糖的2’-位置处按照如上定义的修饰a)和c)来修饰。
按照另一个特别优选的实施方案,本发明的复合RNA的至少一个RNA(分子)的至少一个核苷已经在核苷腺苷、肌苷和/或鸟苷的嘌呤碱基的2-,6-,7-或8-位置处和在核糖的2’-位置处按照如上定义的修饰b)和c),更优选如上定义来修饰。
按照甚至更特别优选的实施方案,本发明的复合RNA的至少一个RNA(分子)的至少一个核苷已经被修饰,导致选自以下组的化学修饰的((m)RNA的)核苷酸:4-硫代-尿苷-5′-(一)磷酸,2-氨基嘌呤-核糖核苷-5′-(一)磷酸,5-氨基烯丙基胞苷-5′-(一)磷酸,5-氨基烯丙基尿苷-5′-(一)磷酸,5-溴胞苷-5′-(一)磷酸,5-溴-2′-脱氧胞苷-5′-(一)磷酸,5-溴尿苷-5′-(一)磷酸,5-溴-2′-脱氧尿苷-5′-(一)磷酸,5-碘胞苷-5′-(一)磷酸,5-碘-2′-脱氧胞苷-5′-(一)磷酸,5-碘尿苷-5′(一)磷酸,5-碘-2′-脱氧尿苷-5′-(一)磷酸,5-丙炔基-2′-脱氧胞苷-5′-(一)磷酸,5-丙炔基-2′-脱氧尿苷-5′-(一)磷酸,5-甲酰胞苷-5′-(一)磷酸,5,2′-O-二甲基胞苷-5′-(一)磷酸,5-羟基甲基胞苷-5′-(一)磷酸,5-甲酰-2′-O-甲基胞苷-5′-(一)磷酸,5,2′-O-二甲基尿苷-5′-(一)磷酸,5-甲基-2-硫代尿苷-5′-(一)磷酸,5-羟基尿苷-5′-(一)磷酸,5-甲氧基尿苷-5′-(一)磷酸,尿苷5-氧乙酸-5′-(一)磷酸,尿苷5-氧乙酸甲酯-5′-(一)磷酸,5-(羧基羟基甲基)尿苷-5′-(一)磷酸,5-(羧基羟基甲基)尿苷甲酯-5′-(一)磷酸,5-甲氧基羰基甲基尿苷-5′-(一)磷酸,5-甲氧基羰基甲基-2′-O-甲基尿苷-5′-(一)磷酸,5-甲氧基羰基甲基-2-硫代尿苷-5′-(一)磷酸,5-氨基甲基-2-硫代尿苷-5′-(一)磷酸,5-甲基氨基甲基尿苷-5′-(一)磷酸,5-甲基氨基甲基-2-硫代尿苷-5′-(一)磷酸,5-甲基氨基甲基-2-硒代尿苷-5′-(一)磷酸,5-氨基甲酰基甲基尿苷-5′-(一)磷酸,5-氨基甲酰基甲基-2′-O-甲基尿苷-5′-(一)磷酸,5-羧基甲基氨基甲基尿苷-5′-(一)磷酸,5-羧基甲基氨基甲基-2′-O-甲基尿苷-5′-(一)磷酸,5-羧基甲基氨基甲基-2-硫代尿苷-5′-(一)磷酸,5-羧基甲基尿苷-5′-(一)磷酸,5-甲基二氢尿苷-5′-(一)磷酸,5-牛磺酸甲基尿苷-5′-(一)磷酸,5-牛磺酸甲基-2-硫代尿苷-5′-(一)磷酸,5-(异戊烯基氨基甲基)尿苷-5′-(一)磷酸,5-(异戊烯基氨基甲基)-2-硫代尿苷-5′-(一)磷酸,5-(异戊烯基氨基甲基)-2′-O-甲基尿苷-5′-(一)磷酸,6-氮杂胞苷-5′-(一)磷酸,7-脱氮腺苷-5′-(一)磷酸,7-脱氮鸟苷-5′-(一)磷酸,8-氮杂腺苷-5′-(一)磷酸,8-叠氮腺苷-5′-(一)磷酸,假尿苷-5′-(一)磷酸,2′-氨基-2′-脱氧胞苷-(一)磷酸,2′-氟胸苷-5′-(一)磷酸,肌苷-5′-(一)磷酸,2′-O-甲基-肌苷-5′-(一)磷酸。
如果需要,本发明的复合RNA的至少一个RNA(分子)可以包含核苷酸的置换、添加或缺失,其优选引入来获得功能效果。如果RNA,例如mRNA源自WT序列,可以引入这些不同类型的核苷酸修饰。由此,DNA基质通过公知位点定向诱变技术,用于制备按照本发明的复合RNA的RNA(参见例如Maniatis等,MolecularCloning:ALaboratoryManual(分子克隆:实验室手册),ColdSpringHarborLaboratoryPress(冷泉港实验室出版社),第三版,ColdSpringHarbor(冷泉港),NY,2001)。在该过程中,为了制备RNA,可以在体外转录相应的DNA分子。该DNA基质具有合适的启动子,例如T7或SP6启动子,以用于体外转录,其后跟随着待制备RNA的理想核苷酸序列和体外转录的终止信号。按照本发明,形成目的RNA基质的DNA分子可以通过发酵增殖和随后分离为可以在细菌内复制的质粒的一部分来制备。可以作为适合于本发明提及的质粒是例如质粒pT7Ts(GenBank编号U26404;Lai等,Development(发育)1995,121:2349-2360),系列,例如(GenBank编号X65300;来自Promega)和pSP64(GenBank编号X65327);还参考:Mezei和Storts,PurificationofPCRProducts(PCR产物的纯化),在:Griffin和Griffin(编),PCRTechnology:CurrentInnovation(PCR技术:当前改革)中,CRCPress(CRC出版社),BocaRaton,FL,2001。
按照本发明的RNA复合物的组分的质量或摩尔比,其意指RNA(单-链或双-链)与一种或多种寡肽的质量或摩尔比,典型地决不被局限并选择为适合于特定的应用。然而,一种或多种寡肽和RNA的质量或摩尔比可以小于1∶1,1∶2,1∶3,1∶4,1∶5,1∶6,1∶7,1∶8,1∶9,1∶10,1∶11,1∶12,1∶13,1∶14,1∶15,1∶16,1∶17,1∶18,或小于1∶20。备选地,一种或多种寡肽和RNA的质量或摩尔比可以高于1∶1,2∶1,3∶1,4∶1,5∶1,6∶1,7∶1,8∶1,9∶1,10∶1,11∶1,12∶1,13∶1,14∶1,15∶1,16∶1,17∶1,18∶1,19∶1,20∶1。优选地,关于一种或多种寡肽的含量,一种或多种寡肽和RNA的质量或摩尔比可以不小于1∶5。更优选地,一种或多种寡肽和RNA的(质量或)摩尔比是1∶5-20∶1,更优选1∶3-15∶1。
按照特别优选的实施方案,按照本发明的RNA复合物的组分的质量比,特别地所述复合RNA的至少一个RNA(分子)与一种或多种寡肽的质量比优选在约1∶100-约1∶0,5的范围内,更优选地,关于该复合物中的RNA:肽比具有约1∶50-约1∶1,或甚至更优选约1∶100,约1∶90,约1∶80,约1∶70,约1∶60,约1∶50,约1∶45,约1∶40,约1∶35,约1∶30,约1∶25,约1∶20,约1∶15,约1∶10,约1∶5,约1∶4,约1∶3,约1∶2,约1∶1或甚至约1∶0,5的数值,其中任何范围可以通过组合以上具体指定的数值中的2个来形成。最优选地,所述复合RNA的至少一个RNA(分子)与一种或多种寡肽的质量比可以在约1∶50-约1∶1的范围内。
同样地,按照本发明的RNA复合物的组分的摩尔比,特别地所述复合RNA的至少一个RNA(分子)与一种或多种寡肽的摩尔比优选地,按照特别优选的实施方案,在约1∶20000-约1∶500或甚至1∶250的范围内,更优选在约1∶10000-约1∶1000的范围内,或甚至更优选关于该复合物中的RNA:肽比具有约1∶9500,约1∶9000,约1∶8500,约1∶8000,约1∶7500,约1∶7000,约1∶6500,约1∶6000,约1∶5500,约1∶5000,约1∶4500,约1∶4000,约1∶3500,约1∶3000,约1∶2500,约1∶2000,约1∶1500,约1∶1000,约1∶500,约1∶450,约1∶400,约1∶350,约1∶300,或约1∶250的数值,其中任何范围可以通过组合以上具体指定的数值中的2个来形成。最优选地,所述复合RNA的至少一个RNA(分子)与一种或多种寡肽的摩尔比可以在约1∶10000-约1∶1000的范围内。为了免疫刺激目的,按照本发明的RNA复合物的组分的摩尔比可以在约1∶10000-约1∶100的范围内或甚至在约1∶10000-约1∶500的范围内。
在本发明的上下文中,摩尔比和质量比典型地彼此依赖,其中这些比例中每一种均可以受到因素诸如RNA长度或肽长度的影响。然而,为了确定目的,质量比和摩尔比可以适合于平均复合物尺寸(averagecomplexsize),其中约1∶50-1∶1的质量比大约对应于约1∶10000-1∶1000的摩尔比。摩尔比和质量比的示范性清单在实施例中给出,其可以另外用于计算。
此外,按照本发明的RNA复合物组分的比,特别地所述复合RNA的至少一个RNA(分子)与一种或多种寡肽的比,也可以基于整个RNA复合物的氮/磷比(N/P-比)计算。例如,1μgRNA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xnmol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700×9=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2μgRNA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235×21=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0,2-50的范围内,优选在约0.5-50的范围内和最优选在约0.75-25或1-25的范围内,甚至更优选在约10-50的范围内和最优选在约25-50的范围内。
本发明的另一个实施方案涉及组合物,优选药物组合物,其包含按照本发明的复合RNA和任选地(药用)适合的载体和/或另外的辅助物质和添加剂。按照本发明使用的(药物)组合物典型地包含安全且有效量的按照本发明的复合RNA。用于本文中时,“安全且有效量”意指按照本发明的复合RNA的量,诸如用于在体外或体内提供细胞或组织中的作用,例如用于显著诱导如上所述的编码蛋白,诸如治疗活性蛋白,抗体或抗原,或以上所述的任何其他蛋白或肽的(体外或体内)表达,用于诱导细胞、组织或生物体中待治疗状态(体内)例如如本文中所述的肿瘤疾病或癌症疾病,心血管疾病,传染病,自身免疫性疾病,(单-)遗传性疾病等的积极变化,和/或用于诱导或增强免疫反应的量。然而,同时,“安全且有效量”足够低以避免严重的副作用,特别是在如本文中提及的疾病的治疗中,即提供可能合理的优势和风险比。这些限制的确定典型地处于合理的医学判断范围内。按照本发明的复合RNA在所述(药物)组合物中的浓度可以因此变化,例如,但不限于,在例如0.1ng-1,000mg/ml的宽范围内或甚至更多。所述按照本发明的复合RNA的“安全且有效量”可以与下述内容相关联而变化:待治疗的具体状态和待治疗患者的年龄和身体状态,状态的严重性,治疗持续期间,伴随治疗的性质,所用的具体(药物)适合载体,和治疗医生的知识和经验范围内的类似因素。本文中所述的(药物)组合物可以用于人和还用于兽医医学目的。
本文中所述按照本发明的(药物)组合物可以任选地包括合适的载体,优选药物合适的载体。本文中使用的术语“合适的载体”优选包括一种或多种适合于对人施药的相容性固体或液体填充剂,或稀释剂或包封化合物。本文中使用的术语“相容性”意指该组合物的成分能够混合以按照本发明的复合RNA和该组合物中任选包含的辅助物质,原样地和以另一种方式,使得不发生将在通常使用条件下实质上减小该组合物的(药物)效力,诸如例如将减小被编码蛋白(药物)活性或甚至抑制或削弱被编码蛋白表达或例如将抑制所述复合RNA的免疫原性潜力的相互作用。合适的载体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。
载体根据施药方式选择是采用固体或液体形式。因此,如上所述(药物)合适的载体的选择特别通过其中施用按照本发明的(药物)组合物的模式来确定。按照本发明的(药物)组合物可以例如全身性施用。施药途径包括例如皮内或经皮,口服,肠胃外,包括皮下,肌内,i.a.或静脉内注射,局部和/或鼻内途径。待使用的按照本发明的(药物)组合物的合适的量通过利用动物模型的常规实验确定。所述模型包括,但不仅限于,兔、山羊、小鼠、大鼠、狗和非人灵长类动物模型。
如果以液体形式,例如通过注射施药,则载体可以选自无致热原的水;等渗盐溶液和缓冲溶液,例如磷酸盐缓冲溶液。对于注射优选的单位剂型形式包括水、生理盐溶液或其混合物的无菌溶液,例如Ringer-Lactat溶液。所述溶液的pH应该调节到约7.0-约7.6,优选约7.4。
优选地,(药物)组合物在水中含有本发明的复合RNA。备选地,按照本发明的(药物)组合物可以含有注射缓冲液作为液体制剂的载体,其优选在细胞、组织或生物体中改善转染且,如果本发明的复合RNA的RNA编码蛋白,则也改善被编码蛋白的翻译。按照本发明的(药物)组合物可以包括例如水性注射缓冲液或水,其包含,关于总(药物)组合物,如果采用液体形式,钠盐,优选至少50mM钠盐,钙盐,优选至少0.01mM钙盐和/或镁盐,和任选地钾盐,优选至少3mM钾盐。按照优选的实施方案,所述注射缓冲液中包含的钠盐、钙盐和/或镁盐和任选地钾盐采用卤化物,例如氯化物、碘化物或溴化物的形式,或采用它们的氢氧化物、碳酸盐、碳酸氢盐或硫酸盐形式。本文中提及的实例关于钠盐有NaCl,NaI,NaBr,Na2CO3,NaHCO3,和/或Na2SO4,关于任选存在的钾盐有KCl,KI,KBr,K2CO3,KHCO3,和/或K2SO4,和关于钙盐和/或镁盐有CaCl2,CaI2,CaBr2,CaCO3,CaSO4,Ca(OH)2,MgCl2,MgI2,MgBr2,MgCO3,MgSO4,和/或Mg(OH)2。注射缓冲液还可以包含前述阳离子的有机阴离子。在特别优选的实施方案中,所述注射缓冲液包含如盐:氯化钠(NaCl),氯化钙(CaCl2)和任选地氯化钾(KCl),也可能存在除氯化物以外的其他阴离子。
这些盐典型地存在于按照本发明的(药物)组合物中任选使用的注射缓冲液中,关于总(药物)组合物(如果其采用液体形式),处于至少50mM氯化钠(NaCl),至少3mM氯化钾(KCl)和至少0.01mM氯化钙和/或镁(CaCl2)的浓度。注射缓冲液可以采用高渗和等渗或低渗注射缓冲液的形式。与本发明有关,在该上下文中,注射缓冲液在各种与具体参考培养基有关的情形中是高渗,等渗或低渗的,即注射缓冲液具有与具体参考培养基相比更高,相同或更低的盐含量,所述不导致由渗透作用或其浓度作用引起的细胞破坏的前述盐浓度是优选使用的。参考培养基在此是,例如,“体内”方法中存在的液体,诸如,例如,血液,淋巴液,细胞溶胶液或身体内存在的其他液体,或“体外”方法中常规使用的液体或缓冲液。所述液体和缓冲液是本领域中技术人员已知的。
按照本发明的(药物)组合物中任选包含的注射缓冲液还可以包含其他成分,例如糖(单-、二-、三-或多糖),具体地葡萄糖或甘露糖醇。然而,在优选的实施方案中,使用的注射缓冲液中不存在糖。对于注射缓冲液也优选的是明确不含有不带电的成分,诸如,例如,糖。注射缓冲液典型排他地包含金属阳离子,具体地来自由下述物质组成的组:碱金属或碱土金属和阴离子,特别地如上所述的阴离子。所用注射缓冲液的pH,关于总(药物)组合物,如果采用液体形式,优选1-8.5,优选3-5,更优选5.5-7.5,具体地5.5-6.5。如果适合,注射缓冲液还可以包含将注射缓冲液固定在缓冲的pH的缓冲系统。这可以是,例如,磷酸盐缓冲系统、HEPES或Na2HPO4/NaH2PO4。然而,使用的注射缓冲液非常特别优选不包含前述缓冲系统或根本不包含缓冲系统。
按照本发明的(药物)组合物中任选包含的注射缓冲液可以,除所述一价和二价阳离子以外或作为其备选方案,包含二价阳离子,特别地来自由下述物质组成的组:碱土金属,诸如,例如,镁(Mg2+),或还有铁(Fe2+),和一价阳离子,特别地来自由碱金属,诸如,例如,锂(Li+)组成的组。这些一价阳离子优选采用其盐形式,例如采用卤化物、例如氯化物、碘化物或溴化物形式,或采用其氢氧化物、碳酸盐、碳酸氢盐或硫酸盐形式。本文中提及的实例关于锂盐为LiCl,LiI,LiBr,Li2CO3,LiHCO3,Li2SO4,关于镁盐为MgCl2,MgI2,MgBr2,MgCO3,MgSO4,和Mg(OH)2,和关于铁盐为FeCl2,FeBr2,FeI2,FeF2,Fe2O3,FeCO3,FeSO4,Fe(OH)2。同样包括如上所述二价和/或一价阳离子的所有组合。所述包含仅二价、仅一价或二价和一价阳离子的注射缓冲液因此可以用于按照本发明的(药物)组合物中。同样可以使用所述仅包含一种类型的二价或一价阳离子,特别优选例如仅包含Ca2+阳离子,或其盐,例如CaCl2的注射缓冲液。还可以考虑以上关于注射缓冲液中的Ca2+(作为二价阳离子)和Na1+(作为一价阳离子)给出的体积摩尔浓度(即典型至少50mMNa+,至少0.01mMCa2+和任选至少3mMK+的浓度),条件是在按照本发明用于制备注射溶液的注射缓冲液中使用另一种二价或一价阳离子,具体地来自由碱土金属和碱金属组成的组的其他阳离子代替一些或全部Ca2+或,分别地,Na1+。全部Ca2+或Na1+,如以上提及地,在所用注射缓冲液中的确可以在各种情形中被其他二价或,分别地,一价阳离子代替,例如也可以被其他二价阳离子的组合(代替Ca2+)和/或其他一价阳离子的组合(代替Na1+)(具体地,来自由碱土金属组成的组的其他二价阳离子的组合或,分别地,来自由碱金属组成的组的其他一价阳离子的组合)代替,但是优选至多代替Ca2+或Na1+中的一些,即被Ca2+和,分别地,Na1+占据的注射液中一价和二价阳离子的具体总体积摩尔浓度的至少20%,优选至少40%,甚至更优选至少60%和仍更优选至少80%。然而,如果按照本发明的药物组合物任选包含的注射缓冲液排他地包含Ca2+作为二价阳离子和Na1+作为一价阳离子,即关于总药物组合物,非常特别优选Ca2+表示二价阳离子总体积摩尔浓度的100%,正如Na1+表示一价阳离子总体积摩尔浓度的100%。注射缓冲液的水性溶液可以包含,关于总药物组合物,至多30mol%的包含在溶液中的盐,优选至多25mol%,优选至多20mol%,进一步更优选至多15mol%,更优选至多10mol%,甚至更优选至多5mol%,同样地更优选至多2mol%不溶性或微溶性盐。本发明的上下文中的微溶性盐是溶度积<10-4的那些。易溶性盐是溶度积>10-4的那些。优选地,按照本发明的药物组合物任选包含的注射缓冲液在氯化钠(NaCl)中是50mM-800mM,优选60mM-500mM,更优选70mM-250mM,特别优选60mM-110mM,在氯化钙(CaCl2)中是0.01mM-100mM,优选0.5mM-80mM,更优选1.5mM-40mM和任选地在氯化钾(KCl)中是3mM-500mM,优选4mM-300mM,更优选5mM-200mM。有机阴离子也可以作为除前述无机阴离子,例如卤素离子、硫酸根或碳酸根以外的其他阴离子存在。在这些中可以存在提及的琥珀酸根、乳糖酸根(lactobionate)、乳酸根、苹果酸根、马来酸根等,其也可以以组合存在。
按照本发明的(药物)组合物任选包含的注射缓冲液优选包含乳酸盐。如果其包含有机阴离子,则所述注射缓冲液特别优选排他地包含乳酸盐作为有机阴离子。在本发明的上下文中,乳酸盐可以是任何需要的乳酸盐,例如,L-乳酸盐和D-乳酸盐。与本发明有关存在的乳酸盐典型地是乳酸钠和/或乳酸钙,特别是如果注射缓冲液仅含有Na+作为一价阳离子和Ca2+作为二价阳离子。按照本发明和如上所述的(药物)组合物中任选使用的注射缓冲液优选含有,关于总药物组合物,15mM-500mM,更优选15mM-200mM,和甚至更最优选15mM-100mM的乳酸盐。
如果以非液体形式(例如以固体或半固体形式)配制,则本发明的药物组合物可含有可作为合适的载体或其成分的化合物,例如糖,诸如,例如,乳糖,葡萄糖和蔗糖;淀粉,诸如,例如,玉米淀粉或马铃薯淀粉;纤维素及其衍生物,诸如,例如,羧基甲基纤维素钠,乙基纤维素,乙酸纤维素;粉状黄蓍胶(tragacanth);麦芽;明胶;牛油;固体润滑剂,诸如,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(oilfromTheobroma);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。然而,以上化合物还可以用于提供液体组合物。
可以在本发明的药物组合物中包括的其他成分是例如乳化剂,诸如,例如,吐润湿剂,诸如,例如,月桂基硫酸钠;着色剂;调味剂;药物载体;成片剂;稳定剂;抗氧化剂;防腐剂。
其他对于注射合适的载体包括水凝胶、用于受控或延迟释放的装置、聚乳酸和胶原蛋白基质。此处可用的合适的载体包括适合于用在洗剂、霜剂、凝胶剂等中的那些。如果该化合物要经口施用,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合适的载体是现有技术中公知的。它们的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。
本发明还提供用于使用如上所述的本发明复合RNA转染细胞或组织(体外或体内)的转染方法。本发明的(体外或体内)转染方法优选包括以下步骤:
a)任选地制备和/或提供按照本发明的复合RNA,其包括至少一个与一个或多个具有实验式(Arg)l;(Lys)m;(His)n;(Orn)o;(Xaa)x的寡肽复合的RNA;
b)利用按照步骤a)制备和/或提供的复合RNA转染细胞、(活)组织或生物体(体外或体内)。
按照本发明用于使用本发明的复合RNA转染细胞或组织的体外或体内转染方法的步骤a)制备和/或提供如上定义的复合RNA可以通过本领域中任何已知的方法进行。如本文中所用的复合RNA包括至少一个与一个或多个具有实验式(Arg)l;(Lys)m;(His)n;(Orn)o;(Xaa)x的寡肽复合的RNA。按照步骤a)制备和/或提供如上定义的复合RNA可以因此包括制备和/或提供至少一个RNA和一种或多种具有实验式(Arg)l;(Lys)m;(His)n;(Orn)o;(Xaa)x的寡肽。
用于制备短肽序列诸如(Arg)l;(Lys)m;(His)n;(Orn)o;(Xaa)x的方法是本领域中广泛已知的,且可以使用例如固相合成诸如Fmoc固相合成或其他合适的方法(参见例如R.Martin,编,ProteinSynthesis:MethodsandProtocols(蛋白合成:方法和方案).MethodsinMolecularBiology(分子生物学方法),卷77HumanaPress(1998))。
制备和/或提供作为如上定义的本发明复合物的成分的所述至少一个RNA(分子)按照步骤a)可以包括第一子步骤a1),即提供和/或制备核酸模板,其典型地包括对应于所需RNA的序列。核酸模板序列可以是任何核酸,例如单链或双链DNA,cDNA,基因组DNA或其片段,等,其可以编码治疗活性蛋白,抗体或抗原,或如上所述的任何其他蛋白或肽。典型地,DNA序列,例如DNA质粒,优选采用线性化形式,可以用于该目的。优选地,核酸模板的序列可以是(表达)载体,更优选具有RNA聚合酶结合位点的(表达)载体。现有技术中已知的任何(表达)载体,例如可商购的(表达)载体(见上),可以用于此。优选的(表达)载体是,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。该载体可以包括编码治疗活性蛋白、抗体或抗原,或如上所述的任何其他蛋白或肽的核酸序列,其典型地克隆到(表达)载体,例如通过所用载体的多克隆位点进行。
转录前,(表达)载体典型地利用合适的限制酶,在将存在未来RNA3’末端的位点用限制酶裂解,并纯化片段。这防止转录的RNA包含载体序列,并且可以获得规定长度的RNA转录物。在该上下文中,优选不使用产生突出末端(诸如,例如,AatII,ApaI,BanII,BglI,Bsp1286,BstXI,CfoI,HaeII,HgiAI,HhaI,KpnI,PstI,PvuI,SacI,SacII,SfiI,SphI,等)的限制酶。然而如果使用这样的限制酶,则突出的3′末端优选可以被补齐,例如利用Klenow或T4DNA聚合酶补齐。
作为以上的备选方案,用于制备和/或提供按照本发明的复合RNA的至少一个RNA(分子)的核酸模板可以通过使用聚合酶链反应(PCR)制备。核酸模板优选地且所用引物之一因此,典型地包含RNA聚合酶结合位点的序列。此外,所用引物的5′末端优选包含约10-50个另外的核苷酸,更优选15-30个另外的核苷酸和最优选约20个核苷酸的延长。
在体外转录前,作为转录模板使用的核酸,例如DNA或cDNA模板典型地被纯化并不含RNA酶,从而确保高产率。在该上下文中,所述模板的纯化可以借助于现有技术中已知的任何方法,例如利用氯化铯梯度、离子交换法或通过琼脂糖凝胶电泳纯化进行。
制备和/或提供核酸模板后,按照第二子步骤a2),可以进行体外转录反应,以利用按照如上定义的第一子步骤a1)制备的核酸模板,制备所需的本发明复合RNA的至少一个RNA(分子)。
按照第二子步骤a2)的体外转录反应典型地在体外转录反应中进行。合适的体外转录培养基最初包括如上所述的核酸模板,例如约0.1-10μg,优选约1-5μg,更优选2,5μg和最优选约1μg所述核酸。合适的体外转录培养基此外任选地包括还原剂,例如DTT,更优选约1-20μl50mMDTT,甚至更优选约5μl50mMDTT。体外转录培养基典型地包括核苷酸,例如核苷酸混合物,在本发明的情形中包括A,G,C或U核苷酸混合物,典型地,约0.1-10mM/核苷酸,优选0.1-1mM/核苷酸,优选总共约4mM。合适的体外转录培养基同样包括RNA聚合酶,例如T7RNA聚合酶(例如T7-OptimRNA试剂盒,CureVac,Tübingen,德国),T3RNA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100URNA聚合酶。体外转录培养基还更优选地保持不含RNA酶,从而避免转录的本发明复合RNA的至少一个RNA(分子)的降解。合适的体外转录培养基因此任选地另外包括RNA酶抑制剂。
核酸模板可以然后在体外转录培养基中温育并转录为本发明的复合RNA的至少一个RNA(分子),其可以编码治疗活性蛋白,抗体或抗原,或如上所述的任何其他蛋白或肽。温育时间典型地是约30-240分钟,优选约40-120分钟和最优选约90分钟。温育温度典型地是约30-45℃,优选37-42℃。温育温度取决于所用的RNA聚合酶,例如,对于T7RNA聚合酶,是约37℃。通过转录获得的本发明的复合RNA的至少一个RNA(分子)优选是mRNA。在体外转录中获得的产率,对于以上使用的指定的起始量,典型地在约30μgRNA/μg使用的模板DNA的区域内。在本发明的上下文中,在体外转录中获得的产率可以通过线性上升比例增加。为了此目的,以上使用的指定的起始量优选按照所需的产率,例如,通过倍增因数5,10,50,100,500,1,000,5,000,10,000,50,000,100,000等而增加。
温育后,可以任选的进行转录的本发明复合RNA的至少一个RNA(分子)的纯化。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,非引入的,即过量的核苷酸和模板DNA可以从体外转录培养基中除去并可以获得干净的RNA。例如,转录后,具有转录的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。转录的本发明复合RNA的至少一个RNA(分子)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IPRP-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,RNA的纯化可以通过用于根据预备等级纯化RNA的方法来进行,其与通过利用多孔反相作为固定相(PURE信使)的HPLC方式纯化RNA不同。例如,为了纯化,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,诸如通过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,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AzaraniA.andHeckerK.H.所述的,逐渐形成太高的压力,由此即使RNA的预备纯化是可能的,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,关于转录的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250-300,900-1,100或3,500-4,500非常特别优选地用于纯化。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特定的分离问题作出。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RNA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法纯化RNA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(pH7)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。RNA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,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。
备选地,按照本发明转染方法的步骤a)的至少一个RNA(分子)可以通过化学合成来良好地制备。由此,可以使用本领域中已知的多种方法。Phosphoroamidite法最广泛用作化学合成寡核苷酸,例如RNA片段的方法(NucleicAcidResearch(核酸研究),17:7059-7071,1989)。通常,该phosphoroamidite法利用核苷phosphoroamidite和核苷之间的缩合反应作为利用四唑作为加速剂的关键反应。因为该反应通常竞争地发生在糖部分的羟基基团和核苷碱基部分的氨基基团二者上,所以需要仅在糖部分的羟基基团上的选择性反应来合成需要的核苷酸。因此,在氨基基团上的副反应通常通过保护氨基基团来防止。在合成完成时,除去保护基团。关于如何合成RNA分子的更具体的信息可以获自Arnold等,″ChloriditeandAmiditeAutomatedSynthesisofOligodeoxyribonucleotidesUsingAmidineProtectedNucleosides(利用脒保护的核苷酸Chloridite和Amidite自动合成寡脱氧核糖核苷酸),″报道于″7thSymposiumChem.NucleicAcidComponents(第7届化学核酸组成讨论会),″NucleicAcidsSymposiumSeries(核酸讨论会系列),18,181-184(Aug.30,1987);ChemicalAbstracts(化学摘要),108(19),第692页,摘要,编号167875z(1988年5月9日);Hayakawa等,″BenzimidazoliumTriflateasanEfficientPromoterforNucleotideSynthesisviathePhosphoramiditeMethod(BenzimidazoliumTriflate作为通过Phosphoramidite法的核苷酸合成的有效促进剂),″J.OrganicChemistry(有机化学杂志),61(23),7996-7997(1996年11月15日);Pirrung等,″ProofingofPhotolithographicDNASynthesiswith3′,5′-Dimethoxybenzoinyloxycarbonyl-ProtectedDeoxynucleosidePhosphoramidites(用3′,5′-二甲氧基安息香基氧羰基-保护的脱氧核苷Phosphoramidites验证光版印刷DNA合成),″J.OrganicChemistry(有机化学杂志),63(2),241-246(1998年1月23日);Effenberger等,TrifluoromethanesulfonicImidazolide--AConvenientReagentforIntroducingtheTriflateGroup(三氟代甲烷磺酸Imidazolide-用于引入Triflate基团的方便的试剂),TetrahedronLetters(四面体书信),1980(45),3947-3948(1980年9月),将其全部通过参考引入本文。
按照本发明的步骤a)制备复合RNA典型地按照子步骤a3),通过将特定量的所述至少一个RNA(分子)加入到一种或多种具有实验式(Arg)l;(Lys)m;(His)n;(Orn)o;(Xaa)x的寡肽中达到特定的量来进行。由此,典型地研究至少一个RNA(分子)和一种或多种具有本文中定义的实验式(Arg)l;(Lys)m;(His)n;(Orn)o;(Xaa)x的寡肽的如上指定的摩尔比或质量比。复合物的形成典型地在混合这两种成分时发生。由此,典型地将肽成分加入到RNA成分中,然而,在一些情形中,反之亦然。
然而,所述按照方法步骤a)的制备步骤是任选的,且如果按照本发明的复合RNA已经可获得时可以不执行。因此,如上定义的子步骤a1),a2)和a3)也是任选的且如果用于所述复合RNA的RNA已经可获得,则不需要执行。类似地,一种或多种具有实验式(Arg)l;(Lys)m;(His)n;(Orn)o;(Xaa)x的寡肽可以直接使用并且,如果已经可例如由供应商获得,则不需要制备。
按照本发明用于体外或体内转染细胞或组织的方法的步骤b),细胞或组织可以利用按照步骤a)提供和/或制备的复合RNA进行转染。细胞或组织的体外或体内转染通常通过将按照步骤a)提供和/或制备的复合RNA加入到细胞或组织中进行。优选地,所述复合RNA然后利用细胞机制,例如胞吞作用进入细胞。向细胞或组织添加复合RNA本身可以按照本发明在不添加任何其他成分的条件下进行,这归因于本发明的复合RNA(分子)的转染潜力。备选地,向细胞或组织添加按照步骤a)提供和/或制备的复合RNA可以以例如作为水溶液的成分的组合物形式进行,优选如上定义的药物组合物,其可以任选地包含另外的成分以进一步增强转染活性。
在该上下文中用于(步骤a)提供和/或制备的)复合RNA的体外转染的细胞包括任何细胞,且优选,但不仅限于,这样的细胞,其应该通过利用本发明的复合RNA被任何RNA分子(如上定义)转染。具体地,RNA转染可以容许由按照本发明的复合RNA的RNA编码的蛋白在细胞中的表达或可以容许本发明复合物的RNA(例如siRNA,反义RNA)削弱或抑制细胞基因的表达。细胞在该上下文中优选包括培养的真核细胞(例如酵母细胞、植物细胞、动物细胞和人细胞)或原核细胞(例如细菌细胞等)或诱导免疫反应。优选选择多细胞生物体的细胞,条件是翻译后修饰,例如被编码蛋白的糖基化是必要的(N-和/或O-偶联的)。与原核细胞相反,所述(更高等的)真核细胞使得合成的蛋白的翻译后修饰成为可能。本领域中技术人员已知大量所述更高等的真核细胞或细胞系,例如293T(胚肾细胞系),HeLa(人宫颈癌细胞),CHO(来自中国仓鼠卵巢的细胞)和另外的细胞系,包括为了实验室目的开发的那些细胞和细胞系,例如,hTERT-MSC,HEK293,Sf9或COS细胞。合适的真核细胞还包括受疾病或感染损伤的细胞或细胞系,例如癌细胞,具体地,本说明书中在此提及的任何癌症类型的癌细胞,受HIV损伤的细胞,和/或免疫系统或中枢神经系统(CNS)的细胞。合适的细胞同样可以源自真核微生物,诸如酵母,例如酿酒酵母(Saccharomycescerevisiae)(Stinchcomb等,Nature(自然),282:39,(1997)),粟酒裂殖酵母(Schizosaccharomycespombe),念珠菌属(Candida),毕赤酵母属(Pichia),和曲霉属(Aspergillus)、青霉属(Penicillium)的丝状真菌,等。合适的细胞同样包括原核细胞,诸如例如细菌细胞,例如来自大肠埃希氏菌(Escherichiacoli)或来自芽孢杆菌属(Bacillus)、乳球菌属(Lactococcus)、乳杆菌属(Lactobacillus)、假单胞菌属(Pseudomonas)、链霉菌属(Streptomyces)、链球菌属(Streptococcus)、葡萄球菌属(Staphylococcus)的细菌,优选大肠埃希氏菌,等。人细胞或动物细胞,例如本文中提及的动物的细胞,特别优选作为真核细胞。此外,抗原呈递细胞(APCs)可以用于按照本发明的复合RNA的先体外再体内转染。特别优选的是树突细胞,其可以用于按照本发明的复合RNA的先体外再体内转染。
按照特别优选的实施方案,血细胞和/或造血细胞,或其部分群体,即可以由(全)血分离和/或可以由源自那些细胞的培养细胞系来源的任何细胞类型,可以用如本文中定义的复合RNA,利用以上转染方法来转染,例如红细胞(红细胞)、粒细胞、单核细胞(外周血单核细胞,PBMC)和/或血小板(凝血细胞)、APSs、DCs,等。优选地,使用血细胞,特别是其部分群体,其特征具体为它们包含一小群充分分化的专职APCs,诸如DCs。转染的细胞在用于转染时,可以包含优选小于5%,特别优选不大于2%DC。在本发明的上下文中,将“血细胞”优选理解为来自全血、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。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。此外,待利用以上用于转染按照本发明的复合RNA的方法转染的血细胞优选源自将使用本发明的药物组合物治疗的实际患者。血细胞、造血细胞或如上定义的其部分群体的应用基于令人惊讶的发现,即为了对待治疗患者接种疫苗以对抗某些由如本文中定义的mRNA编码的抗原,不需要将获自例如个体,特别是待治疗的实际患者的血液的血细胞例如PBMCs,通过费力、冗长且昂贵的细胞培养技术分化为一群具有高比例的专职抗原呈递细胞(APCs),特别地树突细胞(DCs)的细胞,而是为了成功的免疫刺激,直接用编码一种或多种抗原的mRNA转染血细胞是足够的,从而获得这样的药物组合物,所述药物组合物例如在已由其获得血细胞,特别是上述其部分群体的实际患者中实现合适的免疫刺激,所述免疫刺激优选针对一种或多种来自肿瘤的抗原或一种或多种来自致病微生物或试剂的抗原。将如本文中定义的复合RNA转染到血细胞或源自其的细胞(由其分离的或来自各自的培养细胞系的)不局限于抗原且,当然,涉及用于复合RNA的如本文中定义的任何RNA,例如如本文中定义的任何另外的免疫刺激性RNA,任何编码RNA,等。
虽然存在体外转染培养的细胞(例如人或动物细胞)或体外转染移植的细胞(例如人或动物细胞)(在重新移植到宿主生物体前)的需要,但是也设想了将本发明的复合RNA直接施用于患者以进行体内转染。因此,(按照步骤a)提供和/或制备的)复合RNA的转染也可以按照步骤b)在体内进行,即可以施用于活组织和/或生物体。因此,按照本发明转染方法步骤a)提供的复合RNA可以本身或例如作为(液体)组合物,特别地水性组合物,例如如上定义的药物组合物的成分施用于活组织或生物体。在该上下文中,生物体(或生命)典型地意指哺乳动物,其选自,但不限于,包括人、和动物,包括例如猪、山羊、牛、猪、狗、猫、驴、猴、猿或啮齿动物,包括小鼠、仓鼠和兔的组。此外,如上提及的活组织优选源自这些生物体。将所述复合RNA施用于那些活组织和/或生物体可以通过任何合适的施药途径,例如全身地来进行且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。
而且,用于转染的方法,其可以体外或先体外再体内使用,也可良好地适合于体内使用,例如作为治疗本文中提及的多种疾病的方法。在按照本发明的治疗方法的优选形式中,可以包括另一个步骤,其可以包括另一种药物有效物质,例如抗体,抗原(特别地如本文中公开的致病或肿瘤抗原)的施用或至少一种细胞因子的施用。二者可以与复合RNA分开施用,因为编码例如细胞因子或抗原的DNA或RNA或细胞因子或抗原可以原样施用。治疗方法还可以包括另外的佐剂(如本文中公开的)的施用,其可以进一步激活免疫系统。
按照本发明的另一个实施方案,如上定义的复合RNA可以用于治疗和/或预防如本文中提及的具体疾病,所述复合RNA包括至少一个与一种或多种寡肽复合的RNA,其中所述寡肽表现出8-15个氨基酸的长度并具有实验式(Arg)l;(Lys)m;(His)n;(Orn)o;(Xaa)x。具体疾病的治疗和/或预防典型地取决于由本发明的复合RNA的RNA编码的合适蛋白质的选择。治疗在该上下文中可以通过施用按照本发明的复合RNA(编码该蛋白)本身或通过施用如上定义的按照本发明的(药物)组合物来进行。
不受限于此,疾病或状态在该上下文中包括,例如,癌症或肿瘤疾病,所述癌症或肿瘤疾病选自黑素瘤,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(mammarycarcinomas=breastcancer)),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,多样(divese)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(cervixcarcinoma=cervicalcancer),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,acusticusneurinoma,肺癌(lungcarcinomas=lungcancer=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,睾丸癌,甲状腺癌,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(corpuscarcinoma),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(oesophagealcarcinoma=oesophagealcancer),疣病症,小肠瘤,颅咽管瘤,卵巢癌,软组织瘤,卵巢癌(ovariancancer=ovariancarcinoma),胰腺癌(pancreaticcarcinoma=pancreaticcancer),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。
疾病或状态在该上下文中还可以包括传染病,其选自,例如病毒性传染病,选自,不仅限于,SARS,黄热病,莱姆病,炭疽,AIDS,尖锐湿疣,传染性软疣,登革热,三日热,埃博拉病毒,感冒,早夏脑膜脑炎(ESME),流感,带状疱疹,肝炎,单纯疱疹I型,单纯疱疹II型,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,诺沃克病毒感染,传染性单核白细胞增多症,天花,脊髓灰质炎(polio或poliomyelitis),假性哮吼症(pseuodcroup),传染性红斑,狂犬病,疣,西尼罗热,水痘,巨细胞病毒(CMV),细菌性传染病,诸如流产(前列腺炎),炭疽,阑尾炎(盲肠炎),包柔螺旋体病,肉毒中毒,弯曲杆菌属,沙眼衣原体(尿道炎,结膜炎),霍乱,白喉,腹股沟肉芽肿(donavonosis),会厌炎,louse-bornetyphus,伤寒热,气性坏疽,淋病(gonorrhoea),兔瘟,幽门螺杆菌,百日咳,性病性淋巴肉芽肿(climaticbubo),骨髓炎,军团病,麻风,李希特菌病,肺炎,脑膜炎,细菌性脑膜炎,炭疽,中耳炎,人型支原体(Mycoplasmahominis),新生儿脓毒症(neonatalsepsis)(绒膜羊膜炎),坏疽性口炎,副伤寒(paratyphoidfever),鼠疫,赖特综合征,洛矶山斑疹热(RockyMountainspottedfever),沙门氏菌属副伤寒,沙门氏菌属伤寒热,猩红热,梅毒,破伤风,淋病,恙虫热,结核病,斑疹伤寒,阴道炎(vaginitis或colpitis),软下疳和由寄生虫、原生动物或真菌引起的传染病,诸如阿米巴痢疾,裂体吸虫病,恰加斯病,棘球绦虫属,阔节裂头绦虫,鱼卵中毒(鱼肉毒),狐绦虫(foxtapeworm),足癣(mycosispedis),犬绦虫,candiosis,ptyriasis,痒病(疥疮),利什曼病,皮肤利什曼病,鞭毛虫痢疾(lambliandysentery)(贾第鞭毛虫病(giadiasis)),虱,疟疾,显微术,盘尾丝虫病(河盲(riverblindness)),真菌性疾病,牛肉绦虫,血吸虫病,昏睡症,猪肉绦虫,弓形体病,毛滴虫病,锥虫病(昏睡症),内脏利什曼病,尿布皮炎或短小绦虫。
本发明上下文中的疾病同样包括,但不仅限于,由选自但不仅限于以下各项的病毒引起的(传染性)病毒疾病:HIV,正痘天花病毒,正痘类天花病毒,parapoxovis病毒,传染性软疣病毒,单纯疱疹病毒1,单纯疱疹病毒2,B型疱疹病毒,水痘带状病毒,假性狂犬病病毒,人巨细胞(cytomegaly)病毒,人疱疹病毒6,人疱疹病毒7,EB病毒,人疱疹病毒8,乙型肝炎病毒,屈曲病毒,奥尼翁-尼翁病毒,风疹病毒,丙型肝炎病毒,GB病毒C,西尼罗病毒,登革热病毒,黄热病病毒,羊跳跃病病毒,圣路易型脑炎病毒,日本乙型脑炎病毒,波瓦生病毒,FSME病毒,SARS相关的冠状病毒,人冠状病毒229E,人冠状病毒Oc43,环状病毒,人T细胞嗜淋巴病毒I型,人T细胞嗜淋巴病毒II型,人免疫缺陷病毒1型,人免疫缺陷病毒2型,拉沙病毒,淋巴细胞性脉络丛脑膜炎病毒,Tacaribe病毒,胡宁(Junin)病毒,马丘波(Machupo)病毒,伯纳病病毒,布尼安姆维拉(Bunyamwera)病毒,加利福尼亚脑炎病毒,裂谷热病毒,白蛉热病毒,托斯卡纳(Toscana)病毒,克里米亚出血热病毒,哈扎拉(Hazara)病毒,Khasan病毒,汉滩病毒,首尔病毒,ProspectHill病毒,普马拉(Puumala)病毒,多布拉伐贝尔格莱德(DobravaBelgrade)病毒,图拉(Tula)病毒,欣诺柏(sinnombre)病毒,维多利亚湖马尔堡(LakeVictoriaMarburg)病毒,扎伊尔依波拉病毒,苏丹依波拉病毒,象牙海岸依波拉病毒,流感病毒A,流感病毒B,流感病毒C,副流感病毒,麻疹病毒,流行性腮腺炎病毒,呼吸道合胞体病毒,人肺炎后病毒(humanmetapneumovirus),印地安泡状口炎病毒,狂犬病病毒,莫可拉(Mokola)病毒,杜温哈格(Duvenhage)病毒,欧洲蝙蝠狂犬病病毒1+2,澳洲蝙蝠狂犬病病毒,腺病毒A-F,人乳头瘤病毒,湿疣病毒6,湿疣病毒11,多瘤病毒,腺相关病毒2,轮状病毒,或环状病毒等。这些疾病可以例如由按照本发明的疫苗治疗。
另外,疾病或状态可以包括心血管病,其选自,但不仅限于,冠心病,动脉粥样硬化,卒中和高血压,和神经元疾病,其选自阿尔茨海默病,肌萎缩性(脊髓)侧索硬化,(肌)张力障碍,癫痫,多发性硬化症和帕金森症等。
疾病或状态在该上下文中还可以包括过敏性病症或疾病。过敏是典型涉及对某些外来抗原或过敏原的异常获得性免疫学超敏性的病症。过敏通常导致针对这些抗原或过敏原的局部或全身性炎性反应并在身体中引起针对这些过敏原的免疫性。过敏原在该上下文中包括例如草、花粉、霉菌、药物、或许多环境引发物,等。不限于任何理论,认为若干不同的疾病机制参与过敏的发展。根据P.Gell和R.Coombs的分类表,词语“过敏”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,从而导致全身性炎性反应,所述全身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,提供例如药物组合物,其包含例如编码过敏原(例如来自猫过敏原、尘土过敏原,螨类抗原、植物抗原(例如桦树抗原)等)的RNA作为本发明的复合物。由此,编码的过敏原可以脱敏患者的免疫反应。备选地,本发明的药物组合物可以使(过度)免疫反应移动到较强的TH1反应,由此抑制或削弱患病患者的不理想IgE反应。
此外,如本文中定义的疾病或状态可包括自身免疫疾病。自身免疫疾病可以广泛地分为全身性和器官特异性或局部自身免疫病症,这取决于每种疾病的主要临床病理学特性。自身免疫疾病可以分为以下种类:全身性综合征,包括系统性红斑狼疮,斯耶格伦综合征,硬皮病,类风湿性关节炎和多肌炎或局部综合征,其可以是内分泌的(糖尿病1型,桥本甲状腺炎,艾迪生病,等),皮肤的(天疱疮vulgaris),血液的(自身免疫溶血性贫血),神经的(多发性硬化)或可以实质上涉及任何边界清晰的体组织肿块。待治疗的自身免疫疾病可以选自由以下各项组成的组:I型自身免疫疾病或II型自身免疫疾病或III型自身免疫疾病或IV型自身免疫疾病,诸如,例如,多发性硬化(MS),类风湿性关节炎,糖尿病,I型糖尿病(糖尿病),系统性红斑狼疮(SLE),慢性多关节炎,巴塞多病,慢性肝炎的自身免疫形式,溃疡性结肠炎(colitisulcerosa),I型过敏疾病,II型过敏疾病,III型过敏疾病,IV型过敏疾病,纤维肌痛(fibromyalgia),脱发,别赫捷列夫病,局限性回肠炎,重症肌无力,神经性皮炎,多肌痛风湿病,进行性系统硬皮病(PSS),银屑病,赖特综合征,风湿性关节炎,银屑病,脉管炎,等,或II型糖尿病。
尽管至今尚未阐明关于免疫系统为什么诱导针对自身抗原的免疫反应的准确模式,但是存在若干关于病因学的发现。因此,自身反应可以归因于T细胞绕道。正常的免疫系统需要在B细胞可以产生大量抗体前,由T细胞激活B细胞。这种T细胞的需要在非常少的情形中,例如由生成超-抗原的生物体引起的感染中可以绕开,所述超抗原能够通过以非特异性方式直接结合T细胞受体的β-亚单元来起始B细胞,或者甚至T细胞的多克隆活化。另一种解释由分子拟态推理自身免疫疾病。外源性抗原可以与某些宿主抗原共享结构相似性;因此,针对该抗原(其模拟自身抗原)产生的任何抗体也可以,在理论上,结合宿主抗原并增强免疫反应。分子拟态的最显著形式在A组β溶血链球菌中观察到,其与人心肌共享抗原,并负责风湿热的心脏表现。本发明因此容许提供编码自身抗原的RNA作为本发明的复合RNA(或包含所述本发明复合RNA的(液体)组合物)的组分或提供包含自身抗原(如编码自身抗原蛋白的蛋白、mRNA或DNA)和本发明的复合RNA的药物组合物,其全部典型地容许脱敏免疫系统。
最后,待治疗的疾病在本发明的上下文中同样包括单基因病,即(遗传性(hereditary))病,或通常的遗传病(geneticdiseases)。所述遗传病典型地由遗传缺陷引起,例如归因于导致蛋白活性失去的基因突变或不容许蛋白质转录或翻译的调节性突变。经常地,这些疾病导致代谢病症或其他症状,例如肌肉营养不良。因此,本发明通过提供如本文中定义的复合RNA容许治疗这些疾病。目前,可以治疗以下疾病:3-β-羟化类固醇脱氢酶缺乏症(II型);3-酮硫解酶缺乏症;6-巯基嘌呤过敏;阿-斯综合征;血(内)β-脂蛋白缺乏症;缺过氧化氢酶血症;软骨成长不全;软骨成长不全-hypochondrogenesis;软骨发育不全;全色盲;Acromesomelic发育不良(亨特-汤普森(Hunter-Thompson)型);ACTH缺乏症;酰基辅酶A脱氢酶缺乏症(短链,中链,长链);腺瘤性结肠息肉;腺苷脱氨酶缺乏症;腺苷酸琥珀酸酶缺乏症;Adhalinopathy;肾上腺增生,先天性的(由于11-β-羟化酶缺乏症;由于17-α-羟化酶缺乏症;由于21-羟化酶缺乏症);肾上腺发育不良,先天性的,具有促性腺激素分泌不足性性腺功能减退;肾上腺生殖综合征;肾上腺脑白质营养不良;肾上腺脊髓神经病(Adrenomyeloneuropathy);纤维蛋白原缺乏血症;丙球蛋白缺乏血症;阿拉惹综合征;白化病(棕色,眼的,眼皮的,红褐色);酒精不耐症,急性的;醛缩酶A缺乏症;醛固酮过多症,糖皮质类固醇-可补救的;亚历山大病;尿黑酸尿;普遍性脱发(Alopeciauniversalis);α-1-抗胰凝乳蛋白酶缺乏症;α-甲基酰基-CoA消旋酶缺乏症;α地中海贫血/精神发育迟缓综合征;Alport综合征;阿尔茨海默症-1(APP-相关的);阿尔茨海默症-3;阿尔茨海默症-4;釉质生长不全;淀粉样神经病(家族型,若干等位基因型);淀粉样变(Dutch型;Finnish型;遗传性肾的;肾的;老年系统的(senilesystemic));肌萎缩性侧索硬化(Amytrophiclateralsclerosis);清蛋白缺乏血症;雄激素不敏感;贫血(戴-布贫血);贫血(溶血性的,由于PK缺乏);贫血(溶血性的,Rh-无效的,抑制型);贫血(新生儿溶血性的,致命的和接近致命的);贫血(成高铁红细胞的,伴随运动失调);贫血(成高铁红细胞的/血红蛋白过少的);由于G6PD缺乏症的贫血;动脉瘤(家族性动脉的);安吉尔曼综合征;血管性水肿;无虹膜;前段异常和内障(Anteriorsegmentanomaliesandcataract);前段间充质发育不全;前段间充质发育不全和白内障;抗凝血酶III缺乏症;与焦虑相关的个性品质;阿佩尔综合征;窒息(麻醉后);ApoA-I和apoC-III缺乏症(组合的);载脂蛋白A-II缺乏症;载脂蛋白B-100(配体-缺陷的);明显盐皮质激素过剩(由于高血压);精氨酸血症;精氨琥珀酸尿症;关节病(儿童进行性假风湿病);天冬氨酰氨基葡糖尿;运动失调(短暂的);伴有单独的维生素E缺乏症的运动失调;运动失调-毛细管扩张;AtelosteogenesisII;ATP-依赖性DNA连接酶I缺乏症;伴有房室传导缺陷的房中隔缺陷,伴有丘疹病灶的毛发缺乏;孤独症(琥珀酰嘌呤血症的);自身免疫多腺病I型;自主性神经系统功能障碍;阿克森费尔德异常;无精子症;Bamforth-Lazarus综合征;Bannayan-Zonana综合征;Barth综合征;巴特综合征(2型或3型);基底细胞癌;基底细胞痣综合征;BCG感染;Beare-Stevensoncutisgyrata综合征;贝克尔(Becker)肌营养不良;伯-韦综合征;伯-苏综合征(B型;C型);Bethlem肌病;胆酸吸收障碍,原发性的;生物素酶缺乏症;膀胱癌;由于缺陷性血栓烷A2受体的出血症;布卢姆综合征;指(趾)过短(B1型或C型);Branchiootic综合征;Branchiootorenal综合征;乳腺癌(入侵性管内的;小叶的;雄性的,伴有赖芬斯坦综合征;偶发的);乳腺癌-1(早期发作);乳腺癌-2(早期发作);Brody肌病;Brugada综合征;Brunner综合征;伯基特淋巴瘤;蝴蝶营养不良(Butterflydystrophy)(视网膜的);C1q缺乏症(A型;B型;C型);C1r/C1s缺乏症;C1s缺乏症,单独的;C2缺乏症;C3缺乏症;C3b灭活剂缺乏症;C4缺乏症;C8缺乏症,II型;C9缺乏症;伴有常染色体性转换的Campomelic发育不良;屈曲指-关节病-髋varapericarditis综合征;卡纳范病;氨甲酰基磷酸合成酶I缺乏症;缺乏碳水化合物的糖蛋白综合征(I型;Ib型;II型);肺的类癌瘤;心脑肌病(Cardioencephalomyopathy)(致死婴儿的,由于细胞色素c氧化酶缺乏症);心肌病(膨胀的;X-连锁膨胀的;家族性肥大的;肥大的);肉碱缺乏症(系统性原发的);肉碱-酰基肉碱移位酶缺乏症;腕管综合征(家族性的);白内障(蔚蓝色的;先天的;晶体皮刺状的;青年发作;多形态的和薄片状的;点状的;板层的粉状的);内障,Coppock样;CD59缺乏症;中央轴突症(centralcoredisease);小脑运动失调;大脑淀粉样血管病;伴有皮层下梗死的大脑动脉病和脑白质病;大脑多孔状畸形-1;Cerebrooculofacioskeletal综合征;脑腱黄瘤病;脑血管疾病;蜡样质脂褐质沉积症(神经细胞的,不同青少年型,伴有粒状嗜锇沉积(granularosmiophilicdeposits));蜡样质脂褐质沉积症(神经细胞-1,婴儿的);蜡样质脂褐质沉积症(神经细胞-3,青少年的);Char综合征;进行性神经病性肌萎缩;进行性神经病性肌神经病(Charcot-Marie-Toothneuropathy);Charlevoix-Saguenay型;谢迪亚克-东综合征;氯化物腹泻(Chloridediarrhea)(Finnish型);胆汁郁积(良性的复发的肝内的);胆汁郁积(家族性肝内);胆汁郁积(进行性家族性肝内);胆甾烯基酯贮存病;软骨发育不良punctata(brachytelephalangic;肢根的;X-连锁显性;X-连锁隐性;Grebe型);软骨肉瘤;无脉络膜;慢性肉芽肿病(常染色体的,由于缺乏CYBA);慢性肉芽肿病(X-连锁);由于缺乏NCF-1引起的慢性肉芽肿病;由于缺乏NCF-2引起的慢性肉芽肿病症;乳糜微粒血综合征,家族性的;瓜氨酸血症;经典科克因综合征-1;唇裂,颌裂,腭裂;唇/腭裂外胚层发育不良综合征;锁骨头颅发育不良;CMOII缺乏症;渗出性视网膜病;科克因综合征-2,B型;科-洛综合征;秋水仙素抵抗;结肠腺癌;结肠癌;色盲(绿色盲;红色盲;蓝色盲);结肠直肠癌;联合因子V和VIII缺乏症;联合高脂血症(家族性);联合免疫缺陷(X-连锁,中度);复合物I缺乏症;复合神经病症(Complexneurologicdisorder);锥营养不良-3;锥-杆营养不良3;锥-杆营养不良6;锥-杆视网膜营养不良-2;先天性双侧输精管缺乏;木样结膜炎;挛缩性细长指(趾);粪卟啉症;先天性扁平角膜;角膜混浊;角膜营养不良(Avellino型;凝胶滴样;格雷诺I型;晶格I型;Reis-Bucklers型);皮质醇抵抗;香豆素抵抗;考登病;CPT缺乏症,肝的(I型,II型);痛性痉挛(家族性,钾-恶化的);颅面-聋症-手综合征;颅缝早闭(2型);呆小病;克罗伊茨费尔特-雅各布综合征;克-奈综合征;颅面骨发育不全综合征;Currarino综合征;皮肤松弛;周期性血生成;周期性鱼鳞病;Cylindromatosis;囊纤维变性;胱氨酸病(肾病的);胱氨酸尿(II型;III型);道尔顿症;毛囊角化病;D-双功能蛋白缺乏症;聋症,常染色体显性1;聋症,常染色体显性11;聋症,常染色体显性12;聋症,常染色体显性15;聋症,常染色体显性2;聋症,常染色体显性3;聋症,常染色体显性5;聋症,常染色体显性8;聋症,常染色体显性9;聋症,常染色体隐性1;聋症,常染色体隐性2;聋症,常染色体隐性21;聋症,常染色体隐性3;聋症,常染色体隐性4;聋症,常染色体隐性9;聋症,非综合征性感觉神经性13;聋症,X-连锁1;聋症,X-连锁3;异喹胍敏感;进行性肥大性间质性神经病;痴呆(家族性Danish);痴呆(额颞骨的,伴有帕金森病);Dent病;牙异常;齿状核红核苍白球路易氏体(Dentatorubro-pallidoluysian)萎缩;Denys-Drash综合征;隆突性皮肤纤维肉瘤;硬纤维瘤病;尿崩症(肾原性的);尿崩症(神经垂体的);糖尿病(胰岛素-抵抗的);糖尿病(罕见形式);糖尿病(II型);畸形发育不良;二氢嘧啶尿症(Dihydropyrimidinuria);剂量-敏感的性转换;多英蜂窝状视网膜退化;杜-约综合征;杜兴肌营养不良;伴有血小板减少症的异常红细胞生成性(Dyserythropoietic)贫血;异常纤维蛋白原血症(α型;β型;γ型);先天性角化不良-1;Dysprothrombinemia;肌张力障碍(DOPA反应性);肌张力障碍(肌阵挛的);肌张力障碍-1(扭转);外胚层发育不良;晶状体异位;瞳孔异位;缺指(趾)畸形(外胚层发育不良和唇/腭裂综合征3);埃勒斯-当洛斯综合征(progeroid型);埃勒斯-当洛斯综合征(I型;II型;型III;IV型;VI型;VII型);弹性蛋白瓣膜上主动脉瓣狭窄;椭圆形红细胞增多症-1;椭圆形红细胞增多症-2;椭圆形红细胞增多症-3;埃-克综合征;埃-德肌营养不良;肺气肿;脑病;心内膜弹力纤维病-2;子宫内膜癌;终板乙酰胆碱酯酶缺乏症;增强的S-视锥综合征;前庭导水管扩大;大疱性表皮松懈;营养不良性大疱性表皮松懈(显性或隐性);单纯性大疱性表皮松懈;表皮松懈性角化过度;表皮松懈性掌跖(palmoplantar)角皮病;癫痫(一般的;青少年;肌阵挛;夜间额叶;进行性肌阵挛);癫痫,良性的,新生儿的(1型或2型);骺发育不良(多发性);短暂运动失调(2型);短暂运动失调/肌纤维颤搐综合征;红细胞增多症(α-;发育不良);红细胞增多症;红斑角皮病;雌激素抵抗;由于缺乏LDH-A引起的劳累性肌红蛋白尿;多发性外生骨疣,(1型;2型);渗出性玻璃体视网膜病,X-连锁的;法布莱病;H因子缺乏症;VII因子缺乏症;X因子缺乏症;XI因子缺乏症;XII因子缺乏症;XIIIA因子缺乏症;XIIIB因子缺乏症;家族性地中海热;范科尼贫血;Fanconi-Bickel综合征;法伯脂肪肉芽肿病;脂肪肝(急性);蚕豆病;白点(Fish-eye)病;Foveal发育不良;脆性(Fragile)X综合征;Frasier综合征;弗里德赖希共济失调;果糖二磷酸酶果糖不耐症;岩藻糖苷病;延胡索酸酶缺乏症;眼底白斑症(Fundusalbipunctatus);眼底黄斑症(Fundusflavimaculatus);G6PD缺乏症;GABA-转氨酶缺乏症;伴有内障的半乳糖激酶缺乏症;半乳糖表异构酶缺乏症;半乳糖血症;半乳糖唾液酸沉积症;GAMT缺乏症;加德纳综合征;胃癌;戈谢病;伴有热性惊厥附加症的全面性癫痫;胚细胞瘤;格-施病;巨细胞肝炎(新生儿);巨血小板病症;巨细胞成纤维细胞瘤;Gitelman综合征;格兰茨曼血小板功能不全(A型;B型);青光眼1A;青光眼3A;多形性成胶质细胞瘤;肾小球硬化症(局灶性节段性(focalsegmental));葡萄糖转运缺陷(血脑屏障);葡萄糖/半乳糖吸收障碍;葡糖苷酶I缺乏症;戊二酸尿(I型;IIB型;IIC型);谷胱甘肽(Gluthation)合成酶缺乏症;甘油激酶缺乏症;甘氨酸受体(α-1多肽);糖原贮积病I型;糖原贮积病II型;糖原贮积病III型;糖原贮积病IV型;糖原贮积病VI型;糖原贮病VII型;糖原贮积病(肝的,常染色体的);糖原贮积病(X-连锁的肝的);GM1-神经节苷脂沉积症;GM2-神经节苷脂沉积症;甲状腺肿(青少年多结性);甲状腺肿(先天性);甲状腺肿(非地方性,单纯的);性腺发育不全(XY型);腐败性肉芽肿病;格雷夫斯病;Greigcephalopolysyndactyly综合征;格里塞利综合征;生长激素缺乏矮小症;伴有聋症和精神发育迟缓的生长发育迟缓;男子女性性乳房(家族性,由于增加的芳香酶活性);伴有鸟氨酸血的脉络膜和视网膜螺旋状萎缩(B6反应性或无反应性);Hailey-Hailey病;Haim-Munk综合征;手-足-子宫综合征;Harderoporphyrinuria;HDL缺乏症(家族性);心传导阻滞(非进行性或进行性);海因茨体贫血;HELLP综合征;血尿(家族良性);血红素加氧酶-缺乏症;偏瘫性偏头痛;血色素沉着症(Hemochromotosis);血红蛋白H病;由于ADA过量引起的溶血性贫血;由于缺乏腺苷酸激酶引起的溶血性贫血;由于带3(band3)缺陷引起的溶血性贫血;由于缺乏磷酸葡糖异构酶引起的溶血性贫血;由于缺乏谷胱甘肽合成酶引起的溶血性贫血;由于缺乏己糖激酶引起的溶血性贫血;由于缺乏PGK引起的溶血性贫血;溶血-尿毒症综合征;吞噬血细胞淋巴组织细胞病;血友病A;血友病B;由于缺乏V因子引起的出血性体质;含铁血黄素沉着(系统性的,由于无铜蓝蛋白血症(aceruloplasminemia));肝性脂酶缺乏症;肝胚细胞瘤;肝细胞癌;遗传性出血毛细管扩张-1;遗传性出血毛细管扩张-2;海-普综合征;内脏异位(X-连锁内脏的);异位(室周的);希佩尔-林道综合征;先天性巨结肠;由于缺乏HRG引起的富含组氨酸糖蛋白血栓形成倾向;HMG-CoA裂解酶缺乏症;前脑无裂畸形-2;前脑无裂畸形-3;前脑无裂畸形-4;前脑无裂畸形-5;霍-奥综合征;高胱氨酸尿;Hoyeraal-Hreidarsson;HPFH(缺陷型或非缺陷型);与HPRT有关的痛风;亨廷顿病;由于水管狭窄引起的脑积水;胎儿水肿;血β-脂蛋白过多;家族性血胆固醇过多;血铁蛋白过多(Hyperferritinemia)-内障综合征;血甘油过多;血甘氨酸过多;血免疫球蛋白过多D和周期性发热综合征;胰岛素分泌过多;胰岛素分泌过多-血氨过多综合征;血钾过多周期性麻痹;血脂蛋白过多;血赖氨酸过多;血蛋氨酸过多(持续的,常染色体,显性,由于甲硫氨酸,腺苷基转移酶I/III缺乏症);高鸟氨酸血-血氨过多瓜氨酸血症(Hypermethioninemiahomocitrullinemia)综合征;尿草酸盐过多;甲状旁腺功能亢进;由于缺乏蝶呤-4a甲醇胺(pterin-4acarbinolamine)脱水酶引起的血苯丙氨酸过多;血胰岛素原过多;血脯氨酸过多;高血压;甲状旁腺功能亢进(Hyperthroidism)(先天性);血甘油三酯过多;低α脂蛋白血;低β脂蛋白血;低钙血;季肋发育不全;血红蛋白过少性小红细胞贫血;牙发育不全;血纤维蛋白原过少;低珠蛋白血症(Hypoglobulinemia)和缺乏B细胞;性腺功能减退(促性腺激素过多的);促性腺激素分泌不足(性腺功能减退);低血钾周期性麻痹;血镁过少;髓磷脂形成减少(Hypomyelination)(先天性);甲状旁腺功能减退;磷酸酯酶过少(成人;儿童;婴儿;遗传的);血凝血酶原过少;甲状腺功能减退(先天性;先天性遗传;非甲状腺肿的);鳞癣状红皮病;鱼鳞病;Siemens大疱性鱼鳞病;IgG2缺乏症;Immotilecilia综合征-1;免疫缺陷(T-细胞受体/CD3复合物);免疫缺陷(X-连锁,伴有高-IgM);由于CD3-γ缺陷引起的免疫缺陷;免疫缺陷-着丝粒不稳定性面部异常综合征;色素失禁;疼痛不敏感(先天性,伴有无汗症);失眠(致命的家族性的);白细胞介素-2受体缺乏症(α链);锥间盘病;Iridogoniodysgenesis;单一性(Isolated)生长激素缺乏症(伴有缺乏GH的Illig型和伴有生物失活GH的Kowarski型);异戊酸血症;Jackson-Weiss综合征;晏森综合征;耶维尔-朗厄·尼尔逊综合征;儒贝尔综合征;Juberg-Marsidi综合征;卡尔曼综合征;Kanzaki病;角膜炎;角皮病(掌跖(palmoplantar));角化症病掌跖病纹状体(Keratosispalmoplantarisstriata)I;角化症病掌跖病纹状体II;由于缺乏SCOT引起的酮酸中毒;Keutel综合征;克-特综合征;Kniest发育不良;科斯曼中性白细胞减少症;克拉贝病;Kurzripp-Polydaktylie综合征;由于缺乏PDX1引起的乳酸血症;朗格肢中部发育不良;拉隆侏儒;劳伦斯-穆恩-比德尔-Bardet综合征;LCHAD缺乏症;勒伯尔先天性黑曚;左右轴畸形;利氏综合征;平滑肌瘤病(扩散的,伴有Alport综合征);矮妖精貌综合征;Leri-Weill软骨骨生成障碍;莱-尼综合征;白血病(急性骨髓的;急性早幼粒细胞的;急性T细胞淋巴母细胞的;慢性骨髓的;青少年骨髓单核细胞的;白血病-1(T-细胞急性淋巴细胞的);白细胞粘连缺乏症;莱迪希细胞腺瘤;莱尔米特-Duclos综合征;Liddle综合征;Li-Fraumeni综合征;硫辛酰胺脱氢酶缺乏症;脂肪营养不良;类脂肾上腺增生;脂蛋白脂酶缺乏症;无脑回(X-连锁的);无脑回-1;肝糖原贮存病(O型);长QT综合征-1;长QT综合征-2;长QT综合征-3;长QT综合征-5;长QT综合征-6;洛氏综合征;肺癌;肺癌(小细胞);肺癌(小细胞);淋巴水肿;淋巴瘤(B细胞非霍奇金);淋巴瘤(弥漫性大细胞);淋巴瘤(滤泡性);淋巴瘤(MALT);淋巴瘤(套细胞);淋巴组织增生综合征(X-连锁的);赖氨酸尿蛋白不耐症;神经系统亚速尔病;顽固性巨红细胞贫血(5q综合征的);斑(Macular)营养不良;恶性间皮瘤;丙二酸单酰辅酶A脱羧酶缺乏症;甘露糖苷过多症,(α或β);槭糖尿病(Maplesyrupurinedisease)(Ia型;Ib型;II型);马方综合征;马洛托-拉梅综合征;Marshall综合征;MASA综合征;肥大细胞白血病;伴有相关血液病的肥大细胞增生病;麦卡德病;麦-奥多骨纤维发育不良;麦-考综合征;McLeod表现型;髓状甲状腺癌;成神经管细胞瘤;Meesmann角膜营养不良;巨成红细胞贫血-1;黑素瘤;膜增生性(Membroproliferative)肾小球肾炎;梅尼埃病;脑膜瘤(NF2-相关的;SIS-相关的);门克士病;精神发育迟缓(X-连锁的);Mephenytoinpoormetabolizer;间皮瘤;异染性脑白质营养不良;干骺端软骨发育不良(MurkJansen型;Schmid型);高铁血红蛋白血症;甲硫氨酸腺苷基转移酶缺乏症(常染色体隐性);甲钴胺缺乏症(cblG型);甲基丙二酸尿症(变位酶缺乏型);甲羟戊酸尿症;MHCII型缺乏症;小眼(内障和虹膜异常);Miyoshi肌病;MODY;Mohr-Tranebjaerg综合征;钼辅助因子缺乏症(A型或B型);串珠形发;法布莱病;戈谢病(MorbusGaucher);粘多糖病;粘稠物阻塞症;Muencke综合征;缪-托综合征;Mulibrey侏儒症;多发性羧化酶缺乏症(生物素反应性);多发性内分泌腺瘤形成;肌糖原贮积病;肌营养不良(先天性merosindeficient);肌营养不良(福山型先天性);肌营养不良(肢带);肌营养不良)杜兴型);伴有单纯性大疱性表皮松懈的肌营养不良;肌无力综合征(慢通道先天性);分支杆菌感染(非典型,家族性,弥散性);脊髓发育不良综合征;骨髓性白血病;骨髓恶性肿瘤;髓过氧化物酶缺乏症;肌腺苷酸脱氨酶缺乏症;由于缺乏PGK引起的肌红蛋白尿/溶血;肌神经胃肠脑肌病(Myoneurogastrointestinalencephalomyopathy)综合征;肌病(肌动蛋白;先天性;结合蛋白-相关的;心骨的(cardioskeletal);远侧的;杆状体的);由于缺乏CPTII引起的肌病;由于缺乏磷酸甘油酸变位酶引起的肌病;先天性肌强直;levior肌强直;肌强直性营养不良;粘液样脂肉瘤;NAGA缺乏症;指甲髌骨(Nailpatella)综合征;杆状体肌病1(常染色体显性);杆状体肌病2(常染色体隐性);新生儿甲状旁腺功能亢进;肾石病;肾消耗病(青少年);肾病(慢性低补体血症的);肾变病-1;肾变病综合征;内塞顿综合征;成神经细胞瘤;神经纤维瘤病(1型或2型);神经鞘瘤病(Neurolemmomatosis);神经元-5蜡样质脂褐质沉积症;神经病;中性白细胞减少(新生儿同种免疫);尼曼-皮克病(A型;B型;C1型;D型);夜盲症(先天性静止性的);Nijmegenbreakage综合征;左心室心肌的Noncompaction;非表皮松懈性palmoplantar角皮病;诺里病;Norum病;核苷酸磷酸化酶缺乏症;肥胖症;枕骨角综合征;眼白化病(内-福型);Oculopharyngeal肌营养不良;小口病;少牙;奥曼综合征;奥皮茨G综合征;伴有肾病的眼神经缺损;鸟氨酸转氨甲酰酶缺乏症;乳清酸尿;直立不耐症;OSMED综合征;脊骨后纵韧带骨化;骨关节病;成骨不全;骨质溶解;骨硬化症(隐性或自发的);骨肉瘤;卵巢癌;卵巢发育不全;先天性甲肥厚(Jackson-Lawler型或Jadassohn-Lewandowsky型);骨佩吉特病;Pallister-Hall综合征;胰腺发育不全;胰管癌;胰腺炎;巴-勒综合征;神经节细胞瘤;先天性肌强直病;Parietalforamina;帕金森病(家族性或青少年);阵发性睡眠性血红蛋白尿(Paroxysmalnocturnalhemoglobinuria);家族性中叶性硬化;彭德莱综合征;会阴部尿道下裂;间发性发热;过氧物酶体生物发生紊乱;幼年持续性血胰岛素过多性低血糖;持续的副中肾管综合征(II型);彼得斯性异常;佩-吉综合征;Pfeiffersyndrome;苯丙酮尿症;磷酸核糖焦磷酸合成酶相关的痛风;肝和肌肉的磷酸化酶激酶缺乏症;斑驳;毛母质瘤;伴随两侧成视网膜细胞瘤的松果体瘤;垂体促肾上腺皮质激素分泌腺瘤;垂体激素缺乏症;垂体瘤;胎盘类固醇硫酸酯酶缺乏症;血浆酶抑制剂缺乏症;纤维蛋白溶酶原缺乏症(I型和II型);纤维蛋白溶酶原Tochigi病;血小板病(plateletdisorder);血小板糖蛋白IV缺乏症;血小板-活化因子乙酰基水解酶缺乏症;多囊肾病;伴随硬化性leukenencephalophathy的多囊性脂膜(lipomembranous)骨发育异常;多指症,轴后的;息肉病;腘翼状胬肉综合征(Poplitealpterygiumsyndrome);卟啉症(急性肝性或急性间歇性或先天性红细胞生成的);Porphyriacutaneatarda;肝红细胞生成的卟啉症;(Porphyriahepatoerythropoietic);Porphyriavariegata;普-威综合征;青春期早熟;卵巢早熟缺乏;I型早老症;II型早老症;进行性外眼肌麻痹;进行性肝内胆汁郁积-2;泌乳素瘤(甲状旁腺功能亢进,类癌的综合征);氨酰基脯氨酸酶缺乏症;丙酸血;前列腺癌;蛋白质S缺乏症;蛋白尿;原卟啉症(红细胞生成的);假性软骨发育不全;假两性畸形;假性醛固酮减少症;假性甲状旁腺功能减退症;假性阴道的,会阴阴囊的尿道下裂;假性维生素D缺乏症佝偻病;弹力纤维性假黄瘤(Pseudoxanthomaelasticum)(常染色体显性的;常染色体隐性的);肺小泡蛋白沉积症;肺高压;暴发性紫癜(Purpurafulminans);致密性骨发育不全;Pyropoikilocytosis;丙酮酸羧化酶缺乏症;丙酮酸脱氢酶缺乏症;Rabson-Mendenhall综合征;雷弗素姆病;肾细胞癌;肾小管性酸中毒;伴随聋症的肾小管性酸中毒;肾小管酸中毒-骨硬化综合征;网状细胞增多症(家族性组织细胞的);视网膜退化;视网膜发育不良;retinitispigmentosa;白点状视网膜变性(Retinitispunctataalbescens);成视网膜细胞瘤;视黄醇结合蛋白缺乏症;视网膜劈裂症;雷特综合征;Rh(mod)综合征;杆状素质综合征(Rhabdoidpredispositionsyndrome);杆状瘤;横纹肌肉瘤;横纹肌肉瘤(小泡的);肢根点状软骨营养不良(Rhizomelicchondrodysplasiapunctata);Ribbing-Syndrom;佝偻病(抗维生素D的);里格异常;罗宾诺综合征;罗-汤综合征;Rubenstein-Taybi综合征;酵母氨酸尿症;塞-科综合征;Salla病;桑霍夫病(婴儿期,青少年,和成年形式);桑菲利波综合征(A型或B型);Schindler病;脑裂;精神分裂症(慢性的);神经鞘瘤(偶发性的);SCID(常染色体隐性,T-阴性的/B-阳性的类型);分泌性路径w/TMD;先天性SED;Segawa综合征;选择性T-细胞缺陷;SEMD(巴基斯坦型);SEMD(Strudwick型);Septooptic发育不良;严重结合的免疫缺乏症(B细胞阴性的);严重结合性免疫缺乏症(T-细胞阴性的,B-细胞/天然杀伤细胞-阳性类型);严重结合的免疫缺乏症(X-连锁);由于ADA缺乏症的严重结合的免疫缺乏症;性转换(XY,伴随肾上腺衰竭的(adrenalfailure));赛塞利综合征(Sezarysyndrome);Shah-Waardenburg综合征;身材矮小;Shprintzen-Goldberg综合征;唾液酸贮积病;唾液酸沉积症(I型或II型);Sialuria;镰刀型细胞贫血;Simpson-Golabi-Behmel综合征;Situsambiguus;斯-拉综合征;Smith-Fineman-Myers综合征;史-莱-奥综合征(I型或II型);Somatotrophinoma;索斯比基底营养不良(Sorsbyfundusdystrophy);强直性截瘫;球形红细胞症;球形红细胞症-1;球形红细胞症-2;肯尼迪脊柱和延髓肌萎缩;脊柱肌萎缩;脊髓小脑运动失调;脊椎肋骨发育不全(Spondylocostaldysostosis);迟发性骨骺发育不良(Spondyloepiphysealdysplasiatarda);脊柱干骺端发育不良(日本型);施塔加特病-1;多发性皮脂囊肿;Stickler综合征;斯特奇综合征;皮层下板状两眼不等视(Subcorticallaminalheteropia);皮层下层异位;琥珀酸半醛脱氢酶缺乏症;蔗糖不耐症;Sutherland-Haan综合征;无CF的出汗性氯化物升高(SweatchlorideelevationwithoutCF);指关节粘连;骨性联接综合征;Synpolydactyly;丹吉尔病;泰-萨病;急性T-细胞成淋巴细胞的白血病;T-细胞免疫缺乏症;T-细胞前淋巴细胞的白血病;珠蛋白生成障碍性贫血(α或β);由于HbLepore的珠蛋白生成障碍性贫血;致命性发育不良(I型或II型);硫胺-响应的巨成红细胞的贫血综合征;血小板增多;血栓形成倾向(dysplasminogenemic);由于肝素辅因子II缺乏症引起的血栓形成倾向;由于蛋白C缺乏症引起的血栓形成倾向;由于血栓调节素缺陷引起的血栓形成倾向;甲状腺腺瘤;甲状腺激素抗性;甲状腺碘过氧物酶缺乏症;蒂策综合征;1-丁基3-对甲苯磺酰基脲慢代谢型(Tolbutamidepoormetabolizer);Townes-Brocks综合征;运钴胺素II缺乏症;下颌面骨发育不全(TreacherCollinsmandibulofacialdysostosis);Trichodontoosseous综合征;毛发-鼻-指(趾)综合征(Trichorhinophalangealsyndrome);毛发硫营养不良;三功能蛋白酶缺乏症(Trifunctionalproteindeficiency)(I型或II型);胰蛋白酶原缺乏症;结节状硬化-1;结节状硬化-2;蒂尔柯综合征;酪氨酸磷酸酶;酪氨酸血症;Ulnar-mammary综合征;尿石病(2,8-二羟基腺嘌呤);厄舍尔综合征(1B型或2A型);静脉畸形;室性心动过速;女子男性化;微生素K-依赖性凝固缺陷;VLCAD缺乏症;沃温凯尔综合征;希佩尔-林道综合征(vonHippel-Lindausyndrome);冯威勒布兰特病;瓦登伯格综合征;瓦登伯格综合征/眼白化病;Waardenburg-Shahneurologicvariant;瓦登伯格-Shah综合征;胶状粟粒疹;华法林(Warfarin)过敏;Watson综合征;Weissenbacher-Zweymuller综合征;维尔纳综合征;Weyersacrodental骨发育障碍;怀特海棉状痣;Williams-Beuren综合征;维尔姆斯瘤(1型);肝豆状核变性(Wilsondisease);威-奥综合征;Wolcott-Rallison综合征;沃尔弗拉姆综合征;渥尔曼病;黄嘌呤尿(I型);着色性干皮病;X-SCID;也门聋盲色素减退综合征;ypocalciuric高钙血症(I型);泽尔韦格综合征(Zellwegersyndrome);Zlotogora-Ogur综合征。
具有遗传继承的背景并典型地由单基因缺陷引起和按照Mendel法则继承的优选待治疗疾病优选选自由以下各项组成的组:常染色体隐性遗传病,诸如,例如,腺苷脱氨酶缺乏症,家族性高胆固醇血症,卡纳范病,Gaucher病,范科尼贫血症(Fanconianaemia),神经元蜡样质脂褐质沉积症,粘稠物阻塞症(囊性纤维变性),镰刀状细胞贫血症,苯丙酮尿症,尿黑酸尿,白化病,甲状腺功能减退,半乳糖血症(galactosaemia),α-1-抗-胰蛋白酶缺乏症,着色性干皮病,Ribbing综合征,粘多糖病,唇裂,颌裂(jew),腭裂(palate),劳伦斯-比德尔综合征,短肋多指(趾)综合征,呆小病,儒贝尔综合征,II型早老症,指(趾)过短(brachydactylia),adrenogenital综合征,和X染色体遗传病,诸如,例如,色盲,例如红/绿色盲,X染色体易损综合征,肌营养不良(Duchenne和Becker-Kiener型),血友病(haemophilia)A和B,G6PD缺乏症,法布莱病,粘多糖病,诺里综合征,视网膜炎pigmentosa,败血性肉芽肿病,X-SCID,鸟氨酸转氨甲酰酶缺乏症,莱-尼综合征,或来自常染色体-显性遗传病,诸如,例如遗传性angiooedema,Marfan综合征,神经纤维瘤病,I型早老症,成骨不全,克-特综合征,斯特奇-韦伯综合征,希佩尔-林道病综合征和结节状硬化。
本发明还容许治疗这样的疾病,其尚未遗传,或不能被总结到以上种类中。这样的疾病可以包括,例如治疗需要特定蛋白因子,例如如上提及的特定治疗活性蛋白的患者。这可以例如包括透析患者,例如经历(定期)肾(kidney或renal)透析,和可能需要如上定义的特定治疗活性蛋白,例如红细胞生成素(EPO)的患者,等。
按照另一个实施方案,本发明包括至少一种按照本发明的复合RNA用于转染细胞或生物体的用途。细胞或生物体的转染可以优选利用以上用于使用本发明的复合RNA转染细胞或组织的(体外或体内)转染方法来进行。
按照一个另外的实施方案,本发明包括至少一种按照本发明的复合RNA(用于制备试剂的)用于治疗任何以上提及的疾病、病症、状况或病理学状态的用途。试剂在该上下文中可以是例如如上定义的药物组合物或如本文中定义的注射缓冲液,其另外含有本发明的复合RNA,疫苗等。如果使用多于一种复合RNA分子类型,则复合RNA可以通过其RNA(分子)而不同,由此形成至少2种不同复合RNA(分子)类型的混合物。如果使用多于一种复合RNA(用于制备试剂的)治疗任何以上提及的疾病,则这些复合RNA混合物中可以包含相同或(至少2种)不同RNA(分子)类型。在该上下文中,任何以上提及的RNA(分子)可以用于本发明的复合RNA,例如短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,等。更优选地,可以使用编码RNA(分子),甚至更优选线性编码RNA(分子),和最优选mRNA。优选地,所述编码RNA(分子),更优选线性编码RNA(分子),和更优选mRNA用于所述复合RNA,该RNA(分子)典型地编码适合于特定疾病治疗的蛋白或肽,例如在治疗(特定)癌症时,能够结合特定癌症抗原或肿瘤抗原的抗体,等。合适的RNA(分子)的组合是本领域中技术人员已知的且由本发明的公开内容得知。
按照本发明的另一个实施方案,在治疗过程中(另外)引起,例如诱导或增强免疫反应可能是优选的。在该上下文中,免疫反应可以以多种方式发生。关于合适的免疫反应的基本因素是刺激不同的T细胞亚群。T淋巴细胞典型地分为2个亚群,即T辅助1(Th1)细胞和T辅助2(Th2)细胞,免疫系统使用它们能够破坏胞内(Th1)和胞外(Th2)病原体(例如抗原)。这两种Th细胞群在由它们产生的效应子蛋白(细胞因子)的模式中不同。因此,Th1细胞通过激活巨噬细胞和细胞毒性T细胞来协助细胞免疫反应。Th2细胞,在另一方面,通过刺激B细胞转变成浆细胞和通过形成抗体(例如针对抗原)来促进体液免疫反应。Th1/Th2比因此在免疫反应中非常重要。对于多种由本发明治疗的疾病,免疫反应的Th1/Th2比优选向细胞反应(Th1反应)的方向移动,并由此诱导细胞免疫反应。因此,本发明还可以用于逆转该免疫反应移动。因此,本发明还包括至少一种按照本发明的复合RNA(用于制备试剂的)用于治疗任何以上提及的疾病的用途,其中所述试剂(和/或所述复合RNA)能够在如上定义的组织和生物体中引起,例如诱导或增强免疫反应。此外,试剂在该上下文中可以是例如如上定义的药物组合物,或如本文中定义的注射缓冲液,其包含本发明的复合RNA,等。如果多于一种复合RNA在该上下文中(用于制备试剂的)用于治疗任何以上提及的疾病,则复合RNA类型可以关于它们的RNA(分子)而不同,且可以形成不同RNA类型的混合物。
然而,对于本实施方案,优选的是这些复合RNA中的至少一种在治疗过程中诱导或增强免疫反应,而其他复合RNA不需要诱导或增强免疫反应或可以用于防止免疫反应。在该上下文中,任何以上提及的RNA(分子)可以用于本发明的复合RNA,例如短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,等。更优选地,编码RNA(分子),甚至更优选线性编码RNA(分子),和最优选mRNA可以用于所述复合RNA。如果RNA(分子)是编码RNA(分子),更优选线性编码RNA(分子),和更优选mRNA,则其典型地编码适合于特定疾病治疗的蛋白或肽,例如在治疗(特定)癌症时,能够结合特定癌症抗原的抗体,等。如果该试剂中包含多于一种复合RNA,则可以选择蛋白或肽的不同组合。所述合适的RNA(分子)的组合(且,如果使用编码RNA,被编码蛋白或肽的组合)是本领域中技术人员已知的或可以由编码治疗有效蛋白的RNA组合,等,如本发明公开内容中定义地。与利用一种如上定义的药物组合物或试剂治疗特定疾病同时发生的免疫反应诱导或增强在这样的情形中可以是特别有利的,其中诱导或增强的免疫反应支持如上提及的特定疾病的治疗。
备选地,疾病的治疗和免疫反应的诱导或增强可以通过以时间交错的方式使用不同的如上定义的药物组合物或试剂来进行。例如人们可以通过施用如上定义的包含本发明的复合(免疫刺激性)RNA的药物组合物或试剂,随后(或同时)施用另一种如本文中定义的药物组合物或试剂,其可以包含本发明的复合RNA,例如短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,等,来诱导或增强免疫反应,这适合于治疗特定疾病。
按照一个实施方案,本发明还包括至少一种按照本发明的复合RNA(用于制备试剂的)用于在如上定义的组织或生物体内调节,优选用于诱导或增强免疫反应,更优选用于支持如本文中提及的疾病或状态的用途。
由此,本发明的复合RNA可以用于非特异性激活免疫系统,例如用于触发某些细胞因子的生成。所述复合RNA可以因此用于支持由例如源自病原体或肿瘤的抗原引起的特定免疫反应。试剂在该上下文中可以是例如如上定义的药物组合物或如本文中定义的注射缓冲剂,其包含本发明的复合RNA,疫苗,等。免疫反应可以由至少一种复合RNA调节,这归因于一种或多种具有8-15个氨基酸长度并显示实验式(Arg)l;(Lys)m;(His)n;(Orn)o;(Xaa)x的寡肽,和/或由复合RNA的RNA编码的蛋白的免疫刺激特性调节。
本发明因此可以,只要适合,充分起作用以实现多种目的。复合RNA本身或作为本发明组合物的组分可以通过其本身改善作为本发明复合物的组分的RNA的转染特性。本发明的复合RNA这种潜在特性有益于广泛多种的应用。当意欲将RNA引入细胞中时,改善的转染效率由本发明确保。该特性本身可以容许本发明被用于治疗大量多种的疾病,例如治疗如上定义的单基因病或遗传病。
另外,本发明可以在治疗免疫病症,例如研究过敏或自身免疫性疾病时使用。而且,本发明可以通过增强其非特异性或特异性免疫反应激活患者的免疫系统。因此,当适合时,其可以引起非特异性免疫反应,以治愈疾病。而且,当需要时,其自身(例如通过由作为本发明复合物的组分的RNA编码抗原)或通过本发明复合RNA与抗原组合,例如在相同组合物,可以引起特异性免疫反应。当需要时,本发明的复合RNA可以优选是抗原或抗体,或如上定义的任何其他蛋白或肽,其能够调节免疫反应(优选诱导或增强免疫反应或,在过敏或自身免疫性疾病的情形中,通过脱敏患者针对特异性过敏原或自身抗原的免疫系统)。为了调节,例如诱导或增强组织或生物体中的免疫反应,可以将所述复合RNA自身或作为如上定义的试剂施用于如上定义的该组织或生物体。可以使用的施药模式可以与以上关于药物组合物所述的相同。试剂的施用可以在治疗如本文中提及的疾病或状态之前,同时和/或之后,例如通过在治疗之前,同时和/或之后施用所述试剂或施用适合于这些疾病或状态的治疗剂来进行。
按照备选的实施方案,本发明还包括与如本文中定义的RNA(分子)复合的肽(Arg)7或单独的(Arg)7(用于制备试剂的)用于调节的用途,所述调节作用优选通过例如引发细胞因子的产生而在如上定义的组织或生物体中引起例如诱导或增强免疫反应,优选非特异性免疫反应,和优选用于忍耐如本文中提及的疾病或状态。在确定本发明通式(I)的肽的范围时,本发明人惊讶地发现(Arg)7能够显著诱导或增强hPBMCs中的免疫反应,即使没有观察到核酸,特别是RNA转染到hPBMCs中。RNA(分子)可以是如本文中定义的任何RNA(分子),优选,但不限于,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。而且,试剂在该上下文中可以是例如如上定义的药物组合物或如本文中定义的注射缓冲剂,其另外含有本发明的复合RNA等,其中在如本文中定义的试剂中的本发明复合RNA已被与如本文中定义的RNA(分子)复合的肽(Arg)7或单独的肽(Arg)7代替。
按照另一个备选的实施方案,本发明还包括与如本文中定义的RNA(分子)复合的肽(Arg)7或单独的肽(Arg)7(用于制备试剂的)用于治疗任何以上提及的疾病或状态的用途。
按照最后的实施方案,本发明还提供试剂盒,其包括按照本发明的复合RNA和/或按照本发明的药物组合物以及,任选地,具有关于按照本发明的复合RNA和/或按照本发明的药物组合物的施用和剂量的信息技术指导。该试剂盒还可以分开地包含一种或多种以下成分组:至少一种抗原或至少一种抗体或包含抗原或抗体的组合物,另外的佐剂或包含至少一种佐剂和/或至少一种细胞因子的组合物或包含至少一种细胞因子的组合物。抗原、抗体和/或细胞因子可以以自身(蛋白)提供或可以以编码该抗原、抗体或细胞因子的DNA或RNA提供。
本发明还提供试剂盒,其包括与如本文中定义的RNA(分子)复合的肽(Arg)7或单独的肽(Arg)7以及,任选地,具有关于肽(Arg)7的施用和剂量的信息的技术指导。所述试剂盒可以应用于例如任何以上提及的应用或用途,优选应用于至少一种按照本发明的复合RNA(用于制备试剂的)用于治疗任何以上提及的疾病的用途。该试剂盒还可以应用于至少一种按照本发明的复合RNA(用于制备试剂的)用于治疗任何以上提及的疾病的用途,其中所述试剂(和/或复合RNA)可能能够在如上定义的组织或生物体内诱导或增强免疫反应。所述试剂盒还可以应用于至少一种按照本发明的复合RNA(用于制备试剂的)用于在如上定义的组织或生物体内调节,优选用于引起,例如诱导或增强免疫反应,和优选用于支持如本文中提及的疾病或状态。
附图
以下附图意欲进一步举例说明本发明。它们不意欲将本发明的主题局限于此。
图1:描述稳定化荧光素酶mRNA序列的序列,其中用多聚-A/多聚-C-尾部(tag)(A70-C30)修饰天然荧光素酶编码mRNA。该第一构建体(构建体CAP-Ppluc(wt)-muag-A70-C30,SEQIDNO:35)包含以下序列元件:
来自α-球蛋白基因的稳定序列,
3’-末端处的70×腺苷(多聚-A-尾部),
3’-末端处的30×胞嘧啶(多聚-C-尾部),
由以下符号表示:
________=编码序列
=α球蛋白基因的3’-UTR
......................=多聚-A-尾部
-----------=多聚-C-尾部
图2:显示稳定化荧光素酶mRNA序列的序列,其中按照SEQIDNO:35的构建体(参见图1)进一步用为了更好密码子利用的GC-优化序列修饰。最终构建体(构建体CAP-Ppluc(GC)-muag-A70-C30,SEQIDNO:36)包含以下序列元件:
为了更好密码子利用的GC-优化序列
来自α球蛋白基因的稳定序列
3’-末端处的70×腺苷(多聚-A-尾部),
3’-末端处的30×胞嘧啶(多聚-C-尾部),
由以下符号表示:
_________=编码序列
=α球蛋白基因的修饰的3’-UTR
......................=多聚-A-尾部
-----------=多聚-C-尾部
图3:显示按照SEQIDNO:35的序列的编码序列(SEQIDNO:37)(参见图1)。
图4:显示按照SEQIDNO:36的序列的GC-优化编码序列(SEQIDNO:38)(参见图2)。在GC-优化密码子下划线。
图5:通过测量IL-6的生成,显示hPBMC细胞中与九-精氨酸((Arg)9)复合的RNA的免疫刺激性作用。如可见地,hPBMC细胞表现出显著的IL-6生成,即与九-精氨酸((Arg)9)复合的RNA的显著免疫刺激性作用。
图6:通过测量TNF-α的生成,显示hPBMC细胞中与九-精氨酸((Arg)9)复合的RNA的免疫刺激性作用。如可见地,hPBMC细胞表现出显著的TNF-α生成,即与九-精氨酸((Arg)9)复合的RNA的显著免疫刺激性作用。
图7:在比较实施例中显示分别与九-精氨酸((Arg)9)或聚-L-精氨酸复合的RNA在hPBMC中免疫刺激性作用的比较。有利地,对于质量比低于1∶5(RNA∶九-精氨酸)(1∶10;1∶8;1∶5;1∶2;1∶1;2∶1)可以观察到显著的免疫刺激性作用。然而,当使用RNA∶九-精氨酸的质量比(5∶1)时,不能观察到显著的TNFα生成。同样应用于刺激实验,使用单独的九-精氨酸((Arg)9)或mRNA。另外,观察到mRNA与聚-L-精氨酸的复合导致与九-精氨酸((Arg)9)相比显著更低的TNF-α生成诱导。显然,更高浓度的聚-L-精氨酸似乎对受其转染的细胞有毒,特别是当使用1∶2RNA∶聚-L-精氨酸∶RNA或更高质量比时,因为细胞被溶解。
图8:显示HeLa细胞中用RNA与九-精氨酸((Arg)9)的复合物转染时的荧光素酶表达。如可源自图8,小于2∶1(RNA∶九-精氨酸)的质量比似乎是有利的。相反,与(高分子量)聚-L-精氨酸的复合不引起显著的荧光素酶活性。因此,(高分子量)聚-L-精氨酸似乎不适合于转染mRNA。
图9:在比较实施例中描述HeLa细胞中用RNA与七-精氨酸((Arg)7)的复合物转染时的荧光素酶表达。如可源自图9,RNA与七-精氨酸((Arg)7)的复合物的转染不引起显著的荧光素酶活性。因此,(七-精氨酸((Arg)7)似乎也不适合于转染mRNA。
图10:通过测量IL-6的生成,显示hPBMC细胞中与七-精氨酸((Arg)7)复合的RNA的免疫刺激性作用。如可见地,hPBMC细胞表现出显著的IL-6生成,即与七-精氨酸((Arg)7)复合的RNA的显著免疫刺激性作用。
图11:通过测量TNF-α的生成,显示hPBMC细胞中与七-精氨酸((Arg)7)复合的RNA的免疫刺激性作用。如可见地,hPBMC细胞表现出显著的TNF-α生成,即与七-精氨酸((Arg)7)复合的RNA的显著免疫刺激性作用。
图12:显示与R9肽复合的RNA对HeLa细胞中荧光素酶表达的影响。
图13:显示与R9H3肽复合的RNA对HeLa细胞中荧光素酶表达的影响。
图14:显示与H3R9H3肽复合的RNA对HeLa细胞中荧光素酶表达的影响。
图15:显示与YYYR9SSY肽复合的RNA对HeLa细胞中荧光素酶表达的影响。
图16:显示与H3R9SSY肽复合的RNA对HeLa细胞中荧光素酶表达的影响。
图17:显示与(RKH)4肽复合的RNA对HeLa细胞中荧光素酶表达的影响。
图18:显示与Y(RKH)2R肽复合的RNA对HeLa细胞中荧光素酶表达的影响。
图19:显示末端位置处的组氨酸对转染效率的影响。
图20:显示末端位置处的中性氨基酸对转染效率的影响。
图21:显示与R9H3复合的RNA对hPBMCs中TNFα分泌的免疫刺激性作用。
图22:显示与R9H3复合的RNA对hPBMCs中IL-6分泌的免疫刺激性作用。
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局限于此。
实施例1.制备荧光素酶mRNA构建体
在以下实验中,制备稳定化荧光素酶mRNA并将其用于转染实验,其中天然荧光素酶编码mRNA用多聚-A/多聚-C-尾部(A70-C30)修饰并GC-优化以获得更好的密码子利用和进一步稳定。
第一构建体(构建体CAP-Ppluc(wt)-muag-A70-C30,SEQIDNO:35)包含以下序列元件:
来自α-球蛋白基因的稳定序列
3’-末端处的70(腺苷
3’-末端处的30(胞嘧啶
最终构建体(构建体CAP-Ppluc(GC)-muag-A70-C30,SEQIDNO:36)在本文中关于以下实验使用时,包含以下序列元件:
为了更好密码子利用的GC-优化序列
来自α-球蛋白基因的稳定序列
3’-末端处的70(腺苷
3’-末端处的30(胞嘧啶
这些序列也显示在图1和2中(SEQIDNOs:35和36)。各自的编码序列显示在图3和4中(SEQIDNOs:35和36)。
实施例2.体外转录稳定化荧光素酶mRNA
遵从制造商的说明,利用T7-聚合酶(T7-OptimRNA试剂盒,CureVac,Tübingen,德国)体外转录按照SEQIDNO:35或36的稳定化荧光素酶mRNA(Luc-RNActive)。
所有mRNA转录物包含70个碱基的多聚-A-尾部和5’-帽-结构。5’-帽-结构是通过添加过量N7-甲基-鸟苷-5′-三磷酸-5′-鸟苷获得的。
实施例3.形成RNA分别与九-精氨酸((Arg)9),聚-L-精氨酸或其他基于(Arg)9的肽的复合物
将15μg按照SEQIDNO:36的RNA稳定化荧光素酶mRNA(Luc-RNActive)与九-精氨酸(Arg9)或聚-L-精氨酸(Sigma-Aldrich(西格玛-奥德里奇;P4663;5000-15000g/mol)以不同的质量比混合,由此形成复合物。以下质量比如所示示范性用于((Arg)9)。聚-L-精氨酸遵从相同的说明用于比较实施例。
另外,利用以下用于复合的肽,来如上制备其他基于(Arg)9的复合RNA:
R9:Arg-Arg-Arg-Arg-Arg-Arg-Arg-Arg-Arg
R9H3:Arg-Arg-Arg-Arg-Arg-Arg-Arg-Arg-Arg-His-His-His
H3R9H3:His-His-His-Arg-Arg-Arg-Arg-Arg-Arg-Arg-Arg-Arg-His-His-His
YSSR9SSY:Tyr-Ser-Ser-Arg-Arg-Arg-Arg-Arg-Arg-Arg-Arg-Arg-Ser-Ser-Tyr
H3R9SSY:His-His-His-Arg-Arg-Arg-Arg-Arg-Arg-Arg-Arg-Arg-Ser-Ser-Tyr
(RKH)4:Arg-Lys-His-Arg-Lys-His-Arg-Lys-His-Arg-Lys-His
Y(RKH)2R:Tyr-Arg-Lys-His-Arg-Lys-His-Arg
为了复合,将4μg按照SEQIDNO:36的稳定化荧光素酶mRNA(Luc-RNActive)与各种肽(按照通式I)以摩尔比混合,由此形成复合物。然后,用水将由此生成的溶液调节到最终体积50μl并在室温下温育30分钟。所用比例显示在以下给出的表中。然后,在转染前,在24孔微滴定板上接种HeLa细胞(150×103/孔)1天,由此导致进行转染时的70%的汇合。
R9:
R9H3:
H3R9H3:
YSSR9SSY:
H3R9SSY:
(RKH)4:
Y(RKH)2R:
实施例4Hela细胞中的九-精氨酸((Arg)9)-介导按照SEQIDNO:35或36的稳定化荧光素酶mRNA的转染和表达
在转染前,在24孔微滴定板上接种HeLa细胞(150×103/孔)1天,由此导致在进行转染时的70%的汇合。为了转染(40μl),将50μl实施例3中公开的RNA/(肽)-溶液与250μl无血清培养基混合,并添加给细胞(最终RNA浓度:13μg/ml)。在添加转染溶液前,用1mlOptimen(Invitrogen)/孔轻柔并仔细的清洗HeLa细胞2次。然后,将转染溶液(300μl/孔)添加给细胞并将细胞在37℃温育4小时。随后,加入300μl含有10%FCS的RPMI-培养基(Camprex)/孔并在37℃温育细胞另外20h。转染后24h时吸出转染溶液,并在300μl溶胞缓冲液(25mMTris-PO4,2mMEDTA,10%甘油,1%Triton-X100,2mMDTT)中溶解细胞。然后将上清液与荧光素缓冲液(25mM甘氨酰甘氨酸(Glycylglycin),15mMMgSO4,5mMATP,62,5μM荧光素)混合并利用发光计(LumatLB9507(BertholdTechnologies(Berthold技术),BadWildbad,德国))检测荧光。这些实验的结果显示在图8和12-18中。
实施例5.用RNA与九-精氨酸((Arg)9)或聚-L-精氨酸的复合物转染时的免疫刺激(比较实施例)
a)转染实验
来自健康捐献者外周血的HPBMC细胞利用Ficoll梯度分离并随后用1xPBS(磷酸盐缓冲液)清洗。然后将细胞接种在96孔微滴定板上(200×103/孔)。如实施例4所述,见上,将hPBMC细胞与10μlRNA/肽复合物(RNA最终浓度:6μg/ml;使用等量RNA)一起在X-VIVO15培养基(BioWhittaker)(最终RNA浓度:10μg/ml)中温育24h。关于hPBMC细胞的免疫刺激性作用通过检测细胞因子生成(白介素-6肿瘤坏死因子α)来测量。因此,ELISA微滴定板(NuncMaxisorb)与结合缓冲液(0,02%NaN3,15mMNa2CO3,15mMNaHCO3,pH9,7)一起温育过夜(o/n),其另外含有特异性细胞因子抗体。然后用含有1%BSA(牛血清清蛋白)的1xPBS来封闭细胞。加入细胞上清液并在37℃温育4h。随后,微滴定板用1xPBS,0,05%吐温-20清洗并然后与生物素标记的二级抗体(BDPharmingen,Heidelberg,德国)一起温育。将链霉抗生物素蛋白-偶联的辣根过氧化物酶加入到板中。然后,用含有0.05%吐温-20的1xPBS再次清洗板并加入ABTS(2,2′-连氮基-二(3-乙基-苯并噻唑啉-6-磺酸)作为底物。细胞因子的量通过利用重组细胞因子(BDPharmingen,Heidelberg,德国)标准曲线使用来自Tecan(Crailsheim,德国)的日出ELISA读数器(SunriseELISA-Reader)测量405nm处的吸收来确定。
b)结果
i)与九-精氨酸((Arg)9)复合的RNA的免疫刺激性作用
i1)如上公开地用与九-精氨酸((Arg)9)复合的RNA温育HPBMC细胞24h,其中RNA∶(Arg)9质量比是1∶1。然后,利用ELISA在细胞上清液中测量IL-6生成。结果,HPBMC细胞表现出显著的IL-6生成,即与九-精氨酸((Arg)9)复合的RNA的显著免疫刺激性作用(参见图5)。
i2)如上公开地用与九-精氨酸((Arg)9)复合的RNA温育HPBMC细胞24h,其中RNA∶(Arg)9质量比是1∶1。然后,利用ELISA在细胞上清液中测量TNF-α生成。结果,HPBMC细胞表现出显著的TNF-α生成,即与九-精氨酸((Arg)9)复合的RNA的显著免疫刺激性作用(参见图6)。
ii)比较分别与九-精氨酸((Arg)9)或聚-L-精氨酸复合的RNA的免疫刺激性作用(比较实施例)
将hPBMC分别与处于不同质量比(RNA∶九-精氨酸1∶10;1∶8;1∶5;1∶2;1∶1;2∶1,5∶1;8∶1和10∶1)的RNA和九-精氨酸((Arg)9)或聚-L-精氨酸等的复合物一起温育24h。随后利用ELISA测量TNF-α生成。
有利地,显著的免疫刺激性作用可以关于低于5∶1(RNA∶九-精氨酸)(1∶10;1∶8;1∶5;1∶2;1∶1;2∶1)的质量比观察到(参见图7)。当使用RNA∶九-精氨酸质量比(5∶1)时,不能观察到显著的TNFα生成。上述情况也适用于利用单独的九-精氨酸((Arg)9)或mRNA的刺激实验(参见图7,左侧)。
此外,与九-精氨酸((Arg)9)相比,mRNA与聚-L-精氨酸的复合导致显著更低的TNF-α生成诱导(参见图7,右侧)。另外,观察到较高浓度的聚-L-精氨酸似乎对用其转染的细胞有毒,特别是当使用1∶2RNA∶聚-L-精氨酸或更低质量比时,因为细胞被溶解。
实施例6.在HeLa细胞中分别转染RNA与九-精氨酸((Arg)9)或聚-L-精氨酸的复合物时的荧光素酶表达(比较实施例)
a)在HeLa细胞中转染RNA与九-精氨酸((Arg)9)的复合物时的荧光素酶表达。用编码荧光素酶的RNActive转染HeLa细胞,所述编码荧光素酶的RNActive分别与不同比例的九-精氨酸或聚-L-精氨酸复合。24h后,测量荧光素酶活性。显然地,小于2∶1(RNA∶九-精氨酸)的质量比似乎是有利的(见图8)。
b)比较起来,与(高分子量)聚-L-精氨酸的复合不以显著水平增加荧光素酶活性。因此,(高分子量)聚-L-精氨酸似乎不适合于转染mRNA(参见图8)。
实施例7.在HeLa细胞中转染RNA与七-精氨酸((Arg)7)的复合物时的荧光素酶表达(比较实施例)
HeLa细胞用编码荧光素酶的RNActive转染,所述编码荧光素酶的RNActive已与不同比例的七-精氨酸((Arg)7)复合。24h后,测量荧光素酶活性。显然地,与七-精氨酸((Arg)7)的复合不以显著水平增加荧光素酶活性。因此,七-精氨酸((Arg)7)似乎不适合于转染mRNA(参见图9)。
实施例8.转染RNA与七-精氨酸((Arg)7)的复合物时的免疫刺激(比较实施例)
a)转染实验
与如上所示实施例5中的实验类似地对七-精氨酸((Arg)7)进行转染实验。
b)与七-精氨酸((Arg)7)复合的RNA的免疫刺激性作用的结果
i)如上公开地用与七-精氨酸((Arg)7)复合的RNA温育HPBMC细胞24h,其中RNA∶(Arg)7质量比是1∶1。然后,利用ELISA在细胞上清液中测量IL-6生成。结果,HPBMC细胞表现出显著的IL-6生成,即与七-精氨酸((Arg)7)复合的RNA的显著免疫刺激性作用(参见图10)。
ii)如上公开地另外用与七-精氨酸((Arg)7)复合的RNA温育HPBMC细胞24h,其中RNA∶(Arg)7质量比是1∶1。然后,利用ELISA在细胞上清液中测量TNF-α生成。结果,HPBMC细胞也表现出显著的THF-α生成,即与七-精氨酸((Arg)7)复合的RNA的显著免疫刺激性作用(参见图11)。
实施例9.确定组氨酸对转染效率的影响
为了确定组氨酸对转染效率的影响,类似于以上转染实验,利用具有不同组氨酸含量的肽进行转染。因此,将4μg按照SEQIDNO:36的稳定化荧光素酶mRNA(Luc-RNActive)与各种肽(按照通式I),具体R9,R9H3或H3R9H3以摩尔比混合,由此形成复合物。随后,将由此生成的溶液用水调节到最终体积50μl并在室温下温育30分钟。所用的比例在各个实验中是1∶10000,1∶5000和1∶1000。然后,在转染前,在24孔微滴定板上接种HeLa细胞(150×103/孔)1天,由此导致在进行转染时的70%的汇合。为了转染,将50μlRNA/(肽)-溶液与250μl无血清培养基混合,并添加给细胞(最终RNA浓度:13μg/ml)。在添加转染溶液前,用1mlOptimen(Invitrogen)/孔轻柔并仔细的清洗HeLa细胞2次。然后,将转染溶液(300μl/孔)添加给细胞并将细胞在37℃温育4小时。随后,加入300μl含有10%FCS的RPMI-培养基(Camprex)/孔并在37℃温育细胞另外20h。转染后24h时吸出转染溶液,并在300μl溶胞缓冲液(25mMTris-PO4,2mMEDTA,10%甘油,1%Triton-X100,2mMDTT)中溶解细胞。然后将上清液与荧光素缓冲液(25mM甘氨酰甘氨酸(Glycylglycin),15mMMgSO4,5mMATP,62,5μM荧光素)混合并利用发光计(LumatLB9507(BertholdTechnologies(Berthold技术),BadWildbad,德国))检测荧光。
结果显示在图19中。如可见,位于一端的3个组氨酸的序列段已经增高复合的RNA的转染效率,其中位于两末端的3个组氨酸的序列段显著增加复合的RNA的转染效率。
实施例10.确定中性氨基酸对转染效率的影响
为了确定中性氨基酸对转染效率的影响,类似于以上实施例9中的转染实验,利用肽H3R9CCS进行另外的转染实验。该另外的实验的结果显示在图20中。
实施例11.hPBMCs中利用R9H3免疫刺激性
R9H3对免疫刺激性的影响在hPBMCs中测试。因此,制备如上在实施例3中所示的R9H3与RNA的复合物。此外,来自健康捐献者外周血的HPBMC细胞利用Ficoll梯度分离并随后用1xPBS(磷酸盐缓冲液)清洗。然后将细胞接种在96孔微滴定板上(200×103/孔)。如实施例4所述,见上,将hPBMC与10μlRNA/肽复合物(RNA最终浓度:6μg/ml;使用等量RNA)一起在X-VIVO15培养基(BioWhittaker)中温育24h。关于hPBMC细胞的免疫刺激性作用通过检测细胞因子生成(白介素-6肿瘤坏死因子α)来测量。因此,ELISA微滴定板(NuncMaxisorb)与结合缓冲液(0,02%NaN3,15mMNa2CO3,15mMNaHCO3,pH9,7)一起温育过夜(o/n),其另外含有特异性细胞因子抗体。然后用含有1%BSA(牛血清清蛋白)的1xPBS来封闭细胞。加入细胞上清液并在37℃温育4h。随后,微滴定板用1xPBS,0,05%吐温-20清洗并然后与生物素标记的二级抗体(BDPharmingen,Heidelberg,德国)一起温育。将链霉抗生物素蛋白-偶联的辣根过氧化物酶加入到板中。然后,用含有0,05%吐温-20的1xPBS再次清洗板并加入ABTS(2,2′-连氮基-二(3-乙基-苯并噻唑啉-6-磺酸)作为底物。细胞因子的量通过利用重组细胞因子(BDPharmingen,Heidelberg,德国)标准曲线使用来自Tecan(Crailsheim,德国)的日出ELISA读数器(SunriseELISA-Reader)测量405nm(OD405)处的吸收来确定。结果参见图21和22。如可见,在1∶5000RNA∶R9H3比时表现出显著的免疫刺激性。
序列表
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gccgccaccaugg13
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nccancccnnucncc15
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cccccucuagacaauuggaauu1882
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<211>1857
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ccaccggaucguggugugcucggagaacagccugcaguucuucaugccggugcugggcgc300
ccucuucaucggcguggccgucgccccggcgaacgacaucuacaacgagcgggagcugcu360
gaacagcauggggaucagccagccgaccgugguguucgugagcaagaagggccugcagaa420
gauccugaacgugcagaagaagcugcccaucauccagaagaucaucaucauggacagcaa480
gaccgacuaccagggcuuccagucgauguacacguucgugaccagccaccucccgccggg540
cuucaacgaguacgacuucgucccggagagcuucgaccgggacaagaccaucgcccugau600
caugaacagcagcggcagcaccggccugccgaaggggguggcccugccgcaccggaccgc660
cugcgugcgcuucucgcacgcccgggaccccaucuucggcaaccagaucaucccggacac720
cgccauccugagcguggugccguuccaccacggcuucggcauguucacgacccugggcua780
ccucaucugcggcuuccgggugguccugauguaccgguucgaggaggagcuguuccugcg840
gagccugcaggacuacaagauccagagcgcgcugcucgugccgacccuguucagcuucuu900
cgccaagagcacccugaucgacaaguacgaccugucgaaccugcacgagaucgccagcgg960
gggcgccccgcugagcaaggaggugggcgaggccguggccaagcgguuccaccucccggg1020
cauccgccagggcuacggccugaccgagaccacgagcgcgauccugaucacccccgaggg1080
ggacgacaagccgggcgccgugggcaagguggucccguucuucgaggccaagguggugga1140
ccuggacaccggcaagacccugggcgugaaccagcggggcgagcugugcgugcgggggcc1200
gaugaucaugagcggcuacgugaacaacccggaggccaccaacgcccucaucgacaagga1260
cggcuggcugcacagcggcgacaucgccuacugggacgaggacgagcacuucuucaucgu1320
cgaccggcugaagucgcugaucaaguacaagggcuaccagguggcgccggccgagcugga1380
gagcauccugcuccagcaccccaacaucuucgacgccggcguggccgggcugccggacga1440
cgacgccggcgagcugccggccgcggugguggugcuggagcacggcaagaccaugacgga1500
gaaggagaucgucgacuacguggccagccaggugaccaccgccaagaagcugcggggcgg1560
cgugguguucguggacgaggucccgaagggccugaccgggaagcucgacgcccggaagau1620
ccgcgagauccugaucaaggccaagaagggcggcaagaucgccguguaagacuaguuaua1680
agacugacuagcccgaugggccucccaacgggcccuccuccccuccuugcaccgagauua1740
auaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaa1800
aaaaaauauuccccccccccccccccccccccccccccccucuagacaauuggaauu1857
<210>37
<211>1653
<212>RNA
<213>人工的
<220>
<223>序列描述:按照SEQIDNO:35的序列的编码序列
<400>37
auggaagacgccaaaaacauaaagaaaggcccggcgccauucuauccgcuggaagaugga60
accgcuggagagcaacugcauaaggcuaugaagagauacgcccugguuccuggaacaauu120
gcuuuuacagaugcacauaucgagguggacaucacuuacgcugaguacuucgaaaugucc180
guucgguuggcagaagcuaugaaacgauaugggcugaauacaaaucacagaaucgucgua240
ugcagugaaaacucucuucaauucuuuaugccgguguugggcgcguuauuuaucggaguu300
gcaguugcgcccgcgaacgacauuuauaaugaacgugaauugcucaacaguaugggcauu360
ucgcagccuaccgugguguucguuuccaaaaagggguugcaaaaaauuuugaacgugcaa420
aaaaagcucccaaucauccaaaaaauuauuaucauggauucuaaaacggauuaccaggga480
uuucagucgauguacacguucgucacaucucaucuaccucccgguuuuaaugaauacgau540
uuugugccagaguccuucgauagggacaagacaauugcacugaucaugaacuccucugga600
ucuacuggucugccuaaaggugucgcucugccucauagaacugccugcgugagauucucg660
caugccagagauccuauuuuuggcaaucaaaucauuccggauacugcgauuuuaaguguu720
guuccauuccaucacgguuuuggaauguuuacuacacucggauauuugauauguggauuu780
cgagucgucuuaauguauagauuugaagaagagcuguuucugaggagccuucaggauuac840
aagauucaaagugcgcugcuggugccaacccuauucuccuucuucgccaaaagcacucug900
auugacaaauacgauuuaucuaauuuacacgaaauugcuucugguggcgcuccccucucu960
aaggaagucggggaagcgguugccaagagguuccaucugccagguaucaggcaaggauau1020
gggcucacugagacuacaucagcuauucugauuacacccgagggggaugauaaaccgggc1080
gcggucgguaaaguuguuccauuuuuugaagcgaagguuguggaucuggauaccgggaaa1140
acgcugggcguuaaucaaagaggcgaacugugugugagagguccuaugauuauguccggu1200
uauguaaacaauccggaagcgaccaacgccuugauugacaaggauggauggcuacauucu1260
ggagacauagcuuacugggacgaagacgaacacuucuucaucguugaccgccugaagucu1320
cugauuaaguacaaaggcuaucagguggcucccgcugaauuggaauccaucuugcuccaa1380
caccccaacaucuucgacgcaggugucgcaggucuucccgacgaugacgccggugaacuu1440
cccgccgccguuguuguuuuggagcacggaaagacgaugacggaaaaagagaucguggau1500
uacgucgccagucaaguaacaaccgcgaaaaaguugcgcggaggaguuguguuuguggac1560
gaaguaccgaaaggucuuaccggaaaacucgacgcaagaaaaaucagagagauccucaua1620
aaggccaagaagggcggaaagaucgccguguaa1653
<210>38
<211>1653
<212>RNA
<213>人工的
<220>
<223>序列描述:按照SEQIDNO:36的序列的GC-最优化编码序列
<400>38
auggaggacgccaagaacaucaagaagggcccggcgcccuucuacccgcuggaggacggg60
accgccggcgagcagcuccacaaggccaugaagcgguacgcccuggugccgggcacgauc120
gccuucaccgacgcccacaucgaggucgacaucaccuacgcggaguacuucgagaugagc180
gugcgccuggccgaggccaugaagcgguacggccugaacaccaaccaccggaucguggug240
ugcucggagaacagccugcaguucuucaugccggugcugggcgcccucuucaucggcgug300
gccgucgccccggcgaacgacaucuacaacgagcgggagcugcugaacagcauggggauc360
agccagccgaccgugguguucgugagcaagaagggccugcagaagauccugaacgugcag420
aagaagcugcccaucauccagaagaucaucaucauggacagcaagaccgacuaccagggc480
uuccagucgauguacacguucgugaccagccaccucccgccgggcuucaacgaguacgac540
uucgucccggagagcuucgaccgggacaagaccaucgcccugaucaugaacagcagcggc600
agcaccggccugccgaaggggguggcccugccgcaccggaccgccugcgugcgcuucucg660
cacgcccgggaccccaucuucggcaaccagaucaucccggacaccgccauccugagcgug720
gugccguuccaccacggcuucggcauguucacgacccugggcuaccucaucugcggcuuc780
cgggugguccugauguaccgguucgaggaggagcuguuccugcggagccugcaggacuac840
aagauccagagcgcgcugcucgugccgacccuguucagcuucuucgccaagagcacccug900
aucgacaaguacgaccugucgaaccugcacgagaucgccagcgggggcgccccgcugagc960
aaggaggugggcgaggccguggccaagcgguuccaccucccgggcauccgccagggcuac1020
ggccugaccgagaccacgagcgcgauccugaucacccccgagggggacgacaagccgggc1080
gccgugggcaagguggucccguucuucgaggccaaggugguggaccuggacaccggcaag1140
acccugggcgugaaccagcggggcgagcugugcgugcgggggccgaugaucaugagcggc1200
uacgugaacaacccggaggccaccaacgcccucaucgacaaggacggcuggcugcacagc1260
ggcgacaucgccuacugggacgaggacgagcacuucuucaucgucgaccggcugaagucg1320
cugaucaaguacaagggcuaccagguggcgccggccgagcuggagagcauccugcuccag1380
caccccaacaucuucgacgccggcguggccgggcugccggacgacgacgccggcgagcug1440
ccggccgcggugguggugcuggagcacggcaagaccaugacggagaaggagaucgucgac1500
uacguggccagccaggugaccaccgccaagaagcugcggggcggcgugguguucguggac1560
gaggucccgaagggccugaccgggaagcucgacgcccggaagauccgcgagauccugauc1620
aaggccaagaagggcggcaagaucgccguguaa1653
<210>39
<211>12
<212>PRT
<213>人工序列
<220>
<223>序列描述:按照通式(I)的示范性寡肽
<400>39
ArgArgArgArgArgArgArgArgArgHisHisHis
1510
<210>40
<211>15
<212>PRT
<213>人工序列
<220>
<223>序列描述:按照通式(I)的示范性寡肽
<400>40
HisHisHisArgArgArgArgArgArgArgArgArgHisHisHis
151015
<210>41
<211>15
<212>PRT
<213>人工的序列
<220>
<223>序列描述:按照通式(I)的示范性寡肽
<400>41
TyrSerSerArgArgArgArgArgArgArgArgArgSerSerTyr
151015
<210>42
<211>15
<212>PRT
<213>人工序列
<220>
<223>序列描述:按照通式(I)的示范性寡肽
<400>42
HisHisHisArgArgArgArgArgArgArgArgArgSerSerTyr
151015
<210>43
<211>12
<212>PRT
<213>人工序列
<220>
<223>序列描述:按照通式(I)的示范性寡肽
<400>43
ArgLysHisArgLysHisArgLysHisArgLysHis
1510
<210>44
<211>8
<212>PRT
<213>人工的
<220>
<223>序列描述:按照通式(I)的示范性寡肽
<400>44
TyrArgLysHisArgLysHisArg
15
Claims (17)
1.在免疫系统调节中用于治疗应用以通过活化模式识别受体来激活非特异性免疫系统的复合的RNA,其包含至少一个与一种或多种寡肽复合的RNA分子,其中氮/磷比,即N/P-比是0.75-25,其中所述寡肽具有8-15个氨基酸的长度并具有以下实验式:
(Arg)l;(Lys)m;(His)n;(Orn)o;(Xaa)x通式I
其中
●l+m+n+o+x=8-15,且
l,m,n或o可以彼此独立地是选自0,1,2,3,4,5,6,7,8,9,10,11,12,13,14或15的任一数值,条件是Arg,Lys,His和Orn的总含量代表该寡肽所有氨基酸的至少50%;和
●Xaa可以是选自除Arg,Lys,His或Orn以外的天然或非天然氨基酸中的任一氨基酸;和
●X可以是选自0,1,2,3,4,5,6,7或8的任一数值,条件是Xaa的总含量不超过该寡肽所有氨基酸的50%,
其中实验式(Arg)l;(Lys)m;(His)n;(Orn)o;(Xaa)x中的Xaa选自具有中性侧链的氨基酸,包括具有中性疏水性侧链的氨基酸和具有中性极性侧链的氨基酸。
2.按照权利要求1的复合的RNA,其中所述至少一个RNA分子是mRNA。
3.按照权利要求1的复合的RNA,其中所述寡肽具有8-14,8-13,8-12,或9-12或9-11个氨基酸的长度。
4.按照权利要求1的复合的RNA,其中Arg,Lys,His和Orn的总含量代表所述复合RNA的寡肽所有氨基酸的至少60%,70%,80%,90%,或95%。
5.按照权利要求1的复合的RNA,其中按照实验式(Arg)l;(Lys)m;(His)n;(Orn)o;(Xaa)x的寡肽在一个末端或两个末端包含的氨基酸不包含酸性侧链。
6.按照权利要求1的复合的RNA,其中按照实验式(Arg)l;(Lys)m;(His)n;(Orn)o;(Xaa)x的寡肽在一个末端或两个末端包含中性或碱性氨基酸,或在一个末端或两个末端包含碱性氨基酸,或在两末端包含至少1个碱性氨基酸。
7.按照权利要求6的复合的RNA,其中按照实验式(Arg)l;(Lys)m;(His)n;(Orn)o;(Xaa)x的寡肽在两末端包含至少2个碱性氨基酸。
8.按照权利要求6的复合的RNA,其中按照实验式(Arg)l;(Lys)m;(His)n;(Orn)o;(Xaa)x的寡肽在两末端包含至少3个碱性氨基酸。
9.按照权利要求1的复合的RNA,其中按照实验式(Arg)l;(Lys)m;(His)n;(Orn)o;(Xaa)x的寡肽在其序列中包含至少3个连续碱性氨基酸的序列段。
10.按照权利要求1的复合的RNA,其中按照实验式(Arg)l;(Lys)m;(His)n;(Orn)o;(Xaa)x的寡肽在一个末端或两个末端包含至少1个,2个,或3个非阳离子氨基酸。
11.按照权利要求10的复合的RNA,其中所述非阳离子氨基酸是组氨酸。
12.按照权利要求1的复合的RNA,其中所述复合RNA的至少一个RNA分子是mRNA,其中所述mRNA编码治疗活性蛋白或肽,免疫刺激性蛋白或肽,肿瘤抗原或抗体。
13.按照权利要求1的复合的RNA,其中与wtRNA相比,所述RNA是修饰的RNA,具体地,稳定化的RNA。
14.按照权利要求13的复合的RNA,其中所述修饰的RNA的编码区的G/C含量与野生型RNA编码区的G/C含量相比提高,且其中与野生型RNA的编码氨基酸序列相比,所述修饰的RNA的编码氨基酸序列是不修饰的。
15.按照权利要求1的复合的RNA,其中所述复合RNA的至少一个RNA分子与一种或多种寡肽的质量比在1∶100-1∶0.5的范围内,或具有1∶50-1∶1,1∶100,1∶90,1∶80,1∶70,1∶60,1∶50,1∶45,1∶40,1∶35,1∶30,1∶25,1∶20,1∶15,1∶10,1∶5,1∶4,1∶3,1∶2,1∶1或1∶0.5的数值。
16.按照权利要求1的复合的RNA,其中所述复合RNA的至少一个RNA分子与一种或多种寡肽的摩尔比在1∶20000-1∶500或1∶250的范围内,或在1∶10000-1∶1000的范围内,或具有1∶9500,1∶9000,1∶8500,1∶8000,1∶7500,1∶7000,1∶6500,1∶6000,1∶5500,1∶5000,1∶4500,1∶4000,1∶3500,1∶3000,1∶2500,1∶2000,1∶1500,1∶1000,1∶500,1∶450,1∶400,1∶350,1∶300,或1∶250的数值。
17.按照权利要求1的复合的RNA,其中所述寡肽选自由以下各项组成的组:
Arg9His3,His3Arg9His3,TyrSerSerArg9SerSerTyr,His3Arg9SerSerTyr,(ArgLysHis)4,Tyr(ArgLysHis)2Arg;
或选自
Arg8,Arg9,Arg10,Arg11,Arg12,Arg13,Arg14,Arg15,SEQIDNOs:1-8;
Lys8,Lys9,Lys10,Lys11,Lys12,Lys13,Lys14,Lys15,SEQIDNOs:9-16;
His8,His9,His10,His11,His12,His13,His14,His15,SEQIDNOs:17-24;和
Orn8,Orn9,Orn10,Orn11,Orn12,Orn13,Orn14,Orn15,SEQIDNOs:25-32。
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