CN116064623A - 增加环状dna分子复制的方法 - Google Patents
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Abstract
本发明涉及共价闭合的环状重组DNA分子,其包含复制起点和包含均聚区域的插入片段,其中均聚区域在复制方向上位于距离复制起点至少500bp处和/或其中包含均聚区域的插入片段被定向以使得插入片段的转录方向与复制起点的复制方向相同。本发明进一步涉及共价闭合的环状重组DNA分子在发酵过程中用于增加产量和/或缩短发酵时间的用途。
Description
技术领域
本发明涉及共价闭合的环状重组DNA分子,其包含复制起点和包含均聚区域的插入片段,其中均聚区域在复制方向上位于与复制起点至少500bp的距离处和/或其中包含均聚区域的插入片段被定向为使得插入片段的转录方向与复制起点的复制方向相同。本发明还涉及共价闭合的环状重组DNA分子用于在发酵过程中增加产量和/或缩短发酵时间的用途。
背景技术
在基因治疗和许多其它治疗相关的生物化学和生物技术应用中,用于治疗和诊断目的的核酸的使用是非常重要的。例如,近年来在基因治疗领域出现了快速的发展,并取得了有希望的成果。因此,核酸被认为是用于基因治疗和针对感染性和恶性疾病预防性和治疗性疫苗的重要工具。例如,将从肿瘤细胞扩增的信使RNA转染到树突细胞中以诱导肿瘤免疫(Boczkowski等人(2000)Cancer Research 60,1028-1034)。
治疗性核糖核酸(RNA)分子代表着一类有希望的药物。基于RNA的治疗剂包括编码用作疫苗的抗原的mRNA分子(Fotin-Mleczek等人(2012)J.Gene Med.14(6):428-439)。另外,可以设想使用RNA分子进行替代疗法,例如,用于向患者提供丢失的蛋白质诸如生长因子或酶(Karikó等人(2012)Mol.Ther.20(5):948-953;Kormann等人(2012)Nat.Biotechnol.29(2):154-157)。此外,考虑了非编码免疫刺激RNA分子(Heidenreich等人,Int J Cancer.2014 Dec 21.doi:10.1002/ijc.29402.)和其它非编码RNA(如微RNA和长非编码RNA)的治疗用途(Esteller(2011)Nat.Rev.Genet.15(12):861-74)。
基于RNA的治疗剂显示出比DNA细胞转染更优异的一些性质。如通常所知,DNA分子的转染可能导致严重的问题。例如DNA分子的应用具有DNA整合到宿主基因组的风险。外源DNA整合到宿主基因组中可能会影响宿主基因的表达,并可能触发致癌基因的表达或肿瘤抑制基因的破坏。此外,通过将外来DNA整合到基因的编码区中,可以使宿主必需的该基因-和由此的该基因产物灭活。如果DNA的整合发生在涉及调控细胞生长的基因中,则可能存在特别的危险。然而,即使一些风险与DNA的应用有关,DNA仍然是一个重要的工具。如果使用RNA,特别是mRNA代替DNA,则不会发生这些风险。使用RNA而不使用DNA的优点在于,不需要在体内施用病毒来源的启动子元件,并且不会发生与基因组的整合。此外,RNA不必跨越核的屏障。
在基因治疗方法中,通常使用DNA,尽管RNA在近来的发展中也是已知的。重要的是,在所有这些基因治疗方法中,无论使用DNA、病毒RNA或者mRNA,mRNA都起到编码蛋白的序列信息的信使作用。一般来说,RNA被认为是不稳定的分子:RNA酶无处不在,并众所周知地难以灭活。而且,RNA在化学上也比DNA更不稳定。因此,可能令人惊讶的是,真核细胞中mRNA的“默认状态”以相对稳定性为特征,并且需要特定的信号来加速单个mRNA的降解。这个发现的主要原因似乎是细胞内的mRNA降解几乎完全由核酸外切酶催化。然而,真核mRNA的末端通过特定的末端结构及其相关蛋白被保护而抵抗这些酶:在5'末端的m7GpppN帽子,通常在3'末端的多聚(A)序列。去除这两个末端修饰因此被认为是限制mRNA降解的速度。尽管稳定元件已经在α-珠蛋白mRNA的3'UTR中进行了表征,但是影响真核mRNA代谢回转(turnover)的RNA序列通常通过加速去腺苷化作用起到降解的启动子的作用(Meyer,S.,C.Temme等人综述(2004),Crit Rev Biochem Mol Biol 39(4):1 97-21 6.)。
为了制造基于核苷酸的治疗剂,需要有效生产质粒载体。然而,本发明人已经发现均聚序列破坏(deteriorate)复制过程,从而导致复制速度降低或者甚至中断复制过程。结果使得发酵生产包含均聚序列的质粒的产量与不含这种序列的质粒的产量相比降低。此外,发酵生产质粒期间,均聚序列通常至少部分地被删除。
因此,需要以高保真度有效地复制包含均聚序列的载体。
发明内容
解决这些问题的方法是提供共价闭合的环状重组DNA分子,其中均聚序列在复制方向上不直接位于复制起点旁边,而是其中,在均聚序列与复制起点之间存在一定的距离。
因此,本发明涉及共价闭合的环状重组DNA分子,其包含:
-复制起点,
-包含均聚区域的插入片段,
其中均聚区域在复制方向上位于与复制起点至少500bp的距离处。
本发明的另一方面涉及共价闭合的环状重组DNA分子,其包含:
-复制起点,
-包含均聚区域的插入片段,
其中包含均聚区域的插入片段被定向为使得插入片段的转录方向与复制起点的复制方向相同。
与其中均聚区域在复制方向上位于与复制起点小于500bp的距离处的共价闭合的环状重组DNA分子的产量相比,其中均聚区域在复制方向上位于与复制起点至少500bp的距离处的共价闭合的环状重组DNA分子可以提高发酵生产中共价闭合的环状重组DNA分子的产量。
此外,与其中包含均聚区域的插入片段被定向为使得插入片段的转录方向与复制起点的复制方向相反的共价闭合的环状重组DNA分子的产量相比,其中包含均聚区域的插入片段被定向为使得插入片段的转录方向与复制起点的复制方向相同的共价闭合的环状重组DNA分子提高了发酵生产中共价闭合的环状重组DNA分子的产量。
共价闭合的环状重组DNA分子可以是质粒、粘粒、细菌人工染色体(BAC)、噬菌体、病毒载体或其杂交体。优选地,共价闭合的环状重组DNA分子是质粒。
通常地,复制起点是细菌来源的。优选地,复制起点是高拷贝数起点。复制起点可以来源于pBR322质粒、pUC质粒、pMB1质粒、ColE1质粒、R6K质粒、p15A质粒、pSC101质粒或F1噬菌粒。优选地,复制起点来源于pUC质粒。
在一些实施方案中,共价闭合的环状重组DNA分子还包含重链中的引发体组装位点(PAS-BH)。
通常地,共价闭合的环状重组DNA分子还包含选择标记物,例如抗生素抗性基因或蔗糖选择性标记物。
在优选的实施方案中,包含在共价闭合的环状重组DNA分子的插入片段中的均聚区域包含多聚(A)序列和/或多聚(C)序列。在更优选的实施方案中,均聚区域包含多聚(C)序列。在甚至更优选的实施方案中,均聚区域包含多聚(C)和多聚(A)序列。优选地,多聚(A)序列包含约20至约400个腺苷核苷酸、更优选约60至约250个腺苷核苷酸的序列。优选地,多聚(C)序列包含约10至200个胞苷核苷酸、更优选约20至40个胞苷核苷酸的序列。在特别优选的实施方案中,均聚区域包含约60至约70个腺苷核苷酸的多聚(A)序列和约20至30个胞苷核苷酸的多聚(C)序列。
本发明的另一方面涉及其中均聚区域在复制方向上位于与复制起点至少500bp的距离处的共价闭合的环状重组DNA分子用于使发酵生产中共价闭合的环状重组DNA的产量与其中包含均聚区域的插入片段在复制方向上位于与复制起点小于500bp的距离处的共价闭合的环状重组DNA分子的产量相比增加的用途。
本发明的再另一方面涉及其中包含均聚区域的插入片段被定向为使得插入片段的转录方向与复制起点的复制方向相同的共价闭合的环状重组DNA分子用于使发酵生产中共价闭合的环状重组DNA的产量与其中包含均聚区域的插入片段被定向为使得插入片段的转录方向与复制起点的复制方向相反的共价闭合的环状重组DNA分子的产量相比增加。
与其中包含均聚区域的插入片段在复制方向上位于与复制起点小于500bp的距离处的共价闭合的环状重组DNA分子的发酵时间相比,当使用其中均聚区域在复制方向上位于与复制起点至少500bp的距离处的闭合的环状重组DNA分子时,可以缩短发酵时间。
与其中包含均聚区域的插入片段被定向为使得插入片段的转录方向与复制起点的复制方向相反的共价闭合的环状重组DNA分子的发酵时间相比,当使用其中包含均聚区域的插入片段被定向为使得插入片段的转录方向与复制起点的复制方向相同的共价闭合的环状重组DNA分子时,可以缩短发酵时间。
本发明的另一方面涉及用于发酵生产共价闭合的重组DNA分子的方法,其包括以下步骤:
(a)提供包含根据本发明的共价闭合的环状重组DNA分子的微生物;
(b)使步骤(a)的微生物发酵。
在具体的实施方案中,该方法还包括以下步骤:
(c)从步骤(b)的微生物中分离共价闭合的环状重组DNA分子。
在特别优选的实施方案中,微生物是细菌,优选为大肠杆菌(E.coli)。在优选的实施方案中,微生物是含有共价闭合的环状重组温度诱导型高拷贝DNA质粒的细菌(例如大肠杆菌),并且步骤(b)包括以下步骤:
(i)在补料分批阶段的生长阶段期间,使含有共价闭合的环状重组温度诱导型高拷贝DNA质粒的细菌在25℃至32℃范围内的温度下生长,其中在补料分批阶段期间以使得生长速率为μ=0.05至0.3小时-1(hr-1)的速率供应底物,
(ii)通过将温度升高到36℃至45℃,在生长阶段后诱导产生所述DNA质粒;和
(iii)在(ii)施加的温度下继续发酵以积累所述DNA质粒。
在更具体的实施方案中,步骤(i)中施加的温度为约30℃,并且步骤(ii)中施加的温度为约42℃。
在上述方法中,与其中包含均聚区域的插入片段在复制方向上位于与复制起点小于500bp的距离处的共价闭合的环状重组DNA分子的产量相比,其中均聚区域在复制方向上位于与复制起点至少500bp的距离处的共价闭合的环状重组DNA分子的产量增加。
与其中包含均聚区域的插入片段被定向为使得插入片段的转录方向与复制起点的复制方向相反的共价闭合的环状重组DNA分子的产量相比,其中包含均聚区域的插入片段被定向为使得插入片段的转录方向与复制起点的复制方向相同的共价闭合的环状重组DNA分子的产量增加。此外,与其中包含均聚区域的插入片段被定向为使得插入片段的转录方向与复制起点的复制方向相反的共价闭合的环状重组DNA分子的发酵时间相比,发酵时间缩短。
本发明进一步提供了在发酵生产过程中共价闭合的环状重组DNA分子的序列保持稳定的方法。例如,均聚区域在发酵生产期间保持稳定。
本发明的另一个方面涉及提高共价闭合的环状重组DNA分子的产量的方法,其包括以下步骤:
(a)提供共价闭合的环状重组DNA分子,其具有
-复制起点,和
-包含均聚区域的插入片段,其中均聚区域在复制方向上位于与复制起点小于500bp的距离处;
(b)修饰(a)的共价闭合的环状重组DNA分子以使得均聚区域在复制方向上位于与复制起点至少500bp的距离处。
本发明进一步提供了提高共价闭合的环状重组DNA分子的产量的方法,其包括以下步骤:
(a)提供共价闭合的环状重组DNA分子,其具有
-复制起点,和
-包含均聚区域的插入片段,其中包含均聚区域的插入片段被定向为使得插入片段的转录方向与复制起点的复制方向相反;
(b)修饰(a)的共价闭合的环状重组DNA分子以使得包含均聚区域的插入片段被定向为使得插入片段的转录方向与复制起点的复制方向相同。
最后,本发明涉及根据本发明的共价闭合的环状重组DNA分子在体外转录RNA中的用途。
附图说明
图1:P1140的载体图谱
将P1140定向为使得复制起点(在载体图谱中表示为pUC起点)的复制方向与插入片段(在载体图谱中表示为RNA)的转录方向相反。
图2:P1140-AF2的载体图谱
将P1140-AF2定向为使得复制起点(在载体图谱中表示为pUC起点)的复制方向与插入片段(RNA在载体图谱中表示为RNA)的转录方向相同。
图3:P1140-AF1的载体图谱
将P1140-AF1定向为使得复制起点(在载体图谱中表示为pUC起点)的复制方向与插入片段(在载体图谱中表示为RNA)的转录方向相反。
图4:P1140-K2的载体图谱
将P1140-K2定向为使得复制起点(在载体图谱中表示为pUC起点)的复制方向与插入片段(RNA在载体图谱中表示为RNA)的转录方向相同。
图5:P1140-K1的载体图谱
将P1140-K1定向为使得复制起点(在载体图谱中表示为pUC起点)的复制方向与插入片段(在载体图谱中表示为RNA)的转录方向相反。
图6:编码H1N1(Netherlands2009)-HA(SEQ ID NO:2)的GC优化的mRNA。
定义
为了清楚性和可读性的目的,提供了以下定义。从本发明的每个实施方案中可以理解这些定义中提到的任何技术特征。这些实施方案的上下文中可以具体给出附加定义和解释。除非另外定义,否则本文使用的所有技术术语和科学术语通常具有与本发明所属领域的普通技术人员通常理解的相同的含义。通常,本文使用的命名法和细胞培养、分子遗传学、有机化学和核酸化学和杂交的实验步骤是本领域众所周知的和经常使用的。标准技术用于分子生物技术分析。贯穿本文所提供的技术和步骤通常根据本领域常规方法和各种一般参考文献(例如,Sambrook等人,1989,Molecular Cloning:A Laboratory Manual,2ded.Cold Spring Harbor Laboratory Press,Cold Spring Harbor,NY)进行。
共价闭合的环状重组DNA:共价闭合的环状重组DNA是指完整的环状双链DNA分子,即其中两条链都是未切割的。该分子优选不是天然存在的,而是例如通过分子克隆技术进行过工程改造的。在本发明的上下文中,特别优选是如本文所定义的质粒。
蛋白质:蛋白质通常包括一种或多种肽或多肽。蛋白质通常被折叠成三维形式,这可能是蛋白质发挥其生物学功能所必需的。蛋白质或肽的序列通常被理解为顺序(即连续)的其氨基酸。
RNA,mRNA:RNA是核糖核酸的常规缩写。它是核酸分子,即由核苷酸单体组成的聚合物。这些核苷酸通常是沿着所谓的骨架彼此连接的腺苷-单磷酸单体、尿苷-单磷酸单体、鸟苷-单磷酸单体和胞苷-单磷酸单体。骨架由第一单体的糖(即核糖)与第二相邻单体的磷酸部分之间的磷酸二酯键形成。特定顺序的单体,即该顺序的连接到糖/磷酸骨架上的碱基被称为RNA-序列。通常地,RNA是通过例如在细胞内转录DNA序列能够获得的。在真核细胞中,通常在细胞核或线粒体内进行转录。在体内,DNA的转录通常产生所谓的早熟RNA,其需要被加工成所谓的信使-RNA,通常缩写为mRNA。对早熟RNA的加工(例如在真核生物中)包含多种不同的转录后修饰,例如剪接、5'-加帽、聚腺苷酸化、从细胞核或线粒体输出等。这些过程的总和也被称为RNA的成熟化。成熟的信使RNA通常提供可以被翻译成特定肽或蛋白质的氨基酸序列的核苷酸序列。通常,成熟的mRNA包含5'-帽子、任选的5'UTR、开放阅读框、任选的3'UTR和多聚(A)序列。除了信使RNA之外,还存在可能参与转录和/或翻译的调节以及免疫刺激的几种非编码类型的RNA。术语“RNA”还包括其它编码RNA分子,例如病毒RNA、逆转录病毒RNA和复制子RNA、小干扰RNA(siRNA)、反义RNA、CRISPR RNA、核酶、适配体、核糖开关、免疫刺激RNA、转运RNA(tRNA)、核糖体RNA(rRNA)、核小RNA(snRNA)、核仁小RNA(snoRNA)、微RNA(miRNA)和与Piwi相互作用的RNA(piRNA)。在本发明的上下文中,编码RNA例如mRNA、病毒RNA、逆转录病毒RNA和复制子RNA是特别优选的。
用于根据本发明使用的mRNA的编码区域可以以单顺反子、双顺反子或者甚至多顺反子mRNA出现,即mRNA携带一个、两个或更多个蛋白质或肽的编码序列。在双顺反子或者甚至多顺反子mRNA中的这些编码序列可以通过至少一个内部核糖体进入位点(IRES)序列(例如,如本文所述的)或者通过诱导产生的多肽(其包含几种蛋白质或肽)的切割的信号肽而被分开。
双顺反子/多顺反子RNA:本文所用的术语“双顺反子”或“多顺反子”RNA通常是RNA,优选是mRNA,其通常具有两个(双顺反子)或更多(多顺反子)开放阅读框(ORF)。本文的开放阅读框是能够被翻译成肽或蛋白质的密码子序列。
小干扰RNA(siRNA):“小干扰RNA”(siRNA)是指长度为约10至约30个核苷酸的双链RNA分子,并且因其特异性干扰蛋白质表达的能力而被命名。优选地,siRNA分子的长度为12至28个核苷酸,更优选长度为15至25个核苷酸,还更优选长度为19至23个核苷酸,并且最优选长度为21至23个核苷酸。因此,优选的siRNA分子的长度为12、13、14、15、16、17、18、19、20、21、22、23、24、25、26、27、28或29个核苷酸。
反义RNA:术语“反义RNA”包括适合作为RNA、优选mRNA的区域,和最优选其调控元件的反义RNA的任何RNA分子,并且这种任何RNA分子能够通过与这些区域的互补结合而引起基因表达的抑制。反义RNA也可以包含DNA序列。
CRISPR RNA:术语“CRISPR RNA”来源于CRISPR(成簇规则间隔的短回文重复序列),其在细菌中进化为适应性免疫系统以防御病毒攻击。本文所用的“成簇规则间隔的短回文重复”或“CRISPR”是指含有在约40%测序的细菌和90%测序的古细菌的基因组中发现的多个短直接重复的基因座。CRISPR系统是参与防御侵入噬菌体和质粒的微生物核酸酶系统,提供一种获得性免疫的形式。当暴露于病毒时,病毒DNA的短片段被整合到CRISPR基因座中。“CRISPR RNA”从包含病毒序列的部分CRISPR基因座转录。该RNA含有与病毒基因组互补的序列,介导Cas9蛋白靶向病毒基因组中的序列。Cas9蛋白切割病毒靶标,并由此沉默病毒靶标。CRISPR簇被转录并加工成成熟的CRISPR(成簇规则间隔的短回文重复)RNA(CRISPRRNA)。
核酶:“核酶”通常是RNA分子,该RNA分子具有能够以核苷酸碱基序列特异性的方式反复切割其它单独的RNA靶标分子的酶活性,从而阻断它们的表达并影响其它基因的正常功能。核酶事实上可以靶向任何RNA转录物,并在体外实现有效的切割。
适配体:术语“适配体”在本文中被理解为是指通过除经典沃森-克里克(Watson-Crick)碱基配对以外的相互作用而对分子具有特异性结合亲和力的核酸分子。如本文所用的术语“RNA适配体”是包含核糖核苷单元的适配体。适配体、优选RNA适配体能够特异性结合至选择的靶标并调节靶标的活性。适配体具有用作治疗剂和诊断剂的许多需要的特征,包括高特异性和亲和性、生物功效和优异的药代动力学性质。
核糖开关是RNA元件,该RNA元件存在于基因的5'非翻译区(UTR)中并且利用转录或翻译机制调节其表达(Roth和Breaker(2009)Annu Rev Biochem 78:305-334)。
核小RNA(snRNA):词语“核小RNA”(snRNA)是指在细胞的核质和/或核仁中合成和/或发挥功能的小RNA分子。
核仁小RNA(snoRNAs):“核仁小RNA”(snoRNA)是参与RNA加工的非编码RNA。有两种主要的snoRNA亚类,称为盒C/D(box C/D)和盒H/ACA snoRNA(box H/ACA snoRNA)。这两个类别包含指导序列,已知该指导序列与靶标前体rRNA(pre-rRNA)上的互补区域标准配对,形成RNA双链体并促进甲基化酶和尿苷酶(uridylase)的酶促活性,所述甲基化酶和尿苷酶分别通过2'-O-甲基化或假尿苷化而位点特异性地修饰前体rRNA碱基。这些rRNA的修饰对于核糖体组装和活性是很重要的。
微RNA(miRNA):“微RNA”(miRNA)在调控基因活性方面发挥重要作用。微RNA是由核糖核酸酶III核酸酶从约70个核苷酸的发夹RNA前体加工而来的通常为22个核苷酸的单链RNA。类似于siRNA,miRNA可以通过破坏植物中的同源mRNA或阻断其在植物和动物中的翻译来沉默基因活性。这些20至22个核苷酸的非编码RNA具有通过碱基配对与特定的靶标mRNA杂交、并通过介导RNA切割或翻译抑制来下调这些转录物的表达的能力。最近的研究表明miRNA在发育过程中具有重要的功能。此外,miRNA通过RNA聚合酶II转录为聚腺苷酸化和封端的信使(message),称为初级-miRNA(pri-miRNA)。
与Piwi相互作用的RNA(piRNA):“与Piwi相互作用的RNA”(piRNA)是一类小的非编码RNA分子,其在动物细胞中表达或可被引入动物细胞中(参见例如Seto等人(2007)Molecular Cell,26(5):603-609;Siomi et al.(2011)Nat.Rev.Mol.Cell.Biol.,12:246-258)。piRNA通过与piwi蛋白的相互作用形成RNA-蛋白质复合物。这些piRNA复合物已经与逆转录转座子和其它遗传元件的表观遗传学和转录后基因沉默相关联。
免疫刺激RNA:在本发明上下文中的“免疫刺激RNA(immunstimulating RNA)”或“免疫刺激RNA(immunostimulatory RNA)”(isRNA)通常可以是能够诱导先天性免疫应答的RNA。isRNA通常不具有开放阅读框,因此不提供肽-抗原,但引发先天性免疫应答,例如通过与病原体相关分子模式(PAMP)受体(例如Toll样受体(TLR)或其它细胞内RNA传感器(例如RIG-1、MDA-5或PKR))结合。
均聚序列:均聚序列包含一段相同的核苷酸,如腺嘌呤核苷酸序列、胞嘧啶核苷酸序列、鸟嘌呤核苷酸序列、胸腺嘧啶核苷酸序列,相同修饰的核苷酸序列或相同核苷酸类似物序列。优选地,均聚序列包含一段至少15、20、25、30、35、40、45、50或60个相同的核苷酸,例如包含至少60个腺嘌呤核苷酸的多聚(A)序列和/或包含至少30个胞嘧啶核苷酸的多聚(C)序列。
均聚区域:均聚区域包含至少一个均聚序列。优选地,均聚区域包含至少两个均聚序列。均聚区域可包含至少一个选自由多聚(A)序列、多聚(T)序列、多聚(C)序列或聚(G)序列或其组合组成的组的均聚序列。优选地,均聚区域可以包含多聚(A)序列和选自由多聚(T)序列、多聚(C)序列或聚(G)序列组成的组的均聚序列。更优选地,均聚区域可以包含多聚(A)序列和/或多聚(C)序列。均聚序列可以通过可以是杂聚序列的接头序列连接。因此,均聚区域可以包含不同的核苷酸,即,是杂聚序列。最优选地,均聚区域可以含有多聚(A)序列和多聚(C)序列。通常地,均聚区域是核苷酸序列,例如多达约1000个核苷酸、例如约20至约800、优选约50至约600、更优选约50至约500、甚至更优选约50至约300、最优选约60至约250个核苷酸的核苷酸序列,其优选位于任选地包含在根据本发明的共价闭合的环状重组DNA分子的插入片段中的开放阅读框的3'端。
多聚(N)序列:多聚(N)序列,也称为多聚(N)尾或3'-多聚(N)尾,通常被理解为核苷酸序列,例如多达约400个核苷酸、例如约20至约40、优选约50至约400、更优选约50至约300、甚至更优选约50至约250、最优选约60至约250个核苷酸的核苷酸序列,其优选被添加到RNA、特别是mRNA的3'末端。多聚(N)序列通常位于(m)RNA的3'末端。在本发明的上下文中,多聚(N)序列可以位于(m)RNA或任何其它核酸分子内,例如诸如在载体中,例如在充当用于例如通过载体的转录产生RNA、优选mRNA的模板的载体中。核苷酸可以是腺苷、胞苷、尿苷、鸟苷、修饰的核苷酸、核苷酸类似物及其混合物。
多聚(A)序列:多聚(A)序列,也称为多聚(A)尾或3'-多聚(A)尾,通常被理解为腺嘌呤核苷酸序列,例如多达约400个腺嘌呤核苷酸、例如约20至约400、优选约50至约400、更优选约50至约300、甚至更优选约50至约250、最优选约60至约250个腺嘌呤核苷酸的序列,其优选被添加到编码mRNA的构建体的3'-末端。多聚(A)序列通常位于RNA、特别是mRNA的3'末端。在本发明的上下文中,多聚(A)序列可以位于(m)RNA或任何其它核酸分子内,例如诸如在载体中,例如在充当用于例如通过载体的转录产生RNA、优选mRNA的模板的载体中。通常地,多聚(A)序列由腺苷单磷酸组成。
多聚(C)序列:多聚(C)序列通常被理解为胞嘧啶核苷酸序列,例如多达约400个胞嘧啶核苷酸、例如约10至约400、优选约10至约300、更优选约10至约200、甚至更优选约20至约100、最优选约20至约40个胞嘧啶核苷酸序列,其优选被添加到编码mRNA的构建体的3'-末端。多聚(C)序列通常位于RNA、特别是mRNA的3'末端。在本发明的上下文中,多聚(C)序列可以位于(m)RNA或任何其它核酸分子内,例如诸如在载体中,例如在充当用于例如通过载体的转录产生RNA、优选mRNA的模板的载体中。
多聚(G)序列:多聚(G)序列通常被理解为鸟嘌呤核苷酸序列,例如多达约400个鸟嘌呤核苷酸、例如约20至约400、优选约50至约400、更优选约50至约300、甚至更优选约50至约250、最优选约60至约250个鸟嘌呤核苷酸序列,其优选被添加到编码mRNA的构建体的3'-末端。多聚(G)序列通常位于RNA、特别是mRNA的3'末端。在本发明的上下文中,多聚(G)序列可以位于(m)RNA或任何其它核酸分子内,例如诸如在载体中,例如在充当用于例如通过载体的转录产生RNA、优选mRNA的模板的载体中。
多聚(T)序列:多聚(T)序列通常被理解为胸腺嘧啶核苷酸序列,例如多达约400个胸腺嘧啶核苷酸、例如约20至约400、优选约50至约400、更优选约50至约300、甚至更优选约50至约250、最优选约60至约250个胸腺嘧啶核苷酸序列,其优选被添加到编码mRNA的构建体的3'-末端。多聚(T)序列通常位于RNA、特别是mRNA的3'末端。在本发明的上下文中,多聚(T)序列可以位于(m)RNA或任何其它核酸分子内,例如诸如在载体中,例如在充当用于例如通过载体的转录产生RNA、优选mRNA的模板的载体中。
糖修饰:可以在本发明的上下文中使用的经过修饰的核苷和核苷酸可以在糖的部分被修饰。例如,2'羟基基团(OH)可以被许多不同的“氧基”或“脱氧基”取代基修饰或替代。“氧基”-2'羟基基团修饰物的示例包括但不限于,烷氧基或芳氧基(-OR,例如R=H、烷基、环烷基、芳基、芳烷基、杂芳基或糖);聚乙二醇(PEG)、-O(CH2CH2O)nCH2CH2OR;“锁定”的核酸(LNA),其中2'羟基通过亚甲基桥连接到相同核糖糖的4'碳上;和氨基基团(-O-氨基,其中氨基基团例如NRR可以是烷基氨基、二烷基氨基、杂环基、芳基氨基、二芳基氨基、杂芳基氨基或二杂芳基氨基、乙二胺、聚氨基)或氨基烷氧基。
“脱氧基”修饰包括氢、氨基(例如NH2;烷基氨基、二烷基氨基、杂环基、芳基氨基、二芳基氨基、杂芳基氨基、二杂芳基氨基或氨基酸);或者氨基基团可以通过接头连接到糖上,其中接头包含一个或多个C、N和O原子。
糖基团也可以含有一个或多个具有与核糖中相应碳的立体化学构型相反的碳。因此,经过修饰的核苷酸可以包括含有例如阿拉伯糖作为糖的核苷酸。
骨架修饰:磷酸骨架可以在经过修饰的核苷和核苷酸中被进一步修饰。骨架的磷酸基团可以通过用不同的取代基替代一个或多个氧原子来修饰。此外,经过修饰的核苷和核苷酸可以包括利用如本文所述的经过修饰的磷酸完全替代未经过修饰的磷酸部分。经过修饰的磷酸基团的示例包括但不限于,硫代磷酸盐、硒代磷酸盐、硼烷磷酸盐(boranophosphates)、硼烷磷酸酯(borano phosphate esters)、膦酸氢盐、氨基磷酸盐、烷基或芳基膦酸盐和磷酸三酯。二硫代磷酸盐含有两个由硫替代的非连接氧。磷酸接头还可以通过用氮(桥连的氨基磷酸盐)、硫(桥连的硫代磷酸盐)和碳(桥连的亚甲基膦酸盐)替代连接氧而被修饰。
碱基修饰:可用于本发明的经过修饰的核苷和核苷酸可以在核碱基部分被进一步修饰。在RNA中发现的核碱基的示例包括但不限于腺嘌呤、鸟嘌呤、胞嘧啶和尿嘧啶。例如,本文所述的核苷和核苷酸可以在主沟表面上进行化学修饰。在一些实施方案中,主沟化学修饰可包括氨基团、硫醇基团、烷基基团或卤代基团。
在本发明的特别优选的实施方案中,核苷酸类似物/修饰物选自碱基修饰物,优选选自2-氨基-6-氯嘌呤苷-5'-三磷酸、2-氨基嘌呤-核糖苷-5'-三磷酸、2-氨基腺苷-5'-三磷酸、2'-氨基-2'-脱氧胞苷-三磷酸、2-硫代胞苷-5'-三磷酸、2-硫尿苷-5'-三磷酸、2'-氟胸苷-5'-三磷酸、2'-O-甲基肌苷-5'-三磷酸、4-硫尿苷-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-溴-2'-脱氧胞苷-5'-三磷酸、5-溴-2'-脱氧尿苷-5'-三磷酸、5-碘胞苷-5'-三磷酸、5-碘-2'-脱氧胞苷-5'-三磷酸、5-碘尿苷-5'-三磷酸、5-碘-2'-脱氧尿苷-5'-三磷酸、5-甲基胞苷-5'-三磷酸、5-甲基尿苷-5'-三磷酸、5-丙炔基-2'-脱氧胞苷-5'-三磷酸、5-丙炔基-2'-脱氧尿苷-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、黄嘌呤核苷-5'-三磷酸。特别优选给出的是选自由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'-三磷酸组成的组的碱基修饰的核苷酸。
在一些实施方案中,经过修饰的核苷包括吡啶-4-酮核糖核苷、5-氮杂-尿苷、2-硫代-5-氮杂-尿苷、2-硫代尿苷、4-硫代-假尿苷、2-硫代-假尿苷、5-羟基尿苷、3-甲基尿苷、5-羧甲基-尿苷、1-羧甲基-假尿苷、5-丙炔基-尿苷、1-丙炔基-假尿苷、5-牛磺酰甲基尿苷(taurinomethyluridine)、1-牛磺酰甲基-假尿苷、5-牛磺酰甲基-2-硫代-尿苷、1-牛磺酰甲基-4-硫代-尿苷、5-甲基-尿苷、1-甲基-假尿苷、4-硫代-1-甲基-假尿苷、2-硫代-1-甲基-假尿苷、1-甲基-1-脱氮-假尿苷、2-硫代-1-甲基-1-脱氮-假尿苷、二氢尿苷、二氢假尿苷、2-硫代-二氢尿苷、2-硫代-二氢假尿苷、2-甲氧基尿苷、2-甲氧基-4-硫代-尿苷、4-甲氧基-假尿苷和4-甲氧基-2-硫代-假尿苷。
在一些实施方案中,经过修饰的核苷包括5-氮杂-胞苷、假异胞苷、3-甲基-胞苷、N4-乙酰基胞苷、5-甲酰基胞苷、N4-甲基胞苷、5-羟甲基胞苷、1-甲基-假异胞苷、吡咯-胞苷、吡咯-假异胞苷、2-硫代-胞苷、2-硫代-5-甲基-胞苷、4-硫代-假异胞苷、4-硫代-1-甲基-假异胞苷、4-硫代-1-甲基-1-脱氮-假异胞苷、1-甲基1-脱氮-假异胞苷、4-脱氧尿苷(zebularine)、5-氮杂-4-脱氧尿苷、5-甲基-4-脱氧尿苷、5-氮杂-2-硫代-4-脱氧尿苷、2-硫代-4-脱氧尿苷、2-甲氧基-胞苷、2-甲氧基-5-甲基-胞苷、4-甲氧基-假异胞苷和4-甲氧基-1-甲基-假异胞苷。
在其它实施方案中,经过修饰的核苷包括2-氨基嘌呤、2,6-二氨基嘌呤、7-脱氮-腺嘌呤、7-脱氮-8-氮杂-腺嘌呤、7-脱氮-2-氨基嘌呤、7-脱氮-8-氮杂-2-氨基嘌呤、7-脱氮-2,6-二氨基嘌呤、7-脱氮-8-氮杂-2,6-二氨基嘌呤、1-甲基腺苷、N6-甲基腺苷、N6-异戊烯基腺苷、N6-(顺式-羟基异戊烯基)腺苷、2-甲硫基-N6-(顺式-羟基异戊烯基)腺苷、N6-甘氨酰氨基甲酰腺苷、N6-苏氨酰氨基甲酰腺苷、2-甲硫基-N6-苏氨酰基氨基甲酰腺苷、N6,N6-二甲基腺苷、7-甲基腺嘌呤、2-甲硫基-腺嘌呤和2-甲氧基-腺嘌呤。
在其它实施方案中,经过修饰的核苷包括肌苷、1-甲基-肌苷、怀俄苷(wyosine)、怀丁苷(wybutosine)、7-脱氮-鸟苷、7-脱氮-8-氮杂-鸟苷、6-硫代-鸟苷、6-硫代-7-脱氮-鸟苷、6-硫代-7-脱氮-8-氮杂-鸟苷、7-甲基-鸟苷、6-硫代-7-甲基-鸟苷、7-甲基肌苷、6-甲氧基-鸟苷、1-甲基鸟苷、N2-甲基鸟苷、N2,N2-二甲基鸟苷、8-氧代-鸟苷、7-甲基-8-氧代-鸟苷、1-甲基-6-硫代-鸟苷、N2-甲基-6-硫代-鸟苷和N2,N2-二甲基-6-硫代-鸟苷。
在一些实施方案中,可以在核苷酸的主沟表面上进行修饰,并且可以包括用甲基基团或卤代基团替代尿嘧啶C-5上的氢。在具体实施方案中,经过修饰的核苷是5'-O-(1-硫代磷酸)-腺苷、5'-O-(1-硫代磷酸)-胞苷、5'-O-(1-硫代磷酸)-鸟苷、5'-O-(1-硫代磷酸)-尿苷或5'-O-(1-硫代磷酸)-假尿苷。
在其它具体实施方案中,经过修饰的核苷酸包括选自6-氮杂-胞苷、2-硫代-胞苷、α-硫代-胞苷、伪-异-胞苷、5-氨基烯丙基-尿苷、5-碘-尿苷、N1-甲基-假尿苷、5,6-二氢尿苷、α-硫代-尿苷、4-硫代-尿苷、6-氮杂-尿苷、5-羟基-尿苷、脱氧-胸苷、5-甲基-尿苷、吡咯-胞苷、肌苷、α-硫代-鸟苷、6-甲基-鸟苷、5-甲基-胞苷、8-氧代-鸟苷、7-脱氮-鸟苷、N1-甲基-腺苷、2-氨基-6-氯-嘌呤、N6-甲基-2-氨基-嘌呤、伪-异-胞苷、6-氯-嘌呤、N6-甲基-腺苷、α-硫代-腺苷、8-叠氮基-腺苷、7-脱氮-腺苷的核苷修饰物。
先前已经描述了其它经过修饰的核苷酸(例如参见WO 2013/052523和WO2015/089511)。
5'-帽子(5'-cap):5'-帽子是实体,通常是经过修饰的核苷酸实体,其通常给成熟的mRNA的5'末端加帽并增加其稳定性。5'-帽子通常可以由经过修饰的核苷酸(帽子类似物)形成,特别是由鸟嘌呤核苷酸的衍生物形成。优选地,5'-帽子通过5'-5'-三磷酸键连接到RNA的5'-末端。5'-帽子可以被甲基化,例如m7GpppN(例如m7G(5')ppp(5')G(m7G)),其中N是携带5'-帽子的核酸的末端5'核苷酸,通常是RNA的5'-末端,m7是连接到第7位的鸟嘌呤(G)上的甲基基团,ppp是三磷酸。5'帽子结构的其它示例包括甘油基、反式脱氧脱碱残基(部分)、4',5'亚甲基核苷酸、1-(β-D-赤式呋喃糖基)核苷酸、4'-硫代核苷酸、碳环核苷酸、1,5-脱水己糖核苷酸、L-核苷酸、α-核苷酸、经过修饰的碱基核苷酸、苏式戊呋喃糖基核苷酸、非环3',4'-断核苷酸、非环3,4-二羟基丁基核苷酸、非环3,5-二羟基戊基核苷酸、3'-3'-反式核苷酸部分、3'-3'-反式脱碱基部分、3'-2'-反式核苷酸部分、3'-2'-反式脱碱基部分、1,4-丁二醇磷酸、3'-磷酰胺、己基磷酸、氨基己基磷酸、3'-磷酸、3'硫代磷酸、二硫代磷酸、或者桥连或非桥连的甲基磷酸酯部分。可以在本发明上下文中使用的其它经过修饰的5'-帽子结构是CAP1(m7GpppN的相邻核苷酸的核糖的另外甲基化)、CAP2(m7GpppN下游的第二个核苷酸的核糖的另外甲基化)、CAP3(m7GpppN下游的第三个核苷酸的核糖的另外甲基化)、CAP4(m7GpppN下游的第四个核苷酸的核糖的另外甲基化)、ARCA(抗反式帽子类似物)、经过修饰的ARCA(例如硫代磷酸酯修饰的ARCA)、肌苷、N1-甲基-鸟苷、2'-氟-鸟苷、7-脱氮-鸟苷、8-氧代-鸟苷、2-氨基-鸟苷、LNA-鸟苷和2-叠氮-鸟苷。
RNA,mRNA:RNA是核糖核酸的常规缩写。它是核酸分子,即由核苷酸组成的聚合物。这些核苷酸通常是单磷酸腺苷、单磷酸尿苷、单磷酸鸟苷和单磷酸胞苷单体,它们沿着所谓的骨架彼此连接。骨架由第一单体的糖(即核糖)与第二相邻单体的磷酸部分之间的磷酸二酯键形成。特定顺序的单体被称为RNA-序列。通常地,通过例如在细胞内转录DNA序列能够获得RNA。在真核细胞中,转录通常在细胞核或线粒体内进行。在体内,DNA的转录通常产生所谓的早熟RNA,其需要被加工成所谓的信使-RNA,通常缩写为mRNA。对早熟RNA的加工(例如在真核生物中)包含多种不同的转录后修饰,例如剪接、5'-加帽、聚腺苷酸化、从核或线粒体输出等。这些过程的总和也被称为RNA的成熟化。成熟的信使RNA通常提供了可以被翻译成特定肽或蛋白质的氨基酸序列的核苷酸序列。通常,成熟mRNA包含5'-帽子、5'-UTR、开放阅读框、3'-UTR和多聚(A)序列。除了信使RNA之外,还存在可能参与转录和/或翻译的调控的几种非编码类型的RNA。短RNA分子可通过化学方法合成,而长RNA通常通过体外转录反应产生,体外转录反应含有合适的DNA模板和噬菌体来源的启动子、RNA聚合酶,例如噬菌体SP6、T3或T7RNA聚合酶和核糖核苷三磷酸(NTP)。
DNA:DNA是脱氧核糖核酸的常规缩写。它是核酸分子,即由核苷酸单体组成的聚合物。这些核苷酸通常是脱氧-腺苷-单磷酸、脱氧-胸苷-单磷酸、脱氧-鸟苷-单磷酸和脱氧-胞苷-单磷酸单体,它们本身由糖部分(脱氧核糖)、碱基部分和磷酸部分组成,并由特征骨架结构聚合。骨架结构通常由第一单体的核苷酸(即脱氧核糖)的糖部分与第二相邻单体的磷酸部分之间的磷酸二酯键形成。连接到糖/磷酸骨架上的特定顺序的单体(即特定顺序的碱基)被称为DNA序列。DNA可以是单链的或双链的。在双链形式中,第一链的核苷酸通常与第二链的核苷酸杂交,即通过A/T碱基配对和G/C碱基配对。
核酸分子的序列/核酸序列:核酸分子的序列通常被理解为其核苷酸的特定且独特的顺序(即连续(succession))。
氨基酸分子的序列/氨基酸序列:蛋白质或肽的序列通常被理解为其氨基酸的顺序(即连续)。
序列同一性:如果两个或更多个序列具有相同长度和顺序的核苷酸或氨基酸,则它们是相同的。同一性的百分比通常描述两个序列相同的程度,即它通常描述在其序列位置上对应于参考序列的相同核苷酸的核苷酸的百分比。为了确定同一性的程度,待比较的序列被认为具有相同的长度,即待比较的序列的最长序列的长度。这意味着由8个核苷酸/氨基酸组成的第一序列与由包含第一序列的10个核苷酸/氨基酸组成的第二序列具有80%的同一性。换句话说,在本发明的上下文中,序列的同一性优选地涉及在具有相同长度的两个或更多个序列中具有相同位置的序列的核苷酸/氨基酸的百分比。帽子通常被认为是不相同的位置,不管它们在比对中的实际位置。
复制起点:术语“复制起点”是指能够促进DNA分子(例如,基因组DNA,共价闭合的环状重组DNA)复制的开始的DNA序列。在本发明的上下文中,该术语尤其是指共价闭合的环状重组DNA分子中的DNA序列,其能够促进共价闭合的环状重组DNA分子的复制的开始。通常地,复制起点是单向的。单向复制起点的复制在一个方向上进行。复制起点可具有SEQ IDNO:6(来源于pUC质粒)中确定的序列、SEQ ID NO:7(来源于pBR322质粒)中确定的序列、SEQID NO:8(来源于pMB1质粒)中确定的序列、SEQ ID NO:9(来源于ColE1质粒)中确定的序列、来源于R6K质粒的R6Kγ的序列(SEQ ID NO:10)、来源于R6K质粒的R6Kβ的序列(SEQ ID NO:11)、来源于R6K质粒的R6Kα的序列(SEQ ID NO:12)、SEQ ID NO:13(来源于p15A质粒)中确定的序列、SEQ ID NO:14(来源于pSC101质粒)中确定的序列或者SEQ ID NO:15(来源于F1噬菌粒)中确定的序列。与序列SEQ ID NO:6-14具有70%、80%、90%、95%、98%或99%同一性的序列也包括在内。
载体:术语“载体”是指核酸分子,优选指人工核酸分子。本发明上下文中的载体适用于并入或携带所需的核酸序列,例如包含开放阅读框的核酸序列。这样的载体可以是储存载体、表达载体、克隆载体、转移载体等。储存载体是允许方便地储存核酸分子(例如mRNA分子)的载体。因此,载体可以包含对应于例如所需的mRNA序列或其部分的序列,例如对应于mRNA的开放阅读框和3'-UTR的序列。表达载体可以用于产生表达产物如RNA,例如mRNA,或肽、多肽或蛋白质。例如,表达载体可以包含转录载体序列片段所需的序列,例如启动子序列,例如RNA聚合酶启动子序列。克隆载体通常是含有克隆位点的载体,克隆位点可以用于将核酸序列并入载体中。克隆载体可以是例如质粒载体或噬菌体载体。转移载体可以是适合于将核酸分子转移到细胞或生物体中的载体,例如病毒载体。本发明上下文中的载体可以是例如RNA载体或DNA载体。优选地,载体是DNA分子。优选地,本申请意义上的载体包含克隆位点、选择标记物(例如抗生素抗性因子)和适合于载体增殖的序列,例如复制起点。优选地,本申请上下文中的载体是质粒载体。
3'-非翻译区(3'-UTR):通常地,术语“3'-UTR”是指位于开放阅读框的3'端(即“下游”)的人工核酸分子的一部分,并且没有翻译成蛋白质。通常地,3'-UTR是mRNA的一部分,3'-UTR位于(m)RNA的蛋白质编码区(开放阅读框(ORF)或编码序列(CDS))与多聚(N/A)序列之间。在本发明的上下文中,人工核酸分子的3'-UTR可以包含多于一个的3'-UTR元件,3'-UTR元件可以具有不同的来源,例如来源于几个(无关的)天然存在的基因的3'-UTR的多个序列元件。因此,术语3'-UTR还可以包含没有被编码在模板(RNA由其转录)编码的元件,但这些元件在转录后在成熟过程中添加,例如多聚(N/A)序列。mRNA的3'-UTR不被翻译成氨基酸序列。3'-UTR序列一般由基因编码,该基因在基因表达过程中转录成各自的mRNA。基因组序列首先被转录成包含任选的内含子的早熟mRNA(pre-mature mRNA)。早熟mRNA然后在成熟化过程中被进一步加工成成熟mRNA。该成熟化过程包括5'-加帽、剪接早熟mRNA以切除任选的内含子、和3'末端的修饰(例如早熟mRNA的3'末端的聚核苷酸化/聚腺苷酸化)和任选的核酸内切酶/或核酸外切酶切割等步骤。在本发明的上下文中,3'-UTR对应于位于mRNA的蛋白质编码区域的终止密码子(优选紧接着蛋白质编码区域的终止密码子3'端)与多聚(N/A)序列之间的成熟mRNA的序列。术语“对应于”意思是3'-UTR序列可以是RNA序列,例如在用于定义3'-UTR序列的mRNA序列中的RNA序列,或者对应于这种RNA序列的DNA序列。在本发明的上下文中,术语“基因的3'-UTR”,例如“核糖体蛋白基因的3'-UTR”是对应于来源于该基因的成熟mRNA(即通过基因的转录和早熟mRNA的成熟化而获得的mRNA)的3'-UTR。术语“基因的3'-UTR”包括3'-UTR的DNA序列和RNA序列(3'-UTR的正义链和反义链以及成熟的和未成熟的)。如本文所用,术语“3'-UTR元件”通常是指如本文所定义的3'-UTR的片段。特别地,该术语包含位于根据本发明的人工核酸分子(优选mRNA)中的ORF的3'端的任何核酸序列元件。因此,该术语涵盖例如来源于异源基因的3'-UTR的序列元件以及诸如多聚(A)序列、多聚(C)序列或组蛋白茎环的元件。
组蛋白茎环:组蛋白茎环序列优选选自WO2012/019780中公开的组蛋白茎环序列,其公开内容通过引用并入本文。
适合用于本发明的组蛋白茎环序列优选选自下式(I)或(II)中的至少一个:
式(I)(无茎边界元件的茎环序列):
式(II)(具有茎边界元件的茎环序列):
其中:
茎1或茎2边界元件N1-6为1至6、优选为2至6、更优选为2至5、甚至更优选为3至5、最优选为4至5或5N的连续序列,其中每个N独立于另一个选自A、U、T、G和C的核苷酸或其核苷酸类似物;
茎1[N0-2GN3-5]与元件茎2反向互补或部分反向互补,是5至7个核苷酸之间的连续序列;
其中N0-2为0至2、优选为0至1、更优选为1N的连续序列,其中每个N独立于另一个选自A、U、T、G和C的核苷酸或其核苷酸类似物;
其中N3-5为3至5、优选为4至5、更优选为4N的连续序列,其中每个N独立于另一个选自A、U、T、G和C的核苷酸或其核苷酸类似物,和
其中G是鸟苷或其类似物,并且可以任选地被胞苷或其类似物取代,条件是其在茎2中的互补核苷酸胞苷被鸟苷取代;
环序列[N0-4(U/T)N0-4]位于元件茎1和元件茎2之间,是3到5个核苷酸、更优选4个核苷酸的连续序列;
其中每个N0-4为独立于另一个的0至4、优选1至3、更优选1至2N的连续序列,其中每个N独立于另一个选自A、U、T、G和C的核苷酸或其核苷酸类似物;和
其中U/T代表尿苷或任选的胸苷;
茎2[N3-5CN0-2]与元件茎1反向互补或部分反向互补,是5至7个核苷酸之间的连续序列;
其中N3-5为3至5、优选为4至5、更优选为4N的连续序列,其中每个N独立于另一个选自A、U、T、G和C的核苷酸或其核苷酸类似物;
其中N0-2为0至2、优选为0至1、更优选为1N的连续序列,其中每个N独立于另一个选自A、U、T、G和C的核苷酸或其核苷酸类似物;和
其中C是胞苷或其类似物,并且可以任选地被鸟苷或其类似物取代,条件是其在茎1中的互补核苷鸟苷被胞苷取代;
其中,
茎1和茎2能够彼此碱基配对形成反向互补序列,其中碱基配对可以发生在茎1和茎2之间,例如,通过核苷酸A和U/T或G和C的沃森-克里克碱基配对或通过非沃森-克里克碱基配对例如摆动碱基配对、反向沃森-克里克碱基配对、胡斯坦碱基配对(Hoogsteen basepairing)、反向胡斯坦碱基配对或者能够彼此碱基配对形成部分反向互补序列,其中不完全碱基配对可以发生在茎1和茎2之间,根据一个茎中的一个或多个碱基在另一个茎的反向互补序列中不具有互补碱基。
根据另一个优选的实施方案,组蛋白茎环序列可以根据以下具体式(Ia)或(IIa)中的至少一个进行选择:
式(Ia)(无茎边界元件的茎环序列):
式(IIa)(具有茎边界元件的茎环序列):
其中:
N、C、G、T和U如上所定义。
根据第一方面的另一个更特别优选的实施方案,人工核酸分子序列可以包含至少一个根据以下具体式(Ib)或(IIb)中的至少一个的组蛋白茎环序列:
式(Ib)(无茎边界元件的茎环序列):
式(IIb)(具有茎边界元件的茎环序列):
其中:
N、C、G、T和U如上所定义。
特别优选的组蛋白茎环序列是根据SEQ ID NO:16:CAAAGGCTCTTTTCAGAGCCACCA的序列,或更优选地根据SEQ ID NO:17:caaaggcucuuuucagagccacca的相应RNA序列。
5'-非翻译区(5'-UTR):5'-UTR通常被理解为信使RNA(mRNA)的特定部分。它位于mRNA的开放阅读框的5'端。通常,5'-UTR从转录起始位点开始,并在开放阅读框的起始密码子之前的一个核苷酸处结束。5'-UTR可以包含用于控制基因表达的元件,该元件也称为调控元件。这样的调控元件可以是,例如,核糖体结合位点。5'-UTR可以是经过转录后修饰的,例如通过添加5'-帽子。在本发明的上下文中,5'-UTR对应于位于5'-帽子和起始密码子之间的成熟mRNA的序列。优选地,5'-UTR对应于从位于5'-帽子的3'端的核苷酸(优选从位于5’-帽子的3'端后紧接的核苷酸)延伸至位于蛋白质编码区的起始密码子5'端的核苷酸(优选延伸至蛋白质编码区的起始密码子的5'端后紧接的核苷酸)的序列。位于成熟mRNA的5'-帽子的3'端后紧接的核苷酸通常对应于转录起始位点。术语“对应于”指的是5'-UTR序列可以是RNA序列(例如在用于定义5'-UTR序列的mRNA序列中),或者是对应于这种RNA序列的DNA序列。在本发明的上下文中,术语“基因的5'-UTR”是对应于来源于该基因的成熟mRNA(即通过基因的转录和早熟mRNA的成熟化而获得的mRNA)的5'-UTR的序列。术语“基因的5'-UTR”包含5'-UTR的DNA序列和RNA序列。
克隆位点:克隆位点通常被理解为核酸分子片段,其适用于插入核酸分子例如包含开放阅读框的核酸序列分子。可以通过本领域技术人员已知的任何分子生物学方法来插入核酸分子,例如通过限制和连接。克隆位点通常包含一个或多个限制酶识别位点(限制性位点)。这些一个或多个限制性位点可以被在这些位点切割DNA的限制酶识别。包含多于一个限制性位点的克隆位点也可以被称为多克隆位点(MCS)或多聚接头。
开放阅读框:在本发明上下文中的开放阅读框(ORF)通常可以是可以被翻译成肽或蛋白质的几个核苷酸三联体的序列。开放阅读框优选在其5'末端和随后的区域含有起始密码子,即通常编码氨基酸甲硫氨酸的三个紧接的核苷酸的组合(ATG),通常具有为3个核苷酸倍数的长度。ORF优选由终止密码子(例如TAA、TAG、TGA)终止。通常地,这是开放阅读框的唯一终止密码子。因此,在本发明上下文中,开放阅读框优选为由以起始密码子(例如ATG)开始并且优选以终止密码子(例如TAA、TGA或TAG)终止的多个可被三整除的核苷酸组成的核苷酸序列。开放阅读框可以是单独的,或者可以并入在更长的核酸序列中,例如并入在载体或mRNA中。开放阅读框也可以被称为“蛋白质编码区”。
体外转录:术语“体外转录”涉及其中RNA在无细胞系统(体外)中合成的过程。DNA,特别是质粒DNA,用作产生RNA转录物的模板。RNA可以通过对适当DNA模板进行DNA依赖性体外转录获得,根据本发明适当DNA模板优选为线性化的质粒DNA模板。用于控制体外转录的启动子可以是任何DNA依赖性RNA聚合酶的任何启动子。DNA依赖性RNA聚合酶的具体示例是T7、T3和SP6RNA聚合酶。通过对核酸(特别是对应于待体外转录的相应RNA的cDNA)的克隆并将其引入至用于体外转录的适当载体(例如引入至质粒DNA)可以获得用于体外RNA转录的DNA模板。在本发明的含义之内,在对DNA模板进行体外转录之前,通过本发明的方法对DNA模板进行线性化。cDNA可以通过mRNA的逆转录或化学合成获得。此外,用于体外RNA合成的DNA模板也可以通过基因合成获得。
用于体外转录的方法是本领域已知的(Geall等人(2013)Semin.Immunol.25(2):152-159;Brunelle等人(2013)Methods Enzymol.30:101-14)。
所述方法中使用的试剂通常包括:
1)具有对其各自的RNA聚合酶(如噬菌体编码的RNA聚合酶)具有高结合亲和力的启动子序列的线性化的DNA模板(如上所定义)
2)四种碱基(腺嘌呤、胞嘧啶、鸟嘌呤和尿嘧啶)的核糖核苷三磷酸(NTP);
3)任选地如上定义的帽子类似物(例如m7G(5')ppp(5')G(m7G));
4)能够结合至线性化的DNA模板内的启动子序列的DNA依赖性RNA聚合酶(例如T7、T3或SP6RNA聚合酶);
5)任选的灭活任何污染的核糖核酸酶的核糖核酸酶(RNase)抑制剂;
6)任选的降解可以抑制转录的焦磷酸的焦磷酸酶;
7)提供作为聚合酶的辅因子的Mg2+离子的MgCl2;
8)保持适当的pH值的缓冲液,其还可含有最佳浓度的抗氧化剂(例如DTT)和聚胺如亚精胺。
根据优选的实施方案,(转录)缓冲液选自由4-(2-羟乙基)-1-哌嗪乙磺酸(HEPES)和三(羟甲基)氨基甲烷(Tris)组成的组。优选地,缓冲液以10至100mM、10至75mM、10至50mM、10至40mM、10至30mM或10至20mM的浓度使用。可以用例如NaOH、KOH或HCl调节缓冲液的pH值。优选地,缓冲液具有6至8.5、6.5至8.0、7.0至7.5,甚至更优选7.5的pH值。最优选的是选自由80mM HEPES/KOH(pH 7.5)和40mM Tris/HCl(pH 7.5)组成的组的缓冲液。
根据本发明的优选的实施方案,RNA聚合酶选自由T3、T7和SP6RNA聚合酶组成的组。优选地,RNA聚合酶的浓度为约1至100nM、1至90nM、1至80nM、1至70nM、1至60nM、1至50nM、1至40nM、1至30nM、1至20nM、或约1至10nM。甚至更优选的是,RNA聚合酶的浓度为约10至50nM、20至50nM、或30至50nM。最优选的是约40nM的RNA聚合酶浓度。本领域技术人员可以理解RNA聚合酶浓度的选择受DNA模板浓度的影响。因此,在具体实施方案中,RNA聚合酶的浓度在1至1000U/μg模板DNA之间,优选10至100U/μg DNA之间,特别是如果使用质粒DNA作为模板DNA。
根据本发明的优选的实施方案,线性DNA模板的浓度在约1至50nM、1至40nM、1至30nM、1至20nM或约1至10nM的范围内。甚至更优选DNA模板的浓度为约10至30nM。最优选DNA模板的浓度约为20nM。在使用质粒DNA作为DNA模板的情况下,DNA模板的浓度优选在1至100μg/ml之间,特别是约50μg/ml的浓度。
根据本发明的优选的实施方案,体外转录在焦磷酸酶的存在下进行。优选地,焦磷酸酶的浓度为约1至20单位/ml、1至15单位/ml、1至10单位/ml、1至5单位/ml或1至2.5单位/ml。甚至更优选的焦磷酸酶的浓度为约5单位/ml。
根据本发明的优选的实施方案,体外转录反应混合物包含Mg2+离子。优选地,Mg2+离子以MgCl2或Mg(OAc)2的形式提供。优选地,初始游离Mg2+浓度为约1至100mM、1至75mM、1至50mM、1至25mM或1至10mM。甚至更优选的是,初始游离Mg2+浓度为约10至30mM或约15至25mM。最优选的是约24mM的初始游离Mg2+浓度。本领域技术人员将理解,Mg2+浓度的选择受初始总NTP浓度的影响。
根据本发明的优选的实施方案,体外转录反应混合物包含还原剂(抗氧化剂)以保持RNA聚合酶处于其活性状态。优选地,还原剂选自由二硫苏糖醇(DTT)、二硫赤藓糖醇(DTE)、三(2-羧乙基)膦(TCEP)和β-巯基乙醇组成的组。优选地,还原剂的浓度为约1至50mM、1至40mM、1至30mM、或1至20mM或1至10mM。甚至更优选的还原剂的浓度为10至50mM或20至40mM。最优选的是浓度为40mM的DTT。
根据本发明的优选的实施方案,体外转录反应混合物包含聚胺。优选地,聚胺选自由精胺和亚精胺组成的组。优选地,聚胺的浓度为约1至25mM、1至20mM、1至15mM、1至10mM、1至5mM或约1至2.5mM。甚至更优选的聚胺的浓度为约2mM。最优选浓度为2mM的亚精胺。
根据本发明的优选的实施方案,体外转录反应混合物包含核糖核酸酶抑制剂。优选地,核糖核酸酶抑制剂的浓度为约1至500单位/ml、1至400单位/ml、1至300单位/ml、1至200单位/ml或1至100单位/ml。甚至更优选的核糖核酸酶抑制剂的浓度为约200单位/ml。
根据本发明的优选的实施方案,体外转录反应混合物中的总NTP浓度在1至100mM之间,优选在10至50mM之间,并且最优选在10至20mM之间。
根据本发明,术语总核苷酸浓度是指NTP的总浓度,例如当反应的各种组分已经组装在用于进行体外转录反应的最终体积中时,最初存在于体外转录中的ATP、GTP、CTP、UTP和/或帽子类似物的浓度的总和。当然,随着反应的进行,核苷酸将被纳入RNA分子,因此总核苷酸浓度将从其初始值逐渐降低。
在本文中,特别优选单个核苷酸以在0.1至10mM之间、优选在1至5mM之间的浓度提供,并且最优选以4mM的浓度提供。
如果需要在RNA的5'-末端产生如上定义的5'帽子,则体外转录反应混合物还包含帽子类似物。在本文中,与其它核苷酸(ATP、CTP和UTP)相比,GTP的浓度优选被降低。优选地,以在约1至20mM、1至17.5mM、1至15mM、1至12.5mM、1至10mM、1至7.5mM的范围内的初始浓度加入帽子类似物。最优选地,帽子类似物以5.8mM的浓度加入,并且GTP浓度降低至1.45mM的浓度,而ATP、CTP和UTP各自以4mM的浓度包含在反应中。
核糖核苷三磷酸(NTP)GTP、ATP、CTP和UTP或其类似物可以具有作为反离子的一价或二价阳离子。优选地,一价阳离子选自由Li+、Na+、K+、NH4+或三(羟甲基)-氨基甲烷(Tris)组成的组。优选地,二价阳离子选自由Mg2+、Ba2+和Mn2+组成的组。
根据本发明的优选的实施方案,体外转录反应混合物中的至少一种核糖核苷三磷酸的部分或全部被经过修饰的核苷三磷酸(如本文所定义)所替代。在本发明的优选的实施方案中,所述经过修饰的核苷三磷酸选自由假尿苷-5'-三磷酸、1-甲基假尿苷-5'-三磷酸、2-硫尿苷-5'-三磷酸、4-硫尿苷-5'-三磷酸和5-甲基胞苷-5'-三磷酸组成的组。
体外转录发生后,使RNA产物经受纯化方法。在本文中可以采用任何纯化方法(例如DNA模板消化、苯酚-氯仿萃取、LiCl沉淀、HPLC等)。
质粒DNA:术语“质粒DNA”是指环状核酸分子,优选为人工的核酸分子。本发明上下文中的质粒DNA适用于并入或携带所需的核酸序列,例如包含RNA编码序列和/或编码至少一种肽或多肽的开放阅读框的核酸序列。这样的质粒DNA构建体可以是存储载体、表达载体、克隆载体、转移载体等。存储载体是允许方便地存储核酸分子(例如RNA分子)的载体。因此,质粒DNA可以包含对应于(编码)例如靶标RNA序列或其部分序列(诸如对应于mRNA的开放阅读框和5'和/或3'UTR的序列)的序列。表达载体可用于在称为体外转录的过程中产生表达产物,例如RNA,诸如mRNA。例如,表达载体可以包含对载体的序列片段进行体外转录所需的序列,例如启动子序列,例如RNA启动子序列,优选T3、T7或SP6RNA启动子序列。克隆载体通常是含有可以用于将核酸序列并入(插入)载体中的克隆位点的载体。克隆载体可以是例如质粒载体或噬菌体载体。转移载体可以是适合于将核酸分子转移到细胞或生物体中的载体,例如病毒载体。优选地,本发明含义内的质粒DNA载体包含多克隆位点、RNA启动子序列、任选的选择标记物例如抗生素抗性因子、以及适合于载体复制的序列,例如复制起点。形成待体外转录的RNA模板的DNA可以作为可以在细菌中复制的质粒的部分通过发酵增殖和随后的分离来制备。在本发明的上下文中特别优选的是质粒DNA载体或表达载体,包含DNA依赖性RNA聚合酶例如T3、T7和Sp6的启动子。作为质粒骨架,特别优选的是pUC19和pBR322。
抗原:在本发明的上下文中,“抗原”通常是指可被免疫系统、优选被适应性免疫系统识别的物质,并且能够引发抗原特异性免疫应答,例如通过形成抗体和/或抗原特异性T细胞作为适应性免疫应答的一部分。通常地,抗原可以是或可以包含可由MHC呈递至T细胞并包含至少一个表位的肽或蛋白质。特别地,抗原可以是致病性抗原或肿瘤抗原。
致病性抗原:mRNA可编码包含致病性抗原或其片段、突变体或衍生物的蛋白质或肽。这种致病性抗原来源于致病生物体,特别是细菌、病毒或原生动物(多细胞)致病性生物体,其引起受试者、特别是哺乳动物受试者、更特别是人类的免疫反应。更具体地,致病性抗原优选是表面抗原,例如位于病毒或细菌或原生生物体表面的蛋白质(或蛋白质片段,例如表面抗原的外部部分)。
致病性抗原是优选来源于与感染性疾病有关的病原体的肽或蛋白质抗原,其优选地选自来源于以下病原体的抗原:鲍氏不动杆菌(Acinetobacter baumannii)、无形体属(Anaplasma genus)、嗜吞噬细胞无形体(Anaplasma phagocytophilum)、巴西钩虫(Ancylostoma braziliense)、十二指肠钩虫(Ancylostoma duodenale)、溶血隐秘杆菌(Arcanobacterium haemolyticum)、人蛔虫(Ascaris lumbricoides)、曲霉属(Aspergillus genus)、星状病毒科(Astroviridae)、巴贝斯属(Babesia genus)、炭疽杆菌(Bacillus anthracis)、蜡状芽孢杆菌(Bacillus cereus)、汉赛巴尔通体(Bartonellahenselae)、BK病毒、人芽囊原虫(Blastocystis hominis)、皮炎芽生菌(Blastomycesdermatitidis)、百日咳博德特菌(Bordetella pertussis)、伯氏疏螺旋体(Borreliaburgdorferi)、疏螺旋体属(Borrelia genus)、疏螺旋体属(Borrelia spp)、布鲁氏菌属(Brucella genus)、马来丝虫(Brugia malayi)、布尼亚病毒科(Bunyaviridae family)、洋葱伯克霍尔德氏菌(Burkholderia cepacia)和其它伯克霍尔德氏菌物种、鼻疽伯克霍尔德氏菌(Burkholderia mallei)、类鼻疽伯克霍尔德氏菌(Burkholderia pseudomallei)、杯状病毒科(Caliciviridae family)、弯曲杆菌属(Campylobacter genus)、白色念珠菌(Candida albicans)、念珠菌属(Candida spp)、沙眼衣原体(Chlamydia trachomatis)、肺炎衣原体(Chlamydophila pneumoniae)、鹦鹉热衣原体(Chlamydophila psittaci)、CJD朊病毒(CJD prion)、华支睾吸虫(Clonorchis sinensis)、肉毒梭菌(Clostridiumbotulinum)、艰难梭菌(Clostridium difficile)、产气荚膜梭菌(Clostridiumperfringens)、产气荚膜梭菌(Clostridium perfringens)、梭菌属(Clostridium spp)、破伤风梭菌(Clostridium tetani)、球孢子菌属(Coccidioides spp)、冠状病毒(coronaviruses)、白喉杆菌(Corynebacterium diphtheriae)、贝氏柯克斯体(Coxiellaburnetii)、克里米亚-刚果出血热病毒(Crimean-Congo hemorrhagic fever virus)、新型隐球菌(Cryptococcus neoformans)、隐孢子虫属(Cryptosporidium genus)、巨细胞病毒(Cytomegalovirus,CMV)、登革热病毒(Dengue viruses,DEN-1、DEN-2、DEN-3和DEN-4)、脆双核阿米巴(Dientamoeba fragilis)、埃博拉病毒(Ebolavirus,EBOV)、棘球绦虫属(Echinococcus genus)、查菲埃立克体(Ehrlichia chaffeensis)、伊氏埃立克体(Ehrlichia ewingii)、埃立克体属(Ehrlichia genus)、溶组织内阿米巴(Entamoebahistolytica)、肠球菌属(Enterococcus genus)、肠道病毒属(Enterovirus genus)、肠道病毒(Enteroviruses)、主要地甲类柯萨奇病毒(Coxsackie A virus)和肠道病毒71型(Enterovirus 71)、表皮癣菌属(Epidermophyton spp)、人类疱疹病毒第四型(Epstein-Barr Virus,EBV)、大肠杆菌(Escherichia coli)O157:H7、O111和O104:H4,肝片吸虫(Fasciola hepatica)和巨片吸虫(Fasciola gigantica)、FFI朊病毒(FFI prion)、丝虫目超家族(Filarioidea superfamily)、黄病毒属(Flaviviruses)、土拉弗朗西斯菌(Francisella tularensis)、梭杆菌属(Fusobacterium genus)、白地霉(Geotrichumcandidum)、肠贾第虫(Giardia intestinalis)、颚口线虫属(Gnathostoma spp)、GSS朊病毒(GSS prion)、瓜纳里托病毒(Guanarito virus)、杜克雷嗜血杆菌(Haemophilusducreyi)、流感嗜血杆菌(Haemophilus influenzae)、幽门螺杆菌(Helicobacterpylori)、亨德拉尼帕病毒(Henipavirus)(亨德拉病毒尼帕病毒,Hendra virus Nipahvirus)、甲型肝炎病毒(Hepatitis A Virus)、乙型肝炎病毒(Hepatitis B Virus,HBV)、丙型肝炎病毒(Hepatitis C Virus,HCV)、丁型肝炎病毒(Hepatitis D Virus)、戊型肝炎病毒(Hepatitis E Virus)、单纯疱疹病毒(Herpes simplex virus)1和2(HSV-1和HSV-2)、荚膜组织胞浆菌(Histoplasma capsulatum)、HIV(人类免疫缺陷病毒)、威尼克外瓶霉(Hortaea werneckii)、人博卡病毒(Human bocavirus,HBoV)、人疱疹病毒6(Humanherpesvirus 6,HHV-6)和人疱疹病毒7(Human herpesvirus 7,HHV-7)、人偏肺病毒(Humanmetapneumovirus,hMPV)、人乳头瘤病毒(Human papillomavirus,HPV)、人副流感病毒(Human parainfluenza viruses,HPIV)、日本脑炎病毒(Japanese encephalitis virus)、JC病毒(JC virus)、胡宁病毒(Junin virus)、金氏金氏菌(Kingella kingae)、肉芽肿克雷白式杆菌(Klebsiella granulomatis)、库鲁朊病毒(Kuru prion)、拉沙病毒(Lassavirus)、嗜肺军团菌(Legionella pneumophila)、利什曼原虫属(Leishmania genus)、钩端螺旋体属(Leptospira genus)、单核细胞增生性李斯特菌(Listeria monocytogenes)、淋巴细胞性脉络丛脑膜炎病毒(Lymphocytic choriomeningitis virus,LCMV)、马丘波病毒(Machupo virus)、马拉色菌属(Malassezia spp)、马尔堡病(Marburg virus)、麻疹病毒(Measles virus)、横川后殖吸虫(Metagonimus yokagawai)、微孢子虫门(Microsporidiaphylum)、传染性软疣病毒(Molluscum contagiosum virus,MCV)、腮腺炎病毒(Mumpsvirus)、麻风分枝杆菌(Mycobacterium leprae)和弥漫型麻风分枝杆菌(Mycobacteriumleprae)、结核分枝杆菌(Mycobacterium tuberculosis)、溃疡分枝杆菌(Mycobacteriumulcerans)、肺炎支原体(Mycoplasma pneumoniae)、福氏耐格里阿米巴(Naegleriafowleri)、美洲钩虫(Necator americanus)、淋病奈瑟菌(Neisseria gonorrhoeae)、脑膜炎奈瑟球菌(Neisseria meningitidis)、星状诺卡氏菌(Nocardia asteroides)、诺卡氏菌属(Nocardia spp)、旋盘尾丝虫(Onchocerca volvulus)、恙虫病东方体(Orientiatsutsugamushi)、正粘病毒科(流感)(Orthomyxoviridae family(Influenza))、巴西副球孢子菌(Paracoccidioides brasiliensis)、并殖吸虫属(Paragonimus spp)、卫氏并殖吸虫(Paragonimus westermani)、细小病毒B19(Parvovirus B19)、巴氏杆菌属(Pasteurellagenus)、疟原虫属(Plasmodium genus)、卡氏肺孢子虫(Pneumocystis jirovecii)、脊髓灰质炎病毒(Poliovirus)、狂犬病病毒(Rabies virus)、呼吸道合胞病毒(Respiratorysyncytial virus,RSV)、鼻病毒(Rhinovirus)、鼻病毒(rhinoviruses)、小蛛立克次氏体(Rickettsia akari)、立克次氏体属(Rickettsia genus)、普氏立克次氏体(Rickettsiaprowazekii)、立氏立克次氏体(Rickettsia rickettsii)、斑疹伤寒立克次氏体(Rickettsia typhi)、裂谷热病毒(Rift Valley fever virus)、轮状病毒(Rotavirus)、风疹病毒(Rubella virus)、沙比亚病毒(Sabia virus)、沙门氏菌属(Salmonella genus)、疥螨(Sarcoptes scabiei)、SARS冠状病毒(SARS coronavirus)、血吸虫属(Schistosomagenus)、志贺氏菌属(Shigella genus)、辛诺柏病毒(Sin Nombre virus)、汉坦病毒(Hantavirus)、申克孢子丝菌(Sporothrix schenckii)、葡萄球菌属(Staphylococcusgenus)、葡萄球菌属(Staphylococcus genus)、无乳链球菌(Streptococcus agalactiae)、肺炎链球菌(Streptococcus pneumoniae)、酿脓链球菌(Streptococcus pyogenes)、粪类圆线虫(Strongyloides stercoralis)、绦虫属(Taenia genus)、有钩绦虫(Taeniasolium)、蜱传脑炎病毒(Tick-borne encephalitis virus,TBEV)、犬弓蛔虫(Toxocaracanis)或猫弓蛔虫(Toxocara cati)、刚地弓形虫(Toxoplasma gondii)、梅毒螺旋体(Treponema pallidum)、旋毛虫(Trichinella spiralis)、阴道毛滴虫(Trichomonasvaginalis)、毛癣菌属(Trichophyton spp)、鞭虫(Trichuris trichiura)、布氏锥虫(Trypanosoma brucei)、克氏锥虫(Trypanosoma cruzi)、解脲支原体(Ureaplasmaurealyticum)、水痘带状疱疹病毒(Varicella zoster virus,VZV)、水痘带状疱疹病毒(Varicella zoster virus,VZV)、重型天花(Variola major)或类天花(Variola minor)、vCJD朊病毒(vCJD prion)、委内瑞拉马脑炎病毒(Venezuelan equine encephalitisvirus)、霍乱弧菌(Vibrio cholerae)、西尼罗病毒(West Nile virus)、西部马脑炎病毒(Western equine encephalitis virus)、班氏吴策线虫(Wuchereria bancrofti)、黄热病毒(Yellow fever virus)、小肠结肠炎耶尔森氏菌(Yersinia enterocolitica)、鼠疫耶尔森氏菌(Yersinia pestis)和假结核耶尔森氏菌(Yersinia pseudotuberculosis)。
在本发明的上下文中,特别优选的是来自选自以下的病原体的抗原:流感病毒(Influenza virus)、呼吸道合胞病毒(respiratory syncytial virus,RSV)、单纯疱疹病毒(Herpes simplex virus,HSV)、人乳头瘤病毒(human Papilloma virus,HPV)、人免疫缺陷病毒(Human immunodeficiency virus,HIV)、疟原虫(Plasmodium)、金黄色酿脓葡萄球菌(Staphylococcus aureus)、登革热病毒(Dengue virus)、沙眼衣原体(Chlamydiatrachomatis)、巨细胞病毒(Cytomegalovirus,CMV)、乙型肝炎病毒(Hepatitis B virus,HBV)、结核分枝杆菌(Mycobacterium tuberculosis)、狂犬病病毒(Rabies virus)和黄热病毒(Yellow Fever Virus)。
在优选实施方案中,mRNA编码狂犬病病毒蛋白或肽或其抗原性片段。优选地,mRNA编码选自由狂犬病病毒的糖蛋白G(RAV-G)、核蛋白N(RAV-N)、磷蛋白P(RAV-P)、基质蛋白M(RAV-M)或RNA聚合酶L(RAV-L)或其片段、突变体或衍生物组成的组的抗原蛋白或肽。
在其它优选实施方案中,根据本发明的mRNA编码呼吸道合胞病毒(RSV)蛋白或肽或其抗原性片段。优选地,根据本发明的mRNA编码选自由呼吸道合胞病毒(RSV)的融合蛋白F、糖蛋白G、短疏水蛋白SH、基质蛋白M、核蛋白N、大聚合酶L、M2-1蛋白、M2-2蛋白、磷蛋白P、非结构蛋白NS1或非结构蛋白NS2或其片段、突变体或衍生物组成的组的抗原蛋白或肽。
肿瘤抗原:在另外的实施方案中,根据本发明的mRNA可以编码蛋白质或肽,其包含含有肿瘤抗原、所述肿瘤抗原的片段、突变体或衍生物的肽或蛋白质,优选地,其中肿瘤抗原是黑素细胞特异性抗原、癌症-睾丸抗原或肿瘤特异性抗原,优选为CT-X抗原、非-X CT-抗原、CT-X抗原的结合配偶体或非-X CT-抗原的结合配偶体或肿瘤特异性抗原,更优选为CT-X抗原、非-X CT-抗原的结合配偶体或肿瘤特异性抗原或所述肿瘤抗原的片段、突变体或衍生物;并且其中每个核酸序列编码不同的肽或蛋白质;并且其中至少一个核酸序列编码5T4、707-AP、9D7、AFP、AlbZIP HPG1、α-5-β-1-整合素、α-5-β-6-整合素、α-辅肌动蛋白-4/m、α-甲基酰基-辅酶A消旋酶、ART-4、ARTC1/m、B7H4、BAGE-1、BCL-2、bcr/abl、β-连环蛋白/m、BING-4、BRCA1/m、BRCA2/m、CA 15-3/CA 27-29、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、毛状蛋白样蛋白、胶原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、蛋白酶(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、未成熟的层粘连蛋白受体、激肽释放酶-2、激肽释放酶-4、Ki67、KIAA0205、KIAA0205/m、KK-LC-1、K-Ras/m、LAGE-A1、LDLR-FUT、MAGE-A1、MAGE-A2、MAGE-A3、MAGE-A4、MAGE-A6、MAGE-A9、MAGE-A10、MAGE-A12、MAGE-B1、MAGE-B2、MAGE-B3、MAGE-B4、MAGE-B5、MAGE-B6、MAGE-B10、MAGE-B16、MAGE-B17、MAGE-C1、MAGE-C2、MAGE-C3、MAGE-D1、MAGE-D2、MAGE-D4、MAGE-E1、MAGE-E2、MAGE-F1、MAGE-H1、MAGEL2、乳腺珠蛋白A、MART-1/黑色素-A、MART-2、MART-2/m、基质蛋白22、MC1R、M-CSF、ME1/m、间皮蛋白、MG50/PXDN、MMP11、MN/CA IX-抗原、MRP-3、MUC-1、MUC-2、MUM-1/m、MUM-2/m、MUM-3/m、肌球蛋白类I/m、NA88-A、N-乙酰葡糖胺转移酶-V、Neo-PAP、Neo-PAP/m、NFYC/m、NGEP、NMP22、NPM/ALK、N-Ras/m、NSE、NY-ESO-1、NY-ESO-B、OA1、OFA-iLRP、OGT、OGT/m、OS-9、OS-9/m、骨钙蛋白、骨桥蛋白、p15、p190m型bcr-abl、p53、p53/m、PAGE-4、PAI-1、PAI-2、PAP、PART-1、PATE、PDEF、Pim-1-激酶、Pin-1、Pml/PARα、POTE、PRAME、PRDX5/m、前列腺特异性蛋白(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-1、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、VEGFR1、VEGFR-2/FLK-1、WT1和淋巴血细胞的免疫球蛋白独特型或淋巴血细胞的T细胞受体独特型、或所述肿瘤抗原的片段、突变体或衍生物;优选为存活蛋白或其同源物,来自MAGE家族或其结合配偶体的抗原或所述肿瘤抗原的片段、突变体或衍生物。
在本文中特别优选的是肿瘤抗原NY-ESO-1、5T4、MAGE-C1、MAGE-C2、存活蛋白、Muc-1、PSA、PSMA、PSCA、STEAP和PAP。
以下抗原组合是特别优选的:
·Muc-1、PSA、PSMA、PSCA和STEAP
·Muc-1、PSA、PSMA、PSCA和PAP
·Muc-1、PSA、PSMA、STEAP和PAP
·Muc-1、PSA、PSCA、STEAP和PAP
·Muc-1、PSMA、PSCA、STEAP和PAP
·PSA、PSMA、PSCA、STEAP和PAP
·Muc-1、PSA、PSMA、PSCA、STEAP和PAP
此外,以下抗原组合是特别优选的:
·NY-ESO-1、5T4、MAGE-C1、MAGE-C2、和存活蛋白
·NY-ESO-1、5T4、MAGE-C1、MAGE-C2、和Muc-1
·NY-ESO-1、5T4、MAGE-C1、、存活蛋白和Muc-1
·NY-ESO-1、5T4、MAGE-C2、存活蛋白和Muc-1
·NY-ESO-1、MAGE-C1、MAGE-C2、存活蛋白和Muc-1
·5T4、MAGE-C1、MAGE-C2、存活蛋白和Muc-1
·NY-ESO-1、5T4、MAGE-C1、MAGE-C2、存活蛋白和Muc-1
治疗性蛋白质:如本文所定义的治疗性蛋白质是有利于治疗任何遗传性或获得性疾病或改善个体病症的肽或蛋白质。特别地,治疗性蛋白质在创造能够修改和修复遗传错误、破坏癌细胞或病原体感染的细胞、治疗免疫系统紊乱、治疗代谢或内分泌紊乱和其它功能的治疗剂中起重要作用。例如,促红细胞生成素(EPO)是一种可用于治疗红细胞缺乏症患者的蛋白激素,红细胞缺乏症是肾脏并发症的常见原因。此外,佐剂蛋白质、治疗性抗体包含在治疗性蛋白质和例如用于治疗更年期妇女的激素替代疗法中。在更新的方法中,患者的体细胞被用于将其重编程为多能干细胞,这代替了有争议的干细胞治疗。此外,这些用于重编程体细胞或用于分化干细胞的蛋白质在本文中定义为治疗性蛋白质。此外,治疗性蛋白质可以用于其它目的,例如伤口愈合、组织再生、血管生成等。
因此,治疗性蛋白质可以用于各种目的,包括独立地治疗各种疾病(如果它们是遗传或获得的),如例如,传染性疾病,赘生物(例如癌症或肿瘤疾病),血液和造血器官疾病,内分泌、营养和代谢疾病,神经系统疾病,循环系统疾病,呼吸系统疾病,消化系统疾病,皮肤和皮下组织疾病,肌肉骨骼系统和结缔组织疾病,以及泌尿生殖系统疾病。
在本文中,特别优选可用于尤其是治疗代谢或内分泌疾病的治疗性蛋白质选自:酸性鞘磷脂酶(尼曼-匹克病)、脂肪蛋白(Adipotide)(肥胖症)、半乳糖苷酶-β(人半乳糖苷酶A)(法布里病,防止可能导致肾和心血管并发症的脂质积累)、阿葡糖苷酶(庞贝氏(Pompe)病(Ⅱ型糖原贮积病))、α-半乳糖苷酶A(α-GAL A、半乳糖苷酶-α)(法布里病)、α-葡糖苷酶(糖原贮积病(GSD)、庞贝氏病(Morbus Pompe))、α-L-艾杜糖醛酸酶(粘多糖贮积病(MPS)、赫尔勒综合征、谢伊综合征)、α-N-乙酰葡糖胺糖苷酶(圣菲利普综合征)、双调蛋白(癌症、代谢紊乱)、血管位蛋白(Ang1、Ang2、Ang3、Ang4、ANGPTL2、ANGPTL3、ANGPTL4、ANGPTL5、ANGPTL6、ANGPTL7)(血管生成、稳定血管)、乙胞素(代谢紊乱)、β-葡糖醛酸糖苷酶(Sly综合征)、骨形态发生蛋白BMP(BMP1、BMP2、BMP3、BMP4、BMP5、BMP6、BMP7、BMP8a、BMP8b、BMP10、BMP15)(再生作用、骨相关病症、慢性肾病(CKD))、CLN6蛋白(CLN6疾病-非典型晚期婴儿、迟发型变异、早期青少年(Early Juvenile)、神经元蜡样脂褐质沉积症(NCL))、表皮生长因子(EGF)(伤口愈合、调节细胞生长、增殖和分化)、上皮细胞有丝分裂蛋白抗体(Epigen)(代谢紊乱)、上皮调节蛋白(Epiregulin)(代谢紊乱)、成纤维细胞生长因子(FGF、FGF-1、FGF-2、FGF-3、FGF-4、FGF-5、FGF-6、FGF-7、FGF-8、FGF-9、FGF-10、FGF-11、FGF-12、FGF-13、FGF-14、FGF-16、FGF-17、FGF-17、FGF-18、FGF-19、FGF-20、FGF-21、FGF-22、FGF-23)(伤口愈合、血管生成,内分泌失调,组织再生)、加硫酶(VI型粘多糖贮积症)、饥饿激素(肠易激综合征(IBS)、肥胖症、普拉德-威利综合征、II型糖尿病)、葡糖脑苷脂酶(高歇氏病)、GM-CSF(再生作用、白细胞产生、癌症)、肝素结合EGF样生长因子(HB-EGF)(伤口愈合、心脏肥大和心脏发育和功能)、肝细胞生长因子HGF(再生作用、伤口愈合)、铁调素(铁代谢紊乱、β-地中海贫血)、人白蛋白(白蛋白产生减少(低蛋白血症)、白蛋白损失增加(肾病综合征)、低血容量症、高胆红素血症)、艾杜硫酶(艾杜糖醛酸-2-硫酸酯酶)(II型粘多糖贮积症(亨特综合征))、整合素αVb3、αVb5和α5b1(结合基质大分子和蛋白酶、血管生成)、艾杜糖醛酸硫酸酯酶(亨特综合征)、拉罗尼酶(赫尔勒和赫尔勒-谢伊形式的I型粘多糖贮积症)、N-乙酰基半乳糖胺-4-硫酸酯酶(rhASB;加硫酶、芳基硫酸酯酶A(ARSA)、芳基硫酸酯酶B(ARSB))(芳基硫酸酯酶B缺乏症、Maroteaux-Lamy综合征、VI型粘多糖贮积症)、N-乙酰葡糖胺-6-硫酸酯酶(圣菲利普综合征)、神经生长因子(NGF、脑源性神经营养因子(BDNF)、神经营养因子-3(NT-3)、神经营养因子4/5(NT-4/5)(再生作用、心血管疾病、冠状动脉粥样硬化、肥胖症、2型糖尿病、代谢综合征、急性冠状动脉综合征、痴呆、抑郁症、精神分裂症、自闭症、瑞特综合征、神经性厌食症、神经性暴食症、伤口愈合、皮肤溃疡、角膜溃疡、阿兹海默病)、神经调节蛋白(NRG1、NRG2、NRG3、NRG4)(代谢紊乱、精神分裂症)、神经纤毛蛋白(NRP-1、NRP-2)(血管生成、轴突导向、细胞存活、迁移)、肥胖抑制素(肠易激综合征(IBS)、肥胖症、普拉德-威利综合征、II型糖尿病)、血小板衍生生长因子(PDGF(PDFF-A、PDGF-B、PDGF-C、PDGF-D)(再生作用、伤口愈合、异常血管生成、动脉硬化、纤维化、癌症)、TGFβ受体(内皮因子、TGF-β1受体、TGF-β2受体、TGF-β3受体)(肾纤维化、肾脏疾病、糖尿病、最终终末期肾病(ESRD)、血管生成)、促血小板生成素(THPO)(巨核细胞生长和发育因子(MGDF))(血小板病症、血小板捐献、骨髓抑制化疗后血小板计数的恢复)、转化生长因子(TGF(TGF-α、TGF-β(TGFβ1、TGFβ2和TGFβ3)))(再生作用、伤口愈合、免疫力、癌症、心脏病、糖尿病、马凡综合征、Loeys-Dietis综合征)、VEGF(VEGF-A、VEGF-B、VEGF-C、VEGF-D、VEGF-E、VEGF-F和PIGF)(再生作用、血管生成、伤口愈合、癌症、渗透性)、奈西立肽(急性失代偿性充血性心力衰竭)、胰蛋白酶(褥疮性溃疡、静脉曲张性溃疡、焦痂清创、开裂的伤口、晒伤、胎粪性肠梗阻)、促肾上腺皮质激素(ACTH)(爱迪生氏病、小细胞癌、肾上腺脑白质营养不良、先天性肾上腺皮质增生症、库兴氏综合征、纳尔逊氏综合征、婴儿痉挛症)、心房钠尿肽(ANP)(内分泌失调)、肠促胰酶肽(多种)、胃泌素(高胃泌素血症)、瘦素(糖尿病、高甘油三酯血症、肥胖症)、催产素(刺激母乳喂养、分娩无进展)、生长激素抑制素(类癌综合征的对症治疗、急性静脉曲张出血和肢端肥大症、肝和肾的多囊性疾病、由神经内分泌肿瘤引起的肢端肥大症和症状)、加压素(抗利尿激素)(尿崩症)、降钙素(绝经后骨质疏松症、高钙血症、佩吉特病、骨转移癌、幻肢痛、椎管狭窄)、艾塞那肽(用二甲双胍和磺酰脲治疗耐药的2型糖尿病)、生长激素(GH)、促生长素(由于GH缺乏或慢性肾功能不全引起的生长障碍、普拉德-威利综合征、特纳综合征、艾滋病消瘦症或抗病毒治疗的恶病质)、胰岛素(糖尿病、糖尿病酮症酸中毒、高钾血症)、胰岛素样生长因子1IGF-1(GH基因缺失或重度原发性IGF1缺陷的儿童生长障碍、神经退行性疾病、心血管疾病、心力衰竭)、美卡舍明-林菲培、IGF-1类似物(GH基因缺失或重度原发性IGF1缺陷的儿童生长障碍、神经退行性疾病、心血管疾病、心力衰竭)、美卡舍明、IGF-1类似物(GH基因缺失或重度原发性IGF1缺陷的儿童生长障碍、神经退行性疾病、心血管疾病、心力衰竭)、培维索孟(肢端肥大症)、普兰林肽(糖尿病、与胰岛素联合)、特立帕肽(人甲状旁腺激素残基1-34)(严重骨质疏松症)、贝卡普勒明(糖尿病性溃疡的辅助清创)、阿法地博特明(骨形态发生蛋白2)(脊柱融合手术、骨损伤修复)、乙酸组氨瑞林(促性腺激素释放激素;GnRH)(性早熟)、奥曲肽(肢端肥大症、VIP分泌性腺瘤和转移性类癌肿瘤的症状缓解)和帕利夫明(角质形成细胞生长因子;KGF)(接受化疗的患者的严重口腔粘膜炎、伤口愈合)。
(在括号中的是治疗中使用的治疗性蛋白质的特定疾病)。
这些蛋白质和其它蛋白质被理解为治疗性的,因为它们是用于通过以足够量代替功能性蛋白质的缺陷性内源性产生来治疗受试者。因此,这样的治疗性蛋白质通常是哺乳动物、特别是人蛋白质。
对于血液紊乱、循环系统疾病、呼吸系统疾病、癌症或肿瘤疾病、感染性疾病或免疫缺陷的治疗,可以采用以下治疗性蛋白质:阿替普酶(组织型纤溶酶原激活剂;tPA)(肺栓塞、心肌梗塞、急性缺血性脑卒中、中心静脉通路装置阻塞)、阿尼普酶(血栓溶解)、抗凝血酶III(AT-III)(遗传性AT-III缺陷、血栓栓塞)、比伐卢定(冠状动脉血管成形术中的凝血风险降低和肝素诱导的血小板减少症)、达贝泊汀-α(治疗慢性肾功能不全和慢性肾功能衰竭(+/-透析)患者中的贫血)、Drotrecogin-α(活化的蛋白C)(具有高死亡风险的重症脓毒症)、红细胞生成素、依泊汀-α、促红细胞生成素、erthropoyetin(慢性疾病贫血、骨髓发育不良(myleodysplasia)、由于肾衰竭或化学疗法导致的贫血、术前准备)、因子IX(血友病B)、因子VIIa(血友病A或B的患者的出血和因子VIII或因子IX的抑制剂)、因子VIII(血友病A)、来匹卢定(肝素诱导的血小板减少症)、蛋白质C浓缩物(静脉血栓形成、暴发性紫癜)、瑞替普酶(删除突变蛋白质的tPA)(急性心肌梗塞的治疗、心室功能的改善)、链激酶(急性进展性透壁性心肌梗塞、肺栓塞、深静脉血栓形成、动脉血栓形成或栓塞、动静脉插管的闭塞)、替奈普酶(急性心肌梗塞)、尿激酶(肺栓塞)、血管抑制素(癌症)、抗CD22免疫毒素(复发性CD33+急性髓性白血病)、地尼白介素(皮肤T-细胞淋巴瘤(CTCL))、免疫花青素(膀胱癌和前列腺癌)MPS(金属泛激蛋白)(癌症)、阿柏西普(非小细胞肺癌(NSCLC)、转移性结直肠癌(mCRC)、激素抵抗性转移性前列腺癌、湿性黄斑变性)、内皮抑素(癌症、如类风湿性关节炎以及克罗恩氏病、糖尿病性视网膜病变、银屑病和子宫内膜异位症等炎性疾病)、胶原酶(慢性皮肤溃疡和严重烧伤区的清创术、杜普伊特伦挛缩症、佩罗尼氏病)、人脱氧核糖核酸酶I、链道酶(囊性纤维化;使选定FVC患者呼吸道感染比预期降低高于40%)、透明质酸酶(用作增加注射药物的吸收和分散的佐剂、特别是在眼科手术的麻醉剂和某些显像剂)、木瓜蛋白酶(急性和慢性损伤,如压迫性溃疡、静脉曲张和糖尿病性溃疡、烧伤、术后伤口、藏毛囊肿伤口、痈和其它伤口的坏死组织或液化现象的清创)、L-天冬酰胺酶(急性淋巴细胞白血病,其需要外源性天冬酰胺进行增殖)、Peg-天冬酰胺酶(急性淋巴细胞白血病,其需要外源性天冬酰胺进行增殖)、拉布立酶(白血病、淋巴瘤和实体瘤的儿科患者,他们正在接受可能引起肿瘤溶解综合征的抗癌治疗)、人绒毛膜促性腺激素(HCG)(辅助生殖)、人卵泡刺激激素(FSH)(辅助生殖)、促黄体素-α(促黄体激素缺乏的不孕症)、催乳素(低催乳素血症、血清催乳素缺乏症、女性卵巢功能障碍、焦虑、动脉性勃起功能障碍、早泄、少精子症、弱精子症、精囊功能减退、男性雄激素缺乏)、α1-蛋白酶抑制剂(先天性抗胰蛋白酶缺乏症)、乳糖酶(由于无法消化乳糖的气体、腹胀、腹部绞痛和腹泻)、胰腺酶(脂肪酶、淀粉酶、蛋白酶)(囊性纤维化、慢性胰腺炎、胰腺功能不全、后-Billroth II胃旁路手术、胰管梗阻、脂肪痢、消化不良、气体、腹胀)、腺苷脱氨酶(牛培格脱氨酶,PEG-ADA)(由于腺苷脱氨酶缺乏引起的严重联合免疫缺陷病)、阿巴西普(类风湿性关节炎(特别是对TNFα抑制难以治疗的情况下))、阿法西普(斑块型银屑病)、阿那白滞素(Anakinra)(类风湿性关节炎)、依那西普(类风湿性关节炎、多关节型幼年型类风湿关节炎、银屑病性关节炎、强直性脊柱炎、斑块型银屑病,强直性脊柱炎)、白细胞介素-1(IL-1)受体拮抗剂、阿那白滞素(与类风湿性关节炎有关的炎症和软骨退化)、胸腺肽(神经退行性疾病、风湿病、神经性厌食症)、TNF-α拮抗剂(例如类风湿性关节炎、强直性脊柱炎、克罗恩氏病、银屑病、化脓性汗腺炎、顽固性哮喘等自身免疫失调)、恩夫韦地(HIV-1感染)和胸腺素α1(乙型肝炎和丙型肝炎)。
(在括号中的是治疗中使用的治疗性蛋白质的特定疾病)
此外,佐剂或免疫刺激蛋白也包含在术语治疗性蛋白质中。佐剂或免疫刺激蛋白可用于本文中以诱导、改变或改善个体的免疫应答以治疗特定疾病或改善个体的病症。
在本文中,佐剂蛋白质可以选自哺乳动物、特别是人佐剂蛋白质,其通常包含能够引发先天性免疫应答(在哺乳动物中)的任何人蛋白质或肽,例如作为外源性TLR配体与TLR结合的反应。更优选地,人佐剂蛋白质选自由以下蛋白质组成的组,这些蛋白质是包括TLR、NLR和RLH的模式识别受体信号转导网络的元件和配体,其包括TLR1、TLR2、TLR3、TLR4、TLR5、TLR6、TLR7、TLR8、TLR9、TLR10、TLR11;NOD1、NOD2、NOD3、NOD4、NOD5、NALP1、NALP2、NALP3、NALP4、NALP5、NALP6、NALP6、NALP7、NALP7、NALP8、NALP9、NALP10、NALP11、NALP12、NALP13、NALP14、1IPAF、NAIP、CIITA、RIG-I、MDA5和LGP2,包括接头蛋白的TLR信号转导的信号转导子,接头蛋白包括例如Trif和Cardif;小GTP酶信号转导组件(RhoA、Ras、Rac1、Cdc42、Rab等)、PIP信号转导组件(PI3K、Src-激酶等)、MyD88依赖性信号转导组件(MyD88、IRAK1、IRAK2、IRAK4、TIRAP、TRAF6等)、MyD88非依赖性信号转导组件(TICAM1、TICAM2、TRAF6、TBK1、IRF3、TAK1、IRAK1等);活化的激酶包括例如Akt、MEKK1、MKK1、MKK3、MKK4、MKK6、MKK7、ERK1、ERK2、GSK3、PKC激酶、PKD激酶、GSK3激酶、JNK、p38MAPK、TAK1、IKK和TAK1;活化的转录因子包括例如NF-kB、c-Fos、c-Jun、c-Myc、CREB、AP-1、Elk-1、ATF2、IRF-3、IRF-7。
哺乳动物特别是人佐剂蛋白质可以进一步选自由热休克蛋白(如HSP10、HSP60、HSP65、HSP70、HSP75和HSP90、gp96、纤维蛋白原、纤连蛋白的TypIII重复的额外结构域A);或补体系统组件(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)、或诱导的靶基因(包括例如β-防御素、细胞表面蛋白);或人佐剂蛋白质(包括trif、flt-3配体、Gp96或纤连蛋白等)、或任何上述人佐剂蛋白质的任何物种的同系物组成。
哺乳动物特别是人佐剂蛋白质还可以包含诱导或增强先天性免疫应答的细胞因子,包括IL-1α、IL1β、IL-2、IL-6、IL-7、IL-8、IL-9、IL-12、IL-13、IL-15、IL-16、IL-17、IL-18、IL-21、IL-23、TNFα、IFNα、IFNβ、IFNγ、GM-CSF、G-CSF、M-CSF;趋化因子包括IL-8、IP-10、MCP-1、MIP-1α、RANTES、嗜酸性粒细胞趋化因子、CCL21;从巨噬细胞释放的细胞因子包括IL-1、IL-6、IL-8、IL-12和TNF-α;以及IL-1R1和IL-1α。
用于治疗血液紊乱、循环系统疾病、呼吸系统疾病、癌症或肿瘤疾病、感染性疾病或免疫缺陷的治疗性蛋白质或佐剂蛋白质通常是哺乳动物来源的蛋白质,优选人来源的蛋白质,取决于哪种动物应被治疗。例如,人受试者优选由人来源的治疗性蛋白质进行治疗。
致病性佐剂蛋白质通常包含致病性佐剂蛋白质,其能够引发先天性免疫应答(在哺乳动物中),更优选选自来源于细菌、原生动物、病毒或真菌等的致病性佐剂蛋白质、例如细菌(佐剂)蛋白质、原生动物(佐剂)蛋白质(例如刚地弓形虫的抑制蛋白样蛋白质)、病毒(佐剂)蛋白质或真菌(佐剂)蛋白质等。
特别地,细菌(佐剂)蛋白质可以选自由以下组成的组:细菌热休克蛋白或分子伴侣(包括Hsp60、Hsp70、Hsp90、Hsp100);来自革兰氏阴性菌的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氏杆菌(Bordetella pertussis)的百日咳毒素(PT)、来自百日咳博德氏杆菌的百日咳腺苷酸环化酶毒素CyaA和CyaC、来自百日咳毒素的PT-9K/129G突变体、来自百日咳博德氏杆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亚基、来自霍乱毒素的CTK63突变体、来自CT的CTE112K突变体、大肠杆菌不耐热肠毒素(LT)、来自不耐热肠毒素(LTB)B亚基、减毒的大肠杆菌不耐热肠毒素突变体,包括LTK63、LTR72);酚可溶性调控蛋白;来自幽门螺杆菌(Helicobacterpylori)的中性粒细胞激活蛋白(HP-NAP);表面活性剂蛋白D;来自布氏疏螺旋体(Borreliaburgdorferi)的外表面蛋白A脂蛋白、来自结核分枝杆菌(Mycobacterium tuberculosis)的Ag38(38kDa抗原);来自细菌菌毛的蛋白质;霍乱弧菌的肠毒素CT、革兰氏阴性细菌菌毛的菌毛蛋白和表面活性剂蛋白A;等,或任何上述细菌(佐剂)蛋白质的任何物种的同系物。
细菌(佐剂)蛋白质还可以包含细菌鞭毛蛋白。在本发明的上下文中,细菌鞭毛蛋白可以选自来自有机体的鞭毛蛋白,所述有机体包括但不限于,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)、博德氏属(Bordetella)、疏螺旋体属(Borrelia)、伯克霍尔德氏菌属(Burkholderia)、弯曲菌属(Campylobacter)、柄杆菌属(Caulobacte)、梭菌属(Clostridium)、埃希氏杆菌属(Escherichia)、螺杆菌属(Helicobacter)、毛螺菌科(Lachnospiraceae)、军团菌属(Legionella)、李斯特菌属(Listeria)、变形杆菌属(Proteus)、假单胞菌属(Pseudomonas)、根瘤菌属(Rhizobium)、红细菌属(Rhodobacter)、罗斯氏菌属(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)、沃廉菌属(Wolinella)、耶尔森氏菌属(Yersinia),更优选选自以下物种的鞭毛蛋白,所述物种包括但不限于,根癌土壤杆菌(Agrobacterium tumefaciens)、嗜火产水菌(Aquifex pyrophilus)、巴西固氮螺菌(Azospirillum brasilense)、枯草芽孢杆菌(Bacillus subtilis)、苏云金芽孢杆菌(Bacillus thuringiensis)、杆状巴尔通氏体(Bartonella bacilliformis)、支气管败血性博德氏杆菌(Bordetella bronchiseptica)、布氏疏螺旋体(Borrelia burgdorferi)、洋葱伯克霍尔德氏菌(Burkholderia cepacia)、空肠弯曲杆菌(Campylobacter jejuni)、新月柄杆菌(Caulobacter crescentus)、肉毒杆菌菌株班尼特克隆1(Clostridium botulinum strain Bennett clone 1)、大肠杆菌(Escherichia coli)、幽门螺杆菌(Helicobacter pylori)、毛螺旋菌(Lachnospiraceaebacterium)、嗜肺军团菌(Legionella pneumophila)、单核细胞增生性李斯特氏菌(Listeria monocytogenes)、奇异变形杆菌(Proteus mirabilis)、铜绿假单胞菌(Pseudomonas aeroguinosa)、丁香假单胞菌(Pseudomonas syringae)、苜蓿根瘤菌(Rhizobium meliloti)、球形红细菌(Rhodobacter sphaeroides)、Roseburia cecicola、Roseburis hominis、鼠伤寒沙门氏菌(Salmonella typhimurium)、邦戈沙门菌、伤寒沙门氏菌(Salmonella typhi)、肠炎沙门氏菌(Salmonella enteritidis)、猪痢疾小蛇菌(Serpulina hyodysenteriae)、粘质沙雷氏菌(Serratia marcescens)、鲍氏志贺氏菌(Shigella boydii)、溃蚀密螺旋体(Treponema phagedenis)、解藻酸弧菌(Vibrioalginolyticus)、霍乱弧菌(Vibrio cholerae)、副溶血性弧菌(Vibrioparahaemolyticus)、产琥珀酸沃廉菌(Wolinella succinogenes)和小肠结肠炎耶尔森菌(Yersinia enterocolitica)。
原生动物(佐剂)蛋白是致病性佐剂蛋白质的另外的示例。原生动物(佐剂)蛋白质可以在本文中任何显示佐剂特性的原生动物蛋白质中选择,更优选地,选自由但不限于,来自克氏锥虫的Tc52、来自刚地锥虫的PFTG、原生动物热休克蛋白、来自利什曼原虫属的LeIF、来自刚地弓形虫的抑制蛋白样蛋白质等。
病毒(佐剂)蛋白质是致病性佐剂蛋白质的另外的示例。在本文中,病毒(佐剂)蛋白质可以选自显示佐剂性质的任何病毒蛋白质,更优选地选自由以下组成的组,但不限于此:呼吸道合胞病毒融合糖蛋白(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。
真菌(佐剂)蛋白质是致病性佐剂蛋白质的再另外的示例。在本发明的上下文中,真菌(佐剂)蛋白质可以选自显示佐剂性质的任何真菌蛋白质,更优选地选自由真菌免疫调节蛋白(FIP;LZ-8)等组成的组。
最后,佐剂蛋白质还可以选自由钥孔戚血蓝蛋白(KLH)、OspA等组成的组。
在另外的实施方案中,治疗性蛋白质可以用于激素替代疗法,特别是用于更年期妇女的治疗。这些治疗性蛋白质优选选自雌激素、孕酮或孕激素,有时选择睾酮。
此外,治疗性蛋白质可用于将体细胞重编程为多能或全能干细胞。为了这个目的,描述了各种因子,特别是Oct-3/4、Sox基因家族(Sox1、Sox2、Sox3和Sox15)、Klf家族(Klf1、Klf2、Klf4和Klf5)、Myc家族(c-myc、L-myc和N-myc)、Nanog和LIN28。
如上所述,治疗性抗体在本文中也被定义为治疗性蛋白质。这些治疗性抗体优选选自尤其用于治疗癌症或肿瘤疾病的抗体,例如131I-托西莫单抗(滤泡性淋巴瘤、B细胞淋巴瘤、白血病),3F8(神经母细胞瘤),8H9,阿巴伏单抗(卵巢癌),阿德木单抗(Adecatumumab)(前列腺癌和乳腺癌),阿托珠单抗(Afutuzumab)(淋巴瘤),培化阿珠单抗(Alacizumabpegol)、阿仑单抗(Alemtuzumab)(B细胞慢性淋巴细胞性白血病、T-细胞淋巴瘤),阿姆土西单抗(Amatuximab)、AME-133v(滤泡性淋巴瘤、癌症),AMG102(晚期肾细胞癌),麻安莫单抗(Anatumomab mafenatox)(非小细胞肺癌),阿泊珠单抗(实体瘤、白血病、非霍奇金淋巴瘤、淋巴瘤),巴维昔单抗(癌症、病毒感染),贝妥莫单抗(非霍奇金淋巴瘤),贝利单抗(非霍奇金淋巴瘤),贝伐单抗(结肠癌、乳腺癌、脑和中枢神经系统肿瘤、肺癌、肝细胞癌、肾癌、乳腺癌、胰腺癌、膀胱癌、肉瘤、黑色素瘤、食管癌;胃癌、转移性肾细胞癌;肾癌、成胶质细胞瘤、肝癌、增殖性糖尿病视网膜病、黄斑变性),莫比伐珠单抗(Bivatuzumabmertansi)(鳞状细胞癌),博纳吐单抗(Blinatumomab),本妥昔单抗(Brentuximabvedotin)(血液癌症),坎妥珠单抗(Cantuzumab)(结肠癌、胃癌、胰腺癌、NSCLC),莫坎妥珠单抗(Cantuzumab mertansine)(结直肠癌),拉坎妥珠单抗(Cantuzumab ravtansine)(癌症),卡罗单抗喷地肽(前列腺癌),卡鲁单抗(Carlumab),卡妥索单抗(Catumaxomab)(卵巢癌、输卵管肿瘤、腹膜肿瘤),西妥昔单抗(Cetuximab)(转移性结肠直肠癌和头颈癌),泊-西他珠单抗(Citatuzumab bogatox)(卵巢癌和其它实体瘤),西妥木单抗(Cixutumumab)(实体瘤),克莱维足单抗(Clivatuzumab tetraxetan)(胰腺癌),CNTO328(B-细胞非霍奇金淋巴瘤、多发性骨髓瘤、卡斯尔曼氏病、卵巢癌),CNTO95(黑素瘤),可那木单抗(Conatumumab)、达西珠单抗(Dacetuzumab)(血液癌症),达洛珠单抗(Dalotuzumab),德尼单抗(Denosumab)(骨髓瘤、骨巨细胞瘤、乳腺癌、前列腺癌、骨质疏松症),地莫单抗(Detumomab)(淋巴瘤),卓齐妥单抗(Drozitumab)、依美昔单抗(Ecromeximab)(恶性黑素瘤),依决洛单抗(Edrecolomab)(结直肠癌),埃罗妥珠单抗(Elotuzumab)(多发性骨髓瘤),艾西莫单抗(Elsilimomab)、埃文单抗(Enavatuzumab)、埃斯托西单抗(Ensituximab)、依帕珠单抗(Epratuzumab)(自身免疫性疾病、系统性红斑狼疮、非霍奇金淋巴瘤、白血病),厄妥索单抗(Ertumaxomab)(乳腺癌),埃达珠单抗(Etaracizumab)(黑素瘤、前列腺癌、卵巢癌),法拉图组单抗(Farletuzumab)(卵巢癌),FBTA05(慢性淋巴性白血病),费希腊妥单抗(Ficlatuzumab)(癌症),芬妥木单抗(Figitumumab)(肾上腺皮质癌,非小细胞肺癌),弗兰托单抗(Flanvotumab)(黑素瘤),加利昔单抗(Galiximab)(B细胞淋巴瘤),加利昔单抗(Galiximab)(非霍奇金淋巴瘤),盖尼塔单抗单抗(Ganitumab)、GC1008(晚期肾细胞癌;恶性黑素瘤、肺纤维化),吉妥珠单抗(Gemtuzumab)(白血病),吉妥珠单抗奥佐米星(Gemtuzumab ozogamicin)(急性骨髓性白血病),吉仁土希单抗(Girentuximab)(透明细胞肾细胞癌),维德汀单抗(Glembatumumab vedotin)(黑素瘤、乳腺癌),GS6624(特发性肺纤维化和实体瘤),HuC242-DM4(结肠癌、胃癌、胰腺癌),HuHMFG1(乳腺癌),HuN901-DM1(骨髓瘤),替伊莫单抗(Ibritumomab)(复发性或难治性低级别、滤泡性或转化性B细胞非霍奇金淋巴瘤(NHL)),依库单抗(Icrucumab)、ID09C3(非霍奇金淋巴瘤),拉英达西单抗(Indatuximab ravtansine)、奥英妥珠单抗(Inotuzumab ozogamicin)、英妥木单抗(Intetumumab)(实体瘤(前列腺癌、黑素瘤)),伊匹单抗(Ipilimumab)(肉瘤、黑素瘤、肺癌、卵巢癌、白血球过多症、淋巴瘤、脑和中枢神经系统肿瘤、睾丸癌、前列腺癌、胰腺癌、乳腺癌),伊妥木单抗(Iratumumab)(霍奇金淋巴瘤),拉贝珠单抗(Labetuzumab)(结肠直肠癌),来沙木单抗(Lexatumumab)、林妥珠单抗(Lintuzumab)、劳乌土珠单抗(Lorvotuzumabmertansine)、鲁卡木单抗(Lucatumumab)(多发性骨髓瘤、非霍奇金淋巴瘤、霍奇金淋巴瘤),鲁昔单抗(Lumiliximab)(慢性淋巴细胞性白血病),马帕木单抗(Mapatumumab)(结肠癌、骨髓瘤),马妥珠单抗(Matuzumab)(肺癌、宫颈癌、食道癌),MDX-060(霍奇金淋巴瘤、淋巴瘤),MEDI 522(实体瘤、白血病、淋巴瘤、小肠癌、黑素瘤),米妥莫单抗(Mitumomab)(小细胞肺癌),莫加珠单抗(Mogamulizumab)、MORab-003(卵巢癌、输卵管癌、腹膜癌),MORab-009(胰腺癌、间皮瘤、卵巢癌、非小细胞肺癌、输卵管癌、腹腔癌),莫希土姆单抗(Moxetumomabpasudotox)、MT103(非霍奇金淋巴瘤),他那可单抗(Nacolomab tafenatox)(结直肠癌),他那莫单抗(Naptumomab estafenatox)(非小细胞肺癌、肾细胞癌),纳瑞特单抗(Narnatumab)、耐昔妥珠单抗(Necitumumab)(非小细胞肺癌),尼妥珠单抗(Nimotuzumab)(鳞状细胞癌、头颈癌、鼻咽癌、神经胶质瘤),尼妥珠单抗(Nimotuzumab)(鳞状细胞癌、神经胶质瘤、实体瘤、肺癌),奥拉图单抗(Olaratumab)、欧那土珠单抗(Onartuzumab)(癌症),莫奥珠单抗(Oportuzumab monatox)、奥戈伏单抗(Oregovomab)(卵巢癌),奥戈伏单抗(Oregovomab)(卵巢癌、输卵管癌、腹腔癌),PAM4(胰腺癌),帕尼单抗(Panitumumab)(结肠癌、肺癌、乳腺癌;膀胱癌;卵巢癌),帕图单抗(Patritumab)、帕尼单抗(Pemtumomab)、帕妥珠单抗(Pertuzumab)(乳腺癌、卵巢癌、肺癌、前列腺癌),普托木单抗(Pritumumab)(脑癌),雷库图单抗(Racotumomab)、雷德图单抗(Radretumab)、雷莫芦单抗(Ramucirumab)(实体瘤),利妥木单抗(Rilotumumab)(实体瘤),利妥昔单抗(Rituximab)(荨麻疹、类风湿性关节炎、溃疡性结肠炎、慢性局灶性脑炎、非霍奇金淋巴瘤、淋巴瘤、慢性淋巴细胞性白血病),罗妥木单抗(Robatumumab)、沙玛立珠单抗(Samalizumab)、SGN-30(霍奇金淋巴瘤、淋巴瘤),SGN-40(非霍奇金淋巴瘤、骨髓瘤、白血病、慢性淋巴细胞性白血病),西罗珠单抗(Sibrotuzumab)、司妥昔单抗(Siltuximab)、他贝鲁单抗(Tabalumab)(B细胞癌),他珠单抗(Tacatuzumab tetraxetan)、帕他莫单抗(Taplitumomab paptox)、替妥莫单抗(Tenatumomab)、替普单抗(Teprotumumab)(血液肿瘤),TGN1412(慢性淋巴细胞性白血病、类风湿性关节炎),替西木单抗(Ticilimumab)(=曲美木单抗(tremelimumab))、替加珠单抗(Tigatuzumab)、TNX-650(霍奇金淋巴瘤),托西莫单抗(Tositumomab)(滤泡性淋巴瘤、B细胞淋巴瘤、白血病、骨髓瘤),曲妥珠单抗(Trastuzumab)(乳腺癌、子宫内膜癌、实体瘤)、TRBS07(黑素瘤)、曲美木单抗(Tremelimumab)、TRU-016(慢性淋巴细胞性白血病),TRU-016(非霍奇金淋巴瘤),西莫白介素单抗(Tucotuzumab celmoleukin)、乌波利土西单抗(Ublituximab)、乌瑞鲁单抗(Urelumab)、维妥珠单抗(Veltuzumab)(非霍奇金淋巴瘤),维妥珠单抗(Veltuzumab)、(IMMU-106)(非霍奇金淋巴瘤),伏洛昔单抗(Volociximab)(肾细胞癌、胰腺癌、黑素瘤),伏妥莫单抗(Votumumab)(结直肠肿瘤),WX-G250(肾细胞癌),扎鲁木单抗(Zalutumumab)(头颈部癌、鳞状细胞癌)和扎木单抗(Zanolimumab(T细胞淋巴瘤);
尤其是用于治疗免疫疾病的抗体,例如依法利珠单抗(Efalizumab)(银屑病),依帕珠单抗(Epratuzumab)(自身免疫性疾病、系统性红斑狼疮、非霍奇金淋巴瘤、白血病),埃图力珠单抗(Etrolizumab)(炎症性肠病),芳妥珠单抗(Fontolizumab)(克罗恩氏病),希凯珠单抗(Ixekizumab)(自身免疫性疾病),美泊利单抗(Mepolizumab)(嗜酸性粒细胞增多综合征、哮喘、嗜酸性粒细胞胃肠炎、变应性肉芽肿性血管综合征、嗜酸性粒细胞性食管炎),米拉珠单抗(Milatuzumab)(多发性骨髓瘤和其它血液恶性肿瘤),汇集免疫球蛋白(Pooledimmunoglobulins)(原发性免疫缺陷),普利昔单抗(Priliximab)(克罗恩氏病、多发性硬化症),利妥昔单抗(Rituximab)(荨麻疹、类风湿性关节炎、溃疡性结肠炎、慢性局灶性脑炎、非霍奇金淋巴瘤、淋巴瘤、慢性淋巴细胞性白血病),罗利珠单抗(Rontalizumab)(系统性红斑狼疮),鲁利单抗(Ruplizumab)(风湿性疾病),沙鲁单抗(Sarilumab)(类风湿性关节炎、强直性脊柱炎),维多珠单抗(Vedolizumab)(克罗恩氏病、溃疡性结肠炎),维西珠单抗(Visilizumab)(克罗恩氏病、溃疡性结肠炎),雷珠单抗(Reslizumab)(呼吸道、皮肤和消化道炎症),阿达木单抗(Adalimumab)(类风湿性关节炎、克罗恩氏病、强直性脊柱炎、银屑病性关节炎),阿塞珠单抗(Aselizumab)(严重受伤患者),阿缇努单抗(Atinumab)(神经系统的治疗),阿特立单抗(Atlizumab)(类风湿性关节炎,系统性幼年特发性关节炎),柏替木单抗(Bertilimumab)(严重过敏性疾病),贝索单抗(Besilesomab)(炎性病变和转移),BMS-945429、ALD518(癌症和类风湿性关节炎),贝伐珠单抗(Briakinumab)(银屑病、类风湿性关节炎、炎性肠疾病、多发性硬化症),布达路单抗(Brodalumab)(炎性疾病),卡纳单抗(Canakinumab)(类风湿性关节炎),卡纳单抗(Canakinumab)(cryopyrin相关的周期性综合征(CAPS)、类风湿性关节炎、慢性阻塞性肺病),塞妥珠单抗(Certolizumab pegol)(克罗恩氏病),厄利珠单抗(Erlizumab)(心脏病发作、中风、创伤性休克),非扎奴单抗(Fezakinumab)(类风湿性关节炎、银屑病)、戈利木单抗(Golimumab)(类风湿性关节炎、银屑病性关节炎、强直性脊柱炎),戈利昔单抗(Gomiliximab)(过敏性哮喘),英夫利昔单抗(Infliximab)(类风湿性关节炎、克罗恩氏病、强直性脊柱炎、银屑病性关节炎、斑块型银屑病、白赫列夫症(Morbus Bechterew)、溃疡性结肠炎),美力姆单抗(Mavrilimumab)(类风湿性关节炎),那他珠单抗(Natalizumab)(多发性硬化症),奥瑞珠单抗(Ocrelizumab)(多发性硬化症、类风湿性关节炎、红斑狼疮、血液癌症),奥度莫单抗(Odulimomab)(预防器官移植排斥、免疫性疾病),奥法木单抗(Ofatumumab)(慢性淋巴细胞性白血病、滤泡性非霍奇金淋巴瘤、B细胞淋巴瘤、类风湿性关节炎、复发缓解型多发性硬化症、淋巴瘤、B细胞慢性淋巴细胞性白血病),欧咗立珠单抗(Ozoralizumab)(炎症),培克珠单抗(Pexelizumab)(减少心脏手术的副作用),罗维珠单抗(Rovelizumab)(出血性休克),SBI-087(类风湿性关节炎),SBI-087(系统性红斑狼疮),苏金单抗(Secukinumab)(葡萄膜炎、类风湿性关节炎银屑病),希瑞库单抗(Sirukumab)(类风湿性关节炎),他利珠单抗(Talizumab)(过敏反应),托珠单抗(Tocilizumab)(类风湿性关节炎、系统性幼年特发性关节炎、卡斯尔曼病),托利珠单抗(Toralizumab)(类风湿性关节炎、狼疮性肾炎),TRU-015(类风湿性关节炎),TRU-016(自身免疫疾病和炎症),优特克单抗(Ustekinumab)(多发性硬化症、银屑病、银屑病性关节炎),优特克单抗(Ustekinumab)(IL-12/IL-23阻断剂)(斑块型银屑病、银屑病性关节炎、多发性硬化症、结节病、后者相对),维帕莫单抗(Vepalimomab)(炎症),阿佐莫单抗(Zolimomabaritox)(系统性红斑狼疮、移植物抗宿主病),西法木单抗(Sifalimumab)(SLE、皮肌炎、多肌炎),鲁昔单抗(Lumiliximab)(过敏)和Rho(D)免疫球蛋白(恒河猴症);或选自用于治疗感染性疾病的抗体,例如阿非莫单抗(败血症)、CR6261(传染病/甲型流感)、埃巴单抗(Edobacomab)(由革兰氏阴性菌引起的败血症)、依芬古单抗(Efungumab)(侵入性念珠菌感染)、艾韦单抗(Exbivirumab)(乙型肝炎)、非维珠单抗(Felvizumab)(呼吸道合胞病毒感染)、夫瑞韦如(Foravirumab)(狂犬病(预防)),替伊立珠(Ibalizumab)(HIV感染)、利韦单抗(Libivirumab)(乙型肝炎)、莫维珠单抗(Motavizumab)(呼吸道合胞病毒(预防))、奈巴库单抗(Nebacumab)(败血症)、妥韦单抗(Tuvirumab)(慢性乙型肝炎)、乌珠单抗(Urtoxazumab)(大肠杆菌引起的腹泻)、巴维昔单抗(Bavituximab)(多种病毒感染),帕吉昔单抗(Pagibaximab)(败血症(例如葡萄球菌(Staphylococcus)))、帕利珠单抗(Palivizumab)(预防高危儿科患者呼吸道合胞病毒感染)、帕诺库单抗(Panobacumab)(铜绿假单胞菌感染)、PRO140(HIV感染)、瑞非韦鲁(Rafivirumab)(狂犬病(预防))、瑞西巴库(Raxibacumab)(炭疽(预防和治疗))、瑞加韦单抗(Regavirumab)(巨细胞病毒感染)、司韦单抗(Sevirumab)(巨细胞病毒感染)、索维单抗(Suvizumab)(病毒感染)和替非珠单抗(Tefibazumab)(金黄色葡萄球菌(Staphylococcus aureus)感染);
尤其用于治疗血液疾病的抗体,例如阿昔单抗(Abciximab)(经皮冠状动脉介入治疗)、阿托木单抗(Atorolimumab)(新生儿溶血症)、依库丽单抗(Eculizumab)(阵发性睡眠性血红蛋白尿症)、美泊利单抗(Mepolizumab)(嗜酸性粒细胞增多综合征、哮喘、嗜酸性粒细胞性胃肠炎、变应性肉芽肿性血管综合征、嗜酸性粒细胞性食管炎)和米拉珠单抗(Milatuzumab)(多发性骨髓瘤和其它血液恶性肿瘤);
尤其用于免疫调节的抗体,例如、抗胸腺细胞球蛋白(急性肾移植排斥、再生障碍性贫血)、巴利昔单抗(Basiliximab)(预防接受包括环孢霉素和皮质类固醇的免疫抑制方案的肾移植患者中的同种异体移植排斥)、西利珠单抗(Cedelizumab)(预防器官移植排斥、治疗自身免疫疾病)、达利珠单抗(Daclizumab)(预防接受肾移植的患者中的急性同种异体移植物排斥、多发性硬化症)、加维莫单抗(Gavilimomab)(移植物抗宿主病)、伊诺莫单抗(Inolimomab)(移植物抗宿主病)、莫罗单抗-CD3(Muromonab-CD3)(预防器官移植排斥)、莫罗单抗-CD3(急性肾同种异体移植物排斥或激素抵抗型心脏或肝同种异体移植排斥)、奥度莫单抗(Odulimomab)(预防器官移植排斥、免疫性疾病)和西利珠单抗(Siplizumab)(银屑病、移植物抗宿主病(预防));
用于治疗糖尿病的抗体,例如加沃坦珠单抗(Gevokizumab)(糖尿病)、奥昔珠单抗(Otelixizumab)(1型糖尿病)和替利珠单抗(Teplizumab)(1型糖尿病);
用于治疗阿尔茨海默病的抗体,例如巴匹珠单抗(Bapineuzumab)、克雷内治单抗(Crenezumab)、盖坦德单抗(Gantenerumab)、珀珠单抗(Ponezumab)、R1450和索拉珠单抗(Solanezumab);
用于治疗哮喘的抗体,例如贝纳珠单抗(Benralizumab)、艾诺克单抗(Enokizumab)、凯利昔单抗(Keliximab)、来金珠单抗(Lebrikizumab)、奥马珠单抗(Omalizumab)、欧西鲁单抗(Oxelumab)、帕考珠单抗(Pascolizumab)和曲洛青木单抗(Tralokinumab);
和用于治疗各种病症的抗体,例如,布鲁宗津单抗(Blosozumab)(骨质疏松症)、CaroRx(龋齿)、夫苏木单抗(Fresolimumab)(特发性肺纤维化、局灶性节段性肾小球硬化症、癌症)、弗兰单抗(Fulranumab)(疼痛)、罗姆苏珠单抗(Romosozumab)(骨质疏松症)、司司他芦单抗(Stamulumab)(肌肉萎缩症)、他尼珠单抗(Tanezumab)(疼痛)和兰尼单抗(Ranibizumab)(新生血管性年龄相关性黄斑变性)。
表位:表位(也称为“抗原决定簇”)可以区分为T细胞表位和B细胞表位。本发明上下文中蛋白质的T细胞表位或部分可包含优选长度为约6个至约20个或甚至更多个氨基酸的片段,例如由MHC I类分子处理和呈递的片段,优选长度为约8个至约10个氨基酸,例如8个、9个或10个,(或甚至11个或12个氨基酸),或由MHC II类分子处理和呈递的片段,优选长度为约13个或更多个氨基酸,例如13个、14个、15个、16个、17个、18个、19个、20个或甚至更多个氨基酸的长度,其中这些片段可以选自氨基酸序列的任何部分。这些片段通常被T细胞识别为由肽片段和MHC分子组成的复合物形式,即这些片段通常不以其天然形式被识别。B细胞表位通常是位于本文定义的(天然的)蛋白质或肽抗原的外表面上的片段,优选具有5个至15个氨基酸,更优选具有5个至12个氨基酸,甚至更优选具有6个至9个氨基酸,其可以被抗体识别,即以其天然形式。
这些蛋白质或肽的表位还可以选自这些蛋白质或肽的任何本文提及的变体。在这种情况下,抗原决定簇可以是构象的或不连续的表位或连续的或线性的表位,构象的或不连续的表位由在本文所定义的蛋白质或肽的氨基酸序列中是不连续的、但是在三维结构中汇集在一起的如本文所定义的蛋白质或肽的片段组成,连续的或线性的表位由单个多肽链组成。
蛋白质:蛋白质通常包含一种或多种肽或多肽。蛋白质通常被折叠成三维形式,这可能是蛋白质发挥其生物学功能所必需的。
肽:肽或多肽通常是由肽键连接的氨基酸单体的聚合物。它通常含有少于50个的单体单元。尽管如此,术语肽不是具有多于50个单体单元的分子的放弃。长肽也被称为多肽,通常具有50至600个之间的单体单元。
蛋白质的片段或部分:在本发明的上下文中,蛋白质的片段或部分通常被理解为对应于蛋白质的氨基酸序列的连续部分的肽,优选长度为约6个至约20个或甚至更多个氨基酸,例如由MHC I类分子处理和呈递的部分,优选长度为约8个至约10个氨基酸,例如8个、9个、或10个,(或甚至11个或12个氨基酸)的长度,或由MHC II类分子处理和呈递的片段,优选长度为约13个或更多个氨基酸,例如13个、14个、15个、16个、17个、18个、19个、20个或甚至更多个氨基酸的长度,其中这些片段可以选自氨基酸序列的任何部分。这些片段通常被T细胞识别为由肽片段和MHC分子组成的复合物形式,即这些片段通常不以其天然形式被识别。如本文所定义的蛋白质的片段或部分还可以包含那些蛋白质的表位或功能性位点。优选地,本发明上下文中的蛋白质的片段或部分是抗原,特别是免疫原,例如抗原决定簇(也称为“表位”),或具有抗原特征,从而引发适应性免疫应答。因此,蛋白质或肽的片段可以包含那些蛋白质或肽的至少一个表位。此外,蛋白质的结构域,例如细胞外结构域、细胞内结构域或跨膜结构域、以及蛋白质的缩短或截短形式也可理解为包含蛋白质的片段。
微生物:微生物是一种微观存活的生物体,可以是单细胞或多细胞的。微生物是非常多样的,并包括所有的细菌和古细菌以及几乎所有的原生动物。它们还包括一些真菌、藻类和某些动物,如轮虫类。在本发明的上下文中,能够复制包含复制起点的共价闭合的环状重组DNA分子的微生物是特别优选的,例如质粒。特别优选的是细菌,例如大肠杆菌(E.coli)。在这方面特别优选的是用于质粒生产的大肠杆菌菌株,例如DH1、DH5α、DH10B、BL21(例如BL21ΔrecAΔendA)或JM101。在一些实施方案中,DH5α菌株是特别优选的,例如,DH5αdcm和DH5αdcm-attλ::P5/6 6/6-RNA-IN-SacB。
插入片段:插入片段是DNA序列,该DNA序列任选地包含在根据本发明的共价闭合的环状DNA分子中,编码靶标RNA序列或靶标的肽或蛋白质序列。在插入片段编码肽或蛋白质的情况下,插入片段包含开放阅读框。
发酵:术语“发酵(fermenting)”,“发酵(fermentation)”或“发酵生产”是指在有氧或厌氧条件下微生物在生长培养基上的大量生长。优选地,本文报道的发酵是指在厌氧条件下的细菌。在本发明的上下文中,这些术语特别涉及发酵过程,其中包含复制起点例如质粒的共价闭合的环状重组DNA分子由微生物复制。
补料分批发酵:补料分批发酵是包括至少一个预定或受控添加营养素到发酵培养物中的步骤。预定或受控添加营养素的这个步骤也被称为补料分批阶段,并且允许以速率μ<μ最大控制生长速率。
引发体装配位点:引发体装配位点是支持引发体装配的核苷酸序列。引发体包含蛋白DnaG引发酶、DnaB解旋酶、DnaC解旋酶助剂、DnaT、PriA、PriB和PriC。在每个复制叉上,在DNA的前导链上使用一次引发体,并且反复地在后随DNA链上启动每个冈崎片段。
具体实施方式
为了解决上述问题,本发明采用共价闭合的环状DNA分子,其中均聚区域在复制方向上不直接位于复制起点旁边。
因此,第一方面,本发明涉及共价闭合的环状重组DNA分子,其包含:
-复制起点,
-包含均聚区域的插入片段,
其中均聚区域在复制方向上位于与复制起点至少500bp的距离处。
另一方面,本发明涉及共价闭合的环状重组DNA分子,其包含:
-复制起点,
-均聚区域,
其中均聚区域在复制方向上位于与复制起点至少500bp的距离处。
本发明的另一方面涉及共价闭合的环状重组DNA分子,其包含:
-复制起点,
-包含均聚区域的插入片段,
其中包含均聚区域的插入片段被定向为使得插入片段的转录方向与复制起点的复制方向相同。
共价闭合的环状重组DNA分子可以选自由质粒、粘粒、细菌人工染色体(BAC)、噬菌体,病毒载体或其杂交体组成的组。优选地,共价闭合的环状重组DNA分子是质粒。质粒可以是用于RNA表达的任何质粒,如pUC、pBluescript、pGEM、pTZ、pBR322、pACYC、pSC101、pET、pGEX、PColE1、PR6K、PSC101。
均聚区域在复制方向上位于与复制起点至少100bp、至少200bp、至少300bp、至少400bp、至少500bp、至少600bp、至少700bp、至少800bp、至少900bp、至少1000bp、至少1100bp、至少1200bp、至少1300bp、至少1400bp、至少1500bp、至少1600bp、至少1700bp、至少1800bp、至少1900bp、至少2000bp、至少2100bp、至少2200bp、至少2300bp、至少2400bp的距离处。优选地,均聚区域在复制方向上位于与复制起点至少400bp、至少450bp、至少500bp、至少550bp、至少600bp、至少650bp、至少700bp、至少750bp、至少800bp、至少850bp、至少900bp、至少950bp、至少1000bp、至少1050bp、至少1100bp、至少1200bp、至少1300bp、至少1400bp、至少1500bp、至少1600bp、至少1700bp、至少1800bp、至少1850bp、至少1900bp、至少1950bp、至少2000bp、至少2050bp、至少2100bp、至少2150bp、至少2200bp的距离处。更优选地,均聚区域在复制方向上位于与复制起点至少400bp至300k bp的距离处,更优选至少400bp至10k bp的距离处,甚至更优选至少400bp至5000bp的距离处。
此外,与其中包含均聚区域的插入片段被定向为使得插入片段的转录方向与复制起点的复制方向相反的共价闭合的环状重组DNA分子的产量相比,其中包含均聚区域的插入片段被定向为使得插入片段的转录方向与复制起点的复制方向相同的共价闭合的环状重组DNA分子提高了发酵生产中共价闭合的环状重组DNA分子的产量。
与复制起点的距离是指复制起点的最后一个核苷酸(3'-末端)与均聚区域的第一个核苷酸(5'-末端)之间的距离。本领域技术人员知道通常使用的复制起点的序列,因此可以容易地确认复制起点的最后一个核苷酸(3'末端)。
本申请示例中使用的质粒含有来源于pUC质粒的起点。在一些实例中,复制起点具有在SEQ ID NO:6中确定的序列。因此,在SEQ ID NO:6中确定的序列的最后一个核苷酸是如SEQ ID NO:6中确定的来源于pUC质粒的复制起点的最后一个核苷酸(3'-末端)。
共价闭合的环状重组DNA分子可以例如来自P1140-AF2或来自P1140-K2载体。
因此,共价闭合的环状重组DNA分子可以包含与SEQ ID NO:4或SEQ ID NO:5至少90%相同的序列。优选地,共价闭合的环状重组DNA分子可以包含如SEQ ID NO:4或SEQ IDNO:5所示的序列。
复制起点的“复制方向”表示复制所进行方向。当在复制方向上连续组装前导链时,不连续地组装后随链,即,以5'至3'方向组装的核苷酸聚合物被接合以允许后随链以3'至5'方向的整体生长。常规复制方向显示在质粒的载体图谱上。
插入片段是编码包含均聚区域的靶标RNA的双链DNA序列。因此,插入片段包含均聚区域。优选地,插入片段包含编码靶标RNA和均聚区域的核酸序列。均聚区域位于插入片段的3'末端。优选地,多聚(A)序列和/或多聚(C)序列位于插入片段的3'末端。更优选地,多聚(A)序列和/或多聚(C)序列位于插入片段的3'末端。
靶标RNA的序列可以包含至少20bp、至少30bp、至少50bp、至少100bp、至少200bp、至少300bp、至少400bp、至少500bp、至少600bp、至少700bp、至少800bp、至少900bp、至少1000bp、至少1100bp、至少1200bp、至少1300bp、至少1400bp、至少1500bp、至少1600bp、至少1700bp、至少1800bp、至少1900bp、至少2000bp、至少2100bp,至少2200bp、至少2300bp、至少2400bp。
靶标RNA可以是本文所述的任何RNA类型,或者可以编码治疗活性蛋白质或肽、佐剂蛋白质、抗原(肿瘤抗原、致病性抗原(例如选自动物抗原、病毒抗原、原生动物抗原、来自细菌抗原)、过敏性抗原、自身免疫抗原、或其它抗原)、过敏原、抗体、免疫刺激蛋白或肽、抗原特异性T细胞受体、细胞穿透肽、分泌蛋白、质膜蛋白、细胞质或细胞骨架蛋白、细胞内膜结合蛋白、核蛋白质、与人类疾病相关的蛋白质、靶向部分或由人类基因组编码的那些没有鉴定出治疗适应症但是在研究和发现领域仍然具有实用性的蛋白质。优选地,靶标RNA是免疫刺激RNA或编码RNA。编码RNA可以是例如mRNA、病毒RNA或复制子RNA。
插入片段可以还包含如本文所述的其它元件,例如组蛋白茎环序列、稳定化序列、UTR、IRES序列等。
多聚(C)序列可以是至少15个胞苷,优选至少20个胞苷,更优选至少30个胞苷的序列。特别地,插入片段可以含有或编码通常约10至200个胞苷核苷酸,优选约10至100个胞苷核苷酸,更优选约10至70个胞苷核苷酸或甚至更优选约20至50或者甚至20至30个胞苷核苷酸的多聚(C)序列。优选地,该多聚(C)序列位于插入片段的3'区域,即位于所包含的编码区域的3'末端。
包含在共价闭合的环状重组DNA分子的插入片段中的均聚区域包含至少一个多聚(A)序列和/或至少一个多聚(C)序列。在优选的实施方案中,均聚区域包含至少一个多聚(C)序列。在更优选的实施方案中,均聚区域包含多聚(C)序列。在甚至更优选的实施方案中,均聚区域包含多聚(C)和多聚(A)序列。优选地,多聚(A)序列包含约20至约400个腺苷核苷酸、更优选约60至约250个腺苷核苷酸的序列。优选地,多聚(C)序列包含约10至200个胞苷核苷酸、更优选约20至40个胞苷核苷酸的序列。在特别优选的实施方案中,均聚区域包含约60至约70个腺苷核苷酸的多聚(A)序列和约20至30个胞苷核苷酸的多聚(C)序列。
在具体实施方案中,共价闭合的环状重组DNA分子包含多聚(A)序列和多聚(C)序列。
多聚(A)序列和多聚(C)序列可以通过接头序列连接。接头序列可以是杂聚序列。接头序列可以包含1至400个,优选1至100个,更优选2至50个,甚至更优选3至50个,最优选3至100个核苷酸。接头序列可以包含诸如“tgcat”的序列。因此,包含多聚(A)序列和多聚(C)序列的均聚区域可以具有例如如SEQ ID NO:1所示的序列。
本发明的另一方面涉及共价闭合的环状重组DNA分子,其包含复制起点的和包含均聚区域的插入片段,其中包含均聚区域的插入片段被定向为使得插入片段的转录方向与复制起点的复制方向相同。
特别地,本发明涉及共价闭合的环状重组DNA分子,其包含复制起点和插入片段,该插入片段在其3'末端包含均聚区域,其中插入片段被定向为使得插入片段的转录方向为与复制起点的复制方向相同。
术语“插入片段的转录方向与复制起点的复制方向相同”是指序列在与其被转录相同的方向上被复制,即插入片段的5'末端在复制方向上比插入片段的3'末端更接近复制起点。因此在复制起点和均聚区域之间存在编码靶标RNA的序列。
因此,与其中包含均聚区域的插入片段被定向为使得插入片段的转录方向与复制起点的复制方向相反的共价闭合的环状重组DNA分子相比,在其中包含均聚区域的插入片段被定向为使得插入片段的转录方向与复制起点的复制方向相同的共价闭合的环状重组DNA分子中,复制起点与均聚区域之间的距离更大。
与其中均聚区域在复制方向上位于与复制起点少于500bp的距离处的共价闭合的环状重组DNA的产量相比,其中均聚区域在复制方向上位于与复制起点至少500bp的距离处的共价闭合的环状重组DNA分子的产量在发酵生产中得以提高。可以理解的是,两个共价闭合的环状重组DNA分子的发酵条件是相同的。
此外,与其中包含均聚区域的插入片段被定向为插入片段的转录方向与复制起点的复制方向相反的共价闭合的环状重组DNA分子的产量相比,其中包含均聚区域的插入片段被定向为使得插入片段的转录方向与复制起点的复制方向相同的共价闭合的环状重组DNA分子使得共价闭合的环状重组DNA分子在发酵生产中的产量得以提高。可以理解的是,两种共价闭合的环状重组DNA分子的发酵条件是相同的。
当将其中均聚区域在复制方向上位于与复制起点至少500bp的距离处的共价闭合的环状重组DNA分子的产量和/或发酵时间与其中均聚区域在复制方向上位于与复制起点小于500bp的距离处的共价闭合的环状重组DNA分子的产量相比时,可以理解的是,两种共价闭合的环状重组DNA分子的发酵条件是相同的。
相应地,当其中包含均聚区域的插入片段被定向为使得插入片段的转录方向与复制起点的复制方向相同的共价闭合的环状重组DNA分子的产量和/或发酵时间与其中包含均聚区域的插入片段被定向为使得插入片段的转录方向与复制起点的复制方向相反的共价闭合的环状重组DNA分子的产量相比时,可以理解的是,两种共价闭合的环状重组DNA分子的插入片段是相同的。
从图2所示的载体图谱可以看出,P1140-AF2被定向为使得复制起点的复制方向与插入片段的转录方向相同。图3中的P1140-AF1的载体图谱显示插入片段的转录方向与复制起点的复制方向相反。从表1可以看出,构建体P1140-AF1的质粒产量是3.0mg/L/OD600,而当采用质粒P1140-AF2时,质粒产量提高到7.5mg/L/OD600。因此,与P1140-AF1相比,质粒P1140-AF2的质粒产量提高到2.5倍。
从图4所示的载体图谱可以看出,P1140-K2被定向为使得复制起点的复制方向与插入片段的转录方向相同。图5中的P1140-K1的载体图谱显示插入片段的转录方向与复制起点的复制方向相反。从表1可以看出,构建体P1140-K1的质粒产量为1.9mg/L/OD600,而当采用质粒P1140-K2时,质粒产量提高到9.3mg/L/OD600。因此,与P1140-K1相比,质粒P1140-K2的质粒产量提高到4.9倍。
与其中包含均聚区域的插入片段被定向为使得插入片段的转录方向与复制起点的复制方向相反的共价闭合的环状重组DNA分子的产量相比,其中包含均聚区域的插入片段被定向为使得插入片段的转录方向与复制起点的复制方向相同的共价闭合的环状重组DNA分子的产量可以在发酵生产中提高至少1.1倍、至少1.2倍、至少1.3倍、至少1.4倍、至少1.5倍、至少1.6倍、至少1.7倍、至少1.8倍、至少1.9倍、至少2.0倍、至少2.1倍、至少2.2倍、至少2.3倍、至少2.4倍、至少2.5倍、至少2.6倍、至少2.7倍、至少2.8倍、至少2.9倍、至少3.0倍、至少3.1倍、至少3.2倍、至少3.3倍、至少3.4倍、至少3.5倍、至少3.6倍、至少3.7倍、至少3.8倍、至少3.9倍、至少4.0倍、至少4.1倍、至少4.2倍、至少4.3倍、至少4.4倍、至少4.5倍、至少4.6倍、至少4.7倍、至少4.8倍、至少4.9倍、至少5.0倍、至少5.1倍、至少5.2倍、至少5.3倍、至少5.4倍、至少5.5倍或更多。可以理解的是,两种共价闭合的环状重组DNA分子的发酵条件是相同的。
与其中均聚区域在复制方向上位于与复制起点小于500bp的距离处的共价闭合的环状重组DNA分子的产量相比,其中均聚区域在复制方向上位于与复制起点至少500bp的距离处的共价闭合的环状重组DNA分子的产量可以使共价闭合的环状重组DNA分子在发酵生产中的产量增加至少1.1倍、至少1.2倍、至少1.3倍、至少1.4倍、至少1.5倍、至少1.6倍、至少1.7倍、至少1.8倍、至少1.9倍、至少2.0倍、至少2.1倍、至少2.2倍、至少2.3倍、至少2.4倍、至少2.5倍、至少2.6倍、至少2.7倍、至少2.8倍、至少2.9倍、至少3.0倍、至少3.1倍、至少3.2倍、至少3.3倍、至少3.4倍、至少3.5倍、至少3.6倍、至少3.7倍、至少3.8倍、至少3.9倍、至少4.0倍、至少4.1倍、至少4.2倍、至少4.3倍、至少4.4倍、至少4.5倍、至少4.6倍、至少4.7倍、至少4.8倍、至少4.9倍、至少5.0倍、至少5.1倍、至少5.2倍、至少5.3倍、至少5.4倍、至少5.5倍或更多。可以理解的是,两种共价闭合的环状重组DNA分子的发酵条件是相同的。
通常地复制起点是细菌来源的。一般地,复制起点是单向的。单向复制起点的复制是在一个方向上进行的。优选地,复制起点是高拷贝数起点。复制起点可以来源于pBR322质粒、pUC质粒、pMB1质粒、ColE1质粒、R6K质粒、p15A质粒、pSC101质粒或F1噬菌粒。不同的复制起点是本领域技术人员已知的。上面提到的一些复制起点是相关的。例如,来源于pUC质粒的复制起点是来源于pMB1质粒的复制起点的变体,其与pMB1起点仅有两处突变上的不同,这导致与pMB1质粒相比更高的拷贝数。优选地,复制起点来源于pUC质粒。
在一些实施方案中,共价闭合的环状重组DNA分子还包含引发体组装位点,例如前导链(PAS-BH)中的引发体组装位点。该引发体组装位点可以例如包含序列SEQ ID NO:3。
通常地,共价闭合的环状重组DNA分子还包含编码选择标记物的序列。
术语“编码选择标记物的序列”是指编码RNA或多肽的序列,该序列为包含编码选择标记物的序列的细胞提供表型,允许对含有编码选择标记物的序列的细胞进行阳性或阴性选择。编码选择标记物的序列可以用于区分转化的细胞和未转化的细胞,或者可以用于鉴定已经经历重组或其它种类的遗传修饰的细胞。
技术人员知晓不同的选择标记物,例如抗生素抗性基因,例如氨苄青霉素或卡那霉素抗性基因。或者,可以使用无抗生素选择系统。可以在本发明的上下文中使用的这种抗生素选择系统描述于Luke J等人;Vaccine.2009 Oct 30;27(46):6454-9中。例如,蔗糖选择性标记性物可以用作选择标记物。蔗糖选择性标记物是例如来自Nature TechnologyCorporation的RNA-OUT系统(描述于Luke J等人;Vaccine.2009 Oct 30;27(46):6454-9中)。载体含有并表达150bp的RNA-OUT反义RNA。RNA-OUT抑制整合到染色体中的组成型表达的反选择性标记物(sacB)的表达,从而允许对蔗糖上质粒进行选择。SacB编码在蔗糖的存在下有毒的果聚糖蔗糖酶。
另一方面涉及其中均聚区域在复制方向上位于与复制起点至少500bp的距离处的共价闭合的环状重组DNA分子用于使发酵生产中共价闭合的环状重组DNA分子的产量与其中均聚区域在复制方向上位于与复制起点小于500bp的距离处的共价闭合的环状重组DNA分子的产量相比增加的用途。
共价闭合的环状重组DNA分子可以包含至少一个用于体外转录的启动子,如T3、Sp6或T7以及转录终止子,例如trpA。此外,共价闭合的环状重组DNA分子可以包含多个插入位点,插入位点可以作为多克隆位点的一部分聚集。共价闭合的环状重组DNA分子还可以包含多于一个的多克隆位点,多克隆位点可以是相同的。
另一方面涉及其中包含均聚区域的插入片段被定向为使得插入片段的转录方向与复制起点的复制方向相同的共价闭合的环状重组DNA分子用于使发酵生产中共价闭合的环状重组DNA分子的产量与其中包含均聚区域的插入片段被定向为使得插入片段的转录方向与复制起点的复制方向相反的共价闭合的环状重组DNA分子的产量相比增加的用途。
在具体的实施方案中,与其中包含均聚区域的插入片段在复制方向上位于与复制起点小于500bp的距离处的共价闭合的环状重组DNA分子的发酵时间相比,其中均聚区域在复制方向上位于与复制起点至少500bp的距离处的共价闭合的环状重组DNA分子的发酵时间优选减少。
减少的发酵时间意味着在更短的发酵时间内获得相同的产量。
与其中包含均聚区域的插入片段被定向为使得插入片段的转录方向与复制起点的复制方向相反的共价闭合的环状重组DNA分子的发酵时间相比,其中包含均聚区域的插入片段被定向为使得插入片段的转录方向与复制起点的复制方向相同的共价闭合的环状重组DNA分子的发酵时间优选减少。
这意味着,例如,发酵时间优选减少超过5%、超过10%、超过15%、超过16%、超过17%、超过18%、通过超过19%、超过20%、超过21%、超过22%、超过23%、超过24%、超过25%、超过26%、超过27%、超过28%、超过29%、超过30%、超过31%、超过32%。优选地,发酵时间减少5%至70%之间,更优选10%至50%之间,甚至更优选15%至35%之间。
本发明的另一方面涉及用于发酵生产共价闭合的重组DNA分子的方法,其包括以下步骤:
(a)提供包含根据本发明的共价闭合的环状重组DNA分子的微生物;
(b)使步骤(a)的微生物发酵。
在具体的实施方案中,该方法还包括以下步骤:
(c)从步骤(b)的微生物中分离共价闭合的环状重组DNA分子。
技术人员知晓用于分离共价闭合的环状重组DNA分子的标准技术。
在优选的实施方案中,微生物是含有共价闭合的环状重组体温度诱导型高拷贝DNA质粒的细菌(例如大肠杆菌),并且步骤(b)包括以下步骤:
(i)在补料分批阶段的生长阶段期间,使含有共价闭合的环状重组体温度诱导型高拷贝DNA质粒的细菌在25℃至32℃范围内的温度下生长,其中在补料分批阶段期间以使得生长速率为μ=0.05至0.3小时-1(hr-1)的速率供应底物,
(ii)通过将温度升高到36℃至45℃,在生长阶段后诱导产生所述DNA质粒;和
(iii)在(ii)施加的温度下继续发酵以积累所述DNA质粒。
在更具体的实施方案中,步骤(b)包括以下步骤:
(i)在补料分批阶段的生长阶段期间,使含有共价闭合的环状重组体温度诱导型高拷贝DNA质粒的细菌在约30℃的温度下生长,其中在补料分批阶段期间以使得生长速率为μ=0.05至0.3小时-1(hr-1)的速率供应底物,
(ii)通过将温度升高到约42℃,在生长阶段后诱导产生所述DNA质粒;和
(iii)在(ii)施加的温度下继续发酵以积累所述DNA质粒。
补料分批发酵的这种方法详细描述于EP 1781800 B1中,其通过引用并入本文,在本文中称为HyperGRO发酵。通常,该方法是用温度诱导型共价闭合的环状重组DNA分子(例如含有pUC或pMM1起点的质粒)在生长阶段以受限的细胞生长速率和降低的温度进行的;然后通过升高温度来诱导质粒生产。由此质粒DNA发酵产量增加,而共价闭合的环状重组DNA分子的稳定性得以保持或改善。
步骤(b)中的生长阶段(i)可以在25至37℃、优选30至37℃的温度下进行。对于高拷贝质粒,生长阶段优选在30至32℃、更优选在30℃下进行。步骤(b)中的诱导阶段(ii)可以在33至45℃、优选37至42℃、最优选42℃的温度下进行。
技术人员知晓步骤(b)(i)中的不同限制补料策略。例如可以采用限碳指数补料策略。简而言之,在分批阶段期间以特定生长速率μ最大消耗初始量的碳底物。在碳底物耗竭后,补料分批阶段开始,并且以由以下方程确定的速率自动添加饲料营养物
其中μ=补料分批阶段所需的特定生长速率,
XB=分批阶段结束时的生物质浓度,g DCW/L
VB=培养物的初始液体体积,L;
Sf=营养物补料培养液中的限制性底物浓度,g/L:
YX/S=来自底物生物质的产量系数,g/g,
t=补料分批阶段开始以来的时间
本发明的共价闭合的环状重组DNA分子的优点在于,共价闭合的环状重组DNA分子的序列在发酵生产过程中保持稳定。
例如,在发酵生产期间均聚区域保持稳定。具体而言,在发酵生产期间多聚(A)序列和/或多聚(C)序列保持稳定。本文所用的术语“保持稳定”是指没有突变,即,诸如在发酵生产期间引入的核苷酸置换、核苷酸缺失或核苷酸添加。
本发明的另一方面涉及提高共价闭合的环状重组DNA分子的产量的方法,其包括以下步骤:
(a)提供共价闭合的环状重组DNA分子,其包含
-复制起点,和
-包含均聚区域的插入片段,其中均聚序列在复制方向上位于与复制起点小于500bp的距离处;
(b)修饰(a)的共价闭合的环状重组DNA分子以使得包含均聚区域(例如插入片段的3'-末端)的插入片段在复制方向上位于与复制起点至少500bp的距离处(例如复制起点的5'末端)。
修饰共价闭合的环状重组DNA分子以使得包含均聚区域的插入片段在复制方向上位于与复制起点至少500bp的距离处是指,例如但不限于,将间隔序列插入复制起点和包含均聚区域的插入片段之间。或者,将插入片段从共价闭合的环状重组DNA中去除,并以相反的方向导入。共价闭合的环状重组DNA可以通过本领域技术人员已知的常规克隆技术进行修饰。
本发明进一步提供了提高共价闭合的环状重组DNA分子的产量的方法,其包括以下步骤:
(a)提供共价闭合的环状重组DNA分子,其包含
-复制起点,和
-包含均聚区域的插入片段,其中包含均聚区域的插入片段被定向为使得插入片段的转录方向与复制起点的复制方向相反;
(b)修饰(a)的共价闭合的环状重组DNA分子以使得包含均聚区域的插入片段被定向为使得插入片段的转录方向与复制起点的复制方向相同。
修饰共价闭合的环状重组DNA分子以使得包含均聚区域的插入片段被定向为使得插入片段的转录方向与复制起点的复制方向相同是指,例如,将插入片段从共价闭合的环状重组DNA中去除,并以相反的方向导入。本领域技术人员知晓从共价闭合的环状重组DNA分子中去除核酸序列和将核酸序列导入共价闭合的环状重组DNA分子所需的常规克隆技术。
最后,本发明涉及根据本发明的共价闭合的环状重组DNA分子用于体外转录RNA的用途。
本发明是在DARPA授予的协议号为HR0011-11-3-0001的政府支持下完成的。政府对本发明有一定的权利。
示例
下面所示的示例仅仅是说明性的,并且将以另外的方式描述本发明。这些示例不应被解释为将本发明限制于此。
质粒:
产生编码GC优化的mRNA(编码H1N1(Netherlands2009)-HA(如图6所示,SEQ IDNO:2))的不同载体。
P1140(如图1所示):
P1140被定向为使得复制起点(在载体图谱中表示为pUC起点)的复制方向与插入片段(在载体图谱中表示为RNA)的转录方向相反。
载体编码卡那霉素(在载体图谱中表示为KanR)作为选择标记物。
P1140-AF1(如图3所示):
P1140-AF1被定向为使得复制起点(在载体图谱中表示为pUC起点)的复制方向与插入片段(在载体图谱中表示为RNA)的转录方向相反。
载体编码RNA-OUT作为选择标记物,RNA-OUT是抑制整合到染色体中的组成型表达的反选择标记物(sacB)表达的反义RNA,从而允许对蔗糖上质粒进行选择(在载体图谱中表示为RNA-OUT)。
P1140-AF2(如图2所示):
P1140-AF2被定向为使得复制起点(在载体图谱中表示为pUC起点)的复制方向与插入片段(RNA在载体图谱中表示为RNA)的转录方向相同。
载体编码RNA-OUT作为选择标记物,RNA-OUT是抑制整合到染色体中的组成型表达的反选择标记物(sacB)表达的反义RNA,从而允许对蔗糖上质粒进行选择(在载体图谱中表示为RNA-OUT)。
P1140-K1(如图5所示):
P1140-K1被定向为使得复制起点(在载体图谱中表示为pUC起点)的复制方向与插入片段(在载体图谱中表示为RNA)的转录方向相反。
载体编码卡那霉素(在载体图谱中表示为KanR)作为选择标记物。
P1140-K2(如图4所示):
P1140-K2被定向为使得复制起点(在载体图谱中表示为pUC起点)的复制方向与插入片段(RNA在载体图谱中表示为RNA)的转录方向相同。
载体编码卡那霉素(在载体图谱中表示为KanR)作为选择标记物。
HyperGRO发酵:
将质粒P1140(图1)、P1140-AF1(图3)、P1140-AF2(图2)、P1140-K1(图5)和P1140-K2(图4)转化到DH5α衍生的大肠杆菌菌株DH5α、DH5αdcm或DH5αdcm-attλ::P5/66/6-RNA-IN-SacB(如表1所示)中并通过HyperGRO发酵繁殖。这种补料分批发酵的方法在EP 1781800中进行了详细描述。P1140载体在HyperGRO发酵中生长缓慢并且产量低。P1140-AF1和P1140-K1细胞株在HyperGRO发酵过程中也生长缓慢且产量低(参见表1)。相比之下,P1140-AF2和P1140-K2细胞系具有正常生长和高生产量(参见表1)。通过对质粒进行测序,可以证实的是在所有测试的质粒中发酵期间多聚(A)序列是稳定的。
表1:HyperGRO发酵的总结
分批发酵:
通过在37℃下采用标准分批发酵证实的这些结果表明增加质粒产量独立于特定的发酵方案。
Claims (13)
1.一种发酵生产共价闭合的重组DNA分子的方法,包括以下步骤:
(a)提供包含共价闭合的环状重组DNA分子的细菌,
其中所述共价闭合的环状重组DNA分子包含:
-复制起点,其中所述复制起点是细菌来源的并且所述复制起点是高拷贝数起点,
-编码选择标记物的序列,其中所述序列是卡那霉素抗性基因或者所述选择标记物是蔗糖选择性标记物,
-DNA依赖性RNA聚合酶的启动子,其中所述启动子是噬菌体启动子,
-包含均聚区域的插入片段,
其中所述均聚区域在复制方向上位于与所述复制起点至少500bp的距离处,其中所述均聚区域包含至少40个相同核苷酸的序列;和
(b)使步骤(a)的所述细菌发酵。
2.根据权利要求1所述的方法,其中所述均聚区域包含至少一个多聚(A)序列。
3.根据权利要求1或2所述的方法,其中所述包含均聚区域的插入片段被定向为使得所述插入片段的转录方向与所述复制起点的所述复制方向相同。
4.根据前述权利要求中任一项所述的方法,其中所述共价闭合的环状重组DNA分子选自由质粒、粘粒、细菌人工染色体(BAC)、噬菌体、病毒载体或其杂交体组成的组。
5.根据前述权利要求中任一项所述的方法,其中所述共价闭合的环状重组DNA分子是质粒。
6.根据前述权利要求中任一项所述的方法,其中所述复制起点来源于pBR322质粒、pUC质粒、pMB1质粒、ColE1质粒、R6K质粒、p15A质粒、pSC101质粒或F1噬菌粒。
7.根据前述权利要求中任一项所述的方法,其中所述复制起点来源于所述pUC质粒。
8.根据前述权利要求中任一项所述的方法,其中所述共价闭合的重组DNA分子还包含引发体组装位点,优选地,所述共价闭合的环状重组DNA分子还包含重链中的引发体组装位点(PAS-BH)。
9.根据权利要求4所述的方法,其中所述质粒来源于具有SEQ ID NO:4中确定的序列或具有SEQ ID NO:5中确定的序列的骨架。
10.共价闭合的环状重组DNA分子,包含:
-复制起点,其中所述复制起点是细菌来源的并且所述复制起点是高拷贝数起点,
-编码选择标记物的序列,其中所述序列是卡那霉素抗性基因或者所述选择标记物是蔗糖选择性标记物,
-DNA依赖性RNA聚合酶的启动子,其中所述启动子是噬菌体启动子,
-包含均聚区域的插入片段,其中所述均聚区域在复制方向上位于与所述复制起点至少500bp的距离处,其中所述均聚区域包含至少40个相同核苷酸的序列。
11.根据权利要求10所述的共价闭合的环状重组DNA分子,进一步由权利要求2至9中任一项所定义。
12.根据权利要求10或11所述的共价闭合的环状重组DNA分子,其中所述多聚(A)序列包含约60至约250个腺苷核苷酸的序列。
13.如权利要求1至11中任一项所定义的共价闭合的环状重组DNA分子用于体外转录RNA中的用途。
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