CN112513270A - 基于逆转录转座子的递送媒介物及其使用方法 - Google Patents
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Abstract
本公开提供了一种基因递送系统,所述基因递送系统包含:a)R2逆转录转座子R2多肽,或包含编码所述R2多肽的核苷酸序列的第一核酸;以及b)核酸,所述核酸包含编码一种或多种异源基因产物的异源核苷酸序列,其中所述异源核苷酸序列由R2逆转录转座子3’非翻译区(UTR)和R2逆转录转座子5’UTR侧接,并且其中所述异源核苷酸序列具有至少200个核苷酸的长度。本公开提供了一种将一种或多种目标基因产物递送至真核细胞的方法,所述方法包括使所述细胞与所述基因递送媒介物系统接触。
Description
交叉引用
本申请要求2018年7月13日提交的美国临时专利申请号62/697,829的权益,所述申请以引用的方式整体并入本文。
引言
基因疗法正在成为治疗人疾病的越来越成功的技术。基因疗法涉及递送核酸,所述核酸包含编码目标基因产物的编码区,其中所述基因产物可提供功能性获得或功能性丧失,以校正特定细胞中的异常行为。递送通常分为两个主要类别:病毒介导的和非病毒介导的递送。另外,核酸的递送产生所述核酸的全部或一部分的瞬时表达或不可逆整合至宿主细胞的DNA中。病毒介导的整合方法最常用于分裂细胞,其中例如通过使用经工程化以将治疗性DNA携带至细胞中的慢病毒和逆转录病毒来介导递送。此类病毒可有效地稳定整合到宿主细胞的基因组中;然而,它们具有许多缺点。整合到细胞基因组中的随机位置可导致细胞功能的破坏,并且表达甚至可能最终因细胞自身的机制而沉默。此外,当待递送的编码区的大小对于逆转录病毒和慢病毒而言分别超过6千碱基(kb)或8kb时,病毒方法在它们的包装和递送编码目标基因产物的编码区的能力方面遭受严重损害。尽管许多基因疗法涉及在包装限制内的编码区域,但基因产物的编码区的长度已接近8kb的最大限制,并且添加更大的cDNA、调控元件或多个基因将使插入片段大小达到大于当前病毒递送媒介物所能够容纳的大小。
诸如piggyBac、睡美人(Sleeping Beauty)和Tol2的II类转座子可整合更大的有效负载;然而,此类转座子具有缺点。例如,DNA转座子可整合在基因组中特定但常见的位点处(值得注意的是,可转座元件通常占基因组的45%),并且一些倾向于整合在发生活性转录的区域中。
在本领域中需要较大编码区的递送的递送媒介物。
发明内容
本公开提供了一种基因递送系统,所述基因递送系统包含:a)第一核酸,所述第一核酸包含编码R2逆转录转座子R2多肽的核苷酸序列;以及b)第二核酸,所述第二核酸包含编码一种或多种异源基因产物的异源核苷酸序列,其中所述异源核苷酸序列由R2逆转录转座子3’非翻译区(UTR)和R2逆转录转座子5’UTR侧接,并且其中所述异源核苷酸序列具有多达约15千碱基的长度。本公开提供了一种将一种或多种目标基因产物递送至真核细胞的方法,所述方法包括使所述细胞与所述基因递送媒介物系统接触。
附图说明
图1A-1B描绘:(图1A)双载体整合系统的示意图,所述双载体整合系统编码由R2UTR靶向序列侧接的转基因;以及(图1B)所提出的R2整合机制的机制。
图2描绘使用本公开的基因递送系统递送的基因的28S rDNA中的基因组整合接点的分析。
图3描绘使用本公开的基因递送系统递送的基因的28S rDNA中的基因组整合接点的分析。
图4描绘用于细胞转染和传代的方案,并且呈现示出用本公开的基因递送系统转染后绿色荧光蛋白(GFP)表达的数据。
图5A和5B描绘优化的R2(“OR2”)对转基因表达的影响。
图6A和6B描绘在用本公开的基因递送系统转染细胞后嵌合抗原受体(CAR)的表达,其中异源核酸包含编码CAR的核苷酸序列。
图7提供R2多肽的氨基酸序列(SEQ ID NO:37)。
图8提供5’UTR的核苷酸序列(SEQ ID NO:38)。
图9提供3’UTR的核苷酸序列(SEQ ID NO:39)。
图10描绘在用本公开的基因递送系统转染14天后稳定表达绿色荧光蛋白(GFP)的HEK293细胞的百分比。
图11描绘在用本公开的基因递送系统转染14天后的潮霉素抗性HEK293集落的数量。
图12描绘在用本公开的基因递送系统转染14天后c-myc+HEK293细胞的百分比。
定义
如本文所用,“异源的”意指分别不存在于天然(例如,天然存在的)核酸或蛋白质中的核苷酸或多肽序列。
在本文中可互换使用的术语“多核苷酸”和“核酸”是指任何长度的核苷酸(核糖核苷酸或脱氧核糖核苷酸)的聚合形式。因此,此术语包括但不限于单链、双链或多链DNA或RNA、基因组DNA、cDNA、DNA-RNA杂交体、或包含嘌呤碱基和嘧啶碱基或其他天然的、化学或生物化学修饰的、非天然的或衍生的核苷酸碱基的聚合物。
“可操作地连接”是指并置,其中所述组分处于容许其以预期的方式起作用的关系中。例如,如果启动子影响编码序列的转录或表达,则启动子可操作地连接至所述编码序列。
在本文可互换使用的术语“多肽”、“肽”和“蛋白质”是指具有任何长度的氨基酸的聚合形式,其可包括遗传编码和非遗传编码的氨基酸、化学或生物化学修饰的或衍生的氨基酸以及具有修饰的肽主链的多肽。所述术语包括融合蛋白,包括但不限于具有异源氨基酸序列的融合蛋白、具有异源和同源前导序列的融合体,具有或不具有N末端甲硫氨酸残基;免疫标记蛋白;等。
本文可互换使用的术语“嵌合抗原受体”和“CAR”是指能够触发或抑制免疫细胞的激活的人工多模块分子,所述分子通常但不排他性地包含细胞外结构域(例如,配体/抗原结合结构域)、跨膜结构域和一个或多个细胞内信号传导结构域。术语“CAR”不具体限于CAR分子,而且包括CAR变体。CAR变体包括分离的CAR,其中CAR的细胞外部分(例如,配体结合部分)和细胞内部分(例如,细胞内信号传导部分)存在于两个单独的分子上。CAR变体还包括作为条件可激活的CAR的ON-开关CAR,例如,包含分离的CAR,其中分离的CAR的两个部分的条件性异二聚化是通过药理学控制的。CAR变体还包括双特异性CAR,所述双特异性CAR包含可扩增或抑制初级CAR活性的二级CAR结合结构域。CAR变体还包括抑制性嵌合抗原受体(iCAR),其可例如用作双特异性CAR系统的组分,其中二级CAR结合结构域的结合导致一级CAR激活的抑制。CAR分子及其衍生物(即,CAR变体)描述于例如PCT申请号US2014/016527;Fedorov等人Sci Transl Med(2013);5(215):215ra172;Glienke等人Front Pharmacol(2015)6:21;Kakarla和Gottschalk 52Cancer J(2014)20(2):151-5;Riddell等人CancerJ(2014)20(2):141-4;Pegram等人Cancer J(2014)20(2):127-33;Cheadle等人ImmunolRev(2014)257(1):91-106;Barrett等人Annu Rev Med(2014)65:333-47;Sadelain等人Cancer Discov(2013)3(4):388-98;Cartellieri等人,J Biomed Biotechnol(2010)956304中,所述文献的公开内容以引用的方式整体并入本文。
“单链Fv”或“sFv”抗体片段包含抗体的VH和VL结构域,其中这些结构域存在于单个多肽链中。在一些实施方案中,Fv多肽还包含在VH结构域与VL结构域之间的多肽接头,所述多肽接头使得sFv能够形成抗原结合所需的结构。关于sFv的综述,参见Pluckthun in ThePharmacology of Monoclonal Antibodies,第113卷,Rosenburg and Moore编辑,Springer-Verlag,New York,第269-315页(1994)。
如本文中所用,术语“纳米抗体”(Nb)是指源自天然存在的重链抗体的最小抗原结合片段或单一可变结构域(VHH),并且是本领域技术人员已知的。它们源自见于骆驼科动物中的仅有重链的抗体(Hamers-Casterman等人,1993;Desmyter等人,1996)。在“骆驼科动物”家族中,发现了没有轻多肽链的免疫球蛋白。“骆驼科动物”包括旧世界骆驼科动物(双峰驼和单峰驼)和新世界骆驼科动物(例如,羊驼(Llama paccos)、大羊驼(Llama glama)、原驼(Llama guanicoe)和骆马(Llama vicugna))。单一可变结构域重链抗体在本文中称为纳米抗体或VHH抗体。
如本文所用,术语“治疗(treatment)”、“治疗(treating)”、“治疗(treat)”等是指获得所需药理学和/或生理学作用。所述作用就完全或部分预防疾病或其症状而言可为防治性的和/或就部分或完全治愈疾病和/或可归因于所述疾病的不利作用而言可为治疗性的。如本文所用的“治疗(Treatment)”涵盖对哺乳动物,特别是人的疾病的任何治疗,并且包括:(a)预防所述疾病在可易患所述疾病但尚未诊断为患有所述疾病的受试者中发生;(b)抑制所述疾病,即遏止其发展;以及(c)减轻所述疾病,即导致所述疾病消退。
本文中可互换使用的术语“个体”、“受试者”、“宿主”和“患者”是指哺乳动物,包括但不限于鼠科动物(大鼠、小鼠)、非人灵长类动物、人、犬科动物、猫科动物、有蹄类动物(例如,马科动物、牛科动物、绵羊科动物、猪科动物、山羊科动物)、兔类动物等。在一些情况下,个体是人在一些情况下,个体是非人灵长类动物。在一些情况下,个体是啮齿类动物,例如大鼠或小鼠。在一些情况下,个体是兔类动物,例如兔。
在进一步描述本发明之前,应当理解本发明不限于所描述的特定实施方案,因而,当然也可有所变化。还应当理解,本文所用的术语仅用于描述特定实施方案的目的,而不是旨在进行限制,因为本发明的范围将仅由所附权利要求书限制。
在提供值的范围时,应当理解,除非上下文另外明确指出,否则介于该范围上限与下限之间的每个居间值(至下限单位的十分之一)以及该规定范围内的任何其它规定值或居间值均涵盖在本发明的范围内。这些较小范围的上限和下限可独立地包括在较小范围内并且也涵盖在本发明内,以规定范围内任何明确排除的限值为条件。当规定范围包括一个或两个限值时,排除了那些所包括的限值中的任一个或两个的范围也包括在本发明中。
除非另外定义,否则本文使用的所有技术和科学术语均具有与本发明所属领域的普通技术人员通常所理解的相同含义。尽管与本文所述的那些类似或等同的任何方法和材料也可用于本发明的实践或测试,但现在描述优选的方法和材料。本文提及的所有出版物均以引用方式并入本文以公开和描述与所引用的出版物相关的方法和/或材料。
必须指出,除非上下文另外明确地规定,否则如本文和所附权利要求书中所用,单数形式“一个/种(a/an)”和“所述”包括复数指示物。因此,例如,提及“R2多肽”包括多种此类多肽,并且提及“异源基因产物”包括一种或多种异源基因产物和本领域技术人员已知的其等效物,等等。此外应注意权利要求书可经起草以排除任何可选择的要素。同样,该声明旨在作为与权利要求要素的叙述一起使用此类排他性术语如“只”、“仅”等,或使用“否定性”限制的前置基础。
应当理解,为了清楚起见在单独的实施方案的上下文中描述的本发明的某些特征也可在单个实施方案中组合提供。相反,为了简洁起见,在单个实施方案的上下文中描述的本发明的各种特征也可单独地或以任何合适的子组合提供。本发明特别地涵盖与本发明有关的实施方案的所有组合,并且在此公开,就如同单独地和明确地公开了每个组合一样。另外,本发明也特别地涵盖各种实施方案及其元素的所有子组合,并且在此公开,就如同每个此类子组合单独地和明确地在此公开一样。
本文所讨论的出版物仅提供其在本申请的提交日期之前的公开内容。本文的任何内容均不应解释为承认本发明无权凭借在先发明而先于此类出版物。此外,所提供的出版日期可能与实际出版日期不同,这可能需要独立地确认。
具体实施方式
本公开提供了一种基因递送系统,所述基因递送系统包含:a)R2逆转录转座子R2多肽,或包含编码所述R2多肽的核苷酸序列的第一核酸;以及b)核酸,所述核酸包含编码一种或多种异源基因产物的异源核苷酸序列,其中所述异源核苷酸序列由R2逆转录转座子3’非翻译区(UTR)和R2逆转录转座子5’UTR侧接,并且其中所述异源核苷酸序列具有至少200个核苷酸的长度。所述R2多肽、5’UTR和3’UTR将异源核酸插入真核细胞基因组的28S区域中。本公开提供了一种将一种或多种目标基因产物递送至真核细胞的方法,所述方法包括使所述细胞与所述基因递送媒介物系统接触。
R2蛋白识别28S rDNA中在许多物种中保守的DNA序列的5’和3’位点。R2蛋白相互作用并结合R2编码序列的转录的RNA 5’和3’。基于R2蛋白是结合5’UTR还是3’UTR,它随后将与靶位点上游或下游的28S DNA相互作用。当前的整合模型是,与3’UTR RNA结合的R2蛋白将结合切割位点的上游,并经由所述蛋白质中的核酸内切酶结构域在3’端形成切口。从这里,R2将开始靶标引发的逆转录(TPRT)的过程,并如Eickbush等人所提出在28S区域内合成DNA的3’链(图1)。Eickbush,等人Microbiol.Spectr.3,MDNA3-0011-2014(2015)。
一旦完成,下游缔合R2蛋白或天然复制机制开始第二条链合成。最终结果是将目标转基因(“异源核酸”或“异源核苷酸序列”)整合至天然28S rDNA位点中。
基因递送系统
本公开提供了一种基因递送系统,所述基因递送系统包含:a)第一核酸,所述第一核酸包含编码R2逆转录转座子R2多肽的核苷酸序列;以及b)第二核酸,所述第二核酸包含编码一种或多种异源基因产物的异源核苷酸序列,其中所述异源核苷酸序列由R2逆转录转座子3’UTR和R2逆转录转座子5’UTR侧接,并且其中所述异源核苷酸序列具有至少200个核苷酸的长度。所述第一和第二核酸可以是RNA。所述第一和第二核酸可以是DNA。
在一些情况下,所述第二核酸按5’至3’顺序包含:i)R2 5’UTR;ii)启动子;iii)编码一种或多种异源基因产物的异源核苷酸序列;以及iv)R2 3’UTR。在一些情况下,所述第二核酸按5’至3’顺序包含:i)R25’UTR;ii)启动子;iii)编码一种或多种异源基因产物的异源核苷酸序列;iv)聚腺苷酸化(polyA)序列;以及v)R2 3’UTR。在一些情况下,例如,当启动子是RNA聚合酶II启动子时,编码一种或多种异源基因产物的异源核苷酸序列相对于R2 5’UTR和R2 3’UTR处于相反(反向)取向;即,编码一种或多种异源基因产物的异源核苷酸序列处于3’至5’取向。在一些情况下,例如,当启动子是RNA聚合酶I启动子时,编码一种或多种异源基因产物的异源核苷酸序列与R2 5’UTR和R2 3’UTR处于相同取向;即,编码一种或多种异源基因产物的异源核苷酸序列处于5’至3’取向。所述启动子可操作地连接至编码一种或多种异源基因产物的异源核苷酸序列。在一些情况下,所述启动子与编码一种或多种异源基因产物的核苷酸序列异源。
本公开提供了一种基因递送系统,所述基因递送系统包含:a)R2逆转录转座子R2多肽;以及b)核酸,所述核酸包含编码一种或多种异源基因产物的异源核苷酸序列,其中所述异源核苷酸序列由R2逆转录转座子3’UTR和R2逆转录转座子5’UTR侧接,并且其中所述异源核苷酸序列具有至少200个核苷酸的长度。
R2多肽
由本公开的基因递送系统的第一核酸编码的R2多肽(其中所述基因递送系统包含第一核酸和核酸),或存在于本公开的基因递送系统中的R2多肽(其中所述基因递送系统包含R2多肽和核酸)可包含与图7中描绘的R2氨基酸序列具有至少85%、至少90%、至少95%、至少98%、至少99%或100%氨基酸序列同一性的氨基酸序列。所述R2多肽可具有1105个氨基酸至1125个氨基酸,例如约1105个氨基酸至约1110个氨基酸、约1110个氨基酸至约1115个氨基酸、约1115个氨基酸至约1120个氨基酸或约1120个氨基酸至约1125个氨基酸的长度。在一些情况下,所述R2多肽具有1114个氨基酸的长度。
5’UTR和3’UTR
合适的5’UTR是R2逆转录转座子的任何5’UTR。R2逆转录转座子5’UTR的核苷酸序列是本领域已知的;并且任何这样的5’UTR可包含在本公开的基因递送系统中。
在一些情况下,合适的5’UTR包含与图8中描绘的核苷酸序列具有至少85%、至少90%、至少95%、至少98%、至少99%或100%核苷酸序列同一性的核苷酸序列。在一些情况下,合适的5’UTR具有约1000个核苷酸(nt)至约1100nt,例如约1000nt至约1025nt、约1025nt至约1050nt、约1050nt至约1075nt或约1075nt至约1100nt的长度。在一些情况下,合适的5’UTR具有约1050nt至约1060nt的长度。在一些情况下,合适的5’UTR具有1056nt的长度。
在一些情况下,合适的3’UTR包含与图9中描绘的核苷酸序列具有至少85%、至少90%、至少95%、至少98%、至少99%或100%核苷酸序列同一性的核苷酸序列。在一些情况下,合适的3’UTR具有约475nt至约550nt,例如约475nt至约500nt、约500nt至约525nt或约525nt至约550nt的长度。在一些情况下,合适的3’UTR具有约500nt至约510nt的长度。在一些情况下,合适的3’UTR具有502nt的长度。
异源核苷酸序列
如上所述,本公开的基因递送系统的第二核酸包含编码一种或多种异源基因产物的异源核苷酸序列(本文也称为“异源核酸”),其中所述异源核苷酸序列具有至少200个核苷酸(nt)的长度。例如,在一些情况下,所述异源核苷酸序列具有约200nt至约300nt、约300nt至约400nt、约400nt至约500nt、约500nt至约750nt、约750nt至约1千碱基(kb)、约1kb至约1.5kb、约1.5kb至约2kb、约2kb至约2.5kb、约2.5kb至约3kb或约3kb至约3.5kb的长度。作为另一个实例,在一些情况下,所述异源核苷酸序列具有约3.5kb至约4kb、约4kb至约4.5kb、约4.5kb至约5kb、约5kb至约5.5kb、约5.5kb至约6kb、约6kb至约6.5kb、约6.5kb至约7kb、约7kb至约8kb、约8kb至约9kb、约9kb至约10kb、约10kb至约11kb、约11kb至约12kb、约12kb至约13kb、约13kb至约14kb或约14kb至约15kb的长度。在一些情况下,所述异源核苷酸序列具有约200nt至约1kb的长度。在一些情况下,所述异源核苷酸序列具有约1kb至约5kb的长度。在一些情况下,所述异源核苷酸序列具有约3.5kb至约6kb的长度。在一些情况下,所述异源核苷酸序列具有约6kb至约8kb的长度。在一些情况下,所述异源核苷酸序列具有约8kb至约15kb的长度。在一些情况下,所述异源核苷酸序列具有约9kb至约15kb的长度。在一些情况下,所述异源核苷酸序列具有约10kb至约15kb的长度。
在一些情况下,当所述异源基因产物是多肽时,所述异源核苷酸序列可编码长度超过50个氨基酸的单一异源基因产物。在一些情况下,当所述异源基因产物是多肽时,所述异源核苷酸序列可编码长度超过200个氨基酸的单一异源基因产物。在一些情况下,当所述异源基因产物是多肽时,所述异源核苷酸序列可编码长度为约50个氨基酸(aa)至约100aa、约100aa至约200aa、约200aa至约300aa、约300aa至约400aa、约400aa至约500aa、约500aa至约750aa、约750aa至约1000aa、约1000aa至约1500aa、约1500aa至约2000aa、约2000aa至约2500aa或约2500aa至约3000aa的单一异源基因产物。在一些情况下,当所述异源基因产物是多肽时,所述异源核苷酸序列可编码长度多达3000个氨基酸的单一异源基因产物。在一些情况下,当所述异源基因产物是多肽时,所述异源核苷酸序列可编码长度为约3000aa至约5,000aa的单一异源基因产物。当所述异源基因产物是两种或更多种多肽时,所述异源核苷酸序列可编码组合长度多达3000个氨基酸(aa)、多达4000aa或多达5000aa的两种或更多种异源基因产物。当所述异源基因产物是两种或更多种多肽时,所述异源核苷酸序列可编码组合长度超过5,000aa的两种或更多种异源基因产物。在所述异源基因产物是核酸的情况下,所述异源核苷酸序列可编码长度为至少200nt(例如,约200nt至约500nt、约500nt至约1kb、约1kb至约3.5kb、约3.5kb至约6kb、约6kb至约10kb或约10kb至约15kb)的单一异源基因产物。在所述异源基因产物是两种或更多种核酸的情况下,所述异源核苷酸序列可编码组合长度为至少200nt(例如,约200nt至约500nt、约500nt至约1kb、约1kb至约3.5kb、约3.5kb至约6kb、约6kb至约10kb或约10kb至约15kb)的异源基因产物。在异源核苷酸序列编码为核酸的第一基因产物和为多肽的第二基因产物的情况下,所述异源核苷酸序列可编码例如基因产物的长度的任何组合,以使得编码两种基因产物的编码序列的总组合物长度是至少200nt(例如,约200nt至约500nt、约500nt至约1kb、约1kb至约3.5kb、约3.5kb至约6kb、约6kb至约10kb或约10kb至约15kb)。
在一些情况下,本公开的基因递送系统的第二核酸包含编码单一异源多肽的核苷酸序列。在一些情况下,本公开的基因递送系统的第二核酸包含编码单一异源核酸的核苷酸序列。在一些情况下,本公开的基因递送系统的第二核酸包含:a)编码第一异源多肽的第一核苷酸序列;和b)编码第二异源多肽的第二核苷酸序列。在一些情况下,本公开的基因递送系统的第二核酸包含:a)编码第一异源多肽的第一核苷酸序列;b)编码第二异源多肽的第二核苷酸序列;以及c)编码第三异源多肽的第三核苷酸序列。在一些情况下,本公开的基因递送系统的第二核酸包含:a)编码异源多肽的第一核苷酸序列;和b)编码异源核酸的第二核苷酸序列。在一些情况下,本公开的基因递送系统的第二核酸包含:a)编码异源多肽的第一核苷酸序列;b)编码异源核酸的第二核苷酸序列;以及c)编码第三异源核酸的第三核苷酸序列。
当异源核苷酸序列编码两种或更多种基因产物(例如,当异源核苷酸序列包含编码第一异源基因产物的第一核苷酸序列和编码第二异源基因产物的第二核苷酸序列等)时,在一些情况下,在第一核苷酸序列与第二核苷酸序列之间(或在编码基因产物的任何两个核苷酸序列之间)提供核酸接头。核酸接头可以是内部核糖体进入位点(IRES)。核酸接头可包含编码将第一核苷酸序列的3’端连接至第二核苷酸序列的5’端的自裂解2A肽(如P2A、T2A、E2A或F2A)的核苷酸序列。
在一些情况下,本公开的基因递送系统的第二核酸包含:a)编码第一异源多肽的第一核苷酸序列;b)编码第二异源多肽的第二核苷酸序列;其中所述第一和第二核苷酸序列在单个启动子的控制下。在一些情况下,所述启动子可操作地连接至第一核苷酸序列的5’端,并且存在选自由以下组成的组的核酸接头:IRES和编码将第一核苷酸序列的3’端连接至第二核苷酸序列的5’端的自裂解2A肽(如P2A、T2A、E2A或F2A)的核酸,其中所述第一核苷酸序列和所述第二核苷酸序列在所述启动子的控制下转录为单一RNA。在一些情况下,所述启动子可操作地连接至第二核苷酸序列的5’端,并且存在选自由以下组成的组的核酸接头:IRES和编码将第二核苷酸序列的3’端连接至第一核苷酸序列的5’端的自裂解2A肽(如P2A、T2A、E2A或F2A)的核酸,其中所述第一核苷酸序列和所述第二核苷酸序列在所述启动子的控制下转录为单一RNA。在一些情况下,所述启动子是诱导型的。
适合使用的自裂解病毒2A肽包括病毒2A肽,其是猪捷申病毒-1(P2A)、口蹄疫病毒(F2A)、明脉扁刺蛾病毒(T2A)、马鼻炎A病毒(E2A)和病毒猪捷申病毒1(P2A)肽。P2A(GSGATNFSLLKQAGDVEENPGP(SEQ ID NO:1))、T2A(GSGEGRGSLLTCGDVEENPGP(SEQ ID NO:2))、E2A(GSGQCTNYALLKLAGDVESNPGP(SEQ ID NO:3))和F2A(GSGVKQTLNFDLLKLAGDVESNPGP(SEQ ID NO:4))可被认为是“蛋白水解裂解位点”或“核糖体跳跃信号”(CHYSEL)参见例如,Kim等人(2011)PLoS ONE 6:e18556.。产生编码的多肽作为两条多肽链的机制可以是通过接头的自裂解、通过核糖体跳跃或翻译分流。
作为一个实例,在一些情况下,本公开的基因递送系统的第二核酸包含:a)第一核苷酸序列,所述第一核苷酸序列编码作为异二聚体的第一链的第一异源多肽;b)第二核苷酸序列,所述第二核苷酸序列编码作为异二聚体的第二链的第二异源多肽;其中所述第一和第二核苷酸序列在单个启动子的控制下。在一些情况下,本公开的基因递送系统的第二核酸包含:a)第一核苷酸序列,所述第一核苷酸序列编码作为异二聚体的第一链的第一异源多肽;b)核酸接头,所述核酸接头选自由IRES和编码自裂解2A肽的核酸;以及c)第二核苷酸序列,所述第二核苷酸序列编码作为异二聚体的第二链的第二异源多肽;其中所述第一和第二核苷酸序列在单个启动子的控制下。
在一些情况下,所述异源核苷酸序列编码单一多肽链,所述单一多肽链在翻译后裂解以产生两条多肽链。例如,在一些情况下,所述异源核苷酸序列编码单一多肽链,所述单一多肽链按N末端至C末端顺序包含:i)第一多肽;ii)可蛋白水解裂解接头;和iii)第二多肽。
所述可蛋白水解裂解接头可包括由选自由以下组成的组的蛋白酶识别的蛋白酶识别序列:丙氨酸羧肽酶、蜜环菌虾红素、细菌亮氨酰氨肽酶、癌促凝物质、组织蛋白酶B、梭菌蛋白酶、胞质溶胶丙氨酰氨肽酶、弹性蛋白酶、内切蛋白酶Arg-C、肠激酶、胃亚蛋白酶、明胶酶、Gly-X羧肽酶、甘氨酰基内肽酶、人鼻病毒3C蛋白酶、皮蝇素C、IgA-特异性丝氨酸内肽酶、亮氨酰基氨肽酶、亮氨酰基内肽酶、lysC、溶酶体pro-X羧肽酶、赖氨酰基氨肽酶、甲硫氨酰基氨肽酶、粘球菌(myxobacter)、苯乙肼裂解酶(nardilysin)、胰腺内肽酶E、细小核糖核酸病毒内肽酶(picornain)2A、细小核糖核酸病毒内肽酶3C、内肽酶原、脯氨酰基氨肽酶、原蛋白转化酶I、原蛋白转化酶II、拉塞尔溶素(russellysin)、糖胃蛋白酶(saccharopepsin)、semenogelase、T-纤维蛋白溶酶原激活因子、凝血酶、组织激肽释放酶、烟草蚀刻病毒(tobacco etch virus)(TEV)、批膜病毒素(togavirin)、色氨酰基氨肽酶、U-纤维蛋白溶酶原激活因子、V8、蛇毒凝血酶样酶A(venombin A)、蛇毒凝血酶样酶AB和Xaa-pro氨基肽酶。
例如,可蛋白水解裂解接头可包含基质金属蛋白酶裂解位点,例如选自胶原酶-1、-2和-3(MMP-1、-8和-13)、明胶酶A和B(MMP-2和-9)、溶基质素1、2和3(MMP-3、-10和-11)、基质溶解因子(MMP-7)和膜金属蛋白酶(MT1-MMP和MT2-MMP)的MMP的裂解位点。例如,MMP-9的裂解序列是Pro-X-X-Hy(其中,X表示任意残基;Hy,疏水性残基;SEQ ID NO:5),例如Pro-X-X-Hy-(Ser/Thr)SEQ ID NO:6,例如Pro-Leu/Gln-Gly-Met-Thr-Ser(SEQ ID NO:7)或Pro-Leu/Gln-Gly-Met-Thr(SEQ ID NO:8)。蛋白酶裂解位点的另一个实例是纤溶酶原激活物裂解位点,例如uPA或组织纤溶酶原激活物(tPA)裂解位点。合适的蛋白酶裂解位点的另一个实例是催乳素裂解位点。uPA和tPA的裂解序列的具体实例包括包含Val-Gly-Arg的序列。可包括在可蛋白水解裂解接头中的蛋白酶裂解位点的另一个实例为烟草蚀刻病毒(TEV)蛋白酶裂解位点,例如其中蛋白酶在谷氨酰胺与丝氨酸之间裂解的ENLYTQS(SEQ IDNO:9)。可包括在可蛋白水解裂解接头中的蛋白酶裂解位点的另一个实例是肠激酶裂解位点,例如其中裂解发生在赖氨酸残基之后的DDDDK(SEQ ID NO:10)。可包括在可蛋白水解裂解接头中的蛋白酶裂解位点的另一个实例是凝血酶裂解位点,例如LVPR(SEQ ID NO:11)。包含蛋白酶裂解位点的另外合适的接头包括包含以下氨基酸序列中的一者或多者的接头:LEVLFQGP(SEQ ID NO:12),由PreScission蛋白酶(包含人鼻病毒3C蛋白酶和谷胱甘肽-S-转移酶的融合蛋白;Walker等人(1994)Biotechnol.12:601)裂解;凝血酶裂解位点,例如CGLVPAGSGP(SEQ ID NO:13);SLLKSRMVPNFN(SEQ ID NO:14)或SLLIARRMPNFN(SEQ ID NO:15),由组织蛋白酶B裂解;SKLVQASASGVN(SEQ ID NO:16)或SSYLKASDAPDN(SEQ ID NO:17),由爱泼斯坦-巴尔(Epstein-Barr)病毒蛋白酶裂解;由MMP-3(溶基质素)裂解的RPKPQQFFGLMN(SEQ ID NO:18);由MMP-7(基质溶解因子)裂解的SLRPLALWRSFN(SEQ ID NO:19);由MMP-9裂解的SPQGIAGQRNFN(SEQ ID NO:20);由嗜热菌蛋白酶样MMP裂解的DVDERDVRGFASFL SEQ ID NO:21);由基质金属蛋白酶2(MMP-2)裂解的SLPLGLWAPNFN(SEQID NO:22);由组织蛋白酶L裂解的SLLIFRSWANFN(SEQ ID NO:23);由组织蛋白酶D裂解的SGVVIATVIVIT(SEQ ID NO:24);由基质金属蛋白酶1(MMP-1)裂解的SLGPQGIWGQFN(SEQ IDNO:25);由尿激酶型纤溶酶原激活物裂解的KKSPGRVVGGSV(SEQ ID NO:26);由1型膜基质金属蛋白酶(MT-MMP)裂解的PQGLLGAPGILG(SEQ ID NO:27);由溶基质素3(或MMP-11)、嗜热菌蛋白酶、成纤维细胞胶原酶和溶基质素-1裂解的HGPEGLRVGFYESDVMGRGHARLVHVEEPHT(SEQID NO:28);由基质金属蛋白酶13(胶原酶-3)裂解的GPQGLAGQRGIV(SEQ ID NO:29);由组织型纤溶酶原激活物(tPA)裂解的GGSGQRGRKALE(SEQ ID NO:30);由人前列腺-特异性抗原裂解的SLSALLSSDIFN(SEQ ID NO:31);由激肽释放酶(hK3)裂解的SLPRFKIIGGFN(SEQ ID NO:32);由嗜中性粒细胞弹性蛋白酶裂解的SLLGIAVPGNFN(SEQ ID NO:33);和由钙蛋白酶(钙激活的中性蛋白酶)裂解的FFKNIVTPRTPP(SEQ ID NO:34)。
在一些情况下,本公开的基因递送系统的第二核酸包含:a)编码第一异源多肽的第一核苷酸序列;和b)编码第二异源多肽的第二核苷酸序列;其中所述第一和第二核苷酸序列在两种不同启动子的控制下。例如,在一些情况下,本公开的基因递送系统的第二核酸包含:a)编码第一异源多肽的第一核苷酸序列,其中所述第一核苷酸序列在第一启动子的控制下;和b)编码第二异源多肽的第二核苷酸序列,其中所述第二核苷酸序列在第二启动子的控制下。在一些情况下,所述第一启动子和第二启动子均是可调控(例如,诱导型)启动子。在一些情况下,所述第一启动子和第二启动子均是组成型启动子。在一些情况下,第一启动子是诱导型的,并且第二启动子是组成型的。在一些情况下,第一启动子是组成型,并且第二启动子是。
转录控制元件
存在于本公开的基因递送系统的第二核酸中的异源核苷酸序列能够可操作地连接至一种或多种转录控制元件。在一些情况下,所述转录控制元件是诱导型的。在一些情况下,所述转录控制元件是组成型的。在一些情况下,所述转录控制元件是启动子。在一些情况下,所述启动子在真核细胞中具有功能。在一些情况下,所述启动子是细胞类型特异性启动子。在一些情况下,所述启动子是组织特异性启动子。在一些情况下,所述启动子是组成型活性的。在一些情况下,所述启动子是可调控启动子。
启动子可以是组成型活性启动子(即,组成性地处于活性/“ON”状态的启动子),它可以是诱导型启动子(即,通过外界刺激例如特定温度、化合物或蛋白质的存在控制其状态(活性/”ON”或非活性/“OFF”)的启动子),它可以是空间限制的启动子(即,转录控制元件、增强子等)(例如,组织特异性启动子、细胞类型特异性启动子等),并且它可以是时间限制的启动子(即,启动子在胚胎发育的特定阶段过程中或在生物过程的特定阶段(例如,小鼠体内的毛囊周期)过程中处于“ON”状态或“OFF”状态)。
合适的启动子和增强子元件是本领域已知的。为了在真核细胞中表达,合适的启动子包括但不限于,轻链和/或重链免疫球蛋白基因启动子和增强子元件;巨细胞病毒立即早期启动子;单纯疱疹病毒胸苷激酶启动子;早期和晚期SV40启动子;存在于逆转录病毒的长末端重复序列中的启动子;小鼠金属硫蛋白-I启动子;以及各种本领域已知的组织特异性启动子。
合适的可逆启动子,包括可逆诱导型启动子,在本领域中是已知的。此类可逆启动子可分离自并源自许多生物体,例如真核生物和原核生物。用于第二生物体的源自第一生物体(例如,第一原核生物和第二真核生物、第一真核生物和第二原核生物等)的可逆启动子的修饰在本领域中是众所周知的。此类可逆启动子和基于此类可逆启动子但还包含另外的控制蛋白的系统包括但不限于醇调控的启动子(例如,醇脱氢酶I(alcA)基因启动子、响应于醇反式激活因子蛋白(AlcR)的启动子等)、四环素调控的启动子(例如,包括Tet激活因子、TetON、TetOFF等的启动子系统)、类固醇调控的启动子(例如,大鼠糖皮质激素受体启动子系统、人雌激素受体启动子系统、类视黄醇启动子系统、甲状腺启动子系统、蜕皮激素启动子系统、米非司酮启动子系统等)、金属调控的启动子(例如,金属硫蛋白启动子系统等)、发病原相关的调控启动子(例如,水杨酸调控的启动子、乙烯调控的启动子、苯并噻二唑调控的启动子等)、温度调控的启动子(例如,热休克诱导型启动子(例如,HSP-70、HSP-90、大豆热休克启动子等))、光调控的启动子、合成诱导型启动子等。合适的启动子可以是RNApol I启动子。合适的启动子可以是RNA pol II启动子。
适合使用的诱导型启动子包括本文所述或本领域的普通技术人员已知的任何诱导型启动子。诱导型启动子的实例包括但不限于化学/生物化学调控的启动子和物理调控的启动子,诸如醇调控的启动子、四环素调控的启动子(例如,无水四环素(aTc)-响应性启动子和其他四环素响应性启动子系统,其包括四环素阻遏蛋白(tetR)、四环素操作序列(tetO)和四环素反式激活因子融合蛋白(tTA))、类固醇调控的启动子(例如,基于大鼠糖皮质激素受体、人雌激素受体、蛾蜕皮激素受体的启动子以及来自类固醇/类视黄醇/甲状腺受体超家族的启动子)、金属调控的启动子(例如,衍生自来自酵母、小鼠和人的金属硫蛋白(结合并螯合金属离子的蛋白质)基因的启动子)、发病原调控的启动子(例如,由水杨酸、乙烯或苯并噻二唑(BTH)诱导的启动子)、温度/热诱导型启动子(例如,热休克启动子)和光调控的启动子(例如,来自植物细胞的光响应性启动子)。
在一些情况下,所述启动子是CD8细胞特异性启动子、CD4细胞特异性启动子、嗜中性粒细胞特异性启动子或NK特异性启动子。例如,可使用CD4基因启动子。参见例如,Salmon等人(1993)Proc.Natl.Acad.Sci.USA 90:7739;和Marodon等人(2003)Blood 101:3416。作为另一个实例,可使用CD8基因启动子。NK细胞特异性表达可通过使用Ncr1(p46)启动子来实现;参见例如,Eckelhart等人(2011)Blood 117:1565。
在一些情况下,所述启动子是心肌细胞特异性启动子。在一些情况下,所述启动子是平滑肌细胞特异性启动子。在一些情况下,所述启动子是神经元特异性启动子。在一些情况下,所述启动子是脂肪细胞特异性启动子。其他细胞类型特异性启动子是本领域已知的,并且适用于本文。
异源基因产物
多种异源基因产物中的任一种都可由存在于本公开的基因递送系统的第二核酸中的异源核苷酸序列编码。所述异源基因产物可以是单一异源多肽。所述异源基因产物可以是单一核酸。所述异源基因产物可以是两种或更多种异源多肽。所述异源基因产物可以是两种或更多种异源核酸。所述异源基因产物可以是:i)异源多肽;和ii)异源核酸。
当所述异源基因产物是多肽时,合适的多肽包括但不限于受体、酶、抗体、同二聚体多肽、异二聚体多肽、多肽激素、细胞外基质蛋白、蛋白聚糖、核酸酶、RNA的CRISPR/Cas效应物多肽、嵌合多肽、融合多肽等。在一些情况下,所述异源基因产物是CAR。在一些情况下,所述异源基因产物是synNotch多肽。在一些情况下,所述异源基因产物是synNotch多肽和CAR。
当所述异源基因产物是核酸时,合适的核酸包括但不限于,包含编码多肽的核苷酸序列的RNA;微小RNA;核酶;抑制性RNA;RNA,所述RNA包含与靶核酸中的核苷酸序列互补的第一片段和与RNA的效应物多肽结合的第二片段等。在一些情况下,所述异源基因产物是短干扰RNA(siRNA)、短发夹RNA(shRNA)、核酶、微小RNA(miRNA)、小时序RNA(stRNA)、反义RNA、小RNA诱导的基因激活(RNAa)或小激活RNA(saRNA)。
嵌合抗原受体
作为一个非限制性实例,异源多肽是嵌合抗原受体(CAR)。在一些情况下,所述CAR是单一多肽链CAR。在其他情况下,所述CAR是包含两条多肽链的异二聚体CAR。单一多肽链CAR可包含:i)抗原结合结构域;ii)跨膜结构域;和iii)细胞内信号传导结构域。单一多肽链CAR可包含:i)抗原结合结构域;ii)跨膜结构域;iii)免疫调节结构域;和iv)细胞内信号传导结构域。
CAR的抗原结合部分可以是抗体或抗体片段。“抗体片段”包括完整抗体的一部分,例如完整抗体的抗原结合区或可变区。抗体片段的实例包括Fab、Fab'、F(ab')2和Fv片段;单链Fv(scFv);双抗体;线性抗体(Zapata等人,Protein Eng.8(10):1057-1062(1995));嵌合抗体;人源化抗体;单链抗体(scAb);单结构域抗体(dAb);单结构域重链抗体;单结构域轻链抗体;纳米抗体;双特异性抗体;多特异性抗体;以及包含抗体和非抗体蛋白的抗原结合(在本文中也称为抗原结合)部分的融合蛋白。在一些情况下,所述抗原结合结构域是scFv。在一些情况下,所述抗原结合结构域是纳米抗体。其他基于抗体的抗原结合结构域(cAb VHH(骆驼科动物抗体可变结构域)和人源化型式、IgNAR VH(鲨鱼抗体可变结构域)和人源化型式、sdAb VH(单结构域抗体可变结构域)以及“骆驼化”抗体可变结构域适合使用。
CAR的抗原结合结构域可具有多种抗原结合特异性。在一些情况下,所述抗原结合结构域对存在于由癌细胞表达(由其合成)的抗原(即,癌细胞相关抗原)中的表位具有特异性。癌细胞相关抗原可以是与以下细胞相关的抗原:例如乳腺癌细胞、B细胞淋巴瘤、霍奇金淋巴瘤细胞、卵巢癌细胞、前列腺癌细胞、间皮瘤、肺癌细胞(例如,小细胞肺癌细胞)、非霍奇金B细胞淋巴瘤(B-NHL)细胞、卵巢癌细胞、前列腺癌细胞、间皮瘤细胞、肺癌细胞(例如,小细胞肺癌细胞)、黑素瘤细胞、慢性淋巴细胞性白血病细胞、急性淋巴细胞性白血病细胞、成神经细胞瘤细胞、神经胶质瘤、成胶质细胞瘤、成神经管细胞瘤、结肠直肠癌细胞等。癌细胞相关抗原也可由非癌性细胞表达。
CAR的抗原结合结构域可结合的抗原的非限制性实例包括,例如,CD19、CD20、CD38、CD30、Her2/neu、ERBB2、CA125、MUC-1、前列腺特异性膜抗原(PSMA)、CD44表面粘附分子、间皮素、癌胚抗原(CEA)、表皮生长因子受体(EGFR)、EGFRvIII、血管内皮生长因子受体-2(VEGFR2)、高分子量黑素瘤相关抗原(HMW-MAA)、MAGE-A1、IL-13R-a2、GD2等。
合适的免疫调节结构域(也称为“共刺激结构域”或“共刺激多肽”)包括例如,4-1BB(CD137)、CD28、ICOS、OX-40、BTLA、CD27、CD30、GITR和HVEM。
合适的细胞内信号传导结构域包括例如,包含一个或多个基于免疫受体酪氨酸的激活基序(ITAM)的多肽。ITAM基序是YX1X2L/I,其中X1和X2独立地是任何氨基酸。合适的含ITAM基序的多肽的实例包括但不限于:DAP12;FCER1G(Fcε受体Iγ链);CD3D(CD3δ);CD3E(CD3ε);CD3G(CD3γ);CD3Z(CD3ζ);和CD79A(抗原受体复合物相关蛋白α链)。
在一些情况下,CAR是包含两条多肽链的异二聚体CAR。参见例如,美国专利号9,821,012和9,587,020。例如,在一些情况下,异二聚体CAR包含:a)第一多肽链,所述第一多肽链包含:i)特异性结合靶细胞上的抗原的细胞外抗原结合结构域;ii)跨膜结构域;和iii)二聚化对的第一成员;以及b)第二多肽,所述第二多肽包含:i)跨膜结构域;ii)二聚化对的第二成员;和iii)包含ITAM的细胞内信号传导结构域,其中所述细胞内信号传导结构域提供信号转导活性。所述异二聚体CAR的第一多肽、第二多肽或第一和第二多肽均包含共刺激多肽。当存在于真核细胞膜中时,所述CAR的第一多肽结合抗原,并且所述CAR在小分子二聚化因子(dimerizer)存在下二聚化。
在一些情况下,异二聚体CAR包含:a)第一多肽,所述第一多肽按N末端至C末端顺序包含:i)抗原结合结构域(例如,抗原结合单链Fv(scFv)或纳米抗体);ii)跨膜结构域;和iii)二聚化对的第一成员;以及b)第二多肽,所述第二多肽按N末端至C末端顺序包含:i)跨膜结构域;ii)所述二聚化对的第二成员;和iii)包含ITAM的细胞内信号传导结构域,其中所述细胞内信号传导结构域提供信号转导活性,其中所述第一多肽、所述第二多肽或所述第一和第二多肽两者包含插入在所述跨膜结构域与所述二聚化对的成员之间的共刺激多肽。在一些情况下,所述共刺激多肽是4-1BB多肽。在一些情况下,所述共刺激多肽是CD28多肽。在一些情况下,所述共刺激多肽是OX-40多肽。在一些情况下,所述第一多肽在抗原结合结构域(例如,scFv、纳米抗体等)与跨膜结构域之间包含铰链区。在一些情况下,包含ITAM的细胞内信号传导结构域选自由CD3-ζ和ZAP70组成的组。
合适的二聚化对包括,例如,a)FK506结合蛋白(FKBP)和FKBP;b)FKBP和钙调磷酸酶催化亚基A(CnA);c)FKBP和亲环蛋白;d)FKBP和FKBP雷帕霉素相关蛋白(FRB);e)促旋酶B(GyrB)和GyrB;f)二氢叶酸还原酶(DHFR)和DHFR;g)DmrB和DmrB;h)PYL和ABI;i)Cry2和CIB1;和j)GAI和GID1。
可二聚化因子-结合对的第一成员和二聚化因子-结合对的第二成员的二聚化的合适的二聚化因子(“二聚化剂”)包括例如(其中二聚化因子在二聚化因子-结合对之后的括号内):a)FKBP和FKBP(雷帕霉素);b)FKBP和CnA(雷帕霉素);c)FKBP和亲环蛋白(雷帕霉素);d)FKBP和FRG(雷帕霉素);e)GyrB和GyrB(香豆素);f)DHFR和DHFR(甲氨蝶呤);g)DmrB和DmrB(AP20187);h)PYL和ABI(脱落酸);i)Cry2和CIB1(蓝光);以及j)GAI和GID1(赤霉素)。
synNotch
作为另一个非限制性实例,异源核苷酸序列可编码synNotch多肽(在本文中也称为“嵌合Notch受体多肽”。合适的synNotch多肽描述于例如美国专利号9,670,281;Morsut等人(2016)Cell 164:780;和Roybal等人(2016)Cell 167:419中。synNotch多肽包含:i)抗原结合结构域;ii)Notch多肽的一部分;和iii)细胞内结构域(例如,转录因子(例如,转录激活因子或转录抑制因子)、位点特异性核酸酶等)。synNotch多肽不结合δ(Notch的天然存在的配体)。相反,synNotch多肽结合由synNotch多肽中存在的抗原结合结构域所结合的抗原。抗原结合结构域与抗原(例如,存在于细胞,如癌细胞上的抗原)的结合诱导Notch多肽中S2蛋白水解裂解位点和/或S3蛋白水解裂解位点的裂解,从而释放细胞内结构域。
在一些情况下,synNotch多肽包含:i)抗原结合结构域;ii)Notch调控区,所述Notch调控区包含Lin 12-Notch重复序列、包含S2蛋白水解裂解位点的异二聚化结构域和包含S3蛋白水解裂解位点的跨膜结构域;以及iii)与Notch调控区异源的细胞内结构域,所述细胞内结构域包含含有DNA结合结构域的转录激活因子,其中所述抗原结合结构域与抗原的反式结合诱导在S2和S3蛋白水解裂解位点的裂解,从而释放细胞内结构域。
在一些情况下,synNotch多肽包含:i)抗原结合结构域;ii)Notch调控区,所述Notch调控区包含Lin 12-Notch重复序列、S2蛋白水解裂解位点和包含S3蛋白水解裂解位点的跨膜结构域;和iii)细胞内结构域,所述细胞内结构域包含与所述Notch调控区异源的转录激活因子或转录阻遏因子,其中存在于细胞或其他固体载体上的所述特异性结合对的第一成员与所述特异性结合对的第二成员的结合在所述S2和S3蛋白水解裂解位点诱导裂解,从而释放细胞内结构域。
synNotch多肽的抗原结合部分可以是抗体或抗体片段。“抗体片段”包括完整抗体的一部分,例如完整抗体的抗原结合区或可变区。抗体片段的实例包括Fab、Fab'、F(ab')2和Fv片段;单链Fv(scFv);双抗体;线性抗体(Zapata等人,Protein Eng.8(10):1057-1062(1995));嵌合抗体;人源化抗体;单链抗体(scAb);单结构域抗体(dAb);单结构域重链抗体;单结构域轻链抗体;纳米抗体;双特异性抗体;多特异性抗体;以及包含抗体和非抗体蛋白的抗原结合(在本文中也称为抗原结合)部分的融合蛋白。在一些情况下,所述抗原结合结构域是scFv。在一些情况下,所述抗原结合结构域是纳米抗体。其他基于抗体的抗原结合结构域(cAb VHH(骆驼科动物抗体可变结构域)和人源化型式、IgNAR VH(鲨鱼抗体可变结构域)和人源化型式、sdAb VH(单结构域抗体可变结构域)以及“骆驼化”抗体可变结构域适合使用。
synNotch多肽的抗原结合结构域可具有多种抗原结合特异性。在一些情况下,所述抗原结合结构域对存在于由癌细胞表达(由其合成)的抗原(即,癌细胞相关抗原)中的表位具有特异性。癌细胞相关抗原可以是与以下细胞相关的抗原:例如乳腺癌细胞、B细胞淋巴瘤、霍奇金淋巴瘤细胞、卵巢癌细胞、前列腺癌细胞、间皮瘤、肺癌细胞(例如,小细胞肺癌细胞)、非霍奇金B细胞淋巴瘤(B-NHL)细胞、卵巢癌细胞、前列腺癌细胞、间皮瘤细胞、肺癌细胞(例如,小细胞肺癌细胞)、黑素瘤细胞、慢性淋巴细胞性白血病细胞、急性淋巴细胞性白血病细胞、成神经细胞瘤细胞、神经胶质瘤、成胶质细胞瘤、成神经管细胞瘤、结肠直肠癌细胞等。癌细胞相关抗原也可由非癌性细胞表达。
synNotch多肽的抗原结合结构域可结合的抗原的非限制性实例包括,例如,CD19、CD20、CD38、CD30、Her2/neu、ERBB2、CA125、MUC-1、前列腺特异性膜抗原(PSMA)、CD44表面粘附分子、间皮素、癌胚抗原(CEA)、表皮生长因子受体(EGFR)、EGFRvIII、血管内皮生长因子受体-2(VEGFR2)、高分子量黑素瘤相关抗原(HMW-MAA)、MAGE-A1、IL-13R-a2、GD2等。
在一些情况下,synNotch的抗原结合结构域是scFv。作为另一个实例,在一些情况下,synNotch多肽的抗原结合结构域是纳米抗体。
在一些情况下,存在于synNotch多肽中的Notch多肽包含与以下序列具有至少75%、至少80%、至少85%、至少90%、至少95%、至少98%或100%氨基酸序列同一性的氨基酸序列:PPQIEEACELPECQVDAGNKVCNLQCNNHACGWDGGDCSLNFNDPWKNCTQSLQCWKYFSDGHCDSQCNSAGCLFDGFDCQLTEGQCNPLYDQYCKDHFSDGHCDQGCNSAECEWDGLDCAEHVPERLAAGTLVLVVLLPPDQLRNNSFHFLRELSHVLHTNVVFKRDAQGQQMIFPYYGHEEELRKHPIKRSTVGWATSSLLPGTSGGRQRRELDPMDIRGSIVYLEIDNRQCVQSSSQCFQSATDVAAFLGALASLGSLNIPYKIEAVKSEPVEPPLPSQLHLMYVAAAAFVLLFFVGCGVLLS(SEQ ID NO:35)。在一些情况下,存在于synNotch多肽中的Notch多肽包含与以下序列具有至少75%、至少80%、至少85%、至少90%、至少95%、至少98%或100%氨基酸序列同一性的氨基酸序列:PCVGSNPCYNQGTCEPTSENPFYRCLCPAKFNGLLCHILDYSFTGGAGRDIPPPQIEEACELPECQVDAGNKVCNLQCNNHACGWDGGDCSLNFNDPWKNCTQSLQCWKYFSDGHCDSQCNSAGCLFDGFDCQLTEGQCNPLYDQYCKDHFSDGHCDQGCNSAECEWDGLDCAEHVPERLAAGTLVLVVLLPPDQLRNNSFHFLRELSHVLHTNVVFKRDAQGQQMIFPYYGHEEELRKHPIKRSTVGWATSSLLPGTSGGRQRRELDPMDIRGSIVYLEIDNRQCVQSSSQCFQSATDVAAFLGALASLGSLNIPYKIEAVKSEPVEPPLPSQLHLMYVAAAAFVLLFFVGCGVLLS(SEQ ID NO:36)。
在一些情况下,所述细胞内结构域是转录因子。合适的转录因子包括,例如ASCL1、BRN2、CDX2、CDX4、CTNNB1、EOMES、JUN、FOS、HNF4a、HOXAs(例如,HOXA1、HOXA2、HOXA3、HOXA4、HOXA5、HOXA10、HOXA11、HOXA13)、HOXBs(例如,HOXB9)、HOXCs(例如,HOXC4、HOXC5、HOXC6、HOXC8、HOXC9、HOXC10、HOXC11、HOXC12、HOXC13)、HOXDs(例如,HOXD1、HOXD3、HOXD4、HOXD8、HOXD9、HOXD10、HOXD11、HOXD12、HOXD13)、SNAI1-3、MYOD1、MYOG、NEUROD1-6(例如,NEUROD1、NEUROD2、NEUROD4、NEUROD6)、PDX1、PU.1、SOX2、Nanog、Klf4、BCL-6、SOX9、STAT1-6、TBET、TCF、TEAD1-4(例如,TEAD1、TEAD2、TEAD3、TEAD4)、TAF6L、CLOCK、CREB、GATA3、IRF7、MycC、NFkB、RORyt、RUNX1、SRF、TBX21、NFAT、MEF2D以及FoxP3。
在一些情况下,所述细胞内结构域是在一种或多种免疫细胞中具有调控作用的转录因子(即,免疫细胞调控性转录因子)。合适的免疫细胞调控性转录因子包括,例如2210012G02Rik、Akap8l、Appl2、Arid4b、Arid5b、Ash1l、Atf7、Atm、C430014K11Rik、Chd9、Dmtf1、Fos、Foxo1、Foxp1、Hmbox1、Kdm5b、Klf2、Mga、Mll1、Mll3、Myst4、Pcgf6、Rev3l、Scml4、Scp2、Smarca2、Ssbp2、Suhw4、Tcf7、Tfdp2、Tox、Zbtb20、Zbtb44、Zeb1、Zfml、Zfp1、Zfp319、Zfp329、Zfp35、Zfp386、Zfp445、Zfp518、Zfp652、Zfp827、Zhx2、Eomes、Arntl、Bbx、Hbp1、Jun、Mef2d、Mterfd1、Nfat5、Nfe2l2、Nr1d2、Phf21a、Taf4b、Trf、Zbtb25、Zfp326、Zfp451、Zfp58、Zfp672、Egr2、Ikzf2、Taf1d、Chrac1、Dnajb6、Aplp2、Batf、Bhlhe40、Fosb、Hist1h1c、Hopx、Ifih1、Ikzf3、Lass4、Lin54、Mxd1、Mxi1、Prdm1、Prf1、Rora、Rpa2、Sap30、Stat2、Stat3、Taf9b、Tbx21、Trps1、Xbp1、Zeb2、Atf3、Cenpc1、Lass6、Rb1、Zbtb41、Crem、Fosl2、Gtf2b、Irf7、Maff、Nr4a1、Nr4a2、Nr4a3、Obfc2a、Rbl2、Rel、Rybp、Sra1、Tgif1、Tnfaip3、Uhrf2、Zbtb1、Ccdc124、Csda、E2f3、Epas1、H1f0、H2afz、Hif1a、Ikzf5、Irf4、Nsbp1、Pim1、Rfc2、Swap70、Tfb1m、2610036L11Rik、5133400G04Rik、Apitd1、Blm、Brca1、Brip1、C1d、C79407、Cenpa、Cfl1、Clspn、Ddx1、Dscc1、E2f7、E2f8、Ercc6l、Ezh2、Fen1、Foxm1、Gen1、Gsg2、H2afx、Hdac1、Hdgf、Hells、Hist1h1e、Hist3h2a、Hjurp、Hmgb2、Hmgb3、Irf1、Irf8、Kif22、Kif4、Lig1、Lmo2、Lnp、Mbd4、Mcm2、Mcm3、Mcm4、Mcm5、Mcm6、Mcm7、Mybl2、Neil3、Nusap1、Orc6l、Pola1、Pola2、Pole、Pole2、Polh、Polr2f、Polr2j、Ppp1r8、Prim2、Psmc3ip、Rad51、Rad51c、Rad54l、Rfc3、Rfc4、Rnps1、Rpa1、Smarcc1、Spic、Ssrp1、Taf9、Tfdp1、Tmpo、Topbp1、Trdmt1、Uhrf1、Wdhd1、Whsc1、Zbp1、Zbtb32、Zfp367、Car1、Polg2、Atr、Lef1、Myc、Nucb2、Satb1、Taf1a、Ift57、Apex1、Chd7、Chtf8、Ctnnb1、Etv3、Irf9、Myb、Mybbp1a、Pms2、Preb、Sp110、Stat1、Trp53、Zfp414、App、Cdk9、Ddb1、Hsf2、Lbr、Pa2g4、Rbms1、Rfc1、Rfc5、Tada2l、Tex261、Xrcc6等。
RNA的效应物多肽和RNA
作为另一个非限制性实例,异源核苷酸序列可编码RNA的效应物多肽。作为另一个非限制性实例,异源核苷酸序列可包含:i)第一核苷酸序列,所述第一核苷酸序列编码RNA的效应物多肽;和ii)第二核苷酸序列,所述第二核苷酸序列编码RNA。作为另一个非限制性实例,异源核苷酸序列可包含:i)第一核苷酸序列,所述第一核苷酸序列编码RNA的效应物多肽;ii)第二核苷酸序列,所述第二核苷酸序列编码第一RNA;和iii)第三核苷酸序列,所述第三核苷酸序列编码第二RNA。
合适的RNA的效应物多肽包括,例如,CRISPR/Cas核酸内切酶(例如,2类CRISPR/Cas核酸内切酶,如II型、V型或VI型CRISPR/Cas核酸内切酶)。合适的RNA的效应物多肽是CRISPR/Cas核酸内切酶(例如,2类CRISPR/Cas核酸内切酶,如II型、V型或VI型CRISPR/Cas核酸内切酶)。在一些情况下,RNA的效应物多肽是2类CRISPR/Cas核酸内切酶。在一些情况下,合适的RNA的效应物多肽是2类II型CRISPR/Cas核酸内切酶(例如,Cas9蛋白)。在一些情况下,合适的RNA的效应物多肽是2类V型CRISPR/Cas核酸内切酶(例如,Cpf1蛋白、C2c1蛋白或C2c3蛋白)。在一些情况下,合适的RNA的效应物多肽是2类VI型CRISPR/Cas核酸内切酶(例如,C2c2蛋白;也称为“Cas13a”蛋白)。还适合使用的是CasX蛋白。还适合使用的是CasY蛋白。还适合使用的是RNA的效应物多肽,所述效应物多肽具有降低的核酸酶活性,但是当与RNA复合时仍保留靶核酸结合活性。还适合使用的是RNA的效应物多肽,所述效应物多肽基本上没有核酸酶活性,但是当与RNA复合时仍保留靶核酸结合活性。还适合使用的是表现出切口酶活性的RNA的效应物多肽。还适合使用的是裂解RNA的RNA的效应物多肽。
各种Cas9蛋白(和Cas9结构域结构)和Cas9 RNA(以及有关与靶核酸中存在的原型间隔区相邻基序(PAM)序列有关的要求的信息)的例子可在本领域中找到,例如,参见Jinek等人,Science.2012年8月17日;337(6096):816-21;Chylinski等人,RNA Biol.2013年5月;10(5):726-37;Ma等人,Biomed Res Int.2013;2013:270805;Hou等人,Proc Natl AcadSci USA.2013年9月24日;110(39):15644-9;Jinek等人,Elife.2013;2:e00471;Pattanayak等人,Nat Biotechnol.2013年9月;31(9):839-43;Qi等人,Cell.2013年2月28日;152(5):1173-83;Wang等人,Cell.2013年5月9日;153(4):910-8;Auer等人,GenomeRes.2013年10月31日;Chen等人,Nucleic Acids Res.2013年11月1日;41(20):e19;Cheng等人,Cell Res.2013年10月;23(10):1163-71;Cho等人,Genetics.2013年11月;195(3):1177-80;DiCarlo等人,Nucleic Acids Res.2013年四月;41(7):4336-43;Dickinson等人,Nat Methods.2013年10月;10(10):1028-34;Ebina等人,Sci Rep.2013;3:2510;Fujii等人,Nucleic Acids Res.2013年11月1日;41(20):e187;Hu等人,Cell Res.2013年11月;23(11):1322-5;Jiang等人,Nucleic Acids Res.2013年11月1日;41(20):e188;Larson等人,Nat Protoc.2013年11月;8(11):2180-96;Mali等人,Nat Methods.2013年10月;10(10):957-63;Nakayama等人,Genesis.2013年12月;51(12):835-43;Ran等人,Nat Protoc.2013年11月;8(11):2281-308;Ran等人,Cell.2013年9月12日;154(6):1380-9;Upadhyay等人,G3(Bethesda).2013年12月9日;3(12):2233-8;Walsh等人,Proc Natl Acad Sci USA.2013年9月24日;110(39):15514-5;Xie等人,Mol Plant.2013年10月9日;Yang等人,Cell.2013年9月12日;154(6):1370-9;Briner等人,Mol Cell.2014年10月23日;56(2):333-9;Shmakov等人,Nat Rev Microbiol.2017年3月;15(3):169-182;以及美国专利和专利申请:8,906,616;8,895,308;8,889,418;8,889,356;8,871,445;8,865,406;8,795,965;8,771,945;8,697,359;20140068797;20140170753;20140179006;20140179770;20140186843;20140186919;20140186958;20140189896;20140227787;20140234972;20140242664;20140242699;20140242700;20140242702;20140248702;20140256046;20140273037;20140273226;20140273230;20140273231;20140273232;20140273233;20140273234;20140273235;20140287938;20140295556;20140295557;20140298547;20140304853;20140309487;20140310828;20140310830;20140315985;20140335063;20140335620;20140342456;20140342457;20140342458;20140349400;20140349405;20140356867;20140356956;20140356958;20140356959;20140357523;20140357530;20140364333;以及20140377868;其各自特此以引用的方式整体并入。
在一些情况下,合适的RNA的效应物多肽是变体Cas9蛋白。当与相应野生型Cas9蛋白的氨基酸序列相比时,变体Cas9蛋白具有因至少一个氨基酸而不同的氨基酸序列(例如,具有缺失、插入、取代、融合)。在一些实例中,变体Cas9蛋白具有降低Cas9蛋白的核酸酶活性的氨基酸变化(例如,缺失、插入或取代)。例如,在一些情况下,变体Cas9蛋白具有50%或更低、40%或更低、30%或更低、20%或更低、10%或更低、5%或更低或1%或更低的相应野生型Cas9蛋白的核酸酶活性。在一些情况下,变体Cas9蛋白基本上没有核酸酶活性。当Cas9蛋白是基本上没有核酸酶活性的变体Cas9蛋白时,它可被称为核酸酶缺陷型Cas9蛋白或对于“死”Cas9的“dCas9”。裂解双链靶核酸的一条链但不裂解另一条链的蛋白(例如,2类CRISPR/Cas蛋白,例如Cas9蛋白)在本文中被称为“切口酶”(例如,“切口酶Cas9”)。
还适合使用的是融合RNA的效应物多肽,其中融合RNA的效应物多肽包括:a)RNA的效应物多肽;和b)异源融合配偶体。在一些情况下,融合配偶体具有修饰靶核酸(例如,ssRNA、dsRNA、ssDNA、dsDNA)的酶活性。可由融合配偶体提供的酶活性的实例包括但不限于:核酸酶活性,诸如由限制性酶(例如,FokI核酸酶)提供的活性;甲基转移酶活性,诸如由甲基转移酶(例如,HhaI DNA m5c-甲基转移酶(M.HhaI)、DNA甲基转移酶1(DNMT1)、DNA甲基转移酶3a(DNMT3a)、DNA甲基转移酶3b(DNMT3b)、METI、DRM3(植物)、ZMET2、CMT1、CMT2(植物)等)提供的活性;脱甲基酶活性,诸如由脱甲基酶(例如;10-11易位(TET)双加氧酶1(TET1CD)、TET1、DME、DML1、DML2、ROS1等)提供的活性;DNA修复活性;DNA损伤活性;脱氨基活性,诸如由脱氨酶(例如,胞嘧啶脱氨酶,诸如大鼠APOBEC1)提供的活性;歧化酶活性;烷基化活性;脱嘌呤活性;氧化活性;嘧啶二聚体形成活性;整合酶活性,诸如由整合酶和/或解离酶(例如,Gin转化酶诸如Gin转化酶的过度活跃突变体GinH106Y、人免疫缺陷病毒1型整合酶(IN)、Tn3解离酶等)提供的活性;转座酶活性;重组酶活性,诸如由重组酶(例如,Gin重组酶的催化结构域)提供的活性;聚合酶活性;连接酶活性;解旋酶活性;光裂合酶活性和糖基化酶活性)。在一些情况下,融合配偶体是核酸酶,例如FokI核酸酶。在一些情况下,异源融合配偶体是脱氨酶。合适的脱氨酶包括胞苷脱氨酶和腺苷脱氨酶。
在一些情况下,RNA的效应物多肽或融合RNA的效应物多肽包含一个或多个核定位信号(NLS)。在一些情况下,RNA的效应物多肽或融合RNA的效应物多肽包含细胞穿透肽。在一些情况下,RNA的效应物多肽或融合RNA的效应物多肽包含核内体溶解肽。
在一些情况下,RNA包含两个分开的核酸分子:“激活因子”和“靶标”,并且在本文中被称为“双RNA”、“双分子RNA”、“两分子RNA”或“dgRNA”。在一些情况下,RNA是一个分子(例如,对于一些2类CRISPR/Cas蛋白,相应的RNA是单个分子;并且在一些情况下,激活因子和靶标彼此共价连接,例如经由插入核苷酸),并且RNA被称为“单RNA”、“单分子RNA(single-molecule guide RNA)”、“单分子RNA(one-molecule guide RNA)”或简称为“sgRNA”。
组合物
本公开提供了一种包含本公开的基因递送系统的组合物。
本公开的组合物包含:a)本公开的基因递送系统;和b)至少一种另外的组分,其中合适的另外的组分包括例如盐、缓冲剂、蛋白酶抑制剂、核酸酶抑制剂、脂质等。在一些情况下,本公开的组合物包含:a)本公开的基因递送系统;和b)脂质。在一些情况下,本公开的组合物包括:a)本公开的基因递送系统;和b)脂质体、水凝胶、微颗粒、纳米颗粒或嵌段共聚物胶束。
本公开的组合物可包含:a)本公开的基因递送系统;和b)以下中的一者或多者:缓冲剂、表面活性剂、抗氧化剂、亲水性聚合物、糊精、螯合剂、悬浮剂、增溶剂、增稠剂、稳定剂、抑菌剂、润湿剂以及防腐剂。合适的缓冲剂包括但不限于(如N,N-双(2-羟乙基)-2-氨基乙磺酸(BES)、双(2-羟乙基)氨基-三(羟甲基)甲烷(BIS-Tris)、N-(2-羟乙基)哌嗪-N'3-丙磺酸(EPPS或HEPPS)、甘氨酰甘氨酸、N-2-羟乙基哌嗪-N'-2-乙磺酸(HEPES)、3-(N-吗啉代)丙磺酸(MOPS)、哌嗪-N,N'-双(2-乙烷-磺酸)(PIPES)、碳酸氢钠、3-(N-三(羟甲基)-甲基-氨基)-2-羟基-丙磺酸)TAPSO、(N-三(羟甲基)甲基-2-氨基乙磺酸(TES)、N-三(羟甲基)甲基-甘氨酸(Tricine)、三(羟甲基)-氨基甲烷(Tris)等)。合适的盐包括例如,NaCl、MgCl2、KCl、MgSO4等。
本公开的组合物可包含:a)本公开的基因递送系统;和b)药学上可接受的赋形剂。药学上可接受的赋形剂已充分描述于多种出版物中,所述出版物包括例如A.Gennaro(2000)"Remington:The Science and Practice of Pharmacy",第20版,Lippincott,Williams,&Wilkins;Pharmaceutical Dosage Forms and Drug Delivery Systems(1999)H.C.Ansel等人编,第7版,Lippincott,Williams,&Wilkins;以及Handbook ofPharmaceutical Excipients(2000)A.H.Kibbe等人编,第3版Amer.PharmaceuticalAssoc。
在一些情况下,本公开的基因递送系统位于颗粒中或与颗粒缔合。术语“颗粒”和“纳米颗粒”可适当地互换使用。
本公开的基因递送系统可存在于颗粒中或与颗粒缔合,例如包含脂质或类脂质和亲水性聚合物(例如阳离子脂质和亲水性聚合物)的递送颗粒;例如,其中所述阳离子脂质包括1,2-二油酰基-3-三甲基铵-丙烷(DOTAP)或1,2-二十四烷酰基-sn-甘油基-3-磷酸胆碱(DMPC),和/或其中所述亲水性聚合物包括乙二醇或聚乙二醇(PEG);和/或其中所述颗粒还包含胆固醇(例如,来自制剂1的颗粒=DOTAP 100、DMPC 0、PEG 0、胆固醇0;制剂编号2=DOTAP 90、DMPC 0、PEG 10、胆固醇0;制剂编号3=DOTAP 90、DMPC 0、PEG 5、胆固醇5)。例如,可使用多步骤方法形成颗粒,其中将本公开的基因递送系统例如以1:1的摩尔比、例如在室温下、例如持续30分钟、例如在无菌无核酸酶的1x磷酸盐缓冲盐水(PBS)中混合在一起;并且将适用于制剂的DOTAP、DMPC、PEG和胆固醇单独地溶于醇(例如,100%乙醇);并且将两种溶液混合在一起以形成含有本公开的基因递送系统的颗粒)。
本公开的基因递送系统可以是纳米颗粒的一部分。例如,可使用具有由磷脂双层壳包封的聚(β-氨基酯)(PBAE)核的可生物降解的核壳结构的纳米颗粒。在一些情况下,使用基于自组装生物粘附聚合物的颗粒/纳米颗粒;此类颗粒/纳米颗粒可应用于口服递送、静脉内递送和鼻内递送。
在一些情况下,本公开的组合物包含本公开的基因递送系统和聚(β-氨基醇)(PBAA)。美国专利公开号20130302401涉及使用组合聚合制备的一类聚(β-氨基醇)(PBAA)。
在一些情况下,本公开的组合物包含本公开的基因递送系统和一个或多个脂质纳米颗粒(LNP)。带负电的聚合物(诸如RNA)可在低pH值(例如,pH 4)下负载到LNP中,其中可电离脂质显示正电荷。然而,在生理pH值下,LNP表现出与较长的循环时间相容的低表面电荷。已经关注了四种可电离的阳离子脂质,即1,2-二亚油酰基-3-二甲基铵-丙烷(DLinDAP)、1,2-二亚油基氧基-3-N,N-二甲基氨基丙烷(DLinDMA)、1,2-二亚油基氧基-酮基-N,N-二甲基-3-氨基丙烷(DLinKDMA)和1,2-二亚油基-4-(2-二甲基氨基乙基)-[1,3]-二氧戊环(DLinKC2-DMA)。LNP的制备描述于例如Rosin等人(2011)Molecular Therapy 19:1286-2200)中。可使用阳离子脂质1,2-二亚油酰基-3-二甲基铵-丙烷(DLinDAP)、1,2-二亚油基氧基-3-N,N-二甲基氨基丙烷(DLinDMA)、1,2-二亚油基氧基酮基-N,N-二甲基-3-氨基丙烷(DLinK-DMA)、1,2-二亚油基-4-(2-二甲基氨基乙基)-[1,3]-二氧戊环(DLinKC2-DMA)、(3-o-[2”-(甲氧基聚乙二醇2000)琥珀酰基]-1,2-二肉豆蔻酰基-sn-乙二醇(PEG-S-DMG),以及R-3-[(ω-甲氧基-聚(乙二醇)2000)氨甲酰基]-1,2-二肉豆蔻酰氧基丙基-3-胺(PEG-C-DOMG)。核酸(例如,指导RNA;本公开的核酸等)可包封在含有DLinDAP、DLinDMA、DLinK-DMA和DLinKC2-DMA(阳离子脂质:DSPC:CHOL:PEGS-DMG或PEG-C-DOMG的摩尔比为40:10:40:10)的LNP中。在一些情况下,使用0.2%SP-DiOC18。
在一些情况下,本公开的组合物包含本公开的基因递送系统和球形核酸(SNATM)构建体或其他纳米颗粒(特别是金纳米颗粒)。参见例如,Cutler等人,J.Am.Chem.Soc.2011133:9254-9257;Hao等人,Small.2011 7:3158-3162;Zhang等人,ACS Nano.2011 5:6962-6970;Cutler等人,J.Am.Chem.Soc.2012 134:1376-1391;Young等人,Nano Lett.2012 12:3867-71;Zheng等人,Proc.Natl.Acad.Sci.USA.2012109:11975-80;Mirkin,Nanomedicine2012 7:635-638;Zhang等人,J.Am.Chem.Soc.2012 134:16488-1691;Weintraub,Nature2013 495:S14-S16;Choi等人,Proc.Natl.Acad.Sci.USA.2013 110(19):7625-7630;Jensen等人,Sci.Transl.Med.5,209ra152(2013);以及Mirkin,等人,Small,10:186-192。
在一些情况下,本公开的基因递送系统存在于纳米颗粒中或与纳米颗粒缔合。一般来说,“纳米颗粒”是指具有小于1000nm的直径的任何颗粒。在一些情况下,适用于将本公开的基因递送系统递送至靶细胞的纳米颗粒具有500nm或更小,例如,25nm至35nm、35nm至50nm、50nm至75nm、75nm至100nm、100nm至150nm、150nm至200nm、200nm至300nm、300nm至400nm或400nm至500nm的直径。在一些情况下,适用于将本公开的基因递送系统递送至靶细胞的纳米颗粒具有25nm至200nm的直径。在一些情况下,适用于将本公开的基因递送系统递送至靶细胞的纳米颗粒具有100nm或更小的直径。在一些情况下,适用于将本公开的基因递送系统递送至靶细胞的纳米颗粒具有35nm至60nm的直径。
可以各种形式提供纳米颗粒,例如,作为固体纳米颗粒(例如,金属如银、金、铁、钛)、非金属、基于脂质的固体、聚合物)、纳米颗粒的悬浮液或它们的组合。可制备金属、介电和半导体纳米颗粒,以及混合结构(例如,核壳纳米颗粒)。如果由半导体材料制成的纳米颗粒足够小(通常低于10nm)以致发生电子能级的量子化,则也可将它们标记量子点。此类纳米级颗粒在生物医学应用中用作药物运载体或成像剂,并且可适用于本公开中的相似目的。
半固体和软纳米颗粒也适合包含在本公开的包含本公开的基因递送系统的组合物中。具有半固体性质的原型纳米颗粒是脂质体。
在一些情况下,本公开的组合物包含本公开的基因递送系统和脂质体。脂质体是球形囊泡结构,其由围绕内部水性隔室的单层或多层脂质双层和相对不可渗透的外部亲脂性磷脂双层构成。脂质体可由若干种不同类型的脂质制成;然而,磷脂最常用于生成脂质体。尽管当脂质膜与水性溶液混合时,脂质体形成是自发的,但是也可通过使用匀化器、超声波破碎仪或挤出装置以摇动的形式施加力来加速脂质体的形成。可将若干种其他添加剂添加到脂质体中以便改变它们的结构和特性。例如,可将胆固醇或鞘磷脂添加到脂质体混合物中,以便帮助稳定脂质体结构并防止脂质体内容物(inner cargo)的泄漏。脂质体制剂可主要由以下组成:天然磷脂和脂质,诸如1,2-二硬脂酰基-sn-甘油基-3-磷脂酰胆碱(DSPC)、鞘磷脂、卵磷脂酰胆碱和单唾液酸神经节苷脂。
在一些情况下,本公开的组合物包含本公开的基因递送系统和稳定的核酸-脂质颗粒(SNALP)。SNALP制剂可含有2:40:10:48摩尔百分比的脂质3-N-[(甲氧基聚(乙二醇)2000)氨基甲酰基]-1,2-二肉豆蔻酰氧基-丙胺(PEG-C-DMA)、1,2-二亚油基氧基-N,N-二甲基-3-氨基丙烷(DLinDMA)、1,2-二硬脂酰基-sn-甘油基-3-磷酸胆碱(DSPC)和胆固醇。所得的SNALP脂质体的尺寸可以是约80-100nm。SNALP可包含合成胆固醇(Sigma-Aldrich,StLouis,Mo.,USA)、二棕榈酰磷脂酰胆碱(Avanti Polar Lipids,Alabaster,Ala.,USA)、3-N-[(w-甲氧基聚(乙二醇)2000)氨基甲酰基]-1,2-二肉豆蔻酰氧基丙胺和阳离子1,2-二亚油基氧基-3-N,N二甲基氨基丙烷。SNALP可包含合成胆固醇(Sigma-Aldrich)、1,2-二硬脂酰基-sn-甘油基-3-磷酸胆碱(DSPC;Avanti Polar Lipids Inc.)、PEG-cDMA和1,2-二亚油基氧基-3-(N;N-二甲基)氨基丙烷(DLinDMA)。
其他阳离子脂质,如氨基脂质2,2-二亚油基-4-二甲基氨基乙基-[1,3]-二氧戊环(DLin-KC2-DMA)可包含于本公开的组合物中。可考虑具有以下脂质组成的预成形的囊泡:摩尔比分别为40/10/40/10的并且FVII siRNA/总脂质比为大约0.05(w/w)的氨基脂质、二硬脂酰磷脂酰胆碱(DSPC)、胆固醇和(R)-2,3-双(十八烷氧基)丙基-1-(甲氧基聚(乙二醇)2000)丙基氨基甲酸酯(PEG-脂质)。为了确保在70-90nm范围内的窄粒度分布和0.11.+-.0.04(n=56)的低多分散指数,可在添加基因递送系统之前将颗粒通过80nm膜挤出最高达三次。可使用含有高效氨基脂质16的颗粒,其中四种脂质组分16、DSPC、胆固醇和PEG-脂质的摩尔比(50/10/38.5/1.5)可进一步优化以增强体内活性。
脂质可与本公开的系统或其一种或多种组分或编码其的核酸一起配制以形成脂质纳米颗粒(LNP)。合适的脂质包括但不限于DLin-KC2-DMA4、C12-200和辅脂质(colipid)二硬脂酰磷脂酰胆碱、胆固醇和PEG-DMG可与本公开的系统或其组分一起使用自发的囊泡形成程序配制。组分摩尔比可以是约50/10/38.5/1.5(DLin-KC2-DMA或C12-200/二硬脂酰磷脂酰胆碱/胆固醇/PEG-DMG)。
本公开的基因递送系统可包封在PLGA微球中,所述微球诸如在美国公布申请20130252281和20130245107和20130244279中进一步描述的微球。
在一些情况下,本公开的组合物包含本公开的基因递送系统和超电荷蛋白。超电荷蛋白是一类工程化或天然存在的蛋白质,其具有异常高的正或负净理论电荷。超负电荷蛋白和超正电荷蛋白均表现出耐受热或化学诱导的聚集的能力。超正电荷蛋白也能够穿透哺乳动物细胞。使货物与这些蛋白质(诸如质粒DNA、RNA或其他蛋白质)缔合可有助于这些大分子在体外和体内向哺乳动物细胞的功能性递送。
本公开还提供了一种包含本公开的基因递送系统的可植入装置。可植入装置可包括容器(例如,储库、基质等),所述容器包括本公开的基因递送系统,例如,包含含有本公开的基因递送系统的组合物。合适的可植入装置可包括例如用作装置主体的聚合物基底(诸如基质),并且在一些情况下包括另外的支架材料(诸如金属或另外的聚合物),以及增强可见性和成像的材料。可植入递送装置局部且在长时间段内提供释放方面可能是有利的,其中待递送的核酸直接释放至靶位点,例如细胞外基质(ECM)、肿瘤周围的脉管系统、患病组织等。
合适的可植入递送装置包括适用于递送至诸如腹腔的空腔和/或其中递送系统未锚定或附接的任何其他施用类型的装置,所述装置包括生物稳定的和/或可降解的和/或生物可吸收的聚合物基底,其例如可任选地是基质。在一些情况下,合适的可植入递送装置包括可降解聚合物,其中主要释放机制是整体侵蚀(bulk erosion)。在一些情况下,合适的可植入递送装置包含不可降解或缓慢降解的聚合物,其中主要释放机制是扩散而不是整体侵蚀,使得外部部分用作膜并且其内部部分用作储库,实际上,所述药物储库长时间内(例如约一周至约几个月)不会受到周围环境的影响。也可任选地使用具有不同释放机制的不同聚合物的组合。
在一些情况下,可植入递送系统被设计成保护基于核苷酸的治疗剂(本公开的基因递送系统)免于降解,无论是化学性质还是由于受试者体内酶和其他因素的攻击而引起的降解。
药盒
本公开提供了一种药盒,所述药盒包含:a)第一核酸,所述第一核酸包含编码R2逆转录转座子R2多肽的核苷酸序列;和b)第二核酸,所述第二核酸包含用于插入编码一种或多种异源基因产物的异源核苷酸序列的插入位点,其中所述插入位点由R2逆转录转座子3'非翻译区(UTR)和R2逆转座子5'UTR侧接,并且其中所述异源核苷酸序列具有至少200个核苷酸的长度。因此,所述第二核酸允许插入编码任何所需的异源基因产物的异源核苷酸序列。在一些情况下,所述第一核酸和第二核酸位于分开的容器中。在一些情况下,所述第二核酸还包含插入位点5'的转录控制元件。所述转录控制元件相对于所述插入位点定位,以使得一旦将异源核苷酸序列插入所述第二核酸中,就将所述转录控制元件可操作地连接至所述异源核苷酸序列。合适的转录控制元件如上所述。
本公开提供了一种,所述药盒包含:a)R2逆转录转座子R2多肽;和b)核酸,所述核酸包含用于插入编码一种或多种异源基因产物的异源核苷酸序列的插入位点,其中所述插入位点由R2逆转录转座子3'UTR和R2逆转座子5'UTR侧接,并且其中所述异源核苷酸序列具有至少200个核苷酸的长度。因此,所述核酸允许插入编码任何所需的异源基因产物的异源核苷酸序列。在一些情况下,所述R2多肽和所述核酸位于分开的容器中。在一些情况下,所述核酸还包含插入位点5'的转录控制元件。所述转录控制元件相对于所述插入位点定位,以使得一旦将异源核苷酸序列插入所述核酸中,就将所述转录控制元件可操作地连接至所述异源核苷酸序列。合适的转录控制元件如上所述。
如上所述,允许插入编码任何所需的异源基因产物的异源核苷酸序列的核酸提供了至少200个核苷酸(nt)的异源核苷酸序列的插入。例如,在一些情况下,所述异源核苷酸序列具有约200nt至约300nt、约300nt至约400nt、约400nt至约500nt、约500nt至约750nt、约750nt至约1千碱基(kb)、约1kb至约1.5kb、约1.5kb至约2kb、约2kb至约2.5kb、约2.5kb至约3kb或约3kb至约3.5kb的长度。作为另一个实例,在一些情况下,所述异源核苷酸序列具有约3.5kb至约4kb、约4kb至约4.5kb、约4.5kb至约5kb、约5kb至约5.5kb、约5.5kb至约6kb、约6kb至约6.5kb、约6.5kb至约7kb、约7kb至约8kb、约8kb至约9kb、约9kb至约10kb、约10kb至约11kb、约11kb至约12kb、约12kb至约13kb、约13kb至约14kb或约14kb至约15kb的长度。在一些情况下,所述异源核苷酸序列具有约200nt至约1kb的长度。在一些情况下,所述异源核苷酸序列具有约1kb至约5kb的长度。在一些情况下,所述异源核苷酸序列具有约3.5kb至约6kb的长度。在一些情况下,所述异源核苷酸序列具有约6kb至约8kb的长度。在一些情况下,所述异源核苷酸序列具有约8kb至约15kb的长度。在一些情况下,所述异源核苷酸序列具有约9kb至约15kb的长度。在一些情况下,所述异源核苷酸序列具有约10kb至约15kb的长度。
向真核宿主细胞递送一种或多种基因产物的方法
本公开提供了一种将一种或多种目标基因产物递送至真核细胞的方法,所述方法包括使所述细胞与本公开的基因递送媒介物系统接触。所述R2多肽、5'UTR和3'UTR将所述异源核酸插入真核细胞基因组的28S区域中。
在一些情况下,真核细胞是在体外。在一些情况下,真核细胞是在体内。在一些情况下,真核细胞是离体的。
合适的真核细胞包括例如,人细胞、非人动物细胞、植物细胞、脊椎动物细胞、无脊椎动物细胞、鸟细胞、节肢动物细胞、蛛形纲动物细胞、昆虫细胞、爬行动物细胞、两栖细胞等。在一些情况下,真核细胞是人细胞。在一些情况下,真核细胞是非人动物细胞。在一些情况下,真核细胞是植物细胞。在一些情况下,真核细胞是无脊椎动物细胞。在一些情况下,所述细胞是患病细胞。
合适的细胞包括干细胞(例如胚胎干(ES)细胞、诱导型多能干(iPS)细胞;生殖细胞(例如,卵母细胞、精子、卵原细胞、精原细胞等);体细胞,例如成纤维细胞、少突胶质细胞、神经胶质细胞、造血细胞、神经元、肌细胞、骨细胞、肝细胞、胰腺细胞等。
合适的细胞包括人胚胎干细胞、胚胎心肌细胞、肌成纤维细胞、间充质干细胞、心肌细胞、脂肪细胞、全能细胞、多能细胞、血液干细胞、成肌细胞、成体干细胞、骨髓细胞、间充质细胞、胚胎干细胞、实质细胞、上皮细胞、内皮细胞、间皮细胞、成纤维细胞、成骨细胞、软骨细胞、外源细胞、内源细胞、干细胞、造血干细胞、骨髓衍生祖细胞、心肌细胞、骨骼细胞、胎儿细胞、未分化细胞、多能祖细胞、单能祖细胞、单核细胞、心脏成肌细胞、骨骼成肌细胞、巨噬细胞、毛细血管内皮细胞、异种细胞、同种异体细胞和产后干细胞。合适的细胞包括外周血单核细胞(PBMC)。
在一些情况下,细胞是免疫细胞、神经元、上皮细胞和内皮细胞或干细胞。在一些情况下,免疫细胞是T细胞、B细胞、单核细胞、天然杀伤细胞、树突状细胞或巨噬细胞。在一些情况下,免疫细胞是细胞毒性T细胞。在一些情况下,免疫细胞是辅助性T细胞。在一些情况下,免疫细胞是调节性T细胞(Treg)。
在一些情况下,细胞是干细胞。干细胞包括成体干细胞。成体干细胞也称为体细胞干细胞。
成体干细胞驻留在分化组织中,但保留自我更新的特性和产生多种细胞类型的能力,通常是干细胞所存在于的组织中的典型细胞类型。体细胞干细胞的许多实例是本领域的技术人员已知的,包括肌肉干细胞;造血干细胞;上皮干细胞;神经干细胞;间充质干细胞;乳腺干细胞;肠干细胞;中胚层干细胞;内皮干细胞;嗅干细胞;神经嵴干细胞等。
目标干细胞包括哺乳动物干细胞,其中术语“哺乳动物”是指被分类为哺乳动物的任何动物,包括人;非人灵长类动物;家畜和农场动物;以及动物园、实验室、运动或宠物动物,诸如狗、马、猫、牛、小鼠、大鼠、兔等。在一些情况下,干细胞是人干细胞。在一些情况下,干细胞是啮齿动物(例如,小鼠;大鼠)干细胞。在一些情况下,干细胞是非人灵长类动物干细胞。
干细胞可表达一种或多种干细胞标志物,例如SOX2、OCT4、NANOG、NESTIN、SOX1、PAX6、KLF4、SOX9、KRT19、KRT7、LGR5、CA9、FXYD2、CDH6、CLDN18、TSPAN8、BPIFB1、OLFM4、CDH17和PPARGC1A。
在一些情况下,干细胞是造血干细胞(HSC)。HSC是中胚层衍生的细胞,其可从骨髓、血液、脐带血、胎儿肝脏和卵黄囊中分离。HSC的特征在于CD34+和CD3-。HSC可在体内重新生成红系细胞、中性粒细胞-巨噬细胞、巨核细胞和淋巴样造血细胞谱系。在体外,可诱导HSC经历至少一些自我更新的细胞分裂,并且可诱导HSC分化成与体内所见相同的谱系。因此,可诱导HSC分化成红系细胞、巨核细胞、中性粒细胞、巨噬细胞和淋巴细胞中的一种或多种。
在其他情况下,干细胞是神经干细胞(NSC)。神经干细胞(NSC)能够分化成神经元和神经胶质细胞(包括少突胶质细胞和星形胶质细胞)。神经干细胞是能够进行多次分裂的多能干细胞,并且在特定条件下可产生作为神经干细胞的子细胞,或可作为成神经细胞或成胶质细胞的神经祖细胞,例如,分别致力于成为一种或多种类型的神经元和神经胶质细胞的细胞。获得NSC的方法在本领域中是已知的。
在其他情况下,干细胞是间充质干细胞(MSC)。MSC最初源自胚胎中胚层并从成人骨髓中分离,可分化形成肌肉、骨、软骨、脂肪、骨髓基质和肌腱。分离MSC的方法在本领域中是已知的;并且可使用任何已知的方法来获得MSC。参见例如美国专利号5,736,396,其描述了人MSC的分离。
在一些情况下,细胞是植物细胞。植物细胞可以是单子叶植物的细胞。细胞可以是双子叶植物的细胞。
在一些情况下,细胞是节肢动物细胞。例如,细胞可以是以下的亚目、家族、亚家族、群体、亚群或物种的细胞:例如,有螯肢亚门(Chelicerata)、多足亚门(Myriapodia)、Hexipodia、蛛形纲(Arachnida)、昆虫纲(Insecta)、石蛃目(Archaeognatha)、缨尾目(Thysanura)、古翅下纲(Palaeoptera)、蜉蝣目(Ephemeroptera)、蜻蜓目(Odonata)、差翅亚目(Anisoptera)、束翅亚目(Zygoptera)、新翅亚纲(Neoptera)、外翅总目(Exopterygota)、襀翅目(Plecoptera)、纺足目(Embioptera)、直翅目(Orthoptera)、缺翅目(Zoraptera)、革翅目(Dermaptera)、网翅目(Dictyoptera)、蛩蠊目(Notoptera)、蛩蠊科(Grylloblattidae)、螳科(Mantophasmatidae)、竹节虫目(Phasmatodea)、蜚蠊目(Blattaria)、等翅目(Isoptera)、螳螂目(Mantodea)、Parapneuroptera、啮虫目(Psocoptera)、缨翅目(Thysanoptera)、虱毛目(Phthiraptera)、半翅目(Hemiptera)、内翅类(Endopterygota)或全变态类(Holometabola)、膜翅目(Hymenoptera)、鞘翅目(Coleoptera)、捻翅目(Strepsiptera)、蛇蛉目(Raphidioptera)、广翅目(Megaloptera)、脉翅目(Neuroptera)、长翅目(Mecoptera)、蚤目(Siphonaptera)、双翅目(Diptera)、毛翅目(Trichoptera)或鳞翅目(Lepidoptera)。
在一些情况下,细胞是昆虫细胞。例如,在一些情况下,细胞是蚊子、蚱蜢、半翅目昆虫、苍蝇、跳蚤、蜜蜂、黄蜂、蚂蚁、虱子、蛾或甲虫的细胞。
可通过多种方法中的任一种将本公开的基因递送系统引入真核细胞中,其中许多方法是本领域已知的。合适的方法包括例如,病毒感染、转染、脂转染、电穿孔、磷酸钙沉淀、聚乙烯亚胺(PEI)介导的转染、DEAE-葡聚糖介导的转染、脂质体介导的转染、粒子枪技术、磷酸钙沉淀、直接微注射、纳米颗粒介导的核酸递送等。
可使用良好开发的转染技术(参见例如Angel和Yanik(2010)PLoS ONE 5(7):e11756);以及可从Qiagen商购获得的试剂、可从Stemgent商购获得的StemfectTMRNA转染试剂盒和可从Mirus Bio LLC商购获得的转染试剂盒将核酸引入真核细胞中。还参见Beumer等人(2008)PNAS 105(50):19821-19826。
在一些情况下,将本公开的基因递送系统施用至有需要的个体。本公开的基因递送系统可通过多种施用途径中的任一种施用至个体。常规和药学上可接受的施用途径包括肿瘤内、肿瘤周围、肌内、气管内、颅内、皮下、皮内、局部施加、静脉内、动脉内、直肠、鼻、口服和其他肠内和肠胃外施用途径。如果需要,可将施用途径组合,或根据基因递送系统和/或所需的作用进行调整。本公开的基因递送系统可以单一剂量或多剂量施用。
在一些实施方案中,静脉内施用本公开的基因递送系统。在一些情况下,肌内施用本公开的基因递送系统。在一些情况下,局部施用本公开的基因递送系统。在一些情况下,肿瘤内施用本公开的基因递送系统。在一些情况下,肿瘤周围施用本公开的基因递送系统。在一些情况下,颅内施用本公开的基因递送系统。在一些情况下,皮下施用本公开的基因递送系统。
在一些情况下,从个体除去(获得)靶细胞或靶细胞群体;使所述靶细胞或靶细胞群体与本公开的基因递送系统离体接触,以产生遗传修饰的靶细胞或遗传修饰的靶细胞群体;将所述遗传修饰的靶细胞或遗传修饰的靶细胞群体施用至从起获得所述靶细胞或所述靶细胞群体的个体。因此,在一些情况下,本公开的方法包括:a)使靶细胞或靶细胞群体与本公开的基因递送系统离体接触,从而产生遗传修饰的靶细胞或遗传修饰的靶细胞群体,其中所述靶细胞或靶细胞群体从需要治疗的个体获得;和b)将所述遗传修饰的靶细胞或遗传修饰的靶细胞群体施用至所述个体,从而治疗所述个体。在一些情况下,本公开的方法包括:a)从个体获得靶细胞或靶细胞群体;b)使所述靶细胞或靶细胞群体与本公开的基因递送系统离体接触,从而产生遗传修饰的靶细胞或遗传修饰的靶细胞群体;以及c)将所述遗传修饰的靶细胞或遗传修饰的靶细胞群体施用至个体。作为一个非限制性实例,所述细胞可以是T细胞;并且所述一种或多种异源多肽可以是CAR(例如,单一多肽链CAR;或异二聚体CAR)。作为另一个实例,所述细胞可以是患病细胞,并且所述异源基因产物可以是:i)RNA的效应物多肽,如Cas9多肽;ii)RNA。
本公开的非限制性方面的实例
上述主题的方面(包括实施方案)可单独或与一个或多个其他方面或实施方案组合有益。在不限制前述描述的情况下,下文提供了编号1-33的本公开的某些非限制性方面。对于本领域技术人员在阅读本公开内容时将显而易见的是,每个单独编号的方面可与任一前面或后面单独编号的方面一起使用或组合。这意图为方面的所有此类组合提供支持,并且不限于下文明确提供的方面的组合:
方面1.一种基因递送媒介物系统,所述基因递送媒介物系统包含:a)第一核酸和第二核酸,其中:i)所述第一核酸包含编码R2逆转录转座子R2多肽的核苷酸序列;并且ii)所述第二核酸包含编码一种或多种异源基因产物的异源核苷酸序列,其中所述异源核苷酸序列由R2逆转录转座子3'非翻译区(UTR)和R2逆转录转座子5'UTR侧接,并且其中所述异源核苷酸序列具有至少200个核苷酸的长度;或b)多肽和核酸,其中:i)所述多肽是R2逆转录转座子R2多肽;并且ii)所述核酸包含编码一种或多种异源基因产物的异源核苷酸序列,其中所述异源核苷酸序列的由R2逆转录转座子3'UTR和R2逆转录转座子5'UTR侧接,并且其中所述异源核苷酸序列具有至少200个核苷酸的长度。
方面2.如方面1所述的基因递送媒介物系统,其中所述R2多肽包含与图7中描绘的氨基酸序列具有至少85%氨基酸序列同一性的氨基酸序列。
方面3.如方面1或方面2所述的基因递送媒介物系统,其中所述异源核苷酸序列编码单一异源基因产物。
方面4.如方面3所述的基因递送媒介物系统,其中所述单一异源基因产物是多肽。
方面5.如方面3所述的基因递送媒介物系统,其中所述单一异源基因产物是RNA。
方面6.如方面1或方面2所述的基因递送媒介物系统,其中所述异源核苷酸序列至少编码第一异源基因产物和第二异源基因产物。
方面7.如方面6所述的基因递送媒介物系统,其中所述第一异源基因产物是多肽,并且其中所述第二异源基因产物是RNA。
方面8.如方面4所述的基因递送媒介物系统,其中所述多肽是嵌合抗原受体。
方面9.如方面6所述的基因递送媒介物系统,其中所述第一异源基因产物是第一异源多肽,并且其中所述第二异源基因产物是第二异源多肽。
方面10.如方面9所述的基因递送媒介物系统,其中所述异源核苷酸序列按5’至3’顺序包含:i)编码所述第一异源多肽的核苷酸序列;ii)内部核糖体进入位点或编码自裂解多肽的核苷酸序列;以及iii)编码所述第二异源多肽的核苷酸序列。
方面11.如方面9所述的基因递送媒介物系统,其中所述第一多肽和所述第二多肽一起形成异二聚体嵌合抗原受体。
方面12.如方面7所述的基因递送媒介物系统,其中所述多肽是RNA的效应物多肽,并且其中所述RNA是结合至所述RNA的效应物多肽的RNA。
方面13.如方面1-12中任一项所述的基因递送媒介物系统,其中所述编码R2多肽的核苷酸序列经密码子优化以用于在真核细胞中表达。
方面14.如方面1-13中任一项所述的基因递送媒介物系统,其中所述编码一种或多种异源基因产物的异源核苷酸序列可操作地连接至转录控制元件。
方面15.如方面14所述的基因递送媒介物系统,其中所述转录控制元件是可调控启动子。
方面16.如方面14所述的基因递送媒介物系统,其中所述转录控制元件是组成型启动子。
方面17.如方面1-16中任一项所述的基因递送媒介物系统,其中所述异源核苷酸序列具有至少3kb的长度。
方面18.如方面1-16中任一项所述的基因递送媒介物系统,其中所述异源核苷酸序列具有约5kb至约10kb的长度。
方面19.如方面1-16中任一项所述的基因递送媒介物系统,其中所述异源核苷酸序列具有约10kb至约15kb的长度。
方面20.一种药盒,所述药盒包括:
a1)第一核酸,所述第一核酸包含编码R2逆转录转座子R2多肽的核苷酸序列;以及
b1)第二核酸,所述第二核酸包含用于插入编码一种或多种异源基因产物的异源核苷酸序列的插入位点,其中所述插入位点由R2逆转录转座子3'非翻译区(UTR)和R2逆转录转座子5’UTR侧接,并且其中所述异源核苷酸序列具有至少200个核苷酸的长度;或
a2)R2逆转录转座子R2多肽;以及
b2)核酸,所述核酸包含用于插入编码一种或多种异源基因产物的异源核苷酸序列的插入位点,其中所述插入位点由R2逆转录转座子3’UTR和R2逆转录转座子5’UTR侧接,并且其中所述异源核苷酸序列具有至少200个核苷酸的长度。
方面21.如方面20(a1和b1)所述的药盒,其中所述第一核酸和所述第二核酸位于分开的容器中。
方面22.如方面20(a1)所述的药盒,其中所述编码R2多肽的核苷酸序列经密码子优化以用于在真核细胞中表达。
方面23.如方面20(b1)所述的药盒,其中所述第二核酸还包含所述插入位点5'的转录控制元件。
方面24.如方面20(a2和b2)所述的药盒,其中所述R2多肽和所述核酸位于分开的容器中。
方面25.如方面20(b2)所述的药盒,其中所述核酸还包含所述插入位点5'的转录控制元件。
方面26.一种将一种或多种目标基因产物递送至真核细胞的方法,所述方法包括使所述细胞与如方面1-19中任一项所述的基因递送媒介物系统接触,其中所述R2多肽、所述5’UTR和所述3’UTR将所述异源核酸插入所述真核细胞的基因组的28S区中。
方面27.如方面26所述的方法,其中所述接触是在体外。
方面28.如方面26所述的方法,其中所述接触是在体内。
方面29.如方面26所述的方法,其中所述接触是离体。
方面30.如方面26-29中任一项所述的方法,其中所述真核细胞是非人动物细胞。
方面31.如方面26-29中任一项所述的方法,其中所述真核细胞是人细胞。
方面32.如方面26-29中任一项所述的方法,其中所述真核细胞是植物细胞。
方面33.如方面26-29中任一项所述的方法,其中所述真核细胞是无脊椎动物细胞。
实施例
给出以下实施例以便向本领域普通技术人员提供对如何制备和使用本发明的完整公开和描述,并且不旨在限制发明者所视为的他们的发明的范围,它们也不旨在表示以下实验是所进行的所有或仅有实验。已努力确保关于所用数值(例如数量、温度等)的准确性,但应考虑一些实验误差和偏差。除非另有说明,否则份为重量份,分子量为重均分子量,温度为摄氏度,压力为大气压或接近大气压。可使用标准缩写,例如,bp,碱基对;kb,千碱基;pl,皮升;s或sec,秒;min,分钟;h或hr,小时;aa,氨基酸;kb,千碱基;bp,碱基对;nt,核苷酸;i.m.,肌内的(肌内地);i.p.,腹膜内的(腹膜内地);s.c.,皮下的(皮下地)等。
实施例1
产生了基于来自蚕家蚕(Bombyx mori)的DNA两种DNA质粒。一种质粒包含蛋白R2的编码序列的优化型式(OR2Bm),而第二种质粒含有侧接5’和3’非翻译区(UTR)、在3’至5’方向上定向的转基因),全部在单个rDNA启动子的控制下,所述启动子控制完整rDNA转录物的转录。
将HEK 293细胞和HEK 293T细胞用两种质粒构建体进行PEI转染,并在48小时后提取基因组DNA,并通过整合的5’接点进行测序,以确保所述转基因整合在正确的位点并且发生全长整合(图2)。还扩增了转基因盒以包含潮霉素抗性基因,然后用于定量整合频率并进行滴定以确定最有效的比率。含有UTR和转基因的质粒的转染通过同源驱动重组(HDR)产生了1%的整合效率。当与OR2质粒共转染时,效率提高至总细胞群体的4%。
图2:基因组DNA跨28S rDNA中的整合接点扩增,并且当用OR2Bm(泳道1)和不使用(泳道3)扩增CMV启动子下的由5’和3’UTR侧接的转基因时,显示特异性条带。在RNA pol I启动子控制下的转基因盒(泳道2)仅在OR2Bm存在下显示特异性整合条带,并且在不存在OR2Bm的情况下不显示(泳道4)。
图3示出当仅用由UTR侧接而无OR2的转基因转染细胞时,从基因组DNA扩增了全长扩增子而没有条带。
用由UTR侧接的转基因或由UTR和OR2侧接的转基因转染细胞。图4示意性地描绘了方案。三天后,使细胞以1:10的比例传代,并取得一部分以经由流式细胞术进行筛选。6天后再次使细胞以1:10的比例传代,并在第14天,经由流式细胞术筛选细胞以分析转基因(GFP)的稳定表达。数据呈现在图4中。比较了两个样品之间的GFP表达,并且表明OR2有助于介导3.4%GFP阳性细胞的稳定群体的产生。用OR2转染的细胞具有多4倍的GFP表达。*表示p<0.005
以不同量的OR2和转基因转染细胞。然后将细胞保持在抗生素选择(200μg/mL潮霉素B)下两周,并且数次洗涤之后计数存活集落。数据呈现在图5中。如图5所示,发现OR2介导了更高水平的持续表达。*表示p<0.005
用CAR-T受体和OR2转染细胞,并在两周内传代。图6示意性地描绘了方案。之后,用针对所述受体的抗体标记细胞,并经由流式细胞术进行筛选。然后提取基因组DNA,并扩增完整转录物以进一步确认整合。数据呈现在图6中。*表示p<0.005。
实施例2
制备了两种基因递送构建体。第一构建体是重组表达载体,所述重组表达载体包含编码R2逆转录转座子R2多肽的核苷酸序列。第二构建体是重组表达载体,所述重组表达载体包含以3’至5’方向定向的异源核苷酸序列,所述异源核苷酸序列编码条件活性CAR的2条多肽链。所述异源核苷酸序列由R2 5’UTR和R2 3’UTR侧接。R2多肽是优化的R2(OR2)多肽。条件活性CAR的第一多肽链包含:i)特异性地结合至靶细胞(例如,癌细胞)上的抗原的细胞外抗原结合结构域;ii)跨膜结构域;以及iii)二聚化对的第一成员。条件活性CAR的第二多肽链包含:i)跨膜结构域;ii)二聚化对的第二成员;和iii)包含基于免疫受体酪氨酸的激活基序(ITAM)的细胞内信号传导结构域,其中所述细胞内信号传导结构域提供信号转导活性。条件活性CAR的第一多肽、条件活性CAR的第二多肽或条件活性CAR的第一多肽和第二多肽两者均包含细胞内共刺激多肽。
将2种基因递送构建体在体外引入T细胞(例如,CD8+T细胞)中,从而对T细胞进行遗传修饰。将遗传修饰的T细胞施用至个体,例如患有癌症的个体,其中所述癌症包括表达由条件活性CAR识别的抗原的细胞。
实施例3
制备了两种基因递送构建体。第一构建体是重组表达载体,所述重组表达载体包含编码R2逆转录转座子R2多肽的核苷酸序列。第二构建体是重组表达载体,所述重组表达载体包含以3’至5’方向定向的异源核苷酸序列,所述异源核苷酸序列编码CAR和synNotch多肽。所述异源核苷酸序列由R2 5’UTR和R2 3’UTR侧接。R2多肽是优化的R2(OR2)多肽。所述CAR可操作地连接至由synNotch多肽的细胞内信号传导结构域激活的启动子。
实施例4
将人胚肾(HEK)293细胞用以下转染:1)2.5μg含有GFP表达构建体(包含编码GFP的核苷酸序列,其中所述核苷酸序列可操作地连接至巨细胞病毒启动子)的质粒,所述GFP表达构建体由R2 5’UTR和R2 3’UTR侧接并且相对于所述UTR以3’至5’方向定向;和ii)5μg含有编码OR2的表达盒的质粒或5μg含有填充片段DNA(不编码OR2多肽的对照DNA)的质粒。然后使转染的HEK293细胞生长14天以稀释并降解未整合的质粒。14天后,经由流式细胞术对转染的HEK293细胞进行定量,以测定已经整合了GFP转基因的稳定细胞群体。
结果在图10中示出。平均而言,在用含有OR2和GFP转基因的构建体转染的细胞中,5.6%稳定地表达GFP。相比之下,平均而言,在用填充片段和GFP转基因转染的细胞中,1.3%表达了GFP。
实施例5
将HEK293细胞用以下转染:i)0.5μg含有潮霉素B(HygB)抗性盒(包含编码潮霉素B磷酸转移酶的核苷酸序列,其中所述核苷酸序列可操作地连接至SV40启动子)的质粒,所述抗性盒由R2 5’UTR和R2 3’UTR侧接并且相对于所述UTR以3’至5’方向定向;和ii)0.5μg含有编码OR2的表达盒的质粒或0.5μg含有填充片段DNA(不编码OR2多肽的对照DNA)的质粒。将转染的HEK293细胞在含有200μg/m潮霉素的培养基中。使转染的HEK293细胞在含有潮霉素的培养基中生长14天,以稀释并降解未整合的质粒。将HEK293细胞用亚甲基蓝染色,然后手动计数以定量集落数量,其中每个集落将代表一个整合事件。
结果在图11中示出。在用OR2和HygB抗性盒转染的细胞中发生平均177个整合事件。在用填充片段和HygB抗性盒转染的细胞中发生平均39.33个整合事件。
实施例6
将HEK293细胞用以下转染:i)2.5μg含有编码具有c-myc标签的嵌合抗原受体(CAR)(CAR-c-myc的)的表达构建体(其中所述表达构建体包含编码CAR-c-myc的核苷酸序列,其中所述核苷酸序列可操作地连接至EF1-α启动子)的质粒,所述表达构建体由R2非翻译区(R2 5’UTR和R2 3’UTR)侧接并且相对于所述UTR以3’至5’方向定向;和ii)5μg含有针对OR2的表达盒的质粒或5μg含有填充片段DNA(不编码OR2多肽的对照DNA)的质粒。然后使转染的HEK293细胞生长14天以稀释并降解未整合的质粒。14天后,通过针对c-myc标签的细胞表面表达染色经由流式细胞术对转染的HEK293细胞进行定量,以测定已经整合了所述转基因的稳定细胞群体。
数据在图12中示出。平均而言,在用含有OR2和CAR-c-myc转基因的构建体转染的细胞中,1.85%稳定地表达了c-myc标签。相比之下,平均而言,在用填充片段和GFP转基因转染的细胞中,0.87%表达了c-myc标签。
虽然本发明已经参考其特定实施方案进行了描述,但是本领域技术人员应理解,可在不脱离本发明的真实精神和范围下进行各种变化且可取代等效物。此外,可进行许多修改以使特定的情况、材料、物质的组成、过程、一个或多个过程步骤适应本发明的目的、精神和范围。所有这些修改旨在落入所附权利要求的范围内。
序列表
<110> 加州大学评议会(The Regents of the University of California)
谢弗·大卫V (Schaffer, David V)
巴恩斯·克里斯托弗(Barnes, Christopher)
<120> 基于逆转录转座子的递送媒介物及其使用方法
<130> BERK-392WO
<150> US62/697,829
<151> 2018-07-13
<160> 39
<170> PatentIn version 3.5
<210> 1
<211> 22
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成序列
<400> 1
Gly Ser Gly Ala Thr Asn Phe Ser Leu Leu Lys Gln Ala Gly Asp Val
1 5 10 15
Glu Glu Asn Pro Gly Pro
20
<210> 2
<211> 21
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成序列
<400> 2
Gly Ser Gly Glu Gly Arg Gly Ser Leu Leu Thr Cys Gly Asp Val Glu
1 5 10 15
Glu Asn Pro Gly Pro
20
<210> 3
<211> 23
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成序列
<400> 3
Gly Ser Gly Gln Cys Thr Asn Tyr Ala Leu Leu Lys Leu Ala Gly Asp
1 5 10 15
Val Glu Ser Asn Pro Gly Pro
20
<210> 4
<211> 25
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
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Gly Ser Gly Val Lys Gln Thr Leu Asn Phe Asp Leu Leu Lys Leu Ala
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Gly Asp Val Glu Ser Asn Pro Gly Pro
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<210> 5
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<212> PRT
<213> 人工序列(Artificial Sequence)
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<220>
<221> Misc_feature
<222> (2)..(3)
<223> Xaa可以是任何氨基酸残基
<220>
<221> Misc_feature
<222> (4)..(4)
<223> Xaa是疏水性氨基酸残基
<400> 5
Pro Xaa Xaa Xaa
1
<210> 6
<211> 5
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成序列
<220>
<221> Misc_feature
<222> (2)..(3)
<223> Xaa可以是任何氨基酸残基
<220>
<221> Misc_feature
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<223> Xaa是疏水性氨基酸残基
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<221> Misc_feature
<222> (5)..(5)
<223> Xaa是Ser或Thr残基
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Pro Xaa Xaa Xaa Xaa
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<212> PRT
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<220>
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<223> Xaa是Lue或Gln氨基酸残基
<400> 7
Pro Xaa Gly Met Thr Ser
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Pro Xaa Gly Met Thr
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Glu Asn Leu Tyr Thr Gln Ser
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Asp Asp Asp Asp Lys
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Leu Val Pro Arg
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Leu Glu Val Leu Phe Gln Gly Pro
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Cys Gly Leu Val Pro Ala Gly Ser Gly Pro
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Ser Leu Leu Lys Ser Arg Met Val Pro Asn Phe Asn
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<212> PRT
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Ser Leu Leu Ile Ala Arg Arg Met Pro Asn Phe Asn
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Ser Lys Leu Val Gln Ala Ser Ala Ser Gly Val Asn
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<210> 17
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Ser Ser Tyr Leu Lys Ala Ser Asp Ala Pro Asp Asn
1 5 10
<210> 18
<211> 12
<212> PRT
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<220>
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Arg Pro Lys Pro Gln Gln Phe Phe Gly Leu Met Asn
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<210> 19
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<220>
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Ser Leu Arg Pro Leu Ala Leu Trp Arg Ser Phe Asn
1 5 10
<210> 20
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<212> PRT
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Ser Pro Gln Gly Ile Ala Gly Gln Arg Asn Phe Asn
1 5 10
<210> 21
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Asp Val Asp Glu Arg Asp Val Arg Gly Phe Ala Ser Phe Leu
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<212> PRT
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Ser Leu Pro Leu Gly Leu Trp Ala Pro Asn Phe Asn
1 5 10
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Ser Leu Leu Ile Phe Arg Ser Trp Ala Asn Phe Asn
1 5 10
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<212> PRT
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Ser Gly Val Val Ile Ala Thr Val Ile Val Ile Thr
1 5 10
<210> 25
<211> 12
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
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Ser Leu Gly Pro Gln Gly Ile Trp Gly Gln Phe Asn
1 5 10
<210> 26
<211> 12
<212> PRT
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<220>
<223> 合成序列
<400> 26
Lys Lys Ser Pro Gly Arg Val Val Gly Gly Ser Val
1 5 10
<210> 27
<211> 12
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成序列
<400> 27
Pro Gln Gly Leu Leu Gly Ala Pro Gly Ile Leu Gly
1 5 10
<210> 28
<211> 31
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成序列
<400> 28
His Gly Pro Glu Gly Leu Arg Val Gly Phe Tyr Glu Ser Asp Val Met
1 5 10 15
Gly Arg Gly His Ala Arg Leu Val His Val Glu Glu Pro His Thr
20 25 30
<210> 29
<211> 12
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成序列
<400> 29
Gly Pro Gln Gly Leu Ala Gly Gln Arg Gly Ile Val
1 5 10
<210> 30
<211> 12
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成序列
<400> 30
Gly Gly Ser Gly Gln Arg Gly Arg Lys Ala Leu Glu
1 5 10
<210> 31
<211> 12
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成序列
<400> 31
Ser Leu Ser Ala Leu Leu Ser Ser Asp Ile Phe Asn
1 5 10
<210> 32
<211> 12
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成序列
<400> 32
Ser Leu Pro Arg Phe Lys Ile Ile Gly Gly Phe Asn
1 5 10
<210> 33
<211> 12
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成序列
<400> 33
Ser Leu Leu Gly Ile Ala Val Pro Gly Asn Phe Asn
1 5 10
<210> 34
<211> 12
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成序列
<400> 34
Phe Phe Lys Asn Ile Val Thr Pro Arg Thr Pro Pro
1 5 10
<210> 35
<211> 306
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成序列
<400> 35
Pro Pro Gln Ile Glu Glu Ala Cys Glu Leu Pro Glu Cys Gln Val Asp
1 5 10 15
Ala Gly Asn Lys Val Cys Asn Leu Gln Cys Asn Asn His Ala Cys Gly
20 25 30
Trp Asp Gly Gly Asp Cys Ser Leu Asn Phe Asn Asp Pro Trp Lys Asn
35 40 45
Cys Thr Gln Ser Leu Gln Cys Trp Lys Tyr Phe Ser Asp Gly His Cys
50 55 60
Asp Ser Gln Cys Asn Ser Ala Gly Cys Leu Phe Asp Gly Phe Asp Cys
65 70 75 80
Gln Leu Thr Glu Gly Gln Cys Asn Pro Leu Tyr Asp Gln Tyr Cys Lys
85 90 95
Asp His Phe Ser Asp Gly His Cys Asp Gln Gly Cys Asn Ser Ala Glu
100 105 110
Cys Glu Trp Asp Gly Leu Asp Cys Ala Glu His Val Pro Glu Arg Leu
115 120 125
Ala Ala Gly Thr Leu Val Leu Val Val Leu Leu Pro Pro Asp Gln Leu
130 135 140
Arg Asn Asn Ser Phe His Phe Leu Arg Glu Leu Ser His Val Leu His
145 150 155 160
Thr Asn Val Val Phe Lys Arg Asp Ala Gln Gly Gln Gln Met Ile Phe
165 170 175
Pro Tyr Tyr Gly His Glu Glu Glu Leu Arg Lys His Pro Ile Lys Arg
180 185 190
Ser Thr Val Gly Trp Ala Thr Ser Ser Leu Leu Pro Gly Thr Ser Gly
195 200 205
Gly Arg Gln Arg Arg Glu Leu Asp Pro Met Asp Ile Arg Gly Ser Ile
210 215 220
Val Tyr Leu Glu Ile Asp Asn Arg Gln Cys Val Gln Ser Ser Ser Gln
225 230 235 240
Cys Phe Gln Ser Ala Thr Asp Val Ala Ala Phe Leu Gly Ala Leu Ala
245 250 255
Ser Leu Gly Ser Leu Asn Ile Pro Tyr Lys Ile Glu Ala Val Lys Ser
260 265 270
Glu Pro Val Glu Pro Pro Leu Pro Ser Gln Leu His Leu Met Tyr Val
275 280 285
Ala Ala Ala Ala Phe Val Leu Leu Phe Phe Val Gly Cys Gly Val Leu
290 295 300
Leu Ser
305
<210> 36
<211> 358
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成序列
<400> 36
Pro Cys Val Gly Ser Asn Pro Cys Tyr Asn Gln Gly Thr Cys Glu Pro
1 5 10 15
Thr Ser Glu Asn Pro Phe Tyr Arg Cys Leu Cys Pro Ala Lys Phe Asn
20 25 30
Gly Leu Leu Cys His Ile Leu Asp Tyr Ser Phe Thr Gly Gly Ala Gly
35 40 45
Arg Asp Ile Pro Pro Pro Gln Ile Glu Glu Ala Cys Glu Leu Pro Glu
50 55 60
Cys Gln Val Asp Ala Gly Asn Lys Val Cys Asn Leu Gln Cys Asn Asn
65 70 75 80
His Ala Cys Gly Trp Asp Gly Gly Asp Cys Ser Leu Asn Phe Asn Asp
85 90 95
Pro Trp Lys Asn Cys Thr Gln Ser Leu Gln Cys Trp Lys Tyr Phe Ser
100 105 110
Asp Gly His Cys Asp Ser Gln Cys Asn Ser Ala Gly Cys Leu Phe Asp
115 120 125
Gly Phe Asp Cys Gln Leu Thr Glu Gly Gln Cys Asn Pro Leu Tyr Asp
130 135 140
Gln Tyr Cys Lys Asp His Phe Ser Asp Gly His Cys Asp Gln Gly Cys
145 150 155 160
Asn Ser Ala Glu Cys Glu Trp Asp Gly Leu Asp Cys Ala Glu His Val
165 170 175
Pro Glu Arg Leu Ala Ala Gly Thr Leu Val Leu Val Val Leu Leu Pro
180 185 190
Pro Asp Gln Leu Arg Asn Asn Ser Phe His Phe Leu Arg Glu Leu Ser
195 200 205
His Val Leu His Thr Asn Val Val Phe Lys Arg Asp Ala Gln Gly Gln
210 215 220
Gln Met Ile Phe Pro Tyr Tyr Gly His Glu Glu Glu Leu Arg Lys His
225 230 235 240
Pro Ile Lys Arg Ser Thr Val Gly Trp Ala Thr Ser Ser Leu Leu Pro
245 250 255
Gly Thr Ser Gly Gly Arg Gln Arg Arg Glu Leu Asp Pro Met Asp Ile
260 265 270
Arg Gly Ser Ile Val Tyr Leu Glu Ile Asp Asn Arg Gln Cys Val Gln
275 280 285
Ser Ser Ser Gln Cys Phe Gln Ser Ala Thr Asp Val Ala Ala Phe Leu
290 295 300
Gly Ala Leu Ala Ser Leu Gly Ser Leu Asn Ile Pro Tyr Lys Ile Glu
305 310 315 320
Ala Val Lys Ser Glu Pro Val Glu Pro Pro Leu Pro Ser Gln Leu His
325 330 335
Leu Met Tyr Val Ala Ala Ala Ala Phe Val Leu Leu Phe Phe Val Gly
340 345 350
Cys Gly Val Leu Leu Ser
355
<210> 37
<211> 1114
<212> PRT
<213> 家蚕(Bombyx mori)
<400> 37
Met Met Ala Ser Thr Ala Leu Ser Leu Met Gly Arg Cys Asn Pro Asp
1 5 10 15
Gly Cys Thr Arg Gly Lys His Val Thr Ala Ala Pro Met Asp Gly Pro
20 25 30
Arg Gly Pro Ser Ser Leu Ala Gly Thr Phe Gly Trp Gly Leu Ala Ile
35 40 45
Pro Ala Gly Glu Pro Cys Gly Arg Val Cys Ser Pro Ala Thr Val Gly
50 55 60
Phe Phe Pro Val Ala Lys Lys Ser Asn Lys Glu Asn Arg Pro Glu Ala
65 70 75 80
Ser Gly Leu Pro Leu Glu Ser Glu Arg Thr Gly Asp Asn Pro Thr Val
85 90 95
Arg Gly Ser Ala Gly Ala Asp Pro Val Gly Gln Asp Ala Pro Gly Trp
100 105 110
Thr Cys Gln Phe Cys Glu Arg Thr Phe Ser Thr Asn Arg Gly Leu Gly
115 120 125
Val His Lys Arg Arg Ala His Pro Val Glu Thr Asn Thr Asp Ala Ala
130 135 140
Pro Met Met Val Lys Arg Arg Trp His Gly Glu Glu Ile Asp Leu Leu
145 150 155 160
Ala Arg Thr Glu Ala Arg Leu Leu Ala Glu Arg Gly Gln Cys Ser Gly
165 170 175
Gly Asp Leu Phe Gly Ala Leu Pro Gly Phe Gly Arg Thr Leu Glu Ala
180 185 190
Ile Lys Gly Gln Arg Arg Arg Glu Pro Tyr Arg Ala Leu Val Gln Ala
195 200 205
His Leu Ala Arg Phe Gly Ser Gln Pro Gly Pro Ser Ser Gly Gly Cys
210 215 220
Ser Ala Glu Pro Asp Phe Arg Arg Ala Ser Gly Ala Glu Glu Ala Gly
225 230 235 240
Glu Glu Arg Cys Ala Glu Asp Ala Ala Ala Tyr Asp Pro Ser Ala Val
245 250 255
Gly Gln Met Ser Pro Asp Ala Ala Arg Val Leu Ser Glu Leu Leu Glu
260 265 270
Gly Thr Gly Arg Arg Arg Ala Cys Arg Ala Met Arg Pro Lys Thr Ala
275 280 285
Gly Arg Arg Asn Asp Leu His Asp Asp Arg Thr Ala Ser Ala His Lys
290 295 300
Thr Ser Arg Gln Lys Arg Arg Ala Val Tyr Ala Arg Val Gln Glu Leu
305 310 315 320
Tyr Lys Lys Cys Arg Ser Arg Ala Ala Ala Glu Val Ile Asp Gly Ala
325 330 335
Cys Gly Gly Val Gly His Ser Leu Glu Glu Met Glu Thr Tyr Trp Arg
340 345 350
Pro Ile Leu Glu Arg Val Ser Asp Ala Pro Gly Pro Thr Pro Glu Ala
355 360 365
Leu His Ala Leu Gly Arg Ala Glu Trp His Gly Gly Asn Arg Asp Tyr
370 375 380
Thr Gln Leu Trp Lys Pro Ile Ser Val Glu Glu Thr Lys Ala Ser Arg
385 390 395 400
Phe Asp Trp Arg Thr Ser Pro Gly Pro Tyr Gly Ile Arg Ser Gly Gln
405 410 415
Trp Arg Ala Val Pro Val His Leu Lys Ala Glu Met Phe Asn Ala Trp
420 425 430
Met Ala Arg Gly Glu Ile Pro Glu Val Leu Arg Gln Cys Arg Thr Val
435 440 445
Phe Val Pro Lys Val Glu Arg Pro Gly Gly Pro Gly Glu Tyr Arg Pro
450 455 460
Ile Ser Ile Ala Ser Ile Pro Leu Arg His Phe His Ser Ile Leu Ala
465 470 475 480
Arg Arg Leu Leu Ala Cys Cys Pro Pro Asp Ala Arg Gln Arg Gly Phe
485 490 495
Ile Cys Ala Asp Gly Thr Leu Glu Asn Ser Ala Val Leu Asp Ala Val
500 505 510
Leu Gly Asp Ser Arg Lys Lys Leu Trp Glu Cys His Val Ala Val Leu
515 520 525
Asp Phe Ala Lys Ala Phe Asp Thr Val Ser His Glu Ala Leu Val Glu
530 535 540
Leu Leu Arg Leu Arg Gly Met Pro Val Gln Phe Cys Gly Tyr Ile Ala
545 550 555 560
His Leu Tyr Asp Thr Ala Ser Thr Thr Leu Ala Val Asn Asn Glu Met
565 570 575
Ser Ser Pro Val Lys Val Gly Arg Gly Val Arg Gln Gly Asp Pro Leu
580 585 590
Ser Pro Ile Leu Phe Asn Val Val Met Asp Leu Ile Leu Ala Ser Leu
595 600 605
Pro Glu Arg Val Gly Tyr Arg Leu Glu Met Glu Pro Val Ser Ala Leu
610 615 620
Ala Tyr Ala Asp Asp Leu Val Leu Leu Ala Gly Ser Lys Val Gly Met
625 630 635 640
Gln Glu Ser Ile Ser Ala Val Asp Cys Val Gly Arg Gln Met Gly Leu
645 650 655
Arg Leu Asn Cys Arg Lys Ser Ala Val Leu Ser Met Ile Pro Gly Gly
660 665 670
His Arg Lys Lys His His Tyr Leu Thr Glu Arg Thr Phe Asn Ile Gly
675 680 685
Gly Lys Pro Leu Arg Gln Val Ser Cys Val Glu Arg Trp Arg Tyr Leu
690 695 700
Gly Val Asp Phe Glu Ala Ser Gly Cys Val Thr Leu Glu His Ser Ile
705 710 715 720
Ser Ser Ala Leu Asn Asn Ile Ser Arg Ala Pro Leu Lys Pro Gln Gln
725 730 735
Arg Leu Glu Ile Leu Arg Ala His Leu Ile Pro Arg Phe Gln His Gly
740 745 750
Phe Val Leu Gly Asn Ile Ser Asp Asp Arg Leu Arg Met Leu Asp Val
755 760 765
Gln Ile Arg Lys Ala Val Gly Gln Trp Leu Arg Leu Pro Ala Asp Val
770 775 780
Pro Lys Ala Tyr Tyr His Ala Ala Val Gln Asp Gly Gly Leu Ala Ile
785 790 795 800
Pro Ser Val Arg Ala Thr Ile Pro Asp Leu Ile Val Arg Arg Phe Gly
805 810 815
Gly Leu Asp Ser Ser Pro Trp Ser Val Ala Arg Ala Ala Ala Lys Ser
820 825 830
Asp Lys Ile Arg Lys Lys Leu Arg Trp Ala Trp Lys Gln Leu Arg Arg
835 840 845
Phe Ser Arg Val Asp Ser Thr Thr Gln Arg Pro Ser Val Arg Leu Phe
850 855 860
Trp Arg Glu His Leu His Ala Ser Val Asp Gly Arg Glu Leu Arg Glu
865 870 875 880
Ser Thr Arg Thr Pro Thr Ser Thr Lys Trp Ile Arg Glu Arg Cys Ala
885 890 895
Gln Ile Thr Gly Arg Asp Phe Val Gln Phe Val His Thr His Ile Asn
900 905 910
Ala Leu Pro Ser Arg Ile Arg Gly Ser Arg Gly Arg Arg Gly Gly Gly
915 920 925
Glu Ser Ser Leu Thr Cys Arg Ala Gly Cys Lys Val Arg Glu Thr Thr
930 935 940
Ala His Ile Leu Gln Gln Cys His Arg Thr Arg Gly Gly Arg Ile Leu
945 950 955 960
Arg His Asn Lys Ile Val Ser Phe Val Ala Lys Ala Met Glu Glu Asn
965 970 975
Lys Trp Thr Val Glu Leu Glu Pro Arg Leu Arg Thr Ser Val Gly Leu
980 985 990
Arg Lys Pro Asp Ile Ile Ala Ser Arg Asp Gly Val Gly Val Ile Val
995 1000 1005
Asp Val Gln Val Val Ser Gly Gln Arg Ser Leu Asp Glu Leu His
1010 1015 1020
Arg Glu Lys Arg Asn Lys Tyr Gly Asn His Gly Glu Leu Val Glu
1025 1030 1035
Leu Val Ala Gly Arg Leu Gly Leu Pro Lys Ala Glu Cys Val Arg
1040 1045 1050
Ala Thr Ser Cys Thr Ile Ser Trp Arg Gly Val Trp Ser Leu Thr
1055 1060 1065
Ser Tyr Lys Glu Leu Arg Ser Ile Ile Gly Leu Arg Glu Pro Thr
1070 1075 1080
Leu Gln Ile Val Pro Ile Leu Ala Leu Arg Gly Ser His Met Asn
1085 1090 1095
Trp Thr Arg Phe Asn Gln Met Thr Ser Val Met Gly Gly Gly Val
1100 1105 1110
Gly
<210> 38
<211> 1056
<212> DNA
<213> 家蚕(Bombyx mori)
<400> 38
ggccgcctcg tcaacgtgaa gaaattcaag caagcgcggg taaacggcgg gagtaactat 60
gactctctta agcgggagta actatgactc tcttaggggc gatacgcata attttaattt 120
ttcgattcaa atccagtcgt cttaatctgg tgaccagtgg cgcggtcacc agtatagtgc 180
acaggacgtg aatggctccg aggctggcgg agtcactcac tataagtgtg agagacgatg 240
tcctgtgcca agtatacgtc caaccctaac gggttaagtg aaattagttg ctcataacag 300
ggacggtgta cctgtttgct cgtggctggc tatcgaatgg acgggaccaa tacacccccc 360
tgttagtaat ggggtaagag agagcggtct gaaactatgg ccgagatcac gacgccccac 420
tcctacccat aacctgcacg tggtaccgcc gcacattgac cgatacggga ggaggggcag 480
cacttgaatc acgtagtctt ggtgtagcca ttgcgggact acagccctcg taagtgccgc 540
cttagaacgc aacggggcaa taggtgggcc ggggcgctag cgggggggag taatctcccc 600
tgttggcgtg caccgcactg ctccctctgg gggcagtgtc atccggaaac aggtgggccg 660
gggcgccacc aggggggagc aatccctcct gatgatggcg agcaccgcac tgtcccttat 720
gggacggtgt aacccggatg gctgtacacg tggtaaacac gtgacagcag ccccgatgga 780
cggaccgcga ggaccgtcaa gcctagcagg taccttcggg tggggccttg cgatacctgc 840
gggcgaaccc tgtggtcggg tttgcagccc ggccacagtg ggtttttttc ctgttgcaaa 900
aaagtcaaat aaagaaaata gacctgaagc ctctggcctc ccgctggagt cagagaggac 960
aggcgataac ccgactgtgc ggggttccgc cggcgcagat cctgtgggtc aggatgcgcc 1020
tggttggacc tgccagttct gcgaacgaac cttttc 1056
<210> 39
<211> 502
<212> DNA
<213> 家蚕(Bombyx mori)
<400> 39
gagttaaggt ccataatcgg gcttcgggaa ccgacactac aaatcgttcc gatactggcg 60
ttgagaggtt cacacatgaa ctggaccagg ttcaatcaga tgacgtccgt catggggggc 120
ggcgttggtt gagccttgca cagtagtcca gcggtaaggg tgtagatcag gcccgtctgt 180
ttctcccccg gagctcgctc ccttggcttc ccttatatat tttaacatca gaaacagaca 240
ttaaacatct actgatccaa tttcgccggc gtacggccac gatcgggagg gtgggaatct 300
cgggggtctt ccgatcctaa tccatgatga ttacgacctg agtcactaaa gacgatggca 360
tgatgatccg gcgatgaaaa tagccaaatg cctcgtcatc taattagtga cgcgcatgaa 420
tggattaacg agattcccac tgtccctatc tactatctag cgaaaccaca gccaagggaa 480
cgggcttggg agaatcagcg gg 502
Claims (33)
1.一种基因递送媒介物系统,所述基因递送媒介物系统包括:
a)第一核酸和第二核酸,其中:
i)所述第一核酸包含编码R2逆转录转座子R2多肽的核苷酸序列;并且
ii)所述第二核酸包含编码一种或多种异源基因产物的异源核苷酸序列,其中所述异源核苷酸序列由R2逆转录转座子3’非翻译区(UTR)和R2逆转录转座子5’UTR侧接,并且其中所述异源核苷酸序列具有至少200个核苷酸的长度;或
b)多肽和核酸,其中:
i)所述多肽是R2逆转录转座子R2多肽;并且
ii)所述核酸包含编码一种或多种异源基因产物的异源核苷酸序列,其中所述异源核苷酸序列由R2逆转录转座子3’UTR和R2逆转录转座子5’UTR侧接,并且其中所述异源核苷酸序列具有至少200个核苷酸的长度。
2.如权利要求1所述的基因递送媒介物系统,其中所述R2多肽包含与图7中描绘的氨基酸序列具有至少85%氨基酸序列同一性的氨基酸序列。
3.如权利要求1或权利要求2所述的基因递送媒介物系统,其中所述异源核苷酸序列编码单一异源基因产物。
4.如权利要求3所述的基因递送媒介物系统,其中所述单一异源基因产物是多肽。
5.如权利要求3所述的基因递送媒介物系统,其中所述单一异源基因产物是RNA。
6.如权利要求1或权利要求2所述的基因递送媒介物系统,其中所述异源核苷酸序列至少编码第一异源基因产物和第二异源基因产物。
7.如权利要求6所述的基因递送媒介物系统,其中所述第一异源基因产物是多肽,并且其中所述第二异源基因产物是RNA。
8.如权利要求4所述的基因递送媒介物系统,其中所述多肽是嵌合抗原受体。
9.如权利要求6所述的基因递送媒介物系统,其中所述第一异源基因产物是第一异源多肽,并且其中所述第二异源基因产物是第二异源多肽。
10.如权利要求9所述的基因递送媒介物系统,其中所述异源核苷酸序列按5’至3’顺序包含:
i)编码所述第一异源多肽的核苷酸序列;
ii)内部核糖体进入位点或编码自裂解多肽的核苷酸序列;以及
iii)编码所述第二异源多肽的核苷酸序列。
11.如权利要求9所述的基因递送媒介物系统,其中所述第一多肽和所述第二多肽一起形成异二聚体嵌合抗原受体。
12.如权利要求7所述的基因递送媒介物系统,其中所述多肽是RNA指导的效应物多肽,并且其中所述RNA是结合至所述RNA指导的效应物多肽的指导RNA。
13.如权利要求1-12中任一项所述的基因递送媒介物系统,其中所述编码R2多肽的核苷酸序列经密码子优化以用于在真核细胞中表达。
14.如权利要求1-13中任一项所述的基因递送媒介物系统,其中所述编码一种或多种异源基因产物的异源核苷酸序列可操作地连接至转录控制元件。
15.如权利要求14所述的基因递送媒介物系统,其中所述转录控制元件是可调控启动子。
16.如权利要求14所述的基因递送媒介物系统,其中所述转录控制元件是组成型启动子。
17.如权利要求1-16中任一项所述的基因递送媒介物系统,其中所述异源核苷酸序列具有至少3kb的长度。
18.如权利要求1-16中任一项所述的基因递送媒介物系统,其中所述异源核苷酸序列具有约5kb至约10kb的长度。
19.如权利要求1-16中任一项所述的基因递送媒介物系统,其中所述异源核苷酸序列具有约10kb至约15kb的长度。
20.一种药盒,所述药盒包括:
a1)第一核酸,所述第一核酸包含编码R2逆转录转座子R2多肽的核苷酸序列;以及
b1)第二核酸,所述第二核酸包含用于插入编码一种或多种异源基因产物的异源核苷酸序列的插入位点,其中所述插入位点由R2逆转录转座子3’非翻译区(UTR)和R2逆转录转座子5’UTR侧接,并且其中所述异源核苷酸序列具有至少200个核苷酸的长度;或
a2)R2逆转录转座子R2多肽;以及
b2)核酸,所述核酸包含用于插入编码一种或多种异源基因产物的异源核苷酸序列的插入位点,其中所述插入位点由R2逆转录转座子3’UTR和R2逆转录转座子5’UTR侧接,并且其中所述异源核苷酸序列具有至少200个核苷酸的长度。
21.如权利要求20(a1和b1)所述的药盒,其中所述第一核酸和所述第二核酸位于分开的容器中。
22.如权利要求20(a1)所述的药盒,其中所述编码R2多肽的核苷酸序列经密码子优化以用于在真核细胞中表达。
23.如权利要求20(b1)所述的药盒,其中所述第二核酸还包含所述插入位点5’的转录控制元件。
24.如权利要求20(a2和b2)所述的药盒,其中所述R2多肽和所述核酸位于分开的容器中。
25.如权利要求20(b2)所述的药盒,其中所述核酸还包含所述插入位点5’的转录控制元件。
26.一种将一种或多种目标基因产物递送至真核细胞的方法,所述方法包括使所述细胞与如权利要求1-19中任一项所述的基因递送媒介物系统接触,其中所述R2多肽、所述5’UTR和所述3’UTR实现将所述异源核酸插入所述真核细胞的基因组的28S区中。
27.如权利要求26所述的方法,其中所述接触是在体外。
28.如权利要求26所述的方法,其中所述接触是在体内。
29.如权利要求26所述的方法,其中所述接触是离体的。
30.如权利要求26-29中任一项所述的方法,其中所述真核细胞是非人动物细胞。
31.如权利要求26-29中任一项所述的方法,其中所述真核细胞是人细胞。
32.如权利要求26-29中任一项所述的方法,其中所述真核细胞是植物细胞。
33.如权利要求26-29中任一项所述的方法,其中所述真核细胞是无脊椎动物细胞。
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