CN112368377A - 用于治疗重症联合免疫缺陷的包含细胞穿透肽和腺苷脱氨酶的融合蛋白的药物组合物 - Google Patents
用于治疗重症联合免疫缺陷的包含细胞穿透肽和腺苷脱氨酶的融合蛋白的药物组合物 Download PDFInfo
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Abstract
本发明涉及包含细胞穿透肽和腺苷脱氨酶的融合蛋白作为活性成分的组合物,其中所述组合物由于腺苷脱氨酶的细胞通透性的提高而可有效用于治疗重症复合免疫缺陷。
Description
技术领域
本公开内容涉及细胞穿透肽和腺苷脱氨酶的缀合物,以及用于治疗重症联合免疫缺陷的包含所述缀合物的药物组合物。
背景技术
重症联合免疫缺陷(severe combined immunodeficiency,SCID)是一种原发性免疫缺陷病,其特征在于由于参与免疫系统发育的基因异常而导致T淋巴细胞缺陷和B淋巴细胞介导的免疫功能受损。患有重症联合免疫缺陷的患者非常易受细菌、病毒或真菌的感染,因为几乎没有或没有T淋巴细胞和B淋巴细胞参与患者的免疫系统。另外,在健康人群中不引起重度感染的微生物可在患有重症联合免疫缺陷的患者中引起威胁生命的感染。甚至不引起疾病的微生物也可在患有重症联合免疫缺陷的患者中引起重度感染。
重症联合免疫缺陷可分类为X连锁重症联合免疫缺陷(X-linked severecombined immunodeficiency,X-SCID)和常染色体隐性重症联合免疫缺陷。常染色体隐性联合免疫缺陷的一些已知实例包括腺苷脱氨酶(adenosine deaminase,ADA)缺乏症、Jak3(Janus激酶3)缺陷、IL-7Rα(白介素-7受体α)缺陷、RAG1(重组激活基因1)、RAG2缺陷、Artemis缺陷和CD45缺陷。
ADA缺陷是由20号染色体的长臂(20q12-13.11)中的基因突变引起的,该基因编码腺苷脱氨酶(ADA)。ADA是T淋巴细胞代谢必不可少的酶,并且如果缺乏该酶,则毒性代谢产物积累在淋巴细胞中,导致淋巴细胞死亡。治疗ADA的方法包括移植具有正常ADA基因的造血干细胞的方法,以及通过肌内注射施用PEG-ADA(经聚乙二醇修饰的腺苷脱氨酶;Andagen)的酶替代治疗方法。
同时,细胞穿透肽(cell-penetrating peptide,CPP)是细胞膜可渗透肽,其各自由约10至60个氨基酸的短肽组成,并且主要来源于蛋白质转导结构域或膜转运序列。已知的是,与外来物质的一般的胞内转导途径不同,CPP可在不损伤细胞膜的情况下移入细胞内,并且甚至可胞内递送已知不通过细胞膜的DNA或蛋白质。
本发明人已经对来源于HIV(人免疫缺陷病毒)核衣壳的细胞穿透肽进行了研究,并且已发现该细胞穿透肽可提高ADA的细胞通透性,从而完成了本公开内容。
发明内容
技术问题
本公开内容的一个目的是提供包含细胞穿透肽和腺苷脱氨酶的缀合物、用于治疗重症联合免疫缺陷的包含所述缀合物作为活性成分的药物组合物、用于治疗重症联合免疫缺陷的方法,及其用途。
技术解决方案
本公开内容的一个方面提供了缀合物,其包含:包含SEQ ID NO:1的氨基酸序列的细胞穿透肽;以及如SEQ ID NO:2的氨基酸序列所示的腺苷脱氨酶。
本公开内容的另一个方面提供了编码所述缀合物的多核苷酸。
本公开内容的又一个方面提供了包含所述多核苷酸的重组载体。
本公开内容的另一个方面提供了包含所述重组载体的宿主细胞。
本公开内容的又一个方面提供了用于产生缀合物的方法,该方法包括步骤:(a)在培养基中培养宿主细胞;以及(b)从培养基中回收缀合物。
本公开内容的另一个方面提供了用于治疗重症联合免疫缺陷的包含缀合物作为活性成分的药物组合物。
根据本公开内容的一个实施方案,所述重症联合免疫缺陷可以是腺苷脱氨酶缺乏症。
本公开内容的另一个方面提供了用于治疗重症联合免疫缺陷的方法,该方法包括将所述组合物施用于对象的步骤。
本公开内容的又一个方面提供了缀合物在制备用于治疗重症联合免疫缺陷的药物中的用途。
有益效果
由于腺苷脱氨酶具有提高的细胞通透性,因此细胞穿透肽和腺苷脱氨酶的缀合物可用于治疗重症联合免疫缺陷。
附图说明
图1A举例说明了改进细胞穿透肽-腺苷脱氨酶(ACP-ADA或ADA-ACP)蛋白质的示意性结构,并且图1B示出了分析重组蛋白是否在293FT细胞中表达的结果。
图2A示出了在将ACP-ADA或ADA-ACP表达载体与pDsRed载体共转染之后观察荧光信号的结果,并且图2B示出了测量ACP-ADA和ADA-ACP的活性的结果。
图3A示出了经纯化的ACP-ADA在大肠杆菌(E.coli)中表达之后的结果,并且图3B示出了测量经纯化的ACP-ADA的活性的结果。
图4A示出了在用经纯化的ACP-ADA处理HeLa细胞之后观察荧光信号的结果,并且图4B是示出对荧光信号进行定量的结果的图。
图5示出了将ADA递送到ADA缺陷细胞中并在所述细胞中鉴定ADA的结果。图5A示出了观察穿透细胞的ACP-ADA蛋白质的结果,并且图5B示出了测量ADA活性的结果。
图6示出了通过将牛ADA和ACP-ADA中的每一种注射到表达ADA基因的异种(+/-)小鼠中并测量从血液中分离的单个核细胞中的ADA活性而获得的结果。
具体实施方式
为了实现上述目的,本公开内容的一个方面提供了缀合物,其包含:包含SEQ IDNO:1的氨基酸序列的细胞穿透肽;以及如SEQ ID NO:2的氨基酸序列所示的腺苷脱氨酶。
如本文中使用的,术语“细胞穿透肽(CPP)”是指由约10至约60个氨基酸的短肽组成的细胞膜可渗透肽,其可在不损伤细胞膜的情况下移入细胞内,并且甚至可胞内递送不能穿过细胞膜的DNA或蛋白质。
如本文中使用的,术语“腺苷脱氨酶”是使腺苷的氨基脱氨并催化其中腺苷被水解以产生肌苷和氨(NH3)的过程的酶。
如本文中使用的,术语“缀合物”是指其中细胞穿透肽和生物学或药学活性蛋白质通过化学/物理共价键或非共价键连接在一起的物质。
在本公开内容的一个实施方案中,能够通过与细胞穿透肽结合形成缀合物的表达“生物学或药学活性蛋白质”意指可调节体内生理现象的蛋白质。表达包括蛋白质、肽、与蛋白质或肽连接的脂质、碳水化合物、化学化合物或荧光标记。例如,具有SEQ ID NO:2的氨基酸序列的腺苷脱氨酶可被用作蛋白质。细胞穿透肽可与腺苷脱氨酶的C末端或N末端连接以形成缀合物。
在本公开内容的一个实施方案中,包含SEQ ID NO:1的氨基酸序列的细胞穿透肽可由SEQ ID NO:5的多核苷酸序列编码,以及如SEQ ID NO:2的氨基酸序列所示的腺苷脱氨酶可由SEQ ID NO:6的多核苷酸序列编码。
在本公开内容的一个实施方案中,缀合物可包含SEQ ID NO:3(ACP-ADA)或SEQ IDNO:4(ADA-ACP)的氨基酸序列。
本公开内容的另一个方面提供了编码缀合物的多核苷酸。
如本文中使用的,术语“多核苷酸”是指以单链或双链形式存在的脱氧核糖核苷酸或核糖核苷酸的聚合物。该术语包含RNA基因组序列、DNA(gDNA和cDNA)以及由其转录的RNA序列,并且包含天然多核苷酸的类似物,除非另有说明。
在本公开内容的一个实施方案中,多核苷酸不仅包含编码缀合物的核苷酸序列,而且还包含与其互补的序列。互补序列不仅包含完全互补序列,而且还包含基本互补序列。另外,多核苷酸序列可被修饰,并且这样的修饰包括核苷酸的添加、缺失或者非保守替换或保守替换。
在本公开内容的一个实施方案中,编码缀合物的多核苷酸可包含如SEQ ID NO:7(ACP-ADA)或SEQ ID NO:8(ADA-ACP)所示的多核苷酸序列。
本公开内容的又一个方面提供了包含编码缀合物的多核苷酸的重组载体。
如本文中使用的,术语“载体”是指用于在宿主细胞中表达靶基因的手段。载体的一些实例包括但不限于质粒载体,黏粒载体和病毒载体(例如噬菌体载体、腺病毒载体、逆转录病毒载体和腺相关病毒载体)。可用作重组载体的载体可通过对本领域中普遍的质粒(例如,pSC101、pGV1106、pACYC177、ColE1、pKT230、pME290、pBR322、pUC8/9、pUC6、pBD9、pHC79、pIJ61、pLAFR1、pHV14、pGEX系列、pET系列和pUC19等),噬菌体(例如,λgt4λB、λ-Charon、λΔz1和M13等)或病毒(例如,CMV、SV40等)进行改造来构建。
重组载体可包含多核苷酸序列和与多核苷酸序列可操作连接的启动子。
如本文中使用的,术语“可操作连接”是指核苷酸表达控制序列(例如,启动子序列)和另一个核苷酸序列之间的功能性连接,由此该控制序列控制另一个核苷酸序列的转录和/或翻译。
可用于本公开内容的重组载体可通过对本领域中普遍使用的质粒(例如,pSC101、ColE1、pBR322、pUC8/9、pHC79、pUC19、pET等)、噬菌体(例如,λgt4λB、λ-Charon、λΔz1和M13等)或病毒(例如,SV40等)进行改造来构建。
重组载体可包含促进纯化细胞穿透肽和腺苷脱氨酶的缀合物的标签序列,例如,连续组氨酸密码子、麦芽糖结合蛋白密码子、Myc密码子等,并且还可包含用于提高缀合物的溶解性的融合配偶体。另外,重组载体可包含被酶特异性切割以便在表达缀合物时去除不必要部分的序列、表达控制序列以及用于鉴定胞内递送的标志物或报道基因序列。
本公开内容的另一个方面提供了包含重组载体的宿主细胞,即,用重组载体转化的细胞。
能够稳定地和连续地克隆或表达重组载体的宿主细胞可以是本领域中公知的任何宿主细胞。原核细胞包括,例如,大肠杆菌JM109、大肠杆菌BL21、大肠杆菌RR1、大肠杆菌LE392、大肠杆菌B、大肠杆菌X 1776和大肠杆菌W3110。当重组载体被转化到真核细胞、酿酒酵母(Saccharomyce cerevisiae)、昆虫细胞、植物细胞和动物细胞中时,例如,SP2/0、CHO(中国仓鼠卵巢)K1、CHO DG44、PER.C6、W138、BHK、COS-7、293、HepG2、Huh7、3T3、RIN和MDCK细胞系可用作宿主细胞。
可使用本领域中广泛已知的转移方法将多核苷酸或包含该多核苷酸的重组载体转移至宿主细胞中。例如,当宿主细胞是原核细胞时,CaCl2法或电穿孔法可用作转移方法,以及当宿主细胞是真核细胞时,显微注射法、磷酸钙沉淀法、电穿孔法、脂质体介导的转染法或基因轰击法可用作转移方法,但是转移方法不限于此。
根据本领域中已知的方法,使用由选择标志物表达的表型可容易地进行选择转化的宿主细胞的方法。例如,当选择标志物是特定的抗生素抗性基因时,可通过在包含该抗生素的培养基中培养转化体来容易地选择转化体。
本公开内容的又一个方面提供了用于产生细胞穿透肽和腺苷脱氨酶的缀合物的方法,该方法包括步骤:在培养基中培养宿主细胞;以及从培养基中回收缀合物。
在本公开内容的一个实施方案中,细胞培养可以是大规模细胞培养,并且可使用常用的细胞培养方法进行细胞培养。例如,细胞培养方法可以是选自分批培养、重复分批培养、补料分批培养、重复补料分批培养、连续培养和灌注培养的任一种或更多种,但不限于此。
在本公开内容的一个实施方案中,从培养基中回收缀合物的步骤可使用本领域中公知的多种分离和纯化方法来进行。通常,可对细胞裂解物进行离心以除去细胞碎片、培养物杂质等,并随后可进行沉淀,例如盐析(硫酸铵沉淀和磷酸钠沉淀)、溶剂沉淀(使用丙酮、乙醇,异丙醇等沉淀蛋白质级分)等,并且可进行透析、电泳和多种柱色谱。
本公开内容的另一个方面提供了用于治疗重症联合免疫缺陷的包含缀合物作为活性成分的药物组合物。
如本文中使用的,术语“重症联合免疫缺陷(SCID)”是指特征在于由于基因异常而导致T淋巴细胞缺陷和B淋巴细胞介导的免疫功能受损的疾病。患有该疾病的患者因为其免疫系统无法正常发挥功能而遭受慢性感染。
在本公开内容的一个实施方案中,重症联合免疫缺陷可以是腺苷脱氨酶缺乏症。如果腺苷脱氨酶缺乏,则毒性代谢产物在淋巴细胞中积累,导致淋巴细胞死亡,并且因此T淋巴细胞和B淋巴细胞不能正常发育。
如果需要的话,除缀合物之外,本公开内容的药物组合物还可包含可药用载体。
这些可药用载体是通常用于制备药物的载体,并且其实例包括但不限于:乳糖、右旋糖、蔗糖、山梨糖醇、甘露糖醇、淀粉、阿拉伯胶、磷酸钙、藻酸盐、明胶、硅酸钙、微晶纤维素、聚乙烯吡咯烷酮、纤维素、水、糖浆、甲基纤维素、羟基苯甲酸甲酯、羟基苯甲酸丙酯、滑石、硬脂酸镁、矿物油等。另外,本公开内容的药物组合物还可包含添加剂,例如润滑剂、润湿剂、甜味剂、矫味剂、乳化剂、助悬剂、防腐剂等。
载体可占基于本公开内容的药物组合物的总重量的约1重量%至约99.99重量%,优选约90重量%至约99.99重量%的量,并且添加剂可占基于本公开内容的药物组合物的总重量的约0.1重量%至约20重量%的量。
同时,本公开内容的药物组合物可经口或肠胃外施用,但是可通过表面施用方法直接施用到皮肤。
本公开内容的药物组合物可与可药用载体和/或赋形剂一起配制,并以单位剂量形式制备或包含在多剂量容器中。在这一方面,制剂可以是以溶液剂、混悬剂或乳剂的形式,或者可包含酏剂、提取物、散剂、颗粒剂、片剂、膏药剂、搽剂、洗剂、软膏剂等。
本公开内容的药物组合物的日剂量通常可在0.001至150mg/kg体重的范围内,并且可施用一次或数次。然而,本公开内容的药物组合物的剂量是鉴于多种相关因素例如施用途径,患者的年龄、性别和体重以及患者的严重程度来确定的,并且因此剂量不应为理解为以任何方式限制本公开内容的范围。
本公开内容的另一个方面提供了用于治疗重症联合免疫缺陷的方法,该方法包括将该组合物施用于对象的步骤。
对象是指动物,并且通常可以是能够通过用本公开内容的缀合物进行处理而表现出有益效果的哺乳动物。这样的对象的优选实例可包括灵长类,例如人。另外,这样的对象可包括具有重症联合免疫缺陷的症状或处于具有这样的症状之风险中的所有对象。
本公开内容的又一个方面提供了缀合物在制备用于治疗重症联合免疫缺陷的药物中的用途。
发明实施方式
在下文中,将参考一个或更多个实施例更详细地描述本公开内容。然而,这些实施例是为了举例说明本公开内容,并且本公开内容的范围不限于这些实施例。
实验方法
1.用于表达细胞穿透肽-腺苷脱氨酶缀合物的重组载体的构建
将ACP(改进细胞穿透肽,以下称为ACP;SEQ ID NO:1)用作细胞穿透肽。为了表达由ACP和腺苷脱氨酶(以下称为ADA;SEQ ID NO:2)的缀合物组成的重组蛋白,构建了重组载体。
1-1.ADA基因的扩增
添加限制性酶识别序列,使得HindIII(New England Biolabs,NEB;USA)可作用于人ADA基因的N末端,并且XhoI(New England Biolabs)可作用于人ADA基因的C末端。为此,使用293FT细胞系的基因组DNA作为模板并使用包含限制性酶识别序列的PCR引物进行聚合酶链反应(以下称为PCR)。下表1和2示出了PCR中使用的引物序列和PCR条件。
[表1]
SEQ ID NO. | 序列 | |
从HindIII-ADA向前 | SEQ ID NO:9 | CCC AAG CTT GGC CCA GAC GCC CGC |
从ADA-XhoI反向 | SEQ ID NO:10 | CCC TCG AGG AGG TTC TGC CCT GCA GAG |
[表2]
1-2.重组载体的构建
对包含ACP序列的pTriEx-1.1载体和以上1-1部分的PCR产物进行处理,并在37℃下用HindIII和XhoI切割2小时,并且根据制造商的方案,使用PCR纯化试剂盒(Cosmo,Korea)分离pTriEx载体片段和PCR产物。
将分离的pTriEx-1.1载体片段和PCR产物在4℃下连接在一起24小时。连接条件在下表3中示出。
[表3]
dH<sub>2</sub>O | 4.1μl |
T4 DNA连接酶缓冲液(10×) | 1μl |
HindIII-ADA-XhoI PCR产物(30ng) | 1.6μl |
包含ACP的pTriEx-1.1载体(50ng) | 2.3μl |
T4 DNA连接酶(400个单位/μl) | 1μl |
总共 | 10μl |
同时,以与上述相同的方式,不同之处在于使用NcoI和HindIII代替HindIII和XhoI,来构建其中ADA基因与ACP的N末端连接的重组载体(ADA-ACP)。
1-3.转化和DNA测序
将感受态细胞和连接产物混合在一起,并随后在42℃下孵育1分钟。此后,将感受态细胞在LB液体培养基中在37℃下培养1小时,并将细胞培养物平板接种在含有抗生素的LB固体培养基上,并在37℃下培养16小时。培养完成之后,将用正确连接的重组载体转化的大肠杆菌菌落接种到LB液体培养基中,并在37℃下振荡培养16小时。培养完成之后,将细胞培养物进行离心,并收集大肠杆菌沉淀物。根据制造商的方案,使用质粒提取小量制备试剂盒(Intron,Korea)从收集的大肠杆菌沉淀物中分离pTriEx ACP-ADA或pTriEx ADA-ACP重组载体。通过紫外分光光度法测量分离的重组载体的浓度,并由Cosmo Co.Ltd.(Korea)进行测序。
1-4.用于细菌表达的ADA-ACP重组载体的构建
用NcoI和XhoI切割构建的pTriEx ACP-ADA和pTriEx ADA-ACP载体,并用相同的限制性酶切割pET28a载体。此后,以与以上1-2和1-3部分描述的相同方式分离重组载体并进行测序。
2.ACP-ADA或ADA-ACP在动物细胞中表达的分析
2-1.ACP-ADA或ADA-ACP表达的分析
在湿润的培养箱中,在37℃下在5%CO2下,用补充有10%FBS和100U/ml青霉素/链霉素的DMEM培养293FT细胞系。将经培养的293FT细胞以5×105个细胞/孔的密度接种到6孔板中,并培养24小时。培养完成之后,根据制造商的方案,使用Lipofector EZ试剂(APTABIO,Korea)用1μg pTriEx ACP-ADA或pTriEx ADA-ACP重组载体DNA转染细胞。此后,将细胞进一步培养48小时。
将经培养的细胞用PBS洗涤并通过移液与板分离。通过向其添加RIPA缓冲液(10mMTris-Cl(pH 8.0)、1mM EDTA、0.5mM EGTA、1%Triton X-100、0.1%脱氧胆酸钠、0.1%SDS、140mM NaCl和1mM PMSF)裂解分离的细胞,并在冰上静置30分钟。此后,将细胞在4℃下离心(以14,000rpm持续20分钟)以去除细胞碎片,并且仅收集细胞裂解物上清液。收集的细胞裂解物的蛋白质浓度用Quick StartTM Bradford 1×染料试剂(Bio-Rad,USA)测量,并通过10%SDS-PAGE(十二烷基硫酸钠-聚丙烯酰胺凝胶电泳)分离20μg蛋白质。将分离的蛋白质转移到PVDF(聚偏二氟乙烯)膜上,并随后将PVDF膜用5%脱脂乳封闭。将PVDF膜用一抗(ACP、His和肌动蛋白抗体)在4℃下孵育16小时,洗涤,并随后用二抗在室温下孵育1小时。此后,根据制造商的方案,使用ECL(PierceTM ECL Western印迹底物(ThermoScientificTM,USA))检测蛋白质条带。使用AmershamTM Imager 600(GE Healthcare LifeScience,USA)进行检测。
2-2.ACP-ADA或ADA-ACP的腺苷脱氨酶活性的测量
根据与以上2-1中描述的相同方法,用1μg pTriEx ACP-ADA或pTriEx ADA-ACP重组载体DNA转染293FT细胞系,并培养48小时。此时,进行pDsRed载体的共转染,以确定是否实现了重组载体的转染。培养之后,将细胞用PBS洗涤一次,并将1ml PBS添加至板,并通过移液分离细胞,并以6,000rpm离心3分钟。去除上清液,收集细胞沉淀物,并随后根据制造商的方案,使用腺苷脱氨酶活性测定试剂盒(BioVision,USA)测量收集的细胞沉淀物中的ADA活性。
3.ACP-ADA或ADA-ACP在大肠杆菌中表达的分析
3-1.大肠杆菌培养与裂解
为了检测以上1-4中构建的pET28a ACP-ADA载体是否表达,进行了如下实验。
用pET28a ACP-ADA载体和pET28a-ADA载体中的每一种转化大肠杆菌BL21(DE3)(Thermo Fisher),并平板接种在LB(Luria-Bertani)固体培养基上,随后在37℃下培养16小时。16小时之后,将形成的菌落接种到LB液体培养基中,并在37℃下另外预培养。约16小时之后,将OD值达到0.5至0.6的250μl细胞预培养物接种到250ml LB液体培养基中,并在37℃下培养3至4小时,直至细胞培养物的OD值达到0.5至0.6。当细胞培养物的OD值达到0.5至0.6时,向细胞培养物添加0.5mM IPTG(异丙基β-D-硫代半乳糖苷),然后在37℃下另外培养5小时。5小时之后,将细胞培养物进行离心,并收集大肠杆菌沉淀物。将收集的沉淀物混悬于裂解缓冲液(20mM Tris缓冲液和HCl 8.0,50mM KCl,20mM咪唑和1mM EDTA)中。然后,通过超声以30%至35%的振幅裂解大肠杆菌细胞。对大肠杆菌细胞裂解物进行离心并收集上清液。收集的上清液通过0.45μm过滤器过滤。
3-2.ACP-ADA的纯化
使用AKTA快速蛋白质液相色谱(Fast Protein Liquid Chromatography,FPLC)系统(GE Healthcare Life Science)进行蛋白质纯化。用预平衡缓冲液(20mM Tris-HCl(pH8.0),300mM NaCl,30mM咪唑)平衡Histap柱(5ml),并用以上3-1中收集的上清液上样。此后,用洗脱缓冲液(20mM Tris-HCl(pH 8.0),300mM NaCl和500mM咪唑)洗脱蛋白质。洗脱的级分通过SDS-PAGE分析,并随后仅收集具有高纯度的级分,用Amicon(Millipore,USA)浓缩,并用储存缓冲液(20mM Tris,20%甘油和1mM DTT(二硫苏糖醇))进行缓冲液交换。不具有高纯度的级分也用Amicon浓缩,并随后通过阴离子交换色谱柱(Q-柱)进行纯化。此时,用预平衡缓冲液(20mM Tris-HCl,pH 8.0)平衡柱,并用洗脱缓冲液(20mM Tris-HCl(pH 8.0)和1M NaCl)洗脱蛋白质。通过SDS-PAGE分析每种洗脱的级分,并以与上述相同的方式浓缩具有高纯度的级分并进行缓冲液交换。
3-3.ACP-ADA的腺苷脱氨酶活性的测量
使用Quick StartTM Bradford 1×染料试剂(Bio-Rad,USA)测量经纯化的ACP-ADA和ADA的浓度。基于所测量的浓度,将1、2、5和10ng的ACP-ADA进行稀释,并将0.1、0.2、0.5和1ng的ADA进行稀释。使用每种经稀释的蛋白质作为底物,使用腺苷脱氨酶活性测定试剂盒(BioVision,USA)测量ADA活性。
4.ACP-ADA的细胞膜通透性的分析
在湿润的培养箱中,在37℃下在5%CO2下,分别用补充有10%FBS和100U/ml青霉素/链霉素的DMEM和补充有15%FBS和100U/ml青霉素/链霉素的RPMI1640培养HeLa细胞和GM02606细胞。将经培养的HeLa细胞和GM02606细胞分别以1×105个细胞/孔和8×105个细胞/孔的密度接种到含有玻璃的12孔板中,并培养24小时。此后,将细胞用3mM的以上3中纯化的ACP-ADA处理,并培养24小时或3小时。然后,将细胞用PBS洗涤3次。将洗涤的细胞用3.7%甲醛固定20分钟,并用包含0.2%Triton X-100的PBS处理以提高细胞膜通透性。接下来,将细胞用3%BSA封闭1小时,并用自主制备的ACP(ACP)抗体在室温下孵育2小时,随后用PBS洗涤3次。洗涤之后,对细胞进行处理,并用Alexa 488二抗在室温下孵育1小时,随后用PBS洗涤3次。将细胞用微管蛋白抗体(Santa Cruz Biotechnology,USA)在室温下孵育2小时,并用PBS洗涤3次。此后,对细胞进行处理并用Cy3缀合的二抗(JacksonImmunoResearch,USA)在室温下孵育1小时,随后用PBS洗涤3次。接下来,将细胞用DAPI(4’,6-二脒基-2-苯基吲哚)染色10分钟。将其上附着有HeLa细胞和GM02606细胞的玻璃分离,置于载玻片上,并通过共聚焦激光扫描显微术(LSM 700,Zeiss,Germany)观察。
5.ADA缺陷细胞中ACP-ADA的细胞膜通透性的分析
5-1.ACP-ADA的通透性的分析
在湿润的培养箱中,在37℃下在5%CO2下用补充有15%FBS和100U/ml青霉素/链霉素的RPMI1640培养GM02606细胞系。将经培养的GM02606细胞以2×106个细胞/孔的密度接种到6孔板中,并培养24小时。此后,将细胞用3mM的以上3中纯化的ACP-ADA处理,并培养3小时。然后,收获细胞并以5,000rpm离心5分钟。通过向其添加RIPA缓冲液(10mM Tris-Cl(pH 8.0),1mM EDTA,0.5mM EGTA,1%Triton X-100、0.1%脱氧胆酸钠,0.1%SDS,140mMNaCl和1mM PMSF)裂解分离的细胞,并在冰上静置30分钟。此后,将细胞在4℃下离心(以14,000rpm持续20分钟)以去除细胞碎片,并且仅收集细胞裂解物上清液。使用PierceTM BCA蛋白测定试剂盒(Thermo,USA)测量分离的细胞裂解物的蛋白质浓度,并通过10%SDS-PAGE(十二烷基硫酸钠-聚丙烯酰胺凝胶电泳)分离20μg蛋白质。将分离的蛋白质转移到PVDF(聚偏二氟乙烯)膜上,并随后将PVDF膜用5%脱脂乳封闭。将PVDF膜用一抗(ADA、ACP和肌动蛋白抗体)在4℃下孵育16小时,洗涤,并随后用二抗在室温下孵育3小时。此后,根据制造商的方案,使用ECL(PierceTM ECL Western印迹底物(Thermo ScientificTM,USA))检测蛋白质条带。对于蛋白质的检测,使用AmershamTM Imager 600(GE Healthcare Life Science,USA)。
5-2.ACP-ADA的腺苷脱氨酶活性的测量
根据与以上5-1中描述的相同方法,用3mM的以上3中纯化的ACP-ADA处理GM02606细胞系,并培养3小时。培养之后,收获细胞并以5,000rpm离心5分钟。
接下来,去除上清液,并随后收集细胞沉淀物。此后,根据制造商的方案,使用腺苷脱氨酶活性测定试剂盒(BioVision,USA)测量细胞沉淀物中的ADA活性。特别地,为了测量由ADA产生的肌苷进一步反应而产生的尿酸,使细胞和血浆样品与试剂盒中的试剂反应,并随后使用ELISA读取器测量在293nm波长处的吸光度。
6.在表达ADA基因的异种(+/-)小鼠中ACP-ADA的腺苷脱氨酶活性的测量
6-1.实验动物的准备
对于用作实验动物,亲本小鼠(JAX#003265-FVB;129-Adatm1Mw Tg(PLADA)4118Rkmb/J,Michael R.Blackburn et al.,1998,Melissa B.Aldrich et al.,2003)从Jackson实验室购买并进行交配,并随后获得表达ADA基因的异种小鼠并使用。将动物饲养室维持在23±3℃的温度下并且湿度为55±15%。另外,将饲养室维持在12小时光照/黑暗循环下。动物实验经Knotus有限公司的机构动物管理和使用委员会(the InstitutionalAnimal Case and Use Committee of Knotus Co.,Ltd.)批准,并根据方案中的说明对动物进行处理。
6-2.向ADA异种(+/-)小鼠施用蛋白质
静脉内施用100U/kg购买的牛ADA(Creative Enzyme,USA)和经纯化的ACP-ADA蛋白质。来自未向其施用物质的表达ADA基因的异种(+/-)小鼠的血液用作对照。在施用蛋白质之后1、6和24小时,用乙醚麻醉相应的动物,并通过注射器从后腔静脉收集约0.7ml血液。然后,将7μl肝素(500IU/ml肝素钠)添加至血液样品。
6-3.ACP-ADA的腺苷脱氨酶活性的分析
将从小鼠分离的血液以1,000rpm离心10分钟。离心之后,仅收集血液,置于Histopaque-1077溶液中,并以400×g离心30分钟以将其分离为红细胞(red blood cell,RBC)、单个核细胞和血浆。在分离的细胞中,仅收集单个核细胞,并向其添加1×PBS,随后以250×g离心10分钟。此后,去除上清液,并收集细胞沉淀物。然后,根据制造商的方案,使用腺苷脱氨酶活性测定试剂盒(BioVision,USA)测量细胞沉淀物中的ADA活性。
实验结果
1.ACP-ADA和ADA-ACP载体的表达的分析
如图1A中所示,为了检测构建的ACP-ADA和ADA-ACP载体是否在细胞中表达,用每种载体转染293FT细胞,并随后通过Western印迹分析进行分析。图1A中的深灰色正方形代表与每种重组蛋白(ACP-ADA和ADA-ACP)的C末端结合的His标签。
作为结果,如图1B中所示,在使用ACP抗体和与每种重组蛋白(ACP-ADA和ADA-ACP)的C末端结合的His特异性抗体进行的Western印迹分析中,可发现与每种重组蛋白的预测尺寸(48kDa)相对应的条带。该结果表明ACP-ADA和ADA-ACP在细胞中正常表达。
2.ACP-ADA和ADA-ACP的腺苷脱氨酶活性的分析
2-1.细胞中ACP-ADA和ADA-ACP的活性的分析
测量了293FT细胞中ACP-ADA和ADA-ACP的活性,并且作为结果,如图2B中所示,可确定当细胞用ACP-ADA或ADA-ACP转染时,ADA的活性与对照组(pTriEx)相比显著提高了50倍或更多。在另一个方面,如图2A中所示,可看到转染效率在实验组之间没有显著差异。
通过该实验,可确定在细胞中表达的ACP-ADA和ADA-ACP蛋白质具有ADA活性。
2-2.经纯化的ACP-ADA的活性的分析
测量了从大肠杆菌BL21(DE3)中分离和纯化的ACP-ADA的活性,并且作为结果,如图3B中所示,可确定随着蛋白质浓度提高,ACP-ADA活性提高,并随后收敛至恒定值。通过该实验,可看到经纯化的ACP-ADA的比活性为20U/mg。
3.ACP-ADA的细胞膜穿透活性的分析
将HeLa细胞和GM02606细胞用3μM ACP-ADA分别处理24小时和3小时,并随后分析ACP-ADA的细胞通透性。作为结果,如图4A和4C中所示,可确定在用ACP-ADA处理的组中,ACP-ADA进入细胞内,并且因此出现绿色荧光(微管蛋白-红色荧光以及核-蓝色荧光)。另外,如图4B中所示,可确定在用ACP-ADA处理的组中,绿色荧光信号的强度显著高于对照组中的信号的强度。
4.ACP-ADA渗透进入ADA缺陷细胞内以及腺苷脱氨酶活性的分析
为了检测ACP-ADA是否渗透ADA缺陷细胞并具有提高的ADA活性,使用以ADA缺乏症为特征的GM02606细胞系,分析了ACP-ADA的胞内渗透以及ACP-ADA对提高的ADA活性的影响。
4-1.ACP-ADA渗透进入细胞内的分析
为了检测从大肠杆菌纯化的ACP-ADA是否渗透ADA缺陷细胞,允许ACP-ADA渗透GM02606细胞的细胞膜,并随后进行Western印迹分析。
作为结果,如图5A中所示,可确定在使用ADA和ACP抗体进行的Western印迹分析中发现了与重组蛋白的预测尺寸(48kDa)相对应的条带,这表明ACP-ADA渗透了细胞。
4-2.细胞中ACP-ADA的活性的分析
使从大肠杆菌纯化的ACP-ADA渗透ADA缺陷细胞(GM02606)的细胞膜,并随后测量其活性。作为结果,如图5B中所示,可确定其中允许ACP-ADA渗透进入的GM02606细胞中的ADA活性与对照组(GM02606)相比显著提高。
通过该实验,可确定递送到细胞中的ACP-ADA蛋白质具有ADA活性。
5.在ADA异种(+/-)小鼠中ACP-ADA的脱氨酶活性的分析
在将购买的牛ADA和从大肠杆菌纯化的ACP-ADA中的每一种注射到ADA异种(+/-)小鼠中之后1、6和24小时,收集血液,并测量单个核细胞中ADA和ACP-ADA的活性。作为结果,如图6中所示,可确定在注射牛ADA之后1和6小时,以及在注射ACP-ADA之后1、6和24小时,脱氨酶活性与对照组相比在统计学上显著提高。特别地,可确定在注射ACP-ADA之后24小时收集的血液中的单个核细胞中的ADA活性比对照组提高了约3倍。
通过该实验,可确定即使在体内ACP-ADA蛋白质仍保持ADA活性。
本发明所属领域的技术人员将理解,在不脱离本公开内容的本质特征的情况下,本公开内容可以以修改的形式实施。因此,应当理解,所公开的实施方案在所有方面都是举例说明性的,而不是限制性的。本公开内容的范围由权利要求书而不是前述描述来限定,并且等同于权利要求书的范围内的所有差异应被解释为落入本发明的范围内。
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<120> 用于治疗重症联合免疫缺陷的包含细胞穿透肽和腺苷脱氨酶缀合物的药物组合物
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ggcagagagg gccaccagat gaaggactgc acagagagac aggcaaactt aacaagcttg 180
gcccagacgc ccgccttcga caagcccaaa gtagaactgc atgtccacct agacggatcc 240
atcaagcctg aaaccatctt atactatggc aggaggagag ggatcgccct cccagctaac 300
acagcagagg ggctgctgaa cgtcattggc atggacaagc cgctcaccct tccagacttc 360
ctggccaagt ttgactacta catgcctgct atcgcgggct gccgggaggc tatcaaaagg 420
atcgcctatg agtttgtaga gatgaaggcc aaagagggcg tggtgtatgt ggaggtgcgg 480
tacagtccgc acctgctggc caactccaaa gtggagccaa tcccctggaa ccaggctgaa 540
ggggacctca ccccagacga ggtggtggcc ctagtgggcc agggcctgca ggagggggag 600
cgagacttcg gggtcaaggc ccggtccatc ctgtgctgca tgcgccacca gcccaactgg 660
tcccccaagg tggtggagct gtgtaagaag taccagcagc agaccgtggt agccattgac 720
ctggctggag atgagaccat cccaggaagc agcctcttgc ctggacatgt ccaggcctac 780
caggaggctg tgaagagcgg cattcaccgt actgtccacg ccggggaggt gggctcggcc 840
gaagtagtaa aagaggctgt ggacatactc aagacagagc ggctgggaca cggctaccac 900
accctggaag accaggccct ttataacagg ctgcggcagg aaaacatgca cttcgagatc 960
tgcccctggt ccagctacct cactggtgcc tggaagccgg acacggagca tgcagtcatt 1020
cggctcaaaa atgaccaggc taactactcg ctcaacacag atgacccgct catcttcaag 1080
tccaccctgg acactgatta ccagatgacc aaacgggaca tgggctttac tgaagaggag 1140
tttaaaaggc tgaacatcaa tgcggccaaa tctagtttcc tcccagaaga tgaaaagagg 1200
gagcttctcg acctgctcta taaagcctat gggatgccac cttcagcctc tgcagggcag 1260
aacctcctcg agcaccacca ccaccaccac tga 1293
<210> 8
<211> 1296
<212> DNA
<213> 人工序列
<220>
<223> ADA-ACP多核苷酸
<400> 8
atgggcgccc agacgcccgc cttcgacaag cccaaagtag aactgcatgt ccacctagac 60
ggatccatca agcctgaaac catcttatac tatggcagga ggagagggat cgccctccca 120
gctaacacag cagaggggct gctgaacgtc attggcatgg acaagccgct cacccttcca 180
gacttcctgg ccaagtttga ctactacatg cctgctatcg cgggctgccg ggaggctatc 240
aaaaggatcg cctatgagtt tgtagagatg aaggccaaag agggcgtggt gtatgtggag 300
gtgcggtaca gtccgcacct gctggccaac tccaaagtgg agccaatccc ctggaaccag 360
gctgaagggg acctcacccc agacgaggtg gtggccctag tgggccaggg cctgcaggag 420
ggggagcgag acttcggggt caaggcccgg tccatcctgt gctgcatgcg ccaccagccc 480
aactggtccc ccaaggtggt ggagctgtgt aagaagtacc agcagcagac cgtggtagcc 540
attgacctgg ctggagatga gaccatccca ggaagcagcc tcttgcctgg acatgtccag 600
gcctaccagg aggctgtgaa gagcggcatt caccgtactg tccacgccgg ggaggtgggc 660
tcggccgaag tagtaaaaga ggctgtggac atactcaaga cagagcggct gggacacggc 720
taccacaccc tggaagacca ggccctttat aacaggctgc ggcaggaaaa catgcacttc 780
gagatctgcc cctggtccag ctacctcact ggtgcctgga agccggacac ggagcatgca 840
gtcattcggc tcaaaaatga ccaggctaac tactcgctca acacagatga cccgctcatc 900
ttcaagtcca ccctggacac tgattaccag atgaccaaac gggacatggg ctttactgaa 960
gaggagttta aaaggctgaa catcaatgcg gccaaatcta gtttcctccc agaagatgaa 1020
aagagggagc ttctcgacct gctctataaa gcctatggga tgccaccttc agcctctgca 1080
gggcagaacc tcaagcttca gcggggaaac ttcaggaacc agagaaaaac tgtgaagtgc 1140
ttcaattgcg gaaaggaggg ccacatcgct aagaactgcc gcgcccccag aaagaaaggc 1200
tgctggagat gcggcagaga gggccaccag atgaaggact gcacagagag acaggcaaac 1260
ttactcgagc accaccatca ccatcaccat cactaa 1296
<210> 9
<211> 24
<212> DNA
<213> 人工序列
<220>
<223> 从HindIII-ADA向前
<400> 9
cccaagcttg gcccagacgc ccgc 24
<210> 10
<211> 27
<212> DNA
<213> 人工序列
<220>
<223> 从ADA-XhoI反向
<400> 10
ccctcgagga ggttctgccc tgcagag 27
Claims (9)
1.缀合物,其包含:
包含SEQ ID NO:1的氨基酸序列的细胞穿透肽;以及如SEQ ID NO:2的氨基酸序列所示的腺苷脱氨酶。
2.多核苷酸,其编码权利要求1所述的缀合物。
3.重组载体,其包含权利要求2所述的多核苷酸。
4.宿主细胞,其包含权利要求3所述的重组载体。
5.用于产生缀合物的方法,所述方法包括以下步骤:
(a)在培养基中培养权利要求4所述的宿主细胞;以及
(b)从所述培养基中回收所述缀合物。
6.用于治疗重症联合免疫缺陷的药物组合物,所述药物组合物包含权利要求1所述的缀合物作为活性成分。
7.权利要求6所述的药物组合物,其中所述重症联合免疫缺陷是腺苷脱氨酶缺乏症。
8.用于治疗重症联合免疫缺陷的方法,所述方法包括将权利要求6所述的组合物施用于对象的步骤。
9.权利要求1所述的缀合物在制备用于治疗重症联合免疫缺陷的药物中的用途。
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PCT/KR2019/006847 WO2019240429A1 (ko) | 2018-06-14 | 2019-06-07 | 세포 투과 펩티드 및 아데노신 탈아미노화효소의 융합 단백질을 포함하는 중증복합면역결핍증 치료용 약학적 조성물 |
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EP (1) | EP3808842A4 (zh) |
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- 2019-06-07 EP EP19820313.5A patent/EP3808842A4/en not_active Withdrawn
- 2019-06-07 WO PCT/KR2019/006847 patent/WO2019240429A1/ko active Application Filing
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KR102083170B1 (ko) | 2020-03-02 |
EP3808842A1 (en) | 2021-04-21 |
US20210106662A1 (en) | 2021-04-15 |
WO2019240429A1 (ko) | 2019-12-19 |
EP3808842A4 (en) | 2022-11-23 |
KR20190141602A (ko) | 2019-12-24 |
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