CN113402590B - Khl多肽及其在制备tabp-eic细胞中的应用 - Google Patents
Khl多肽及其在制备tabp-eic细胞中的应用 Download PDFInfo
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Abstract
本发明提供了KHL多肽及其在制备TABP‑EIC细胞中的应用,另外本发明还提供了KHL多肽缀合物、包含KHL多肽的肿瘤抗原结合多肽、DNA分子、载体、宿主细胞和药物组合物。所述肿瘤抗原结合多肽由KHL多肽、跨膜结构域和/信号转导结构域组成。
Description
技术领域
本发明涉及生物技术领域,具体涉及一种KHL多肽及其在制备TABP-EIC细胞中的应用。
背景技术
肿瘤嵌合抗原受体(CAR)疗法,指的是一种新型精准靶向疗法,近几年通过优化改良在临床肿瘤治疗上取得很好的效果,是一种非常有前景的,有可能治愈癌症的新型肿瘤免疫治疗方法。通常,CAR通过基因工程技术,将免疫细胞激活,并装上定位导航装置CAR,将普通的T细胞、NK细胞对应地重组为CAR-T细胞、CAR-NK细胞,CAR-T细胞、CAR-NK细胞能够利用其嵌合的CAR,专门识别体内肿瘤细胞,并通过免疫作用释放大量的多种效应因子,能够高效地杀灭肿瘤细胞,从而达到治疗恶性肿瘤的目的。另外,将定位敲入CAR的免疫细胞移植回原患者身体内,可避开自身免疫系统的攻击难题。
自然杀伤(natural killer,缩写NK)细胞是非特异性免疫系统的重要组成部分,先天免疫系统反应的关键性介质细胞。NK细胞是一种广谱免疫细胞,具有快速发现和摧毁异常细胞(如癌症或病毒感染的细胞)的特异功能,而且不需要提前致敏或HLA配型,即可展示强大的溶解异常细胞的活性。但NK细胞数量较少,在外周血中仅占淋巴细胞的10%-15%,在脐带血中NK的含量更低,只有5%左右,正常人体外周血中和脐带血中NK细胞含量远远不能满足临床治疗的需要。NK细胞的数量和纯度是临床疗效的重要影响因素,NK细胞数量太少不能达到治疗的效果,纯度低则会影响对肿瘤的杀伤作用。
嵌合抗原受体(chimeric antigen receptor,缩写CAR)修饰的免疫细胞使用遗传工程手段修饰免疫细胞使其表达外源性抗肿瘤基因。CAR基因主要包括细胞外识别域和细胞内信号转导结构域:前者用于识别肿瘤表面特异性分子,后者用于启动识别肿瘤表面分子后的免疫细胞应答,发挥细胞毒作用。
经过CAR结构修饰后的NK细胞,能够高效的识别肿瘤细胞,并通过释放杀伤介质、诱导靶细胞凋亡等多种手段杀伤肿瘤细胞。但是现有技术制备CAR-NK细胞存在制备方法操作复杂,制备的细胞活性不够、数量少的问题。
本发明通过噬菌体展示技术筛选到了与肿瘤特异性结合效率更好的KHL多肽,并验证了该多肽的特异性。KHL多肽与可检测标记物结合后可用于癌症标记物PSMA的检测,KHL多肽制备成的TABP-EIC(Tumor Antigen Binding Peptide-Engineering ImmuneCell,肿瘤抗原结合肽-工程化免疫细胞)细胞可以精准靶向表达PSMA的细胞。
发明内容
本发明提供了一种与PSMA(前列腺特异性膜抗原)特异性结合的KHL多肽及其缀合物、肿瘤抗原结合肽、DNA分子、载体和宿主细胞。
多肽
一方面,本发明提供了一种与PSMA特异性结合的KHL多肽,所述KHL多肽选自以下任一一种:
1)SEQ ID NO:1所示的多肽;
2)将SEQ ID NO:1所示的多肽经过一个或多个(2个、3个、4个、5个、6个)氨基酸残基的取代、缺失或添加而形成的,且具有PSMA特异性结合功能的多肽;
3)与SEQ ID NO:1所示的多肽有90%以上的同源性的多肽,具体地,所述多肽与SEQ ID NO:1有90%,91%,92%,93%,94%,95%,96%,97%,98%,99%的同源性。
优选地,所述KHL多肽是SEQ ID NO:1所示的多肽。
优选地,所述KHL多肽可以包含一个或多个合成的氨基酸,所述合成的氨基酸在本领域是已知的,并且包括但不限于氨基环己羧酸、正亮氨酸、α-氨基n-癸酸、高丝氨酸、S-乙酰氨甲基-半胱氨酸、反式-3-和反式-4-羟脯氨酸、4-氨基苯丙氨酸、4-硝基苯丙氨酸、4-氯苯丙氨酸、4-羧基苯丙氨酸、β-苯基丝氨酸β-羟基苯丙氨酸、苯基甘氨酸、α-萘基丙氨酸、环己基丙氨酸、环己基甘氨酸、吲哚啉-2-羧酸、1,2,3,4-四氢异喹啉-3-羧酸、氨基丙二酸、氨基丙二酸单酰胺、N’-苯甲基-N’-甲基-赖氨酸、N’,N’-二苄基-赖氨酸、6-羟赖氨酸、鸟氨酸、α-氨基环戊烷羧酸、α-氨基环己羧酸、α-氨基环庚烷羧酸、α-(2-氨基-2-降莰烷)-羧酸、α,γ-二氨基丁酸、α,β-二氨基丙酸、高苯丙氨酸以及α-叔丁基甘氨酸。
缀合物
另一方面,本发明提供了一种与PSMA特异性结合的KHL多肽的缀合物。
优选地,所述KHL多肽的缀合物包括KHL多肽和可检测标记物。
优选地,所述可检测标记物包括荧光染料、荧光分子、化学发光标记物、染料分子、磷光分子、生物素、放射性同位素、在UV光谱中进行吸收的分子、在近红外辐射中能够进行吸收的分子或远红外辐射中能够进行吸收的分子中的一种或多种。
优选地,所述荧光染料包括但不限于罗丹明、对甲氨基酚、荧光素、硫代荧光素、氨基荧光素、羧基荧光素、氯代荧光素、甲基荧光素、磺基荧光素、氨基对甲氨基酚、羧基对甲氨基酚、氯代对甲氨基酚、甲基对甲氨基酚、磺基对甲氨基酚、氨基罗丹明、羧基罗丹明、氯代罗丹明、甲基罗丹明、磺基罗丹明、以及硫代罗丹明、菁、吲哚碳菁、氧杂碳菁、噻碳菁、部花青、菁染料(例如菁2、菁3、菁3.5、菁5、菁5.5、菁7)、噁二唑衍生物、吡啶基噁唑、硝基苯噁二唑、苯并硝基苯、芘衍生物、瀑布蓝、噁嗪衍生物、尼罗红、尼罗蓝、甲酚紫、噁嗪170、吖淀衍生物、前黄素、吖啶橙、吖啶黄、芳基甲川衍生物、金胺、噻吨染料、磺化噻吨染料、亚历克萨荧光(AlexaFluor)(例如亚历克萨荧光594、亚历克萨荧光633、亚历克萨荧光647、亚历克萨荧光700)、结晶紫、孔雀绿、四吡咯衍生物、卟啉、酞菁、胆红素、Cy5.5、吲哚菁绿(ICG)、DyLight750或IRdye800。
优选地,所述荧光分子包括但不限于FAM、FITC、VIC、JOE、TET、CY3、CY5、ROX、TexasRed或LC RED460。
优选地,所述化学发光标记物包括但不限于过氧化物酶、碱性磷酸酶、荧光素酶、水母发光蛋白、官能化的铁-卟啉衍生物、鲁米那、鲁米诺、异鲁米诺、吖啶酯、磺酰胺等。
优选地,所述荧光素酶包括但不限于长腹水蚤(Gaussia)荧光素酶、海肾(Renilla)荧光素酶、腰鞭毛虫荧光素酶、萤火虫荧光素酶、真菌荧光素酶、细菌荧光素酶和弯喉萤(vargula)荧光素酶。
优选地,所述可检测标记物是荧光分子;
优选地,所述荧光分子是FITC。
肿瘤抗原结合肽
另一方面,本发明提供了一种肿瘤抗原结合肽,所述肿瘤抗原结合肽包含与PSMA特异性结合的特异结合结构域。
优选地,所述特异结合结构域包括前述KHL多肽。
优选地,所述特异结合结构域是前述KHL多肽的多次重复。
优选地,所述多次是1-10次;具体地,1次、2次、3次、4次、5次、6次、7次、8次、9次、10次。
优选地,所述特异结合结构域是前述KHL多肽的3次重复。
优选地,所述KHL多肽的多次重复之间由linker连接。
优选地,所述linker是GS、GGS、GGGS。
优选地,所述linker是GGGS。
优选地,所述肿瘤抗原结合肽还包括铰链区、跨膜结构域和/或信号转导结构域;
优选地,所述铰链区包括CD8α铰链区、CD28铰链区、CD4铰链区、CD5铰链区、CD134铰链区、CD137铰链区、ICOS铰链区中的一种或多种的组合。
优选地,所述铰链区选用CD8α铰链区。
优选地,所述铰链区的氨基酸序列如SEQ ID NO:11所示。
优选地,所述铰链区的核酸序列如SEQ ID NO:12所示。
优选地,所述跨膜结构域包括蛋白质的跨膜结构域,所述蛋白质包括:2B4基因的跨膜区、T细胞受体的α、β或ζ链,CD28,CD3ε,CD45,CD4,CD5,CD8,CD9,CD16,CD22,CD33,CD37,CD64,CD80,CD86,CD123,CD134,CD137和CD154。
优选地,所述跨膜结构域选用2B4基因的跨膜区。
优选地,所述跨膜结构域的氨基酸序列如SEQ ID NO:2所示。
优选地,所述跨膜结构域的核酸序列如SEQ ID NO:7所示。
优选地,所述信号转导结构域包含共刺激结构域和/或初级信号传导结构域。
优选地,所述共刺激结构域包括2B4、CD3ζ、OX40、CD2、CD27、CD28、CDS、ICAM-1、LFA-1(CD11a/CD18)、ICOS(CD278)和4-1BB(CD137)的功能性信号传导结构域。
优选地,所述共刺激信号选用2B4基因的胞内信号传导结构。
优选地,所述共刺激信号的氨基酸序列如SEQ ID NO:3所示。
优选地,所述共刺激信号的核酸序列如SEQ ID NO:8所示;
优选地,所述初级信号传导结构域选用NKG2D基因的胞内信号传导结构;
优选地,所述初级信号传导结构域的氨基酸序列如SEQ ID NO:4所示。
优选地,所述初级信号传导结构域的核酸序列如SEQ ID NO:9所示。
优选地,所述肿瘤抗原结合肽的组成顺序为KHL多肽-跨膜结构域-共刺激结构域-初级信号传导结构域。
优选地,所述肿瘤抗原结合肽氨基酸序列是SEQ ID NO:5所示的第22-316位。
优选地,所述肿瘤抗原结合肽还可以与信号肽连接。
优选地,所述连接有信号肽的肿瘤抗原结合肽的氨基酸序列如SEQ ID NO:5所示。
DNA分子
另一方面,本发明提供了一种编码前述KHL多肽的DNA分子。
优选地,所述编码KHL多肽的DNA分子序列如SEQ ID NO:6所示。
另一方面,本发明提供了一种编码前述肿瘤抗原结合肽的DNA分子。
优选地,所述编码权利要求2所述的肿瘤抗原结合肽的DNA分子序列是SEQ ID NO:10的第64-948位。
优选地,所述肿瘤抗原结合肽还可以与信号肽连接。
优选地,所述与信号肽连接的肿瘤抗原结合肽的DNA分子序列如SEQ ID NO:10所示。
载体
另一方面,本发明提供了一种载体,所述载体包含前述编码多肽的DNA分子和/或前述编码肿瘤抗原结合肽的DNA分子。
优选地,所述载体包括质粒(表达质粒、克隆载体、小环、微载体、双微小染色体)、慢病毒载体、腺病毒载体或逆转录病毒载体。
优选地,所述慢病毒载体包括灵长类的重组慢病毒载体,即重组人免疫缺陷病毒载体(human immunodeficiency virus,HIV)或重组猴免疫缺陷病毒载体(simianimmunodeficiency virus,SIV)。
优选地,所述慢病毒载体包括非灵长类的重组慢病毒载体,即重组马感染性贫血病毒(equine infectious anemia virus,EIAV)、重组猫科免疫缺陷型病毒(felineimmunodeficiency virus,FIV)或重组羊关节炎脑炎病毒(caprine arthritis-encephalitis virus,CAEV)。
优选地,所述慢病毒载体包括以下:pLK0.1-puro、pLK0.1-CMV-tGFP、pLKO.1-puro-CMV-tGFP、pLK0.1-CMV-Neo、pLK0.1-Neo、pLKO.1-Neo-CMV-tGFP、pLKO.1-puro-CMV-TagCFP、pLKO.1-puro-CMV-TagYFP、pLKO.l-puro-CMV-TagRFP、pLKO.1-puro-CMV-TagFP635、pLKO.-puro-UbC-TurboGFP、pLKO.l-puro-UbC-TagFP635、pLKO-puro-IPTG-1xLacO、pLKO-puro-IPTG-3xLacO、pLPl、pLP2、pLP/VSV-G、pENTR/U6、pLenti6/BLOCK-iT-DEST、pLenti6-GW/U6-laminshrna、pcDNAl、2/V5-GW/lacZ、pLenti6.2/N-Lumio/V5-DEST、pGCSIL-GFP和Lenti6.2/N-Lumio/V5-GW/lacZ。
优选地,所述载体还包括一种或多种调控元件。
优选地,所述调控元件包含启动子、增强子、翻译起始的核糖体结合位点、终止子、多聚腺苷酸序列、筛选标记基因。
优选地,所述启动子是诱导型启动子、组成型启动子、组织特异性启动子、自杀型启动子或其任意组合。
宿主细胞
另一方面,本发明提供了一种宿主细胞,所述宿主细胞包含前述多肽、前述肿瘤抗原结合肽、前述编码KHL多肽的DNA分子、前述编码肿瘤抗原结合肽的DNA分子和前述载体中的一种或多种。
在一种实施方式中,宿主细胞包括大肠杆菌,链霉菌、农杆菌、酵母细胞、植物细胞、动物细胞或病毒中的一种或多种。
在一种实施方式中,所述病毒是慢病毒。
在一种实施方式中,所述动物细胞是人的细胞。
优选地,所述宿主细胞是免疫细胞。
优选地,所述免疫细胞包括T细胞、B细胞、K细胞和NK细胞中的一种或多种。
优选地,所述免疫细胞是NK细胞。
优选地,所述免疫细胞是自体或异体的。
优选地,所述免疫细胞是商品化的细胞系;优选地,所述细胞系包括NK-92、NKG、YT、NK-YS、HANK-1、YTS或NKL。
本发明具体实施例制备的所述宿主细胞称为TABP-EIC(Tumor Antigen BindingPeptide-Engineering Immune Cell,肿瘤抗原结合肽-工程化免疫细胞)。
药物组合物
另一方面,本发明提供了一种药物组合物,所述药物组合物包括前述多肽、前述肿瘤抗原结合肽、前述编码KHL多肽的DNA分子、前述编码肿瘤抗原结合肽的DNA分子、前述载体和前述宿主细胞中的一种或多种。
优选地,所述药物组合物可以为片剂(包括糖衣片剂,膜包衣片剂,舌下片剂,口腔崩解片,口腔片剂等等),丸剂,粉剂,颗粒剂,胶囊剂(包括软胶囊,微胶囊),锭剂,糖浆剂,液体,乳剂,混悬剂,控制释放制剂(例如,瞬时释放制剂,缓释制剂,缓释微囊),气雾剂,膜剂(例如,口服崩解膜剂,口腔粘膜-粘附膜剂),注射剂(例如,皮下注射,静脉注射,肌内射,腹膜内注射),静脉滴注剂,透皮吸收制剂,软膏剂,洗剂,粘附制剂,栓剂(例如,直肠栓剂,阴道栓剂),小药丸,鼻制剂,肺制剂(吸入剂),眼睛滴剂等等,口服或胃肠外制剂(例如,静脉内,肌内,皮下,器官内,鼻内,皮内,滴注,脑内,直肠内等给药形式,给药至肿瘤的附近和直接给药至病变处)。
优选地,所述药物组合物还包括任选地药学上可接受的免疫调节剂。
优选地,所述免疫调节剂可包括但不限于细胞因子、趋化因子、干细胞生长因子、淋巴毒素、造血因子、集落刺激因子(CSF)、红血球生成素、血小板生成素、肿瘤坏死因子-a(TNF)、TNF-i3、粒细胞-集落刺激因子(G-CSF)、粒细胞巨噬细胞-集落刺激因子(GM-CSF)、干扰素-α、干扰素-β、干扰素-γ、干扰素_λ、指定为“S1因子”的干细胞生长因子、人生长激素、N-甲硫氨酰基人生长激素、牛生长激素、甲状旁腺激素、甲状腺素、胰岛素、胰岛素原、松弛素、松弛素原、卵泡刺激激素(FSH)、甲状腺刺激激素(TSH)、促黄体生成激素(LH)、肝生长因子、前列腺素、纤维母细胞生长因子、促乳素、胎盘催乳素、OB蛋白、苗勒抑制物质(mullerian-inhibiting substance)、小鼠促性腺激素相关肽、抑制素、活化素、血管内皮生长因子、整联蛋白、NGF-β、血小板生长因子、TGF-a、TGF-f3、胰岛素样生长因子-1、胰岛素样生长因子-II、巨噬细胞43、IL-l、IL-la、IL-2、IL-3、IL-4、IL-5、IL-6、IL-7、IL-8、IL-9、IL-10、IL-11、IL-12、IL-13、IL-14、IL-15、IL-16、IL-17、IL-18、IL-21、IL-25、LIF、FLT-3、血管抑素、血栓反应素、内皮抑素或淋巴毒素。
方法
另一方面,本发明提供了一种制备前述宿主细胞的方法,所述方法包括将前述编码KHL多肽的DNA分子、前述编码肿瘤抗原结合肽的DNA分子或前述载体导入细胞中的步骤。
优选地,所述导入细胞的方法可以为基因枪法、电转法、病毒转导法或热激法。
优选地,所述病毒转导法包括制备重组慢病毒的步骤和重组慢病毒感染细胞的步骤。
优选地,所述重组慢病毒是将重组慢病毒载体转染慢病毒包装细胞,然后进行细胞培养后得到的;
另一方面,本发明提供了一种检测PSMA的方法,所述方法包括将前述KHL多肽的缀合物与待检测样品接触的步骤。
优选地,所述方法还包括处理样品的步骤。
优选地,所述检测是非诊断目的的。
优选地,所述待检测样品是疑似含有PSMA的样品。
试剂盒
另一方面,本发明提供了一种检测PSMA的试剂盒,所述试剂盒包括前述检测PSMA的方法使用到的试剂;
优选地,所述试剂盒还包括检测PSMA所需的仪器或装置。
应用
另一方面,本发明提供了前述多肽、肿瘤抗原结合肽、前述编码KHL多肽的DNA分子、前述编码肿瘤抗原结合肽的DNA分子或前述载体或前述宿主细胞在制备中前述药物组合物中的应用;
另一方面,本发明提供了前述多肽、肿瘤抗原结合肽、前述编码KHL多肽的DNA分子、前述编码肿瘤抗原结合肽的DNA分子或前述载体在制备前述宿主细胞中的应用;
另一方面,本发明提供了前述编码KHL多肽的DNA分子、前述编码肿瘤抗原结合肽的DNA分子在制备前述载体中的应用;
另一方面,本发明提供了权利要求1所述的多肽、权利要求2所述的肿瘤抗原结合肽、权利要求3所述的DNA分子、权利要求4所述的载体、权利要求5所述的宿主细胞或权利要求6所述的药物组合物在制备治疗癌症的药物中的应用;
优选地,所述癌症是前列腺癌;
另一方面,本发明提供了前述多肽、肿瘤抗原结合肽、前述编码KHL多肽的DNA分子、前述编码肿瘤抗原结合肽的DNA分子、前述载体或前述宿主细胞或前述药物组合物在制备诊断癌症的试剂盒中的应用。
优选地,所述癌症是前列腺癌。
优选地,所述诊断是检测的PSMA。
优选地,所述试剂盒是前述试剂盒。
一般定义:
除非另有定义,否则本文所用的技术和科学术语具有与所属领域的普通技术人员之一通常理解的相同的含义。
术语“多核苷酸”,“核酸”和“寡核苷酸”可互换使用,是指任何长度的核苷酸的聚合形式,即脱氧核糖核苷酸或核糖核苷酸或其类似物。多核苷酸可在聚合后进一步修饰,例如通过与标记组分缀合。该术语还指双链和单链分子。
如本文所用,术语“载体”是指包含完整复制子的非染色体核酸,使得当置于允许的细胞内时,载体可以被复制,例如通过转化过程。载体可以在一种细胞类型(例如细菌)中复制,但是在另一种细胞(例如哺乳动物细胞)中复制的能力有限。载体可以是病毒的或非病毒的。用于递送核酸的示例性非病毒载体包括裸露的DNA;和单独或与阳离子聚合物结合的与阳离子脂质复合的DNA;阴离子和阳离子脂质体;DNA-蛋白质复合物和包含与阳离子聚合物(如异质聚赖氨酸,定长寡肽和聚乙烯亚胺)缩合的DNA的颗粒,在某些情况下还包含在脂质体中;
如本文所用,术语“肽”,“多肽”和“蛋白质”可互换使用,并且是指具有通过以下方式共价连接的氨基酸残基的化合物:肽键。
术语“表达”或“表达”是指细胞中基因产物的产生。
附图说明
图1为多肽KHL与PSMA表达量较高的Lncap细胞系的免疫荧光结果。
图2为多肽KHL与PSMA表达量低的PC3细胞系的免疫荧光结果。
图3为第14天对小鼠进行荧光检测的图;A是空白对照,B是对照组,TABP-EIC-GTI细胞,C是实验组,TABP-EIC-KHL。
图4为第28天对小鼠进行荧光检测的图;A是空白对照,B是对照组,TABP-EIC-GTI细胞,C是实验组,TABP-EIC-KHL。
图5为第42天对小鼠进行荧光检测的图;A是空白对照,B是对照组,TABP-EIC-GTI细胞,C是实验组,TABP-EIC-KHL。
具体实施方式
下面结合实施例对本发明做进一步的说明,以下所述,仅是对本发明的较佳实施例而已,并非对本发明做其他形式的限制,任何熟悉本专业的技术人员可能利用上述揭示的技术内容加以变更为同等变化的等效实施例。凡是未脱离本发明方案内容,依据本发明的技术实质对以下实施例所做的任何简单修改或等同变化,均落在本发明的保护范围内。
实施例1、肽库筛选
1、实验目的
本发明采用Ph.D.-12噬菌体展示肽库试剂盒筛选出与PSMA特异性结合的多肽KHL。
2、Ph.D.-12噬菌体展示肽库试剂盒组成
随机十二肽噬菌体展示文库:100μL,1.5×1013pfu/mL,贮存于含50%甘油的TBS溶液中,复杂度~2.7×109个转化子;-28gIII测序引物:5’-HOGTATGGGATTTTGCTAAACAAC-3’,100pmol,1pmol/μL;-96gIII测序引物:5’-HOCCCTCATAGTTAGCGTAACG-3’,100pmol/μL,1pmol/μL;E.coli ER2738宿主菌F’lacIqΔ(lacZ)M15 proA+B+zzf::Tn10(TetR)/fhuA2supE thiΔ(lac-proAB)Δ(hsdMS-mcrB)5(rk–mk–McrBC–):该菌株以含50%甘油的菌体培养物形式提供,非感受态细胞,贮存于-70℃;链霉亲和素Streptavidin,冻干粉1.5mg;生物素:10mM 100μL。
3、实验方法
第一天
根据需要同时在其上进行文库淘选的靶分子的数量和种类不同,淘选试验在单个灭菌聚苯乙烯培养皿、12或24孔板、96孔微量板中进行,每种靶分子至少包被一个板(或一个孔),下述方法中给出的量是60×15mm培养皿的用量,括号中为微孔板的用量,其他中等尺寸的孔相应地调整此用量,但每种情况下,加入的噬菌体数量都是相同的:1.5×1011个病毒子;
(1)准备100μg/mL的靶分子溶液(溶于0.1M pH 8.6的NaHCO3),若需要稳定靶分子,也可使用其他相似离子强度的缓冲液(含金属离子等);
(2)每板(孔)加入1.5mL(微孔板每孔150μL)上述溶液,反复旋转直到表面完全湿润;
(3)在增湿容器(如:排列有湿纸巾的可封口塑料盒)中4℃轻微震荡,孵育过夜,平板在此容器中4℃贮存备用;
第二天
(4)挑ER2738单克隆(噬菌体滴度测定时铺的板)于10mL LB液体培养基中,如果同一天扩增洗脱的噬菌体,也可将ER2738接种于20mL LB液体培养基,用250mL三角瓶,37℃剧烈震荡培养;
(5)倒掉每板中的包被液,板倒置在干净的纸巾上用力拍甩以除去残余溶液,每板(或孔)加满封阻液,4℃作用至少1h;
(6)速洗板6次,每次均旋转以使板或孔的底部及边缘均被洗到,倾去缓冲液,倒置在干净纸巾上拍甩以除去残余溶液(或使用自动洗板机);
(7)用1mL(微孔板则用100μL)的TBST缓冲液稀释4×1010的噬菌体(即10μL的原始文库),然后加到已包被好的板上,室温温和摇动10-60min;
(8)倾倒除去未结合噬菌体,倒置板在干净的纸巾上拍甩除去残余溶液;
(9)按6中所述方法用TBST缓冲液洗板10次,每次换一干净纸巾以避免交叉污染;
(10)根据所研究的分子间相互作用,用1mL(微孔板则用100μL)适当的洗脱缓冲液洗脱结合的噬菌体,将靶分子的已知配体以0.1-1mM的浓度溶于TBS溶液中或者用游离靶分子溶液(~100μg/mL溶于TBS中)从固定靶分子上将结合的噬菌体竞争性洗脱下来,室温温和摇动10-60min,将洗脱液吸入另一干净微量离心管中;也可用非特异性缓冲液如0.2MGlycine-HCl(pH 2.2),1mg/mL BSA来分离已结合的分子:温和摇动>10min,洗脱液吸入另一干净微量离心管中,然后再用150μL(微量孔则用15μL)1M Tris-HCl(pH 9.1)中和上述洗脱液;
(11)按上述常规M13方法中的程序测定少量(~1μL)洗脱物的滴度,如需要,可对第一或第二轮洗脱物滴度测定所得的噬菌斑进行测序,方法见下述:必要时可将剩余洗脱物4℃贮存过夜,第二天扩增,这时,可将ER2738在LB-Tet培养基中过夜培养,第二天将培养物1:100稀释于20mL LB中(用250mL三角瓶盛装),加入未扩增洗脱物,37℃剧烈摇动培养4.5h,继续第13步;
(12)扩增剩余洗脱物:将洗脱物加入到20mL ER2738培养物中(菌体处于对数前期),37℃剧烈摇动培养4.5h;
(13)将培养物转入一离心管中,然后,4℃10,000rpm离心10min。上清液转入另一离心管中,再离心;
(14)将上清的上部80%转入一新鲜管中,加入1/6体积的PEG/NaCl,让噬菌体4℃沉淀至少60min,过夜;
第三天
(15)4℃10,000rpm离心PEG沉淀15min,倒掉上清液,再短暂离心,吸去残留上清液;
(16)沉淀物重悬于1mL TBS中,悬液转入微量离心管中,4℃离心5min使残余细胞沉淀;
(17)上清转入另一新鲜微量离心管,用1/6体积的PEG/NaCl再沉淀,冰上孵育15-60min,4℃离心10min,弃上清,再短暂离心,用微量移液器吸去残余上清;
(18)沉淀物重悬于200μL TBS,0.02%NaN3中,离心1min,沉淀任何残余的不溶物,上清转入新鲜管中,此即为扩增后的洗脱物;
(19)根据上述常规M13方法用LB/IPTG/Xgal平板滴定扩增后的洗脱物,4℃贮存;
(20)再包被一个板或孔准备第二轮淘选时用;
第四和第五天
(21)计数板上蓝斑数确定滴度,用这个值来计算相应于1-2×1011pfu的加入量;若滴度太低,接下来的几轮淘选可用低至109pfu的噬菌体加入量进行试验;
(22)进行第二轮淘选:用第一轮淘选扩增的洗脱物中1-2×1011pfu的噬菌体量重复步骤4-18,在清洗步骤中将Tween的浓度增至0.5%(v/v);
(23)在LB/IPTG/Xgal平板上测定第二轮淘选所得洗脱物扩增后的滴度;
(24)再包被一个板或孔准备第三轮淘选时用;
第六天
(25)进行第三轮淘选:用第二轮淘选扩增的洗脱物中2×1011pfu的噬菌体量重复步骤4-11,清洗步骤中同样用0.5%(v/v)的Tween;
(26)在LB/IPTG/Xgal平板上测定第三轮淘选所得洗脱物未扩增时的滴度,第三轮洗脱物不必再扩增,除非还要进行第四轮淘选,滴度测定时得到的噬菌斑可做测序用:只要注意平板培养时间不要超过18h,培养时间过长容易出现缺失,其余洗脱物4℃贮存;
(27)挑一ER2738单克隆于LB-Tet培养基中培养过夜。
4、实验结果
实验结果显示,筛选得到的与PSMA特异性结合的多肽KHL,其氨基酸序列为KHLHYHSSVRYG(SEQ ID NO:1)。
实施例2、KHL多肽特异性的验证
将KHL多肽分别与PSMA表达量较高的Lncap细胞系及PSMA表达量低的PC3细胞系进行免疫荧光检测,所用荧光标记物为FITC。
KHL多肽与Lncap细胞系的荧光检测如图1所示,KHL多肽与PC3细胞系的荧光检测如图2所示。
图1中,圆点中心是细胞核,圆点周围的浅色是KHL与细胞表面抗原PSMA结合而展现的荧光。图2中仅有细胞核的染色。KHL所标记的细胞表面荧光只在图1中出现,证明KHL与细胞表面抗原PSMA的结合具有很高的特异性。
实施例3、TABP-EIC-KHL对肿瘤的抑制作用验证
1、制备NK细胞
本专利涉及实验使用到的NK细胞均为来源于外周血单核细胞(PBMC)扩增获得。
2、肿瘤抗原结合肽表达载体的构建
肿瘤抗原结合肽结构序列均为基因合成获得(通用生物),表达载体为pLenti-EF1a-Backbone(NN)(addgene#27961)。肿瘤抗原结合肽结构插入酶切位点为BsiWI及EcoRI。
3、慢病毒包装
将TABP-EIC骨架载体及辅助载体pMD2.G(addgen#12259)、pMDLg/pRRE(addgene#12251)、pRSV-Rev(addgene#12253)按10:5:3:2比例混合,20ug质粒每10ml转染体系,转染293T细胞。转然后48小时、72小时收集上清,纯化浓缩后获得慢病毒。
4、慢病毒转导
将浓缩后的慢病毒与NK细胞按每100万细胞200ul纯化后慢病毒混合,之后置于37℃培养箱5%CO2条件培养,24小时后完全换液。
5、TABP-EIC-GTL细胞的扩增
将慢病毒感染后获得的TABP-EIC细胞正常培养扩增。
6、TABP-EIC-GTL细胞肿瘤抗原结合肽表达效率的检测
TABP-EIC细胞慢病毒感染后第七天取部分细胞提取基因组,进行RT-PCR检测。
7、实验结果
根据RT-PCR结果,按照公式感染效率(%)=63.21-6.36×△CT(检测组CT-对照组CT),一般需要感染效率超过20%方可使用。
肿瘤抗原结合肽结构中KHL序列可有多个重复,此处示例中为3个重复。所述肿瘤抗原结合肽的氨基酸序列如SEQ ID NO:5所示,所述肿瘤抗原结合肽的核酸序列如SEQ IDNO:10所示。
使用GFP标记的前列腺癌细胞株(Lncap-GFP)对小鼠腹腔成瘤,成瘤第14天时进行腹腔灌注,依次灌注空白对照(生理盐水)、对照组(TABP-EIC-GTI细胞)和TABP-EIC-KHL细胞,按500万细胞/只,每周进行一次腹腔灌注,持续3周。
第14、28和42天对小鼠进行荧光成像检测,观察肿瘤大小。
第14天荧光成像如图3所示,A是空白对照,B是对照组(TABP-EIC-GTI细胞),C是TABP-EIC-KHL。
第28天荧光成像如图4所示,A是空白对照,B是对照组(TABP-EIC-GTI细胞),C是TABP-EIC-KHL。
第42天荧光成像如图5所示,A是空白对照,B是对照组(TABP-EIC-GTI细胞),C是TABP-EIC-KHL。
本实验证明TABP-EIC-GTL和TABP-EIC-KHL细胞均对肿瘤有明显的抑制作用,且TABP-EIC-KHL治疗效果更优。
序列表
<110> 呈诺再生医学科技(珠海横琴新区)有限公司
<120> KHL多肽及其在制备TABP-EIC细胞中的应用
<141> 2021-07-14
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Claims (17)
1.一种肿瘤抗原结合肽,所述肿瘤抗原结合肽的氨基酸序列如SEQ ID NO:5所示。
2.一种DNA分子,其特征在于,所述DNA分子编码权利要求1所述的肿瘤抗原结合肽。
3.如权利要求2所述的DNA分子,其特征在于,所述DNA分子的核苷酸序列如SEQ ID NO:10所示。
4.一种载体,其特征在于,所述载体包含权利要求2所述的DNA分子。
5.如权利要求4所述的载体,其特征在于,所述载体包括质粒、慢病毒载体、腺病毒载体或逆转录病毒载体。
6.如权利要求4所述的载体,其特征在于,所述载体还包括一种或多种调控元件。
7.一种宿主细胞,其特征在于,所述宿主细胞包含权利要求1所述的肿瘤抗原结合肽、权利要求2所述的DNA分子和权利要求4所述的载体中的一种或多种。
8.如权利要求7所述的宿主细胞,其特征在于,所述宿主细胞包括大肠杆菌,链霉菌、农杆菌、酵母细胞、植物细胞、动物细胞或病毒。
9.如权利要求8所述的宿主细胞,其特征在于,所述病毒是慢病毒。
10.如权利要求8所述的宿主细胞,其特征在于,所述动物细胞是人免疫细胞。
11.如权利要求10所述的宿主细胞,其特征在于,所述人免疫细胞是NK细胞。
12.一种药物组合物,其特征在于,所述药物组合物包含权利要求1所述的肿瘤抗原结合肽、权利要求2所述的DNA分子和权利要求4所述的载体和权利要求7所述的宿主细胞中的一种或多种。
13.如权利要求12所述的药物组合物,其特征在于,所述药物组合物还包括药学上可接受的免疫调节剂。
14.一种制备权利要求7所述的宿主细胞的方法,其特征在于,所述方法包括将权利要求2所述的DNA分子和权利要求4所述的载体中的一种或多种导入宿主细胞中的步骤。
15.如权利要求14所述的方法,其特征在于,所述导入宿主细胞的方法包括基因枪法、电转法、病毒转导法或热激法。
16.权利要求1所述的肿瘤抗原结合肽、权利要求2或3所述的DNA分子、权利要求4-6任一所述的载体、权利要求7-11任一所述的宿主细胞或权利要求12或13所述的药物组合物在制备治疗前列腺癌的药物中的应用。
17.氨基酸序列如SEQ ID NO:1所示的KHL多肽在制备诊断前列腺癌的试剂盒中的应用。
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