CN110997903B - 用于癌症治疗的t细胞的活化方法 - Google Patents
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Abstract
本发明涉及由如SEQ ID NO:1‑184任一所示的代表的癌症特异性肿瘤抗原新表位,一种装载有新表位的抗原呈递细胞,以及一种使用该抗原呈递细胞活化用于癌症治疗的T细胞的方法。装载有本发明提供的癌症特异性肿瘤抗原表位的抗原呈递细胞,即树突状细胞,能够快速有效地诱导癌抗原特异性T细胞,优选记忆性T细胞的分化和增殖。如此活化的记忆T细胞可以治疗癌性或肿瘤性疾病或预防癌症的复发、发展、或转移,同时避免癌细胞的防御机制。
Description
技术领域
本发明涉及癌症特异性肿瘤抗原新表位,装载有该新表位的抗原呈递细胞,以及使用该抗原呈递细胞进行癌症治疗的T细胞的活化方法。
背景技术
在世界上,尤其在亚洲,胃癌被认为是高发性恶性肿瘤。已知有多种导致胃癌发展的病因。然而,胃癌通常可分为因爱泼斯坦巴尔病毒(EBV)感染引起的EBV相关性胃癌,和因胃肠道细胞中基因突变积累而引起的胃癌细胞抗原相关性胃癌。对于当前的胃癌治疗,一直以来最有效的是切除癌组织,而化学疗法和放射疗法也有施行。然而,似乎未及早发现的胃癌是一种难以治愈的疾病。另外,尽管几种生物试剂(抗体、小分子)已经进行了临床试验,但是具有良好临床效果的治疗试剂尚未报道。
近来,多个机构已经研究,使用源自患者的自体T细胞的癌细胞特异性靶向疗法,并且多个机构已经使用嵌合抗原受体(CAR)T细胞进行了淋巴瘤的临床试验。结果,由于优良临床效果和低副作用,这种治疗作为抗癌治疗的新领域引起了广泛的关注。
使用患者来源的T细胞会减少免疫应答的诱导,且消除对供体HLA类型的限制,而诱导免疫应答是细胞治疗试剂的最大副作用。因此,这种T细胞被认为是有效的且没有副作用的治疗试剂。迄今为止,CD8+T细胞、CD4+T细胞、NK细胞、树突状细胞和CAR T细胞被认为是在抗癌治疗领域中最广泛使用的细胞治疗试剂类型。NK细胞具有杀伤细胞的功效,由于不具有抗原特异性而具有多种副作用。树突状细胞是疫苗概念的治疗试剂,因为它们不具有直接杀死细胞的功能,并且能够将抗原特异性传递给患者体内的T细胞,从而将癌细胞特异性高效地赋予T细胞。另外,CD4+T细胞通过抗原特异性而起到帮助其他细胞的作用,而CD8+T细胞被认为具有最佳的抗原特异性和细胞杀伤作用。
然而,迄今为止已经使用或开发的大多数细胞治疗试剂具有局限性,故没有临床效果。考虑到这些局限性,癌细胞本身会分泌抑制人体免疫反应的物质,或者不提供产生针对此类癌细胞的抗体所必需的抗原,从而阻止发生适当的免疫反应。
同时,树突状细胞不仅充当检测来自人体外部或内部产生的抗原的监视者,而且还通过这种经识别和吸收的抗原迅速转运至次级淋巴器官,从而充当专门的抗原呈递细胞,所述抗原呈递细胞指将抗原呈递给与抗原反应的免疫细胞,包括T细胞。已经通过几种方法开发了使用树突状细胞的抗癌免疫治疗疫苗,其可以大致分为离体产生的树突状细胞疫苗和体内树突状细胞疫苗。体内树突状细胞疫苗通过将抗原直接递送至体内存在的树突状细胞的方式起作用。另外,使用离体产生的树突状细胞疫苗的方法是:从患者的PBMC中分离树突状细胞,将要呈递的抗原递送至分离的树突状细胞,树突状细胞被其活化随后注射回患者体内,如此抗原从注射的树突状细胞传递到T细胞。在后者中,离体树突状细胞培养方法和抗原递送方法很重要,当前使用的抗原呈递方法包括:使用病毒或核转染或靶向树突状细胞的抗原递送的方法转染待呈递的抗原的DNA,其中抗原与靶向树突状细胞的抗体结合。
目前,树突状细胞疫苗的最大问题是体内出现严重的慢性炎症现象和瓦博格效应,并且在免疫抑制性细胞因子、免疫抑制性T细胞、树突状细胞等存在的癌症微环境下很难有效活化抗癌免疫细胞。
技术问题
本发明的一个目的是提供一种爱泼斯坦-巴尔病毒(EBV)阳性的癌症特异性肿瘤抗原新表位,以及用于活化含有该表位的T细胞的组合物。
本发明的另一个目的是提供一种装载有本发明的新表位的抗原呈递细胞,所述抗原呈递细胞能够活化T细胞以用于癌症治疗。
本发明的又一个目的是提供一种T细胞,所述T细胞由装载有本发明的新表位的抗原呈递细胞活化。
本发明的又一个目的是提供一种用于癌症治疗的T细胞的活化方法。
然而,本发明要解决的技术问题不限于上述问题,并且本领域技术人员将从以下描述中清楚地理解未提及的其他问题。
解决问题
根据本发明的一个实施方案,提供了一种癌症特异性肿瘤抗原表位。
在本发明中,“癌症特异性肿瘤抗原表位”衍生自仅存在于癌细胞中而不存在于正常细胞中的蛋白质抗原。在本发明中,所述癌症特异性肿瘤抗原表位包括至少一种被T细胞受体识别的表位;并且该表位可以优选地包括存在于爱泼斯坦-巴尔病毒(EBV)阳性癌细胞的表位,包括EBV病毒表位或癌细胞表位,且可以更优选地为爱泼斯坦-巴尔病毒(EBV)阳性癌细胞抗原,即爱泼斯坦巴尔病毒潜伏膜蛋白2(LMP2a)、或爱泼斯坦巴尔核抗原1(EBNA-1)、或其新表位。
在本发明中,“爱泼斯坦巴尔病毒潜伏膜蛋白2(LMP2a)”是在所有II型和III型疾病/恶性肿瘤中表达的几种EBV基因之一。对应于跨膜蛋白,LMP2a充当B细胞受体信号转导的负调节剂,并通过螯合酪氨酸激酶促进细胞存活。HLA-A2限制性肽是表位特异性的细胞毒性T淋巴细胞,可在60%至75%的个体中离体检测到,并且是潜伏疾病中免疫显性最强的LMP表位。CLGGLLTMV肽一直被认为是NPC和HL治疗的潜在靶标,因为该表位在NPC和HL患者的活检组织中保守,且其与其他EBV潜伏表位一样免疫功能弱。
在本发明中,“爱泼斯坦-巴尔核抗原1(EBNA-1)”对应于与爱泼斯坦-巴尔病毒相关的多功能二聚体病毒蛋白。这对应于一种EBV蛋白,所述EBV蛋白仅见于所有与EBV相关的恶性肿瘤中。这在维持细胞感染EBV时的变化状态中起着重要作用。另一方面,EBNA-1对应于甘氨酸-丙氨酸重复序列,所述甘氨酸-丙氨酸重复序列将蛋白质分为氨基和羧基末端结构域。该序列起到稳定蛋白质、防止蛋白酶体降解、减弱抗原加工和MHC I类限制性抗原呈递的作用。因此,EBNA-1抑制了针对病毒感染细胞的CD8限制性细胞毒性T细胞反应。EBNA-1在所有潜伏期程序中由Qp启动子表达,并且对应于在潜伏期程序I中唯一表达的病毒蛋白。
在本发明中,“新表位”是指在诸如正常、非癌细胞或种系细胞之类的参照物中不存在而在癌细胞中存在的表位。
在本发明中,所述新表位可以与HLA-A、HLA-B、HLA-C、HLA-E、HLA-F、HLA-G、β2-微球蛋白、HLA-DPA1、HLA-F、DPB1、HLA-DQA1、HLA-DQB1、HLA-DRA1、HLA-DRB1、HLA-DRB3、HLA-DRB4、HLA-DRB5、HLA-DM、HLA-DOA和HLA-DOB位点中的至少一种表现出结合亲和力,因此自人血中提取的T细胞,优选是记忆T细胞可具有功效。其中,所述新表位可以包括与韩国人表达最高的至少一种HLA类型具有高结合亲和力的表位,例如HLA-A*2402、HLA-A*A0201、HLA-A*3303、HLA-A*1101、HLA-A*0206、HLA-A*3101、HLA-B*5101、HLA-B*4403、HLA-B*5401、HLA-B*5801、和HLA-B*3501。
优选地,在本发明中,所述新表位与HLA-A*2402具有高结合亲和力,并且可包括LMP2a抗原的新表位,所述LMP2a抗原是由SEQ ID NOs:1至151中任一所示的肽;或对HLA-A*3101具有高结合亲和力,并且可以包括EBNA-1抗原的新表位,该抗原是由SEQ ID NO:152至184中任一所示的肽。
这里,在本发明中,对于检测新表位-HLA亲和力的方法,可以使用NetMHC 3.4(URL:www.cbs.dtu.dk/services/NetMHC-3.4/)来预测新表位是否结合特定的HLA等位基因。然而,本发明不限于此。
在本发明中,“HLA”或“人白细胞抗原”是指在负责调节免疫系统的细胞表面上编码主要组织相容性复合体(MHC)蛋白的人基因。“HLA-1”或“HLA I类”是指人类MHC I类基因,包括HLA-A、HLA-B、HLA-C、HLA-E、HLA-F、HLA-G、和β2-微球蛋白位点。“HLA-II”或“HLAII类”是指人类MHC II类基因,包括HLA-DPA1、HLA-DPB1、HLA-DQA1、HLA-DQB1、HLA-DRA1、HLA-DRB1、HLA-DRB3、HLA-DRB4、HLA-DRB5、HLA-DM、HLA-DOA、和HLA-DOB位点。
在本发明中,所述癌症可以是爱泼斯坦-巴尔病毒(EBV)阳性癌症,包括EBV阳性胃癌、EBV阳性子宫颈癌、EBV阳性伯基特氏淋巴瘤、EBV阳性T细胞淋巴瘤、EBV阳性乳腺癌、EBV阳性平滑肌肉瘤、EBV阳性平滑肌瘤、EBV阳性霍奇金淋巴瘤、EBV阳性鼻咽癌、或EBV阳性移植后淋巴组织增生性疾病(PTLD),其中优选为EBV阳性胃癌。
根据本发明的另一个实施方案,提供了一种核酸分子,所述核酸分子编码本发明提供的一种癌症特异性肿瘤抗原表位,优选为新表位LMP2a或EBNA-1,所述EBNA-1为爱泼斯坦-巴尔病毒(EBV)阳性癌细胞的抗原。
本发明的核酸分子包括获得的任何核酸分子,所述核酸分子指如本领域技术人员已知的将本发明提供的多肽的氨基酸序列转化为多核苷酸序列。因此,由于开放阅读框(ORF),可以制备各种多核苷酸序列,所有这些也都包括在本发明的核酸分子中。
根据本发明的又一个实施方案,提供了一种表达载体,所述表达载体中插入本发明中提供的分离的核酸分子。
在本发明中,“载体”是能够转运与其连接的另一核酸的核酸分子。一类载体是“质粒”,其是指其中可以连接另外的DNA区段的环状双链DNA。另一类载体是噬菌体载体。另一类载体是病毒载体,外源DNA片段可以连接到所述病毒基因组中。某些载体能够在引入它们的宿主细胞中自主复制(例如,具有细菌复制起点的细菌载体和游离型哺乳动物载体)。其他载体(例如,非游离型哺乳动物载体)能够在导入宿主细胞后整合到宿主细胞的基因组中,并因此与宿主基因组一起复制。另外,某些载体能够指导与其可操作连接的基因的表达。在本文中,此类载体称为“重组表达载体”或简称为“表达载体”。通常,可用于重组DNA技术的表达载体通常为质粒形式。在本说明书中,“质粒”和“载体”可以互换使用,因为质粒是载体中最常用的形式。
本发明中表达载体的具体实施方案可以选自但不限于商业上广泛使用的pCDNA载体,F、R1、RP1、Col、pBR322、ToL、Ti载体,粘粒,噬菌体如λ、λ字形、M13、Mu、p1、P22、Qμ、T-even、T2、T3、T7噬菌体,植物病毒。本领域技术人员已知的,任何表达载体均可用于本发明,并且根据靶宿主细胞的性质选择表达载体。可通过磷酸钙转染、病毒感染、DEAE-葡聚糖介导的转染、脂质转染胺转染或电穿孔法,将载体引入宿主细胞。然而,本发明不限于此,并且本领域技术人员可以采用和使用适合于所使用的表达载体和宿主细胞的引入方法。所述载体可优选包含至少一种选择标记。然而,本发明不限于此,并且可以使用不包含选择标记的载体,而根据是否产生产物来进行筛选。根据靶宿主细胞决定选择标记,这是通过本领域技术人员已知的方法完成,因此本发明不限于此。
在表达载体中可以插入并融合一段标签序列,以助于本发明的核酸分子的纯化。所述标签包括但不限于6-组氨酸标签、血凝素标签、myc标签、或flag标签,并且本领域技术人员已知的有助于纯化的任何标签可以用于本发明。
根据本发明的另一个实施方案,提供了一种用本发明提供的表达载体转染的宿主细胞。
在本发明中,“宿主细胞”包括细胞或细胞培养物,所述细胞或细胞培养物可以是或已经是载体的接受者,用于掺入多肽插入物。所述宿主细胞包括单个宿主细胞的后代,并且由于自然、偶然或有意的突变,所述后代不一定(在形态上或在基因组上)与原始亲代细胞完全相同。所述宿主细胞包括用本文发明的多核苷酸体内转染的细胞。
在本发明中,所述宿主细胞可以包括哺乳动物、植物、昆虫、真菌、或细胞来源的细胞,并且可以是如细菌细胞,例如大肠杆菌、链霉菌、鼠伤寒沙门氏菌;真菌细胞,例如酵母细胞、和巴斯德毕赤酵母;昆虫细胞,如果蝇、和斜纹夜蛾Sf9细胞;动物细胞,例如中国仓鼠卵巢(CHO)细胞、SP2/0(小鼠骨髓瘤)、人淋巴母细胞、COS、NSO(小鼠骨髓瘤)、293T、Bowes黑色素瘤细胞、HT-1080、仓鼠肾(BHK)细胞、人类胚胎肾(HEK)细胞、或PERC.6(人类视网膜细胞);或植物细胞。然而,宿主细胞不限于此,并且本领域技术人员已知的可以用作宿主细胞的任何细胞都是可用的。
根据本发明的又一个实施方案,提供了一种用于活化T细胞的组合物,其包含本发明提供的癌症特异性肿瘤抗原表位,编码该表位的核酸分子,插入该核酸分子的表达载体,或该表达载体转化的宿主细胞。
如本文所用,术语“T细胞的活化”是指具有T细胞受体的单克隆(例如,编码相同的TCR)或多克隆(例如,具有编码不同TCR的克隆)的T细胞群识别至少一种肿瘤抗原肽。活化的T细胞可包括一种或多种T细胞亚型,包括但不限于,一种或多种选自细胞毒性T细胞、辅助性T细胞、天然杀伤性T细胞、γδT细胞、调节性T细胞、记忆T细胞,其中优选记忆T细胞。
在本发明中,活化的T细胞可以治疗癌性或肿瘤性疾病,或预防癌症的复发、发展或转移,同时避开了癌细胞的防御机制。
根据本发明的又一个实施方案,可提供一种载有本发明提供的癌症特异性肿瘤抗原表位的抗原呈递细胞(APC)。
在本发明中,所述抗原呈递细胞可以包括树突状细胞(DC)、B细胞、和巨噬细胞中的至少一种,优选树突状细胞。
在本发明中,“树突状细胞”是指在淋巴组织或非淋巴组织中发现的多种形态相似的细胞群中的任一种。这些细胞的特征在于独特的形态,和高表达水平的表面MHCI类和II类分子,所述MHCI类和II类分子是向T细胞呈递抗原肽的蛋白质。DC、其他APC、和T细胞可以分离或衍生(例如分化)自多种组织来源,方便地来自外周血,例如衍生自外周血的外周血单核细胞(PBMC)。
在本发明中,所述抗原呈递细胞可以诱导癌症抗原特异性T细胞,优选记忆性T细胞的分化和增殖,从而治疗癌性或肿瘤性疾病或预防癌症的复发、发展或转移,同时避免癌细胞的防御机制。
根据本发明的又一个实施方案,提供了一种融合蛋白,其包括:本发明提供的癌症特异性肿瘤抗原表位,和树突状细胞特异性抗体或其片段。
本发明提供的融合蛋白使得本发明提供的癌症特异性肿瘤抗原表位能够装载在树突状细胞上。
在本发明中,所述树突状细胞特异性抗体可以包括但不限于位于树突状细胞上的对DCIR、MHC I类、MHC II类、CD1、CD2、CD3、CD4、CD8、CD11b、CD14、CD15、CD16、CD19、CD20、CD29、CD31、CD40、CD43、CD44、CD45、CD54、CD56、CD57、CD58、CD83、CD86、CMRF-44、CMRF-56、DCIR、DC-ASPGR、CLEC-6、CD40、BDCA-2、MARCO、DEC-205、Clec9A、33D1、甘露糖受体、朗格汉斯蛋白(Langerin)、DECTIN-1、B7-1、B7-2、IFN-γ受体、IL-2受体、ICAM-1、Fcγ受体、LOX-1、或ASPGR具有特异性的抗体。
本发明的融合蛋白中的癌症特异性肿瘤抗原表位可以与树突状细胞特异性抗体或其片段缀合。在此,术语“缀合物”是指通过将两个部分结合在一起而形成的任何材料。根据本发明的一种代表性缀合物包括通过将抗原与抗体和TLR激动剂连接在一起而形成的缀合物。术语“缀合”是指形成缀合物的过程,并且通常表示物理偶联,例如共价键、配位共价键、或第二结合力,例如范德华结合力。抗原与抗体的连接过程也可以通过非共价结合,例如锚定蛋白-凝聚素(dockerin-cohesin)结合(如美国专利公开号20100135994,Banchereau等人的相关部分所述,通过引用并入本文),或形成肽或化学键的直接通过化学键。
根据本发明的另一个实施方案,提供了一种生产抗原呈递细胞的方法,其中所述抗原呈递细胞装载有本发明提供的癌症特异性肿瘤抗原表位。
在本发明中,所述抗原呈递细胞可包括树突状细胞、B细胞、和巨噬细胞中的一种或多种,优选树突状细胞。
在本发明中,所述树突状细胞(例如未成熟树突状细胞)可以从多种来源获得,包括自体来源,即衍生自目标个体。所述树突状细胞可优选获自来源于外周血的外周血单核细胞(PBMC),并且更优选地通过从个体来源的PBMC中分离单核细胞并使单核细胞与多种细胞因子接触而获得。在此,对诱导单核细胞向树突状细胞分化的细胞因子的种类没有特别限制,可以包括例如GM-CSF和IL-4中的一种或多种。
在本发明中,“目标个体”是指患有癌症或处于癌症高风险中的个体。
在本发明中,一旦如上所述制备了抗原呈递细胞,就可以在抗原呈递细胞中装载本发明的癌症特异性肿瘤抗原表位。通常,未成熟的树突状细胞通过吞噬作用或受体介导的内吞作用捕获抗原,通过一系列细胞内过程加工抗原,然后使抗原肽装载在MHC上并呈递给T淋巴细胞。随着加工抗原的过程,所述树突状细胞变得更加成熟,使它们失去用于吞噬和内吞作用的受体,表现出MHC I、II类分子、共刺激分子、和粘附分子表达增加,并表达新的趋化因子受体。这使得所述树突状细胞迁移到周围淋巴结的T淋巴细胞富集区域,并将抗原呈递给T淋巴细胞,从而引起T淋巴细胞免疫应答。
在本发明的一个实施方案中,为了使癌症特异性肿瘤抗原表位装载在抗原呈递细胞上,抗原呈递细胞可接触本发明的癌症特异性肿瘤抗原表位,优选地脉冲化接触本发明的癌症特异性肿瘤抗原表位,可制备所述抗原呈递细胞,例如未成熟树突状细胞,或包含在或衍生于(例如分化)自PBMC的抗原呈递细胞(例如树突状细胞)。如本领域中已知的,脉冲化是指将诸如树突状细胞的细胞与含有本发明的癌症特异性肿瘤抗原表位肽的溶液混合,然后任选地从混合物中除去癌症特异性肿瘤抗原表位肽。在本发明中,当使未成熟树突状细胞与癌症特异性肿瘤抗原表位接触时,可以进行toll样受体激动剂处理,以进一步诱导未成熟树突状细胞群的成熟。此处,示例性的TLR激动剂包括但不限于polyIC、MALP、和R848。
在本发明的另一个实施方案中,为了将癌症特异性肿瘤抗原表位装载在抗原呈递细胞上,可以用表达载体优选质粒对抗原呈递细胞进行核转染,插入编码癌症特异性肿瘤抗原表位的核酸分子中。在此,可以通过本领域中任何有用的手段来进行核转染,包括例如核转染系统或/>核转染系统。
在本发明的又一个实施方案中,为了将癌症特异性肿瘤抗原表位装载在抗原呈递细胞上,可以使用包含本发明提供的癌症特异性肿瘤抗原表位的融合蛋白,及树突状细胞特异性抗体或其片段,来进行这种装载。
根据本发明的又一个实施方案,提供了一种由本发明提供的抗原呈递细胞活化的T细胞。
在本发明中,所述T细胞是指具有识别肿瘤抗原肽的T细胞受体的单克隆(例如,编码相同的TCR)或多克隆(例如,具有编码不同TCR的克隆)的T细胞群。可包括一种或多种T细胞亚型,包括但不限于选自细胞毒性T细胞、辅助性T细胞、天然杀伤性T细胞、γδT细胞、调节性T细胞、和记忆性T细胞的一种或多种,优选记忆T细胞。
在本发明中,“记忆T细胞”是先前已经遇到并对其特异抗原作出反应的T细胞,或者是已经自活化T细胞分化的T细胞。尽管肿瘤特异性记忆T细胞仅占总T细胞数量的一小部分,但其在人整个生命周期中对监视肿瘤细胞起着重要的作用。在肿瘤特异性记忆T细胞遇到表达其特异性肿瘤抗原的肿瘤细胞的情况下,记忆T细胞立即被活化并克隆扩增。所述活化和扩增的T细胞分化成效应T细胞,以高效杀死肿瘤细胞。记忆T细胞对于建立和维持T细胞的长期肿瘤抗原特异性应答很重要。在本发明中,活化的T细胞,优选地活化的记忆T细胞,特异性地识别癌细胞上的抗原,从而这种T细胞可以治疗癌性或赘生性疾病或预防癌症的复发、发展或转移,同时避免了癌细胞的防御机制。
根据本发明的又一个实施方案,提供了一种使用本发明提供的抗原呈递细胞(APC)活化T细胞的方法。
在本发明中,为了活化T细胞,可以将T细胞与装载有本发明的癌症特异性肿瘤抗原表位的抗原呈递细胞共培养。
在本发明中,所述T细胞可以从各种来源获得包括自体来源,即源于目标个体,优选可自来源于外周血的外周血单核细胞(PBMC),并且更优选地可来自外周血单核细胞的非粘附部分。在本发明的一个实施方案中,所述PBMC的非粘附部分可以通过外周血样品的密度梯度离心来获得,或者可以通过用至少一种细胞因子(例如IL-2)在存在或不存在抗CD3抗体(例如OKT3)培养物中进行培养而获得。
在本发明中,所述T细胞是指具有识别肿瘤抗原肽的T细胞受体的单克隆(例如,编码相同的TCR)或多克隆(例如,具有编码不同TCR的克隆)的T细胞群。可包括一种或多种T细胞亚型,包括但不限于选自细胞毒性T细胞、辅助性T细胞、天然杀伤性T细胞、γδT细胞、调节性T细胞、和记忆性T细胞的一种或多种,优选记忆T细胞。
另外,在本发明中,所述T细胞和抗原呈递细胞可以来自同一个体,例如患有癌症,优选EBV阳性癌症(例如,低至中度癌症)的个体。然而,本发明不限于此。
在本发明中,为了活化T细胞,可以将T细胞与本发明的抗原呈递细胞共培养1、2、3、4、6、8、10、12、14、16、18、20、22、24、26、28、或30天的任何一个或多个时间段,优选1到21天、1到14天、2到10天、2到5天、2到5天、3天、5天、7天、10天、14天、16天、18天、或21天。然而,本发明不限于此。
在本发明中,在所述T细胞与本发明的抗原呈递细胞的共培养过程中,可以添加一种或多种细胞因子来启动T细胞,从而促进T细胞的活化、成熟和/或增殖,所述T细胞随后分化为记忆T细胞。该阶段可以使用的示例性细胞因子包括但不限于白介素2(IL-2)、白介素4(IL-4)、白介素7(IL-7)、白介素15(IL-15)、白介素21(IL-21)、或其组合等。
另外,在本发明中,在T细胞与本发明的抗原呈递细胞的共培养过程中,可以添加包含细胞因子和免疫球蛋白重链恒定区的融合蛋白来启动T细胞,从而促进T细胞的活化、成熟和/或增殖,所述T细胞随后分化为记忆T细胞。在此,所述细胞因子可包括但不限于干扰素-γ(IFN-γ)、白介素-2(IL-2)、白介素-4(IL-4)、白介素-12(IL-12)、IL-18、和肿瘤坏死因子(TNF)、或粒细胞巨噬细胞集落刺激因子(GMCSF)。所述免疫球蛋白重链恒定区也可以是但不限于免疫球蛋白铰链区和免疫球蛋白重链恒定区,所述免疫球蛋白重链恒定区任选地选自CH2结构域、CH3结构域、和CH4结构域、或其组合。另外,所述免疫球蛋白重链恒定区可衍生自属于本领域称为免疫球蛋白的IgA(Igα)、IgD(Igδ)、IgE(Igε)、IgG(Igγ)、和IgM(Igμ)之一,并且可以优选是衍生自IgG类的免疫球蛋白重链恒定区。
另外,在本发明中,在T细胞与本发明的抗原呈递细胞的共培养过程中,含有与在记忆T细胞中高表达的细胞表面蛋白结合的配体的融合蛋白,以及免疫球蛋白重链恒定区可以添加,以启动T细胞,从而促进T细胞的活化、成熟和/或增殖,所述T细胞随后分化为记忆T细胞。在此,在记忆T细胞中高表达的细胞表面蛋白可以是CD27、CXCR3、或CD62L。能够结合CD27的配体可以是CD70,能够结合CXCR3的配体可以是CXCR9或CXCR10,能够结合CD62L的配体可以是GlyCAM-1、CD34、MadCAM-1、或PSGL-1。然而,本发明不限于此。另外,所述免疫球蛋白重链恒定区可衍生自属于本领域称为免疫球蛋白的IgA(Igα)、IgD(Igδ)、IgE(Igε)、IgG(Igγ)、和IgM(Igμ)之一,并且可以优选是衍生自IgG类的免疫球蛋白重链恒定区。
根据本发明的又一个实施方案,提供了一种免疫治疗试剂,所述免疫治疗试剂包含作为活性成分的装载有本发明提供的癌症特异性肿瘤抗原表位的抗原呈递细胞。根据本发明的免疫治疗试剂可以增加免疫反应,或可以选择性地增加治疗或预防某些疾病例如癌症所需的一些免疫反应。
根据本发明的又一个实施方案,提供了一种用于预防或治疗癌症的抗癌疫苗或药物组合物,其包含作为活性成分的装载有本发明提供的癌症特异性肿瘤抗原表位的抗原呈递细胞,和/或活化的T细胞。
如本文所用,术语“癌症”是指或借指以非典型方式被调节哺乳动物的细胞生长为特征的生理状况。本发明中待预防、改善、或治疗的癌症可以是爱泼斯坦-巴尔病毒(EBV)阳性的癌症,包括但不限于EBV阳性胃癌、EBV阳性子宫颈癌、EBV阳性伯基特氏淋巴瘤、EBV阳性T细胞淋巴瘤、EBV阳性乳腺癌、EBV阳性平滑肌肉肉瘤、EBV阳性平滑肌瘤、EBV阳性霍奇金淋巴瘤、EBV阳性鼻咽癌、或EBV阳性移植后淋巴组织增生性疾病(PTLD),优选EBV阳性胃癌。
本发明提供的抗原呈递细胞能够诱导EBV阳性癌症抗原特异性T细胞(优选记忆T细胞)的分化和增殖,并且由此活化的记忆T细胞可以治疗癌性或肿瘤性疾病或预防复发、肿瘤的转移或转移,同时避免癌细胞的防御机制。
根据本发明的抗癌疫苗可包括单次施用免疫方法和连续施用免疫方法。在本发明中,“预防”可包括但不限于使用本发明的药物组合物,阻止癌症症状,或抑制或延迟症状的任何行为。
另外,在本发明中,“治疗”可包括但不限于使用本发明的药物组合物,改善或有益地改变癌症症状的任何行为。
在本发明中,所述药物组合物的特征可以在于胶囊、片剂、颗粒剂、注射剂、软膏剂、粉剂、或饮料的形式,并且药物组合物可靶向人。
在本发明中,所述药物组合物可以制成口服制剂的形式,例如粉剂、颗粒剂、胶囊、片剂和水性混悬剂,外用制剂,栓剂和无菌注射溶液剂,并根据常规方法分别使用。然而,所述药物组合物不限于此。本发明的药物组合物可以进一步包含药学上可接受的载体。作为药学上可接受的载体,可以将粘合剂、助流剂、崩解剂、赋形剂、增溶剂、分散剂、稳定剂、助悬剂、颜料、调味剂等用于口服给药;注射剂可以使用缓冲剂、防腐剂、止痛剂、增溶剂、等渗剂、稳定剂等;以及基质、赋形剂、润滑剂、防腐剂等可以用于局部给药。本发明的药物组合物的制剂可与如上所述的药学上可接受的载体混合,以各种方式制备。例如,对于口服给药,可以将药物组合物配制成片剂、锭剂、胶囊剂、酏剂、混悬剂、糖浆剂、糯米纸囊剂等形式。对于注射,所述药物组合物可以配制成单位剂量安瓿或多种剂型的形式。或者,所述药物组合物配制成溶液、悬浮液、片剂、胶囊、缓释制剂等。
同时,可以使用例如载体、稀释剂、或作为适合于制备制剂的赋形剂、乳糖、右旋糖、蔗糖、山梨糖醇、甘露醇、木糖醇、赤藓糖醇、麦芽糖醇、淀粉、阿拉伯胶、藻酸盐、明胶、磷酸钙、硅酸钙、纤维素、甲基纤维素、微晶纤维素、聚乙烯吡咯烷酮、水、羟基苯甲酸甲酯、羟基苯甲酸丙酯、滑石粉、硬脂酸镁、矿物油等。另外,还可包括填充剂、抗凝剂、润滑剂、湿润剂、香料、乳化剂、防腐剂等。
本发明药物组合物的给药途径包括但不限于口服、静脉内、肌内、动脉内、髓内、硬膜内、心内、透皮、皮下、腹膜内、鼻内、肠、局部、舌下、或直肠路线。优选口服或肠胃外给药。
如本文所用,术语“肠胃外”包括皮下、皮内、静脉内、肌肉内、关节内、法氏囊内、胸骨内、硬膜内、病变内、和颅内注射或输注技术。本发明的药物组合物也可以栓剂的形式用于直肠给药。
本发明的药物组合物可根据多种因素而变化,包括所用某种化合物的活性、患者的年龄、体重、总体健康状况、性别、饮食、给药时间、给药途径、排泄率、药物组合、以及要预防或治疗的某些疾病的严重性。所述药物组合物的剂量可以根据患者的状况、体重、疾病的严重程度、药物形式、给药途径、和持续时间而变化,并且可以由本领域技术人员适当地选择。所述药物组合物可以每天0.0001-50mg/kg或0.001-50mg/kg的量施用。给药可以一天一次或一天几次。所述剂量无意以任何方式限制本发明的范围。本发明的药物组合物可以配制成丸剂、糖衣片剂、胶囊、液体剂、凝胶剂、糖浆剂、浆剂、或混悬剂的形式。
根据本发明的又一个实施方案,提供了一种预防或治疗癌症的方法,该方法包括以下步骤:向目标个体施用装载本发明提供的癌症特异性肿瘤抗原表位的抗原呈递细胞,和/或活化的T细胞。
在本发明中,所述癌症可以是爱泼斯坦-巴尔病毒(EBV)阳性癌症,包括但不限于,EBV阳性胃癌、EBV阳性宫颈癌、EBV阳性伯基特淋巴瘤、EBV阳性淋巴瘤、EBV阳性乳腺癌、EBV阳性平滑肌肉瘤、EBV阳性平滑肌瘤、EBV阳性霍奇金淋巴瘤、EBV阳性鼻咽癌、或EBV阳性移植后淋巴增殖性疾病(PTLD),并优选EBV阳性胃癌。
可以根据个体的大小和状况并配合标准制药规范,确定本发明提供的装载有癌症特异性肿瘤抗原表位的抗原呈递细胞或活化的T细胞的剂量、时间表、和施用途径。示例性的给药途径包括静脉内、动脉内、腹膜内、肺内、血管内、肌内、气管内、皮下、眼内、鞘内或透皮途径。
施用给个体的细胞剂量可以例如根据所施用的细胞的具体类型、施用途径,以及所治疗的癌症的具体类型和阶段而变化。所述剂量应足以产生预期的反应,例如对癌症的治疗反应,但无严重的毒性或不良事件。在一些实施方案中,施用的活化T细胞或抗原呈递细胞(例如树突状细胞)的剂量是治疗有效量。在一些实施方案中,与治疗前同一个体中的肿瘤大小,癌细胞数量或肿瘤生长速率,或与未接受治疗的其他个体中的相应活性相比,所述细胞(例如装载有癌症特异性肿瘤抗原表位的树突状细胞或活化T细胞)的剂量足以减少肿瘤的大小,减少癌细胞的数量或减少肿瘤生长速率至少约10%,20%,30%,40%,50%,60%,70%,80%,90%,95%或100%之一。可以使用标准方法(例如,使用纯化的酶进行的体外测定、基于细胞的测定、动物模型、或使用人类的实验)测量效果的大小。
在本发明的一个实施方案中,可以以1×105-5×105、5×105-1×106、1×106-2×106、2×106-3×106,3×106-4×106,4×106-5×106,5×106-6×106,6×106-7×106,7×106-8×106,8×106-1×108,1×106-3×106,3×106-5×106,5×106-7×106,2×106-4×106,1×106-5×106或5×106-1×107细胞/个体中的任何剂量来施用装载有本发明的癌症特异性肿瘤抗原表位的抗原呈递细胞(例如树突状细胞)。然而,本发明不限于此。
在本发明的另一个实施方案中,可以以1×104-5×104、5×104至1×105、1×105-2×105,2×105-4×105,4×105-6×105,6×105-8×105,8×105-1×106,1×106-2×106,2×106-1×107,1×104-1×105,1×105-1×106,1×106-1×107,1×104-1×106,或1×105-1×107细胞/kg中的任何剂量来施用装载有本发明的癌症特异性肿瘤抗原表位的抗原呈递细胞(例如树突状细胞)。然而,本发明不限于此。
另外,在本发明的一个实施方案中,本发明的活化的T细胞可以1×108-5×108、5×108-9×108、9×108-1×109、1×109-2×109、2×109-3×109、3×109-4×109,4×109-5×109,5×109-6×109,6×109-1×1010,1×109-3×109,3×109-5×109,5×109-7×109,7×109-1×1010,1×109-5×109,5×109-1×1010,3×109-7×109,1×1010-1.5×1010,1×1010-2×1010或1×109-1×1010细胞/个体中的任何剂量给药。然而,本发明不限于此。
在本发明的另一个实施方案中,本发明的活化的T细胞可以1×107-1×108、1×108-2×108、2×108-4×108、4×108-6×108、6×108-8×108、8×108-1×109、1×109-2×109、2×109-4×109、4×109-1×10×10、2×108-6×108、6×108-1×109、1×108-2×108、2×108-2×109、1×107-1×108、1×108-1×109、1×109-1×1010、1×107-1×109细胞/kg中的任何剂量来施用。然而,本发明不限于此。
在本发明中,稳定剂或赋形剂例如人白蛋白,可与装载有癌症特异性肿瘤抗原表位的抗原呈递细胞(例如树突状细胞)和/或活化的T细胞一起施用。
在本发明中,基于主治医师的判断,可以在治疗过程中调整载有癌症特异性肿瘤抗原表位和/或活化的T细胞的抗原呈递细胞(例如树突状细胞)的剂量和给药方案。在一些实施方案中,所述活化的T细胞可以在施用载有肿瘤抗原肽的抗原呈递细胞后约1天、2天、3天、4天、5天、6天、7天、8天、9天、10天、11天、12天、13天、14天、15天、16天、17天、18天、19天、20天、21天、或1个月施用,或与抗原呈递细胞同时给药。然而,本发明不限于此。
在本发明中,载有癌症特异性肿瘤抗原表位和/或活化的T细胞的抗原呈递细胞(例如树突状细胞)的施用可以单独进行,也可以与其他疗法组合进行,例如手术、放射疗法、基因疗法、免疫疗法、骨髓移植、干细胞移植、激素疗法、靶向疗法、冷冻疗法、超声疗法、光动力疗法、化学疗法等。另外,高危发展成增生性疾病的人可以接受治疗以抑制和/或延缓该疾病的发展。
发明的有益效果
本发明提供的载有爱泼斯坦-巴尔病毒(EBV)阳性的癌症特异性肿瘤抗原表位的抗原呈递细胞,即树突状细胞,能够快速有效地诱导癌抗原特异性T细胞优选记忆性T细胞的分化和增殖,及由此活化的记忆性T细胞可以治疗爱泼斯坦-巴尔病毒(EBV)阳性的癌性或肿瘤性疾病,或防止癌症的复发、发展或转移,同时避免了癌细胞的防御机制。
在传统的过继性T细胞疗法中,生产大量用于治疗癌症患者的T细胞需要花费长达3至6个月,这是免疫细胞疗法的细胞生产过程中很大的问题。然而,根据本发明,应用于患者治疗的109自体记忆T细胞可以在三周内产生,并且可以实现成本降低和对外部污染物的感染风险因素最小化。因此,根据本发明,提供了一种可以应用于晚期癌症患者的技术,因为这种技术使得快速治疗方法可用于大量实体癌症患者。
附图说明
图1说明了,根据本发明的一个实施方案,对各个EBNA-1衍生的新表位进行ELISPOT以鉴定由这种新表位引起的SNU719细胞系中的T细胞活化程度的结果。
图2说明了,根据本发明的一个实施方案,对各个EBNA-1衍生的新表位进行ELISPOT,以鉴定由这种新表位在EBV感染的MKN74细胞系中引起的T细胞活化程度的结果。
图3说明了,根据本发明的一个实施方案,对相应的LMP-2A衍生的新表位进行ELISPOT,以鉴定由这种新表位在SNU719细胞系中引起的T细胞活化程度的结果。
图4说明了,根据本发明的一个实施方案,对各个LMP-2A衍生的新表位进行ELISPOT,以鉴定由这种新表位在EBV感染的MKN74细胞系中引起的T细胞活化程度的结果。
图5说明了,在SNU-719细胞系中对三种HLA类型的新表位(分别选自EBNA-1衍生的新表位)进行Cr51释放测定而获得的结果,以鉴定由根据本发明的一个实施方案产生的人源性记忆T细胞引起的靶向EBV阳性胃癌细胞抗原的杀伤活性。
图6说明了,在EBV感染的MKN74细胞系中对三种HLA类型的新表位(选自EBNA-1衍生的新表位)进行Cr51释放测定而获得的结果,以鉴定由根据本发明的一个实施方案产生的人源性记忆T细胞引起的靶向EBV阳性胃癌细胞抗原的杀伤活性。
图7说明了,在SNU-719细胞系中对三种HLA类型的新表位(分别选自LMP-2A衍生的新表位)进行Cr51释放测定而获得的结果,以鉴定由根据本发明的一个实施方案产生的人源性记忆T细胞引起的靶向EBV阳性胃癌细胞抗原的杀伤活性。
图8说明了,在EBV感染的MKN74细胞系中对三种HLA类型的新表位(选自LMP-2A衍生的新表位)进行Cr51释放测定而获得的结果,以鉴定由根据本发明的一个实施方案产生的人源性记忆T细胞引起的靶向EBV阳性胃癌细胞抗原的杀伤活性。
图9说明了,在EBV阴性的MKN74细胞系中对三种HLA类型的新表位(选自EBNA-1衍生的新表位)进行Cr51释放测定而获得的结果,以鉴定由根据本发明的一个实施方案产生的人源性记忆T细胞引起的靶向EBV阳性胃癌细胞抗原的杀伤活性。
图10说明了,在EBV阴性的MKN74细胞系中对三种HLA类型的新表位(选自EBNA-1衍生的新表位)进行Cr51释放测定而获得的结果,以鉴定由根据本发明的一个实施方案产生的人源性记忆T细胞引起的靶向EBV阳性胃癌细胞抗原的杀伤活性。
图11说明了,在EBV阴性的MKN74细胞系中对三种HLA类型的新表位(选自LMP-2A衍生的新表位)进行Cr51释放测定而获得的结果,以鉴定由根据本发明的一个实施方案产生的人源性记忆T细胞引起的靶向EBV阳性胃癌细胞抗原的杀伤活性。
图12说明了,在EBV阴性的MKN74细胞系中对三种HLA类型的新表位(选自LMP-2A衍生的新表位)进行Cr51释放测定而获得的结果,以鉴定由根据本发明的一个实施方案产生的人源性记忆T细胞引起的靶向EBV阳性胃癌细胞抗原的杀伤活性。
图13说明了新表位特异性细胞毒性的实验结果,根据本发明的一个实施方案,在BALB/c裸鼠异种移植模型(SNU-719)中,以证实EBNA-1衍生的新表位的体内抗癌作用。
图14说明了新表位特异性细胞毒性的实验结果,根据本发明的一个实施方案,在BALB/c裸鼠异种移植模型(EBV感染的MKN74)中,以证实EBNA-1衍生的新表位的体内抗癌作用。
图15说明了新表位特异性细胞毒性的实验结果,根据本发明的一个实施方案,在BALB/c裸鼠异种移植模型(SNU-719)中,以证实LMP-2A衍生的新表位的体内抗癌作用。
图16说明了新表位特异性细胞毒性的实验结果,根据本发明的一个实施方案,在BALB/c裸鼠异种移植模型(EBV感染的MKN74)中,以证实LMP-2A衍生的新表位的体内抗癌作用。
发明详述
根据本发明的一个实施方案,提供了一种爱泼斯坦-巴尔病毒(EBV)阳性的癌症特异性肿瘤抗原新表位,如SEQ ID NO.:1-184任一所示。
根据本发明的另一个实施方案,提供了一种装载有本发明提供的癌症特异性肿瘤抗原新表位的抗原呈递细胞(APC)。
根据本发明的又一个实施方案,提供了一种由本发明提供的抗原呈递细胞活化的T细胞。
根据本发明的又一个实施方案,提供了一种用于预防或治疗癌症的抗癌疫苗或药物组合物,其包含作为活性成分的装载有本发明提供的癌症特异性肿瘤抗原表位的抗原呈递细胞,和/或活化的T细胞。
在下文中,将通过实施例更详细地描述本发明。这些实施例仅用于更详细地描述本发明,并且对于本领域技术人员而言显而易见的是,根据本发明的主旨,本发明的范围不受这些实施例的限制。
实施例
[实施例1]特异性针对EBV阳性胃癌细胞的自体记忆T细胞的生产方法及其临床应
用
1.EBV阳性胃癌细胞抗原新表位的选择
利用生物信息学和蛋白质组学,开发了用于预测在胃癌细胞中积累基因突变的最重要的序列的算法,以及用于预测该序列与T细胞的HLA结合的表位的算法。使用了NetMHC和NetCTLpan预测新表位的算法。在此,鉴定了预期的与各种HLA类型具有高结合亲和力的肽序列,所述HLA类型包括HLA-A*1101,HLA-A*0206,HLA-A*3101,HLA-B*5101,HLA-B*4403,HLA-B*5401,HLA-B*5801和HLA-B*3501,以及韩国人表达最多的HLA类型的HLA-A*2402,HLA-A*A0201和HLA-A*3303。最后,对现有的EBV阳性胃癌细胞系进行HLA分型以研究每种细胞系的HLA类型,并以代表性蛋白质——LMP-2A和EBNA-1蛋白,通过NetMHC程序预测并鉴定了与每种HLA类型具有高结合亲和力的新表位,所述蛋白仅存在于EBV病毒导致的EBV阳性胃癌细胞中并引起恶性肿瘤。结果分别示于表1和2。
[表1]LMP-2A蛋白的新表位
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[表2]EBNA-1蛋白的新表位
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如上表1和表2所示,通过计算机预测,鉴定出对HLA-A*2402,HLA-A*A0201,HLA-A*3303,HLA-A*1101,HLA-A*0206,HLA-A*3101,HLA-B*5101,HLA-B*4403,HLA-B*5401,HLA-B*5801或HLA-B*3501具有高结合亲和力的新表位,并预测它们与各HLA的结合亲和力的IC50(nM)值。根据它们与HLA的结合亲和力,选择存在于实际人胃癌细胞中并可由体内T细胞识别的序列。如表1所示,对于LMP-2A的新表位,在HLA-A*2402的情况下,选择TYGPVFMCL(IC50=43.1nM),LLWTLVVLL(IC50=22368.6nM),LTEWGSGNR(IC50=45205.3nM),以从高到低的结合亲和力的顺序;在HLA-A*3101的情况下,选择LAYRRRWRR(IC50=5.2nM),LTVMTNTLL(IC50=14004.8nM),YPSASGSYG(IC50=42032nM)。此外,如表2所示,对于EBNA-1的新表位,在HLA-A*2402的情况下,选择MVFLQTHIF(IC50=773.1nM),AIKDLVMTK(IC50=39676.1nM),GSERARGR(IC50=47184.8nM),以从高到低的结合亲和力的顺序进行;在HLA-A*3101的情况下,选择KTSLYNLRR(IC50=18.8nM),RGRGGSGGR(IC50=289.3nM),FPPMGEGAA(IC50=43126.1nM)。将如上所述选择的新表位合成为肽,用于以下实验。
2.装载有选定新表位的树突状细胞活化T细胞的ELISPOT结果
通过流式细胞术,从健康人血中提取的PBMC分离为单核细胞和白细胞,并将单核细胞在补充有细胞因子GM-CSF和IL-4的培养物中培养2天,以分化为树突状细胞。另外,将白细胞与抗CD3/CD28抗体一起培养3天,然后在补充有细胞因子IL-2的培养物中培养。如上选择的新表位肽通过电穿孔转染入单核细胞分化的树突状细胞。随后,进行培养2天以鉴定新表位在树突状细胞表面上的表达。然后,在补充有抗CD3/CD28抗体的培养物中将所述树突状细胞与白细胞以1:20的比例(树突状细胞:白细胞)进行共培养。在共培养的情况下,将培养物与细胞因子混合物混合,并进行培养,所述细胞因子混合物包含增加树突状细胞的抗原呈递功能的细胞因子IL-4,和有助于T细胞转化成记忆细胞的细胞因子IL-2和IL-7。16小时后,用ELISPOT测量如此活化的T细胞中IFN-γ的表达水平,结果示于图1至4中。在此,实验中使用的阴性对照肽,其氨基酸序列为9-mer(序列为GGSRERARG),所述阴性对照肽在EBNA-1和LMP-2A的NetMHC中尚未提取出任何EBNA-1或LMP-2A蛋白。
结果,发现与装载本发明新表位肽的树突状细胞一起培养的T细胞比对照分泌更多的IFN-γ,与该肽对HLA的结合亲和力无关。
从这些结果中发现,在本发明中,可以用装载有各种新表位的树突状细胞活化细胞毒性T淋巴细胞(CTL),用如上表1和2所述各个细胞系的HLA-A类型选择新表位。如此活化的T细胞具有抗原特异性,该抗原特异性使得能够识别作为新抗原的新表位。
3.由装载有选定新表位的树突状细胞活化的T细胞的癌细胞裂解作用
如上第2点中,在共培养72小时后,为了选择通过所述树突状细胞向其抗原呈递的记忆性T细胞,使用能够提取分泌细胞因子IFN-γ的T细胞的磁活化细胞分选仪(MACS)来提取EBV抗原特异性记忆T细胞。提取的记忆T细胞在补充有细胞因子IL-2、IL-7、和IL-15的培养物中进行培养,以维持其记忆功能并增加细胞数量,直至记忆T细胞达到可注入小鼠的细胞数量。
将这种活化的T细胞与SNU-719细胞系(即EBV阳性胃癌细胞)共培养,以及与EBV感染的MKN74细胞系共培养,通过Cr51释放测定鉴定癌细胞的裂解。结果在图5至8中示出。另外,将这种活化的T细胞与MKN-74细胞系(即EBV阴性胃癌细胞)共培养,通过Cr51释放测定来鉴定癌细胞的裂解。结果在图9至12中示出。在此,实验中使用的阴性对照肽,其氨基酸序列为9-mer(序列为GGSRERARG),所述阴性对照肽在EBNA-1和LMP-2A的NetMHC中尚未提取出任何EBNA-1或LMP-2A蛋白。
结果发现,根据本发明的新表位活化的T细胞对EBV阳性胃癌细胞显示出优异的溶解能力,而对EBV阴性胃癌细胞显示出微不足道的溶解能力。换句话说,可以看出,由装载有根据本发明的EBV癌症特异性抗原新表位的树突状细胞活化的T细胞特异性地裂解了EBV阳性癌细胞。
另外,由本发明的新表位活化的T细胞倾向于显示出以混合浓度依赖性的方式溶解能力的增加,特别是在与EBV阳性胃癌细胞共培养的情况下。并且发现,在各个HLA类型的新表位中,特别是使用与HLA的结合亲和力更高的新表位的情况下,活化的T细胞对EBV阳性胃癌细胞系的裂解能力更高。
4.鉴定装载有选定新表位的树突状细胞活化的T细胞的体内抗癌作用
将数量为1×107细胞的EBV阳性胃癌细胞系SNU-719(HLA类型:HLA-A*2402)或EBV感染的MKN74(HLA类型:HLA-A*3101)与基质胶混合,并将该混合物移植到BALB/c裸鼠的腹侧面,以产生异种移植模型。4周后,在观察到癌组织的情况下,每周一次肿瘤内注射1×107个如上第2点中活化的T细胞,然后测量癌组织的大小。结果在图13至16中示出。在此,实验中使用的阴性对照肽,其氨基酸序列为9-mer(序列为GGSRERARG),所述阴性对照肽在EBNA-1和LMP-2A的NetMHC中尚未提取出任何EBNA-1或LMP-2A蛋白。
结果发现,在用根据本发明的新表位对活化的T细胞进行治疗的情况下,与对照相比,EBV阳性胃癌的大小显著减小。并且发现,在各个HLA类型的新表位中,特别是使用与HLA的结合亲和力更高的新表位的情况下,胃癌大小的缩小率更高。
如上所述,发现通过每个细胞系的HLA-A类型选择的所有新表位均表现出优异的增强T细胞活性的作用,并且随着通过生物信息学获得的结合亲和力增加(即,IC50值降低),所述T细胞的活性增强,并且其用于靶向杀死癌细胞的活性增加。根据这些结果,可以容易地预测出与表1和表2所示的新表位一起的树突状细胞可以用于增强T细胞的活性,并且这还产生优异的靶向癌症治疗效果。
尽管已经如上所述详细描述了本发明的特定部分,但是对于本领域技术人员显而易见的是,这样的特定描述仅是优选实施例,并且本发明的范围不限于此。因此,本发明的实质范围将由所附权利要求及其对等来限定。
工业适用性
本发明涉及一种癌症特异性肿瘤抗原新表位,一种装载有该新表位的抗原呈递细胞,以及一种使用该抗原呈递细胞进行癌症治疗的T细胞的活化方法。
序列表
<110> 古德T细胞有限公司
<120> 用于癌症治疗的T细胞的活化方法
<130> POPB187234PCT
<150> KR 10-2017-0101800
<151> 2017-08-10
<160> 184
<170> KoPatentIn 3.0
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Ala Pro Tyr Leu Phe Trp Leu Ala Ala
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Pro Tyr Leu Phe Trp Leu Ala Ala Ile
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Tyr Leu Phe Trp Leu Ala Ala Ile Ala
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Leu Ala Ala Ile Ala Ala Ser Cys Phe
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Ala Ile Ala Ala Ser Cys Phe Thr Ala
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Ala Ala Ser Cys Phe Thr Ala Ser Val
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Phe Thr Ala Ser Val Ser Thr Val Val
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Ala Ser Val Ser Thr Val Val Thr Ala
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Gly Leu Ala Leu Ser Leu Leu Leu Leu
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Leu Ala Leu Ser Leu Leu Leu Leu Ala
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Leu Ser Leu Leu Leu Leu Ala Ala Val
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Leu Leu Ala Ala Val Ala Ser Ser Tyr
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Ala Ala Val Ala Ser Ser Tyr Ala Ala
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Ala Val Ala Ser Ser Tyr Ala Ala Ala
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Ala Ser Ser Tyr Ala Ala Ala Gln Arg
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Ser Ser Tyr Ala Ala Ala Gln Arg Lys
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Ala Gln Arg Lys Leu Leu Thr Pro Val
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Ala Leu Leu Thr Leu Ala Ala Ala Leu
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Leu Ala Ala Ala Leu Ala Leu Leu Ala
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Ala Ala Leu Ala Leu Leu Ala Ser Leu
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Ala Leu Ala Leu Leu Ala Ser Leu Ile
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Leu Ala Leu Leu Ala Ser Leu Ile Leu
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Tyr Pro Ser Ala Ser Gly Ser Tyr Gly
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Leu Leu Ala Ser Leu Ile Leu Gly Thr
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Ser Leu Ile Leu Gly Thr Leu Asn Leu
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Leu Ile Leu Gly Thr Leu Asn Leu Thr
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Gly Thr Leu Asn Leu Thr Thr Met Phe
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Thr Leu Asn Leu Thr Thr Met Phe Leu
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<211> 9
<212> PRT
<213> 人工序列(Artificial sequence)
Asn Leu Thr Thr Met Phe Leu Leu Met
1 5
<210> 93
<211> 9
<212> PRT
<213> 人工序列(Artificial sequence)
Thr Thr Met Phe Leu Leu Met Leu Leu
1 5
<210> 94
<211> 9
<212> PRT
<213> 人工序列(Artificial sequence)
Thr Met Phe Leu Leu Met Leu Leu Trp
1 5
<210> 95
<211> 9
<212> PRT
<213> 人工序列(Artificial sequence)
Phe Leu Leu Met Leu Leu Trp Thr Leu
1 5
<210> 96
<211> 9
<212> PRT
<213> 人工序列(Artificial sequence)
Leu Leu Met Leu Leu Trp Thr Leu Val
1 5
<210> 97
<211> 9
<212> PRT
<213> 人工序列(Artificial sequence)
Leu Met Leu Leu Trp Thr Leu Val Val
1 5
<210> 98
<211> 9
<212> PRT
<213> 人工序列(Artificial sequence)
Met Leu Leu Trp Thr Leu Val Val Leu
1 5
<210> 99
<211> 9
<212> PRT
<213> 人工序列(Artificial sequence)
Leu Leu Trp Thr Leu Val Val Leu Leu
1 5
<210> 100
<211> 9
<212> PRT
<213> 人工序列(Artificial sequence)
Cys Pro Leu Thr Lys Ile Leu Leu Ala
1 5
<210> 101
<211> 9
<212> PRT
<213> 人工序列(Artificial sequence)
Ile Leu Leu Ala Arg Leu Phe Leu Tyr
1 5
<210> 102
<211> 9
<212> PRT
<213> 人工序列(Artificial sequence)
Leu Leu Ala Arg Leu Phe Leu Tyr Ala
1 5
<210> 103
<211> 9
<212> PRT
<213> 人工序列(Artificial sequence)
Arg Leu Phe Leu Tyr Ala Leu Ala Leu
1 5
<210> 104
<211> 9
<212> PRT
<213> 人工序列(Artificial sequence)
Phe Leu Tyr Ala Leu Ala Leu Leu Leu
1 5
<210> 105
<211> 9
<212> PRT
<213> 人工序列(Artificial sequence)
Leu Tyr Ala Leu Ala Leu Leu Leu Leu
1 5
<210> 106
<211> 9
<212> PRT
<213> 人工序列(Artificial sequence)
Tyr Ala Leu Ala Leu Leu Leu Leu Ala
1 5
<210> 107
<211> 9
<212> PRT
<213> 人工序列(Artificial sequence)
Leu Ala Leu Leu Leu Leu Ala Ser Ala
1 5
<210> 108
<211> 9
<212> PRT
<213> 人工序列(Artificial sequence)
Ala Leu Leu Leu Leu Ala Ser Ala Leu
1 5
<210> 109
<211> 9
<212> PRT
<213> 人工序列(Artificial sequence)
Leu Leu Leu Leu Ala Ser Ala Leu Ile
1 5
<210> 110
<211> 9
<212> PRT
<213> 人工序列(Artificial sequence)
Leu Leu Leu Ala Ser Ala Leu Ile Ala
1 5
<210> 111
<211> 9
<212> PRT
<213> 人工序列(Artificial sequence)
Ala Leu Ile Ala Gly Gly Ser Ile Leu
1 5
<210> 112
<211> 9
<212> PRT
<213> 人工序列(Artificial sequence)
Gly Ser Ile Leu Gln Thr Asn Phe Lys
1 5
<210> 113
<211> 9
<212> PRT
<213> 人工序列(Artificial sequence)
Lys Ser Leu Ser Ser Thr Glu Phe Ile
1 5
<210> 114
<211> 9
<212> PRT
<213> 人工序列(Artificial sequence)
Ser Ser Thr Glu Phe Ile Pro Asn Leu
1 5
<210> 115
<211> 9
<212> PRT
<213> 人工序列(Artificial sequence)
Phe Ile Pro Asn Leu Phe Cys Met Leu
1 5
<210> 116
<211> 9
<212> PRT
<213> 人工序列(Artificial sequence)
Ile Pro Asn Leu Phe Cys Met Leu Leu
1 5
<210> 117
<211> 9
<212> PRT
<213> 人工序列(Artificial sequence)
Asn Leu Phe Cys Met Leu Leu Leu Ile
1 5
<210> 118
<211> 9
<212> PRT
<213> 人工序列(Artificial sequence)
Met Leu Leu Leu Ile Val Ala Gly Ile
1 5
<210> 119
<211> 9
<212> PRT
<213> 人工序列(Artificial sequence)
Leu Leu Ile Val Ala Gly Ile Leu Phe
1 5
<210> 120
<211> 9
<212> PRT
<213> 人工序列(Artificial sequence)
Leu Ile Val Ala Gly Ile Leu Phe Ile
1 5
<210> 121
<211> 9
<212> PRT
<213> 人工序列(Artificial sequence)
Ile Val Ala Gly Ile Leu Phe Ile Leu
1 5
<210> 122
<211> 9
<212> PRT
<213> 人工序列(Artificial sequence)
Phe Ile Leu Ala Ile Leu Thr Glu Trp
1 5
<210> 123
<211> 9
<212> PRT
<213> 人工序列(Artificial sequence)
Leu Thr Glu Trp Gly Ser Gly Asn Arg
1 5
<210> 124
<211> 9
<212> PRT
<213> 人工序列(Artificial sequence)
Arg Thr Tyr Gly Pro Val Phe Met Cys
1 5
<210> 125
<211> 9
<212> PRT
<213> 人工序列(Artificial sequence)
Thr Tyr Gly Pro Val Phe Met Cys Leu
1 5
<210> 126
<211> 9
<212> PRT
<213> 人工序列(Artificial sequence)
Phe Met Cys Leu Gly Gly Leu Leu Thr
1 5
<210> 127
<211> 9
<212> PRT
<213> 人工序列(Artificial sequence)
Met Cys Leu Gly Gly Leu Leu Thr Met
1 5
<210> 128
<211> 9
<212> PRT
<213> 人工序列(Artificial sequence)
Cys Leu Gly Gly Leu Leu Thr Met Val
1 5
<210> 129
<211> 9
<212> PRT
<213> 人工序列(Artificial sequence)
Gly Leu Leu Thr Met Val Ala Gly Ala
1 5
<210> 130
<211> 9
<212> PRT
<213> 人工序列(Artificial sequence)
Leu Leu Thr Met Val Ala Gly Ala Val
1 5
<210> 131
<211> 9
<212> PRT
<213> 人工序列(Artificial sequence)
Leu Thr Met Val Ala Gly Ala Val Trp
1 5
<210> 132
<211> 9
<212> PRT
<213> 人工序列(Artificial sequence)
Thr Met Val Ala Gly Ala Val Trp Leu
1 5
<210> 133
<211> 9
<212> PRT
<213> 人工序列(Artificial sequence)
Met Val Ala Gly Ala Val Trp Leu Thr
1 5
<210> 134
<211> 9
<212> PRT
<213> 人工序列(Artificial sequence)
Val Ala Gly Ala Val Trp Leu Thr Val
1 5
<210> 135
<211> 9
<212> PRT
<213> 人工序列(Artificial sequence)
Trp Leu Thr Val Met Thr Asn Thr Leu
1 5
<210> 136
<211> 9
<212> PRT
<213> 人工序列(Artificial sequence)
Leu Thr Val Met Thr Asn Thr Leu Leu
1 5
<210> 137
<211> 9
<212> PRT
<213> 人工序列(Artificial sequence)
Val Met Thr Asn Thr Leu Leu Ser Ala
1 5
<210> 138
<211> 9
<212> PRT
<213> 人工序列(Artificial sequence)
Met Thr Asn Thr Leu Leu Ser Ala Trp
1 5
<210> 139
<211> 9
<212> PRT
<213> 人工序列(Artificial sequence)
Thr Leu Leu Ser Ala Trp Ile Leu Thr
1 5
<210> 140
<211> 9
<212> PRT
<213> 人工序列(Artificial sequence)
Leu Leu Ser Ala Trp Ile Leu Thr Ala
1 5
<210> 141
<211> 9
<212> PRT
<213> 人工序列(Artificial sequence)
Ser Ala Trp Ile Leu Thr Ala Gly Phe
1 5
<210> 142
<211> 9
<212> PRT
<213> 人工序列(Artificial sequence)
Trp Ile Leu Thr Ala Gly Phe Leu Ile
1 5
<210> 143
<211> 9
<212> PRT
<213> 人工序列(Artificial sequence)
Ile Leu Thr Ala Gly Phe Leu Ile Phe
1 5
<210> 144
<211> 9
<212> PRT
<213> 人工序列(Artificial sequence)
Leu Thr Ala Gly Phe Leu Ile Phe Leu
1 5
<210> 145
<211> 9
<212> PRT
<213> 人工序列(Artificial sequence)
Phe Leu Ile Phe Leu Ile Gly Phe Ala
1 5
<210> 146
<211> 9
<212> PRT
<213> 人工序列(Artificial sequence)
Ile Phe Leu Ile Gly Phe Ala Leu Phe
1 5
<210> 147
<211> 9
<212> PRT
<213> 人工序列(Artificial sequence)
Phe Leu Ile Gly Phe Ala Leu Phe Gly
1 5
<210> 148
<211> 9
<212> PRT
<213> 人工序列(Artificial sequence)
Leu Ile Gly Phe Ala Leu Phe Gly Val
1 5
<210> 149
<211> 9
<212> PRT
<213> 人工序列(Artificial sequence)
Gly Phe Ala Leu Phe Gly Val Ile Arg
1 5
<210> 150
<211> 9
<212> PRT
<213> 人工序列(Artificial sequence)
Leu Phe Gly Val Ile Arg Cys Cys Arg
1 5
<210> 151
<211> 9
<212> PRT
<213> 人工序列(Artificial sequence)
Val Pro Met Gly Ala Gly Pro Pro Ser
1 5
<210> 152
<211> 9
<212> PRT
<213> 人工序列(Artificial sequence)
Arg Gly Arg Gly Gly Ser Gly Gly Arg
1 5
<210> 153
<211> 9
<212> PRT
<213> 人工序列(Artificial sequence)
Arg Gly Arg Gly Gly Ser Gly Gly Arg
1 5
<210> 154
<211> 9
<212> PRT
<213> 人工序列(Artificial sequence)
Arg Gly Arg Gly Gly Ser Gly Gly Arg
1 5
<210> 155
<211> 9
<212> PRT
<213> 人工序列(Artificial sequence)
Arg Gly Arg Gly Arg Glu Arg Ala Arg
1 5
<210> 156
<211> 9
<212> PRT
<213> 人工序列(Artificial sequence)
Arg Ala Arg Gly Gly Ser Arg Glu Arg
1 5
<210> 157
<211> 9
<212> PRT
<213> 人工序列(Artificial sequence)
Gly Ser Arg Glu Arg Ala Arg Gly Arg
1 5
<210> 158
<211> 9
<212> PRT
<213> 人工序列(Artificial sequence)
Arg Ala Arg Gly Arg Gly Arg Gly Arg
1 5
<210> 159
<211> 9
<212> PRT
<213> 人工序列(Artificial sequence)
Arg Gly Arg Gly Arg Gly Glu Lys Arg
1 5
<210> 160
<211> 9
<212> PRT
<213> 人工序列(Artificial sequence)
Arg Gly Arg Gly Glu Lys Arg Pro Arg
1 5
<210> 161
<211> 9
<212> PRT
<213> 人工序列(Artificial sequence)
Ser Ser Ser Ser Gly Ser Pro Pro Arg
1 5
<210> 162
<211> 9
<212> PRT
<213> 人工序列(Artificial sequence)
His Pro Val Gly Asp Ala Asp Tyr Phe
1 5
<210> 163
<211> 9
<212> PRT
<213> 人工序列(Artificial sequence)
Lys Gly Gly Trp Phe Gly Lys His Arg
1 5
<210> 164
<211> 9
<212> PRT
<213> 人工序列(Artificial sequence)
Arg Gly Arg Gly Arg Gly Arg Gly Arg
1 5
<210> 165
<211> 9
<212> PRT
<213> 人工序列(Artificial sequence)
Glu Gly Leu Arg Val Leu Leu Ala Arg
1 5
<210> 166
<211> 9
<212> PRT
<213> 人工序列(Artificial sequence)
Arg Val Leu Leu Ala Arg Ser His Val
1 5
<210> 167
<211> 9
<212> PRT
<213> 人工序列(Artificial sequence)
Leu Leu Ala Arg Ser His Val Glu Arg
1 5
<210> 168
<211> 9
<212> PRT
<213> 人工序列(Artificial sequence)
Arg Gly Arg Gly Arg Gly Gly Gly Arg
1 5
<210> 169
<211> 9
<212> PRT
<213> 人工序列(Artificial sequence)
Gly Val Phe Val Tyr Gly Gly Ser Lys
1 5
<210> 170
<211> 9
<212> PRT
<213> 人工序列(Artificial sequence)
Lys Thr Ser Leu Tyr Asn Leu Arg Arg
1 5
<210> 171
<211> 9
<212> PRT
<213> 人工序列(Artificial sequence)
Ile Ala Leu Ala Val Pro Gln Cys Arg
1 5
<210> 172
<211> 9
<212> PRT
<213> 人工序列(Artificial sequence)
Ile Thr Pro Leu Ser Arg Leu Pro Phe
1 5
<210> 173
<211> 9
<212> PRT
<213> 人工序列(Artificial sequence)
Arg Glu Ser Ile Val Cys Tyr Phe Met
1 5
<210> 174
<211> 9
<212> PRT
<213> 人工序列(Artificial sequence)
Glu Ser Ile Val Cys Tyr Phe Met Val
1 5
<210> 175
<211> 9
<212> PRT
<213> 人工序列(Artificial sequence)
Ser Ile Val Cys Tyr Phe Met Val Phe
1 5
<210> 176
<211> 9
<212> PRT
<213> 人工序列(Artificial sequence)
Ile Val Cys Tyr Phe Met Val Phe Leu
1 5
<210> 177
<211> 9
<212> PRT
<213> 人工序列(Artificial sequence)
Phe Met Val Phe Leu Gln Thr His Ile
1 5
<210> 178
<211> 9
<212> PRT
<213> 人工序列(Artificial sequence)
Met Val Phe Leu Gln Thr His Ile Phe
1 5
<210> 179
<211> 9
<212> PRT
<213> 人工序列(Artificial sequence)
Phe Leu Gln Thr His Ile Phe Ala Glu
1 5
<210> 180
<211> 9
<212> PRT
<213> 人工序列(Artificial sequence)
Leu Gln Thr His Ile Phe Ala Glu Val
1 5
<210> 181
<211> 9
<212> PRT
<213> 人工序列(Artificial sequence)
Ala Ile Lys Asp Leu Val Met Thr Lys
1 5
<210> 182
<211> 9
<212> PRT
<213> 人工序列(Artificial sequence)
Asn Ile Lys Val Thr Val Cys Ser Phe
1 5
<210> 183
<211> 9
<212> PRT
<213> 人工序列(Artificial sequence)
Thr Val Cys Ser Phe Asp Asp Gly Val
1 5
<210> 184
<211> 9
<212> PRT
<213> 人工序列(Artificial sequence)
Phe Pro Pro Met Val Glu Gly Ala Ala
1 5
Claims (15)
1.一种爱泼斯坦-巴尔病毒(EBV)阳性的癌症特异性肿瘤抗原表位肽,如SEQ ID NO:136所示。
2.如权利要求1所述的爱泼斯坦-巴尔病毒(EBV)阳性的癌症特异性肿瘤抗原表位肽,其中所述癌症特异性肿瘤抗原表位肽表现出与HLA-A *3101的结合的亲和力。
3.如权利要求1所述的爱泼斯坦-巴尔病毒(EBV)阳性的癌症特异性肿瘤抗原表位肽,其中所述癌症是EBV阳性胃癌、EBV阳性宫颈癌、EBV阳性伯基特淋巴瘤、EBV阳性T细胞淋巴瘤、EBV阳性乳腺癌、EBV阳性平滑肌肉瘤、EBV阳性平滑肌瘤、EBV阳性霍奇金淋巴瘤、EBV阳性鼻咽癌、或EBV阳性移植后淋巴组织增生性疾病(PTLD)。
4.一种核酸分子,其编码根据权利要求1至3中任一项所述的癌症特异性肿瘤抗原表位肽。
5.一种表达载体,其中插入了权利要求4所述的核酸分子。
6.一种宿主细胞,其中转染有权利要求5所述的表达载体。
7.一种用于活化T细胞的组合物,其包含:如SEQ ID NO:136所示的癌症特异性肿瘤抗原表位肽。
8.如权利要求7所述的组合物,其中所述T细胞用于预防或治疗癌症,所述癌症为EBV阳性胃癌。
9.如权利要求7所述的组合物,其中,所述T细胞包括选自细胞毒性T细胞和记忆性T细胞中的一种或多种。
10.一种抗原呈递细胞,其中装载有如SEQ ID NO:136所示的癌症特异性肿瘤抗原表位肽。
11.如权利要求10所述的抗原呈递细胞,其中所述抗原呈递细胞包括树突状细胞、B细胞、和巨噬细胞中的一种或多种。
12.如权利要求11所述的抗原呈递细胞,其中所述抗原呈递细胞促进T细胞的增殖或分化。
13.一种T细胞,其由权利要求10至12中任一项所述的抗原呈递细胞活化获得。
14.一种用于预防或治疗癌症的药物组合物,其包含作为活性成分的如权利要求10至12中任一项所述的抗原呈递细胞,所述癌症为EBV阳性胃癌。
15.一种用于预防或治疗癌症的药物组合物,其包含作为活性成分的如权利要求13所述的T细胞,所述癌症为EBV阳性胃癌。
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WO2020162696A1 (ko) * | 2019-02-08 | 2020-08-13 | 주식회사 굳티셀 | 암 치료를 위한 t 세포의 활성화 방법 |
EP3927361A4 (en) * | 2019-02-21 | 2022-11-30 | Ramot at Tel-Aviv University Ltd. | TREATMENT OF DISEASES WITH MULTIMERIC PEPTIDES |
KR102182555B1 (ko) * | 2019-03-14 | 2020-11-24 | 한국과학기술연구원 | T 세포 면역 반응 활성화를 위한 암 치료용 암항원 발굴 플랫폼 |
KR102322832B1 (ko) * | 2019-04-22 | 2021-11-12 | 한국과학기술연구원 | 인간 백혈구 항원 a24:02 대립유전자에 특이적으로 결합하는 펩타이드 및 이의 용도 |
KR102335916B1 (ko) * | 2019-04-22 | 2021-12-08 | 한국과학기술연구원 | 인간 백혈구 항원 a02:01 대립유전자에 특이적으로 결합하는 펩타이드 및 이의 용도 |
US20220364079A1 (en) * | 2019-09-23 | 2022-11-17 | Dana-Farber Cancer Institute, Inc. | Methods of high-throughput identification of t cell epitopes by capturing cytokines on the surface of antigen-presenting cells |
KR20210102091A (ko) | 2020-02-11 | 2021-08-19 | 주식회사 리스큐어바이오사이언시스 | 미성숙 수지상 세포의 성숙화 유도를 이용한 암의 예방 또는 치료용 조성물 |
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KR20220136957A (ko) | 2022-10-11 |
EP3666888A4 (en) | 2021-09-01 |
WO2019031939A2 (ko) | 2019-02-14 |
JP2023113855A (ja) | 2023-08-16 |
KR20190017702A (ko) | 2019-02-20 |
CN110997903A (zh) | 2020-04-10 |
US11969463B2 (en) | 2024-04-30 |
KR102148866B1 (ko) | 2020-10-14 |
EP3666887A2 (en) | 2020-06-17 |
JP7364237B2 (ja) | 2023-10-18 |
WO2019031938A2 (ko) | 2019-02-14 |
KR20200102402A (ko) | 2020-08-31 |
BR112020002816A2 (pt) | 2020-08-04 |
EP3666887A4 (en) | 2021-09-01 |
KR20200141424A (ko) | 2020-12-18 |
WO2019031938A3 (ko) | 2019-07-04 |
US20200289630A1 (en) | 2020-09-17 |
JP2020532956A (ja) | 2020-11-19 |
US20210009952A1 (en) | 2021-01-14 |
CN111433355B (zh) | 2024-03-29 |
CN111433355A (zh) | 2020-07-17 |
KR20190017705A (ko) | 2019-02-20 |
US11918634B2 (en) | 2024-03-05 |
EP3666888A2 (en) | 2020-06-17 |
KR102190890B1 (ko) | 2020-12-15 |
WO2019031939A3 (ko) | 2019-07-18 |
JP2020532957A (ja) | 2020-11-19 |
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