CN110799212A - 特异性存在于调节性t细胞中的dkk1蛋白及其用途 - Google Patents
特异性存在于调节性t细胞中的dkk1蛋白及其用途 Download PDFInfo
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Abstract
本发明涉及Dickkopf‑1(DKK1)蛋白、其特异性抗体及其用途,DDK1蛋白特异性存在于免疫细胞,特别是调节性T细胞(Treg细胞)的表面上。在本发明中,由于DKK1蛋白特异性存在于免疫细胞,特别是调节性T细胞的表面,DKK1蛋白可用作各种免疫相关疾病治疗剂的新靶标。
Description
技术领域
本发明涉及Dickkopf-1(DKK1)蛋白、其特异性抗体及其用途,DDK1蛋白特异性存在于免疫细胞,特别是调节性T细胞(Treg细胞)的表面上。
背景技术
免疫细胞中,T细胞是在骨髓中产生并在胸腺中成熟的免疫细胞,其功能是调节B细胞的抗体产生或调节天然免疫细胞的功能。T细胞,也称为T淋巴细胞,不仅可以充当其他免疫细胞的助手,还可以直接消灭入侵物。
在免疫细胞的功能中,最重要的是这些免疫细胞对构成自身的抗原物质和免疫细胞周围的抗原物质显示出抑制的免疫应答,同时识别非自身抗原物质并诱导对其的免疫应答。在发育过程中,通过杀伤识别自身的细胞、在自身抗原的特异性受体中诱导突变或失活识别自身抗原的免疫细胞,免疫细胞不会对自身抗原产生应答,这称为免疫无反应性或免疫耐受。这种自我耐受的失效会诱导对自身抗原的免疫应答,从而导致疾病。这种疾病称为自身免疫疾病。
在19世纪70年代初期,为了诱导或维持自身耐受性,引入了调节性T细胞的概念,其可以控制常规T细胞的效应功能(RK Gershon和K.Kondo,免疫学,1970,18:723-37)。自此,阐明抑制性T细胞的免疫学性质和功能的研究一直在进行。
在正常个体中,调节性T细胞控制常规T细胞的功能,诱导过度的免疫应答或自我耐受。但是,据报道,在自身免疫性和慢性炎症性疾病中,调节性T细胞的功能和数量显著降低,调节性T细胞因而不能发挥正常功能。因此,在患有自身免疫性和慢性炎症性疾病的患者中,使调节性T细胞的功能和数量恢复正常水平可能是该疾病的治疗方法之一。
已经有人通过研究提出CD25、CTLA4、CD38、CD62L、GITR、CD45RB等作为靶向调节性T细胞的细胞表面蛋白,并已经进行了动物和临床试验。然而,迄今为止尚未发现只靶向调节性T细胞的细胞表面蛋白。
技术问题
本发明的目的是提供特异性存在于调节性T细胞表面的Dickkopf-1(DKK1)蛋白或其表位。
本发明的又一个目的是提供特异性存在于调节性T细胞表面的DKK1蛋白的特异性抗体。
本发明的又一个目的是提供在其细胞表面表达有DKK1蛋白的调节性T细胞。
本发明的又一个目的是提供一种筛选免疫抑制剂或免疫活化剂的方法。
本发明的又一个目的是提供一种预防或治疗免疫相关疾病的方法。
本发明的又一个目的是提供一种诊断免疫相关疾病的方法。
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可从以下描述中清楚地理解未提及的其他问题。
解决问题的技术方案
本发明人发现了特异性存在于免疫细胞,特别是调节性T细胞表面的Dickkopf-1(DKK1)蛋白,并筛选了该蛋白的表位。另外,本发明人发现,在选择性地筛选表达DKK1蛋白的免疫细胞(特别是调节性T细胞)并与效应T细胞共孵育的情况下,效应T细胞的活性会被抑制,从而完成了本发明。
在本发明中,DKK1是DKK家族基因DKK1、DKK2、DKK3、DKK4之一,编码分泌的蛋白。DKK蛋白通常由255至350个氨基酸组成。DKK1的大小为24KDa至29KDa,其N端以糖基化形式存在。作为本发明的一个实例,DKK1的氨基酸序列可以如SEQ ID NO:1所示,并且可以由SEQID NO:2所示的核苷酸编码。
[表1]
在本发明中,与诸如Wnt3a的配体相比,DKK1强烈结合涉及细胞增殖和伤口恢复的Wnt信号传导***中的受体,从而竞争性地抑制Wnt信号。因此,DKK1可在胚胎发育过程中,如在心脏、头、手等的发育中发挥重要作用。此外,通过以分泌蛋白形式存在于骨髓血浆中的DKK1水平的增加,DKK1可用于鉴定多发性骨髓瘤患者的溶骨性骨病变,并可以用于确定DKK1癌症或骨病的等级。
然而,在本发明中,DKK1可以存在于免疫细胞,特别是调节性T细胞的表面,而不像通常情况那样从细胞中分泌出来。这可以使免疫细胞在调节性T细胞的自身耐受中发挥作用。
根据本发明的一种实施方式,提供了SEQ ID NO:3所示的DKK1的调节性T细胞外表面蛋白(表2)。
[表2]
本发明提供了DKK1的调节性T细胞外表面蛋白,其可与效应T细胞上存在的配体相互作用以降低调节性T细胞的活性。
根据本发明的另一种实施方式,提供了DKK1的表位,其是调节性T细胞表面蛋白,如SEQ ID NO:4-36中任一所示(表3)。
[表3]
如本文所用,术语“表位”是指与抗体结合并且可以被抗体识别的抗原分子的一部分。通常,抗体不识别整个抗原分子,而仅识别其特定部分。即使是相同的抗原分子,也可根据抗体的种类识别不同的表位区域。用于本发明目的的表位包括这样的表位,即使DKK1蛋白暴露于细胞外的部分被局部切割并分泌到细胞外,剩余的部分区域也可以与抗体有效结合。
在本发明中,作为表位的多肽可以包括可与抗体结合的根据本发明的DKK1蛋白一部分的连续和不连续序列。
另外,本发明提供了一种作为调节性T细胞表面蛋白DKK1的表位的多肽片段,其可以与效应T细胞中存在的配体相互作用从而降低调节性T细胞的活性。
根据本发明的另一种实施方式,提供了一种多核苷酸,该多核苷酸编码如SEQ IDNO:3所示的DKK1的胞外表面蛋白,或编码本发明提供的SEQ ID NO:4-36中任一所示的DKK1表位。
根据本发明的另一种实施方式,提供了一种***有本发明提供的多核苷酸的表达载体。
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”,质粒是指可以接入其他DNA区段的环状双链DNA。另一类载体是噬菌体载体。还有一类载体是病毒载体,其中可以将其他DNA区段连接到所述病毒的基因组中。某些载体能够在导进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附加型哺乳动物载体(episomal mammalian vector))。其他载体(例如,非附加型哺乳动物载体)可以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。此外,某些载体能够指导与其可操作连接的基因表达。此类载体在本文中称为“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,因为质粒是最常用的载体形式。
本发明中表达载体的具体实例可以选自但不限于下组: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噬菌体、人字形噬菌体、M13、Mu、p1 P22、Qμ、T-even、T2、T3、T7噬菌体;植物病毒。作为表达载体,本领域技术人员已知的任何表达载体,均可用于本发明,并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、脂质体转染、或电穿孔将载体导入宿主细胞。然而,本发明不限于此,本领域技术人员可以采取和使用适合于所用表达载体和宿主细胞的导入方法。所述的载体可优选包含至少一种选择标记。然而,本发明不限于此,可以使用不包筛选标记的载体来进行筛选,这取决于是否产生产物。筛选标记取决于靶宿主细胞,这可以采用本领域技术人员已知的方法完成,因此本发明对此没有限制。
为了便于本发明核酸分子的纯化,可以将标签序列***表达载体中并与之融合。标签包括但不限于:六组氨酸标签、血凝素标签、myc标签、或flag标签,本领域技术人员已知的便于纯化的任何标签均可以用于本发明。
根据本发明的另一种实施方式,提供了一株用本发明提供的表达载体转染的宿主细胞系。
在本发明中,“宿主细胞”包括单个细胞或细胞培养物,所述单个细胞或细胞培养物可以或已经是一个或多个掺入多肽***物的载体的受体。所述的宿主细胞包括单个宿主细胞的后代,并且由于天然的、偶然的或有意的突变,后代不一定与原始亲本细胞完全相同(在形态上或在基因组DNA互补上)。所述的宿主细胞包括用本文的一种或多种多核苷酸体内转染的细胞。
在本发明中,所述的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,例如,细菌细胞,如大肠杆菌(E.coli)、链霉菌(Streptomyces),鼠伤寒沙门氏菌(Salmonella typhimurium);真菌细胞,如酵母细胞和巴斯德毕赤酵母(Pichiapastoris);昆虫细胞,如果蝇(Drosophila)和斜纹夜蛾(Spodoptera)Sf9细胞;动物细胞,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鲍斯黑色素瘤细胞、HT-1080、幼仓鼠肾(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,本领域技术人员已知的可以用作宿主细胞系的任何细胞都是可用的。
根据本发明的另一种实施方式,提供了一种调节性T细胞,其包含本发明的DKK1的胞外表面蛋白或DKK1的表位。
通过与效应T细胞的相互作用,表面表达有本发明的DKK1的胞外表面蛋白或其表位的调节性T细胞能够抑制效应T细胞的活性并抑制免疫应答。
根据本发明的另一种实施方式,提供了一种用于预防或治疗免疫相关疾病的药物组合物,其包含调节性T细胞作为活性成分,该调节性T细胞包含本发明的DKK1的胞外表面蛋白或其表位。
通过与效应T细胞的相互作用,包含本发明的DKK1的胞外表面蛋白的调节性T细胞能够抑制效应T细胞的活性并抑制免疫应答。
在本发明中,在细胞表面表达DKK1蛋白的调节性T细胞能够有效地预防、改善或治疗超免疫应答引起的免疫相关疾病,例如自身免疫病、移植物抗宿主病、器官移植排斥、哮喘、特应性疾病、急性或慢性炎症性疾病等。
根据本发明的另一种实施方式,提供了一种用于预防或治疗免疫相关疾病的药物组合物,其包含本发明的DKK1的胞外表面蛋白或其表位作为活性成分。
本发明提供的DKK1的胞外表面蛋白或表位片段与存在于效应T细胞上的配体相互作用,从而可以抑制调节性T细胞的活性,藉此有效地预防、改善或治疗免疫相关疾病,例如癌症。
如本文所用,术语“癌症”是指哺乳动物中以不被典型方式调节的细胞生长为特征的生理状况。在本发明中,预防、改善或治疗的癌症可以是实体瘤,其是由实体器官中的细胞异常生长引起的附聚物所形成,根据实体器官的位置,可以是但不限于胃癌、肝癌、胶质瘤、卵巢癌、结肠直肠癌、头颈癌、膀胱癌、肾细胞癌、乳腺癌、转移性癌、***癌、胰腺癌、黑素瘤、肺癌等,优选为黑素瘤。
根据本发明的另一种实施方式,提供了一种用于预防或治疗免疫相关疾病的药物组合物,其包含本发明的DKK1的胞外表面蛋白或其表位的特异性抗体作为活性成分。
另外,在本发明中,DKK1胞外表面蛋白可以存在于调节性T细胞的表面。
在本发明中,抗体可以抑制调节性T细胞的活性,从而有效地预防、改善或治疗癌症。
如本文所用,术语“抗体”是本领域已知的术语,是指针对抗原区域的特异性蛋白分子。用于本发明目的的抗体是指与本发明的蛋白特异性结合的抗体。并且,这样的抗体可以通过以下方法制备:将各基因按常规方法克隆到表达载体中,获得由标记基因编码的蛋白,并将获得的蛋白按常规方法进行处理。其中,包括可以由上述蛋白制成的亚肽,并且本发明的亚肽至少包括七个氨基酸,优选九个氨基酸,并且更优选十二个或更多个氨基酸。
本发明抗体的形式没有特别限制。本发明的抗体包括多克隆抗体或单克隆抗体或其一部分,只要该部分具有抗原结合能力即可,并且包括所有免疫球蛋白抗体。此外,本发明的抗体还包括特殊抗体,例如人源化抗体。
本发明的抗体包括具有两条全长轻链和两条全长重链的完整形式,以及抗体分子的功能片段。抗体分子的功能片段是指至少具有抗原结合功能的片段,包括Fab,F(ab’),F(ab’)2,Fv等。
作为本发明的一个实例,该抗体与调节性T细胞表面表达的DKK1蛋白或其表位特异性结合,从而可以抑制调节性T细胞的活性,藉此有效地预防、改善或治疗免疫相关疾病,例如癌症。
在本发明中,癌症可以是实体瘤,其是由实体器官中的细胞异常生长引起的附聚物所形成,根据实体器官的位置,可以是但不限于胃癌、肝癌、胶质瘤、卵巢癌、结肠直肠癌、头颈癌、膀胱癌、肾细胞癌、乳腺癌、转移性癌、***癌、胰腺癌、黑素瘤、肺癌等,优选为黑素瘤。
作为本发明的另一个实例,该抗体与调节性T细胞表面表达的DKK1蛋白或其表位特异性结合,从而可以增强调节性T细胞的活性,藉此有效地预防、改善或治疗免疫相关疾病,例如自身免疫病、移植物抗宿主病、器官移植排斥、哮喘、特应性疾病、急性或慢性炎症性疾病等。
根据本发明的另一种实施方式,提供了一种用于免疫相关疾病的药物组合物,其包含选自下组任一种作为活性成分:反义寡核苷酸、siRNA、shRNA和microRNA,它们各自对编码本发明的DKK1的胞外表面蛋白或表位的基因具有特异性。
在本发明中,反义寡核苷酸是与特定DNA或RNA靶标反义(或互补)的短长度合成DNA链(或DNA类似物),并用于实现体内和体外的基因特异性抑制。已有人提出,在转录,翻译或剪接阶段,反义寡核苷酸通过与靶标结合并停止其表达来阻止DNA或RNA靶标编码的蛋白质的表达。反义寡核苷酸也已成功用于细胞培养和疾病动物模型中。使反义寡核苷酸更稳定和更具抗性从而使得寡核苷酸不被降解的其他修饰是本领域技术人员已知和理解的。本文所用的反义寡核苷酸包括双螺旋或单螺旋DNA,双螺旋或单螺旋RNA,DNA/RNA杂交体,DNA和RNA类似物,以及具有碱基,糖或骨架修饰的寡核苷酸。通过本领域已知的方法修饰寡核苷酸,以增加其稳定性并增加其对核酸酶降解的抗性。这些修饰包括但不限于本领域已知的对寡核苷酸主链,糖部分或碱基的修饰。
在本发明中,“siRNA(小干扰RNA)”是可以介导RNA干扰或基因沉默的核酸分子,并且由于其抑制靶基因表达的能力而被用于高效基因敲除方法或基因治疗方法。在本发明的使用siRNA分子的情况下,siRNA分子可以具有下述结构,正义链(与WLS mRNA序列相对应的序列)和反义链(与WLS mRNA序列互补的序列)的位置彼此相对,以形成具有互补的正义链和反义链的单链或双链结构。siRNA不仅限于双链RNA部分(RNA相互配对的位置)完全配对的那些,还可能包含由错配(相应的碱基不互补),延伸/突出(没有碱基对应于另一链)等引起的未配对部分。siRNA末端结构可以是平末端或粘性末端,只要该末端允许WLS基因的表达受到RNA干扰(RNAi)效应的抑制即可。粘性末端结构可以是3’-突出结构或5’-突出结构。siRNA分子的总长度可以为15至30个碱基,优选为19至21个碱基。然而,总长度不限于此。
在本发明中,“shRNA(短发夹RNA)”是具有45至70个核苷酸长度的单链RNA,并且shRNA如下产生。合成寡聚DNA,其中具有靶基因的siRNA碱基序列的正义链和与之互补的反义链通过3至10个碱基的接头连接。然后,将寡聚DNA克隆到质粒载体中,或者将shRNA***慢病毒(逆转录病毒和腺病毒)中;产物表达产生具有环状发夹结构的shRNA。shRNA通过胞内核糖核酸酶(dicer)转化为siRNA,从而展示出RNAi作用。
在本发明中,“微小RNA(microRNA)”调控各种生物学过程,例如发育、分化、增殖、保育和凋亡。通常,微小RNA使靶mRNA不稳定或中断其翻译,从而调控编码靶mRNA的基因的表达。
在本发明中,可用于含反义寡核苷酸、siRNA、shRNA或微小RNA的表达构建体/载体的调控序列(例如组成型启动子、诱导型启动子、组织特异性启动子或其组合)是本领域技术人员可以选择的。
作为本发明的一个实例,反义寡核苷酸、siRNA、shRNA或微小RNA与调节性T细胞表面表达的DKK1蛋白或其表位的编码基因特异性结合,从而抑制该基因的表达,藉此有效地预防、改善或治疗免疫相关疾病,例如癌症。
在本发明中,癌症可以是实体瘤,其是由实体器官中的细胞异常生长引起的附聚物所形成,根据实体器官的位置,可以是但不限于胃癌、肝癌、胶质瘤、卵巢癌、结肠直肠癌、头颈癌、膀胱癌、肾细胞癌、乳腺癌、转移性癌、***癌、胰腺癌、黑素瘤、肺癌等,优选为黑素瘤。
作为本发明的另一个实例,反义寡核苷酸、siRNA、shRNA或微小RNA与调节性T细胞表面表达的DKK1蛋白或其表位的编码基因特异性结合,从而增强该基因的表达,从而有效地预防、改善或治疗免疫相关疾病,例如自身免疫性疾病、移植物抗宿主病、器官移植排斥、哮喘、特应性疾病、急性或慢性炎症性疾病等。
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来阻断疾病症状、或抑制/延迟症状的任何行为。
此外,在本发明中,“治疗”可以包括但不限于使用本发明的药物组合物来减轻或有益地改变疾病症状的任何行为。
在本发明中,所述的药物组合物可以为胶囊、片剂、颗粒剂、注射剂、软膏剂、粉剂或冲剂形式,并且所述的药物组合物可以靶向人。优选地,本发明的药物组合物可以制成注射剂形式并直接注射到发生癌症或免疫疾病的区域。然而,本发明不限于此。
本发明的药物组合物可以按照常规方法分别制成口服制剂,如散剂、颗粒剂、胶囊剂、片剂和水性混悬剂,外用制剂,栓剂,和无菌注射溶液剂的形式,并被使用。但是,药物组合物不限于此。本发明的药物组合物还可以包含药学上可接受的载体。作为药学上可接受的载体,粘合剂、助流剂、崩解剂、赋形剂、增溶剂、分散剂、稳定剂、助悬剂、色素、调味剂等可以用于口服给药,缓冲剂、防腐剂、止痛剂、增溶剂、等渗剂、稳定剂等可以用作注射剂,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可以通过与上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,可以将药物组合物配制成单位剂量安瓿或多剂量的形式。或者,可以将药物组合物配制成溶液、悬浮液、片剂、胶囊、缓释制剂等。
同时,作为适合于制备制剂的载体,稀释剂或赋形剂的实例,乳糖、右旋糖、蔗糖、山梨糖醇、甘露醇、木糖醇、赤藓醇、麦芽糖醇、淀粉、***胶、藻酸盐、明胶、磷酸钙、硅酸钙、纤维素、甲基可以使用纤维素、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。此外,还可以包括填充剂、抗凝剂、润滑剂、润湿剂、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、或直肠途径。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、囊内(intrabursal)、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采用栓剂形式直肠给药。
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、***率、药物组合以及要预防或治疗的特定疾病的严重性。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。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。所述的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、胶囊剂、液体剂、凝胶剂、糖浆剂、浆剂、或混悬剂的形式。
另外,本发明的药物组合物可以与其他抗癌剂组合施用,从而有效地抑制普通癌细胞增殖和癌症转移,使得该药物组合物可以用于治疗癌症。
在此,对于抗癌剂,可以使用选自下组的一种或多种抗癌剂:氮芥子碱、伊马替尼、奥沙利铂、利妥昔单抗、厄洛替尼、纳拉替尼、拉帕替尼、吉非替尼、凡德他尼、尼洛替尼、塞马克尼布、波舒替尼、阿昔替尼、西地尼单抗、来他替尼、曲妥珠单抗、吉非替尼、硼替佐米、舒尼替尼、卡铂、索拉非尼、贝伐单抗、顺铂、西妥昔单抗、白檞寄生、天冬酰胺酶、维甲酸、羟基卡巴脲、达沙替尼、阿司匹马汀、奥格他新、丙卡巴肼、前列地尔、钬硝酸壳聚糖(holmiumnitrate chitosan)、吉西他滨、多西氟啶、培美曲塞、替加氟、卡培他滨、吉美拉西、奥他拉西、阿扎胞苷、甲氨蝶呤、尿嘧啶、阿糖胞苷、氟尿嘧啶、氟达拉滨、依卡他汀、氟哌丁胺、卡西他滨、卡巴他汀、氟哌啶、雷替曲塞、多西他赛、紫杉醇、伊立替康、贝洛特坎、托泊替康、长春瑞滨、依托泊苷、长春碱、伊达柔比星、丝裂霉素、博来霉素、放线菌素、吡柔比星、阿克拉霉素、倍洛霉素、替西罗莫司、替莫唑胺、白消安、异环磷酰胺、环磷酰胺、美法仑、阿司他汀、达卡巴嗪、硫替巴、尼莫司汀、苯丁酸氮芥、二溴卫矛醇、亚叶酸、维甲酸、依西美坦、氨鲁米特、阿那格雷、奥拉帕尼、奈韦宾、法得唑、他莫昔芬、托瑞米芬、睾丸内酯、阿那曲唑、来曲唑、伏洛唑、比卡鲁胺、洛莫司汀、5FU、伏立诺他、恩替司他、和卡莫斯汀。然而,所述抗癌剂不限于此。
另外,本发明的药物组合物可以与其他免疫抑制剂组合施用,从而有效地抑制由一般的超免疫应答引起的疾病。
在本发明中,对于免疫抑制剂,可以使用选自下组的一种或多种免疫抑制剂:糖皮质激素、环磷酰胺、环孢菌素、他克莫司、雷帕霉素、IV型PDE抑制剂、p38激酶抑制剂、硫唑嘌呤、霉酚酸酯、咪唑啉、甲氨蝶呤、来氟米特和布喹那。但是,所述免疫抑制剂不限于此。
根据本发明的另一种实施方式,提供了一种预防或治疗免疫相关疾病的方法,包括以下步骤:向需要治疗的受试者施用本发明的DKK1的胞外表面蛋白或其表位的特异性抗体。
在本发明中,需要治疗的受试者是患有免疫相关疾病或具有其症状的疑似个体。其中免疫相关疾病的一个实例可以是癌症,例如胃癌、肝癌、胶质瘤、卵巢癌、结直肠癌、头颈癌、膀胱癌、肾细胞癌、乳腺癌、转移性癌、***癌、胰腺癌、黑素瘤或肺癌;另一个实例可以是自身免疫性疾病、移植物抗宿主病、器官移植排斥、哮喘、特应性疾病、急性或慢性炎症性疾病等。
作为本发明的一个实例,该抗体与调节性T细胞表面表达的DKK1蛋白或其表位特异性结合,从而可以抑制调节性T细胞的活性,藉此有效地预防、改善或治疗免疫相关疾病,例如癌症。
作为本发明的另一个实例,该抗体与调节性T细胞表面表达的DKK1蛋白或其表位特异性结合,从而可以增强调节性T细胞的活性,从而有效地预防、改善或治疗免疫相关疾病,例如自身免疫性疾病、移植物抗宿主病、器官移植排斥、哮喘、特应性疾病、急性或慢性炎症性疾病等。
根据本发明的另一种实施方式,存在一种用于预防或治疗免疫相关疾病的方法,包括以下步骤:向需要治疗的受试者施用选自下组的任一种:反义寡核苷酸、siRNA、shRNA和microRNA,它们各自对编码本发明的DKK1的胞外表面蛋白或表位的基因具有特异性。
在本发明中,需要治疗的受试者是患有免疫相关疾病或具有其症状的疑似个体。其中免疫相关疾病的一个实例可以是癌症,例如胃癌、肝癌、胶质瘤、卵巢癌、结直肠癌、头颈癌、膀胱癌、肾细胞癌、乳腺癌、转移性癌、***癌、胰腺癌、黑素瘤或肺癌;另一个实例可以是自身免疫性疾病、移植物抗宿主病、器官移植排斥、哮喘、特应性疾病、急性或慢性炎症性疾病等。
作为本发明的一个实例,反义寡核苷酸、siRNA、shRNA或微小RNA与调节性T细胞表面表达的DKK1蛋白或其表位的编码基因特异性结合,从而抑制该基因的表达,藉此有效地预防、改善或治疗免疫相关疾病,例如癌症。
作为本发明的另一个实例,反义寡核苷酸、siRNA、shRNA或微小RNA与调节性T细胞表面表达的DKK1蛋白或其表位的编码基因特异性结合,从而增强该基因的表达,藉此有效地预防、改善或治疗免疫相关疾病,例如自身免疫性疾病、移植物抗宿主病、器官移植排斥、哮喘、特应性疾病、急性或慢性炎症性疾病等。
在本发明的一种实施方式中,术语“施用”或“给药”是指以任何合适的方式将本发明的组合物引入患者。对于给药途径,本发明的组合物可以通过任何常规途径给药,只要该途径允许组合物到达靶组织即可。可以进行口服给药、腹膜内给药、静脉内给药、肌肉内给药、皮下给药、皮内给药、鼻内给药、肺部给药、直肠给药、腔内给药、腹膜内给药、硬膜内给药。然而,本发明不限于此。本发明的治疗方法可以包括以药学有效量施用抗体,反义寡核苷酸、siRNA、shRNA或微小RNA。在本发明中,可以根据各种因素来调节有效量,所述因素包括疾病的类型,疾病的严重程度,组合物中所含的活性成分和其他成分的类型和剂量,制剂的类型,患者的年龄、体重、总体健康状况、性别和饮食,给药时间,给药途径,组合物的分泌率,治疗的持续时间以及同时使用的药物。对于成年人,一天一次或几次给药时,该基因的表达抑制剂或该蛋白的活性抑制剂的给药剂量如下:对于siRNA,为0.01ng/kg至10mg/kg;对于针对该基因mRNA的反义寡核苷酸,为0.01ng/kg至10mg/kg;对于化合物,为0.1ng/kg至10mg/kg,对于该蛋白的单克隆抗体,为0.1ng/kg至10mg/kg。
在本发明中,当以上述方式给药时,可以在施用时进一步组合施用另一种抗癌剂或免疫抑制剂。
根据本发明的另一种实施方式,提供了一种筛选免疫活化剂或免疫抑制剂的方法,包括以下步骤:(a)将待测样品与含有DKK1的胞外表面蛋白或表位的调节性T细胞接触;(b)检测胞外表面蛋白或表位的表达水平;和(c)当检测的胞外表面蛋白或表位表达水平下调或上调时,确定该样品是免疫激活剂或免疫抑制剂。
在本发明中,“筛选”是通过特定的操作或评估方法从各种物质组成的候选组中选择具有特定的目标特征的物质。用于本发明的目的,本发明的筛选是一种筛选方法,其是将用于治疗免疫相关疾病的候选物质施用于疑似患有该疾病的个体,随后本发明蛋白的表达降低或增加,在此情况下,确定候选物质是免疫抑制剂或免疫活化剂。***性方法,如分子生物学测定、数字成像、细胞学和组织学检测,可以用于测定本发明基因和蛋白对于患病病变或疑似患有疾病的组织的活性。
在本发明中,DKK1的胞外表面蛋白或表位的表达水平,数量或活性可以使用能够特异性结合DKK1的胞外表面蛋白或表位的抗体进行测量。在本发明中,使用了这样的方法,使生物样品中所讨论的抗体和蛋白形成抗原-抗体复合物,并对抗原-抗体复合物进行检测。
如本文所用,术语“抗原-抗体复合物”是指蛋白抗原和识别该抗原的抗体的组合,该蛋白抗原用于鉴定生物学样品中是否存在所讨论的基因。抗原-抗体复合物的检测可以使用本领域已知的方法来实现,例如,光谱法、光化学法、生物化学法、免疫化学法、电学法、基于吸光度的方法、化学法和其他方法。
在本发明中,用于测定或比较分析蛋白表达水平的方法可以包括但不限于:蛋白芯片分析、免疫测定、配体结合测定、基质辅助激光解吸/电离飞行时间质谱(MALDI-TOF)测定、表面增强激光解吸/电离飞行时间质谱(SELDI-TOF)测定、放射免疫测定、放射免疫扩散此欧氏免疫扩散(Ouchterlony immunodiffusion)、火箭免疫电泳(rocketimmunoelectrophoresis)、组织免疫染色、补体固定测定、二维电泳测定、液相色谱-质谱联用(LC-MS)、液相二级质谱(LC-MS/MS)、免疫印迹、酶联免疫吸附测定(ELISA)等。
根据本发明的另一种实施方式,提供了一种筛选免疫活化剂或免疫抑制剂的方法,包括以下步骤:(a)使待测样品与含有DKK1的胞外表面蛋白或表位编码基因的调节性T细胞接触;(b)检测基因的表达水平;(c)当检测的基因表达水平下调或上调时,确定样品是免疫激活剂或免疫抑制剂。
在本发明中,DKK1的胞外表面蛋白或表位的编码基因表达水平可以用能够特异性结合该基因的引物、探针或反义核苷酸进行检测。关于本发明的DKK1的胞外表面蛋白或表位及其编码基因的信息是已知的。因此,基于该信息,本领域技术人员可以容易地设计与该蛋白的编码基因特异性结合的引物、探针或反义核苷酸。
如本文所用,术语“引物”是指具有短的游离3’-羟基的核酸序列,该核酸序列是可以与其互补模板碱基配对并用作模板链复制起始位点的短核酸序列。引物可以在适当的缓冲液和适当的温度下,在聚合试剂(即DNA聚合酶或逆转录酶)和四种不同的核苷三磷酸存在的情况下,启动DNA合成。在本发明中,可以通过使用针对DKK1胞外表面蛋白编码基因的正义和反义引物进行PCR扩增并检查是否产生所需产物来诊断癌症。可以基于本领域已知的那些优化PCR条件,正义和反义引物的长度。
另外,如本文所用,术语“探针”是指核酸片段,例如RNA或DNA,其能够与mRNA特异性结合,长度范围从短至几个碱基到长至数百个碱基。探针是被标记的,从而可以鉴定是否存在特定的mRNA。探针可以制成寡核苷酸探针、单链DNA探针、双链DNA探针、RNA探针等形式。在本发明中,可以通过使用与DKK1胞外表面蛋白编码基因互补的探针进行杂交并检查是否发生杂交来诊断癌症。可以基于本领域已知的那些对合适探针的选择和杂交条件进行修饰。
可以使用固相亚磷酰胺支撑法或其他众所周知的方法进行本发明引物或探针的化学合成。此类核酸序列也可以使用本领域已知的任何方式进行修饰。此类修饰的非限制性实例包括:甲基化、“帽化”、用其同源物替换一个或多个天然核苷酸、以及核苷酸内部修饰,例如,用不带电荷的键(例如,膦酸甲酯、磷酸三酯、氨基磷酸酯、氨基甲酸酯等)或带电荷的键(例如,硫代磷酸酯、二硫代磷酸酯等)进行修饰。
在本发明中,逆转录聚合酶反应、竞争性逆转录聚合酶反应、实时逆转录聚合酶反应,RNA酶保护测定,Northern印迹,DNA芯片等可以用作测定或比较分析基因表达水平的方法。然而,所述方法不限于此。
根据本发明的另一种实施方式,提供了一种用于诊断免疫相关疾病的诊断组合物,其包含本发明的DKK1的胞外表面蛋白或其表位的特异性抗体作为活性成分。
如本文所用,术语“诊断”是指鉴定病理状态的存在或特征。用于本发明目的的诊断是鉴定胃癌的发生和转移。
另外,在本发明中,DKK1胞外表面蛋白可以存在于调节性T细胞的表面。
在本发明中,通过使用抗体测定存在于调节性T细胞表面的DKK1胞外表面蛋白或表位的表达水平,可以对免疫相关疾病进行诊断。
作为本发明的一个实例,免疫相关疾病可以是但不限于癌症,更具体地,癌症、肝癌、胶质瘤、卵巢癌、结直肠癌、头颈癌、膀胱癌、肾细胞癌、乳腺癌、转移性癌、***癌、胰腺癌、黑素瘤、肺癌等,优选为黑素瘤。
作为本发明的另一个实例,免疫相关疾病可以是但不限于自身免疫性疾病、移植物抗宿主疾病、器官移植排斥、哮喘、特应性疾病、急性或慢性炎症性疾病等。
根据本发明的另一种实施方式,提供了一种用于免疫相关疾病的诊断组合物,其包含选自下组任一种:引物、探针和反义核苷酸,它们各自对编码本发明的DKK1的胞外表面蛋白或表位的基因具有特异性。
另外,在本发明中,DKK1胞外表面蛋白可以存在于调节性T细胞的表面。
在本发明中,通过使用抗体测定存在于调节性T细胞表面的DKK1胞外表面蛋白或表位的编码基因的表达水平,可以对免疫相关疾病进行诊断。
作为本发明的一个实例,免疫相关疾病可以是但不限于癌症,更具体地,癌症、肝癌、胶质瘤、卵巢癌、结直肠癌、头颈癌、膀胱癌、肾细胞癌、乳腺癌、转移性癌、***癌、胰腺癌、黑素瘤、肺癌等,优选为黑素瘤。
作为本发明的另一个实例,免疫相关疾病可以是但不限于自身免疫性疾病,移植物抗宿主疾病、器官移植排斥、哮喘、特应性疾病、急性或慢性炎症性疾病等。
根据本发明的另一种实施方式,提供了一种用于免疫相关疾病的诊断试剂盒,其包含本发明的诊断组合物。
如本文所用,术语“试剂盒”是指特定目的所需的一套组合物和配件。用于本发明的目的,本发明的试剂盒可用于诊断免疫相关疾病,例如癌症、自身免疫性疾病、移植物抗宿主疾病、器官移植排斥、哮喘、特应性疾病或急性或慢性炎症性疾病,这通过在mRNA或蛋白质表达水平上测定DKK1胞外表面蛋白(其是此类免疫相关疾病的诊断标志物)的表达水平来实现。本发明的试剂盒中可包含以下物质:用于检测免疫相关疾病的诊断标志物表达水平的引物或探针,或任选的识别该标志物的抗体,以及一种或多种其他适合检测的组合物,溶液或装置。
根据本发明的另一种实施方式,提供了一种提供有关免疫相关疾病的信息的方法,包括通过使用DKK1胞外表面蛋白或表位的特异性抗体来测定存在于调节性T细胞的DKK1胞外表面蛋白或表位的表达水平。
作为本发明的一个实例,免疫相关疾病可以是但不限于癌症,更具体地,癌症、肝癌、胶质瘤、卵巢癌、结直肠癌、头颈癌、膀胱癌、肾细胞癌、乳腺癌、转移性癌、***癌、胰腺癌、黑素瘤、肺癌等,优选为黑素瘤。
作为本发明的另一个实例,免疫相关疾病可以是但不限于自身免疫性疾病、移植物抗宿主疾病、器官移植排斥、哮喘、特应性疾病、急性或慢性炎症性疾病等。
在本发明中,在被诊断为免疫相关疾病的情况下,该方法可以进一步包括施用免疫相关疾病的治疗剂的步骤。
根据本发明的另一种实施方式,提供了一种提供有关免疫相关疾病的信息的方法,包括使用选自下组的任一种来测定调节性T细胞中本发明的DKK1胞外表面蛋白或表位的编码基因的表达水平:引物,探针和反义核苷酸,它们各自对该基因具有特异性。
作为本发明的一个实例,免疫相关疾病可以是但不限于癌症,更具体地,癌症、肝癌、胶质瘤、卵巢癌、结直肠癌、头颈癌、膀胱癌、肾细胞癌、乳腺癌、转移性癌、***癌、胰腺癌、黑素瘤、肺癌等,优选为黑素瘤。
作为本发明的另一个实例,免疫相关疾病可以是但不限于自身免疫性疾病、移植物抗宿主疾病、器官移植排斥、哮喘、特应性疾病、急性或慢性炎症性疾病等。
在本发明中,在被诊断为免疫相关疾病的情况下,该方法可以进一步包括施用免疫相关疾病的治疗剂的步骤。
发明的有益效果
在本发明中,由于DKK1蛋白特异性存在于免疫细胞,特别是调节性T细胞的表面,DKK1蛋白可用作各种免疫相关疾病治疗剂的新靶标。
附图的简要说明
图1显示了根据本发明实施方式的DKK1蛋白的结构。
图2显示了根据本发明的一种实施方式的DKK1蛋白的表位的预测结果。
图3显示了根据本发明的一种实施方式的DKK1蛋白的表位的预测结果。
图4显示了根据本发明的一种实施方式的DKK1蛋白的表位的预测结果。
图5显示了根据本发明的一种实施方式的DKK1蛋白的3S8V链X中的表位的预测结果。
图6显示了根据本发明的一种实施方式的DKK1蛋白的3SOQ链Z中的表位的预测结果。
图7显示了根据本发明的一种实施方式的DKK1蛋白的5FWW链B中的表位的预测结果。
图8显示了根据本发明的一种实施方式的DKK1蛋白的5FWW链B中的表位的预测结果。
图9显示了根据本发明的一种实施方式的mRNA表达水平。
图10显示了根据本发明的一种实施方式的mRNA表达水平。
图11显示了根据本发明的一种实施方式的调节性T细胞表面的DKK1蛋白的表达。
发明详述
根据本发明的一种实施方式,提供了SEQ ID NO:3所示的DKK1的调节性T细胞外表面蛋白。
根据本发明的另一种实施方式,提供了作为调节性T细胞表面蛋白的DKK1的表位,如SEQ ID NO:4-36中任一所示。
根据本发明的另一种实施方式,提供了一种多核苷酸,该多核苷酸编码如SEQ IDNO:3所示的DKK1的胞外表面蛋白,或编码本发明提供的SEQ ID NO:4-36中任一所示的DKK1表位。
根据本发明的另一种实施方式,提供了一种***有本发明提供的多核苷酸的表达载体。
根据本发明的另一种实施方式,提供了用本发明提供的表达载体转染的宿主细胞系。
根据本发明的另一种实施方式,提供了一种调节性T细胞,其包含本发明的DKK1的胞外表面蛋白或DKK1的表位。
根据本发明的另一种实施方式,提供了一种用于预防或治疗免疫相关疾病的药物组合物,其包含调节性T细胞作为活性成分,该调节性T细胞包含本发明的DKK1的胞外表面蛋白或其表位。
根据本发明的另一种实施方式,提供了一种用于预防或治疗免疫相关疾病的药物组合物,其包含本发明的DKK1的胞外表面蛋白或其表位作为活性成分。
根据本发明的另一种实施方式,提供了一种用于预防或治疗免疫相关疾病的药物组合物,其包含本发明的DKK1的胞外表面蛋白或其表位的特异性抗体作为活性成分。
根据本发明的另一种实施方式,提供了一种用于免疫相关疾病的药物组合物,其包含选自下组任一种作为活性成分:反义寡核苷酸、siRNA、shRNA和microRNA,它们各自对编码本发明的DKK1的胞外表面蛋白或表位的基因具有特异性。
根据本发明的另一种实施方式,提供了一种预防或治疗免疫相关疾病的方法,包括以下步骤:向需要治疗的受试者施用本发明的DKK1的胞外表面蛋白或其表位的特异性抗体。
根据本发明的另一种实施方式,存在一种用于预防或治疗免疫相关疾病的方法,包括以下步骤:向需要治疗的受试者施用选自下组的任一种:反义寡核苷酸、siRNA、shRNA和microRNA,它们各自对编码本发明的DKK1的胞外表面蛋白或表位的基因具有特异性。
根据本发明的另一种实施方式,提供了一种筛选免疫活化剂或免疫抑制剂的方法,包括以下步骤:(a)将待测样品与含有DKK1的胞外表面蛋白或表位的调节性T细胞接触;(b)检测胞外表面蛋白或表位的表达水平;和(c)当检测的胞外表面蛋白或表位表达水平下调或上调时,确定该样品是免疫激活剂或免疫抑制剂。
根据本发明的另一种实施方式,提供了一种筛选免疫活化剂或免疫抑制剂的方法,包括以下步骤:(a)使待测样品与含有DKK1的胞外表面蛋白或表位编码基因的调节性T细胞接触;(b)检测基因的表达水平;(c)当检测的基因表达水平下调或上调时,确定样品是免疫激活剂或免疫抑制剂。
根据本发明的另一种实施方式,提供了一种提供有关免疫相关疾病的信息的方法,包括通过使用DKK1胞外表面蛋白或表位的特异性抗体来测定存在于调节性T细胞的DKK1胞外表面蛋白或表位的表达水平。
根据本发明的另一种实施方式,提供了一种提供有关免疫相关疾病的信息的方法,包括使用特异性针对本发明的DKK1胞外表面蛋白或表位编码基因的选自下组的任一种来测定调节性T细胞中本发明的DKK1胞外表面蛋白或表位的编码基因的表达水平:引物、探针和反义核苷酸,它们各自对该基因具有特异性。
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,并且本领域技术人员会明白,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]DKK1
C端结构的鉴定
已知DKK1以分泌蛋白的形式与LRP6结合,对应于对其具有特异性的配体。其中,DKK1 C端区域的第182-266位氨基酸结构对于DKK1与配体的结合至关重要,并且这种结构使得DKK1和LRP6彼此具有高结合能力。因此,与其结合在Wnt细胞信号传导***中发挥重要作用。DKK1的C端蛋白的结构如图2所示。1.
[实施例2]DKK1表位的氨基酸序列的预测
基于DKK1蛋白的结构,使用表位预测软件ABCpred(图2)、BCEpred(图3)、Discotope服务器和Ellipro服务器(http://tools.iedb.org/ellipro/)(图4-8)对上述碱基序列进行预测。之所以使用Ellipro和Discotope搜索引擎,是由于其与现行的预测表位算法中最可靠的搜索引擎相对应。
将实施例1中分析的胞外结构域输入到表位预测软件中,随后对预测表位的连续或不连续的氨基酸序列进行预测,如图2-8所示。
如图2-8所示,共预测得到19个连续表位氨基酸序列,如SEQ ID NO:4-22所示,共预测得到14个不连续表位氨基酸序列,如SEQ ID NO:23-36所示。
[实施例3]在调节性T细胞中DKK1
mRNA的特异性表达的鉴定
对DKK1蛋白是否可以用作调节性T细胞的特异性生物标志物进行验证。
为了进行验证,使用磁激活细胞分选(MACS),用CD4磁珠从小鼠脾脏中分离CD4+T细胞,其中,小鼠脾脏已按常规手段进行了C57BL/6或Foxp3和FRP的表达。
随后,使用CD25抗体,通过荧光激活细胞分选仪(FACS)分离调节性T(CD4+CD25+T)细胞和非调节性T(CD4+CD25-T)细胞。对于各细胞,使用Trizol提取mRNA,并根据制造商提供的方案使用gDNA提取试剂盒(Qiagen)从基因组RNA中去除gDNA。使用BDsprint cDNA合成试剂盒(Clonetech),将去除gDNA的mRNA合成为cDNA。
进行实时聚合酶链式反应(RT PCR),从而定量鉴定cDNA中DKK1 mRNA的表达水平。根据制造商提供的方案,使用SYBR Green(分子探针)和下表4所示的引物进行实时聚合酶链式反应,按如下条件进行40个循环,包括95℃3分钟,61℃15秒,72℃ 30秒,使用ΔCT方法计算相对基因表达水平,并使用HPRT将其标准化。结果如图9所示。
[表4]
如图9所示,在调节性T细胞中几乎未发现DKK家族基因和Wnt基因的表达。然而,已经确定DKK1基因的表达非常高。结果表明,DKK1很可能被用作调节性T细胞的生物标志物。
[实施例4]免疫细胞中DKK1
mRNA的表达的鉴定
对DKK1蛋白是否可以用作调节性T细胞的特异性生物标志物进行验证。
在实施例3分离的CD4+T细胞中,使用CD62L抗体(eBioscience)和荧光激活的细胞分选仪分离Treg(CD4+RFP+)细胞,天然T细胞和效应T细胞。使用针对CD8β链的抗体和针对CD19的抗体分离CD8+T细胞和B细胞,随后在有或没有CD3和CD28抗体(eBioscience)的条件下,或在可以分化成CD4+T细胞亚群的条件下进行孵育。以与实施例3相同的方式从中提取mRNA,并鉴定DKK1 mRNA的表达。结果如图10所示。
如图10所示,本发明的DKK1基因仅在调节性T细胞中高水平表达。在相同的调节性T细胞中,用CD3和CD28抗体处理的一组细胞表现出较高的DKK1表达;与诱导型调节性T细胞(诱导型Tregs)相比,在胸腺中产生的天然调节性T细胞(天然Tregs)中观察到的DKK1表达更高,该诱导型调节性T细胞是通过分化信号分化成处于身体中处于外周的(periphery)调节性T细胞而获得,或这通过实验分化成调节性T细胞而获得。
[实施例5]在调节性T细胞中DKK1蛋白的特异性表达的鉴定
从以下观点出发:为了成为细胞治疗的靶标,DKK1蛋白必须在调节性T细胞的表面表达,从而可以更有效地进行靶向治疗。对DKK1蛋白是否在调节性T细胞表面表达进行鉴定。
用抗CD4-APC和抗DKK1-PE抗体对实施例4的各分化的T细胞亚群进行染色,并使用荧光激活细胞分选仪(FACS)在各细胞的表面检测DKK1的表达水平。结果如图11所示。
如图11所示,与不表达Foxp3的其他效应T细胞相比,当T细胞受体信号被激活时,调节性T细胞(CD4+Foxp+)以更高的水平表达DKK1。
尽管上面已经详细描述了本发明,但是本发明的范围不限于此。对于本领域技术人员将显而易见的是,在不脱离权利要求中描述的本发明的技术精神的情况下,可以进行各种修改和改变。
工业实用性
本发明涉及Dickkopf-1(DKK1)蛋白、其特异性抗体及其用途,DDK1蛋白特异性存在于免疫细胞,特别是调节性T细胞(Treg细胞)的表面上。
序列表自由文本
SEQ ID NO:1:dickkopf-1(DKK-1)氨基酸序列
SEQ ID NO:2:dickkopf-1(DKK-1)mRNA,完整的cds序列(GenBank:AF177394.2)
SEQ ID NO:3:DKK1胞外结构域
TLNSVLNSNAIKNLPPPLGGAAGHPGSAVSAAPGILYPGGNKYQTIDNYQPYPCAEDEECGTDEYCASPTRGGDAGVQICLACRKRRKRCMRHAMCCPGNYCKNGICVSSDQNHFRGEIEETITESFGNDHSTLDGYSRRTTLSSKMYHTKGQEGSVCLRSSDCASGLCCARHFWSKICKPVLKEGQVCTKHRRKGSHGLEIFQRCYCGEGLSCRIQKDHHQASNSSRLHTCQRH
SEQ ID NO:4:3S2K链C线性表位
RIQKRL
SEQ ID NO:5:3S2K链C线性表位
HRRKGSHGLE IF
SEQ ID NO:6:3S2K链C线性表位
KGQEGSVCLR SSDCASG
SEQ ID NO:7:3S8V链X线性表位
RIQSRL
SEQ ID NO:8:3S8V链X线性表位
HRRKGSHGLE IF
SEQ ID NO:9:3S8V链X线性表位
GEGL
SEQ ID NO:10:3S8V链X线性表位
QEGSVCLRSS DCASG
SEQ ID NO:11:3S8V链X线性表位
KEGQ
SEQ ID NO:12:3S8V链X线性表位
NSNAIKN
SEQ ID NO:13:5FWW链B线性表位
RVPGASHIH
SEQ ID NO:14:5FWW链B线性表位
GTQNWTALQG GKPCLFWNET FQHPYNTLKY PNGE
SEQ ID NO:15:5FWW链B线性表位
KDHGNPPPLT GTSKTSNKL
SEQ ID NO:16:5FWW链B线性表位
FSDRINQ
SEQ ID NO:17:5FWW链B线性表位
CYVGVYWK
SEQ ID NO:18:5FWW链B线性表位
IRDSADMVEL LDGYTHRVLA RFHGRSRPPL SFNVSLDFVI
SEQ ID NO:19:5FWW链B线性表位
LGEHNYC
SEQ ID NO:20:5FWW链B线性表位
FCGNNPDYWK YGE
SEQ ID NO:21:5FWW链B线性表位
SQRFK
SEQ ID NO:22:5FWW链B线性表位
ATGRV
SEQ ID NO:23:3S2K链C不连续表位
HKGSGL
SEQ ID NO:24:3S2K链C不连续表位
IQL
SEQ ID NO:25:3S2K链C不连续表位
FWIF
SEQ ID NO:26:3S2K链C不连续表位
EGQGEGRH
SEQ ID NO:27:3S2K链C不连续表位
KGQEGSVCLR SDASG
SEQ ID NO:28:3S8V链X不连续表位
IQSRL
SEQ ID NO:29:3S8V链X不连续表位
HKGSGL
SEQ ID NO:30:3S8V链X不连续表位
QGSVCRSD
SEQ ID NO:31:3S8V链X不连续表位
FWIF
SEQ ID NO:32:3S8V链X不连续表位
EGQGGLR
SEQ ID NO:33:3S8V链X不连续表位
ASG
SEQ ID NO:34:5FWW链B不连续表位
GTQNWTALQG GKPCLFWNET FQHPYNTLKY PNGELGEHNY CPCYVGVYWK C
SEQ ID NO:35:5FWW链B不连续表位
AMYATGRVRV PGASHIHIRD SADMELDGYT HRVLARHGRS PPLSFNVSLD FVIFSDRINQAQAVK
SEQ ID NO:36:5FWW链B不连续表位
KDHGNPPPLT GTSKTSNKLF SQRFKSGYFC GNNPDYWKYG ECFGGDG
序列表
<110> 古德T细胞有限公司
<120> 特异性存在于调节性T细胞中的DKK1蛋白及其用途
<130> P2019-1947
<150> KR 10-2017-0058336
<151> 2017-05-10
<150> KR 10-2017-0058337
<151> 2017-05-10
<160> 36
<170> SIPOSequenceListing 1.0
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atgatggctc tgggcgcagc gggagctacc cgggtctttg tcgcgatggt agcggcggct 60
ctcggcggcc accctctgct gggagtgagc gccaccttga actcggttct caattccaac 120
gctatcaaga acctgccccc accgctgggc ggcgctgcgg ggcacccagg ctctgcagtc 180
agcgccgcgc cgggaatcct gtacccgggc gggaataagt accagaccat tgacaactac 240
cagccgtacc cgtgcgcaga ggacgaggag tgcggcactg atgagtactg cgctagtccc 300
acccgcggag gggacgcagg cgtgcaaatc tgtctcgcct gcaggaagcg ccgaaaacgc 360
tgcatgcgtc acgctatgtg ctgccccggg aattactgca aaaatggaat atgtgtgtct 420
tctgatcaaa atcatttccg aggagaaatt gaggaaacca tcactgaaag ctttggtaat 480
gatcatagca ccttggatgg gtattccaga agaaccacct tgtcttcaaa aatgtatcac 540
accaaaggac aagaaggttc tgtttgtctc cggtcatcag actgtgcctc aggattgtgt 600
tgtgctagac acttctggtc caagatctgt aaacctgtcc tgaaagaagg tcaagtgtgt 660
accaagcata ggagaaaagg ctctcatgga ctagaaatat tccagcgttg ttactgtgga 720
gaaggtctgt cttgccggat acagaaagat caccatcaag ccagtaattc ttctaggctt 780
cacacttgtc agagacacta a 801
<210> 3
<211> 235
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<213> 智人(Homo sapiens)
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Thr Leu Asn Ser Val Leu Asn Ser Asn Ala Ile Lys Asn Leu Pro Pro
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Pro Leu Gly Gly Ala Ala Gly His Pro Gly Ser Ala Val Ser Ala Ala
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Asn His Phe Arg Gly Glu Ile Glu Glu Thr Ile Thr Glu Ser Phe Gly
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Arg Ile Gln Lys Arg Leu
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<210> 5
<211> 12
<212> PRT
<213> 智人(Homo sapiens)
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His Arg Arg Lys Gly Ser His Gly Leu Glu Ile Phe
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<210> 6
<211> 17
<212> PRT
<213> 智人(Homo sapiens)
<400> 6
Lys Gly Gln Glu Gly Ser Val Cys Leu Arg Ser Ser Asp Cys Ala Ser
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Gly
<210> 7
<211> 6
<212> PRT
<213> 智人(Homo sapiens)
<400> 7
Arg Ile Gln Ser Arg Leu
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<210> 8
<211> 12
<212> PRT
<213> 智人(Homo sapiens)
<400> 8
His Arg Arg Lys Gly Ser His Gly Leu Glu Ile Phe
1 5 10
<210> 9
<211> 4
<212> PRT
<213> 智人(Homo sapiens)
<400> 9
Gly Glu Gly Leu
1
<210> 10
<211> 15
<212> PRT
<213> 智人(Homo sapiens)
<400> 10
Gln Glu Gly Ser Val Cys Leu Arg Ser Ser Asp Cys Ala Ser Gly
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<210> 11
<211> 4
<212> PRT
<213> 智人(Homo sapiens)
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Lys Glu Gly Gln
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Asn Ser Asn Ala Ile Lys Asn
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Gly Thr Gln Asn Trp Thr Ala Leu Gln Gly Gly Lys Pro Cys Leu Phe
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Trp Asn Glu Thr Phe Gln His Pro Tyr Asn Thr Leu Lys Tyr Pro Asn
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Phe Ser Asp Arg Ile Asn Gln
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Claims (26)
1.一种筛选免疫激活剂或免疫抑制剂的方法,包括以下步骤:
(a)使待测样品与含有Dickkopf-1(DKK1)胞外表面蛋白或表位的调节性T细胞接触,所述表位如SEQ ID NO:4-36中任一所示;
(b)检测所述胞外表面蛋白或表位的表达水平;和
(c)在所述胞外表面蛋白或表位的表达水平检测为下调或上调的情况下,判定所述样品是免疫激活剂或免疫抑制剂。
2.如权利要求1所述的方法,
其中,所述胞外表面蛋白或表位的表达水平利用能够特异性结合所述胞外表面蛋白或表位的抗体进行检测。
3.如权利要求1所述的方法,
其中,所述的DKK1胞外表面蛋白如SEQ ID NO:3所示。
4.如权利要求1所述的方法,
其中,所述胞外表面蛋白或表位的表达水平利用选自下组的方法进行检测:蛋白芯片分析、免疫测定、配体结合测定、基质辅助激光解吸/电离飞行时间质谱(MALDI-TOF)测定、表面增强激光解吸/电离飞行时间质谱(SELDI-TOF)测定、放射免疫测定、放射免疫扩散、欧氏免疫扩散(Ouchterlony immunodiffusion)、火箭免疫电泳(rocketimmunoelectrophoresis)、组织免疫染色、补体固定测定、二维电泳测定、液相色谱-质谱联用(LC-MS)、液相二级质谱(LC-MS/Ms)、免疫印迹、和酶联免疫吸附测定(ELISA)。
5.一种筛选免疫激活剂或免疫抑制剂的方法,包括以下步骤:
(a)使待测样品与含有Dickkopf-1(DKK1)胞外表面蛋白或表位的编码基因的调节性T细胞接触,所述表位如SEQ ID NO:4-36中任一所示;
(b)检测所述基因的表达水平;和
(c)在所述基因的表达水平检测为下调或上调的情况下,判定所述样品是免疫激活剂或免疫抑制剂。
6.如权利要求5所述的方法,
其中,利用能够与所述基因特异性结合的引物、探针或反义核苷酸检测所述基因的表达水平。
7.如权利要求5所述的方法,
其中,所述的DKK1胞外表面蛋白如SEQ ID NO:3所示。
8.如权利要求5所述的方法,
其中,所述基因的表达水平利用选自下组的方法进行检测:逆转录聚合酶反应、竞争性逆转录聚合酶反应、实时逆转录聚合酶反应、RNA酶保护测定、Northern印迹和DNA芯片法。
9.一种如SEQ ID NO:4-36中任一所示的Dickkopf-1(DKK1)表位。
10.一种用于预防或治疗免疫相关疾病的药物组合物,包含
调节性T细胞(Treg细胞)作为活性成分,所述的调节性T细胞含有SEQ ID NO:3所示的Dickkopf-1(DKK1)胞外表面蛋白。
11.如权利要求10所述的药物组合物,
其中,所述的免疫相关疾病选自下组:自身免疫性疾病、移植物抗宿主病、器官移植排斥、哮喘、特应性疾病和急性或慢性炎症性疾病。
12.一种用于预防或治疗免疫相关疾病的药物组合物,包含
调节性T细胞(Treg细胞)作为活性成分,所述的调节性T细胞含有SEQ ID NO:4-36中任一所示的Dickkopf-1(DKK1)表位。
13.如权利要求12所述的药物组合物,
其中,所述的免疫相关疾病选自下组:自身免疫性疾病、移植物抗宿主病、器官移植排斥、哮喘、特应性疾病和急性或慢性炎症性疾病。
14.一种用于预防或治疗免疫相关疾病的药物组合物,包含
DKK1胞外表面蛋白或表位的特异性抗体,所述表位如SEQ ID NO:4-36中任一所示。
15.如权利要求14所述的药物组合物,
其中,所述的免疫相关疾病是癌症。
16.如权利要求14所述的药物组合物,
其中,所述的免疫相关疾病选自下组:自身免疫性疾病、移植物抗宿主病、器官移植排斥、哮喘、特应性疾病和急性或慢性炎症性疾病。
17.一种用于免疫相关疾病的药物组合物,包含
选自下组的任一种作为活性成分:反义寡核苷酸、siRNA、shRNA和microRNA,它们各自对DKK1胞外表面蛋白或表位的编码基因具有特异性,所述的表位如SEQ ID NO:4-36中任一所示。
18.如权利要求17所述的药物组合物,
其中,所述的免疫相关疾病是癌症。
19.如权利要求17所述的药物组合物,
其中,所述的免疫相关疾病选自下组:自身免疫性疾病、移植物抗宿主病、器官移植排斥、哮喘、特应性疾病和急性或慢性炎症性疾病。
20.一种用于免疫相关疾病的诊断组合物,其包含:
DKK1胞外表面蛋白或SEQ ID NO:4-36中任一所示蛋白的特异性抗体。
21.一种用于免疫相关疾病的诊断组合物,其包含:
针对DKK1胞外表面蛋白或表位编码基因具有特异性的引物、探针或反义核苷酸,所述表位如SEQ ID NO:4-36中任一所示。
22.一种用于免疫相关疾病的诊断试剂盒,其包含:
如权利要求20或21所述的药物组合物。
23.一种提供有关免疫相关疾病的信息的方法,包括:
通过使用DKK1胞外表面蛋白或表位的特异性抗体来测定存在于调节性T细胞的DKK1胞外表面蛋白或表位的表达水平,所述表位如SEQ ID NO:4-36中任一所示。
24.一种提供有关免疫相关疾病的信息的方法,包括:
通过使用选自引物、探针和反义核苷酸的任何一种来测定存在于调节性T细胞的DKK1胞外表面蛋白或表位编码基因的表达水平,所述的引物、探针和反义核苷酸各自对所述基因具有特异性,所述表位如SEQ ID NO:4-36中任一所示。
25.一种用于预防或治疗免疫相关疾病的方法,包括以下步骤:
向需要治疗的受试者施用本发明的DKK1胞外表面蛋白或表位的特异性抗体。
26.一种用于预防或治疗免疫相关疾病的方法,包括以下步骤:
向需要治疗的受试者施用选自下组的任一种:反义寡核苷酸、siRNA、shRNA和microRNA,它们各自对编码本发明的DKK1的胞外表面蛋白或表位的基因具有特异性。
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PCT/KR2018/005398 WO2018208108A1 (ko) | 2017-05-10 | 2018-05-10 | 조절 t 세포에 특이적으로 존재하는 dkk1 단백질 및 그 용도 |
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