CN112812154A - 癌症抗原肽 - Google Patents
癌症抗原肽 Download PDFInfo
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- CN112812154A CN112812154A CN202110097214.5A CN202110097214A CN112812154A CN 112812154 A CN112812154 A CN 112812154A CN 202110097214 A CN202110097214 A CN 202110097214A CN 112812154 A CN112812154 A CN 112812154A
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Abstract
本公开涉及一种肽,其由10至45个氨基酸组成并包含:KILQQSRIVQX的氨基酸序列,其中,X不存在或者是S;DVQKIVESQINFHGKKLKLGPAIRKQNLCAYHVQPRPL(SEQ ID NO:16)的氨基酸序列中的10个以上的连续氨基酸的氨基酸序列;或QNLNHYIQVLENLVRSVPS(SEQ ID NO:9)的氨基酸序列;或者一种具有与前述肽的氨基酸序列不同的氨基酸序列并且能够激活辅助T细胞的肽,其中,不同之处在于1‑3个氨基酸被取代、缺失或添加。本公开还涉及与所述肽有关的产品,例如多核苷酸。本公开还提供了所述肽和所述产品作为用于激活辅助T细胞的药物或组合物的用途。
Description
本申请是申请号201980016100.4、申请日为2019年2月15日、发明名称为“癌症抗原肽”的原申请的分案申请。
技术领域
本申请要求日本专利申请号2018-024972的优先权的权益,其全部内容通过引用合并于此。
本公开涉及一种新型的癌症抗原肽。
背景技术
免疫系统具有通过识别正常细胞癌变时表达的高度免疫原性癌症抗原蛋白来消除癌细胞的机制。由于最近的研究表明免疫系统的有效激活对于控制癌症生长极为重要,因此如免疫检查点抑制剂(例如抗PD-1抗体)的显着治疗效果所证明的那样,癌症疫苗疗法引起了人们的关注。
在常规的癌症疫苗治疗中被选作靶标的大多数抗原分子是在正常组织中很少或中等表达但仅在“生长的”癌组织中高度表达的分子。但是,癌细胞具有多种免疫编辑机制可以逃避免疫系统。当正常细胞癌变时,细胞随着容易被免疫系统靶向的分子的表达的减少而生长(非专利文献1)。换言之,这表明,在“生长的”癌组织中表达的抗原难以被免疫系统所靶向,因此癌组织在“生长”过程中不必降低此类抗原的表达。相应地,在常规的癌症疫苗疗法中已经被选择的靶抗原可能是不足以激活免疫系统的抗原。
已报道的癌细胞减少不利于自身的抗原表达的机制中的一种是通过启动子区域的甲基化来抑制免疫原性癌症抗原基因的表达(非专利文献2)。这表明已经逃避免疫监控而形成癌组织的癌细胞通过使它们的启动子区域甲基化而隐藏了不利于自身的免疫原性癌抗原蛋白。
为了建立更有效的癌症疫苗疗法,需要识别“不利于癌细胞”的免疫原性癌症抗原,其在癌症生长过程中被癌细胞下调,即,隐形癌症抗原。
参考文献
非专利文献
【非专利文献1】Schreiber RD et al.Science 2011,Mar 25;331(6024):1565-70
【非专利文献2】DuPage et al.Nature 2012Feb 8;482(7385):405-9
发明内容
本公开的目的是提供一种新型的癌症抗原肽及其用途。
发明人通过使用DNA转甲基酶抑制剂发现了一些隐形癌抗原,并识别出了它们能够激活辅助T细胞的部分肽。
相应地,本公开的一个方面提供了一种肽,所述肽由10至45个氨基酸组成并且包含:
KILQQSRIVQX的氨基酸序列,其中,X不存在或者是S;
在DVQKIVESQINFHGKKLKLGPAIRKQNLCAYHVQPRPL(SEQ ID NO:16)的氨基酸序列中的10个以上的连续氨基酸的氨基酸序列;或
QNLNHYIQVLENLVRSVPS(SEQ ID NO:9)的氨基酸序列;或者
一种具有与前述肽的氨基酸序列不同的氨基酸序列(其中,1-3个氨基酸被取代、缺失或添加)并且能够激活辅助T细胞的肽。
本公开的一个方面提供了一种编码所述肽的核酸。
本公开的一个方面提供了一种包含所述核酸的表达载体。
本公开的一个方面提供了包含所述肽和HLA II类分子的HLA多聚体。
本公开的一个方面提供了呈递所述肽和HLA II类分子的复合物的抗原呈递细胞。
本公开的一个方面提供了能够识别所述肽和HLA II类分子的复合物的辅助T细胞。
本公开的一个方面提供了一种药物组合物,其包含所述肽、所述核酸、所述表达载体、所述抗原呈递细胞或所述辅助T细胞。
本公开的一个方面提供了用于激活辅助T细胞的组合物,其包含所述肽、所述核酸、所述表达载体或所述抗原呈递细胞。
本公开中公开的肽可以激活对隐形癌抗原有特异性的辅助T细胞,可应用于治疗或预防可以表达隐形癌抗原的癌症。
附图说明
图1示出了用5-AZA处理的癌细胞系EBC1和Lu65的细胞中SYCP3的基因表达水平。
图2示出了用5-AZA处理的癌细胞系HT-29和SAS中SYCP3的基因表达水平。
图3示出了用5-AZA处理的癌细胞系SW839、5637、LC2/Ad和EBC1的细胞中SPESP1的基因表达水平。
图4示出了用5-AZA处理的癌细胞系HT-29、Lu65和SAS中SPESP1的基因表达水平。
图5示出了用5-AZA处理的癌细胞系WEHI-3的细胞中DAZL1的基因表达水平。
图6示出了从免疫缺陷小鼠收集的肿瘤组织中SYCP3的基因表达水平,所述免疫缺陷小鼠注射了大肠癌细胞系的细胞并施用了5-AZA。
图7示出了从免疫缺陷小鼠收集的肿瘤组织中SPESP1的基因表达水平,所述免疫缺陷小鼠注射了肺癌细胞系的细胞并施用了5-AZA。
图8示出了CD4阳性T细胞对部分SYCP3-A肽的反应性。
图9示出了DAZL-1C肽激活小鼠中辅助T细胞的能力。
图10示出了SYCP3-A特异性Th细胞对SYCP3-A刺激的反应性。
图11示出了SYCP3-A特异性Th细胞对部分SYCP3-A肽的反应性。
图12示出了SYCP3-A特异性Th细胞对部分SYCP3-A肽的反应性。
图13示出了SPESP1-B特异性Th细胞对SPESP1-B刺激的反应性。
图14示出了DAZL1特异性Th细胞对部分DAZL1肽的反应性。
图15示出了SYCP3-A特异性Th细胞对用5-AZA处理的DR53阳性癌细胞的反应性。
图16示出了5-AZA和SYCP3-A特异性的人类Th细胞的组合的肿瘤生长抑制效果。
图17示出了人SYCP3(SEQ ID NO:1)、人SPESP1(SEQ ID NO:2)和人DAZL1(SEQ IDNO:15)的氨基酸序列。
具体实施方式
除非另有定义,否则本文所使用的术语应理解为技术领域的技术人员通常所理解的,所述技术领域例如为有机化学、医学、药学、分子生物学和微生物学。本文中使用的几个术语如下所述地定义。本文中的定义优先于一般性理解。
如本文所用,术语“隐形癌抗原”是指一种蛋白质,该蛋白质的表达被癌细胞的免疫编辑系统通过基因的启动子区域的甲基化所抑制。隐形癌抗原的实例包括SYCP3(联会复合体蛋白3)、SPESP1(精子赤道段蛋白1)和DAZL1(无精症样缺失1)。SYCP3是参与减数分裂中的染色体配对、重组和分离的联会复合体的重要组成部分。SYCP3中的突变与无精症和不育症有关。人SYCP3可具有SEQ ID NO:1的氨基酸序列。SPESP1是参与精-卵结合和融合的人同种抗原。人SPESP1可具有SEQ ID NO:2的氨基酸序列。DAZL1是DAZ家族的成员并且是在男女的产前和产后生殖细胞中表达的RNA结合蛋白。人DAZL1可具有SEQ ID NO:15的氨基酸序列。
如本文所用,术语“辅助肽”是指衍生自癌症抗原蛋白并且能够激活辅助T细胞的肽。
衍生自SYCP3的辅助肽的实例包括这些肽,其包含选自KILQQSRIVQ(SEQ ID NO:3)和KILQQSRIVQS(SEQ ID NO:4)的氨基酸序列。在一个实施例中,辅助肽包含选自SEQ IDNO:3和SEQ ID NO:4的氨基酸序列,并由SEQ ID NO:1的氨基酸序列中的连续氨基酸组成。在一个实施例中,辅助肽由选自SEQ ID NO:3和SEQ ID NO:4的氨基酸序列组成。在一个实施例中,辅助肽包含选自KILQQSRIVQSQ(SEQ ID NO:5)、QKILQQSRIVQS(SEQ ID NO:6)、QQKILQQSRIVQ(SEQ ID NO:7)和QQQKILQQSRIVQSQRLKT(SEQ ID NO:8)的氨基酸序列,或者由选自SEQ ID NO:5至SEQ ID NO:8的氨基酸序列组成、特别是由选自SEQ ID NO:5和SEQID NO:6的氨基酸序列组成。
包含选自SEQ ID NO:5至SEQ ID NO:8的氨基酸序列的所述肽的示例包括:包含选自RQQQKILQQSRIVQSQRLKT(SEQ ID NO:22)、LNMFRQQQKILQQSRIVQSQRLKT(SEQ ID NO:23)、QQQKILQQSRIVQSQRLKTI(SEQ ID NO:24)、和QQQKILQQSRIVQSQRLKTIKQLY(SEQ ID NO:25)的氨基酸序列的肽;以及由选自SEQ ID NO:22至SEQ ID NO:25的氨基酸序列组成的肽。
衍生自SYCP3的辅助肽的进一步示例包括:包含选自KILQQSRVVQ(SEQ ID NO:26)和KILQQSRVVQS(SEQ ID NO:27)的氨基酸序列的肽,以及由选自SEQ ID NO:26和SEQ IDNO:27的氨基酸序列组成的肽。在一种实施例中,辅助肽包含选自KILQQSRVVQSQ(SEQ IDNO:28)、QKILQQSRVVQS(SEQ ID NO:29)、QQKILQQSRVVQ(SEQ ID NO:30)、QQQKILQQSRVVQSQRLKT(SEQ ID NO:31)、RQQQKILQQSRVVQSQRLKT(SEQ ID NO:32)、LNMFRQQQKILQQSRVVQSQRLKT(SEQ ID NO:33)、QQQKILQQSRVVQSQRLKTI(SEQ ID NO:34)和QQQKILQQSRVVQSQRLKTIKQLY(SEQ ID NO:35)的氨基酸序列,或者由SEQ ID NO:28至SEQ IDNO:35的氨基酸序列组成。
SEQ ID NO:3和SEQ ID NO:4的氨基酸序列在本文中也可以由序列(I):KILQQSRIVQX表示,其中,X不存在或者是S。SEQ ID NO:26和SEQ ID NO:27的氨基酸序列可以全面地由序列(I’):KILQQSRVVQX表示,其中,X不存在或者是S。
衍生自SPESP1的辅助肽的示例包括:包含QNLNHYIQVLENLVRSVPS(SEQ ID NO:9)的氨基酸序列的肽。在一个实施例中,辅助肽包含SEQ ID NO:9的氨基酸序列并且由SEQ IDNO:2的氨基酸序列中的连续氨基酸组成。在一个实施例中,辅助肽由SEQ ID NO:9的氨基酸序列组成。
衍生自DAZL1的辅助肽的示例包括:包含DVQKIVESQINFHGKKLKLGPAIRKQNLCAYHVQPRPL(SEQ ID NO:16)的氨基酸序列中的10个以上的连续的氨基酸的氨基酸序列的肽。在一个实施例中,辅助肽包含SEQ ID NO:16的氨基酸序列中的20个以上的连续的氨基酸的氨基酸序列。在一个实施例中,辅助肽包含SEQ ID NO:16的氨基酸序列中的10个以上或者20个以上的连续的氨基酸的氨基酸序列,并且由SEQ ID NO:15的氨基酸序列中的连续氨基酸组成。在一个实施例中,辅助肽包含选自SEQ ID NO:16,DVQKIVESQINFHGKKLKLG(SEQ ID NO:17)、INFHGKKLKLGPAIRKQNLC(SEQ ID NO:18)、LGPAIRKQNLCAYHVQPRPL(SEQ ID NO:19)、DVQKIVESQINFHGKKLKLGPAIRKQNLC(SEQ ID NO:20)和INFHGKKLKLGPAIRKQNLCAYHVQPRPL(SEQ ID NO:21)的氨基酸序列,或者由选自SEQ ID NO:16至SEQ ID NO:21的氨基酸序列组成。
本文中公开的辅助肽具有允许其结合MHC II类分子的长度,例如10至45、10至40、10至35、10至30、或10至25个氨基酸的长度。例如,辅助肽可以由10至18、10至19、10至20、11至18、11至19、11至20、12至18、12至19、或12至20个氨基酸组成。通常认为与MHC II类分子结合的抗原肽可以更长,因为该肽具有由大约9个氨基酸组成的MHC II类分子结合基序,该基序与MHC II类分子的肽结合凹部结合,因此肽的两端可能会从该凹部中伸出。例如,辅助肽可以由10至45、15至40或20至38个氨基酸组成。但是,较长的肽通常被肽酶切割成13至17个氨基酸的长度(Immunobiology,第5版,116-117,Garland Publishing(2001))。
辅助肽可以由与上述任一氨基酸序列不同(其中一个或多个氨基酸被取代、缺失或添加)的氨基酸序列组成。只要保留激活辅助T细胞的能力,在任何位置上的任意数量的氨基酸残基都可以被取代、缺失或添加。例如,辅助肽可以由与上述任一氨基酸序列不同的氨基酸序列组成,其中,不同在于1至9、1至5、1至4、1至3、或1至2个氨基酸被取代、缺失或添加。由于如上所述的辅助肽的性质,可以在N-或C-末端添加任何数目的氨基酸,例如1至20、1至15、或1至10个氨基酸。
取代可以发生在任何氨基酸之间。保守氨基酸取代是优选的。术语“保守氨基酸取代”是指氨基酸残基被具有相似性质的侧链的另一个氨基酸残基取代。根据侧链,将氨基酸残基划分为多个家族。侧链的实例包括:碱性侧链(例如赖氨酸、精氨酸和组氨酸)、酸性侧链(例如天冬氨酸和谷氨酸)、不带电荷的极性侧链(例如天冬酰胺、谷氨酰胺、丝氨酸、苏氨酸、酪氨酸和半胱氨酸)、非极性侧链(例如甘氨酸、丙氨酸、缬氨酸、亮氨酸、异亮氨酸、脯氨酸、苯丙氨酸、蛋氨酸和色氨酸)、β-支链侧链(例如苏氨酸、缬氨酸和异亮氨酸)、脂肪族侧链(例如甘氨酸、丙氨酸、缬氨酸、亮氨酸、异亮氨酸、丝氨酸和苏氨酸)、芳香族侧链(例如酪氨酸、苯丙氨酸和色氨酸)、酰胺侧链(例如天冬酰胺和谷氨酰胺)、以及含硫的侧链(例如半胱氨酸和蛋氨酸)。保守氨基酸取代优选是在相同家族内的氨基酸残基之间的取代。保守氨基酸取代的实例包括谷氨酸残基取代为天冬氨酸残基、苯丙氨酸残基取代为酪氨酸残基、亮氨酸残基取代为异亮氨酸残基、异亮氨酸残基取代为缬氨酸残基、丙氨酸残基取代为丝氨酸残基以及组氨酸残基取代为精氨酸残基。
可以取代一个或多个氨基酸,从而保留能够结合所需的MHC II类分子的抗原肽中共有的序列特征(基序)。通常,抗原肽进入MHC II类分子的肽结合凹部并被固定。通过肽的氨基酸残基的侧链与肽结合凹部的结合以及肽的主链与保留在所有MHC II类分子的肽结合凹部中的氨基酸残基的侧链的结合来实现固定。通过分析通常能够与MHC II类分子结合的肽中常见的氨基酸残基的模式可以推导与所期望的MHC II类分子的肽结合凹部结合的氨基酸残基的基序。在构成肽结合凹部的小口袋和大口袋的氨基酸残基中观察到氨基酸多态性。对于衍生自每个等位基因的每个MHC II类分子,可以推导每个氨基酸基序。
在一个实施例中,衍生自SYCP3或SPESP1的辅助肽可通过与HLA-DR、尤其是HLA-DR53结合而无限制地激活辅助T细胞。在一个实施例中,衍生自DAZL1的辅助肽可以通过与HLA-DR、尤其是HLA-DR4、8、9、15或53的结合而无限制地激活辅助T细胞。在一个实施例中,衍生自DAZL1并包含SEQ ID NO:17的氨基酸序列的辅助肽可通过与HLA-DR4、9或53结合而无限制地激活辅助T细胞。在一个实施例中,衍生自DAZL1并且包含SEQ ID NO:18的氨基酸序列的辅助肽可以通过与HLA-DR15结合而无限制地激活辅助T细胞。在一个实施例中,衍生自DAZL1并包含SEQ ID NO:19的氨基酸序列的辅助肽可通过与HLA-DR8结合而无限制地激活辅助T细胞。
肽的一个或多个氨基酸残基可通过任何已知方法修饰。修饰的实例包括:在氨基酸残基的侧链上的官能团、在N末端的氨基酸的氨基、在C末端的氨基酸的羧基上进行酯化、烷基化、酰化(例如乙酰化)、卤化和磷酸化。在一个实施例中,辅助肽的N末端被乙酰化。也可以将一种或多种物质,例如氨基酸、肽及其类似物添加到辅助肽的N末端和/或C末端。例如,可以添加组氨酸标签,或者可以与诸如硫氧还蛋白之类的蛋白质一起形成融合蛋白。替代地,可将可检测标记结合至辅助肽。当这种物质与辅助肽结合时,该物质可以例如用生物酶或通过细胞内加工而被加工,以产生辅助肽。此类物质可以调节辅助肽的溶解度,改善肽的稳定性(例如蛋白酶抗性),允许将辅助肽特异性地递送至所期望的组织或器官,或增强抗原呈递细胞对辅助肽的摄取。这样的物质可以是增加肽诱导CTL的能力的物质,例如,另一种激活辅助T细胞的肽。
可以使用本领域通常使用的方法或修改过的方法来合成肽。这类合成方法公开于例如Peptide Synthesis,Interscience,New York,1966;The Proteins,Vol 2,AcademicPress Inc.,New York,1976;Peptide Synthesis,Maruzen Co.,Ltd.,1975;Basis和Experiments of Peptide Synthesis,Maruzen Co.,Ltd.,1985;和Development ofMedicines(continuation),Vol.14,Peptide Synthesis,Hirokawa Shoten Co.,1991。还可使用遗传工程技术基于编码肽的核苷酸序列的信息来制备肽。这样的基因工程技术是本领域技术人员众所周知的。例如,可以根据文献中描述的方法(例如,Molecular Cloning,T.Maniatis et al.,CSH Laboratory(1983)和DNACloning,DM.Glover,IRL PRESS(1985))。
通常,当T细胞表面上的TCR-CD3复合体识别与抗原呈递细胞表面的MHC II类分子复合的抗原肽时,辅助T细胞被激活,并且T细胞表面的整联蛋白被抗原呈递细胞的表面上的整联蛋白配体刺激。在本公开中,辅助T细胞的激活包括诱导辅助T细胞、增强辅助T细胞的增殖以及诱导辅助T细胞的细胞因子产生。
变体肽激活辅助T细胞的能力可以通过合成所述肽并测试所述肽是否可以激活辅助T细胞来确定。对于这种测试,可以使用在Hassane M.Zarour et al.,Cancer Research62,213-218(2002年1月1日)中描述的方法、在实施例中描述的方法或以下方法。
树突状细胞(贴壁细胞)是通过收集人类受试者的外周血单个核细胞(PBMC)并去除非贴壁细胞而制备的。例如,通过Ficoll-Paque密度梯度离心或磁性细胞分选法,从同一受试者分别制备辅助T细胞(CD4阳性T细胞)。树突细胞用候选肽培养并与辅助T细胞混合培养。然后回收并用与候选肽一起培养的树突状细胞以相似的方式刺激辅助T细胞数次。辅助T细胞的激活(诱导)可以例如通过确定(1)辅助T细胞的增殖活性或(2)辅助T细胞的细胞因子产生活性来确认。增殖活性(1)可以通过例如测定辅助T细胞中掺入的[3H]-胸苷的量来确定。例如,可以通过诸如酶联免疫吸附法(ELISA)的方法测量细胞因子的量来确定细胞因子的产生活性(2),其中,细胞因子例如是由激活的辅助T细胞产生的IFN-γ。
一方面,本公开提供了编码辅助肽的多核苷酸。多核苷酸可以是任何核酸的形式,例如DNA或RNA。基于关于肽的氨基酸序列或编码肽的DNA的多核苷酸序列的信息,可以容易地制备多核苷酸。具体地,可以通过常规的DNA合成或通过PCR扩增的方法制备多核苷酸。
所提供的多核苷酸可包括在严格条件下与编码辅助肽的多核苷酸的互补序列杂交的并且编码激活辅助T细胞的肽的多核苷酸。关于“在严格条件下杂交”,可以根据任何常规方法进行杂交,例如在Molecular Cloning,T.Maniatis et al.,CSH Laboratory(1983)中描述的那些。严格条件可以是这样的条件,即,在45℃下在含有6x SSC的溶液(10x SSC是含有1.5M NaCl和0.15M柠檬酸三钠)和50%甲酰胺的溶液中进行杂交,然后在50℃下在2xSSC中进行冲洗(Molecular Biology,John Wiley&Sons,N.Y.(1989),6.3.1-6.3.6)。
可通过将如上制备的多核苷酸掺入表达载体来构建用于表达辅助肽的重组表达载体。取决于宿主和目的,可以使用任何表达载体。载体的实例包括质粒、噬菌体载体和病毒载体。例如,当宿主是大肠杆菌时,载体的实例包括:质粒载体,例如pUC118、pUC119、pBR322和pCR3;以及噬菌体载体,例如λZAPII和λgt11。当宿主是酵母时,载体的实例包括pYES2和pYEUra3。当宿主是昆虫细胞时,载体的实例包括pAcSGHisNT-A。当宿主是动物细胞时,载体的实例包括:质粒载体,例如pKCR、pCDM8、pGL2、pcDNA3.1、pRc/RSV和pRc/CMV;以及病毒载体,例如逆转录病毒载体、腺病毒载体和腺相关病毒载体。
表达载体可以任选地包含因子(例如能够诱导表达的启动子)、编码信号序列的基因、用于选择的标记基因、和终止子。
此外,表达载体可能还包含一个额外的序列,以用于产生具有便于分离和纯化的部分的融合蛋白,例如硫氧还蛋白、His标签或GST(谷胱甘肽S-转移酶)。这类载体的例子包括GST融合蛋白载体(例如pGEX4T)、含有标签序列(例如Myc或His)的载体(例如pcDNA3.1/Myc-His)和能够表达具有硫氧还蛋白和His标签的融合蛋白的载体(例如,pET32a),其含有在宿主细胞中有功能的适当启动子(例如lac、tac、trc、trp、CMV或SV40早期启动子)。
含有表达载体的转化细胞可以通过用如上所述获得的载体转化宿主细胞来制备。宿主的实例包括大肠杆菌、酵母、昆虫细胞和动物细胞。大肠杆菌菌株的实例包括大肠杆菌K-12菌株,例如HB101、C600、JM109、DH5α和AD494(DE3)。酵母种类的实例包括酿酒酵母。动物细胞的实例包括L929、BALB/c3T3细胞、C127细胞、CHO细胞、COS细胞、Vero细胞和Hela细胞。昆虫细胞的例子包括sf9。
可以通过使用适合宿主细胞的常规方法将表达载体引入宿主细胞,例如磷酸钙方法、DEAE-葡聚糖方法、电穿孔方法和将脂质(例如Lipofectamine、Lipofectin;Gibco-BRL)用于基因转移的方法。导入后,可以在含有选择标记的常规培养基中培养细胞以获得含有表达载体的转化细胞。
辅助肽可以通过在适当条件下培养转化细胞来产生。可以根据标准生化纯化程序进一步分离和纯化产生的肽。纯化步骤的实例包括盐析、离子交换色谱、吸收色谱、亲和色谱和凝胶过滤色谱。如前所述,当辅助肽表达为硫氧还蛋白、His标签或GST的融合肽时,可以利用融合蛋白或标签的特性通过适当的纯化程序分离和纯化该肽。
一方面,本公开提供了一种特异性结合辅助肽的抗体。该抗体可以是多克隆或单克隆抗体。可以按照常规方法制备抗体(Current protocols in Molecular Biologyedit.Ausubel et al.(1987)Publish.John Wiley and Sons.,Antibodies;ALaboratoryManual,Lane,H,D.et al.,ed.,Cold Spring Harber Laboratory Press,New York1989)。通过使用该肽作为抗原免疫非人类动物(例如兔),并以常规方式从被免疫动物的血清中回收抗体,可以获得多克隆抗体。通过用该肽免疫诸如小鼠的非人类动物,使脾细胞与骨髓瘤细胞融合而产生杂交瘤细胞,并从杂交瘤细胞中回收单克隆抗体,可以得到单克隆抗体。用适合宿主动物的佐剂可以增强免疫应答。
可以识别辅助肽并中和其活性的抗体可以用于例如亲和色谱或免疫学诊断方法。免疫学诊断方法可以例如通过使用免疫印迹、放射免疫法(RIA)、酶联免疫吸附法(ELISA)或荧光或发光法来进行。这种免疫学诊断方法对于癌症(例如:诸如白血病的血液系统疾病、恶性黑色素瘤、乳腺癌、头颈肿瘤、泌尿系统肿瘤、食道癌、肝癌、肺癌或结肠癌)的诊断是有效的,其中,通过抑制DNA甲基化来诱导SYCP3、SPESP1或DAZL1的表达。
在一个方面,本公开提供了包含辅助肽和MHC II类分子的HLA多聚体。本文所用的HLA多聚体是指HLA单体的多聚体,其通过使两个以上HLA单体通过已知方法彼此结合而获得。HLA单体是肽与HLA蛋白缔合的复合物。衍生自SYCP3或SPESP1的辅助肽可不受限制地与HLA-DR53形成复合物。衍生自DAZL1的辅助肽可以不受限制地与HLA-DR4、8、9、15或53形成复合物。可以对多聚体进行荧光标记,从而可以通过已知的检测手段(例如流式细胞术或荧光显微镜术)容易地选择或检测被多聚体结合的辅助T细胞。HLA多聚体可以是四聚体、五聚体或树状聚体,例如,通过使生物素化的HLA单体与亲和素分子结合而制备的HLA四聚体。由于含有各种抗原肽的HLA四聚体是可商购的,因此可以以类似的方式容易地制备含有辅助肽的HLA四聚体(Science 279:2103-2106(1998),Science 274:94-96(1996))。
在一个方面,本公开提供了呈递肽和HLAII类分子的复合物的抗原呈递细胞。在一个实施例中,衍生自SYCP3或SPESP1的辅助肽可不受限制地与HLA-DR53形成复合物。在一个实施例中,衍生自DAZL1的辅助肽可以不受限制地与HLA-DR4、8、9、15或53形成复合物。抗原呈递细胞可源自能够将肽和HLAII类分子的复合物呈递给辅助T细胞的细胞,例如外周血单核细胞或树突状细胞。
抗原呈递细胞可以通过使用本领域技术人员已知的技术将肽添加到具有抗原呈递能力的细胞中来制备。所述肽可以作为肽本身被直接地添加,或通过多核苷酸、载体或转化细胞而被间接地添加。例如,可以通过使具有抗原呈递能力的细胞与所述肽接触或将多核苷酸或表达载体引入该细胞中来添加所述肽(Cancer Immunol.Immunother.46:82,1998;J.Immunol.,158:p1796,1997;Cancer Res.,59:p1184,1999;Cancer Res.,56:p5672,1996;J.Immunol.,161:p5607,1998;J.Exp.Med.,184:p465,1996)。如本文所用,具有抗原呈递能力的细胞是在细胞表面表达MHC II类分子的细胞,包括外周血单核细胞和树突状细胞。可以通过确定辅助T细胞的活性来确认抗原呈递,如以下示例所示。辅助T细胞的活性可以例如通过产生细胞因子(例如干扰素-γ)来确认。抗原呈递细胞可以用作细胞疗法(例如树突细胞疗法)中的活性成分。
在另一方面,本公开提供了用于制备抗原呈递细胞的辅助肽、多核苷酸、载体、多聚体或包含这些组分中的任意一种细胞。在另一方面,本公开提供了辅助肽、多核苷酸、载体、多聚体或包含这些组分中的任意一种的细胞用于制备抗原呈递细胞的用途。
所述抗原呈递细胞可以激活辅助T细胞,辅助T细胞识别辅助肽和HLAII类分子的复合物。因此,在一个方面,本公开提供了用于激活辅助T细胞的组合物,其包含前述的辅助肽、多核苷酸、载体、多聚体、包含这些组分中的任意一种的细胞、或抗原呈递细胞。
激活的辅助T细胞可通过增强B细胞和细胞毒性T细胞的诱导、增殖和激活来激活免疫系统。因此,用于激活辅助T细胞的组合物或被激活的辅助T细胞可用于增强B细胞和/或细胞毒性T细胞的诱导增殖和激活,或由此激活免疫系统。
用于激活辅助T细胞的组合物可以包含除活性成分以外的成分,例如载体、赋形剂或添加剂。该组合物可以在体外或体内使用。组合物的体内用途可以是按照以下描述的药物组合物的用途。可以根据诸如辅助T细胞激活的期望程度和抗原呈递细胞的状况等因素来适当地选择组合物的用途。例如,可以将组合物通过皮内施用、皮下施用、肌内施用、静脉内施用、经鼻施用或口服施用施用给受试者,或者可以不受限制地添加到培养基中。组合物的使用(例如组合物中所含的活性成分的量、组合物的类型或使用频率)可以根据例如辅助T细胞激活的期望程度和抗原呈递细胞的状况等因素适当选择。
在一个方面,本公开提供了用于激活辅助T细胞的辅助肽、多核苷酸、载体、多聚体、包含这些组分中的任一种的细胞、或抗原呈递细胞。在一个方面,本公开提供了辅助肽、多核苷酸、载体、多聚体、包含这些组分中的任一种的细胞、或抗原呈递细胞在制备用于激活辅助T细胞的组合物中的用途。在一个方面,本公开提供了一种激活辅助T细胞的方法,其包括将辅助肽、多核苷酸、载体、多聚体、包含这些组分中的任一种的细胞、或抗原呈递细胞施用给需要的受试者。在一个方面,本公开提供了一种激活辅助T细胞的方法,其包括将辅助肽、多核苷酸、载体、多聚体、包含这些组分中的任一种的细胞、或抗原呈递细胞在体外添加至辅助T细胞。
在一个方面,本公开提供了识别辅助肽与MHC II类分子的复合物的辅助T细胞。衍生自SYCP3或SPESP1的辅助肽可不受限制地与HLA-DR53形成复合物。衍生自DAZL1的辅助肽可不受限制地与HLA-DR4、8、9、15或53形成复合物。辅助T细胞可以由本领域技术人员使用本领域已知的技术容易地制备(Iwata,M.et al.,Eur.J.Immunol,26,2081(1996))。
在另一方面,本公开内容提供了一种药物组合物,其包含前述的辅助肽、多核苷酸、载体、多聚体、包含这些组分中的任一种的细胞、或抗原呈递细胞、或辅助T细胞作为活性成分。该药物组合物可用于治疗或预防癌症或用于辅助治疗或预防癌症。在一个实施例中,该药物组合物是癌症疫苗。
药物组合物可以治疗或预防癌症,其中,通过抑制DNA甲基化诱导SYCP3、SPESP1或DAZL1表达。癌症可以是实体瘤或血液肿瘤,例如:诸如白血病的血液学疾病、恶性黑色素瘤、乳腺癌、头颈肿瘤、泌尿道肿瘤、食道癌、肝癌、肺癌或结肠癌。在一个实施例中,当辅助肽衍生自SYCP3或SPESP1时,可以将药物组合物不受限制地给予具有HLA-DR53的受试者。在一个实施例中,当辅助肽衍生自DAZL1时,可以将药物组合物不受限制地给予具有HLA-DR4、8、9、15或53的受试者。
药物组合物可以包含除活性成分以外的一种或多种组分,例如载体或赋形剂。组合物的施用方法可以根据疾病的种类、受试者的状态、靶部位等因素适当地选择。施用方法包括但不限于:皮内施用、皮下施用、肌肉内施用、静脉内施用、经鼻施用和口服施用。施用的细节(例如药物组合物中所含的活性成分的量、组合物的剂型和给药频率)可以根据诸如疾病类型、受试者的状态和靶部位等因素适当地选择。
该药物组合物可以包含至少一种另外的活性成分或与至少一种另外的活性成分结合使用。另外的活性成分的实例包括:化学治疗剂,例如抗代谢物、烷基化剂、抗癌抗生素、抗微管剂、铂类药物、拓扑异构酶抑制剂、分子靶向药物、癌症疫苗、免疫调节剂、免疫检查点抑制剂和DNA转甲基酶抑制剂;以及辅助T细胞或细胞毒性T细胞的激活剂、增殖剂或诱导剂。具有常规技能的临床医生可以在其技能和判断力范围内决定另外的有效成分及其治疗有效量。所述药物组合物可以与其他疗法(例如化学疗法、放射疗法、免疫疗法、造血干细胞移植或手术)平行使用或在其之前或之后使用。
在一个实施例中,所述另外的活性成分是DNA转甲基酶抑制剂。DNA转甲基酶抑制剂的实例包括在J.Med.Chem.2015,58,2569-2583中公开的药物,包括:地西他滨(decitabine)、瓜德希他滨(guadecitabine)、阿扎胞苷(azacitidine)、泽布拉林(zebularine)、四氢尿苷、四氢尿苷及其衍生物,特别是地西他滨和阿扎胞苷。
当“组合”使用某些成分时,可以施用包含所有成分的剂型或者可以施用包含每种成分的剂型的组合,即,试剂盒。替代地,可以通过同时、依次或分开施用所有成分来实现组合,即,可以在稍后的时间点施用一种或多种成分,只要这些成分用于治疗相同的疾病即可。
在一个方面,本公开内容提供了一种治疗或预防癌症的方法,该方法包括对有需要的受试者施用有效量的辅助肽、多核苷酸、载体、多聚体、包含这些组分中的任一种的细胞、抗原呈递细胞、或者辅助T细胞。
在一个方面,本公开提供了用作药物的辅助肽、多核苷酸、载体、多聚体、包含这些组分中的任一种的细胞、抗原呈递细胞、或者辅助T细胞,例如在治疗或预防癌症中使用的药物。
在一个方面,本公开提供了将辅助肽、多核苷酸、载体、多聚体、包含这些组分中的任一种的细胞、抗原呈递细胞、或者辅助T细胞用于制备药物的用途,例如用于治疗或预防癌症的药物。
在另一方面,本公开内容提供了一种用于确定受试者中对隐形癌抗原具有特异性的辅助T细胞的存在或量的方法,其包括:
(a)用辅助肽刺激从受试者获得的样品,和
(b)确定辅助T细胞或由辅助T细胞产生的细胞因子的量,
其中,在步骤(b)中确定的量的增加指示对隐形癌抗原具有特异性的辅助T细胞的存在或量。
可以使用任何样品,只要其包含抗原呈递细胞,例如外周血单核细胞,侵袭性淋巴细胞、肿瘤细胞、腹水中的细胞、胸腔积液中的细胞、脑脊液中的细胞、骨髓细胞和淋巴结细胞。样品可以来自健康的供体或癌症患者。来自健康供体的样品可用于诊断供体是否实际上患有癌症,或供体是否有患癌的倾向。来自癌症患者的样品可以用于诊断使用隐形癌症抗原的免疫疗法在患者中是否有效。在一个实施例中,在HLA-DR阳性受试者、特别是HLA-DR53阳性受试者中,不受限制地对衍生自SYCP3或SPESP1的辅助肽具有特异性的辅助T细胞的量进行测定。在一个实施例中,在HLA-DR阳性受试者、尤其是HLA-DR4、8、9、15或53阳性受试者中,不受限制地对衍生自DAZL1的辅助肽特异的辅助T细胞的量进行确定。可以在用辅助肽刺激之前和/或之后培养获得的样品,并且培养条件可以由本领域技术人员适当地确定。用辅助肽刺激这些细胞可以使用已知技术进行,并且可以在体外或体内进行。辅助T细胞或由辅助T细胞产生的细胞因子的量可以通过已知方法确定。
例如,本公开提供了以下实施例:
[1]一种由10-25个氨基酸组成的肽,所述肽包含KILQQSRIVQX的氨基酸序列(其中,X不存在或者是S)或者QNLNHYIQVLENLVRSVPS(SEQ ID NO:9)的氨基酸序列。
[2]根据项目1所述的肽,包含KILQQSRIVQX的氨基酸序列,其中,X不存在或者是S。
[3]根据项目1或2所述的肽,由SEQ ID NO:1的氨基酸序列中的连续氨基酸组成。
[4]根据项目1至3中任一项所述的肽,包含选自KILQQSRIVQ(SEQ ID NO:3)、KILQQSRIVQS(SEQ ID NO:4)、KILQQSRIVQSQ(SEQ ID NO:5)、QKILQQSRIVQS(SEQ ID NO:6)、QQKILQQSRIVQ(SEQ ID NO:7)和QQQKILQQSRIVQSQRLKT(SEQ ID NO:8)的氨基酸序列。
[5]根据项目1至4中任一项所述的肽,由选自SEQ ID NO:3至SEQ ID NO:8的氨基酸序列组成。
[6]根据项目1至3中任一项所述的肽,包含选自SEQ ID NO:3和SEQ ID NO:4的氨基酸序列。
[7]根据项目1至3和6中任一项所述的肽,由选自SEQ ID NO:3和SEQ ID NO:4的氨基酸序列组成。
[8]根据项目1至3中任一项所述的肽,包含SEQ ID NO:3的氨基酸序列。
[9]根据项目1至3和8中任一项所述的肽,由SEQ ID NO:3的氨基酸序列组成。
[10]根据项目1至3中任一项所述的肽,包含SEQ ID NO:4的氨基酸序列。
[11]根据项目1至3和10中任一项所述的肽,由SEQ ID NO:4的氨基酸序列组成。
[12]根据项目1至3中任一项所述的肽,包含选自SEQ ID NO:5至SEQ ID NO:8的氨基酸序列。
[13]根据项目1至3和12中任一项所述的肽,由选自SEQ ID NO:5至SEQ ID NO:8的氨基酸序列组成。
[14]根据项目1至3中任一项所述的肽,包含选自SEQ ID NO:5至SEQ ID NO:7的氨基酸序列。
[15]根据项目1至3和14中任一项所述的肽,由选自SEQ ID NO:5至SEQ ID NO:7的氨基酸序列组成。
[16]根据项目1至3中任一项所述的肽,包含选自SEQ ID NO:5和SEQ ID NO:6的氨基酸序列。
[17]根据项目1至3和16中任一项所述的肽,由选自SEQ ID NO:5和SEQ ID NO:6的氨基酸序列组成。
[18]根据项目1至3中任一项所述的肽,包含SEQ ID NO:5的氨基酸序列。
[19]根据项目1至3中任一项所述的肽,由SEQ ID NO:5的氨基酸序列组成。
[20]根据项目1所述的肽,包含QNLNHYIQVLENLVRSVPS(SEQ ID NO:9)的氨基酸序列。
[21]根据项目1或20所述的肽,由SEQ ID NO:2的氨基酸序列中的连续氨基酸组成。
[22]根据项目1、20或21所述的肽,由SEQ ID NO:9的氨基酸序列组成。
[23]一种由10-25个氨基酸组成的肽,所述肽包含KILQQSRIVQX的氨基酸序列(其中,X不存在或者是S)或者QNLNHYIQVLENLVRSVPS(SEQ ID NO:9)的氨基酸序列,或者
一种具有与前述肽的氨基酸序列不同的氨基酸序列并且能够激活辅助T细胞的肽,其中,不同之处在于1至3个氨基酸被取代、缺失或添加。
[24]一种编码根据项目1至23中任一项所述的肽的核酸。
[25]一种包含根据项目24所述的核酸的表达载体。
[26]一种包含根据项目25所述的表达载体的转化细胞。
[27]一种特异性结合根据项目1至23中任一项所述的肽的抗体。
[28]一种HLA多聚体,其包含根据项目1至23中任一项所述的肽和HLA II类分子。
[29]一种抗原呈递细胞,其呈递根据项目1至23中任一项所述的肽和HLAII类分子的复合物。
[30]一种能够识别根据项目1至23中任一项所述的肽和HLAII类分子的复合物的辅助T细胞。
[31]一种药物组合物,其包含根据项目1至23中任一项所述的肽、根据项目24所述的核酸、根据项目25所述的表达载体、根据项目28所述的HLA多聚体、根据项目29所述的抗原呈递细胞、或者根据项目30的辅助T细胞。
[32]根据项目31所述的药物组合物,用于治疗或预防癌症。
[33]根据项目31或32所述的药物组合物,是癌症疫苗。
[34]根据项目32或33所述的药物组合物,其中,所述癌症是肺癌或结肠癌。
[35]一种用于激活辅助T细胞的组合物,其包含根据项目1至23中任一项所述的肽、根据项目24的核酸、根据项目25的表达载体、根据项目28的HLA多聚体、或根据项目29的抗原呈递细胞。
例如,本公开进一步提供了以下实施例。
[1]一种由10-45个氨基酸组成的肽,所述肽包含:KILQQSRIVQX的氨基酸序列,其中,X不存在或者是S;
DVQKIVESQINFHGKKLKLGPAIRKQNLCAYHVQPRPL(SEQ ID NO:16)的氨基酸序列中10个以上连续氨基酸的氨基酸序列;或
QNLNHYIQVLENLVRSVPS(SEQ ID NO:9)的氨基酸序列,或者一种具有与前述肽的氨基酸序列不同的氨基酸序列并且能够激活辅助T细胞的肽,其中,不同之处在于1至3个氨基酸被取代、缺失或添加。
[2]根据项目1所述的肽,其是
一种由10-25个氨基酸组成的肽,所述肽包含KILQQSRIVQX的氨基酸序列,其中,X不存在或者是S,
或者
一种具有与前述肽的氨基酸序列不同的氨基酸序列并且能够激活辅助T细胞的肽,其中,不同之处在于1个氨基酸被取代、缺失或添加。
[3]根据项目2所述的肽,其由10至25个氨基酸组成并且包含KILQQSRIVQX的氨基酸序列(其中,X不存在或者是S)或KILQQSRVVQX的氨基酸序列(其中,X不存在或者是S)。
[4]根据项目2或3所述的肽,包含选自SEQ ID NO:5至SEQ ID NO:7以及SEQ IDNO:28至SEQ ID NO:30的氨基酸序列。
[5]根据项目2或3所述的肽,由选自SEQ ID NO:3至SEQ ID NO:8以及SEQ ID NO:22至SEQ ID NO:35的氨基酸序列组成。
[6]根据项目2所述的肽,由10至25个氨基酸组成并且包括KILQQSRIVQX的氨基酸序列,其中,X不存在或者是S。
[7]根据项目6所述的肽,由SEQ ID NO:1的氨基酸序列中的连续氨基酸组成。
[8]根据项目6或7所述的肽,包含选自SEQ ID NO:5至SEQ ID NO:7的氨基酸序列。
[9]根据项目6或7所述的肽,由选自SEQ ID NO:3至SEQ ID NO:8以及SEQ ID NO:22至SEQ ID NO:25的氨基酸序列组成。
[10]根据项目6、7或9所述的肽,由选自SEQ ID NO:3至SEQ ID NO:8的氨基酸序列组成。
[11]根据项目1所述的肽,其是
一种由10-45个氨基酸组成的肽,所述肽包含SEQ ID NO:16的氨基酸序列中的10个以上的连续的氨基酸的氨基酸序列,或者
一种具有与前述肽的氨基酸序列不同的氨基酸序列并且能够激活辅助T细胞的肽,其中,不同之处在于1个氨基酸被取代、缺失或添加。
[12]根据项目11所述的肽,由10至45个氨基酸组成并包含SEQ ID NO:16的氨基酸序列中的10个以上的连续的氨基酸的氨基酸序列。
[13]根据项目11或12所述的肽,由20至38个氨基酸组成并包含SEQ ID NO:16的氨基酸序列中的20个以上的连续氨基酸的氨基酸序列。
[14]根据项目11至13中任一项所述的肽,由SEQ ID NO:15的氨基酸序列中的连续氨基酸组成。
[15]根据项目11至14中任一项所述的肽,包含选自SEQ ID NO:16至SEQ ID NO:21的氨基酸序列。
[16]根据项目11至15中任一项所述的肽,由选自SEQ ID NO:16至SEQ ID NO:21的氨基酸序列组成。
[17]根据项目1所述的肽,其是
一种由10-25个氨基酸组成的肽,所述肽包含SEQ ID NO:9的氨基酸序列,或者
一种具有与前述肽的氨基酸序列不同的氨基酸序列并且能够激活辅助T细胞的肽,其中,不同之处在于1个氨基酸被取代、缺失或添加。
[18]根据项目17所述的肽,由19至25个氨基酸组成并且包括SEQ ID NO:9的氨基酸序列。
[19]根据项目17或18所述的肽,由SEQ ID NO:2的氨基酸序列中的连续氨基酸组成。
[20]根据项目17至19中任一项所述的肽,由SEQ ID NO:9的氨基酸序列组成。
[21]一种编码根据项目1至20中任一项所述的肽的核酸。
[22]一种包含根据项目21所述的核酸的表达载体。
[23]一种HLA多聚体,其包含根据项目1至20中任一项所述的肽和HLA II类分子。
[24]一种抗原呈递细胞,其呈递根据项目1至20中任一项所述的肽和HLAII类分子的复合物。
[25]一种能够识别根据项目1至20中任一项所述的肽和HLAII类分子的复合物的辅助T细胞。
[26]一种药物组合物,其包含根据项目1至20中任一项所述的肽、根据项目21所述的核酸、根据项目22所述的表达载体、根据项目23所述的HLA多聚体、根据项目24所述的抗原呈递细胞、或者根据项目25所述的辅助T细胞。
[27]根据项目26所述的药物组合物,还包含DNA转甲基酶抑制剂或与DNA转甲基酶抑制剂结合使用。
[28]根据项目27所述的药物组合物,其中,DNA转甲基酶抑制剂选自由地西他滨、瓜德希他滨、阿扎胞苷、泽布拉林、四氢尿苷、四氢尿苷及其衍生物组成的组。
[29]根据项目27或29所述的药物组合物,其中,DNA转甲基酶抑制剂选自由地西他滨和阿扎胞苷组成的组。
[30]根据项目26至29中任一项所述的药物组合物,用于治疗或预防癌症。
[31]根据项目26至30中任一项所述的药物组合物,是癌症疫苗。
[32]根据项目30或31所述的药物组合物,其中,所述癌症是血液肿瘤、恶性黑色素瘤、乳腺癌、头颈肿瘤、泌尿道肿瘤、食道癌、肝癌、肺癌或结肠癌。
[33]根据项目26至32中任一项所述的药物组合物,其中,所述所述癌症是肺癌或结肠癌。
[34]一种用于激活辅助T细胞的药物组合物,其包含根据项目1至20中任一项所述的肽、根据项目21所述的核酸、根据项目22所述的表达载体、根据项目23所述的HLA多聚体或根据项目24所述的抗原呈递细胞。
本文引用的文件的全部内容通过引用并入本文。
以下实施例不限制本发明。上述实施例是非限制性的,并且可以在不脱离由所附权利要求限定的本发明的范围的情况下进行改进。
实施例
实验1:探索候选基因
通过以下过程识别在用DNA转甲基酶抑制剂(5-氮杂-2'-脱氧胞苷(地西他滨):5-AZA)处理后上调的基因。用5-AZA(10μM)处理肺癌细胞系A549的细胞3天,并提取RNA。使用DNA微阵列测量基因表达水平。识别候选基因的标准是在未处理的细胞中表达水平接近0,而在5-AZA处理的细胞中表达水平增加30倍以上。发现了一些候选基因,包括:SYCP3(未处理:3.0,5-AZA处理:340.9,倍数变化:112.3)、SPESP1(未处理:1.7,5-AZA处理:65.3,倍数变化:38.8)和DAZL1(未处理:2.8,5-AZA处理:341.3,倍数变化:123.6)。
实验2:5-AZA处理诱导的SYCP3、SPESP1和DAZL1基因表达上调的研究
在完全培养基(RPMI 1640培养基(nacalai tesque 30264-56),具有100U/mL的青霉素(Meiji Seika)和100μg/L的链霉素(Meiji Seika),添加有10%胎牛血清(bioseraFB-1365/500),其已在56℃固定30分钟)中,培养癌细胞系(肺癌细胞系EBC1、肺癌细胞系Lu65、结肠癌细胞系HT-29和口腔鳞状细胞癌细胞系SAS)的细胞,该完全培养基包含5-AZA(10μM),以2x 105个细胞/孔的方式在6孔板(Falcon 353046)中在培养箱(SANYO)中培养三天,该培养箱被设定为37℃、5%的CO2和95%的湿度。在以下实验中,相同的培养箱用于所有细胞培养。用2mL磷酸盐缓冲盐水(PBS,KANTO CHEMICAL CO.,INC 73111)洗涤细胞。用RNeasy Mini试剂盒(Qiagen 74106)提取RNA,并用PrimeScript 1st strandcDNA合成试剂盒(Takara Bio 6110A)合成cDNA,GAPDH(Applied Biosystems Hs02786624_g1)和SYCP3(Applied Biosystems Hs00538146_m1)的基因表达水平使用LightCycler480(Roche)通过实时PCR分析。每一步都是按照每种试剂附带的说明书进行的。结果如图所1和2示。5-AZA处理上调了所有受试细胞系的SYCP3
类似地,肾癌细胞系SW839、膀胱癌细胞系5637、肺腺癌细胞系LC2/Ad、肺癌细胞系EBC1、结肠癌细胞系HT-29、肺癌细胞系Lu65和口腔鳞状细胞癌细胞SAS的细胞在5-AZA存在的条件下培养,分析GAPDH和SPESP1(Applied Biosystems Hs00377364_m1)的基因表达水平。结果示于图3和4中。在所有测试的细胞系中,通过5-AZA处理使SPESP1上调。
类似地,在5-AZA存在条件下培养小鼠白血病细胞系WEHI-3(Balb/c)的细胞,并且分析小鼠GAPDH(Applied Biosystems Mm99999915_g1)和小鼠DAZL1(Applied BiosystemsMm01273546_m1)的基因表达水平。结果示于图5。在WEHI-3中,通过5-AZA处理上调了DAZL1。
通过Western印迹分析用5-AZA处理的EBC1和Lu65中SYCP3蛋白的量。以1:200稀释的抗SYCP3抗体(小鼠抗SCP3,BD Bioscience611230)用作第一抗体。还在蛋白质水平观察到5-AZA处理对SYCP3的上调。
小鼠癌细胞系(E0771:C57BL/6小鼠乳腺癌细胞系和C1498:C57BL/6小鼠急性髓系白血病细胞系)的细胞用5-AZA(10μM)处理,并通过Western印迹分析DAZL1蛋白的量。在两种细胞系中,通过5-AZA处理均可上调DAZL1。
另一方面,当在吉西他滨(gemcitabine,一种DNA合成抑制剂)的存在下培养癌细胞系EBC1、Lu65和HT-29的细胞时,SYCP3、SPESP1和DAZL1的基因表达水平等同于对照的基因表达水平。结果表明,在实验2中观察到的每个基因的上调均基于DNA转甲基酶抑制剂的独特作用。
实验3:确认免疫缺陷小鼠中5-AZA处理诱导的SYCP3和SPESP1基因表达上调
使用Myjector(TERUMO SS_05M2913)将BALB/c裸鼠(10至14周大,CHARLES RIVERLABORATORIES JAPAN)皮内注射大肠癌细胞系HT-29(5x 105个细胞)或WiDr(5x 105个细胞),并在第5、10、15和20天,使用Myjector腹腔注射200μL的含5-AZA(1.6μg/g小鼠体重)的PBS。向对照小鼠腹腔施用200μL的PBS。在第25天,通过腹腔注射200μL的500μg/mL戊巴比妥(nacalai tesque 02095-04)安乐死,并用剪刀切除肿瘤组织进行解剖(NONAKARIKAKICo.,Ltd,11301)并用BioMasher II(Nippi,Incorporated,320103)压碎。如实验2中所述,通过实时PCR分析SYCP3和GAPDH的基因表达水平。结果如图6所示。与仅用PBS处理的小鼠相比,从用5-AZA处理的小鼠收集的肿瘤组织中SYCP3得到上调。
类似地,裸鼠皮内注射肺癌细胞系EBC1(5×105个细胞)或Lu65(5×105个细胞)和5-AZA或PBS(对照)。从在第25天收集的肿瘤组织中提取RNA,并通过实时PCR分析SPESP1和GAPDH的基因表达水平。结果如图7所示。与仅用PBS处理的小鼠相比,在用5-AZA处理的小鼠收集的肿瘤组织中SPESP1被上调。
实验4:探索候选蛋白中具有HLA结合的氨基酸序列的区域
为了识别实验1中选择的能够与HLA结合的蛋白质的氨基酸序列,通过计算机算法分析了每个序列与在日本人和西方人常表达的五种类型的HLA结合的可能性,HLA-DRB1*01:01(约10%)、HLA-DRB1*04:05(约25%)、HLA-DRB1*09:01(约26%)、HLA-DRB1*15:01(约15%)和HLA-DR53(60%以上)。识别出包含SYCP3-A(SEQ ID NO:8)、SPESP1-B(SEQ ID NO:9)和DAZL-1C(SEQ ID NO:20)的氨基酸序列。
实验5:使用HLA转基因小鼠研究候选氨基酸序列的免疫刺激能力
HLA-A*02:01/DRB1*01:01转基因小鼠(A2.DR1-Tg小鼠,10至16周龄;PasteurInstitute,France)使用Myjector在第0天和第10天被皮内注射溶解于100μL的PBS中的SYCP3-A肽(由GenScript合成)。在第15天腹腔注射200μL的500μg/mL戊巴比妥使小鼠安乐死。剖腹手术后,收集肿瘤引流的淋巴结(dLN)和脾脏,分别分离淋巴细胞和脾细胞。
将淋巴细胞(3x 105个细胞)和脾细胞(3x 105个细胞)添加到ELISPOT板(EMDMillipore,MAHAS4510)中,并在对照肽(具有未包括在SYCP3中的序列的15个氨基酸的肽)或实验4中选择的SYCP3-A肽的存在下在以150μL/孔的完全培养基中共培养细胞24小时。为了检测特异性针对SYCP3-A肽而产生IFN-γ的细胞,使用小鼠IFN-γELISpotBASIC(ALP)试剂盒(MABTECH 3321-2A)进行了ELISPOT测定。该过程与所附包装插页的描述一致。将用于ELISpot(MABTECH 3650-10)的BCIP-NBT-plus底物用作发色底物,并在每个步骤中使用PBS-T进行洗涤。此外,为了确认反应是由CD4阳性T细胞产生的,将抗小鼠CD4抗体(BioLegend 100435)或抗小鼠CD8抗体(BioLegend 100735)以最终浓度5μg/mL加入到某些培养物中。
结果如下表所示。通过刺激SYCP3-A肽诱导特异性的T细胞应答。该反应被针对CD4的抗体抑制的事实表明该应答是由CD4阳性的T细胞诱导的。
[表1]
此外,为了鉴定SYCP3-A肽中与CD4阳性T细胞相互作用的区域,在SYCP3-A肽序列中具有连续12个氨基酸的部分肽(其中,起始氨基酸顺序地移位了一个氨基酸)使用Sigma-aldrich Pepscreen合成(下表)。
[表2]
如上所述,给A2.DR1-Tg小鼠接种这些部分肽,从每只小鼠中收集dLN和脾脏,分离淋巴细胞和脾细胞,用每种部分肽(3μg/mL)刺激细胞24小时,并通过ELISPOT测定T细胞应答。结果如图8所示。CD4阳性T细胞对部分肽T2、T3和T4有应答。结果表明,SYCP3-A肽中与CD4阳性T细胞相互作用的区域是T2、T3和T4肽共有的氨基酸序列KILQQSRIVQ。
实验6:使用小鼠研究DAZL1候选肽的免疫刺激能力
使用Myjector(TERUMO SS_05M2913)在第0天和第10天向两只BALB/cAnNCrlCrlj小鼠(Balb/c,10至16周龄,Charles river)皮内注射溶于磷酸盐缓冲盐水(PBS,KANTOCHEMICAL CO.,INC.73111)的100μg/50μL的LDAZL-1C肽(DVQKIVESQINFHGKKLKLGPAIRKQNLC(SEQ ID NO:20):由GenScript合成)。在第12天腹腔注射200μL的500μg/mL戊巴比妥(nacalai tesque 02095-04),对小鼠实施安乐死。剖腹手术后,收集dLN和脾脏,分别分离淋巴细胞和脾细胞。
将淋巴细胞(3x 105个细胞)和脾细胞(3x 105个细胞)添加到96孔平底培养板(Falcon 353072)中,并将细胞在对照肽或DAZL-1C肽(2.5μg/mL)的存在下以200μL/孔在完全培养基中培养24小时。为了检测DAZL-1C肽特异的IFN-γ产生,24小时后收集每100μL培养上清液,并使用ELISA装置(BD Biosciences 551866)根据随附的包装说明书测定IFN-γ的浓度。为了确认该反应是由CD4阳性T细胞产生的,抗小鼠CD4抗体(aCD4;BioLegend100435)或抗小鼠CD8抗体(aCD8;BioLegend100735)以5μg/mL的最终浓度添加到某些培养物中。
结果显示在图9中。抗CD4抗体抑制DAZL-1C肽特异的IFN-γ产生的事实表明,DAZL-1C肽激活了小鼠的辅助T细胞。
实验7:使用健康供体的外周血单个核细胞(PBMC)诱导SYCP3-A肽或SPESP1-B肽特
异性辅助T(Th)细胞
使用Lymphoprep(Alere Technologies AS 1114547),通过密度梯度分离法从健康供体的外周血样本中收集PBMC。使用磁性细胞分离系统(Miltenyi 130-050-201)从PBMC中分离CD14阳性细胞。在50ng/mL的GM-CSF(peprotech AF-300-03)和50ng/mL的IL-4(peprotech AF-200-04)的存在下,在6孔培养板(Falcon 353046)中,以3mL人细胞培养基培养7天,诱导分化为树突状细胞(DC)。培养基为AIM-V培养基(ThermoFisher SCIENTIFIC0870112DK),其添加了3%的人AB血清(Innovative RESEARCH IPLA-SERAB)并在56℃灭活了30分钟。类似地,从PBMC中分离出CD4阳性T细胞(Miltenyi 130-045-101),并且在SYCP3-A肽或SPESP1-B肽(3μg/mL)的存在下,在96孔平底培养板(Falcon 353072)中以200μL的体积将1×105个CD4阳性T细胞与5×105个DC共培养。7天后,为了通过所述肽刺激CD4阳性T细胞,从每个孔中取出100μL培养上清液,然后加入SYCP3-A肽或SPESP1-B肽(3μg/mL)和通过γ射线辐照(40Gy)灭活的PBMC(2×105)以达到100μL的体积。2天后,去除50μL培养上清液,并以10U/mL的终浓度添加50μL的IL-2(Imunace35,Shionogi)。为了使激活的CD4阳性T细胞连续增殖,每隔一周用SYCP3-A肽或SPESP1-B肽和灭活的PBMC(1x 106个细胞)刺激细胞(1x106个细胞),,并用于以下描述的实验。
实验8:SYCP3-A肽特异性辅助T细胞系的HLA限制
为了研究增殖的CD4阳性T细胞对SYCP3-A肽的特异性反应性,在SYCP3-A肽(3μg/mL)存在下,使用200μL人类细胞的培养基在96孔平底培养皿中共培养CD4阳性T细胞(5×104个细胞)和PBMC(1×105个细胞)。为了研究CD4阳性T细胞的HLA限制性,将抗DR抗体(BioLegend 307612)或抗HLA I类抗体(BioLegend 311412)以5μg/mL的最终浓度加入到某些培养基中,作为对照。在24至48小时后,从每个孔中收集100μL的培养上清液,并使用ELISA试剂盒(BD Biosciences555142)根据所附包装说明书的描述确定IFN-γ的浓度。
结果显示在图10中。从三个健康供体中建立了多个SYCP3-A特异性Th细胞克隆。当抗HLA-DR抗体(aDR)被添加到克隆中时,可抑制肽特异性IFN-γ的产生。结果表明SYCP3-A肽以HLA-DR限制刺激Th细胞。
此外,为了识别肽所限制于的HLA类型,在SYCP3-A肽(3μg/mL)的存在下,使用200μL人类细胞的培养基在96孔平底培养皿中共培养CD4阳性T细胞(5×104个细胞)和具有HLA-DR4、DR8、DR9或DR53基因(L-DR4,L-DR8,L-DR9,or L-DR53)的小鼠成纤维细胞系的3×104个细胞,并在24至48小时后,如上所述确定培养上清液中的IFN-γ浓度。
所有实验的SYCP3-A肽特异性Th细胞均表现出对L-DR53细胞强烈的肽特异性反应(INF-γ高表达水平)。即使在没有DR53等位基因的样品中,SYCP3-A肽也显示出一定的反应性。结果表明该肽对除DR53以外的其他等位基因有效。
为了识别Th细胞识别所需的SYCP3-A肽中的最小序列,在部分SYCP3-A肽T1至T8(见实验5)中的任何一种存在下,使用200μL人类细胞的培养基在96孔平底培养皿中以3μg/mL的浓度共培养5×104个SYCP3-A肽特异性Th细胞(来自健康供体3的细胞系ID号#14)和1×105个来自同一供体的PBMC。结果显示在图11中。针对T3和T4肽观察到IFN-γ的产生增加。结果表明,SYCP3-A肽特异性Th细胞识别所需的最小序列是T3和T4中共有的氨基酸序列KILQQSRIVQS。
对下表中列出的肽进行了相似的实验。
[表3]
结果显示在图12中。观察到所有肽的IFN-γ产生增加。结果表明,即使将一个或多个氨基酸被添加到最小序列的N或C末端,反应性仍得以保留。乙酰基的添加不会改变反应性。这表明允许对肽进行修饰。在两个克隆之间没有发现反应性的差异。
用缬氨酸残基取代SYCP3-A肽的第11个异亮氨酸残基,并对该肽(SEQ ID NO:31)进行类似实验。反应性没有降低。这表明与CD4阳性T细胞相互作用的SYCP3-A肽的区域允许某些氨基酸突变。
实验9:SPESP1-B肽特异性辅助T细胞系的HLA限制
除了使用SPESP1-B肽代替SYCP3-A肽外,以与实验8相同的方式测定培养物上清液中IFN-γ的浓度。结果显示在图13中。从一位健康供体建立了两个SPESP1-B特异性Th细胞克隆(HK15和HK18)。当抗HLA-DR抗体(aDR)被添加到克隆中时,抑制了肽特异性IFN-γ的产生。结果表明,SPESP1-B肽以HLA-DR限制刺激Th细胞。如实验8中所述,使用L-DR53进行的进一步实验表明SPESP1-B肽结合HLA-DR53并刺激Th细胞。
为了研究SPESP1-B肽特异性Th细胞对肽的反应性,用SPESP1-B肽(依次稀释至0.0003至30μg/mL)刺激Th细胞。即使在低浓度(0.0003μg/mL)下,SPESP1-B肽也能诱导足够的IFN-γ产生。
实验10:诱导DAZL-1肽特异性Th细胞和HLA限制的研究
除了使用部分DAZL-1肽p11、p12或p13(表4)代替SYCP3-A或SPESP1-B肽外,以与实验7相同的方式诱导DAZL-1肽特异的Th细胞。
[表4]
肽序列
p11D VQKIVESQINFHGKKLKLG(SEQ ID NO:17)
p12 INFHGKKLKLGPAIRKQNLC(SEQ ID NO:18)
p13 LGPAIRKQNLCAYHVQPRPL(SEQ ID NO:19)
除了使用部分DAZL-1肽p11、p12或p13代替SYCP3-A肽外,用与实验8相同的方法测定培养上清液中IFN-γ的浓度。为了研究HLA限制,使用了抗HLA-DP抗体、抗HLA-DQ抗体(SPV-L3:Abcam ab85614)和抗HLA-DR抗体(BRAFB6:Santa Cluz sc-33719)。结果显示在图14中。当使用抗HLA-DR抗体(aDR)时,肽特异性IFN-γ的产生被抑制。结果表明,部分DAZL-1肽以HLA-DR限制地刺激Th细胞。抗HLA-DQ抗体也抑制了p13诱导的IFN-γ产生。结果表明,衍生自DAZL-1的肽对多种HLA有效。
如实验8所述,使用L-DR4、L-DR8、L-DR9、L-DR15和L-DR53进行的进一步实验显示,p11、p12和p13分别结合HLA-DR4/9/53、HLA-DR15和HLA-DR8,以刺激Th细胞。
实验11:SYCP3-A肽特异性CD4阳性T细胞对癌细胞的反应性
为研究SYCP3-A肽特异性CD4阳性T细胞对癌细胞系的细胞的反应性,使用DR53阳性癌细胞系(WiDr、Lu65和Calu1)。使用2mL含10μM的M5-AZA和500U/mL的IFN-γ(ImmunoMax-γ注射50,Shionogi)的完全培养基(其可诱导HLA II类分子在癌细胞表面的表达),将癌细胞在6孔培养板中培养3天。用PBS充分洗涤培养板,加入1mL的5mM EDTA(乙二胺四乙酸,nacalai tesque 14347-21)以悬浮细胞,并回收细胞。以与实验8相同的方式,将每种细胞系的1×104个细胞和5×104个CD4阳性T细胞使用200μL人类细胞培养基在96孔平底培养板上共培养。为了证实反应性取决于HLA-DR,将抗HLA-DR抗体以5μg/mL的终浓度加入培养物中。24小时后,从每个孔中收集100μL的培养物上清液,并且使用ELISA试剂盒测定IFN-γ的浓度。
结果显示在图15中。5-AZA处理增加了IFN-γ的产生。结果表明,用SYCP3-A肽激活的Th细胞对经5-AZA处理的DR53阳性癌细胞有效反应。
实验12:DNA转甲基酶抑制剂和SYCP3特异性Th细胞对免疫缺陷小鼠的肿瘤生长抑
制作用
使用Myjector向BALB/c裸鼠(10至14周龄,CHARLES RIVER LABORATORIES JAPAN)皮内注射3x 106个肺癌细胞系Lu65的细胞,并在第7、12、17和22天,分别使用Myjector腹腔施用200μL的包含5-AZA(150nmol/g小鼠体重)的PBS。向对照小鼠腹腔施用200μL的PBS。在第13、20和27天,通过尾静脉给施用方式施用200μL的SYCP3特异性人Th细胞(3至5x 106个细胞)。通过尾静脉施用向对照小鼠施用200μL的PBS。随时间测量肿瘤表面积。结果显示在图16中。仅5-AZA没有观察到作用,而对于5-AZA和SYCP3特异性人Th细胞的组合却观察到了肿瘤生长抑制作用。
工业适用性
本文公开的癌症抗原肽激活了对所述肽特异的辅助T细胞,因此可用作癌症疫苗。所述肽与包括HLA-DR53(其是以较高频率共有的)在内的HLA结合,因此对许多癌症患者有效。
序列表
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Claims (15)
1.一种肽,所述肽由10至45个氨基酸组成并且包含:
KILQQSRIVQX的氨基酸序列,其中,X不存在或者是S;
DVQKIVESQINFHGKKLKLGPAIRKQNLCAYHVQPRPL(SEQ ID NO:16)的氨基酸序列中的10个以上的连续氨基酸的氨基酸序列;或
QNLNHYIQVLENLVRSVPS(SEQ ID NO:9)的氨基酸序列;或者
一种具有与前述肽的氨基酸序列不同的氨基酸序列并且能够激活辅助T细胞的肽,其中不同之处在于1-3个氨基酸被取代、缺失或添加。
2.根据权利要求1所述的肽,其是由10至25个氨基酸组成并包含KILQQSRIVQX的氨基酸序列的肽,其中,X不存在或者是S;或者
其是一种具有与前述肽的氨基酸序列不同的氨基酸序列并且能够激活辅助T细胞的肽,其中,不同之处在于一个氨基酸被取代、缺失或添加。
3.根据权利要求2所述的肽,其由10至25个氨基酸组成并且包含KILQQSRIVQX的氨基酸序列,其中,X不存在或者是S。
4.根据权利要求3所述的肽,其由SEQ ID NO:1的氨基酸序列中的连续氨基酸组成。
5.根据权利要求3或4所述的肽,其包含选自由KILQQSRIVQSQ(SEQ ID NO:5)、QKILQQSRIVQS(SEQ ID NO:6)和QQKILQQSRIVQ(SEQ ID NO:7)组成的组的氨基酸序列。
6.根据权利要求1所述的肽,其由10至45个氨基酸组成,并且包含
DVQKIVESQINFHGKKLKLGPAIRKQNLCAYHVQPRPL(SEQ ID NO:16)的氨基酸序列中的10个以上的连续氨基酸的氨基酸序列。
7.根据权利要求1或6所述的肽,其包含选自由DVQKIVESQINFHGKKLKLG(SEQ ID NO:17)、INFHGKKLKLGPAIRKQNLC(SEQ ID NO:18)和LGPAIRKQNLCAYHVQPRPL(SEQ ID NO:19)组成的组的氨基酸序列。
8.根据权利要求1、6和7中任一项所述的肽,其由选自由DVQKIVESQINFHGKKLKLG(SEQID NO:17)、INFHGKKLKLGPAIRKQNLC(SEQ ID NO:18)和LGPAIRKQNLCAYHVQPRPL(SEQ ID NO:19)组成的组的氨基酸序列组成。
9.根据权利要求1所述的肽,其由19至25个氨基酸组成并且包含QNLNHYIQVLENLVRSVPS(SEQ ID NO:9)的氨基酸序列。
10.根据权利要求1或9所述的肽,其由QNLNHYIQVLENLVRSVPS(SEQ ID NO:9)的氨基酸序列组成。
11.一种编码根据权利要求1至10中任一项所述的肽的核酸。
12.一种药物组合物,其包含根据权利要求1至10中任一项所述的肽、根据权利要求11所述的核酸、表达载体、HLA多聚体、抗原呈递细胞或辅助T细胞,其中,所述表达载体包含根据权利要求11所述的核酸,所述HLA多聚体包含根据权利要求1至10中任一项所述的肽和HLA II类分子,所述抗原呈递细胞呈递根据权利要求1至10中任一项所述的肽与HLA II类分子的复合物,所述辅助T细胞能够识别根据权利要求1至10中任一项所述的肽与HLAII类分子的复合物。
13.根据权利要求12所述的药物组合物,其还包含DNA转甲基酶抑制剂,或者其与DNA转甲基酶抑制剂组合使用。
14.根据权利要求12或13所述的药物组合物,其用于治疗或预防癌症。
15.根据权利要求12或13所述的药物组合物,其是癌症疫苗。
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- 2019-02-15 EP EP22156092.3A patent/EP4043569A1/en not_active Withdrawn
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US20220152174A1 (en) | 2022-05-19 |
CN112812153A (zh) | 2021-05-18 |
CN111788214B (zh) | 2021-06-22 |
EP3754022A4 (en) | 2021-09-29 |
EP4036235A1 (en) | 2022-08-03 |
US20220152173A1 (en) | 2022-05-19 |
CN112812154B (zh) | 2022-04-05 |
MX2020008558A (es) | 2021-01-08 |
CN112812153B (zh) | 2022-06-14 |
KR102267463B1 (ko) | 2021-06-21 |
JP6857930B2 (ja) | 2021-04-14 |
EP4043569A1 (en) | 2022-08-17 |
CA3091099A1 (en) | 2019-08-22 |
WO2019160099A1 (ja) | 2019-08-22 |
MY182816A (en) | 2021-02-05 |
EP3754022A1 (en) | 2020-12-23 |
US20210038703A1 (en) | 2021-02-11 |
CA3091099C (en) | 2021-11-23 |
KR20200111264A (ko) | 2020-09-28 |
SG11202007750PA (en) | 2020-09-29 |
JPWO2019160099A1 (ja) | 2021-02-04 |
CN111788214A (zh) | 2020-10-16 |
US20220152172A1 (en) | 2022-05-19 |
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