CN107428815A - 源于gpc3的肽、使用其的用于治疗或预防癌症的医药组合物、免疫诱导剂、及抗原呈递细胞的制造方法 - Google Patents
源于gpc3的肽、使用其的用于治疗或预防癌症的医药组合物、免疫诱导剂、及抗原呈递细胞的制造方法 Download PDFInfo
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Classifications
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- C07K14/46—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates
- C07K14/47—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates from mammals
- C07K14/4701—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates from mammals not used
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- C07K14/705—Receptors; Cell surface antigens; Cell surface determinants
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- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N5/00—Undifferentiated human, animal or plant cells, e.g. cell lines; Tissues; Cultivation or maintenance thereof; Culture media therefor
- C12N5/06—Animal cells or tissues; Human cells or tissues
- C12N5/0602—Vertebrate cells
- C12N5/0634—Cells from the blood or the immune system
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- A61K2039/57—Medicinal preparations containing antigens or antibodies characterised by the type of response, e.g. Th1, Th2
- A61K2039/572—Medicinal preparations containing antigens or antibodies characterised by the type of response, e.g. Th1, Th2 cytotoxic response
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- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N2501/00—Active agents used in cell culture processes, e.g. differentation
- C12N2501/998—Proteins not provided for elsewhere
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- Chemical & Material Sciences (AREA)
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Abstract
本发明提供一种肽,所述肽含有序列号1~11中的任一项表示的氨基酸序列中连续8个以上的氨基酸残基,并且所述肽包含11个以下的氨基酸残基。
Description
技术领域
本发明涉及源于GPC3的肽,更具体而言,涉及经由与人白细胞抗原的结合而向T细胞呈递抗原的免疫原性肽、使用所述肽的用于治疗或预防癌症的医药组合物、免疫诱导剂及抗原呈递细胞的制造方法等。
背景技术
虽然认为在生物体内经常偶然地产生癌细胞,但推测通常会发生基于自然免疫的对源于癌细胞的特异性癌抗原的排斥反应,接着,特异性免疫应答被诱导出来,发生淋巴细胞等对癌细胞的排斥反应。
为了识别出源于癌细胞的抗原,存在于细胞表面上的人白细胞抗原(HLA)与淋巴细胞形成复合体是必需的。主要组织相容性抗原即HLA分子可被大致分类为I类分子(HLA-A型、B型、C型)和II类分子(HLA-DP型、DQ型、DR型)。由细胞毒性T细胞(CTL)引起的癌细胞排斥反应是通过癌细胞表面的HLA I类分子所呈递的由8~11个氨基酸组成的癌抗原(CTL表位)被CTL上的T细胞抗原受体(TCR)特异性识别而诱导出的。
目前,出于将免疫原性肽应用于治疗或预防各种免疫相关疾病的期望而进行了各种研究,例如,日本特开平8-151396号公报中公开了由特定氨基酸序列构成的寡肽具有HLA结合性。
现有技术文献
专利文献
专利文献1:日本特开平8-151396号公报
发明内容
发明所要解决的课题
尽管已知有多种具有HLA结合性的肽,但仍然进一步需求可用于治疗或预防各种癌症的肽。另外,HLA是多态性丰富的基因,因此,也需求对应于多种HLA基因型的多型性(multi-type)免疫原性肽。
用于解决课题的手段
本发明是鉴于上述情况而作出的,其目的在于提供与HLA I类分子结合的免疫原性肽、尤其是能够诱导CTL的肽、使用所述肽的用于治疗或预防癌症的医药组合物、免疫诱导剂、及抗原呈递细胞的制造方法等。
即,本发明包括以下的发明。
(1)一种肽,其含有序列号1~11中的任一项表示的氨基酸序列中连续8个以上的氨基酸残基,并且,所述肽包含11个以下的氨基酸残基。
(2)如(1)所述的肽,其中,所述氨基酸序列中,1个或数个氨基酸被取代、插入、缺失或添加,并且,所述肽具有免疫原性。
(3)如(2)所述的肽,其中,所述氨基酸序列中的第2位的氨基酸被酪氨酸、苯丙氨酸、甲硫氨酸、色氨酸、缬氨酸、亮氨酸或谷氨酰胺取代,以及/或者,C末端的氨基酸被苯丙氨酸、亮氨酸、异亮氨酸、色氨酸、甲硫氨酸或缬氨酸取代。
(4)用于治疗或预防癌症的医药组合物,其含有(1)~(3)中任一项所述的肽。
(5)如(4)所述的医药组合物,所述医药组合物为疫苗的形式。
(6)如(4)或(5)所述的医药组合物,其中,所述肽能够与1种或多种类型的HLA分子结合。
(7)免疫诱导剂,其含有(1)~(3)中任一项所述的肽。
(8)如(7)所述的免疫诱导剂,其用于诱导细胞毒性T细胞。
(9)如(7)或(8)所述的免疫诱导剂,其中,所述肽能够与1种或多种类型的HLA分子结合。
(10)具有CTL诱导活性的抗原呈递细胞的制造方法,所述方法包括使(1)~(3)中任一项所述的肽与抗原呈递细胞在体外(in vitro)接触的工序。
发明的效果
近年来,作为癌症的治疗方法,免疫疗法受到关注。本发明的肽因其HLA结合性高,并且CTL诱导能力也强,因此作为癌症疫苗的有用性备受期待。另外,还预计其可应用于各种免疫疗法、尤其是树突细胞疗法。
磷脂酰肌醇蛋白多糖-3(Glypican-3)(GPC3)是属于磷脂酰肌醇蛋白多糖家族的蛋白质。磷脂酰肌醇蛋白多糖是一种蛋白多糖,其可与细胞表面的糖基磷脂酰肌醇(glycosyl-phosphatidylinositol)结合是已知的。磷脂酰肌醇蛋白多糖会对包括Wnts在内的多种细胞生长因子的活性加以控制,但认为该作用是因为磷脂酰肌醇蛋白多糖对这些细胞生长因子与它们的受体之间的相互作用加以促进或组在。特别地,已发现,GPC3在几乎全部肝癌(肝细胞癌,hepatocellular carcinoma(HCC))中表达,而另一方面,其在正常的肝脏、肝硬化等中几乎不表达。另外,除了在肝细胞癌中以外,还已知GPC3在黑色素瘤、卵巢癌等中高表达。
1.“Glypican-3:a marker and a therapeutic target in hepatocellularcarcinoma.”Jorge Filmus and Mariana Capurro,FEBS J.,280:2471-2476,2013.
2.“Glypican-3:a new target for cancer immunotherapy.”Mitchell Ho andHeungnam Kim,Eur.J.Cancer,47,333-338,2011.
针对肝细胞癌,使用源于在肝细胞癌细胞中高表达的GPC3的肽的癌症疫苗的临床研究已在进行,对其安全性和免疫诱导能力也有报道。
3.“Peptide vaccines for hepatocellular carcinoma.”Daisuke Nobuoka,Toshiaki Yoshikawa,Yu Sawada,Toshiyoshi Fujiwara and Tetsuya Nakatsura,HumanVaccines&Immunotherapeutics,9,210-212,2013.
4.“Phase I Trial of a Glypican-3-Derived Peptide Vaccine for AdvancedHepatocellular Carcinoma:Immunologic Evidence and Potential fo ImprovingOverall Survival.”Yu Sawada,et.al.,Clin.Cancer.Res.,18,3636-3696,2012.
本发明中,鉴定了多种与以上临床研究中报道的肽不同的源于GPC3的肽,并且,所述肽不仅能与与HLA分子结合,并且还具有免疫诱导能力。另外,本发明的肽中,特定的一些能与多种类型的HLA结合。由此,根据本发明的肽,能够提供涵盖范围极广的癌患者群体的癌症疫苗、树突细胞疗法等。
附图说明
[图1]图1示出了用序列号1的肽对来自接受了HSP70树突细胞疗法的患者[0](HLA基因型:24:02/24:02)的样品进行刺激时的ELISPOT检验的结果(IFN-γ产生细胞数)。
[图2]图2示出了用序列号1、2或4的肽对来自接受了HSP70树突细胞疗法的患者(HLA基因型:02:01/24:02)的样品进行刺激时的ELISPOT检验的结果(IFN-γ产生细胞数)。
[图3]图3示出了用序列号1、2或4的肽对来自接受了HSP70树突细胞疗法的患者(HLA基因型:02:01/33:03)的样品进行刺激时的ELISPOT检验的结果(IFN-γ产生细胞数)。
[图4]图4示出了用序列号1、2或4的肽对来自接受了HSP70树突细胞疗法的患者(HLA基因型:24:02/26:01)的样品进行刺激时的ELISA检验的结果(IFN-γ产生细胞数)。
[图5]图5示出了用序列号1、2或4的肽对来自接受了HSP70树突细胞疗法的患者(HLA基因型:24:02/24:02)的样品进行刺激时的ELISA检验的结果(IFN-γ产生细胞数)。
[图6]图6示出了用序列号1、2或4的肽对来自接受了HSP70树突细胞疗法的肝癌患者(HLA基因型:11:01/24:02)的样品进行刺激时的ELISA检验的结果(IFN-γ产生细胞数)。
[图7]图7示出了用序列号1、2或4的肽对来自接受了HSP70树突细胞疗法的患者(HLA基因型:02:01/24:02)的样品进行刺激时的ELISA检验的结果(IFN-γ产生细胞数)。
[图8]图8示出了用序列号1、2或4的肽对来自接受了HSP70树突细胞疗法的患者(HLA基因型:02:01/33:03)的样品进行刺激时的ELISA检验的结果(IFN-γ产生细胞数)。
具体实施方式
1.免疫原性肽
本发明涉及的肽含有序列号1~11中的任一项表示的氨基酸序列中连续8个以上的氨基酸残基,并且,其是包含共计11个以下、优选10个以下、更优选9个以下的氨基酸残基的肽。本发明的肽可以是包含序列号1~11中的任一项表示的氨基酸序列的肽。本发明的肽源于作为磷脂酰肌醇蛋白多糖之一的GPC3。基于构成GPC3的氨基酸序列、通过使用主动学习实验法(active learning experiment)(日本特开平8-151396号)得到的假想理论而预测的与HLA分子的结合性为3(换算为-logKd值)以上的氨基酸序列被选出。
构成本发明的肽的氨基酸序列及它们的HLA预测结合分值示于下述表1。
[表1]
本发明的肽具有HLA结合性,并且具有免疫原性(后文中有时也简称为“HLA肽”或“免疫原性肽”)。在本说明书中使用时,“免疫原性”是指能够诱导出免疫反应,例如,是指具有CTL诱导活性、进而具有对癌细胞的细胞损伤活性。
在优选的实施方式中,本发明的肽是能够与HLA-A基因A的等位基因型中的多种结合的多型性HLA肽。例如,序列号7的肽可与HLA-A*24:02基因的产物(HLA-A*24:02分子)、HLA-A*0201基因的产物(HLA-A*02:01分子)及HLA-A*02:06基因的产物(HLA-A*02:06分子)牢固地结合,并且具有高免疫原性。
本发明的肽所能够结合的HLA亚型不限于HLA-A*24:02、HLA-A*02:01及HLA-A*02:06。然而,鉴于上述HLA亚型已涵盖了东亚人群(包括日本人)的85%左右、及西方人群的55%左右,因此,认为本发明的多型性HLA肽在免疫疗法等中具有广泛的患者覆盖率。
对于本发明的肽而言,只要保持免疫原性,构成序列号1~11的氨基酸序列的氨基酸残基或其一部分也可以是经修饰的。虽然序列号1~11表示的氨基酸序列来表现在抗原呈递细胞上呈递的状态,但在将本发明的肽直接施予至体内的情况下,有时因施予途径的不同而导致发生在消化器官等中其末端被消化等变化。因此,本发明的肽在被抗原呈递细胞摄入之前可以以在N末端及/或C末端添加有1个或多个氨基酸残基等的前体的状态存在,以使得其在抗原呈递细胞上与规定的HLA I类分子结合时可保持序列号1~11表示的氨基酸残基。
进而,本发明的肽只要具有所期望的免疫原性即可,构成本发明的肽的1个或多个的氨基酸残基可被取代、插入、缺失或添加,以及/或者,进行糖链添加、侧链氧化、及/或磷酸化等修饰。本说明书中,“氨基酸”取其最为宽泛的含义,除了天然氨基酸以外,还包括人造的氨基酸突变体、衍生物。本说明书中,就氨基酸而言,可举出:天然蛋白质性的L-氨基酸;D-氨基酸;氨基酸突变体及衍生物等经化学修饰的氨基酸;正亮氨酸、β-丙氨酸、鸟氨酸等天然非蛋白质性氨基酸;以及具有本领域中已知的作为氨基酸特征的特性的以化学方式合成的化合物等。作为非天然氨基酸的例子,可举出α-甲基氨基酸(α-甲基丙氨酸等)、D-氨基酸、类组氨酸的氨基酸(β-羟基-组氨酸、高组氨酸、α-氟甲基-组氨酸及α-甲基-组氨酸等)、在侧链具有多余的亚甲基的氨基酸(“高(homo)”氨基酸)及侧链中的羧酸官能团被磺酸基取代的氨基酸(半胱氨酸等)。
关于氨基酸残基的取代等,考虑到对HLA显示出结合性的肽序列的规则性(J.Immunol.,152:p3913,1994;Immunogenetics,41:p178,1995;J.Immunol.,155:p4307,1994),本领域技术人员可以适宜地对构成本发明的肽的氨基酸残基进行取代。
更具体而言,对于与HLA-A*24:02分子结合的肽而言,构成肽的第2位氨基酸可被酪氨酸、苯丙氨酸、甲硫氨酸或色氨酸取代,以及/或者,C末端的氨基酸可被苯丙氨酸、亮氨酸、异亮氨酸、色氨酸或甲硫氨酸取代。另外,对于与HLA-A*02:01分子结合的肽而言,第2位氨基酸可被亮氨酸或甲硫氨酸取代,以及/或者,C末端的氨基酸可被缬氨酸或亮氨酸取代。此外,对于与HLA-A*02:06分子结合的肽而言,第2位氨基酸可被缬氨酸或谷氨酰胺取代,以及/或者,C末端的氨基酸可被缬氨酸或亮氨酸取代。
本发明的肽均可使用本领域技术人员已知的方法来制造。例如,可利用Fmoc法、tBoc法等固相法或液相法进行人工合成。另外,也可通过使编码本发明的肽的多核苷酸或含有该多核苷酸的重组载体表达来制造所期望的肽。另外,这样得到的肽均可使用领域技术人员已知的方法来鉴定。例如,可使用Edman降解法、质谱法等进行鉴定。
2.医药组合物
本发明涉及的用于治疗或预防癌症的医药组合物含有例如下述的肽作为有效成分,所述肽含有选自由序列号1~11组成的组中的1种以上氨基酸序列中连续8个以上的氨基酸残基,并且包含共计11个以下、优选10个以下、更优选9个以下的氨基酸残基。医药组合物中含有的肽也可以是包含序列号1~11中的任一项表示的氨基酸序列的肽。所述肽如上文所定义。
本发明的肽通过在抗原呈递细胞上被呈递而诱导CTL,该经诱导的CTL杀伤癌细胞。因此,本发明的医药组合物中的有效成分不限于本发明的肽,也可以是能够直接或间接诱导CTL的成分、例如编码该肽的多核苷酸或含有所述多核苷酸的载体、或者将该肽与HLA分子的复合体呈递至表面的抗原呈递细胞或由抗原呈递细胞分泌的外泌体(exosome)、或它们的组合。作为所使用的抗原呈递细胞,可举出巨噬细胞、树突细胞等,优选使用CTL诱导能力强的树突细胞。本发明的医药组合物中也可含有已知用于癌症治疗的其他成分、例如趋化因子、细胞因子、肿瘤坏死因子、化疗剂等。对于肽的用量而言,例如,患者为成年人时,可以为每天约1~10mg。但是,由于用量因患者的年龄、体重、施予方法等的不同而发生变化,因此,可由本领域技术人员来适当确定。
认为本发明的医药组合物通过下述作用机理而在癌细胞的杀伤等方面是有用的(但这并非意图对本发明加以限定)。通过向特定的癌患者施予本发明的医药组合物,从而医药组合物中的肽以与HLA分子结合的状态被呈递至抗原呈递细胞表面。CTL在识别出这样的抗原呈递细胞上的肽后发生活化,进行增殖并进入全身循环。当肽特异性的CTL侵入癌组织时,会识别与位于癌细胞的表面的HLA分子自然结合的源于特异性癌抗原的相同的肽,从而杀伤该癌细胞。可以通过该作用而有助于癌症的治疗。
除了癌症的治疗以外,本发明的医药组合物也可用于癌症的预防。例如,通过将本发明的医药组合物施予至健康的人体,从而可诱导出CTL,诱导出的细胞毒性T细胞在体内蓄积,因此,在产生特定的癌细胞时能够损伤该癌细胞。同样地,通过施予至癌症治疗后的人体,可预防癌症的复发。
作为治疗或预防的癌症,可为表达GPC3的任何癌症。更具体地可举出肝细胞癌、黑色素瘤等皮肤癌、卵巢癌等作为对象(但这并非意图对本发明加以限定)。例如,作为本发明的肽的来源的GPC3在肝细胞癌中过量表达,因此,认为本发明的肽尤其对于肝细胞癌症的治疗或预防有效。在存在有多种需要治疗或预防的癌症的情况下,可以在本发明的医药组合物中含有多种免疫原性肽等有效成分。
本发明的医药组合物可溶解于水溶性溶剂中从而以制药上允许的盐的形式制成制剂后施予至患者。作为这样的制药上允许的盐的形式,可举出以生理上可接受的水溶性盐(例如钠、钾、镁、钙等盐)的形式缓冲为生理pH值的形态。另外,除了水溶性溶剂以外,还可使用非水溶性溶剂,作为这样的非水溶性溶剂,例如,可举出乙醇、丙二醇等醇。
另外,在包含本实施方式的医药组合物的制剂中,可包含针对各种目的的化学药剂,作为这样的化学药剂,可举出例如防腐剂、缓冲剂等。作为防腐剂,可举出重亚硫酸钠、重硫酸钠、硫代硫酸钠、苯扎氯铵、氯丁醇、硫柳汞(thimerosal)、乙酸苯汞、硝酸苯汞、对羟基苯甲酸甲酯、聚乙烯醇、苯乙醇、氨、二硫代苏糖醇、β-巯基乙醇等。另外,作为缓冲剂,可举出碳酸钠、硼酸钠、磷酸钠、乙酸钠、重碳酸钠等。这些化学药剂可以以能够将体系pH维持在2~9、优选4~8之间的量存在。
对本发明的医药组合物的剂型也没有特别限制,在以疫苗形式使用的情况下,其剂型可示例注射剂(肌肉、皮下、皮内)、口服制剂、滴鼻制剂等。本发明的医药组合物为疫苗的形式时,也可以是含有多种有效成分的混合鸡尾酒式疫苗(cocktail vacine)。例如,这样的疫苗可含有序列号1~11表示的肽中的任意2种以上,或可与其他有效成分组合而含有多种有效成分。
另外,本发明的疫苗也可以是含有下述非活性成分的疫苗,所述非活性成分是医药组合物以外的成分,其自身不具有活性,但具有进一步提高医药组合物的作为疫苗的效果。作为非活性成分,可举出佐剂、类毒素等。作为佐剂的例子,可举出氢氧化铝、磷酸铝、磷酸钙等沉降性类型的佐剂,弗氏完全佐剂、弗氏不完全佐剂等油性类型的佐剂(但这并非意图对本发明加以限定)。
本发明的医药组合物以疫苗形式存在时,优选地,通过基于皮内、皮下、静脉内、肌肉内施予等的注射或注入,或通过自皮肤、或鼻腔、咽喉等的粘膜吸收等而施予至体内。其单次施予量可被设定为从能够显著地诱导细胞毒性T细胞的量到显著数量的非癌细胞不受损伤的量之间。
本发明的医药组合物不仅可施予至人体中,而且也意图在体外进行使用。更具体而言,本发明的医药组合物可用于对抗原呈递细胞进行体外或离体(ex vivo)刺激来增强CTL诱导活性。例如,以用于癌症的树突细胞疗法的情况为例进行说明时,可使本发明的医药组合物与来源于需要治疗或预防癌症的患者的树突细胞等抗原呈递细胞预先进行接触,然后将该抗原呈递细胞输回至患者的体内,由此施予至患者。可利用例如脂质体转染法、注射法等将医药组合物中含有的肽导入至抗原呈递细胞内。在上述用途中使用编码本发明的肽的多核苷酸时,可利用本领域已知的方法将多核苷酸导入至抗原呈递细胞。例如,可利用脂质体转染法、电穿孔法、显微注射法、细胞融合法、DEAE葡聚糖法、磷酸钙法等,使用对象多核苷酸或编码多核苷酸的载体对来自患者的抗原呈递细胞进行体外转化等。
3.免疫诱导剂
本发明涉及的免疫诱导剂含有例如下述的肽作为有效成分,所述的肽含有选自由序列号1~11组成的组中的1种以上氨基酸序列中连续8个以上的氨基酸残基,并且包含11个以下、优选10个以下、更优选9个以下的氨基酸残基。免疫诱导剂中含有的肽也可以是包含序列号1~11中的任一项表示的氨基酸序列的肽。所述肽如上文所定义。
认为本发明的肽通过在抗原呈递细胞上被呈递而诱导免疫。因此,本发明的免疫诱导剂的有效成分不限于本发明的肽,还可以是能够直接或间接地诱导免疫的成分,例如编码本发明的肽的多核苷酸或含有所述多核苷酸的表达载体、或者将该肽与HLA分子的复合体呈递至表面的抗原呈递细胞或由抗原呈递细胞分泌的外泌体、或它们的组合。作为所使用的抗原呈递细胞,可举出巨噬细胞、树突细胞等,优选使用CTL诱导能力强的树突细胞。
本发明的免疫诱导剂不仅可施予至人体中,而且也意图在体外进行使用。更具体而言,本发明的医药组合物可用于对抗原呈递细胞进行体外或离体刺激来增强CTL诱导活性。例如,以用于树突细胞疗法的情况为例进行说明时,可使本发明的免疫诱导剂与来源于需要治疗或预防癌症的患者的树突细胞等抗原呈递细胞预先进行接触,然后将该抗原呈递细胞送回至患者的体内,由此施予至患者。可利用例如介由脂质体的转染(脂质体转染法)、注射法等将免疫诱导剂中含有的肽导入至抗原呈递细胞内。在上述用途中使用编码本发明的肽的多核苷酸时,可利用本领域已知的方法将多核苷酸导入至抗原呈递细胞。例如,可利用脂质体转染法、电穿孔法、显微注射法、细胞融合法、DEAE葡聚糖法、磷酸钙法等,使用对象多核苷酸或表达多核苷酸的载体对来自患者的抗原呈递细胞进行体外转化等。
在本说明书中使用时,“免疫诱导”是指诱导免疫反应,例如增大抗原呈递细胞的CTL诱导活性,进而增大CTL对癌细胞的细胞损伤活性。另外,在本说明书中使用时,“CTL诱导”是指:在体外或体内,通过将本发明的肽呈递至抗原呈递细胞表面上来诱导特异性识别某种抗原的CTL或使其增殖;或者使幼稚T细胞分化为具有杀伤癌细胞等靶细胞的能力(细胞损伤活性)的效应器细胞;以及/或者,增大CTL的细胞损伤活性。CTL诱导活性可通过对由CTL导致的细胞因子(例如干扰素(IFN)-γ)的产生进行评价来测定。例如,可使用ELISPOT(酶联免疫斑点试验,Enzyme-Linked Immuno Spot)或ELISA(酶联免疫吸附测定,Enzyme-Linked ImmunoSorbent Assay)等已知的高感度免疫检验,对通过经本发明的肽刺激的末梢血单核细胞等抗原呈递细胞从前体细胞诱导出的细胞因子产生细胞的增加加以评价,由此来测定CTL诱导活性。细胞损伤活性还可利用51Cr游离法等已知方法进行测定。上述活性与对照相比显著地增加时,例如增加5%以上、10%以上、20%以上、优选50%以上时,可评价为免疫或CTL被诱导。
4.抗原呈递细胞的制造方法
本发明涉及的抗原呈递细胞的制造方法包括使例如下述的肽与抗原呈递细在体外进行接触的工序,所述的肽含有选自由序列号1~11组成的组中的1种以上氨基酸序列中连续8个以上的氨基酸残基,并且包含共计11个以下、优选10个以下、更优选9个以下的氨基酸残基。本发明的制造方法中使用的肽也可以包含序列号1~11中的任一项表示的氨基酸序列。所述的肽如上文所定义。
认为本发明的制造方法中使用的肽与抗原呈递细胞表面的HLAI类分子结合,以抗原肽的形式被呈递至CTL,由此诱导抗原呈递细胞的CTL活性。因此,与抗原呈递细胞接触的不限于本发明的肽,还可以是能够直接或间接诱导CTL的成分,例如编码该肽的多核苷酸或含有所述多核苷酸的载体、或者将该肽与HLA分子的复合体呈递至表面的抗原呈递细胞或由抗原呈递细胞分泌的外泌体(exosome)、或它们的组合。作为所使用的抗原呈递细胞,可举出巨噬细胞、树突细胞等,优选使用CTL诱导能力强的树突细胞。
通过本发明的制造方法制造的抗原呈递细胞不仅可作为上述医药组合物或免疫诱导剂的有效成分使用,将其用于免疫疗法等也在本发明的范畴内。例如,以用于癌症的树突细胞疗法的情况为例进行说明时,可以将制造的抗原呈递细胞与来源于需要免疫诱导的患者的、CTL诱导能力弱的树突细胞等抗原呈递细胞预先进行接触,然后将该抗原呈递细胞输回患者的体内,由此施予至患者。可利用例如介由脂质体的转染(脂质体转染法)、注射法等将本发明的肽导入至抗原呈递细胞内。在上述用途中使用编码本发明的肽的多核苷酸时,可利用本领域已知的方法将多核苷酸导入至抗原呈递细胞。例如,可利用脂质体转染法、电穿孔法、显微注射法、细胞融合法、DEAE葡聚糖法、磷酸钙法等,使用对象多核苷酸或编码多核苷酸的载体对来自患者的抗原呈递细胞进行体外转化等。
实施例1
以下,举出实施例更具体地说明本发明,但本发明不限于这些实施例。
具体而言,本实施例中的预测/实验/评价的步骤基于国际公开2006/004182号小册子中记载的主动学习实验计划进行,并创建了将以下步骤作为整体重复的规则。
(1)试行一次下文所述的低阶学习算法(low rank learning algorithm)。即,由累积数据的随机重复取样产生多种假想理论,选择相对于随机产生的备选查询点(肽)而言的预测值的分散最大的点作为应进行实验的查询点。
(2)利用后述的合成/纯化方法来制造所选择的查询点的肽,利用后述的实验来测定实际的结合能力,从而添加至累积数据中。
通过进行这样的主动学习法,从而对于由9个氨基酸残基构成的肽而言,原本共需要进行5000亿(=209)次以上的备选HLA结合性肽的结合实验的数量得以被削减。
通过上文说明的规则,从而抽取出了序列号1~11所示的氨基酸序列。
<肽的合成和纯化>
使用Fmoc氨基酸、通过Merrifield的固相法对具有序列号1~11的氨基酸序列的肽进行人工合成。在脱保护之后,使用C18柱实施反相HPLC纯化,使得纯度达到95%以上。肽的鉴定和纯度的确认通过MALDI-TOF质谱法来进行(AB SCIEX MALDI-TOF/TOF5800)。以BSA为标准蛋白,通过Micro BCA检验(Thermo Scientific公司)来进行对肽的定量。
<肽与HLA-A*24:02分子的结合实验>
使用表达HLA-A*24:02分子的C1R-A24细胞(所述细胞是熊本大学滝口雅文教授制备的,在得到许可后由爱媛大学安川正贵助理教授提供),对肽与HLA-A*24:02分子(其为HLA-A*24:02基因的产物)的结合能力进行测定。
首先,将C1R-A24细胞在pH为3.3的酸性条件下暴露30秒,将原本与HLA-A*24:02分子结合的内源性肽、和与HLA I类分子共通缔合的轻链β2m解离、除去。进行中和后,向C1R-A24细胞中添加经纯化的β2m,然后将细胞添加至肽的稀释系列中,在冰上孵育4小时。使用识别此期间重新缔合的HLA-A*24:02分子、肽、β2m这三者的缔合物(MHC-pep)的经荧光标记的单克隆抗体17A12进行染色。
然后,使用荧光细胞分析装置FACScan(Becton-Dickinson公司),对相对每一C1R-A24细胞而言的MHC-pep量(与上述荧光抗体的荧光强度成比例)进行定量测定。使用本申请的发明人发表于论文(Udaka et al.,Immunogenetics,51,816-828,2000)中的方法,从相对于每一细胞而言的平均荧光强度计算出HLA-A*24:02分子与肽之间的结合解离常数Kd值。
<肽与HLA-A*02:01分子的结合实验>
使用表达HLA-A*02:01分子的细胞株T2(购自ATCC),对肽与HLA-A*02:01分子(其为HLA-A*02:01基因的产物)的结合能力进行测定。
向将要测定结合能力的肽的阶段(stepwise)稀释系列中添加T2细胞和纯化的β2m,然后于37℃孵育4小时。使用缔合型特异性荧光标记单克隆抗体BB7.2,对表达量在直至该时间点为止以肽浓度依赖性方式增加的HLA-A*02:01分子进行染色。
然后,使用流式细胞仪测定相对每一细胞而言的荧光量进行,通过本申请的发明人发表于论文(Udaka et al.,Immunogenetics,51,816-828,2000)中的方法计算出解离常数Kd值。
<肽与HLA-A*02:06分子的结合实验>
使用向RMAS(小鼠TAP(抗原加工相关转运体,transporter associated withantigen processing)缺陷细胞株)中导入HLA-A*02:06基因的cDNA而得到的RA2.6细胞(高知大学新制备的细胞株),对肽与HLA-A*02:06分子(其为HLA-A*02:06基因的产物)的结合能力进行测定。
首先,将RA2.6细胞于26℃过夜培养,未结合肽的HLA-A*02:06分子在细胞表面蓄积后,向其中添加肽的稀释系列,于26℃进行60分钟的结合。
然后,通过于35℃培养4小时,未结合肽的空HLA-A*02:06分子发生变性,丧失立体结构。向其中添加特异性识别肽结合型HLA-A*02:06分子的经荧光标记的单克隆抗体BB7.2,在冰上孵育20分钟,对细胞进行染色。
然后,使用流式细胞仪测定相对每一细胞而言的荧光量,通过本申请的发明人发表于论文(Udaka et al.,Immunogenetics,51,816-828,2000)中的方法计算出解离常数Kd值。
<结合实验的评价结果>
结果,得到了下表中所示的本发明的肽与各HLA分子的结合实验数据。
[表2]
需要说明的是,序列号1~11的氨基酸序列来自于登录于GENBANK中的GPC3所规定基因组蛋白质的全长序列(序列号12)(>gi|4758462|ref|NP_004475.1|glypican-3isoform 2precursor[Homo sapiens])。
<肽免疫诱导试验>
(1)肽刺激树突细胞的制备
·第0~9天(树突细胞的诱导)
将通过分离术(pheresis)从接受HSP70树突细胞疗法的患者[0]得到的末梢血单核细胞中的、粘附于培养烧瓶的细胞组分在AIM-CM培养基(Gibco公司制)中于37℃培养10天。在培养期间,分别在第0天及第3天向培养基中添加15μl的IL-4、30μl粒细胞单核细胞集落刺激因子(GM-CSF),并在第5天添加15μl的IL-4、30μl的GM-CSF、75μl肿瘤坏死因子(TNF)-α。
·第10天(肽刺激及树突细胞的回收)
将已诱导的树突细胞重新回收至AIM-CM培养基中,添加本发明的肽(序列号1~11),以使得肽浓度成为20μg/ml。然后,将含有树突细胞的培养基于37℃培养2小时。作为阳性对照及阴性对照,使用了以下的肽。
HLA-A*24:02用阳性对照(EBV LMP2,419-427:TYGPVFMCL(序列号13))
HLA-A*24:02用阴性对照(HIV env gp160,584-592:RYLRDQQLL(序列号14))
HLA-A*02:01用阳性对照(Flu A MP,58-66:GILGFVFTL(序列号15))
HLA-A*02:01用阴性对照(HIV gap p17,77-85:SLYNTVATL(序列号16))
HLA-A*02:06用阳性对照(EBV LMP2 453-461:LTAGFLIFL(序列号17))
HLA-A*02:06用阴性对照(HIV gap p24 341-349:ATLEEMMTA(序列号18))
回收树突细胞,使用足量的AIM-CM培养基洗涤3次以上,然后进行细胞计数。
(2)CD8T细胞的制备
·第0~9天
将通过分离术从使用疫苗进行了2次以上治疗后的患者得到的末梢血单核细胞中的、未粘附于培养烧瓶的悬浮细胞组分(包含淋巴细胞)在AIM-CM培养基(Gibco公司制)中于37℃培养10天。在培养期间,分别在第4天及第6天向培养基中添加40μl的IL-2。
·第10天
使用CD8阴性选择试剂盒(Negative Selection Kit)(Miltenyi公司制)从培养基中分离CD8T细胞,并进行细胞计数。
(3)共培养
在下述条件下,将上述(1)及(2)中得到的树突细胞和CD8T细胞在AIM培养基中于37℃共培养。
·CD8T细胞:5×105个细胞/孔
·树突细胞:2×105个细胞/孔
·第12或第13天
向上述培养基中以0.4ml/孔的量添加含有20U/ml的IL-2的AIM-CM培养基。
(4)ELISPOT检验
·第17天
以每孔为2×104个细胞/孔的方式,向涂覆有抗TFN-γ单克隆抗体(MABTECH公司制)的ELISPOT用96孔培养板(Millipore公司制)中添加上述CD8T细胞。对于各样品,使用3个孔以上。向各孔中添加100μl的AIM-V(Gibco公司制)。于37℃对ELISPOT用96孔培养板进行培养。
·第18天
向各孔中添加抗TFN-γ抗体,进而使HRP酶标记的二抗与其反应,利用呈色反应测定IFN-γ产生细胞的数量。作为代表性的ELISPOT检验结果,将HLA基因型为24:02/24:02的患者的结果示于图1,将HLA基因型为02:01/24:02的患者的结果示于图2,另外,将HLA基因型为02:01/33:03的患者的结果示于图3。各图中,示出了3次检验结果的平均值。
(5)ELISA检验
·第17天
在对T细胞和经上述肽冲击的树突细胞进行共培养的第7天,将培养上清液稀释为×1、×5、×25、×125这四个阶段,使用Human IFN-γELISA MAX Deluxe Set(BioLegend公司制),对测定限度内的稀释阶段进行鉴定。然后,在已鉴定的稀释阶段,针对各样品分别进行3次测定。作为代表性的ELISA检验结果,将HLA基因型为24:02/26:01的患者、24:02/24:02的患者、11:01/24:02的患者、02:01/24:02的患者、02:01/33:03的患者的结果依次示于图4~8。
以上,基于实施例对本发明进行了说明。上述实施例仅为例示,本领域技术人员能够理解的是,可以进行各种变形例,并且这些变形例也在本发明的范围内。
序列表
<110> 日本电气株式会社
<120> 源于GPC3的肽、使用其的用于治疗或预防癌症的医药组合物、免疫诱导剂、及抗原呈递细胞的制造方法
<130> 6470A98014
<150> JP2015-46463
<151> 2015-03-09
<160> 18
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<210> 2
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Leu Phe Asp Ser Leu Phe Pro Val Ile
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<210> 3
<211> 9
<212> PRT
<213> 智人(Homo sapiens)
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Ser Ala Leu Asp Ile Asn Glu Cys Leu
1 5
<210> 4
<211> 9
<212> PRT
<213> 智人(Homo sapiens)
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Ser Leu Gln Val Thr Arg Ile Phe Leu
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<210> 5
<211> 9
<212> PRT
<213> 智人(Homo sapiens)
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Ser Leu Thr Pro Gln Ala Phe Glu Phe
1 5
<210> 6
<211> 9
<212> PRT
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<400> 6
Gly Tyr Ile Cys Ser His Ser Pro Val
1 5
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<212> PRT
<213> 智人(Homo sapiens)
<400> 7
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<210> 8
<211> 9
<212> PRT
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<212> PRT
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<210> 11
<211> 9
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<213> 智人(Homo sapiens)
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1 5
<210> 12
<211> 580
<212> PRT
<213> 智人(Homo sapiens)
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Ser Met Glu Leu Lys Phe Leu Ile Ile Gln Asn Ala Ala Val Phe Gln
100 105 110
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115 120 125
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130 135 140
Val Gly Glu Phe Phe Thr Asp Val Ser Leu Tyr Ile Leu Gly Ser Asp
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Ile Asn Val Asp Asp Met Val Asn Glu Leu Phe Asp Ser Leu Phe Pro
165 170 175
Val Ile Tyr Thr Gln Leu Met Asn Pro Gly Leu Pro Asp Ser Ala Leu
180 185 190
Asp Ile Asn Glu Cys Leu Arg Gly Ala Arg Arg Asp Leu Lys Val Phe
195 200 205
Gly Asn Phe Pro Lys Leu Ile Met Thr Gln Val Ser Lys Ser Leu Gln
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225 230 235 240
Asn Thr Thr Asp His Leu Lys Phe Ser Lys Asp Cys Gly Arg Met Leu
245 250 255
Thr Arg Met Trp Tyr Cys Ser Tyr Cys Gln Gly Leu Met Met Val Lys
260 265 270
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275 280 285
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290 295 300
Glu Leu Val Asn Gly Met Tyr Arg Ile Tyr Asp Met Glu Asn Val Leu
305 310 315 320
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325 330 335
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340 345 350
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355 360 365
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370 375 380
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405 410 415
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435 440 445
Glu Leu Lys Met Lys Gly Pro Glu Pro Val Val Ser Gln Ile Ile Asp
450 455 460
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Claims (10)
1.一种肽,其含有序列号1~11中的任一所表示的氨基酸序列中连续8个以上的氨基酸残基,并且,所述肽包含11个以下的氨基酸残基。
2.如权利要求1所述的肽,其中,所述氨基酸序列中的1个或数个氨基酸被取代、插入、缺失或添加,并且,所述肽具有免疫原性。
3.如权利要求2所述的肽,其中,所述氨基酸序列中,第2位的氨基酸被酪氨酸、苯丙氨酸、甲硫氨酸、色氨酸、缬氨酸、亮氨酸或谷氨酰胺取代,以及/或者,C末端的氨基酸被苯丙氨酸、亮氨酸、异亮氨酸、色氨酸、甲硫氨酸或缬氨酸取代。
4.用于治疗或预防癌症的医药组合物,其含有权利要求1~3中任一项所述的肽。
5.如权利要求4所述的医药组合物,所述医药组合物为疫苗的形式。
6.如权利要求4或5所述的医药组合物,其中,所述肽能够与1种或多种类型的HLA分子结合。
7.免疫诱导剂,其含有权利要求1~3中任一项所述的肽。
8.如权利要求7所述的免疫诱导剂,其用于诱导细胞毒性T细胞。
9.如权利要求7或8所述的免疫诱导剂,其中,所述肽能够与1种或多种类型的HLA分子结合。
10.具有CTL诱导活性的抗原呈递细胞的制造方法,所述方法包括使权利要求1~3中任一项所述的肽与抗原呈递细胞在体外接触的工序。
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BR112017018703A2 (pt) | 2015-03-09 | 2018-04-17 | Cytlimic Inc. | peptídeo derivado de gpc3, composição farmacêutica para tratamento ou prevenção de câncer usando o mesmo, indutor de imunidade, e método para produzir células de apresentação de antígeno |
BR112017020404A2 (pt) | 2015-04-07 | 2018-07-10 | Cytlimic Inc. | medicamento |
TW201813664A (zh) | 2016-10-11 | 2018-04-16 | 賽多利克公司 | 醫藥 |
WO2023163094A1 (ja) * | 2022-02-25 | 2023-08-31 | 日本電気株式会社 | 成人t細胞白血病の治療又は予防のための医薬組成物 |
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US10526388B2 (en) | 2020-01-07 |
EP3269733A4 (en) | 2018-08-01 |
TW202115102A (zh) | 2021-04-16 |
ES2805829T3 (es) | 2021-02-15 |
US20190062389A1 (en) | 2019-02-28 |
WO2016143816A1 (ja) | 2016-09-15 |
CN107428815B (zh) | 2021-07-09 |
CA2979168A1 (en) | 2016-09-15 |
US20200157163A1 (en) | 2020-05-21 |
EP3269733B1 (en) | 2020-06-17 |
RU2017135038A (ru) | 2019-04-08 |
RU2017135038A3 (zh) | 2019-08-30 |
US10875900B2 (en) | 2020-12-29 |
JP6898225B2 (ja) | 2021-07-07 |
RU2714117C2 (ru) | 2020-02-11 |
JPWO2016143816A1 (ja) | 2018-03-01 |
US10590179B2 (en) | 2020-03-17 |
AU2016230125B2 (en) | 2020-07-16 |
BR112017018703A2 (pt) | 2018-04-17 |
US20180105567A1 (en) | 2018-04-19 |
TW201639869A (zh) | 2016-11-16 |
EP3269733A1 (en) | 2018-01-17 |
AU2016230125A1 (en) | 2017-09-21 |
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