CN101580817A - 含有细胞因子诱导杀伤细胞的细胞群的制造方法 - Google Patents
含有细胞因子诱导杀伤细胞的细胞群的制造方法 Download PDFInfo
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Abstract
本发明提供了一种含有细胞因子诱导杀伤细胞的细胞群的制造方法,其中包括如下工序:在纤维连接蛋白片段的存在下,培养含有能分化为细胞因子诱导杀伤细胞的细胞的细胞群。本发明还提供了一种细胞群,其中含有通过上述方法而得的细胞因子诱导杀伤细胞。本发明还提供了一种药品,其中含有上述细胞群作为有效成分。本发明还提供了所述细胞群在药物制备上的应用。
Description
技术领域
本发明涉及过继免疫疗法中高效的含有细胞因子诱导杀伤(CIK)细胞的细胞群以及该细胞群的制造方法等。本发明涉及的含有CIK细胞的细胞群中调节性T细胞(regulatory T cells;Treg细胞)的增殖被抑制,可用于早期和晚期癌症以及包括造血细胞和实体瘤在内的各种细胞增殖性疾病的治疗。
背景技术
近年来,人们重新审视药物疗法和放射疗法之类的给患者带来严重肉体痛苦的治疗方法,开始越来越关注痛苦小的免疫疗法。该疗法包括过继免疫疗法,其将取出至体外的免疫相关细胞进行培养使其细胞数目增加,和/或增强与治疗效果相关的活性后,再移植给患者。
过继免疫疗法中作为效应细胞利用的细胞,已知有淋巴因子激活的杀伤(lymphokine activated killer;LAK)细胞、肿瘤浸润淋巴细胞(tumourinfiltrating lymphocyte;TIL)以及细胞因子诱导杀伤(cytokine-inducedkiller;CIK)细胞。
LAK细胞是通过在白细胞介素(IL)-2存在下使淋巴细胞增殖而得到的细胞群,具有能溶解肿瘤细胞但不溶解正常细胞的性质。关于LAK细胞的制备,已开发出在培养时使抗CD3抗体与IL-2共存的方法。
TIL是浸润于肿瘤组织的T细胞,与LAK细胞相比,具有更显著的肿瘤抗原特异性。该细胞也可以在体外增殖并用于治疗。但是,TIL必须摘取患者的肿瘤组织才能获得,因此采集操作繁杂,得到的细胞数也很少。
CIK细胞可由末梢血单核细胞(PBMC)在干扰素(IFN)-γ、抗CD3抗体以及IL-2的存在下进行培养来制备。CIK细胞是以CD3阳性、CD56阳性为特征的PBMC中稀有的细胞群,但在没有靶细胞的存在下可以使该细胞群优先增殖。CIK细胞在体内发挥比LAK细胞更胜一筹的针对肿瘤细胞的细胞杀伤活性(例如非专利文献1)。
纤维连接蛋白是存在于动物血液、培养细胞表面、组织的细胞外基质中的分子量25万的巨大糖蛋白,已知具有多种功能。其结构域有7个(参照图1)。而且,其氨基酸序列中含有3种类似的序列,由上述各序列的重复构成整体。3种类似的序列分别被称为I型、II型、III型。其中,III型由71~96个氨基酸残基构成,这些氨基酸残基的一致率为17~40%。
利用DNA重组技术,制得多种纤维连接蛋白的片段,可期待其中有些具有抑制癌转移的作用(非专利文献2)。此外,还报道具有肝素结合域的纤维连接蛋白片段具有促进逆转录病毒感染细胞的功能(非专利文献3)。
针对移入由体外诱导的细胞毒T细胞(cytotoxic T cell;CTL)或末梢血淋巴细胞等在IL-2和抗CD3抗体的作用下经放大培养得到的淋巴因子激活的细胞的免疫疗法中,如何在将体外诱导的抗原特异性CTL放大培养时维持细胞毒活性、如何能在体外高效地放大培养淋巴细胞等问题,探讨了使用纤维连接蛋白或其片段所产生的效果(例如专利文献1~3)。
非专利文献1 J.Immunol.,1994年,Vol.153,p1687-1696
非专利文献2 J.Biochem.,1991年,Vol.110,No.2,p284-291
非专利文献3 Nature Medicine,1996年,Vol.2,No.8,p876-882
专利文献1 国际公开第03/016511号小册子
专利文献2 国际公开第03/080817号小册子
专利文献3 国际公开第2005/019450号小册子
发明内容
在CIK细胞的放大培养过程中,PBMC分化为多个性质不同的细胞群,因此放大后的细胞群中的CIK细胞比例必定不高。另一方面,在分化得到的细胞群中还含有具有控制或抑制免疫的功能的细胞群。本发明的目的在于提供用于制造被称为过继免疫疗法的优选细胞群的CIK细胞的、不必要的细胞群含量少的癌治疗用细胞群的放大培养方法。
下面,对本发明进行概述。本发明的第1发明涉及含有CIK细胞的细胞群的制造方法,其特征在于,包含如下工序,即在纤维连接蛋白片段的存在下,培养含有能分化成细胞因子诱导杀伤细胞的细胞的细胞群。第1发明的方式可提供在含有选自VLA-4结合域、VLA-5结合域以及肝素结合域中的区域的纤维连接蛋白片段的存在下,实施培养的含有CIK细胞的细胞群的制造方法。
另外,作为第1发明中使用的纤维连接蛋白片段的优选例子,可例举含有选自序列号1、2以及5中的氨基酸序列的纤维连接蛋白片段。此外,作为第1发明的优选方式,还提供在CD3配体、干扰素-γ以及白细胞介素-2的共存下实施纤维连接蛋白片段存在下的培养的含有CIK细胞的细胞群的制造方法。作为CD3配体,只要能在本发明中使用即可,没有限制,优选使用抗CD3抗体来实施。
本发明的第2发明涉及用本发明第1发明的方法得到的含有CIK细胞的细胞群。
本发明的第3发明涉及含有本发明第2发明的细胞群为有效成分的药品。
本发明的第4发明涉及包含如下工序的疾病治疗方法或预防方法,所述工序中向受试体给予有效量的本发明第2发明的细胞群。另外,所述疾病只要是对本发明第2发明的细胞群具有感受性的疾病即可。此外,第2发明的细胞群可以是来自身患需要治疗或预防的疾病且接受该细胞群给药的受试体(患者)的细胞群,根据情况也可以是来自受试体以外的供者的细胞群。
本发明的第5发明涉及用于药品制造的第2发明的细胞群的使用。
本发明的制造方法提供能大量放大培养富含具有高细胞毒活性的CIK细胞的细胞群的制造方法。由该制造方法大量得到的高品质细胞群在生物体内发挥高效的治疗效果,因此对利用细胞医疗的疾病治疗极其有用。
附图说明
图1是表示纤维连接蛋白的结构域的示意图。
图2是表示用放大培养得到的细胞群的表型。
具体实施方式
本发明发现通过在纤维连接蛋白片段的存在下培养PBMC,在得到的细胞群中含有高比例在细胞表面表达CD3、CD56两分子的细胞,从而完成了本发明。
下面,具体说明本发明。
(1)本发明中使用的纤维连接蛋白的片段
本说明书中所述的纤维连接蛋白的片段可以是天然得到的片段(天然的纤维连接蛋白经酶解片段化后得到的片段等)或通过DNA重组技术得到的片段中的任一种。纤维连接蛋白片段,例如可根据鲁斯特(ルオスラ一テイ)E.等[J.Biol.Chem.,第256卷,第14号,第7277~7281页(1981)]中公开的内容,由来自天然的物质以实质上为纯物质的形态来制造。这里,本说明书中所述的实质上纯的纤维连接蛋白片段指本质上不含有天然情况下与纤维连接蛋白一起存在的其他蛋白质。本发明中,纤维连接蛋白片段可以使用单一的分子种,也可以混合使用多个分子种。
本发明中能使用的纤维连接蛋白片段及该片段的制备相关的有用信息可通过非专利文献2以及Koarnblihtt A.R.等[EMBO J.,第4卷,第7号,1755~1759(1985)]、Sekiguti K.等[Biochemistry,第25卷,第17号,4936~4941(1986)]等而得。另外,编码纤维连接蛋白的核酸序列或纤维连接蛋白的氨基酸序列已在Genbank Accession No.NM_002026,NP_002017中公开。
本发明可优选使用具有细胞粘附活性和/或肝素结合活性的纤维连接蛋白片段。
纤维连接蛋白中存在具有与细胞表面的整合蛋白结合的活性的区域。作为上述区域,可例举VLA(极晚抗原)-4、VLA-5结合域。
在纤维连接蛋白的靠近C末端侧的部位存在被称为IIICS的区域。其中含有被称为CS-1的由25个氨基酸序列构成的区域,该区域对VLA-4表现出结合活性。CS-1区域的氨基酸序列如序列表的序列号1所示。
另外,在纤维连接蛋白中存在被称为III型的重复序列,在从N末端侧开始第10个III型重复序列中存在与细胞结合的区域。第10个III型重复序列的氨基酸序列如序列表的序列号2所示。上述序列中在与VLA-5的结合中起主要作用的序列为序列表的序列号3所示的Arg-Gly-Asp-Ser(RGDS)四氨基酸。由序列表的序列号4所示的氨基酸序列组成的C-274是含有序列号2的氨基酸序列的多肽,是具有强的细胞粘附活性的重组纤维连接蛋白片段。
此外,纤维连接蛋白具有与肝素结合的活性。纤维连接蛋白的肝素结合域相当于上述III型重复序列的N末端侧开始的第12~第14个。由序列表的序列号5所示的氨基酸序列组成的H-271是由此肝素结合域组成的重组纤维连接蛋白片段。
本发明除了可以使用单独含有各区域的片段外,还可以使用上述区域中2个以上直接或介以合适的接头(leader)结合而成的片段。上述片段中含有的来自纤维连接蛋白的区域可以相同也可以不同。作为分子内具有多个结合域的纤维连接蛋白的片段,可例举含有VLA-4结合域和肝素结合域的H-296(序列表的序列号6表示的氨基酸序列)、含有VLA-5结合域和肝素结合域的CH-271(序列表的序列号7表示的氨基酸序列)、含有VLA-4结合域、VLA-5结合域和肝素结合域的CH-296(序列表的序列号8表示的氨基酸序列)、含有VLA-4结合域和VLA-5结合域的C-CS1(序列表的序列号9表示的氨基酸序列)等多肽。上述各种多肽在非专利文献2中有记载,可以根据其公开的内容来制作。宝生物工程株式会社以乐透露奈库秦(レトロネクチン)(Retronectin:注册商标)的名称出售CH-296。
作为本发明中使用的片段,只要能获得本发明所希望的效果,也可以是与上述例举的含有天然纤维连接蛋白的氨基酸序列中的至少一部分的片段具有同等功能的、由具有构成该片段的多肽的氨基酸序列经1个或多个氨基酸取代、缺失、插入或添加的氨基酸序列的多肽构成的片段。例如,使C-274或H-271缺失1个或2个III型重复序列而得到的片段。
关于细胞粘附活性,可以用公知的方法测定本发明中使用的片段(其细胞结合域)与细胞的结合而获得。例如,上述方法包括威廉姆斯(ウイリアブズ)D.A.等的方法[Nature,第352卷,第438~441页(1991)]。该方法是测定细胞与培养板上固定化的片段的结合的方法。关于肝素结合活性,可以用公知的方法测定本发明中使用的片段(其肝素结合域)与肝素的结合来获得。例如,将上述威廉姆斯D.A.等的方法中的细胞换成肝素,例如使用标记肝素,即可用同样的方法评价片段与肝素的结合。
从获取、操作的容易性以及品质均一性、病毒等混入的危险性低的安全层面考虑,本发明优选使用重组纤维连接蛋白片段。本发明中使用的纤维连接蛋白片段的分子量没有特殊限制,优选1~200kD、进一步优选5~190kD、更优选10~180kD。该分子量例如可通过SDS-聚丙烯酰胺凝胶电泳来测定。
(2)含有CIK细胞的细胞群的制造方法
下面,对本发明涉及的含有CIK细胞的细胞群的制造方法进行具体说明。本发明涉及富含CIK细胞、即以CD3阳性和CD56阳性为特征的细胞亚群的细胞群的制造方法。本发明方法的特征在于,包含如下工序,即:在上述纤维连接蛋白片段的存在下,培养含有能分化为CIK细胞的细胞的细胞群。
作为本发明制造方法中使用的含有能分化为CIK细胞的细胞的细胞群,可例举由末梢血、骨髓、脐带血等得到的细胞群或从这些材料中分离得到的血细胞类细胞群。本发明优选使用PBMC。上述细胞群可以是从生物体采集的新鲜细胞群或冷冻保存过的细胞群,均可用于本发明。
本发明的制造方法中对纤维连接蛋白片段的浓度没有特殊限制,但优选例如为0.001~500μg/mL、特别是0.01~500μg/mL。纤维连接蛋白片段除了在培养基中溶解而共存外,还可以在合适的固相例如皮氏培养皿、烧瓶、袋子等细胞培养用器材(培养用容器;包括开放体系和封闭体系)或珠子、膜、载玻片等细胞培养用载体上固定化后使用。这些固相的材质只要是可以在细胞培养中使用的材料即可,没有特殊限制。关于纤维连接蛋白的固定化量,根据将上述器材或载体供培养用时,按与将该成分在培养基中溶解使用时所需的浓度相同的比例进行选择,只要能得到所需效果,没有特殊限制。
作为纤维连接蛋白片段在固相上的固定化方法,没有特殊限制,例如可通过使溶解于适当缓冲液中的片段与固相接触进行固定化。另外,也可以用国际公开第97/18318号小册子以及国际公开第00/09168号小册子中记载的方法来实施纤维连接蛋白片段的固定化。
本发明优选的方式中,在CD3配体的存在下进行纤维连接蛋白片段存在下的培养。作为CD3配体,只要是具有CD3结合活性的物质即可,没有特殊限制,可例举例如抗CD3抗体,特别优选抗CD3单克隆抗体,例如OKT3[J.Immunol.,第124卷,第6号,2708~2713(1980)]。CD3配体在培养基中的浓度没有特殊限制,例如在使用抗CD3单克隆抗体的情况下,优选例如0.001~500μg/mL、特别是0.01~100μg/mL。CD3抗体也可以通过与纤维连接蛋白片段同样的操作在细胞培养用器材或细胞培养用载体上固定化后使用。
若将纤维连接蛋白片段、CD3配体在固相上固定化,则培养结束后,只要将细胞与固相分离即可容易地将上述成分与得到的细胞群分离,能防止上述成分混入细胞群。
本发明的含有CIK细胞的细胞群的制造方法中使用的培养基,没有特殊限制,可以使用淋巴细胞放大培养等中能使用的公知的培养基,例如可以适当地选择使用市售培养基。上述培养基除其原有的构成成分外,还可以含有细胞因子类、适当的蛋白质及其他成分。通常,本发明使用含有IFN-γ、IL-2的培养基。IFN-γ在培养基中的浓度没有特殊限制,可以是50~10000U/mL,更优选100~5000U/mL。IL-2在培养基中的浓度也没有特殊限制,可以是10~5000U/mL,优选50~2000U/mL。此外,还可以在培养基中添加IL-1α、IL-7、IL-12等细胞因子类。只要能获得所需效果,该成分在培养基中的浓度不受特殊限制。
在培养基中可以添加血清或血浆进行培养。它们在培养基中的添加量不受特殊限制,如大于0容量%至20容量%,且可以根据不同的培养阶段而改变血清或血浆的用量。例如,可以阶段性减少血清或血浆浓度来使用。另外,作为血清或血浆的来源,可以是自己(意味着与所培养的细胞来源相同)或非自己(意味着与所培养的细胞的来源不同)中的任一种,从安全性的观点出发,优选自己来源的血清或血浆。另外,也可以添加如人血清白蛋白之类经分离纯化的血清成分。
本发明的含有CIK细胞的细胞群的制造除了使用纤维连接蛋白片段外,使用上述各种成分及培养基来实施。本发明中使用的培养开始时的细胞数没有特殊限制,例如优选1×104cell/mL~1×108cells/mL、更优选1×105cell/mL~5×107cells/mL。另外,培养条件也没有特殊限制,可以使用通常的细胞培养中使用的条件。例如,可在37℃、5%CO2等条件下培养。还可以实施如下等操作:间隔适当的时间添加新鲜培养基来稀释细胞培养液,或更换培养基,或更换细胞培养用器材等。
本发明的制造方法中可以使用例如皮氏培养皿、烧瓶、袋子、大型培养槽、生物反应器等细胞培养用器材(容器)。作为袋子,优选细胞培养用CO2气体透过性袋子。在需要大量细胞的情况下,可以使用大型培养槽。培养可以在开放体系或封闭体系中的任一体系中实施,但优选在封闭体系中实施培养。
本发明含有CIK细胞的细胞群的制造方法中,对培养期没有特殊限制,例如可以实施总天数为4~30天、优选6~25天的培养。在本发明的制造方法中,纤维连接蛋白片段存在下的培养可以是培养期的整个期间,也可以是任意的一部分期间。即,只要在细胞培养工序的一部分中包含纤维连接蛋白片段存在下的培养工序的培养即属于本发明。特别优选整个培养期的至少初期阶段在纤维连接蛋白片段的存在下实施培养,更优选在纤维连接蛋白片段的存在下开始培养。最好是将本发明的有效成分存在下的培养在培养开始后至少实施1天以上、更优选2天以上。当培养时使用CD3配体时,其使用时期没有特殊限制,例如在纤维连接蛋白片段使用时使CD3配体共存。
本发明的一个优选方式中,仅在整个培养期的初期阶段使用纤维连接蛋白片段和CD3配体。例如,从培养开始时到第7天为止,优选从培养开始时到第5天为止,在纤维连接蛋白片段和CD3配体的共同存在下实施培养,之后在这两种成分均不存在的条件下继续培养,制造含有CIK细胞的细胞群,但本发明不限于此。
此外,本发明的制造方法还可以包含如下工序,即从用上述方法得到的细胞群中进一步分离出CD3阳性、CD56阳性的细胞群。关于分离,例如可以用使用细胞分选仪、磁珠、亲和柱等的公知手段来进行。如此分离得到的细胞群富含具有高细胞毒活性的细胞,可期待其发挥更好的治疗效果。
(3)含有CIK细胞的细胞群
本发明提供用上述本发明的含有CIK细胞的细胞群的制造方法得到的含有CIK细胞的细胞群。本发明的含有CIK细胞的细胞群与用现有方法制得的含有CIK细胞的细胞群相比,由于含有高比例的CIK细胞即CD3阳性CD56阳性细胞,因此在生物体内发挥更强的细胞毒活性,达到很好的治疗效果。此外,上述细胞群还具有如下优点,即具有抑制细胞性免疫作用的调节性T细胞(regulatory T cells;Treg细胞)的含量低,因此非常利于在治疗上应用。
本发明还提供以含有CIK细胞的细胞群为有效成分的药品(治疗剂或预防剂)。含有该细胞群的上述治疗剂适用于免疫疗法。免疫疗法中,例如通过注射或点滴等的静脉、动脉、皮下、腹腔内等给药方法向患者给予适于患者治疗的含有CIK细胞的细胞群。本发明的治疗剂对于例如癌症、白血病、恶性肿瘤、肝炎或感染性疾病(例如流感、结核、AIDS、MRSA感染症、VRE感染症、深层真菌症)等对CIK细胞具有感受性的疾病的治疗非常有用,但本发明并不限于此。另外,该治疗剂也可以在以防治骨髓移植或放射线照射后的感染症、缓减复发白血病症状为目的的供者淋巴细胞输注等中应用。
本发明的治疗剂、预防剂可以根据制药领域的公知方法来制备,例如以用本发明的方法制得的细胞群为有效成分,与公知的适于非口服给药的有机或无机的载体、赋形剂、稳定剂等混合,制成点滴剂、注射剂。另外,治疗剂中本发明的含有CIK细胞的细胞群的含量、治疗剂的给药量、与该治疗剂相关的各种条件可根据公知的免疫疗法来适当地决定。例如,药品中本发明的含有CIK细胞的细胞群的含量,没有特殊限制,例如优选1×103~1×1011cells/mL,进一步优选1×104~1×1010cells/mL,更优选1×105~2×109cells/mL。另外,作为本发明药品的给药量,没有特殊限制,例如成人每日优选为1×106~1×1012cells/天,进一步优选为1×107~5×1011cells/天,更优选为1×108~2×1011cells/天。此外,采用该治疗剂的免疫疗法可以与公知的通过给予药物的药物治疗或放射治疗、外科手术治疗并用。
本发明的含有CIK细胞的细胞群的制造方法还可以进一步包括在该细胞群中导入外源基因的工序。另外,“外源基因”指向基因导入对象的CIK细胞中人为导入的基因,也包括来自与作为基因导入对象的细胞同种细胞的基因。
外源基因的导入手段没有特殊限制,可以从公知的基因导入方法中选择使用适当的方法。基因导入工序可以在本发明制造方法中的任意时刻实施。从作业效率的观点出发,例如优选与上述细胞群的制造同时或中途或在该工序后实施。可以用病毒载体来实施基因导入,也可以不使用病毒载体。其方法的具体内容已在众多文献中公开。
上述病毒载体没有特殊限制,通常使用基因导入方法中使用的公知的病毒载体,例如逆转录病毒载体、慢病毒载体、腺病毒载体、腺伴随病毒载体、猿猴病毒载体、痘苗病毒载体或仙台病毒载体等。特别优选能将外源基因稳定地整合到被导入的细胞的染色体DNA中的逆转录病毒载体、慢病毒载体。作为上述病毒载体,优选在感染的细胞中无法自我复制的复制能力欠缺的载体。另外,在基因导入时,也可以使用乐透露奈库秦(注册商标,宝生物工程株式会社制)等能提高基因导入效率的物质。
作为不使用病毒载体的基因导入方法,可以采用使用核糖体、配体-聚赖氨酸等载体的方法或磷酸钙法、电穿孔法、基因枪法等。此时,整合在质粒DNA、直链状DNA或RNA中的外源基因被导入。
导入的外源基因没有特殊限制,可以使用希望导入上述细胞的任意基因(例如编码酶、细胞因子类、受体类等蛋白质的基因以及编码反义核酸或siRNA(小干扰RNA)、核酶的基因)。这些外源基因例如以在适宜启动子的控制下表达的方式插入载体或质粒等中来使用。另外,载体中也可以存在增强序列或终止序列之类的控制序列。
根据本法明的方法,可以通过导入与对癌症等患者的治疗中所用的药物的耐性相关的酶的编码基因(例如多药抗药性基因)来赋予含有CIK细胞的细胞群以抗药性。若使用这样的细胞群,则可以将免疫疗法与药物疗法组合,因而可以得到更好的治疗效果。另一方面,与上述方式相反,通过导入赋予针对特定药物感受性的基因(例如胸苷激酶基因)也可以赋予含有CIK细胞的细胞群以针对该药物的感受性。此时,通过给予该药物即可除去移植到生物体后的细胞。
本发明还提供包括向受试体给予有效量的通过上述方法得到的含有CIK细胞的细胞群的疾病治疗方法或预防方法。本说明书中的受试体例如为身患上述疾病的患者。
本说明书中的有效量指给予上述含有CIK细胞的细胞群后能达到治疗或预防效果的该细胞群的量。具体的有效量因给药形态、给药方法、使用目的以及受试体的年龄、体重、症状等来适当设定,并非定值。给药方法没有限制,例如可以与上述药品同样,通过点滴或注射等来给药。
另外,本发明还提供用于药品制造的含有CIK细胞的细胞群的使用。该药品的制造方法与上述药品相同。此外,对给予该药品的疾病没有特殊限制,与上述药品相同。
实施例
下面,结合实施例对本发明做更具体的描述,但本发明不限于此。
实施例1 使用了纤维连接蛋白片段CH-296的CIK细胞的放大培养
(1)PBMC的分离
对知情同意的5位患者(肾癌2名、肺癌、肝癌和甲状腺癌各1名)进行成分采血后,将含有PBMC的细胞组分在Ficoll上重叠离心,回收中间层的末梢血单核细胞(PBMC)。
(2)抗人CD3抗体和CH-296的固定化
在T225烧瓶中添加含有最终浓度为5μg/mL的抗人CD3抗体和最终浓度为15μg/mL的CH-296(乐透露奈库秦(注册商标),宝生物工程株式会社制)的磷酸缓冲生理盐水(PBS)40mL或仅含有最终浓度为5μg/mL的抗人CD3抗体的PBS 40mL,然后在4℃培养过夜。使用前从该培养器材吸引除去含有抗体、CH-296的PBS,然后用PBS清洗2次,供各试验用。
(3)CIK细胞的放大培养
将实施例1-(2)中分离得到的PBMC 9×108cells悬浮在含有0.2%人血清白蛋白、1000U/mL IFN-γ、300U/mL IL-2的60ml的GT-T503培养基(宝生物工程株式会社制、以下记作“完全GT-T503培养基”)中,添加到实施例1-(2)中制作的4个抗CD3抗体以及CH-296固定化T225烧瓶或4个抗CD3抗体固定化T225烧瓶中,在5%CO2中在37℃下开始培养(培养第0天)。
第1天(培养开始的次日),向各烧瓶添加150mL的完全GT-T503培养基,继续培养。
第4天,将各烧瓶内的细胞悬浮在培养基中全部收集,转移到未固定化透气性培养袋CultiLife Eva(宝生物工程株式会社制)。此时,添加完全GT-T503培养基使每只袋子为700mL,在5%CO2中在37℃下培养。
第7天和第9天,向各袋子中添加完全GT-T503培养基400mL进行继代培养,继续培养至第14天。最终每只袋子的培养液为1500mL。
计算培养最后一天的活细胞数,与培养开始时的细胞数进行比较,算出放大培养率。结果如表1所示。另外,用抗CD3抗体和CH-296刺激而增加的CIK细胞记为R-CIKs,仅用抗CD3抗体刺激而增加的CIK细胞记为C-CIKs。
表1
放大培养率(倍) | |
C-CIKs | 9.2 |
R-CIKs | 35.7 |
由表1可知,通过在培养初期使纤维连接蛋白片段共存,可以显著提高CIK细胞增加率。
(4)CIK细胞表型分析
用荧光标记的抗体将细胞染色后,提供给流式细胞仪,对实施例1-(3)中制备的C-CIKs和R-CIKs的表型进行分析。CD3+细胞、CD4+细胞、CD8+细胞分别用抗CD3抗体、抗CD4抗体、抗CD8抗体进行染色。CD3+CD56+细胞用抗CD3抗体和抗CD56抗体进行染色,作为双阳性细胞进行评价。Treg细胞用抗CD4抗体、抗CD25抗体以及抗CD127抗体进行染色,作为CD4+CD25+CD127-细胞进行评价。
其结果如图1所示。图中,横坐标表示检测到的表面抗原,纵坐标表示表面抗原的阳性率。
由图1可知,刺激时使用纤维连接蛋白片段而制备的细胞群中,Treg细胞的比率显著下降。众所周知Treg细胞具有使抗肿瘤免疫活性下降的作用,因此将要移入的CIK细胞中的Treg细胞比率低这就意味着能得到好的抗肿瘤效果。
实施例2 CIK细胞的抗肿瘤效果
(1)向癌症患者移入CIK细胞
向各癌症患者,以4天间移入2次实施例1制备的来自自己的R-CIKs作为一轮给药,平均给予3.9×1010个。对所有患者至少进行2轮给药,对其中的一名患者进行3轮给药。
(2)抗肿瘤效果
在所有R-CIKs给药的癌症患者中均未发现伴随细胞给药而产生的严重的不良迹象。
通过R-CIKs给药,在所有患者中均发现临床症状改善、生理功能恢复。另外,在甲状腺癌患者中发现作为肿瘤标记的降钙素显著减少。此外,通过PET-CT测定肺癌患者肿瘤大小,结果发现肿瘤缩小约50%。
综上所述可知,R-CIKs是非常安全的抗肿瘤效果好的细胞制剂。
产业上利用的可能性
PBMC经放大培养而分化成多个细胞群,分化得到的细胞群中含有控制或抑制免疫的细胞群。根据本发明,通过将被称为现有过继免疫疗法中优选细胞群的CIK细胞进行放大培养,能提供大量非必要细胞群的含量少的高品质细胞群。通过本发明得到的细胞群是使用该细胞群的过继免疫疗法中极为有用的具有显著效果的细胞群。
序列表自由内容
SEQ ID NO:1;纤维连接蛋白的局部区域CS-1。
SEQ ID NO:2;纤维连接蛋白的局部区域III-10。
SEQ ID NO:3;III-10中的纤维连接蛋白的局部区域。
SEQ ID NO:4;纤维连接蛋白片段C-274。
SEQ ID NO:5;纤维连接蛋白片段H-271。
SEQ ID NO:6;纤维连接蛋白片段H-296。
SEQ ID NO:7;纤维连接蛋白片段CH-271。
SEQ ID NO:8;纤维连接蛋白片段CH-296。
SEQ ID NO:9;纤维连接蛋白片段C-CS1。
序列表
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500 505 510
Val Thr Glu Ala Thr Ile Thr Gly Leu Glu Pro Gly Thr Glu Tyr Thr
515 520 525
Ile Tyr Val Ile Ala Leu Lys Asn Asn Gln Lys Ser Glu Pro Leu Ile
530 535 540
Gly Arg Lys Lys Thr
545
<210>8
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<223>纤维连接蛋白片段CH-296
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35 40 45
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50 55 60
Tyr Val Val Ser Val Ser Ser Val Tyr Glu Gln His Glu Ser Thr Pro
65 70 75 80
Leu Arg Gly Arg Gln Lys Thr Gly Leu Asp Ser Pro Thr Gly Ile Asp
85 90 95
Phe Ser Asp Ile Thr Ala Asn Ser Phe Thr Val His Trp Ile Ala Pro
100 105 110
Arg Ala Thr Ile Thr Gly Tyr Arg Ile Arg His His Pro Glu His Phe
115 120 125
Ser Gly Arg Pro Arg Glu Asp Arg Val Pro His Ser Arg Asn Ser Ile
130 135 140
Thr Leu Thr Asn Leu Thr Pro Gly Thr Glu Tyr Val Val Ser Ile Val
145 150 155 160
Ala Leu Asn Gly Arg Glu Glu Ser Pro Leu Leu Ile Gly Gln Gln Ser
165 170 175
Thr Val Ser Asp Val Pro Arg Asp Leu Glu Val Val Ala Ala Thr Pro
180 185 190
Thr Ser Leu Leu Ile Ser Trp Asp Ala Pro Ala Val Thr Val Arg Tyr
195 200 205
Tyr Arg Ile Thr Tyr Gly Glu Thr Gly Gly Asn Ser Pro Val Gln Glu
210 215 220
Phe Thr Val Pro Gly Ser Lys Ser Thr Ala Thr Ile Ser Gly Leu Lys
225 230 235 240
Pro Gly Val Asp Tyr Thr Ile Thr Val Tyr Ala Val Thr Gly Arg Gly
245 250 255
Asp Ser Pro Ala Ser Ser Lys Pro Ile Ser Ile Asn Tyr Arg Thr Glu
260 265 270
Ile Asp Lys Pro Ser Met Ala Ile Pro Ala Pro Thr Asp Leu Lys Phe
275 280 285
Thr Gln Val Thr Pro Thr Ser Leu Ser Ala Gln Trp Thr Pro Pro Asn
290 295 300
Val Gln Leu Thr Gly Tyr Arg Val Arg Val Thr Pro Lys Glu Lys Thr
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Gly Pro Met Lys Glu Ile Asn Leu Ala Pro Asp Ser Ser Ser Val Val
325 330 335
Val Ser Gly Leu Met Val Ala Thr Lys Tyr Glu Val Ser Val Tyr Ala
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Leu Lys Asp Thr Leu Thr Ser Arg Pro Ala Gln Gly Val Val Thr Thr
355 360 365
Leu Glu Asn Val Ser Pro Pro Arg Arg Ala Arg Val Thr Asp Ala Thr
370 375 380
Glu Thr Thr Ile Thr Ile Ser Trp Arg Thr Lys Thr Glu Thr Ile Thr
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Gly Phe Gln Val Asp Ala Val Pro Ala Asn Gly Gln Thr Pro Ile Gln
405 410 415
Arg Thr Ile Lys Pro Asp Val Arg Ser Tyr Thr Ile Thr Gly Leu Gln
420 425 430
Pro Gly Thr Asp Tyr Lys Ile Tyr Leu Tyr Thr Leu Asn Asp Asn Ala
435 440 445
Arg Ser Ser Pro Val Val Ile Asp Ala Ser Thr Ala Ile Asp Ala Pro
450 455 460
Ser Asn Leu Arg Phe Leu Ala Thr Thr Pro Asn Ser Leu Leu Val Ser
465 470 475 480
Trp Gln Pro Pro Arg Ala Arg Ile Thr Gly Tyr Ile Ile Lys Tyr Glu
485 490 495
Lys Pro Gly Ser Pro Pro Arg Glu Val Val Pro Arg Pro Arg Pro Gly
500 505 510
Val Thr Glu Ala Thr Ile Thr Gly Leu Glu Pro Gly Thr Glu Tyr Thr
515 520 525
Ile Tyr Val Ile Ala Leu Lys Asn Asn Gln Lys Ser Glu Pro Leu Ile
530 535 540
Gly Arg Lys Lys Thr Asp Glu Leu Pro Gln Leu Val Thr Leu Pro His
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Pro Asn Leu His Gly Pro Glu Ile Leu Asp Val Pro Ser Thr
565 570
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<211>302
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<223>纤维连接蛋白片段C-CS1
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Pro Thr Asp Leu Arg Phe Thr Asn Ile Gly Pro Asp Thr Met Arg Val
1 5 10 15
Thr Trp Ala Pro Pro Pro Ser Ile Asp Leu Thr Asn Phe Leu Val Arg
20 25 30
Tyr Ser Pro Val Lys Asn Glu Glu Asp Val Ala Glu Leu Ser Ile Ser
35 40 45
Pro Ser Asp Asn Ala Val Val Leu Thr Asn Leu Leu Pro Gly Thr Glu
50 55 60
Tyr Val Val Ser Val Ser Ser Val Tyr Glu Gln His Glu Ser Thr Pro
65 70 75 80
Leu Arg Gly Arg Gln Lys Thr Gly Leu Asp Ser Pro Thr Gly Ile Asp
85 90 95
Phe Ser Asp Ile Thr Ala Asn Ser Phe Thr Val His Trp Ile Ala Pro
100 105 110
Arg Ala Thr Ile Thr Gly Tyr Arg Ile Arg His His Pro Glu His Phe
115 120 125
Ser Gly Arg Pro Arg Glu Asp Arg Val Pro His Ser Arg Asn Ser Ile
130 135 140
Thr Leu Thr Asn Leu Thr Pro Gly Thr Glu Tyr Val Val Ser Ile Val
145 150 155 160
Ala Leu Asn Gly Arg Glu Glu Ser Pro Leu Leu Ile Gly Gln Gln Ser
165 170 175
Thr Val Ser Asp Val Pro Arg Asp Leu Glu Val Val Ala Ala Thr Pro
180 185 190
Thr Ser Leu Leu Ile Ser Trp Asp Ala Pro Ala Val Thr Val Arg Tyr
195 200 205
Tyr Arg Ile Thr Tyr Gly Glu Thr Gly Gly Asn Ser Pro Val Gln Glu
210 215 220
Phe Thr Val Pro Gly Ser Lys Ser Thr Ala Thr Ile Ser Gly Leu Lys
225 230 235 240
Pro Gly Val Asp Tyr Thr Ile Thr Val Tyr Ala Val Thr Gly Arg Gly
245 250 255
Asp Ser Pro Ala Ser Ser Lys Pro Ile Ser Ile Asn Tyr Arg Thr Glu
260 265 270
Ile Asp Lys Pro Ser Asp Glu Leu Pro Gln Leu Val Thr Leu Pro His
275 280 285
Pro Asn Leu His Gly Pro Glu Ile Leu Asp Val Pro Ser Thr
290 295 300
Claims (8)
1.含有细胞因子诱导杀伤细胞的细胞群的制造方法,其特征在于,包括如下工序:在纤维连接蛋白片段的存在下,培养含有能分化为细胞因子诱导杀伤细胞的细胞的细胞群。
2.根据权利要求1所述的制造方法,其特征在于,在含有选自VLA-4结合域、VLA-5结合域以及肝素结合域中的区域的纤维连接蛋白片段的存在下,实施培养。
3.根据权利要求2所述的制造方法,其特征在于,在含有选自序列号1、2以及5的氨基酸序列的纤维连接蛋白片段的存在下,实施培养。
4.根据权利要求1所述的制造方法,其特征在于,在CD3配体、干扰素-γ以及白细胞介素-2的共同存在下,实施纤维连接蛋白片段存在下的培养。
5.细胞群,其特征在于,含有通过权利要求1~4中任一项所述的方法而得的细胞因子诱导杀伤细胞。
6.药品,其特征在于,含有权利要求5所述的细胞群作为有效成分。
7.疾病的治疗方法或预防方法,其特征在于,包括向受试体给予有效量的权利要求5所述的细胞群的工序。
8.权利要求5所述的细胞群的使用,其特征在于,用于药品的制备。
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PCT/JP2009/058917 WO2009139413A1 (ja) | 2008-05-16 | 2009-05-13 | サイトカイン誘導キラー細胞含有細胞集団の製造方法 |
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CN102191219A (zh) * | 2011-03-29 | 2011-09-21 | 上海复仁生物科技有限公司 | 一种高效制备cik细胞的方法 |
CN103483454A (zh) * | 2012-06-13 | 2014-01-01 | 深圳市阳溪生物科技有限公司 | 一种用于制备人细胞因子诱导的杀伤细胞的融合蛋白 |
CN107812013A (zh) * | 2017-10-20 | 2018-03-20 | 胥萍 | 一种治疗耐药结核的新型生物制剂及其制备方法 |
CN109762785A (zh) * | 2018-12-10 | 2019-05-17 | 吴江近岸蛋白质科技有限公司 | 一种高效应用于人nk细胞非滋养层体外培养的方法 |
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JP5097856B2 (ja) * | 2009-10-28 | 2012-12-12 | タカラバイオ株式会社 | サイトカイン誘導キラー細胞の製造方法 |
WO2012096376A1 (ja) * | 2011-01-14 | 2012-07-19 | タカラバイオ株式会社 | 制御性t細胞の製造方法 |
DE102011106914B4 (de) | 2011-07-08 | 2015-08-27 | Zellwerk Gmbh | Mäander- Bioreaktor und Verfahren zu dynamischen Expansion, Differenzierung und Ernte von hämatopoetischen Zellen |
CN105154398A (zh) * | 2015-07-17 | 2015-12-16 | 深圳爱生再生医学科技有限公司 | Cik及其制备方法 |
CN114717187B (zh) * | 2022-03-09 | 2023-11-07 | 中科东方细胞科技有限公司 | 一种cik细胞及其制备方法与应用 |
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CN102191219A (zh) * | 2011-03-29 | 2011-09-21 | 上海复仁生物科技有限公司 | 一种高效制备cik细胞的方法 |
CN103483454A (zh) * | 2012-06-13 | 2014-01-01 | 深圳市阳溪生物科技有限公司 | 一种用于制备人细胞因子诱导的杀伤细胞的融合蛋白 |
CN103483454B (zh) * | 2012-06-13 | 2015-05-27 | 深圳市阳溪生物科技有限公司 | 一种用于制备人细胞因子诱导的杀伤细胞的融合蛋白 |
CN107812013A (zh) * | 2017-10-20 | 2018-03-20 | 胥萍 | 一种治疗耐药结核的新型生物制剂及其制备方法 |
CN107812013B (zh) * | 2017-10-20 | 2020-07-28 | 胥萍 | 一种治疗耐药结核的生物制剂及其制备方法 |
CN109762785A (zh) * | 2018-12-10 | 2019-05-17 | 吴江近岸蛋白质科技有限公司 | 一种高效应用于人nk细胞非滋养层体外培养的方法 |
CN109762785B (zh) * | 2018-12-10 | 2022-06-24 | 苏州近岸蛋白质科技股份有限公司 | 一种高效应用于人nk细胞非滋养层体外培养的方法 |
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