CN114853899B - 一种il-12和il-18变体的融合蛋白及其制备方法和用途 - Google Patents
一种il-12和il-18变体的融合蛋白及其制备方法和用途 Download PDFInfo
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Abstract
本发明公开了一种IL‑12和IL‑18变体的融合蛋白及其制备方法和用途。本发明的融合蛋白包含第一结构域:其包括IL‑18和/或其变体;第二结构域:其包括IL‑12p40和/或IL‑12p35。本发明的融合蛋白能够在体内和体外都特异性激活NK细胞,从而实现其杀肿瘤的作用。本发明还提供了一种低成本的体外高效扩增NK细胞的方法,适合于临床过继性NK细胞疗法的使用。
Description
技术领域
本发明属于生物制药领域。具体地,本发明涉及一种IL-12和IL-18变体的融合蛋白及其制备方法和用途。
背景技术
肿瘤免疫疗法在过去的几十年里取得了较大的发展,包括使用细胞因子来激活免疫细胞、免疫检查点抑制剂、溶瘤病毒、肿瘤疫苗和过继性细胞免疫治疗。
NK细胞介导的天然免疫反应在对抗病原微生物和肿瘤中起到重要的作用。与T细胞不同的是,NK细胞对肿瘤和病毒感染的细胞的杀伤并不需要接触到靶细胞抗原,而是通过释放穿孔素和颗粒酶B来杀伤靶细胞。并且NK细胞通过分泌多种细胞因子如IFN-γ、TNF-α、IL-13和GM-CSF等与参与T-细胞识别感染的细胞或者与抗原呈递细胞(APC)相互作用。NK细胞在体内的激活可以通过膜结合的受体和由APC分泌的细胞因子来实现。其中,研究表明IL-18和IL-12在增强NK细胞活性和刺激IFN-γ分泌以及调节后续免疫反应中起到重要作用。IL-18具有IL-1蛋白质家族的结构特征,但是IL-18本身不会诱导IFN-γ。单独使用IL-12的毒副作用较大,因此目前的临床实验主要是与其他抗肿瘤的单克隆抗体或者免疫检查点抑制剂联用,而其有效性还未可知。
目前有多种临床研究表明过继性NK细胞疗法能安全有效的对抗肿瘤。然而这种疗法的一大难点就是如何通过体外扩增的方法得到足够数目的激活的NK细胞来满足临床的需求。目前,NK细胞的体外扩增主要有3种:(1)通过磁珠分选的方法先从外周血单个核细胞(PBMCs)或者脐带血中分离得到纯度较高的CD3-CD56+的NK细胞,再将这一群细胞扩大培养。此法的分选过程步骤繁琐且分选用的磁珠价格昂贵;(2)用修饰或者未修饰过的K562细胞做饲养层细胞来培养。此法获得的NK细胞在纯度和数量上有很好的效果,但是用肿瘤细胞做饲养层给临床的使用带来了风险。(3)用抗CD3单克隆抗体和CD16单克隆抗体包被或者不包被培养瓶,并结合多种细胞因子如IL-2、IL-12、IL-15、IL-18和IL-21等刺激NK细胞扩增。但此法得到的NK细胞纯度和扩增倍数都有限。
因此找到一种优化的方法来制备NK细胞对过继性NK细胞疗法至关重要。
发明内容
因此,本发明的目的是针对现有技术的不足,提供一种同时具有IL-12和IL-18活性的融合蛋白以及该融合蛋白的制备方法和用途。本发明提供的融合蛋白能够在体内和体外都特异性激活NK细胞,从而实现其杀肿瘤的作用。本发明还提供了一种低成本的体外高效扩增NK细胞的方法,适合于临床过继性NK细胞疗法的使用。
具体来说,本发明的目的在于提供以下方面:
第一方面,本发明提供一种融合蛋白。该融合蛋白包括至少二个结构域,其中
第一结构域:其包括IL-18和/或其变体;
第二结构域:其包括IL-12p40和/或IL-12p35。
优选地,当第二结构域包括IL-12p40和IL-12p35时,IL-12p40和IL-12p35两者之间通过连接子连接或者不连接。
优选地,还包括:连接结构域,其用于连接第一结构域和第二结构域,包括人或动物的免疫球蛋白和/或其亚型和/或其变体、人或动物白蛋白和/或其变体。
第二方面,本发明提供一种融合基因。其中该融合基因含有第一方面的融合蛋白的编码核苷酸序列。
第三方面,本发明提供一种表达构建体。其中该表达构建体中含有第一方面的融合蛋白的编码核苷酸序列。
第四方面,本发明提供一种融合蛋白的制备方法。该制备方法包括将融合蛋白的编码核苷酸序列克隆至表达构建体的步骤。
第五方面,本发明提供一种NK细胞体外扩增和培养方法。该方法包括以下步骤:
(2-1)分离单个核细胞;
(2-2)重悬单个核细胞:第0天收集的单个核细胞,用活化培养基重悬后,转入培养瓶,置于培养箱中培养;
(2-3)诱导NK细胞:第3天补加活化培养基;
(2-4)扩增NK细胞:第5天后,每1~3天补加扩增培养基,并控制细胞浓度在0.4~0.7×106/mL;培养至第10~17天后将细胞培养液转入离心管,离心、洗涤,获得高纯度,高活性的NK细胞;
其中活化培养基和/或扩增培养基中添加有第一方面的融合蛋白。
第六方面,本发明提供一种如第一方面的融合蛋白、如第二方面的融合基因、如第三方面的表达构建体在制备肿瘤药物中的应用;和/或
如第五方面的NK细胞体外扩增和培养方法制备的NK细胞在制备肿瘤药物中的应用。
与现有技术相比,本发明具有以下优点:
(1)本发明的融合蛋白能够特异性地激活并扩增NK细胞;
(2)利用本发明NK细胞体外高效扩增和培养方法培养的NK细胞纯度高,分泌大量的IFN-γ,对K562和肝癌HepG2细胞都具有较强的杀伤作用。
附图说明
图1为本发明两种不同结构式的IL-18和IL-12融合蛋白的结构示意图;
图2为SYPro-3和对照蛋白扩增的CD3-CD56+细胞中自然细胞杀伤受体NKp46的表达结果图;
图3为SYPro-3对不同志愿者外周血来源的NK细胞培养前和培养后CD3-CD56+细胞的流式结果图;
图4为SYPro-3和对照蛋白对扩增的NK细胞分泌IFN-γ的数据图;
图5为SYPro-3扩增的NK细胞对K562细胞株的杀伤活性的数据图;
图6为SYPro-3和对照蛋白对扩增的NK细胞对HepG2细胞株的杀伤活性的数据图;
图7为实施例Y0024918-1的质粒谱图;
图8为实施例Y0024918-2的质粒谱图。
具体实施方式
下面通过优选实施方式和实施例对本发明进一步详细说明。通过这些说明,本发明的特点和优点将变得更为清楚明确。
需要说明的是,在本文中,诸如第一和第二等之类的关系术语仅仅用来将一个实体或者操作与另一个实体或操作区分开来,而不一定要求或者暗示这些实体或操作之间存在任何这种实际的关系或者顺序。而且,术语“包括”、“包含”或者其任何其他变体意在涵盖非排他性的包含,从而使得包括一系列要素的过程、方法、物品或者设备不仅包括那些要素,而且还包括没有明确列出的其他要素,或者是还包括为这种过程、方法、物品或者设备所固有的要素。在没有更多限制的情况下,由语句“包括……”限定的要素,并不排除在包括所述要素的过程、方法、物品或者设备中还存在另外的相同要素。
第一方面,本发明提供一种融合蛋白(图1为两种不同结构式的IL-18和IL-12融合蛋白的结构示意图)。该融合蛋白从N段到C段包括至少二个结构域,即第一结构域、第二结构域。
其中,第一结构域包括IL-18和/或其变体,优选为IL-18或IL-18变体,更优选为IL-18变体。
在本发明的一个优选实施方式中,IL-18如SEQ ID NO:1所示的氨基酸序列。
和/或,IL-18变体如SEQ ID NO:2所示的氨基酸序列。
其中,IL-18在体内与诱骗受体IL-18BP结合,会减少体内抗肿瘤的效果。有很多文献表明IL-18和IL-12对NK细胞的活化和扩增有协同效应,但是因为体内有IL-18BP的存在,会减少IL-18的有效浓度,也就减少了这种协同效果。而经研究发现,IL-18变体不与IL-18BP结合,在小鼠实验中可以激发强大的抗肿瘤效应,因此,本发明第一结构域优选选用IL-18变体。
另外,IL-18和/或IL-18变体的氨基酸序列可以参考专利US20190070262A1。
其中,第二结构域包括IL-12p40和/或IL-12p35,优选为IL-12p40和IL-12p35。
其中,IL-12p40优选如SEQ ID NO:5所示的氨基酸序列;
IL-12p35优选如SEQ ID NO:18所示的氨基酸序列。
更优选地,IL-12p40和IL-12p35两者之间通过连接子连接或者不连接。例如,连接子是G6S(购自北京义翘神州科技有限公司),IL-12p40的C端的氨基酸S通过G6S连接IL-12p35的N端的R。
在本发明提供的融合蛋白中,第一结构域和第二结构域之间可以通过融合蛋白技术中现有的任意方式进行连接。出于便于生产的目的,第一结构域和第二结构域优选通过连接结构域连接。
其中该连接结构域包括人或动物的免疫球蛋白和/或其亚型和/或其变体、人或动物白蛋白和/或其变体。
优选地,连接结构域选自人或动物的免疫球蛋白和/或其变体,更优选选自IgG1Fc、IgG1 Fc变体、IgG4 Fc、IgG4 Fc变体中的至少一者,例如,IgG1 Fc变体和/或IgG4Fc变体。这是由于IgG1 Fc变体具有增强的ADCC效应。
也就是融合蛋白包括3个结构域,第一结构域是IL-18或IL-18变体,连接结构域是IgG1Fc或IgG4Fc,第二结构域是IL12,即前一结构域的C端通过连接子(L1、L2、L3)与下一结构域的N端连接。
其中,IgG1 Fc优选如SEQ ID NO:19所示的氨基酸序列;
IgG1 Fc变体优选如SEQ ID NO:20所示的氨基酸序列;该IgG1 Fc变体具有增强的ADCC效应和稳定性的功能。
IgG4 Fc优选如SEQ ID NO:21所示的氨基酸序列;
IgG4 Fc变体优选如SEQ ID NO:22所示的氨基酸序列;该IgG4 Fc变体具有减少的ADCC效应和增强的稳定性的功能。
在本发明的一个优选实施方式中,本发明提供的融合蛋白包含如SEQ ID NO:3、5、7、9、11中至少一者所示的氨基酸序列。优选地,融合蛋白包含如SEQ ID NO:3或5、7或5、9或11所示的氨基酸序列。
经研究发现,选择该氨基酸序列的融合蛋白能够同时激活IL-12和IL-18的信号通路,特异性地激活并扩增NK细胞,从而实现对肿瘤的杀伤。
第二方面,本发明提供一种融合基因。其中该融合基因含有第一方面的融合蛋白的编码核苷酸序列。优选地,融合蛋白的编码核苷酸序列如SEQ ID NO:4、6、8、10、12中至少一者所示。
其中,选择该编码核苷酸序列时,序列经过优化,更适合在CHO细胞中表达。
本领域技术人员应当知晓,本发明提供的融合基因中,还可以包括如启动子、增强子、非编码区等核苷酸序列,以实现提高融合基因的表达量、表达效率、产物活性等方面性能的目的。另外,融合基因中还可以包括方便检测产物表达情况等效果的标签的核苷酸序列,例如组氨酸标签或GST标签等。
第三方面,本发明提供一种表达构建体。其中该表达构建体中含有第一方面的融合蛋白的编码核苷酸序列。
本发明提供的表达构建体可以为本领域现有技术中任意现有载体连接如前所述的基因后制得的表达构建体。
其中,该表达构建体可以是原核表达构建体;优选地,原核表达构建体为pET载体系列;
同理,该表达构建体也可以是真核表达构建体;优选地,真核表达构建体为质粒DNA载体,pVAX1载体和pSV1.0载体;重组病毒载体,优选重组痘苗病毒载体、重组腺病毒载体或重组腺相关病毒载体;或逆转录病毒载体,优选HIV病毒载体,或慢病毒载体。
在本发明的一个优选实施方式,为了提高本发明提供的融合蛋白的表达量,表达构建体中除含有如前所述的编码核苷酸序列外,还可以含有启动子和编码分泌信号肽的编码核苷酸序列。
第四方面,本发明提供了一种宿主细胞,其中该宿主细胞包括第三方面的表达构建体;
优选地,当表达构建体是原核表达构建体时,宿主细胞是原核生物细胞,优选细菌细胞;或当表达构建体是真核表达构建体时,宿主细胞是真核生物细胞,优选哺乳动物细胞,更优选CHO细胞。
第五方面,本发明提供一种药物组合物。该药物组合物包括根据第一方面的融合蛋白。
在本发明的一个优选实施方式中,该药物组合物中还可以含有药学上可接受的载体。载体是指制备药物过程中对融合蛋白的活性没有影响或者影响很小的辅料,用于使该药物组合物形成指定的剂型。
或者,该药物组合物还可以与其他药物组合给药,以提高药物组合物的治疗效果。
本发明提供的药物组合物可以为任意本领域现有用于治疗和/或预防肿瘤的药物剂型。在不破坏药物组合物的治疗效果的情况下,本领域技术人员可以根据实际需要对药物组合物的剂型进行选择。
本发明提供的药物组合物可以通过任意本领域现有的给药方式进行给药。出于方便给药的目的,根据本发明的一个优选实施方式,其中,药物组合物的给药方式可以选自口服给药、经鼻给药、皮内给药、皮下给药、肌内给药、静脉给药、腹腔内给药中的至少一种。
第六方面,本发明提供一种融合蛋白的制备方法。该制备方法包括将融合蛋白的编码核苷酸序列克隆至表达构建体的步骤。
优选地,制备方法可以包括以下步骤:
(1-1)构建第一方面的融合蛋白的编码核苷酸序列;
(1-2)构建包含步骤(1-1)的编码核苷酸序列的表达构建体;
(1-3)将步骤(1-2)的表达构建体用于转染或转化宿主细胞,并使编码核苷酸序列在宿主细胞中表达;更优选地,在步骤(1-3)中,宿主细胞为CHO-S细胞;
更优选地,还包括(1-4)将步骤(1-3)中表达的蛋白进行纯化。
第七方面,本发明提供一种NK细胞体外扩增体系。该体外扩增体系包括用于NK细胞活化的活化培养基和用于NK细胞增殖的扩增培养基;其中活化培养基和/或扩增培养基中添加有第一方面的融合蛋白。
优选地,活化培养基为添加有融合蛋白的X VIVO-15培养基,优选还添加有自体灭活血浆、IL-2、注射用A群链球菌、抗CD16单克隆抗体和抗CD3单克隆抗体中的至少一者。
例如,活化培养基中lL-2的浓度为500-1000IU/mL、注射用A群链球菌的浓度为0-0.01KE/mL、抗CD16单克隆抗体的浓度为0-1μg/mL、抗CD3单克隆抗体的浓度为0-1μg/mL、自体灭活血浆10%。
优选地,扩增培养基为添加有融合蛋白的X VIVO-15培养基,优选还添加有胎牛血清和/或IL-2。
例如,扩增培养基中lL-2的浓度为500-1000IU/mL、胎牛血清10%。
更优选地,融合蛋白在活化培养基和扩增培养基中的浓度相同,例如融合蛋白的浓度为0-500ng/μL。
第八方面,本发明提供一种NK细胞体外扩增和培养方法。该方法包括以下步骤:
(2-1)分离单个核细胞;
优选地,步骤(2-1)包括以下子步骤:
(2-1-1)分离血浆和全血细胞:取新鲜的血液置于离心管中,离心,得到血浆和全血细胞;例如取800g,离心20min;
优选地,步骤(2-1-1)中可以对血液进行检测:血液梯度离心获取单个核细胞后,检测乙型肝炎表面抗原、丙型肝炎抗体、人免疫缺陷病毒抗体、梅毒螺旋体抗体和巨细胞病毒lgM抗体均为阴性。
(2-1-2)灭活血清;56℃灭活30min,4℃冷却后,1600rpm离心8min;
(2-1-3)获取单个核细胞:全血细胞与生理盐水混合,缓慢加入淋巴细胞分离液,离心,吸取白膜层,再用生理盐水清洗后离心,得到单个核细胞;
(2-2)重悬单个核细胞:第0天收集的单个核细胞,用活化培养基重悬后,转入培养瓶,置于培养箱中培养;例如重悬成1-2×106/mL的细胞,转入培养瓶,置于37℃、5%CO2的培养箱中培养;
(2-3)诱导NK细胞:第3天补加等量的活化培养基;
(2-4)扩增NK细胞:第5天后,每1~3天补加扩增培养基,并控制细胞浓度在0.4~0.7×106/mL,如0.5×106/mL;培养至第10~17天(如14天)后将细胞培养液转入离心管,离心、洗涤(例如用生理盐水洗涤2-3次),获得高纯度,高活性的NK细胞;
其中活化培养基和/或扩增培养基中添加有如第一方面的融合蛋白。
综上所述,本发明不需要包被和滋养层,操作简单,经过活化培养基培养和扩增培养基使得NK细胞能够优势生长,NK的流式含量和扩增倍数较高,能够适用于NK细胞临床实验研究及大规模制备。
第九方面,本发明提供一种如第一方面的融合蛋白、如第二方面的融合基因、如第三方面的表达构建体、如第四方面的宿主细胞或如第五方面的药物组合物在制备肿瘤药物中的应用;和/或
如第八方面的NK细胞体外扩增和培养方法制备的NK细胞在制备肿瘤药物中的应用。
以下将通过实施例对本发明进行详细描述。应当能够理解的是,以下实施例仅用于进一步解释和说明本发明的内容,而不用于限制本发明。
值得注意的是,以下实施例中所用的试剂均为分析纯级试剂,且可从正规渠道商购获得。
实施例1融合蛋白的制备
图1为两种不同结构式的IL-18和IL-12融合蛋白的结构示意图。其中wtIL-18为野生型IL-18,如SEQ ID NO:1所示的氨基酸序列;muIL-18为IL18变体,如SEQ ID NO:2所示的氨基酸序列。
其中,该融合蛋白通过以下方法获得:
(1)载体的构建:
表达融合蛋白的第一质粒(Y0024918-1,即plasmid1),其质粒谱图如图7所示。该第一质粒包括muIL-18、IgG1Fc变体和IL-12p40-p35的序列。优选地,第一质粒的氨基酸序列如SEQ ID NO:3所示,编码核苷酸序列如SEQ ID NO:4所示。
其中,其他质粒的构建可以以该第一质粒做为基础质粒,首先通过点突变和(或)融合PCR得到表达其他融合蛋白的核苷酸序列,再连接到pcDNA3.4骨架质粒上即可。
具体地,按照表1-1的引物和模板,用Extaq酶(购自Takara公司,货号:RR001Q)参照商品说明书进行普通PCR和融合PCR扩增,其中融合PCR扩增时用的模板为表1-1中各个融合片段按照1:1摩尔比的混合物。普通PCR和融合PCR扩增的反应条件视模板、引物等的结构条件不同而各异,根据Extaq酶商品说明书选择最佳的反应条件(温度、时间等),例如反应体系和反应条件按表1-2、1-3所示,从而得到表1-1中的各个目的片段,再将目的片段采用pcDNA3.4-TOPOTA cloning kit(购自英潍捷基(上海)贸易有限公司)构建表达融合蛋白的第二到第五质粒。
表1-1
表1-2
反应体系 | 体积 |
TaKaRa ExTaq(5U/μL) | 0.25μL |
10×ExTaq Buffer(Mg2+Plus) | 5μL |
dNTP Mixture(各2.5mM) | 4μL |
引物F(10μM) | 2.5μL |
引物R(10μM) | 2.5μL |
灭菌蒸馏水 | 补至50μL |
模板DNA | 1μL |
模板DNA*:普通PCR为50ng/μL;融合PCR将各个融合片段按照1:1摩尔比混合
表1-3
其中表1-1中模板Y0024918-2的质粒谱图如图8所示。该模板包括含有wtIL-18和IgG4Fc变体的序列。优选地,编码核苷酸序列如SEQ ID NO:17所示。
具体地,根据表1-1可以得到:
第二质粒(plasmid2),包括含有IL-12p40亚基的序列。优选地,第二质粒的氨基酸序列如SEQ ID NO:5所示,编码核苷酸序列如SEQ ID NO:6所示。
第三质粒(plasmid3),包括含有muIL-18、IgG1Fc变体和IL-12p35的序列。优选地,第三质粒的氨基酸序列如SEQ ID NO:7所示,编码核苷酸序列如SEQ ID NO:8所示。
第四质粒(plasmid4),包括含有wtIL-18、IgG1Fc变体和IL-12p35的序列。优选地,第四质粒的氨基酸序列如SEQ ID NO:9所示,编码核苷酸序列如SEQ ID NO:10所示。
第五质粒(plasmid5),包括含有muIL-18、IgG4Fc变体和IL-12p40-p35的序列。优选地,第五质粒的氨基酸序列如SEQ ID NO:11所示,编码核苷酸序列如SEQ ID NO:12所示。
(2)融合蛋白的表达:
将第二质粒转染ExpiCHO-S细胞(购自英潍捷基(上海)贸易有限公司),按照ExpiCHO表达系统试剂盒(购自英潍捷基(上海)贸易有限公司)的方法进行转染,转染后48h用500μg/mL G418 Sulfate(购自上海懋康生物科技有限公司)加压筛选稳定表达IL-12p40亚基的细胞系。再用有限稀释法获得高表达IL-12p40的单克隆细胞系,记为ExpiCHO-S/IL-12p40细胞。
用第三质粒和第四质粒分别转染ExpiCHO-S/IL-12p40细胞,并于转染后第10天收集细胞上清,分别获得第一融合蛋白(记为SYPro-1)和第二融合蛋白(记为SYPro-2)。
用第一质粒和第五质粒分别转染ExpiCHO-S细胞,并于转染后第10天收集细胞上清,分别获得第三融合蛋白(记为SYPro-3)和第四融合蛋白(记为SYPro-4)。
(3)融合蛋白的纯化:
上述四种融合蛋白均分别通过下述方法进行纯化。具体操作过程为:上清用0.45μm滤膜过滤去除细胞碎片。用5倍柱体积的平衡缓冲液(5.6mM NaH2PO4,14.4mM Na2HPO4,0.15M NaCl,pH7.2)处理protein A亲和柱HiTrap MabSelect SuRe(购自GE通用公司),再将上清进行上样,上样结束后,用缓冲液(5.6mM NaH2PO4·H2O,14.4mM Na2HPO4,0.5M NaCl,pH7.2)冲洗结合不牢固的杂蛋白至基线。再用洗脱液50mM柠檬酸/柠檬酸钠缓冲液(含0.02%吐温-80+5%甘露醇,pH3.2)洗脱蛋白,再用1M Tris-Cl(pH8.0)调节pH至7.0。纯化后的样品经0.22μm滤膜过滤除菌后保存于4℃。
具体地,本发明的第一融合蛋白SYPro-1含有如SEQ ID NO:5、7所示的氨基酸序列;含有如SEQ ID NO:6、8所示的编码核苷酸序列;
第二融合蛋白SYPro-2含有如SEQ ID NO:5、9所示的氨基酸序列;含有如SEQ IDNO:6、10所示的编码核苷酸序列;
第三融合蛋白SYPro-3含有如SEQ ID NO:3所示的氨基酸序列;含有如SEQ ID NO:4所示的编码核苷酸序列;
第四融合蛋白SYPro-4含有如SEQ ID NO:11所示的氨基酸序列;含有如SEQ IDNO:12所示的编码核苷酸序列。
实施例2融合蛋白体外扩增外周血来源的NK细胞
上述四种融合蛋白均分别通过下述方法扩增外周血来源的NK细胞,只是在NK细胞的体外扩增过程中将NK细胞活化培养基和NK细胞扩增培养基中添加对应的融合蛋白。具体操作过程为:
(1)外周血单个核细胞(PBMCs)的分离:
采集健康志愿者的外周血,800g离心20min,吸取上层的血浆至新的离心管中,56℃灭活30min,备用。下层全血细胞中按照1:1体积比加入生理盐水,混匀后加入等体积的淋巴细胞分离液(购自天津市灏洋生物制品科技有限责任公司)。800g离心20min后取第二层的淋巴细胞层至新的离心管里。加入生理盐水清洗细胞2次以上,500g离心20min,得到PBMCs。
(2)NK细胞的体外扩增:
NK细胞活化培养基:含10%自体灭活血浆、500-1000IU/mL IL-2(购自北京远策药业有限责任公司)、0-0.01KE/mL注射用A群链球菌(购自国药集团鲁亚(山东)制药有限公司)、0-1μg/mL抗CD 16单克隆抗体(购自北京同立海源生物科技有限公司)、0-1μg/mL抗CD3单克隆抗体(购自北京同立海源生物科技有限公司)、0-500ng/mL融合蛋白的X VIVO-15无血清培养基(购自Lonza公司)。
NK细胞扩增培养基:含10%胎牛血清(购自Hyclone公司)、500-1000IU/mL IL-2、0-500ng/mL融合蛋白的X VIVO-15无血清培养基。
第0天用NK细胞活化培养基将PBMCs细胞重悬成1-2×106/mL接种于细胞培养瓶中;
第3天补加等量NK细胞活化培养基;
从第5天开始按照细胞浓度为0.5×106/mL,用NK细胞扩增培养基传代细胞,1-2天传代一次。第14天收集NK细胞用流式细胞术检测CD3和CD56的表达,以及CD3-CD56+细胞中自然细胞杀伤受体NKp46的表达。
实施例3融合蛋白体外扩增NK细胞的IFN-r的分泌
收集培养第14天实施例2的NK细胞,用RPMI1640培养基(购自西格玛奥德里奇(上海)贸易有限公司)重悬成2.5×106个/mL,取200μL加入96孔板中,37℃培养箱培养4h后收集的上清,用人IFN-γELISA检测试剂盒(购自北京欣博盛生物科技有限公司)检测IFN-γ的分泌情况。
实施例4融合蛋白体外扩增NK细胞对K562的杀伤作用
在96孔板中加入5×105个培养第14天实施例2的NK细胞(效应细胞),按照效靶比为20:1、10:1和5:1加入肿瘤细胞株K562(靶细胞),并设立只有靶细胞的自发释放组、只有效应细胞的自发释放组、只有靶细胞的最大释放组(提前1h加入LDH释放试剂),37℃培养箱培养4h后用500g离心5min收集上清,加入乳酸脱氢酶检测试剂盒(购自上海碧云天生物技术有限公司)的LDH反应液,检测OD490的吸光值A。用下面的公式计算杀伤活性%=(A实验组-A效应细胞自然释放组-A靶细胞自然释放组)/(A靶细胞最大释放组-A靶细胞自然释放组)×100%。
实施例5融合蛋白体外扩增NK细胞对HepG2的杀伤作用
在96孔板中加入1×105个培养第14天实施例2的NK细胞(效应细胞),按照效靶比为10:1加入肿瘤细胞株HepG2(靶细胞),并设立只有靶细胞的自发释放组、只有效应细胞的自发释放组、只有靶细胞的最大释放组(提前1h加入LDH释放试剂),37℃培养箱培养24h后用500g离心5min收集上清,加入乳酸脱氢酶检测试剂盒(购自上海碧云天生物技术有限公司)的LDH反应液,检测OD490的吸光值A。用下面的公式计算杀伤活性%=(A实验组-A效应细胞自然释放组-A靶细胞自然释放组)/(A靶细胞最大释放组-A靶细胞自然释放组)×100%。
对照例1对照蛋白的制备
(1)对照载体的构建:
同理,按照表1-1的引物和模板,用Extaq酶(购自Takara公司)进行普通PCR和融合PCR扩增得到表1-1中的各个目的片段,再将目的片段采用pcDNA3.4-TOPOTA cloning kit(购自英潍捷基(上海)贸易有限公司)构建表达对照蛋白的第一对照质粒和第二对照质粒。
具体地,根据表1-1可以得到:
第一对照质粒(plasmid6),包括含有muIL-18、IgG4Fc变体的序列。优选地,第一对照质粒的氨基酸序列如SEQ ID NO:13所示,编码核苷酸序列如SEQ ID NO:14所示。
第二对照质粒(plasmid7),包括含有IgG1Fc变体和IL-12p40-p35的序列。优选地,第二对照质粒的氨基酸序列如SEQ ID NO:15所示,编码核苷酸序列如SEQ ID NO:16所示。
(2)对照蛋白的表达:
用第一对照质粒和第二对照质粒分别转染ExpiCHO-S细胞,并于转染后第10天收集细胞上清,分别获得第一对照蛋白(记为mu18)和第二对照蛋白(记为IL12)。
(3)对照蛋白的纯化:
上述两种对照蛋白均分别通过下述方法进行纯化。具体操作过程为:上清用0.45μm滤膜过滤去除细胞碎片。用5倍柱体积的平衡缓冲液(5.6mM NaH2PO4,14.4mM Na2HPO4,0.15M NaCl,pH7.2)处理protein A亲和柱HiTrap MabSelect SuRe(购自GE通用公司),再将上清进行上样,上样结束后,用缓冲液(5.6mM NaH2PO4·H2O,14.4mM Na2HPO4,0.5M NaCl,pH7.2)冲洗结合不牢固的杂蛋白至基线。再用洗脱液50mM柠檬酸/柠檬酸钠缓冲液(含0.02%吐温-80+5%甘露醇,pH3.2)洗脱蛋白,再用1M Tris-Cl(pH8.0)调节pH至7.0。纯化后的样品经0.22μm滤膜过滤除菌后保存于4℃。
具体地,第一对照蛋白mu18含有如SEQ ID NO:13所示的氨基酸序列;含有如SEQID NO:14所示的编码核苷酸序列;
第二对照蛋白IL12含有如SEQID NO:15所示的氨基酸序列;含有如SEQ ID NO:16所示的编码核苷酸序列。
对照例2对照蛋白体外扩增外周血来源的NK细胞
与实施例2相似的过程,区别仅在于,NK细胞活化培养基和NK细胞扩增培养基中将融合蛋白替换成等摩尔量的对应的对照蛋白。
对照例3对照蛋白体外扩增NK细胞的IFN-r的分泌
与实施例3相似的过程,即收集培养对照例2的第14天NK细胞,用RPMI1640培养基重悬成2.5×106个/mL,取200μL加入96孔板中,37℃培养箱培养4h后收集的上清,用人IFN-γELISA检测试剂盒检测IFN-γ的分泌情况。
对照例4对照蛋白体外扩增NK细胞对HepG2的杀伤作用
与实施例5相似的过程,即在96孔板中加入1×105个培养对照例2的第14天NK细胞,按照效靶比为10:1加入肿瘤细胞株HepG2,并设立只有靶细胞的自发释放组、只有效应细胞的自发释放组、只有靶细胞的最大释放组(提前1h加入LDH释放试剂),37℃培养箱培养24h后用500g离心5min收集上清,加入乳酸脱氢酶检测试剂盒的LDH反应液,检测OD490的吸光值A。
实验例1 NK扩增倍数和CD3-CD56+细胞含量的检测结果
(1)表2为不同融合蛋白和对照蛋白对NK扩增倍数和CD3-CD56+细胞所占百分比的比较;图2为第三融合蛋白SYPro-3和对照蛋白(第一对照蛋白mu18、第二对照蛋白IL12以及两者联用)扩增的CD3-CD56+细胞中自然细胞杀伤受体NKp46的表达结果图。
表2
扩增倍数 | CD3-CD56+(%) | |
空白对照Con | 67.3 | 21.8 |
第一对照蛋白mu18 | 294.9 | 60.5 |
第二对照蛋白IL12 | 106.1 | 40.1 |
第一对照蛋白mu18+第二对照蛋白IL12 | 357.2 | 75.4 |
第三融合蛋白SYPro-3 | 431.2 | 83.0 |
第二融合蛋白SYPro-2 | 176.3 | 25.3 |
第四融合蛋白SYPro-4 | 305.0 | 84.5 |
第一融合蛋白SYPro-1 | 425.5 | 80.2 |
从表2可以看出,除了第二融合蛋白SYPro-2不能在体外有效的扩增NK细胞外,第一融合蛋白SYPro-1、第三融合蛋白SYPro-3和第四融合蛋白SYPro-4在扩增倍数和CD3-CD56+的阳性率上都明细高于单独使用第一对照蛋白mu18、第二对照蛋白IL12和两者联用。
而第三融合蛋白SYPro-3的扩增倍数高于第四融合蛋白SYPro-4,说明带有增强ADCC效应的IgG1Fc变体比IgG4Fc变体对NK细胞的扩增效果更好。第一融合蛋白SYPro-1和第三融合蛋白SYPro-3的扩增倍数与CD3-CD56+的阳性率相近,说明IL 12的两个亚基的不同连接方式对其活性影响不大。
从图2可以看出,第三融合蛋白SYPro-3扩增的CD3-CD56+细胞中NKp46的表达明显高于单独使用第一对照蛋白mu18、第二对照蛋白IL12和两者联用。
(2)表3为第三融合蛋白SYPro-3对不同志愿者外周血来源的NK细胞扩增倍数结果;图3为第三融合蛋白SYPro-3对不同志愿者外周血来源的NK细胞培养前和培养后CD3-CD56+细胞的流式结果图。
表3
从表3可以看出,第三融合蛋白SYPro-3采用上述方法从不同志愿者的外周血中分离培养NK细胞时,细胞的扩增倍数均可以达到360倍以上。
从图3可以看出,扩增培养后CD3-CD56+细胞的百分比可达到扩增前的3-5倍。
实验例2 NK细胞的IFN-r的分泌的检测结果
图4为第三融合蛋白SYPro-3和对照蛋白(第一对照蛋白mu18、第二对照蛋白IL12以及两者联用)对扩增的NK细胞分泌IFN-γ的数据图。
从图4可以看出,第三融合蛋白SYPro-3扩增的NK细胞分泌的IFN-γ量可以达到330~340ng/mL/106个细胞。第三融合蛋白SYPro-3扩增的NK细胞分泌的IFN-γ明显高于单独使用第一对照蛋白mu18、第二对照蛋白IL 12和两者联用。
实验例3对K562的杀伤作用
图5为第三融合蛋白SYPro-3扩增的NK细胞对K562细胞株的杀伤活性的数据图。
从图5可以看出,随着效靶比的增大,对K562的杀伤活性越大。当效靶比为20:1时,对K562细胞株的杀伤活性能够达到88~95%左右。因此由第三融合蛋白SYPro-3扩增的NK细胞对K562进行有效的杀伤。
实验例4对HepG2的杀伤作用
图6为第三融合蛋白SYPro-3和对照蛋白(第一对照蛋白mu18、第二对照蛋白IL12以及两者联用)对扩增的NK细胞对HepG2细胞株的杀伤活性的数据图。
如图6所示,第三融合蛋白SYPro-3扩增的NK细胞对HepG2细胞株的杀伤活性能够达到80~92%,明显高于单独使用muIL18、第二对照蛋白IL12和两者联用。
以上对本发明具体实施方式的描述并不限制本发明,本领域技术人员可以根据本发明作出各种改变或变形,只要不脱离本发明的精神,均应属于本发明所附权利要求的范围。
SEQUENCE LISTING
<110> 北京双因生物科技有限公司
<120> 一种IL-12和IL-18变体的融合蛋白及其制备方法和用途
<130> 1
<160> 22
<170> PatentIn version 3.5
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aatgcacccc ggaccatatt tattataagt aaatattctg atagcctcgc tagaggtctg 180
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Tyr Phe Gly Lys Leu Glu Ser Lys Leu Ser Val Ile Arg Asn Leu Asn
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355 360 365
Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu
370 375 380
His Asn His Tyr Thr Gln Lys Ser Ala Thr Ala Thr Pro Gly Ala Ala
385 390 395 400
Asn Leu Pro Val Ala Thr Pro Asp Pro Gly Met Phe Pro Cys Leu His
405 410 415
His Ser Gln Asn Leu Leu Arg Ala Val Ser Asn Met Leu Gln Lys Ala
420 425 430
Arg Gln Thr Leu Glu Phe Tyr Pro Cys Thr Ser Glu Glu Ile Asp His
435 440 445
Glu Asp Ile Thr Lys Asp Lys Thr Ser Thr Val Glu Ala Cys Leu Pro
450 455 460
Leu Glu Leu Thr Lys Asn Glu Ser Cys Leu Asn Ser Arg Glu Thr Ser
465 470 475 480
Phe Ile Thr Asn Gly Ser Cys Leu Ala Ser Arg Lys Thr Ser Phe Met
485 490 495
Met Ala Leu Cys Leu Ser Ser Ile Tyr Glu Asp Leu Lys Met Tyr Gln
500 505 510
Val Glu Phe Lys Thr Met Asn Ala Lys Leu Leu Met Asp Pro Lys Arg
515 520 525
Gln Ile Phe Leu Asp Gln Asn Met Leu Ala Val Ile Asp Glu Leu Met
530 535 540
Gln Ala Leu Asn Phe Asn Ser Glu Thr Val Pro Gln Lys Ser Ser Leu
545 550 555 560
Glu Glu Pro Asp Phe Tyr Lys Thr Lys Ile Lys Leu Cys Ile Leu Leu
565 570 575
His Ala Phe Arg Ile Arg Ala Val Thr Ile Asp Arg Val Thr Ser Tyr
580 585 590
Leu Asn Ala Ser
595
<210> 8
<211> 1788
<212> DNA
<213> 核苷酸序列(人工序列)
<400> 8
tactttggca agcttgaatc taaattatca gtcataagaa atttgaatga ccaagttctc 60
ttcattgacc aaggaaatcg gcctctattt gaagatatga ctgattctga ctgtagagat 120
aatgcacccc ggaccatatt tattataagt aaatattctg atagcctcgc tagaggtctg 180
gctgtaacta tctctgtgaa gtgtgagaaa atttcaactc tctcctgtga gaacaaaatt 240
atttccttta aggaaatgaa tcctcctgat aacatcaagg atacaaaaag tgacatcata 300
ttctttcaga gagatgtccc aggacatagt agaaagatgc aatttgaatc ttcatcatac 360
gaaggatact ttctagcttg tgaaaaagag agagaccttt ttaaactcat tttgaaaaaa 420
gaggatgaat tgggggatag atctataatg ttcactgttc aaaacgaaga cggtggtggt 480
ggctccggag gcggcggctc tggtggcggt ggcagcgaca aaactcacac atgcccaccg 540
tgcccagcac ctgaactcct ggggggaccg gacgtcttcc tcttcccccc aaaacccaag 600
gacaccctca tgatctcccg gacccctgag gtcacatgcg tggtggtgga cgtgagccac 660
gaagaccctg aggtcaagtt caactggtac gtggacggcg tggaggtgca taatgccaag 720
acaaagccgc gggaggagca gtacaacagc acgtaccggg tggtcagcgt cctcaccgtc 780
ctgcaccagg actggctgaa tggcaaggag tacaagtgca aggtctccaa caaagccctc 840
ccactccccg aggagaaaac catctccaaa gccaaagggc agccccgaga accacaggtg 900
tacaccctgc ccccatcccg ggaggagatg accaagaacc aggtcagcct gacctgcctg 960
gtcaaaggct tctatcccag cgacatcgcc gtggagtggg agagcaatgg gcagccggag 1020
aacaactaca agaccacgcc tcccgtgctg gactccgacg gctccttctt cctctacagc 1080
aagctcaccg tggacaagag caggtggcag caggggaacg tcttctcatg ctccgtgatg 1140
catgaggctc tgcacaacca ctacacgcag aagagcgcta cagccacccc gggtgccgct 1200
aacctccccg tggccactcc agacccagga atgttcccat gccttcacca ctcccaaaac 1260
ctgctgaggg ccgtcagcaa catgctccag aaggccagac aaactctaga attttaccct 1320
tgcacttctg aagagattga tcatgaagat atcacaaaag ataaaaccag cacagtggag 1380
gcctgtttac cattggaatt aaccaagaat gagagttgcc taaattccag agagacctct 1440
ttcataacta atgggagttg cctggcctcc agaaagacct cttttatgat ggccctgtgc 1500
cttagtagta tttatgaaga cttgaagatg taccaggtgg agttcaagac catgaatgca 1560
aagcttctga tggatcctaa gaggcagatc tttctagatc aaaacatgct ggcagttatt 1620
gatgagctga tgcaggccct gaatttcaac agtgagactg tgccacaaaa atcctccctt 1680
gaagaaccgg atttttataa aactaaaatc aagctctgca tacttcttca tgctttcaga 1740
attcgggcag tgactattga cagagtgacg agctatctga atgcttcc 1788
<210> 9
<211> 596
<212> PRT
<213> 氨基酸序列(人工序列)
<400> 9
Tyr Phe Gly Lys Leu Glu Ser Lys Leu Ser Val Ile Arg Asn Leu Asn
1 5 10 15
Asp Gln Val Leu Phe Ile Asp Gln Gly Asn Arg Pro Leu Phe Glu Asp
20 25 30
Met Thr Asp Ser Asp Cys Arg Asp Asn Ala Pro Arg Thr Ile Phe Ile
35 40 45
Ile Ser Met Tyr Lys Asp Ser Gln Pro Arg Gly Met Ala Val Thr Ile
50 55 60
Ser Val Lys Cys Glu Lys Ile Ser Thr Leu Ser Cys Glu Asn Lys Ile
65 70 75 80
Ile Ser Phe Lys Glu Met Asn Pro Pro Asp Asn Ile Lys Asp Thr Lys
85 90 95
Ser Asp Ile Ile Phe Phe Gln Arg Ser Val Pro Gly His Asp Asn Lys
100 105 110
Met Gln Phe Glu Ser Ser Ser Tyr Glu Gly Tyr Phe Leu Ala Cys Glu
115 120 125
Lys Glu Arg Asp Leu Phe Lys Leu Ile Leu Lys Lys Glu Asp Glu Leu
130 135 140
Gly Asp Arg Ser Ile Met Phe Thr Val Gln Asn Glu Asp Gly Gly Gly
145 150 155 160
Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp Lys Thr His
165 170 175
Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Asp Val
180 185 190
Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr
195 200 205
Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu
210 215 220
Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys
225 230 235 240
Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser
245 250 255
Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys
260 265 270
Cys Lys Val Ser Asn Lys Ala Leu Pro Leu Pro Glu Glu Lys Thr Ile
275 280 285
Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro
290 295 300
Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu
305 310 315 320
Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn
325 330 335
Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser
340 345 350
Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg
355 360 365
Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu
370 375 380
His Asn His Tyr Thr Gln Lys Ser Ala Thr Ala Thr Pro Gly Ala Ala
385 390 395 400
Asn Leu Pro Val Ala Thr Pro Asp Pro Gly Met Phe Pro Cys Leu His
405 410 415
His Ser Gln Asn Leu Leu Arg Ala Val Ser Asn Met Leu Gln Lys Ala
420 425 430
Arg Gln Thr Leu Glu Phe Tyr Pro Cys Thr Ser Glu Glu Ile Asp His
435 440 445
Glu Asp Ile Thr Lys Asp Lys Thr Ser Thr Val Glu Ala Cys Leu Pro
450 455 460
Leu Glu Leu Thr Lys Asn Glu Ser Cys Leu Asn Ser Arg Glu Thr Ser
465 470 475 480
Phe Ile Thr Asn Gly Ser Cys Leu Ala Ser Arg Lys Thr Ser Phe Met
485 490 495
Met Ala Leu Cys Leu Ser Ser Ile Tyr Glu Asp Leu Lys Met Tyr Gln
500 505 510
Val Glu Phe Lys Thr Met Asn Ala Lys Leu Leu Met Asp Pro Lys Arg
515 520 525
Gln Ile Phe Leu Asp Gln Asn Met Leu Ala Val Ile Asp Glu Leu Met
530 535 540
Gln Ala Leu Asn Phe Asn Ser Glu Thr Val Pro Gln Lys Ser Ser Leu
545 550 555 560
Glu Glu Pro Asp Phe Tyr Lys Thr Lys Ile Lys Leu Cys Ile Leu Leu
565 570 575
His Ala Phe Arg Ile Arg Ala Val Thr Ile Asp Arg Val Thr Ser Tyr
580 585 590
Leu Asn Ala Ser
595
<210> 10
<211> 1788
<212> DNA
<213> 核苷酸序列(人工序列)
<400> 10
tactttggca agcttgaatc taaattatca gtcataagaa atttgaatga ccaagttctc 60
ttcattgacc aaggaaatcg gcctctattt gaagatatga ctgattctga ctgtagagat 120
aatgcacccc ggaccatatt tattataagt atgtataaag atagccagcc tagaggtatg 180
gctgtaacta tctctgtgaa gtgtgagaaa atttcaactc tctcctgtga gaacaaaatt 240
atttccttta aggaaatgaa tcctcctgat aacatcaagg atacaaaaag tgacatcata 300
ttctttcaga gaagtgtccc aggacatgat aataagatgc aatttgaatc ttcatcatac 360
gaaggatact ttctagcttg tgaaaaagag agagaccttt ttaaactcat tttgaaaaaa 420
gaggatgaat tgggggatag atctataatg ttcactgttc aaaacgaaga cggtggtggt 480
ggctccggag gcggcggctc tggtggcggt ggcagcgaca aaactcacac atgcccaccg 540
tgcccagcac ctgaactcct ggggggaccg gacgtcttcc tcttcccccc aaaacccaag 600
gacaccctca tgatctcccg gacccctgag gtcacatgcg tggtggtgga cgtgagccac 660
gaagaccctg aggtcaagtt caactggtac gtggacggcg tggaggtgca taatgccaag 720
acaaagccgc gggaggagca gtacaacagc acgtaccggg tggtcagcgt cctcaccgtc 780
ctgcaccagg actggctgaa tggcaaggag tacaagtgca aggtctccaa caaagccctc 840
ccactccccg aggagaaaac catctccaaa gccaaagggc agccccgaga accacaggtg 900
tacaccctgc ccccatcccg ggaggagatg accaagaacc aggtcagcct gacctgcctg 960
gtcaaaggct tctatcccag cgacatcgcc gtggagtggg agagcaatgg gcagccggag 1020
aacaactaca agaccacgcc tcccgtgctg gactccgacg gctccttctt cctctacagc 1080
aagctcaccg tggacaagag caggtggcag caggggaacg tcttctcatg ctccgtgatg 1140
catgaggctc tgcacaacca ctacacgcag aagagcgcta cagccacccc gggtgccgct 1200
aacctccccg tggccactcc agacccagga atgttcccat gccttcacca ctcccaaaac 1260
ctgctgaggg ccgtcagcaa catgctccag aaggccagac aaactctaga attttaccct 1320
tgcacttctg aagagattga tcatgaagat atcacaaaag ataaaaccag cacagtggag 1380
gcctgtttac cattggaatt aaccaagaat gagagttgcc taaattccag agagacctct 1440
ttcataacta atgggagttg cctggcctcc agaaagacct cttttatgat ggccctgtgc 1500
cttagtagta tttatgaaga cttgaagatg taccaggtgg agttcaagac catgaatgca 1560
aagcttctga tggatcctaa gaggcagatc tttctagatc aaaacatgct ggcagttatt 1620
gatgagctga tgcaggccct gaatttcaac agtgagactg tgccacaaaa atcctccctt 1680
gaagaaccgg atttttataa aactaaaatc aagctctgca tacttcttca tgctttcaga 1740
attcgggcag tgactattga cagagtgacg agctatctga atgcttcc 1788
<210> 11
<211> 911
<212> PRT
<213> 氨基酸序列(人工序列)
<400> 11
Tyr Phe Gly Lys Leu Glu Ser Lys Leu Ser Val Ile Arg Asn Leu Asn
1 5 10 15
Asp Gln Val Leu Phe Ile Asp Gln Gly Asn Arg Pro Leu Phe Glu Asp
20 25 30
Met Thr Asp Ser Asp Cys Arg Asp Asn Ala Pro Arg Thr Ile Phe Ile
35 40 45
Ile Ser Lys Tyr Ser Asp Ser Leu Ala Arg Gly Leu Ala Val Thr Ile
50 55 60
Ser Val Lys Cys Glu Lys Ile Ser Thr Leu Ser Cys Glu Asn Lys Ile
65 70 75 80
Ile Ser Phe Lys Glu Met Asn Pro Pro Asp Asn Ile Lys Asp Thr Lys
85 90 95
Ser Asp Ile Ile Phe Phe Gln Arg Asp Val Pro Gly His Ser Arg Lys
100 105 110
Met Gln Phe Glu Ser Ser Ser Tyr Glu Gly Tyr Phe Leu Ala Cys Glu
115 120 125
Lys Glu Arg Asp Leu Phe Lys Leu Ile Leu Lys Lys Glu Asp Glu Leu
130 135 140
Gly Asp Arg Ser Ile Met Phe Thr Val Gln Asn Glu Asp Gly Gly Gly
145 150 155 160
Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Ala Glu Ser Lys
165 170 175
Tyr Gly Pro Pro Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly Gly
180 185 190
Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile
195 200 205
Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser Gln Glu
210 215 220
Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val His
225 230 235 240
Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr Tyr Arg
245 250 255
Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys
260 265 270
Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu
275 280 285
Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr
290 295 300
Thr Leu Pro Pro Ser Gln Glu Glu Met Thr Lys Asn Gln Val Ser Leu
305 310 315 320
Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp
325 330 335
Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val
340 345 350
Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Arg Leu Thr Val Asp
355 360 365
Lys Ser Arg Trp Gln Glu Gly Asn Val Phe Ser Cys Ser Val Met His
370 375 380
Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu
385 390 395 400
Gly Ile Trp Glu Leu Lys Lys Asp Val Tyr Val Val Glu Leu Asp Trp
405 410 415
Tyr Pro Asp Ala Pro Gly Glu Met Val Val Leu Thr Cys Asp Thr Pro
420 425 430
Glu Glu Asp Gly Ile Thr Trp Thr Leu Asp Gln Ser Ser Glu Val Leu
435 440 445
Gly Ser Gly Lys Thr Leu Thr Ile Gln Val Lys Glu Phe Gly Asp Ala
450 455 460
Gly Gln Tyr Thr Cys His Lys Gly Gly Glu Val Leu Ser His Ser Leu
465 470 475 480
Leu Leu Leu His Lys Lys Glu Asp Gly Ile Trp Ser Thr Asp Ile Leu
485 490 495
Lys Asp Gln Lys Glu Pro Lys Asn Lys Thr Phe Leu Arg Cys Glu Ala
500 505 510
Lys Asn Tyr Ser Gly Arg Phe Thr Cys Trp Trp Leu Thr Thr Ile Ser
515 520 525
Thr Asp Leu Thr Phe Ser Val Lys Ser Ser Arg Gly Ser Ser Asp Pro
530 535 540
Gln Gly Val Thr Cys Gly Ala Ala Thr Leu Ser Ala Glu Arg Val Arg
545 550 555 560
Gly Asp Asn Lys Glu Tyr Glu Tyr Ser Val Glu Cys Gln Glu Asp Ser
565 570 575
Ala Cys Pro Ala Ala Glu Glu Ser Leu Pro Ile Glu Val Met Val Asp
580 585 590
Ala Val His Lys Leu Lys Tyr Glu Asn Tyr Thr Ser Ser Phe Phe Ile
595 600 605
Arg Asp Ile Ile Lys Pro Asp Pro Pro Lys Asn Leu Gln Leu Lys Pro
610 615 620
Leu Lys Asn Ser Arg Gln Val Glu Val Ser Trp Glu Tyr Pro Asp Thr
625 630 635 640
Trp Ser Thr Pro His Ser Tyr Phe Ser Leu Thr Phe Cys Val Gln Val
645 650 655
Gln Gly Lys Ser Lys Arg Glu Lys Lys Asp Arg Val Phe Thr Asp Lys
660 665 670
Thr Ser Ala Thr Val Ile Cys Arg Lys Asn Ala Ser Ile Ser Val Arg
675 680 685
Ala Gln Asp Arg Tyr Tyr Ser Ser Ser Trp Ser Glu Trp Ala Ser Val
690 695 700
Pro Cys Ser Gly Gly Gly Gly Gly Gly Ser Arg Asn Leu Pro Val Ala
705 710 715 720
Thr Pro Asp Pro Gly Met Phe Pro Cys Leu His His Ser Gln Asn Leu
725 730 735
Leu Arg Ala Val Ser Asn Met Leu Gln Lys Ala Arg Gln Thr Leu Glu
740 745 750
Phe Tyr Pro Cys Thr Ser Glu Glu Ile Asp His Glu Asp Ile Thr Lys
755 760 765
Asp Lys Thr Ser Thr Val Glu Ala Cys Leu Pro Leu Glu Leu Thr Lys
770 775 780
Asn Glu Ser Cys Leu Asn Ser Arg Glu Thr Ser Phe Ile Thr Asn Gly
785 790 795 800
Ser Cys Leu Ala Ser Arg Lys Thr Ser Phe Met Met Ala Leu Cys Leu
805 810 815
Ser Ser Ile Tyr Glu Asp Leu Lys Met Tyr Gln Val Glu Phe Lys Thr
820 825 830
Met Asn Ala Lys Leu Leu Met Asp Pro Lys Arg Gln Ile Phe Leu Asp
835 840 845
Gln Asn Met Leu Ala Val Ile Asp Glu Leu Met Gln Ala Leu Asn Phe
850 855 860
Asn Ser Glu Thr Val Pro Gln Lys Ser Ser Leu Glu Glu Pro Asp Phe
865 870 875 880
Tyr Lys Thr Lys Ile Lys Leu Cys Ile Leu Leu His Ala Phe Arg Ile
885 890 895
Arg Ala Val Thr Ile Asp Arg Val Thr Ser Tyr Leu Asn Ala Ser
900 905 910
<210> 12
<211> 2733
<212> DNA
<213> 核苷酸序列(人工序列)
<400> 12
tactttggca agcttgaatc taaattatca gtcataagaa atttgaatga ccaagttctc 60
ttcattgacc aaggaaatcg gcctctattt gaagatatga ctgattctga ctgtagagat 120
aatgcacccc ggaccatatt tattataagt aaatattctg atagcctcgc tagaggtctg 180
gctgtaacta tctctgtgaa gtgtgagaaa atttcaactc tctcctgtga gaacaaaatt 240
atttccttta aggaaatgaa tcctcctgat aacatcaagg atacaaaaag tgacatcata 300
ttctttcaga gagatgtccc aggacatagt agaaagatgc aatttgaatc ttcatcatac 360
gaaggatact ttctagcttg tgaaaaagag agagaccttt ttaaactcat tttgaaaaaa 420
gaggatgaat tgggggatag atctataatg ttcactgttc aaaacgaaga cggtggtggt 480
ggctccggag gcggcggctc tggtggcggt ggcagcgctg agtccaaata tggtccccca 540
tgcccaccct gcccagcacc tgaggccgcc gggggaccat cagtcttcct gttcccccca 600
aaacccaagg acactctcat gatctcccgg acccctgagg tcacgtgcgt ggtggtggac 660
gtgagccagg aagaccccga ggtccagttc aactggtacg tggatggcgt ggaggtgcat 720
aatgccaaga caaagccgcg ggaggagcag ttcaacagca cgtaccgtgt ggtcagcgtc 780
ctcaccgtcc tgcaccagga ctggctgaac ggcaaggagt acaagtgcaa ggtctccaac 840
aaaggcctcc cgtcctccat cgagaaaacc atctccaaag ccaaagggca gccccgagag 900
ccacaggtgt acaccctgcc cccatcccag gaggagatga ccaagaacca ggtcagcctg 960
acctgcctgg tcaaaggctt ctaccccagc gacatcgccg tggagtggga gagcaatggg 1020
cagccggaga acaactacaa gaccacgcct cccgtgctgg actccgacgg ctccttcttc 1080
ctctacagca ggctaaccgt ggacaagagc aggtggcagg aggggaatgt cttctcatgc 1140
tccgtgatgc atgaggctct gcacaaccac tacacacaga agagcctctc cctgtctctg 1200
ggtatatggg aactgaagaa agatgtttat gtcgtagaat tggattggta tccggatgcc 1260
cctggagaaa tggtggtcct cacctgtgac acccctgaag aagatggtat cacctggacc 1320
ttggaccaga gcagtgaggt cttaggctct ggcaaaaccc tgaccatcca agtcaaagag 1380
tttggagatg ctggccagta cacctgtcac aaaggaggcg aggttctaag ccattcgctc 1440
ctgctgcttc acaaaaagga agatggaatt tggtccactg atattttaaa ggaccagaaa 1500
gaacccaaaa ataagacctt tctaagatgc gaggccaaga attattctgg acgtttcacc 1560
tgctggtggc tgacgacaat cagtactgat ttgacattca gtgtcaaaag cagcagaggc 1620
tcttctgacc cccaaggggt gacgtgcgga gctgctacac tctctgcaga gagagtcaga 1680
ggggacaaca aggagtatga gtactcagtg gagtgccagg aggacagtgc ctgcccagct 1740
gctgaggaga gtctgcccat tgaggtcatg gtggatgccg ttcacaagct caagtatgaa 1800
aactacacca gcagcttctt catcagggac atcatcaaac ctgacccacc caagaacttg 1860
cagctgaagc cattaaagaa ttctcggcag gtggaggtca gctgggagta ccctgacacc 1920
tggagtactc cacattccta cttctccctg acattctgcg ttcaggtcca gggcaagagc 1980
aagagagaaa agaaagatag agtcttcacg gacaagacct cagccacggt catctgccgc 2040
aaaaatgcca gcattagcgt gcgggcccag gaccgctact atagctcatc ttggagcgaa 2100
tgggcatctg tgccctgcag tggtggcggt ggcggcggat ctagaaacct ccccgtggcc 2160
actccagacc caggaatgtt cccatgcctt caccactccc aaaacctgct gagggccgtc 2220
agcaacatgc tccagaaggc cagacaaact ctagaatttt acccttgcac ttctgaagag 2280
attgatcatg aagatatcac aaaagataaa accagcacag tggaggcctg tttaccattg 2340
gaattaacca agaatgagag ttgcctaaat tccagagaga cctctttcat aactaatggg 2400
agttgcctgg cctccagaaa gacctctttt atgatggccc tgtgccttag tagtatttat 2460
gaagacttga agatgtacca ggtggagttc aagaccatga atgcaaagct tctgatggat 2520
cctaagaggc agatctttct agatcaaaac atgctggcag ttattgatga gctgatgcag 2580
gccctgaatt tcaacagtga gactgtgcca caaaaatcct cccttgaaga accggatttt 2640
tataaaacta aaatcaagct ctgcatactt cttcatgctt tcagaattcg ggcagtgact 2700
attgacagag tgacgagcta tctgaatgct tcc 2733
<210> 13
<211> 401
<212> PRT
<213> 氨基酸序列(人工序列)
<400> 13
Tyr Phe Gly Lys Leu Glu Ser Lys Leu Ser Val Ile Arg Asn Leu Asn
1 5 10 15
Asp Gln Val Leu Phe Ile Asp Gln Gly Asn Arg Pro Leu Phe Glu Asp
20 25 30
Met Thr Asp Ser Asp Cys Arg Asp Asn Ala Pro Arg Thr Ile Phe Ile
35 40 45
Ile Ser Lys Tyr Ser Asp Ser Leu Ala Arg Gly Leu Ala Val Thr Ile
50 55 60
Ser Val Lys Cys Glu Lys Ile Ser Thr Leu Ser Cys Glu Asn Lys Ile
65 70 75 80
Ile Ser Phe Lys Glu Met Asn Pro Pro Asp Asn Ile Lys Asp Thr Lys
85 90 95
Ser Asp Ile Ile Phe Phe Gln Arg Asp Val Pro Gly His Ser Arg Lys
100 105 110
Met Gln Phe Glu Ser Ser Ser Tyr Glu Gly Tyr Phe Leu Ala Cys Glu
115 120 125
Lys Glu Arg Asp Leu Phe Lys Leu Ile Leu Lys Lys Glu Asp Glu Leu
130 135 140
Gly Asp Arg Ser Ile Met Phe Thr Val Gln Asn Glu Asp Gly Gly Gly
145 150 155 160
Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Ala Glu Ser Lys
165 170 175
Tyr Gly Pro Pro Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly Gly
180 185 190
Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile
195 200 205
Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser Gln Glu
210 215 220
Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val His
225 230 235 240
Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr Tyr Arg
245 250 255
Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys
260 265 270
Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu
275 280 285
Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr
290 295 300
Thr Leu Pro Pro Ser Gln Glu Glu Met Thr Lys Asn Gln Val Ser Leu
305 310 315 320
Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp
325 330 335
Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val
340 345 350
Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Arg Leu Thr Val Asp
355 360 365
Lys Ser Arg Trp Gln Glu Gly Asn Val Phe Ser Cys Ser Val Met His
370 375 380
Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu
385 390 395 400
Gly
<210> 14
<211> 1203
<212> DNA
<213> 核苷酸序列(人工序列)
<400> 14
tactttggca agcttgaatc taaattatca gtcataagaa atttgaatga ccaagttctc 60
ttcattgacc aaggaaatcg gcctctattt gaagatatga ctgattctga ctgtagagat 120
aatgcacccc ggaccatatt tattataagt aaatattctg atagcctcgc tagaggtctg 180
gctgtaacta tctctgtgaa gtgtgagaaa atttcaactc tctcctgtga gaacaaaatt 240
atttccttta aggaaatgaa tcctcctgat aacatcaagg atacaaaaag tgacatcata 300
ttctttcaga gagatgtccc aggacatagt agaaagatgc aatttgaatc ttcatcatac 360
gaaggatact ttctagcttg tgaaaaagag agagaccttt ttaaactcat tttgaaaaaa 420
gaggatgaat tgggggatag atctataatg ttcactgttc aaaacgaaga cggtggtggt 480
ggctccggag gcggcggctc tggtggcggt ggcagcgctg agtccaaata tggtccccca 540
tgcccaccct gcccagcacc tgaggccgcc gggggaccat cagtcttcct gttcccccca 600
aaacccaagg acactctcat gatctcccgg acccctgagg tcacgtgcgt ggtggtggac 660
gtgagccagg aagaccccga ggtccagttc aactggtacg tggatggcgt ggaggtgcat 720
aatgccaaga caaagccgcg ggaggagcag ttcaacagca cgtaccgtgt ggtcagcgtc 780
ctcaccgtcc tgcaccagga ctggctgaac ggcaaggagt acaagtgcaa ggtctccaac 840
aaaggcctcc cgtcctccat cgagaaaacc atctccaaag ccaaagggca gccccgagag 900
ccacaggtgt acaccctgcc cccatcccag gaggagatga ccaagaacca ggtcagcctg 960
acctgcctgg tcaaaggctt ctaccccagc gacatcgccg tggagtggga gagcaatggg 1020
cagccggaga acaactacaa gaccacgcct cccgtgctgg actccgacgg ctccttcttc 1080
ctctacagca ggctaaccgt ggacaagagc aggtggcagg aggggaatgt cttctcatgc 1140
tccgtgatgc atgaggctct gcacaaccac tacacacaga agagcctctc cctgtctctg 1200
ggt 1203
<210> 15
<211> 737
<212> PRT
<213> 氨基酸序列(人工序列)
<400> 15
Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly
1 5 10 15
Gly Pro Asp Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met
20 25 30
Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His
35 40 45
Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val
50 55 60
His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr
65 70 75 80
Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly
85 90 95
Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Leu Pro Glu
100 105 110
Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val
115 120 125
Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser
130 135 140
Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu
145 150 155 160
Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro
165 170 175
Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val
180 185 190
Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met
195 200 205
His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Ala Thr Ala Thr
210 215 220
Pro Gly Ala Ile Trp Glu Leu Lys Lys Asp Val Tyr Val Val Glu Leu
225 230 235 240
Asp Trp Tyr Pro Asp Ala Pro Gly Glu Met Val Val Leu Thr Cys Asp
245 250 255
Thr Pro Glu Glu Asp Gly Ile Thr Trp Thr Leu Asp Gln Ser Ser Glu
260 265 270
Val Leu Gly Ser Gly Lys Thr Leu Thr Ile Gln Val Lys Glu Phe Gly
275 280 285
Asp Ala Gly Gln Tyr Thr Cys His Lys Gly Gly Glu Val Leu Ser His
290 295 300
Ser Leu Leu Leu Leu His Lys Lys Glu Asp Gly Ile Trp Ser Thr Asp
305 310 315 320
Ile Leu Lys Asp Gln Lys Glu Pro Lys Asn Lys Thr Phe Leu Arg Cys
325 330 335
Glu Ala Lys Asn Tyr Ser Gly Arg Phe Thr Cys Trp Trp Leu Thr Thr
340 345 350
Ile Ser Thr Asp Leu Thr Phe Ser Val Lys Ser Ser Arg Gly Ser Ser
355 360 365
Asp Pro Gln Gly Val Thr Cys Gly Ala Ala Thr Leu Ser Ala Glu Arg
370 375 380
Val Arg Gly Asp Asn Lys Glu Tyr Glu Tyr Ser Val Glu Cys Gln Glu
385 390 395 400
Asp Ser Ala Cys Pro Ala Ala Glu Glu Ser Leu Pro Ile Glu Val Met
405 410 415
Val Asp Ala Val His Lys Leu Lys Tyr Glu Asn Tyr Thr Ser Ser Phe
420 425 430
Phe Ile Arg Asp Ile Ile Lys Pro Asp Pro Pro Lys Asn Leu Gln Leu
435 440 445
Lys Pro Leu Lys Asn Ser Arg Gln Val Glu Val Ser Trp Glu Tyr Pro
450 455 460
Asp Thr Trp Ser Thr Pro His Ser Tyr Phe Ser Leu Thr Phe Cys Val
465 470 475 480
Gln Val Gln Gly Lys Ser Lys Arg Glu Lys Lys Asp Arg Val Phe Thr
485 490 495
Asp Lys Thr Ser Ala Thr Val Ile Cys Arg Lys Asn Ala Ser Ile Ser
500 505 510
Val Arg Ala Gln Asp Arg Tyr Tyr Ser Ser Ser Trp Ser Glu Trp Ala
515 520 525
Ser Val Pro Cys Ser Gly Gly Gly Gly Gly Gly Ser Arg Asn Leu Pro
530 535 540
Val Ala Thr Pro Asp Pro Gly Met Phe Pro Cys Leu His His Ser Gln
545 550 555 560
Asn Leu Leu Arg Ala Val Ser Asn Met Leu Gln Lys Ala Arg Gln Thr
565 570 575
Leu Glu Phe Tyr Pro Cys Thr Ser Glu Glu Ile Asp His Glu Asp Ile
580 585 590
Thr Lys Asp Lys Thr Ser Thr Val Glu Ala Cys Leu Pro Leu Glu Leu
595 600 605
Thr Lys Asn Glu Ser Cys Leu Asn Ser Arg Glu Thr Ser Phe Ile Thr
610 615 620
Asn Gly Ser Cys Leu Ala Ser Arg Lys Thr Ser Phe Met Met Ala Leu
625 630 635 640
Cys Leu Ser Ser Ile Tyr Glu Asp Leu Lys Met Tyr Gln Val Glu Phe
645 650 655
Lys Thr Met Asn Ala Lys Leu Leu Met Asp Pro Lys Arg Gln Ile Phe
660 665 670
Leu Asp Gln Asn Met Leu Ala Val Ile Asp Glu Leu Met Gln Ala Leu
675 680 685
Asn Phe Asn Ser Glu Thr Val Pro Gln Lys Ser Ser Leu Glu Glu Pro
690 695 700
Asp Phe Tyr Lys Thr Lys Ile Lys Leu Cys Ile Leu Leu His Ala Phe
705 710 715 720
Arg Ile Arg Ala Val Thr Ile Asp Arg Val Thr Ser Tyr Leu Asn Ala
725 730 735
Ser
<210> 16
<211> 2211
<212> DNA
<213> 核苷酸序列(人工序列)
<400> 16
gacaaaactc acacatgccc accgtgccca gcacctgaac tcctgggggg accggacgtc 60
ttcctcttcc ccccaaaacc caaggacacc ctcatgatct cccggacccc tgaggtcaca 120
tgcgtggtgg tggacgtgag ccacgaagac cctgaggtca agttcaactg gtacgtggac 180
ggcgtggagg tgcataatgc caagacaaag ccgcgggagg agcagtacaa cagcacgtac 240
cgggtggtca gcgtcctcac cgtcctgcac caggactggc tgaatggcaa ggagtacaag 300
tgcaaggtct ccaacaaagc cctcccactc cccgaggaga aaaccatctc caaagccaaa 360
gggcagcccc gagaaccaca ggtgtacacc ctgcccccat cccgggagga gatgaccaag 420
aaccaggtca gcctgacctg cctggtcaaa ggcttctatc ccagcgacat cgccgtggag 480
tgggagagca atgggcagcc ggagaacaac tacaagacca cgcctcccgt gctggactcc 540
gacggctcct tcttcctcta cagcaagctc accgtggaca agagcaggtg gcagcagggg 600
aacgtcttct catgctccgt gatgcatgag gctctgcaca accactacac gcagaagagc 660
gctacagcca ccccgggtgc catatgggaa ctgaagaaag atgtttatgt cgtagaattg 720
gattggtatc cggatgcccc tggagaaatg gtggtcctca cctgtgacac ccctgaagaa 780
gatggtatca cctggacctt ggaccagagc agtgaggtct taggctctgg caaaaccctg 840
accatccaag tcaaagagtt tggagatgct ggccagtaca cctgtcacaa aggaggcgag 900
gttctaagcc attcgctcct gctgcttcac aaaaaggaag atggaatttg gtccactgat 960
attttaaagg accagaaaga acccaaaaat aagacctttc taagatgcga ggccaagaat 1020
tattctggac gtttcacctg ctggtggctg acgacaatca gtactgattt gacattcagt 1080
gtcaaaagca gcagaggctc ttctgacccc caaggggtga cgtgcggagc tgctacactc 1140
tctgcagaga gagtcagagg ggacaacaag gagtatgagt actcagtgga gtgccaggag 1200
gacagtgcct gcccagctgc tgaggagagt ctgcccattg aggtcatggt ggatgccgtt 1260
cacaagctca agtatgaaaa ctacaccagc agcttcttca tcagggacat catcaaacct 1320
gacccaccca agaacttgca gctgaagcca ttaaagaatt ctcggcaggt ggaggtcagc 1380
tgggagtacc ctgacacctg gagtactcca cattcctact tctccctgac attctgcgtt 1440
caggtccagg gcaagagcaa gagagaaaag aaagatagag tcttcacgga caagacctca 1500
gccacggtca tctgccgcaa aaatgccagc attagcgtgc gggcccagga ccgctactat 1560
agctcatctt ggagcgaatg ggcatctgtg ccctgcagtg gtggcggtgg cggcggatct 1620
agaaacctcc ccgtggccac tccagaccca ggaatgttcc catgccttca ccactcccaa 1680
aacctgctga gggccgtcag caacatgctc cagaaggcca gacaaactct agaattttac 1740
ccttgcactt ctgaagagat tgatcatgaa gatatcacaa aagataaaac cagcacagtg 1800
gaggcctgtt taccattgga attaaccaag aatgagagtt gcctaaattc cagagagacc 1860
tctttcataa ctaatgggag ttgcctggcc tccagaaaga cctcttttat gatggccctg 1920
tgccttagta gtatttatga agacttgaag atgtaccagg tggagttcaa gaccatgaat 1980
gcaaagcttc tgatggatcc taagaggcag atctttctag atcaaaacat gctggcagtt 2040
attgatgagc tgatgcaggc cctgaatttc aacagtgaga ctgtgccaca aaaatcctcc 2100
cttgaagaac cggattttta taaaactaaa atcaagctct gcatacttct tcatgctttc 2160
agaattcggg cagtgactat tgacagagtg acgagctatc tgaatgcttc c 2211
<210> 17
<211> 1287
<212> DNA
<213> 核苷酸序列(人工序列)
<400> 17
gccgccacca tgccgtcttc tgtctcgtgg ggcatcctcc tgctggcagg cctgtgctgc 60
ctggtccctg tctccctggc ttactttggc aagcttgaat ctaaattatc agtcataaga 120
aatttgaatg accaagttct cttcattgac caaggaaatc ggcctctatt tgaagatatg 180
actgattctg actgtagaga taatgcaccc cggaccatat ttattataag tatgtataaa 240
gatagccagc ctagaggtat ggctgtaact atctctgtga agtgtgagaa aatttcaact 300
ctctcctgtg agaacaaaat tatttccttt aaggaaatga atcctcctga taacatcaag 360
gatacaaaaa gtgacatcat attctttcag agaagtgtcc caggacatga taataagatg 420
caatttgaat cttcatcata cgaaggatac tttctagctt gtgaaaaaga gagagacctt 480
tttaaactca ttttgaaaaa agaggatgaa ttgggggata gatctataat gttcactgtt 540
caaaacgaag acggtggtgg tggctccgga ggcggcggct ctggtggcgg tggcagcgct 600
gagtccaaat atggtccccc atgcccaccc tgcccagcac ctgaggccgc cgggggacca 660
tcagtcttcc tgttcccccc aaaacccaag gacactctca tgatctcccg gacccctgag 720
gtcacgtgcg tggtggtgga cgtgagccag gaagaccccg aggtccagtt caactggtac 780
gtggatggcg tggaggtgca taatgccaag acaaagccgc gggaggagca gttcaacagc 840
acgtaccgtg tggtcagcgt cctcaccgtc ctgcaccagg actggctgaa cggcaaggag 900
tacaagtgca aggtctccaa caaaggcctc ccgtcctcca tcgagaaaac catctccaaa 960
gccaaagggc agccccgaga gccacaggtg tacaccctgc ccccatccca ggaggagatg 1020
accaagaacc aggtcagcct gacctgcctg gtcaaaggct tctaccccag cgacatcgcc 1080
gtggagtggg agagcaatgg gcagccggag aacaactaca agaccacgcc tcccgtgctg 1140
gactccgacg gctccttctt cctctacagc aggctaaccg tggacaagag caggtggcag 1200
gaggggaatg tcttctcatg ctccgtgatg catgaggctc tgcacaacca ctacacacag 1260
aagagcctct ccctgtctct gggttga 1287
<210> 18
<211> 197
<212> PRT
<213> 氨基酸序列(人工序列)
<400> 18
Arg Asn Leu Pro Val Ala Thr Pro Asp Pro Gly Met Phe Pro Cys Leu
1 5 10 15
His His Ser Gln Asn Leu Leu Arg Ala Val Ser Asn Met Leu Gln Lys
20 25 30
Ala Arg Gln Thr Leu Glu Phe Tyr Pro Cys Thr Ser Glu Glu Ile Asp
35 40 45
His Glu Asp Ile Thr Lys Asp Lys Thr Ser Thr Val Glu Ala Cys Leu
50 55 60
Pro Leu Glu Leu Thr Lys Asn Glu Ser Cys Leu Asn Ser Arg Glu Thr
65 70 75 80
Ser Phe Ile Thr Asn Gly Ser Cys Leu Ala Ser Arg Lys Thr Ser Phe
85 90 95
Met Met Ala Leu Cys Leu Ser Ser Ile Tyr Glu Asp Leu Lys Met Tyr
100 105 110
Gln Val Glu Phe Lys Thr Met Asn Ala Lys Leu Leu Met Asp Pro Lys
115 120 125
Arg Gln Ile Phe Leu Asp Gln Asn Met Leu Ala Val Ile Asp Glu Leu
130 135 140
Met Gln Ala Leu Asn Phe Asn Ser Glu Thr Val Pro Gln Lys Ser Ser
145 150 155 160
Leu Glu Glu Pro Asp Phe Tyr Lys Thr Lys Ile Lys Leu Cys Ile Leu
165 170 175
Leu His Ala Phe Arg Ile Arg Ala Val Thr Ile Asp Arg Val Thr Ser
180 185 190
Tyr Leu Asn Ala Ser
195
<210> 19
<211> 227
<212> PRT
<213> 氨基酸序列(人工序列)
<400> 19
Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly
1 5 10 15
Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met
20 25 30
Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His
35 40 45
Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val
50 55 60
His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr
65 70 75 80
Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly
85 90 95
Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile
100 105 110
Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val
115 120 125
Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser
130 135 140
Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu
145 150 155 160
Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro
165 170 175
Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val
180 185 190
Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met
195 200 205
His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser
210 215 220
Pro Gly Lys
225
<210> 20
<211> 220
<212> PRT
<213> 氨基酸序列(人工序列)
<400> 20
Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly
1 5 10 15
Gly Pro Asp Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met
20 25 30
Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His
35 40 45
Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val
50 55 60
His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr
65 70 75 80
Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly
85 90 95
Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Leu Pro Glu
100 105 110
Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val
115 120 125
Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser
130 135 140
Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu
145 150 155 160
Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro
165 170 175
Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val
180 185 190
Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met
195 200 205
His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser
210 215 220
<210> 21
<211> 229
<212> PRT
<213> 氨基酸序列(人工序列)
<400> 21
Glu Ser Lys Tyr Gly Pro Pro Cys Pro Ser Cys Pro Ala Pro Glu Phe
1 5 10 15
Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr
20 25 30
Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val
35 40 45
Ser Gln Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp Gly Val
50 55 60
Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser
65 70 75 80
Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu
85 90 95
Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro Ser
100 105 110
Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro
115 120 125
Gln Val Tyr Thr Leu Pro Pro Ser Gln Glu Glu Met Thr Lys Asn Gln
130 135 140
Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala
145 150 155 160
Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr
165 170 175
Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Arg Leu
180 185 190
Thr Val Asp Lys Ser Arg Trp Gln Glu Gly Asn Val Phe Ser Cys Ser
195 200 205
Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser
210 215 220
Leu Ser Pro Gly Lys
225
<210> 22
<211> 229
<212> PRT
<213> 氨基酸序列(人工序列)
<400> 22
Ala Glu Ser Lys Tyr Gly Pro Pro Cys Pro Pro Cys Pro Ala Pro Glu
1 5 10 15
Ala Ala Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp
20 25 30
Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp
35 40 45
Val Ser Gln Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp Gly
50 55 60
Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe Asn
65 70 75 80
Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp
85 90 95
Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro
100 105 110
Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu
115 120 125
Pro Gln Val Tyr Thr Leu Pro Pro Ser Gln Glu Glu Met Thr Lys Asn
130 135 140
Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile
145 150 155 160
Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr
165 170 175
Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Arg
180 185 190
Leu Thr Val Asp Lys Ser Arg Trp Gln Glu Gly Asn Val Phe Ser Cys
195 200 205
Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu
210 215 220
Ser Leu Ser Leu Gly
225
Claims (8)
1.一种融合蛋白,其特征在于,由第一结构域、连接结构域和第二结构域组成,其中
所述第一结构域为IL-18变体,序列如SEQ ID NO:2所示;
所述第二结构域为IL-12p40和IL-12p35,序列分别如SEQ ID NO:5和SEQ ID NO:18所示;
所述连接结构域为IgG1 Fc变体,序列如SEQ ID NO:20所示;或为IgG4 Fc变体,序列如SEQ ID NO:22所示。
2.根据权利要求1所述的融合蛋白,其特征在于,
IL-12p40和IL-12p35两者之间通过连接子连接或者不连接。
3.一种融合基因,其特征在于,含有权利要求1~2任一所述的融合蛋白的编码核苷酸序列。
4.一种表达构建体,其特征在于,含有权利要求1~2任一所述的融合蛋白的编码核苷酸序列。
5.一种融合蛋白的制备方法,其特征在于,包括将如权利要求1~2任一所述的融合蛋白的编码核苷酸序列克隆至表达构建体的步骤。
6.根据权利要求5所示的制备方法,其特征在于,包括以下步骤:
(1-1)构建如权利要求1~2任一所述的融合蛋白的编码核苷酸序列;
(1-2)构建包含步骤(1-1)的编码核苷酸序列的表达构建体;
(1-3)将步骤(1-2)的表达构建体用于转染或转化宿主细胞,并使所述编码核苷酸序列在宿主细胞中表达。
7.一种NK细胞体外扩增和培养方法,其特征在于,包括以下步骤:
(2-1)分离单个核细胞;
(2-2)重悬单个核细胞:第0天收集的单个核细胞,用活化培养基重悬后,转入培养瓶,置于培养箱中培养;
(2-3)诱导NK细胞:第3天补加所述活化培养基;
(2-4)扩增NK细胞:第5天后,每1~3天补加扩增培养基,并控制细胞浓度在0.4~0.7×106/mL;培养至第10~17天后将细胞培养液转入离心管,离心、洗涤,获得高纯度,高活性的NK细胞;
其中所述活化培养基和/或所述扩增培养基中添加有如权利要求1~2任一所述的融合蛋白。
8.如权利要求1~2任一所述的融合蛋白、如权利要求3所述的融合基因、如权利要求4所述的表达构建体在制备肿瘤药物中的应用;和/或
如权利要求7所述的NK细胞体外扩增和培养方法制备的NK细胞在制备肿瘤药物中的应用。
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A Fusion Protein Complex that Combines IL-12, IL-15, and IL-18 Signaling to Induce Memory-Like NK Cells for Cancer Immunotherapy;Michelle K. Becker-Hapak et al;《CANCER IMMUNOLOGY RESEARCH》;第第9卷卷;第1071-1087页 * |
Porcine interleukin-12 fusion protein and interleukin-18 in combination induce interferon-g production in porcine natural killer and T cells;K. Domeika et al;《Veterinary Immunology and Immunopathology》;第第86卷卷;第11-21页 * |
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