CN110573529A - 激活nk细胞的融合蛋白、nk细胞和包含其的药物组合物 - Google Patents
激活nk细胞的融合蛋白、nk细胞和包含其的药物组合物 Download PDFInfo
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Abstract
本发明涉及用于癌症治疗的融合蛋白及其用途。本发明的用于预防或治疗癌症的融合蛋白包括:结合肿瘤相关抗原的抗体或其片段;接头;以及包含自然杀伤细胞诱导蛋白CXCL16的融合多肽。因此,当与自然杀伤细胞(一种免疫细胞治疗剂)共同施用时,融合多肽大大提高了自然杀伤细胞向表达特定抗原的癌症中的引入,因而对预防或治疗癌症具有显著作用。
Description
技术领域
本发明涉及一种新的抗癌免疫细胞疗法,其使用融合蛋白和自然杀伤细胞以增加自然杀伤细胞向癌症的流入并最大化抗体依赖性细胞毒性(ADCC)。
另外,本发明涉及用融合蛋白治疗癌症的方法以及融合蛋白的各种用途。
背景技术
自然杀伤(NK)细胞是一种在体内免疫系统防御机制的一线中起作用的效应细胞,如无需事先用抗原致敏即可执行去除肿瘤细胞和感染有细菌、细胞内寄生虫或病毒的宿主细胞的功能;排斥不适当的骨髓移植;调节T细胞的免疫应答;等等。
自然杀伤细胞的免疫功能取决于诱导其杀伤功能的刺激信号与抑制杀伤功能的抑制信号之间的平衡。特别地,强烈接收刺激信号的自然杀伤细胞攻击并去除靶细胞,而强烈接收抑制信号的自然杀伤细胞使靶细胞存活。
作为自然杀伤细胞的杀伤功能,有抗体依赖性细胞毒性(ADCC)和自然杀伤。ADCC和自然杀伤的共同点是,它们都需要蛋白酪氨酸激酶(PTK)的激活,并都被自然杀伤细胞抑制受体所递送的抑制信号阻断。NK细胞的杀伤功能取决于刺激信号和抑制信号之间的平衡,因此自然杀伤细胞可以区分正常宿主细胞与感染或癌变的细胞,以去除后者。
可以根据CD56的表达水平对自然杀伤细胞进行分类,至少90%CD56暗的自然杀伤细胞是分布在外周血中的自然杀伤细胞。众所周知,CD56暗比其他表达CD56的自然杀伤细胞具有更高的细胞毒性,并显示出高表达的杀伤Ig样受体(KIR)和穿孔素,它们是自然杀伤细胞的激活受体。还已知与CD56暗自然杀伤细胞相比,CD56明自然杀伤细胞数量较少并且具有较低的细胞毒性能力。然而,据报道,CD56明自然杀伤细胞不仅具有高的免疫调节功能(IFN-γ、TNF-α等),而且还具有高ADCC功能(The Journal of Immunology,2011,186:6753-6761)。特别地,预期CD56明自然杀伤细胞在组合疗法中对抗体和癌症具有改善的作用。
另一方面,众所周知,肿瘤可以表达与其恶性表型相关的独特蛋白质,或者可以比正常细胞在数量上过表达某种蛋白质。独特蛋白质在肿瘤细胞表面上的表达使得有可能探测肿瘤的表型特性、生化组成和活性,从而为诊断和表征疾病提供机会,或者也有可能靶向肿瘤相关抗原,从而开发出一种新的肿瘤治疗方法。
已知对肿瘤相关抗原显示特异性的抗原抗体反应的抗体通过诱导各种体内免疫应答(抗体依赖性细胞毒性(ADCC)活性、补体依赖性细胞毒性(CDC)活性等)攻击癌细胞并导致细胞死亡。因此,目前正在开发可用于肿瘤治疗等的抗体,但是增强其治疗功效的研究和开发则很少。
在这些背景下,需要通过使用自然杀伤细胞和在癌细胞表面上特异性表达的癌抗原对有效治疗癌症的方法进行研究和开发。
[现有技术参考]
[专利文件]
韩国专利公开号10-2006-0079180
韩国专利公开号10-2015-0063145
发明内容
技术问题
本发明提供了一种融合多肽,其包含:结合肿瘤相关抗原的抗体或其片段;
接头;和
自然杀伤细胞诱导蛋白CXCL16。
本发明还提供了编码融合多肽的核酸;包含其的载体;或包含所述载体的宿主细胞。
本发明还提供了用于预防或治疗癌症的药物组合物,其包含融合多肽,所述融合多肽包含:结合肿瘤相关抗原的抗体或其片段;
接头;和
自然杀伤细胞诱导蛋白CXCL16。
本发明还提供了用于预防或治疗癌症的药物组合物,其包含融合多肽和自然杀伤细胞,所述融合多肽包含:结合肿瘤相关抗原的抗体或其片段;
接头;和
自然杀伤细胞诱导蛋白CXCL16。
本发明还提供了包含融合多肽的组合物,其用于癌症治疗。
本发明还提供了融合多肽在制备用于癌症治疗的药物中的用途。
本发明还提供了融合多肽用于癌症治疗的用途。
本发明还提供了一种治疗癌症的方法,其通过向患者施用药学有效量的包含融合多肽的组合物进行。
技术方案
本发明人已经研究和开发了一种方法,其用于有效地将自然杀伤细胞,一种免疫细胞治疗剂引入癌组织。结果,本发明人已经鉴定,在自然杀伤细胞表面上表达的活性诱导物质的受体中,CXCR3和CXCR6在自然杀伤细胞表面上过表达,然后本发明人鉴定,在其配体中,CXCL16对自然杀伤细胞的迁移有效,然后鉴定通过制备和施用肿瘤相关抗原特异性融合蛋白以及具有自然杀伤细胞诱导特性的CXCL16,显著增加了自然杀伤细胞向癌症中的诱导,因此对癌症治疗具有显著作用,从而完成了本发明。
如本文所用,术语“肿瘤相关抗原”是指在正常细胞上不表达、或与正常细胞相反仅在肿瘤细胞上过表达的抗原,优选在肿瘤细胞表面上特异性表达的抗原,其中所述抗原是指由肿瘤细胞产生的抗原性物质。
在肿瘤上特异性表达的肿瘤相关抗原可以包括例如4-1BB(CD137)、5T4、AGS-5、AGS-16、血管生成素2、CD19(分化簇19)、B7.1(CD80)、B7.2(CD86)、B7DC、B7H1、B7H2、B7H3、BT-062、BTLA、CAIX、癌胚抗原、CTLA4、Cripto、ED-B、ErbB1、ErbB2、ErbB3、ErbB4、EGFL7、EpCAM、EphA2、EphA3、EphB2、FAP、纤连蛋白、叶酸受体、神经节苷脂GM3、GD2、糖皮质激素诱导的肿瘤坏死因子受体(GITR)、gp100、gpA33、GPNMB、ICOS、IGFIR、整联蛋白αυ、整联蛋白αυβ、KIR、LAG-3、Lewis Y、间皮素、c-MET、Her2(人EGFR相关的2)、MN碳酸酐酶IX、MUC1、MUC16、粘连蛋白-4、NKGD2、NOTCH、OX40、OX40L、PD-1、PD-L1(程序性死亡配体1)、PSCA、PSMA、RANKL、ROR1、ROR2、SLC44A4、多配体聚糖-1、TACI、TAG-72、腱糖蛋白、TIM3、TRAILR1、TRAILR2、EGFR、VEGFR-1、VEGFR-2、VEGFR-3或等等,但不限于此。在本发明的一个实施例中,鉴定了融合多肽对间皮素、PD-L1、Her2、CD19、MUC1、EGFR和VEGFR的作用。
如本文所用,术语“抗体”包括完整抗体、具有抗原识别和结合能力的抗体片段、单克隆抗体、多克隆抗体和抗体样物质。抗体可以是IgM、IgG(例如,IgG1、IgG2、IgG3或IgG4)、IgD、IgA或IgE。
如本文所用,术语“抗体片段”是指完整抗体的一部分,通常是包含完整抗体的抗原结合或可变区的分子。抗体片段的示例包括Fab、Fab'、F(ab')2和Fv片段;和单结构域抗体。
与非肿瘤细胞或正常细胞相比,“抗体或其片段”可以特异地或优选地结合肿瘤细胞,优选地肿瘤相关抗原特异性地在肿瘤中表达。在本文中,“特异性结合”或“优选结合”是指两个结合伴侣(例如,抗体及其结合伴侣,即抗原)之间的结合对于两个结合伴侣是选择性的,并且可以区别于不需要的或非特异的相互作用。
如本文所用,术语“单链Fv”或“scFv(单链可变片段)”是指抗体,其中常规双链抗体的重链和轻链可变结构域彼此结合以形成一条链。通常,将接头肽插入两条链之间以允许适当折叠并形成活性结合位点。
如本文所用,术语“与抗原结合的抗体”是指可用作治疗剂的抗体,其中该抗体通过以足够的亲和力与抗原结合而靶向抗原。
如本文所用,术语“接头”是指通过化学键等连接第一分子(例如,结合肿瘤相关抗原的抗体或其片段)与第二分子(自然杀伤细胞诱导蛋白CXCL16)的肽。
如本文所用,术语“癌症”或“肿瘤”是指人的病理状况,其特征在于不受控制的细胞增殖。癌症或肿瘤包括癌、淋巴瘤、母细胞瘤和白血病,但不限于此。癌症的更具体的非限制性例子包括肺癌(小细胞和非小细胞)、乳腺癌、前列腺癌、类癌、膀胱癌、胃癌、胰腺癌、肝癌(肝细胞癌)、肝母细胞瘤、结肠癌、头颈部鳞状细胞癌、食道癌、卵巢癌、宫颈癌、子宫内膜瘤、间皮瘤、黑色素瘤、肉瘤、骨肉瘤、脂肪肉瘤、甲状腺癌、硬纤维瘤、急性髓性白血病(AML)和慢性粒性白血病(CML)。
如本文所用,术语“表达载体”包括编码感兴趣分子的核苷酸序列,其与启动子激动性结合。
如本文所用,术语“多肽”、“肽”和“蛋白质”可互换使用,并且包括对氨基酸残基聚合物的引用。该术语不仅适用于天然氨基酸聚合物,而且适用于人工氨基酸聚合物,所述人工氨基酸聚合物是天然氨基酸的化学类似物,至少一个氨基酸残基与之对应。该术语也适用于含有保守氨基酸取代的聚合物,使得蛋白质可以保持激动性。
如本文所用,术语“宿主细胞”是指能够支持表达载体的复制或表达的细胞。宿主细胞可以是原核细胞,例如大肠杆菌,或者是真核细胞,例如酵母、昆虫、两栖或哺乳动物细胞。
关于肿瘤或癌症的生长或进展,术语“抑制”、“减小”和“减少”是指通过使用本领域已知的任何方法抑制患者的肿瘤或癌症的生长、扩散或转移,以至于达到可测量程度的量。例如,如果与共施用本发明的融合多肽和自然杀伤细胞(一种免疫细胞治疗剂)之前或施用融合多肽之前测量的肿瘤大小相比,肿瘤大小减小至少约10%、20%、30%、50%、80%或100%,则肿瘤或癌症的生长、进展或扩散被抑制、减小或减少。
本发明提供了一种融合多肽,其包含:结合肿瘤相关抗原的抗体或其片段;接头;和自然杀伤细胞诱导蛋白CXCL16。
根据本发明的融合多肽可以通过包含与肿瘤相关抗原结合的抗体或其片段而特异性地结合肿瘤的细胞表面,并且还可以通过CXCL16(即自然杀伤细胞诱导蛋白)将自然杀伤细胞诱导至靶向的肿瘤细胞内,所述自然杀伤细胞诱导蛋白在抗原-抗体结合后被切割并释放。
根据本发明的融合多肽通过包含与肿瘤相关抗原特异性结合的抗体或其片段与肿瘤靶向表面抗原结合。肿瘤靶向表面抗原在本领域是众所周知的,并且可以是例如间皮素、PD-L1、Her2、CD19、MUC1、EGFR、VEGFR、B7H1、B7H2、B7H3、BT-062、BTLA、CAIX、4-1BB、5T4、AGS-5或AGS-16,但不限于此。
与肿瘤相关抗原特异性结合的抗体或其片段包括单链Fv(scFv)、Fab、Fab'、F(ab')2、二硫键稳定的抗体等,尤其可以是单链Fv(scFv)。
可以根据本领域已知的制备方法制备与肿瘤相关抗原特异性结合的抗体或其片段。
在根据本发明的示例性实施方案中,抗体是单链Fv(scFv)。scFv抗体的VH和VL区包含一条单链,该链折叠形成的抗原结合位点与在双链抗体中存在的抗原结合位点相似。一旦折叠,单链抗体通过非共价相互作用而稳定。在一个更具体的示例性实施方案中,scFv通过重组形成。可以常规地制备本发明抗体的保守变体,并且在scFv片段中使用的保守变体将维持重要的氨基酸残基,这对于VH和VL区之间的精确折叠和稳定是必需的。
根据本发明的一个示例性实施方案,scFv是间皮素scFv,其具有由SEQ ID NO:1表示的氨基酸序列,特别地可以通过由SEQ ID NO:2表示的碱基序列编码。
根据本发明的其他示例性实施方案,scFv是PD-L1 scFv,其可以包含由SEQ IDNO:3表示的氨基酸序列的重链(VH),特别是通过SEQ ID NO:4表示的碱基序列编码;以及由SEQ ID NO:5表示的氨基酸序列的轻链(VL),特别是由SEQ ID NO:6表示的碱基序列编码;和肿瘤相关抗原,即PD-L1,可以通过SEQ ID NO:7表示的碱基序列编码,但不限于此。
根据本发明的其他示例性实施方案,scFv是Her2 scFv,其可以包含由SEQ ID NO:8表示的氨基酸序列的重链,特别是通过SEQ ID NO:9表示的碱基序列编码;以及由SEQ IDNO:10表示的氨基酸序列的轻链,特别是由SEQ ID NO:11表示的碱基序列编码;和肿瘤相关抗原,即Her2,可以通过SEQ ID NO:12表示的碱基序列编码,但不限于此。
根据本发明的其他示例性实施方案,scFv是CD19 scFv,其可以包含由SEQ ID NO:28表示的氨基酸序列的重链,特别是通过SEQ ID NO:29表示的碱基序列编码;以及由SEQID NO:30表示的氨基酸序列的轻链,特别是由SEQ ID NO:31表示的碱基序列编码,但不限于此。
根据本发明的其他示例性实施方案,scFv是MUC-1scFv,其可以包含由SEQ ID NO:32表示的氨基酸序列的重链,特别是通过SEQ ID NO:33表示的碱基序列编码;以及由SEQID NO:34表示的氨基酸序列的轻链,特别是由SEQ ID NO:35表示的碱基序列编码,但不限于此。
根据本发明的其他示例性实施方案,scFv是EGFR scFv,其可以包含由SEQ ID NO:36表示的氨基酸序列的重链,特别是通过SEQ ID NO:37表示的碱基序列编码;以及由SEQID NO:38表示的氨基酸序列的轻链,特别是由SEQ ID NO:39表示的碱基序列编码,但不限于此。
根据本发明的其他示例性实施方案,scFv是VEGFR scFv,其可以包含由SEQ IDNO:40表示的氨基酸序列的重链,特别是通过SEQ ID NO:41表示的碱基序列编码;以及由SEQ ID NO:42表示的氨基酸序列的轻链,特别是由SEQ ID NO:43表示的碱基序列编码,但不限于此。
scFv抗体可以通过轻链直接结合至肽接头,并且可以通过scFv结合的Fc区结合。
根据本发明的一个示例性实施方案,Fc(恒定区)可以具有SEQ ID NO:13的氨基酸序列,特别地可以通过SEQ ID NO:14表示的碱基序列编码,但不限于此。
除了作为肽接头与区域进行结合,或保留所述区域之间某些最小距离或其他空间关系外,根据本发明的接头不具有一定的生物学活性,但是可以选择组成型氨基酸以影响分子的某些特性,例如折叠、净电荷或疏水性。同样,接头可以包含切割序列,使得在抗体与肿瘤相关抗原结合后可以分离CXCL16。可通过肽接头连接特异性结合肿瘤相关抗原的抗体或其片段,所述肽接头具有至多50个氨基酸、通常至多40个氨基酸、优选至多30个氨基酸、更优选至多20个氨基酸、更优选1至10个氨基酸长度。
例如,肽接头可以包含被任何蛋白酶切割的序列,特别地可以是包含被弗林蛋白酶切割的RVKR连续氨基酸残基的肽接头,但不限于此。
根据本发明的一个示例性实施方案,根据本发明的融合多肽包含弗林蛋白酶切割位点,其被弗林蛋白酶切割,即,包含可以被弗林蛋白酶切割的连续氨基酸残基的弗林蛋白酶切割位点,使得可以从癌细胞中释放自然杀伤细胞诱导蛋白。
弗林蛋白酶切割位点可以是任何多肽位点,其可以通过弗林蛋白酶切割。如Duckert等人所报道(文献[Duckert等人,Protein Engineering,Design&Selection 17(1):107-112(2004)],其通过引用整体并入本文),弗林蛋白酶是一种酶,其是“基于进化保守的二碱基-和一碱基-特异性CA2+依赖性丝氨酸蛋白酶,也称为枯草杆菌蛋白酶/kexin样前蛋白水解酶”。
将该文献等中已知的弗林蛋白酶切割位点的序列并入本文,特别是具有SEQ IDNO:15的氨基酸序列,和可以通过SEQ ID NO:16表示的碱基序列编码,但不限于此。
与肿瘤相关抗原结合的抗体或其片段可以通过弗林蛋白酶切割位点的氨基末端与弗林蛋白酶切割序列结合,并且可以直接结合至抗体的轻链、重链、Fc(恒定区)或框架区。
本发明的融合蛋白包含自然杀伤细胞诱导蛋白CXCL16,从而本发明的融合蛋白可以诱导自然杀伤细胞进入肿瘤细胞,其具有结合肿瘤相关抗原的抗体。
根据本发明的“自然杀伤细胞诱导蛋白”是指用于诱导自然杀伤细胞进入肿瘤细胞的蛋白,即CXCL16,其是能够通过趋化因子使自然杀伤细胞迁移到癌细胞中的蛋白。
特别地,CXCL16可以具有SEQ ID NO:17的氨基酸序列。CXCL16可以通过SEQ IDNO:18的碱基序列编码。
自然杀伤细胞诱导蛋白可以通过肽接头与抗体或其片段连接。除了作为肽接头与区域进行结合或保留区域之间某些最小距离或其他空间关系以外,根据本发明的接头不具有一定的生物学活性,但是可以选择组成型氨基酸以影响分子的某些性质,例如折叠、净电荷或疏水性。同样,接头可以包含切割序列,例如,通过任何蛋白酶的切割序列,使得在抗体结合肿瘤相关抗原后可以分离CXCL16。
根据本发明的一个示例性实施方案,肽接头包含弗林蛋白酶切割位点,其被弗林蛋白酶切割,即,弗林蛋白酶切割位点包含连续的氨基酸残基,其可以被弗林蛋白酶切割。
根据本发明的融合多肽可以通过本领域已知的非重组方法或重组方法制备,优选地通过重组方法制备。
换句话说,可以通过将编码与肿瘤相关抗原结合的抗体或其片段的cDNA;接头;和自然杀伤细胞诱导蛋白CXCL16插入载体来制备表达载体。
根据本发明的一个示例性实施方案,通过将包含间皮素scFv和Fc的碱基序列插入载体,特别是pcDNA3.1载体,并通过在免疫球蛋白序列后插入弗林蛋白酶切割位点和编码自然杀伤细胞诱导蛋白的碱基序列来制备表达载体。制备的表达载体的示例如下图2所示。
可以在细菌、植物、酵母、昆虫和哺乳动物细胞中表达制备的表达载体。本领域技术人员可以通过使用许多表达系统来制备融合多肽,所述表达系统可以用于蛋白质表达,包括大肠杆菌、其他细菌宿主、酵母和各种高级真核细胞,例如COS、CHO、HeLa和骨髓瘤细胞系。
根据本发明的一个示例性实施方案,可以通过用表达载体转染去除了弗林蛋白酶的CHO细胞来制备融合多肽。
可以通过根据本领域的标准方法纯化制备的融合多肽,以提供靶向融合多肽,所述方法包括硫酸铵沉淀、亲和柱、柱色谱法等。
本发明提供了编码融合多肽的核酸。
本发明提供了表达载体,其包含编码融合多肽的核酸序列。特别地,本载体可以提供具有如图2所示的结构的表达载体,其可以具有SEQ ID NO:19的碱基序列。
本发明提供了包含表达载体的宿主细胞。特别地,这样的宿主细胞可以是选自COS、CHO、HeLa和骨髓瘤细胞系的一种细胞,但不限于此。
本发明提供了一种用于预防或治疗癌症的药物组合物,其包含融合多肽,所述融合多肽具有与肿瘤相关抗原结合的抗体或其片段;接头;和自然杀伤细胞诱导蛋白CXCL16。
根据本发明用于预防或治疗癌症的药物组合物是免疫细胞治疗剂,特别是其中该组合物通过将自然杀伤细胞诱导至癌症内对预防或治疗癌症具有显著的作用。根据本发明用于预防或治疗癌症的药物组合物不仅包括直接的治疗作用,而且还包括作为抗癌佐剂的作用。
根据本发明的一个示例性实施方案,已鉴定出,通过本发明制备的融合多肽的CXCL16,自然杀伤细胞的细胞分布从CD56暗变为CD56明,并且还鉴定出本发明的药物组合物通过分化成比CD56暗具有更高ADCC作用的CD56明而有效地预防或治疗癌症。
本发明还提供了一种用于预防或治疗癌症的药物组合物,其包含融合多肽和自然杀伤细胞,所述融合多肽具有与肿瘤相关抗原结合的抗体或其片段;接头;以及自然杀伤细胞诱导蛋白CXCL16。
根据本发明,融合多肽与自然杀伤细胞(一种免疫细胞治疗剂)共施用大大增加了自然杀伤细胞向癌症的流入,从而在预防或治疗癌症方面具有显著的效果。
可以通过使用至少一种生理上可接受的载体或赋形剂的标准技术,将本发明中使用的药物组合物配制成剂型。在本发明和文献中公开了合适的药物载体(Remington:TheScience and Practice of Pharmacy,第21版,University of the Sciences inPhiladelphia,Lippencott Williams&Wilkins(2005))。
可以将这种药物组合物配制成剂型,使得可以通过任何合适的途径施用本发明的融合多肽和/或自然杀伤细胞,例如吸入、局部、鼻、口服、肠胃外或直肠内途径。因此,上述药物组合物的施用可以通过皮内、皮下、静脉内、肌肉内、鼻内、吸入、脑内、气管内、动脉内、腹膜内、膀胱内、胸膜内、冠状动脉内、皮下或肿瘤内注射进行,或使用注射器或其他设备进行。还考虑经皮施用与吸入或气雾一起施用。片剂和胶囊可以口服、直肠或阴道施用。
药物组合物将包含融合多肽,或融合多肽和自然杀伤细胞,其通常溶解于药学上可接受的载体,优选水性载体中。融合多肽和自然杀伤细胞可以一起或分开提供。可以使用各种水性载体,例如缓冲盐水等。这种溶液具有杀菌性能,并且通常不具有不希望的物质。这种组合物可以通过常规的、众所周知的灭菌技术来灭菌。组合物可包含满足生理条件所需的药学上可接受的佐剂,例如pH调节剂和缓冲剂、毒性调节剂等,例如乙酸钠、氯化钠、氯化钾、氯化钙、乳酸钠等。这种剂型中的融合多肽的浓度可以广泛地变化,并且可以根据所选择的某些施用方式和患者需要,主要基于流体的体积、粘度、重量等选择。
本发明的药物组合物适合于肠胃外施用,包括静脉内或腔内施用。
可将本发明的融合多肽和/或自然杀伤细胞配制成通过注射(例如快速浓注或持续注射)进行肠胃外施用的剂型。用于注射的剂型可以与添加的防腐剂一起存在于单位剂型的容器中,例如安瓿或多剂量容器中。可注射组合物优选是等渗水溶液或悬浮液,栓剂优选由脂质乳剂或悬浮液制备。该组合物可以被灭菌和/或包含佐剂,例如,防腐剂、稳定剂、湿润剂或乳化剂、促溶剂、渗透调节盐和/或缓冲剂。另一方面,活性组分可以粉末形式存在,其在使用前通过合适的溶媒(例如无菌无致热源的水)制成。同样,活性组分可以包含其他治疗上有价值的物质。所述组合物分别根据常规的混合、制粒或包衣方法制备,并且包含约0.1至75%,优选1至50%的活性组分。
在口服施用的情况下,药物组合物或药物可以采取片剂或胶囊的形式,其例如通过常规手段与药学上可接受的赋形剂一起制备。优选地,这样的药物组合物或药物应该是含有活性组分的片剂和明胶胶囊,即本发明的组合物,与:(a)稀释剂或填充剂,例如乳糖、右旋糖、蔗糖、甘露醇、山梨醇、纤维素(例如乙基纤维素和微晶纤维素)、甘氨酸、果胶、聚丙烯酸酯和/或磷酸氢钙以及硫酸钙;(b)润滑剂,例如二氧化硅、滑石粉、硬脂酸、其镁或钙盐、硬脂酸金属盐、胶体二氧化硅、氢化植物油、玉米淀粉、苯甲酸钠、乙酸钠和/或聚乙二醇;另外,在片剂的情况下,(c)粘合剂,例如硅酸镁铝、淀粉糊、明胶、黄芪胶、甲基纤维素、羧甲基纤维素钠、聚乙烯吡咯烷酮和/或羟丙基甲基纤维素;在某些情况下,(d)崩解剂,例如淀粉(例如马铃薯淀粉或淀粉钠)、乙醇酸盐、琼脂、藻酸或其钠盐或泡腾混合物;(e)湿润剂,例如月桂基硫酸钠;(f)吸收剂、着色剂、增味剂和甜味剂。
本发明以治疗有效剂量向患者施用药物组合物,以预防、治疗或抑制疾病,如癌症或其恶性病症。药物组合物以足以从患者产生有效治疗或诊断反应的量施用于患者。有效治疗或诊断反应是指至少部分抑制或延迟疾病或恶性病症的症状或并发症的反应。用于进行这种施用的合适量定义为“治疗有效量”。
待施用的融合多肽和/或自然杀伤细胞的剂量根据哺乳动物的种类、体重、年龄、个体情况、待治疗区域的表面积和施用类型而变化。也可以根据伴随某种化合物的施用,特定患者的任何副作用的存在、性质和程度来确定剂量大小。
施用于约50至80kg哺乳动物(优选人)单位剂量可以包含约1mg/kg至5mg/kg量的融合多肽,并且可以包含约1x 105细胞/kg至2x 107细胞/kg量的自然杀伤细胞。
通常,本发明的组合物的剂量是足以实现靶向效应的足够剂量。通过测量融合多肽和/或自然杀伤细胞以及计算其在患者体内的积累,可以确定最佳的施用方案。可以每天、每周、每月或每年至少一次提供这种组合物。本领域技术人员可以容易地确定最佳剂量、施用方法和重复率。本领域技术人员可以根据本领域已知和本发明公开的既定方案,确定用于向人施用融合多肽和/或自然杀伤细胞的最佳施用方式。然而,应理解,应考虑各种相关因素如待治疗的疾病、疾病的严重程度、施用途径、患者的体重、年龄、性别等来确定有效组分的实际剂量,因此,该剂量并不解释为在任何方面限制本发明的范围。
本发明还提供了包含用于癌症治疗的融合多肽的组合物。
本发明还提供了融合多肽在制备用于癌症治疗的药物中的用途。
本发明还提供了融合多肽用于癌症治疗的用途。
本发明还提供了通过向患者施用药学有效量的包含融合多肽的组合物来治疗癌症的方法。癌症的治疗方法可以通过一起施用自然杀伤细胞来进行,由此显示出改善的治疗效果。
本发明的用途、组合物和治疗方法中提及的事项,如果彼此不矛盾,则等同适用。
有利效果
根据本发明用于预防或治疗癌症的融合蛋白包含融合多肽,所述融合多肽包含与肿瘤相关抗原结合的抗体或其片段;接头;和自然杀伤细胞诱导蛋白CXCL16,其中融合多肽与自然杀伤细胞(一种免疫细胞治疗剂)共施用,大大增加了自然杀伤细胞向表达某种抗原的癌症中的流入,从而对预防或治疗癌症具有显著的作用。
附图说明
图1是显示根据趋化因子类型鉴定的扩增的自然杀伤细胞迁移程度结果的图。
图2是显示用于制备根据本发明的融合多肽的表达载体的示意图。
图3是显示鉴定根据本发明制备的融合多肽通过间皮素识别位点识别并结合胰腺癌细胞系表面上存在的间皮素的结果的图。
图4是显示鉴定根据本发明制备的融合多肽通过PD-L1识别位点识别并结合胰腺癌细胞系表面上存在的PD-L1的结果的图。
图5是显示鉴定根据本发明制备的融合多肽通过Her2识别位点识别并结合胰腺癌细胞系表面上存在的Her2的结果的图。
图6是显示鉴定根据本发明制备的融合多肽结合胰腺癌细胞系以释放CXCL16的结果的图。
图7是显示鉴定使用本发明的融合多肽处理各种癌细胞系增加了自然杀伤细胞迁移能力的结果的图,所述本发明的融合多肽包含结合间皮素的抗体。
图8是显示鉴定使用本发明的融合多肽处理Panc-1细胞系增加了自然杀伤细胞流入的结果的图,所述本发明的融合多肽包含结合PD-L1的抗体。
图9是显示鉴定使用本发明的融合多肽处理HT-29细胞系增加了自然杀伤细胞流入的结果的图,所述本发明的融合多肽包含结合PD-L1的抗体。
图10是显示鉴定使用本发明的融合多肽处理Panc-1细胞系增加了自然杀伤细胞流入的结果的图,所述本发明的融合多肽包含结合Her2的抗体。
图11是显示鉴定使用本发明的融合多肽处理MCF7细胞系增加了自然杀伤细胞流入的结果的图,所述本发明的融合多肽包含结合Her2的抗体。
图12是显示鉴定使用本发明的融合多肽处理各种癌细胞系增加了自然杀伤细胞迁移能力的结果的图,所述本发明的融合多肽包含结合CD19的抗体。
图13是显示鉴定使用本发明的融合多肽处理各种癌细胞系增加了自然杀伤细胞迁移能力的结果的图,所述本发明的融合多肽包含结合MUC-1的抗体。
图14是显示鉴定使用本发明的融合多肽处理各种癌细胞系增加了自然杀伤细胞迁移能力的结果的图,所述本发明的融合多肽包含结合EGFR的抗体。
图15是显示鉴定使用本发明的融合多肽处理各种癌细胞系增加了自然杀伤细胞迁移能力的结果的图,所述本发明的融合多肽包含结合VEGFR的抗体。
图16是显示鉴定使用本发明的融合多肽处理各种癌细胞系增加了自然杀伤细胞侵袭能力的结果的图,所述本发明的融合多肽包含结合间皮素的抗体。
图17是显示鉴定使用本发明的融合多肽处理Panc-1细胞系增加了自然杀伤细胞侵袭能力的结果的图,所述本发明的融合多肽包含结合PD-L1的抗体。
图18是显示鉴定使用本发明的融合多肽处理HT-29细胞系增加了自然杀伤细胞侵袭能力的结果的图,所述本发明的融合多肽包含结合PD-L1的抗体。
图19是显示鉴定使用本发明的融合多肽处理Panc-1细胞系增加了自然杀伤细胞侵袭能力的结果的图,所述本发明的融合多肽包含结合Her2的抗体。
图20是显示鉴定使用本发明的融合多肽处理MCF7细胞系增加了自然杀伤细胞侵袭能力的结果的图,所述本发明的融合多肽包含结合Her2的抗体。
图21是显示鉴定使用本发明的融合多肽处理各种癌细胞系增加了自然杀伤细胞侵袭能力的结果的图,所述本发明的融合多肽包含结合CD19的抗体。
图22是显示鉴定使用本发明的融合多肽处理各种癌细胞系增加了自然杀伤细胞侵袭能力的结果的图,所述本发明的融合多肽包含结合MUC-1的抗体。
图23是显示鉴定使用本发明的融合多肽处理各种癌细胞系增加了自然杀伤细胞侵袭能力的结果的图,所述本发明的融合多肽包含结合EGFR的抗体。
图24是显示鉴定使用本发明的融合多肽处理各种癌细胞系增加了自然杀伤细胞侵袭能力的结果的图,所述本发明的融合多肽包含结合VEGFR的抗体。
图25是显示鉴定通过根据本发明制备的识别Her2的融合多肽(Her2 scFv NRP-体)增加了自然杀伤细胞侵袭能力的结果的图。
图26是显示通过施用本发明制备的融合多肽和自然杀伤细胞将自然杀伤细胞诱导进入癌组织的图。
图27是显示鉴定通过向移植胰腺癌的动物模型中施用根据本发明制备的间皮素scFv融合多肽以及自然杀伤细胞的治疗效果的结果的图。
图28是显示鉴定通过向移植胰腺癌的动物模型中施用根据本发明制备的PD-L1scFv融合多肽以及自然杀伤细胞的治疗效果的结果的图。
图29是显示鉴定通过向移植胰腺癌的动物模型中施用根据本发明制备的Her2scFv融合多肽以及自然杀伤细胞的治疗效果的结果的图。
图30是显示短时间用CXCL16和IL-2处理自然杀伤细胞后自然杀伤细胞分布变化的图。
图31是显示长时间用CXCL16和IL-2处理自然杀伤细胞后自然杀伤细胞分布变化的图。
图32是显示鉴定用根据本发明制备的融合多肽处理NK细胞后分布的CD56明 CD16+自然杀伤细胞导致细胞死亡增加的结果的图。
具体实施方式
在下文中,将通过优选的实施例详细描述本发明,以更好地理解本发明。然而,仅出于说明本发明的目的提供以下实施例,因此本发明不限于此。
<实施例1>通过趋化因子鉴定扩增的自然杀伤细胞的迁移
为了根据趋化因子类型鉴定扩增的自然杀伤细胞的迁移程度,收集扩增的NK细胞并以1,500rpm离心。然后,从其中除去上清液并用PBS洗涤,然后计数细胞数。作为趋化因子,将10nM CXCL9、CXCL10、CXCL11和CXCL16分配到Boyden室板的底层上,并将扩展的NK细胞以2x 105个细胞分配到Boyden室板的上层。之后,将所得细胞在CO2培养箱中于37℃培养2小时,然后从其收集底层并以1,500rpm离心。然后,进行PBS洗涤,然后在4℃下进行CD56-PE染色30分钟,并用PBS洗涤。对于FAC分析,将50ul计数明亮绝对计数珠(Count BrightAbsolute Counting Beads(Invitrogen)分配于其上,并进行FACS分析。
其结果示于图1。
如图1鉴定,已鉴定与其他趋化因子类型相比,CXCL16对扩增的自然杀伤细胞迁移显示出显著影响。
<实施例2>融合多肽[NK细胞募集蛋白(NRP)-体]的制备和纯化
制备了重组载体,其结合以下:用于识别癌症靶向抗原的scFv序列;用作接头的弗林蛋白酶序列;用于以最高效率诱导自然杀伤细胞流入的CXCL16(NK细胞募集蛋白;NRP)。
图2显示了特定重组载体的结构,该重组载体结合用于识别靶抗原间皮素的scFv序列。
用Sfi1酶将pcDNA3.1载体分解两个小时,并纯化以制备用于连接的载体。为了制备间皮素scFv,通过基于如下表1所示的引物序列的PCR进行扩增,得到SEQ ID NO:2的间皮素scFv碱基序列,然后,将载体、插入样品和T4连接酶混合在一起,并在25℃下培养2小时,以在载体和插入之间进行连接。将所得产物插入pcDNA3.1载体的Sfi1酶位点。
[表1]
制备间皮素scFv的引物序列
为了制备PD-L1 scFv,通过基于如下表2所示的引物序列的PCR进行扩增,以获得包含SEQ ID NO:4的重链和SEQ ID NO:6的轻链的PD-L1 scFv碱基序列,然后,相较于其中结合有间皮素scFv的所述载体的制备方法,通过相同的方法进行载体和插入之间的连接,从而将所得产物插入到pcDNA3.1载体的Sfi1酶位点中。
[表2]
制备PD-L1 scFv的引物序列
为了制备Her2 scFv,通过基于如下表3所示的引物序列的PCR进行扩增,以获得包含SEQ ID NO:9的重链和SEQ ID NO:11的轻链的Her2 scFv碱基序列,然后,相较于其中结合有间皮素scFv的所述载体的制备方法,通过相同的方法进行载体和插入之间的连接,从而将所得产物插入到pcDNA3.1载体的Sfi1酶位点中。
[表3]
制备Her2 scFv的引物序列
另外,为了制备CD19、MUC-1、EFGR和VEGFR scFv,基于各scFv的氨基酸序列,在scFv的碱基序列上进行合成(包含SEQ ID NO:29的重链和SEQ ID NO:31的轻链的CD19scFv;包含SEQ ID NO:33的重链和SEQ ID NO:35的轻链的MUC-1scFv;包含SEQ ID NO:37的重链和SEQ ID NO:39的轻链的EGFR scFv;和包含SEQ ID NO:41的重链和SEQ ID NO:43的轻链的VEGFR scFv),然后,相较于其中结合有间皮素scFv的所述载体的制备方法,通过相同的方法进行载体和插入之间的连接,从而将所得产物插入到pcDNA3.1载体的Sfi1酶位点中。
通过基于如下表4所示的引物序列的PCR扩增CXCL16和弗林蛋白酶切割位点,使用载体中存在的免疫球蛋白后的Not1酶位点。用Not1酶分解其中插入识别靶抗原的scFv的载体2小时,纯化,然后将载体、插入(即CXCL16样品)和连接酶混合在一起,在25℃下培养两个小时,以进行载体和插入之间的连接。
[表4]
制备CXCL16和弗林蛋白酶切割位点的引物序列
通过用制备的表达载体转染去除了弗林蛋白酶的CHO(中国仓鼠卵巢)细胞来大量生产融合多肽(NRP-体)。将用所述表达载体转染的CHO细胞在150mm平板中培养,然后在滚瓶培养箱中培养72小时,然后从中收集。离心收集的培养液,然后使用AKTA蛋白纯化系统(GE Healthcare Life Sciences)的蛋白A-琼脂糖柱仅纯化其上清液,从而产生融合多肽。
<实施例3>鉴定融合多肽与抗原的结合
将以上实施例2中制备的识别间皮素的融合多肽(间皮素scFv NRP-体)(0.1-2μg/ml)分配至2×105个Panc-1细胞,其为胰腺癌细胞系,并在4℃下培养20分钟。之后,从中收集细胞并用PBS洗涤,之后将结合了FITC的FC抗体(1μl/ml)分配于其上,并在4℃下培养20分钟。之后,再次从中收集细胞,然后用PBS洗涤,然后通过FACS进行分析。
其结果示于图3。
如图3鉴定,鉴定出通过上述实施例2中制备的融合多肽的间皮素识别位点识别存在于胰腺癌细胞系表面的间皮素,从而使融合多肽与细胞表面结合。
另外,即便当抗原识别位点不同时,为了鉴定本发明的融合多肽与靶细胞系表面的结合,在与所述间皮素scFv融合多肽的抗原结合实验相同的条件下,还在PD-L1 scFv融合多肽和Her2 scFv融合多肽上进行了FACS分析,所述PD-L1 scFv融合多肽和Her2 scFv融合多肽在上述实施例2中制备,其结果如图4(PD-L1 scFv NRP-体)和图5(Her2 scFv NRP-体)所示。
如图4和图5所鉴定,鉴定了PD-L1 scFv NRP-体和Her2 scFv NRP-体分别通过抗原识别位点识别存在于胰腺癌细胞系表面的PD-L1或Her2,融合多肽特异性结合细胞表面,因此鉴定了本发明的融合多肽,其中特异性结合靶抗原的抗体可以根据靶肿瘤相关抗原而不同得以应用。
<实施例4>CXCL16释放特性的鉴定
通过人CXCL16 ELISA,鉴定了上述实施例2中制备的融合多肽(NRP-体)的弗林蛋白酶切割位点是否被癌细胞系的弗林蛋白酶切割,并释放CXCL16。
根据R&D系统的人CXCL16 ELISA试剂盒(#DCX160)的方法进行CXCL16ELISA。为了进行ELISA分析,将间皮素scFv融合多肽(间皮素scFv NRP-体)以0.5μg/mL的量、50μl/孔分配至96孔板进行ELISA(R&D),在室温下静置两个小时,以便将得到的吸收结果用于该分析。洗涤所述板,然后以200μl/孔的量向其中添加过氧化物酶标记的二抗,并在室温下静置两个小时。用Tween-PBS洗涤所述板,然后向其中加入ABTS底物溶液以进行显色,从而使用板读数器在OD415nm处测量吸光度。
其结果示于图6。
如图6中所鉴定,已鉴定出融合多肽(NRP-体)与胰腺癌细胞系(即Panc-1)的间皮素结合,然后,由癌细胞的弗林蛋白酶切割所述融合多肽的弗林蛋白酶切割位点,从而释放CXCL16。
<实施例5>从融合多肽释放的CXCL16增加自然杀伤细胞的迁移能力(流入)的鉴定
使用Boyden室系统鉴定上述实施例2中制备的融合多肽是否识别并结合表达靶抗原的癌症,然后释放用于诱导自然杀伤细胞流入的蛋白质CXCL16,以增加自然杀伤细胞的流入。
HPDE、Panc-1(ATCC,Cat.CRL-1469)、HCT116(ATCC,Cat.CCL-247)、MCF7(ATCC,Cat.HTB-22)和HT-29(ATCC,Cat.HTB-38)细胞系以2×105分配到Boyden室测定板(FisherScientific,#07-200-155)的底层上,并在37℃、CO2培养箱中培养2小时。将间皮素scFv-融合多肽以1μg/ml的量分配到上述各细胞系,在37℃、CO2培养箱中培养4小时。自然杀伤细胞用CFSE(BioLegend,#RUO 423801)标记,然后以2x 105分配到上层,然后在37℃、CO2培养箱中培养4小时。之后,从底层收集细胞,并通过FACS鉴定CFSE标记的自然杀伤细胞的分布。
其结果示于图7。
如图7所鉴定,鉴定出从间皮素scFv融合多肽释放的CXCL16增加人扩增的自然杀伤细胞的迁移能力,并且进一步鉴定出自然杀伤细胞流入的增加程度根据癌细胞系类型的不同而变化。
另外,将所述实施例2中制备的PD-L1 scFv融合多肽和Her2 scFv融合多肽分配到Panc-1、HT-29或MCF7细胞系,由此在与所述间皮素scFv融合多肽相同的实验条件下,通过Boyden室系统鉴定出NK细胞的流入增加,其结果如图8(PD-L1 scFv NRP-体用于Panc-1)、图9(PD-L1 NRP-体用于HT-29)、图10(Her2NRP-体用于Panc-1)和图11(Her2 scFv NRP-体用于MCF7)所示。
如图8至11所鉴定,与间皮素scFv融合多肽类似地,已鉴定出从各融合多肽释放的CXCL16增加人扩增的NK细胞的迁移能力。
另外,将上述实施例2中制备的CD-19、MUC-1、EGFR和VEGFR scFv融合多肽分配到HPDE、K562(ATCC,Cat.CCL-243)、HCT116(ATCC,Cat.CCL-247)、Panc-1(ATCC,Cat.CRL-1469)或MCF7(ATCC,Cat.HTB-22)细胞系,由此在与所述间皮素scFv融合多肽实验相同的条件下、通过Boyden室系统鉴定出NK细胞的流入是否增加,其结果分别示于图12(CD19 scFvNRP-体)、图13(MUC-1scFv NRP-体)、图14(EGFR scFv NRP-体)和图15(VEGFR scFv NRP-体)。
如图12至15所鉴定,鉴定出从融合多肽释放的CXCL16增加人扩增的NK细胞的迁移能力,并且进一步鉴定出自然杀伤细胞流入的增加程度根据癌细胞系类型的不同而变化。
<实施例6>从融合多肽释放的CXCL16引起的自然杀伤细胞侵袭能力的鉴定
使用侵袭测定法来鉴定上述实施例2中制备的各融合多肽是否识别并结合癌细胞上表达的靶抗原,然后释放用于诱导自然杀伤细胞流入的蛋白质CXCL16,以增加自然杀伤细胞向癌细胞内的侵袭能力。
具体地,将HPDE、Panc-1、HCT116、MCF7、HT-29和K562细胞系以2×105分配到Boyden室测定板(Fisher Scientific,#07-200-155)的底层上,并在37℃、CO2培养箱中培养2小时,然后将实施例2中制备的融合多肽以1μg/ml的量分配到上述各细胞系。用matrigel(BD,#354234)处理上层,然后将自然杀伤细胞以2×105分配到其上,并在37℃、CO2培养箱中培养48小时。之后,从其收集上层并用结晶紫染色一小时,之后从上层的三个部分随机拍摄照片,从而通过图像J程序测量自然杀伤细胞的侵袭能力。
各融合多肽的结果分别示于图16至24。
如图16至图24所鉴定,鉴定出从融合多肽释放的CXCL16增加人扩增的NK细胞的侵袭性,并且进一步鉴定出自然杀伤细胞侵袭能力的增加程度根据癌细胞系类型的不同而变化。
<实施例7>通过递增引入自然杀伤细胞诱导癌细胞系死亡的鉴定
鉴定了关于自然杀伤细胞对诱导癌细胞系死亡的抗体依赖性细胞毒性(ADCC)的功效,所述自然杀伤细胞在从上述实施例2中制备的融合多肽释放CXCL16后递增引入。
将Panc-1细胞系以2x 105分配到96孔板,并在37℃、CO2培养箱中培养2小时。用1μg/ml量的间皮素scFv融合多肽处理靶细胞,并在37℃、CO2培养箱中培养2小时。将2×105自然杀伤细胞加入其中,设置靶细胞和效应细胞的比例为1:1,并在37℃、CO2培养箱中培养4小时。从其中收集细胞,然后用PBS洗涤,然后用膜联蛋白V(1μg/ml)和PI(1μg/ml)染色30分钟,然后用FACS分析。
其结果示于图25。
如图25所鉴定,已鉴定出自然杀伤细胞显著增加癌细胞的死亡,所述自然杀伤细胞在CXCL16释放后递增引入。
<实施例8>融合多肽在患有移植癌症的动物模型中的治疗功效的鉴定
将实施例2中制备的融合多肽注射到患有移植癌症的动物模型中,以鉴定其在体内的作用。
对于体内实验,使用了六周龄的雌性NSG(NOD.Cg-PrkdcscidIl2rgtm1wjl/SzJ)小鼠。小鼠的管理是在韩国生物科学与生物技术研究所实验室动物资源中心的动物护理委员会的授权下进行的。将Panc-1注射到小鼠胰腺中,然后两周形成肿瘤,并以五天的间隔腹腔内注射间皮素、PD-L1或Her2 scFv融合多肽(5mg/kg)。
对于肿瘤生长的实验,静脉内注射量为1x 107/小鼠的自然杀伤细胞。对于肿瘤生长(表达荧光素酶的Panc-1的生长)的观察,通过使用IVIS Living Image 3.0程序进行观察。对于自然杀伤细胞迁移能力的实验,静脉内注射量为1x107/小鼠的DiR染色的自然杀伤细胞,并用IVIS荧光图像程序和FACS观察。
其结果示于图26至29。图26显示了施用上述实施例2中制备的融合多肽和自然杀伤细胞,诱导自然杀伤细胞进入癌组织,图27、28和29显示了鉴定的间皮素scFv NRP-体、PD-L1 scFv NRP-体和Her2 scFv NRP-体分别与自然杀伤细胞一起施用的治疗效果的结果。
如图26的A所鉴定,NRP-体大大增加了自然杀伤细胞向癌组织的流入。如图26的B所示,仅添加NRP-体发生这种激动作用。
同样,如图27至29所鉴定,将实施例2中制备的融合多肽与自然杀伤细胞一起施用的情况下,肿瘤生长被显著抑制,并且自然杀伤细胞向肿瘤组织的迁移大大增加。
由以上结果可知,鉴定出本发明的融合多肽增加作为免疫细胞治疗剂的自然杀伤细胞的流入,从而显示对癌症治疗的显著效果。
<实施例9>由CXCL16处理引起的自然杀伤细胞特征变化的鉴定
为了鉴定从融合多肽释放的CXCL16引起的自然杀伤细胞的特征变化,分别以200U和100nM的浓度的促进自然杀伤细胞生长的IL-2和CXCL16处理自然杀伤细胞,持续0、1、2、8或16小时,通过FACS鉴定CD56暗和CD56明的分布,其结果示于图30,并且右上角正方形中的细胞表示CD56明细胞。
如图30所鉴定,已经鉴定出通过CXCL16处理,随时间的流逝导致细胞分布从CD56暗变为CD56明。
另外,以与上述实验方法类似的方式,长时间(14天)同时进行IL-2和CXCL16的处理,之后鉴定CD56表达的变化,其结果示于图31。
如图31所鉴定,在一起给予IL2和CXCL16的实验组中鉴定出向CD56明细胞的改变(图31的A中IL-2+CXCL16和图31的B中CXCL16)。
根据以上结果,鉴定出CXCL16将CD56暗变为具有强ADCC作用的CD56明,从而对自然杀伤细胞的特征产生影响。
<实施例10>由融合多肽(NRP-体)处理引起自然杀伤细胞的特性变化
根据CXCL16所致的自然杀伤细胞分布改变,已鉴定出诱导癌细胞死亡的ADCC功效变化。
将Panc-1细胞系以2x 105分配到96孔板,并在37℃、CO2培养箱中培养2小时。将自然杀伤细胞以2×105添加至其中,设置靶细胞和效应细胞的比例为1:1,并在37℃、CO2培养箱中培养4小时。从其中收集细胞,然后用PBS洗涤,然后用膜联蛋白V(1μg/ml)和PI(1μg/ml)染色30分钟,然后用FACS分析。
其结果示于图32。
如图32所鉴定,已鉴定出通过融合多肽的CXCL16增加的CD56明CD16+自然杀伤细胞,增加了癌细胞的死亡。
<110> 韩国生命工学研究院
<120> 激活NK细胞的融合蛋白、NK细胞和包含其的药物组合物
<130> P18013-KRI
<150> KR 10/2017/0043988
<151> 2017-04-05
<160> 43
<170> KoPatentIn 3.0
<210> 1
<211> 242
<212> PRT
<213> 人工序列
<220>
<223> 间皮素scFV
<400> 1
Met Gln Val Gln Leu Gln Gln Ser Gly Pro Glu Leu Glu Lys Pro Gly
1 5 10 15
Ala Ser Val Lys Ile Ser Cys Lys Ala Ser Gly Tyr Ser Phe Thr Gly
20 25 30
Tyr Thr Met Asn Trp Val Lys Gln Ser His Gly Lys Ser Leu Glu Trp
35 40 45
Ile Gly Leu Ile Thr Pro Tyr Asn Gly Ala Ser Ser Tyr Asn Gln Lys
50 55 60
Phe Arg Gly Lys Ala Thr Leu Thr Val Asp Lys Ser Ser Ser Thr Ala
65 70 75 80
Tyr Met Asp Leu Leu Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Phe
85 90 95
Cys Ala Arg Gly Gly Tyr Asp Gly Arg Gly Phe Asp Tyr Trp Gly Gln
100 105 110
Gly Thr Thr Val Thr Val Ser Ser Gly Val Gly Gly Ser Gly Gly Gly
115 120 125
Gly Ser Gly Gly Gly Gly Ser Asp Ile Glu Leu Thr Gln Ser Pro Ala
130 135 140
Ile Met Ser Ala Ser Pro Gly Glu Lys Val Thr Met Thr Cys Ser Ala
145 150 155 160
Ser Ser Ser Val Ser Tyr Met His Trp Tyr Gln Gln Lys Ser Gly Thr
165 170 175
Ser Pro Lys Arg Trp Ile Tyr Asp Thr Ser Lys Leu Ala Ser Gly Val
180 185 190
Pro Gly Arg Phe Ser Gly Ser Gly Ser Gly Asn Ser Tyr Ser Leu Thr
195 200 205
Ile Ser Ser Val Glu Glu Ala Glu Asp Asp Ala Thr Tyr Tyr Cys Gln
210 215 220
Gln Trp Ser Gly Tyr Pro Leu Thr Phe Gly Ala Gly Thr Lys Leu Glu
225 230 235 240
Ile Lys
<210> 2
<211> 723
<212> DNA
<213> 人工序列
<220>
<223> 间皮素scFV
<400> 2
atgcaggtac aactgcagca gtctgggcct gagctggaga agcctggcgc ttcagtgaag 60
atatcctgca aggcttctgg ttactcattc actggctaca ccatgaactg ggtgaagcag 120
agccatggaa agagccttga gtggattgga cttattactc cttacaatgg tgcttctagc 180
tacaaccaga agttcagggg caaggccaca ttaactgtag acaagtcatc cagcacagcc 240
tacatggacc tcctcagtct gacatctgaa gactctgcag tctatttctg tgcaaggggg 300
ggttacgacg ggaggggttt tgactactgg ggccaaggga ccacggtcac cgtctcctca 360
ggtgtaggcg gttcaggcgg cggtggctct ggcggtggcg gatcggacat cgagctcact 420
cagtctccag caatcatgtc tgcatctcca ggggagaagg tcaccatgac ctgcagtgcc 480
agctcaagtg taagttacat gcactggtac cagcagaagt caggcacctc ccccaaaaga 540
tggatttatg acacatccaa actggcttct ggagtcccag gtcgcttcag tggcagtggg 600
tctggaaact cttactctct cacaatcagc agcgtggagg ctgaagatga tgcaacttat 660
tactgccagc agtggagtgg ttaccctctc acgttcggtg ctgggacaaa gttggaaata 720
aaa 723
<210> 3
<211> 118
<212> PRT
<213> 人工序列
<220>
<223> PD-L1scFV重链
<400> 3
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr
20 25 30
Asp Val His Trp Val Arg Gln Ala Pro Gly Gln Arg Leu Glu Trp Met
35 40 45
Gly Trp Leu His Ala Asp Thr Gly Ile Thr Lys Phe Ser Gln Lys Phe
50 55 60
Gln Gly Arg Val Thr Ile Thr Arg Asp Thr Ser Ala Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Glu Arg Ile Gln Leu Trp Phe Asp Tyr Trp Gly Gln Gly Thr
100 105 110
Leu Val Thr Val Ser Ser
115
<210> 4
<211> 354
<212> DNA
<213> 人工序列
<220>
<223> PD-L1scFV重链
<400> 4
caggtccaac ttgtgcagtc tggggctgag gtgaagaagc ctggggcctc agtgaaggtt 60
tcctgcaagg cttctggata caccttcact agctatgatg tacattgggt gcgccaggcc 120
cccggacaaa ggcttgagtg gatgggatgg ctccacgctg acactggtat cacaaaattt 180
tcacagaagt tccagggcag agtcaccatt accagggaca catccgcgag cacagcctac 240
atggagctga gcagcctgag atctgaagac acggctgtgt attactgtgc gagggagagg 300
atacagctat ggtttgacta ctggggccag ggaaccctgg tcaccgtctc ctca 354
<210> 5
<211> 107
<212> PRT
<213> 人工序列
<220>
<223> PD-L1scFV轻链
<400> 5
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Gly Ile Ser Ser Trp
20 25 30
Leu Ala Trp Tyr Gln Gln Lys Pro Glu Lys Ala Pro Lys Ser Leu Ile
35 40 45
Tyr Ala Ala Ser Ser Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Tyr Asn Ser Tyr Pro Tyr
85 90 95
Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys
100 105
<210> 6
<211> 321
<212> DNA
<213> 人工序列
<220>
<223> PD-L1scFV轻链
<400> 6
gacatccaga tgacccagtc tccatcctca ctgtctgcat ctgtaggaga cagagtcacc 60
atcacttgtc gggcgagtca gggtattagc agctggttag cctggtatca gcagaaacca 120
gagaaagccc ctaagtccct gatctatgct gcatccagtt tgcaaagtgg ggtcccatca 180
aggttcagcg gcagtggatc tgggacagat ttcactctca ccatcagcag cctgcagcct 240
gaagattttg caacttatta ctgccaacag tataatagtt acccgtacac ttttggccag 300
gggaccaagc tggagatcaa a 321
<210> 7
<211> 1353
<212> DNA
<213> 人工序列
<220>
<223> PD-L1
<400> 7
aacataaccg gacagagcca ccaccctaca ggtcttcctc agagatcagc ttctgctcga 60
attccacgag gctggctcct ccacgcagca cggtcacttt tgtgccggtg ccgaacactc 120
tggtgctgct gcttgtgtag ctgctgcagt agtagtcggc ctcgtcctcg gcctgcagtc 180
cgctgatggt caggctggcg gtgttgccgc tcttgctgcc gctgaatctg ttggacacgc 240
cgctgggccg gttggacacg tcgtagatca tcagcttggg ggccttgccg gggtgctgct 300
gataccagga cacgtagttg tagccgccca cgtcgctgct ggtgcctgtg cagctgatgg 360
tgatgctctg gccagggctg ccggacacgc tggcaggctg tgtcagggcg ctctgggaac 420
ccacaccgct ggatccaccg gagcctcctc cgccactacc tcctcctccg aggcccccga 480
ggccagagga cacggtgacc agggtgccct ggccccagta gtccacggtg gtcacggtgc 540
ccagcttgat ccgggcgcag tagtacacgg cggtgtcctc ggcccgcagg ctgttcatct 600
gcaggtacag ggtgttcttg ctgttgtccc ggctgatggt gaaccggccc ttcacggtgt 660
cggcgtagaa ggtgatgccg ccgctggggt agatgctgga cacccattcc aggcccttgc 720
caggggcctg tcggacccac atcatgatat agctgctgaa tgtgaagccg ctggcggcgc 780
aagacagtct caggctgccg ccaggctgca ccagtcctcc gccgctttcc agcagctgca 840
cctcggccat ggccggctgg gccgcgagta ataacaatcc agcggctgcc gtaggcaata 900
ggtatttcat gatttgccct cgttatctag aaattcgtaa tcatggtcat agctgtttcc 960
tgtgtgaaat tgttatccgc tcacaattcc acacaacata cgagccggaa gcataaagtg 1020
taaagcctgg ggtgcctaat gagtgagcta actcacatta attgcgttga ggtgggctgc 1080
aaaacaaaac ggcctcctgt caggaagccg cttttatcgg gtaccgctca ctggccgctt 1140
tccagtcggg aaacctgtct tgccagctgc attaatgaat cggccaaccc ccggggaaaa 1200
ggcggttttc gttttggggg cccagggggg tttttttttt tccccgggga acgggggaca 1260
acctgatatg ccctttaccg cctgggcccc ggaaaaaatt taaaaaaagg ggccacccct 1320
ggtttgcccc acaagggaaa aaacttgtgt ttg 1353
<210> 8
<211> 120
<212> PRT
<213> 人工序列
<220>
<223> Her2scFV重链
<400> 8
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Asn Ile Lys Asp Thr
20 25 30
Tyr Ile His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Arg Ile Tyr Pro Thr Asn Gly Tyr Thr Arg Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Ala Asp Thr Ser Lys Asn Thr Ala Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Asx Tyr Tyr Cys
85 90 95
Ser Arg Trp Gly Gly Asp Gly Phe Tyr Ala Met Asp Val Trp Gly Gln
100 105 110
Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 9
<211> 363
<212> DNA
<213> 人工序列
<220>
<223> Her2scFV重链
<400> 9
atggaggttc agctggtgga gtctggcggt ggcctggtgc agccaggggg ctcactccgt 60
ttgtcctgtg cagcttctgg cttcaacatt aaagacacct atatacactg ggtgcgtcag 120
gccccgggta agggcctgga atgggttgca aggatttatc ctacgaatgg ttatactaga 180
tatgccgata gcgtcaaggg ccgtttcact ataagcgcag acacatccaa aaacacagcc 240
tacctgcaga tgaacagcct gcgtgctgag gacactgccg tctattattg ttctagatgg 300
ggaggggacg gcttctatgc tatggacgtg tggggtcaag gaaccctggt caccgtctcc 360
tcg 363
<210> 10
<211> 107
<212> PRT
<213> 人工序列
<220>
<223> Her2scFV轻链
<400> 10
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Asp Val Asn Thr Ala
20 25 30
Val Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Ser Ala Ser Phe Leu Glu Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Arg Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln His Tyr Thr Thr Pro Pro
85 90 95
Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys
100 105
<210> 11
<211> 321
<212> DNA
<213> 人工序列
<220>
<223> Her2scFV轻链
<400> 11
gatatccaga tgacccagtc cccgagctcc ctgtccgcct ctgtgggcga tagggtcacc 60
atcacctgcc gtgccagtca ggatgtgaat actgctgtag cctggtatca acagaaacca 120
ggaaaagctc cgaaactact gatttactcg gcatccttcc tcgagtctgg agtcccttct 180
cgcttctctg gatccagatc tgggacggat ttcactctga ccatcagcag tctgcagccg 240
gaagacttcg caacttatta ctgtcagcaa cattatacta ctcctcccac gttcggacag 300
ggtaccaagg tggagatcaa a 321
<210> 12
<211> 3768
<212> DNA
<213> 人工序列
<220>
<223> Her2
<400> 12
atggagctgg cggccttgtg ccgctggggg ctcctcctcg ccctcttgcc ccccggagcc 60
gcgagcaccc aagtgtgcac cggcacagac atgaagctgc ggctccctgc cagtcccgag 120
acccacctgg acatgctccg ccacctctac cagggctgcc aggtggtgca gggaaacctg 180
gaactcacct acctgcccac caatgccagc ctgtccttcc tgcaggatat ccaggaggtg 240
cagggctacg tgctcatcgc tcacaaccaa gtgaggcagg tcccactgca gaggctgcgg 300
attgtgcgag gcacccagct ctttgaggac aactatgccc tggccgtgct agacaatgga 360
gacccgctga acaataccac ccctgtcaca ggggcctccc caggaggcct gcgggagctg 420
cagcttcgaa gcctcacaga gatcttgaaa ggaggggtct tgatccagcg gaacccccag 480
ctctgctacc aggacacgat tttgtggaag gacatcttcc acaagaacaa ccagctggct 540
ctcacactga tagacaccaa ccgctctcgg gcctgccacc cctgttctcc gatgtgtaag 600
ggctcccgct gctggggaga gagttctgag gattgtcaga gcctgacgcg cactgtctgt 660
gccggtggct gtgcccgctg caaggggcca ctgcccactg actgctgcca tgagcagtgt 720
gctgccggct gcacgggccc caagcactct gactgcctgg cctgcctcca cttcaaccac 780
agtggcatct gtgagctgca ctgcccagcc ctggtcacct acaacacaga cacgtttgag 840
tccatgccca atcccgaggg ccggtataca ttcggcgcca gctgtgtgac tgcctgtccc 900
tacaactacc tttctacgga cgtgggatcc tgcaccctcg tctgccccct gcacaaccaa 960
gaggtgacag cagaggatgg aacacagcgg tgtgagaagt gcagcaagcc ctgtgcccga 1020
gtgtgctatg gtctgggcat ggagcacttg cgagaggtga gggcagttac cagtgccaat 1080
atccaggagt ttgctggctg caagaagatc tttgggagcc tggcatttct gccggagagc 1140
tttgatgggg acccagcctc caacactgcc ccgctccagc cagagcagct ccaagtgttt 1200
gagactctgg aagagatcac aggttaccta tacatctcag catggccgga cagcctgcct 1260
gacctcagcg tcttccagaa cctgcaagta atccggggac gaattctgca caatggcgcc 1320
tactcgctga ccctgcaagg gctgggcatc agctggctgg ggctgcgctc actgagggaa 1380
ctgggcagtg gactggccct catccaccat aacacccacc tctgcttcgt gcacacggtg 1440
ccctgggacc agctctttcg gaacccgcac caagctctgc tccacactgc caaccggcca 1500
gaggacgagt gtgtgggcga gggcctggcc tgccaccagc tgtgcgcccg agggcactgc 1560
tggggtccag ggcccaccca gtgtgtcaac tgcagccagt tccttcgggg ccaggagtgc 1620
gtggaggaat gccgagtact gcaggggctc cccagggagt atgtgaatgc caggcactgt 1680
ttgccgtgcc accctgagtg tcagccccag aatggctcag tgacctgttt tggaccggag 1740
gctgaccagt gtgtggcctg tgcccactat aaggaccctc ccttctgcgt ggcccgctgc 1800
cccagcggtg tgaaacctga cctctcctac atgcccatct ggaagtttcc agatgaggag 1860
ggcgcatgcc agccttgccc catcaactgc acccactcct gtgtggacct ggatgacaag 1920
ggctgccccg ccgagcagag agccagccct ctgacgtcca tcgtctctgc ggtggttggc 1980
attctgctgg tcgtggtctt gggggtggtc tttgggatcc tcatcaagcg acggcagcag 2040
aagatccgga agtacacgat gcggagactg ctgcaggaaa cggagctggt ggagccgctg 2100
acacctagcg gagcgatgcc caaccaggcg cagatgcgga tcctgaaaga gacggagctg 2160
aggaaggtga aggtgcttgg atctggcgct tttggcacag tctacaaggg catctggatc 2220
cctgatgggg agaatgtgaa aattccagtg gccatcaaag tgttgaggga aaacacatcc 2280
cccaaagcca acaaagaaat cttagacgaa gcatacgtga tggctggtgt gggctcccca 2340
tatgtctccc gccttctggg catctgcctg acatccacgg tgcagctggt gacacagctt 2400
atgccctatg gctgcctctt agaccatgtc cgggaaaacc gcggacgcct gggctcccag 2460
gacctgctga actggtgtat gcagattgcc aaggggatga gctacctgga ggatgtgcgg 2520
ctcgtacaca gggacttggc cgctcggaac gtgctggtca agagtcccaa ccatgtcaaa 2580
attacagact tcgggctggc tcggctgctg gacattgacg agacagagta ccatgcagat 2640
gggggcaagg tgcccatcaa gtggatggcg ctggagtcca ttctccgccg gcggttcacc 2700
caccagagtg atgtgtggag ttatggtgtg actgtgtggg agctgatgac ttttggggcc 2760
aaaccttacg atgggatccc agcccgggag atccctgacc tgctggaaaa gggggagcgg 2820
ctgccccagc cccccatctg caccattgat gtctacatga tcatggtcaa atgttggatg 2880
attgactctg aatgtcggcc aagattccgg gagttggtgt ctgaattctc ccgcatggcc 2940
agggaccccc agcgctttgt ggtcatccag aatgaggact tgggcccagc cagtcccttg 3000
gacagcacct tctaccgctc actgctggag gacgatgaca tgggggacct ggtggatgct 3060
gaggagtatc tggtacccca gcagggcttc ttctgtccag accctgcccc gggcgctggg 3120
ggcatggtcc accacaggca ccgcagctca tctaccagga gtggcggtgg ggacctgaca 3180
ctagggctgg agccctctga agaggaggcc cccaggtctc cactggcacc ctccgaaggg 3240
gctggctccg atgtatttga tggtgacctg ggaatggggg cagccaaggg gctgcaaagc 3300
ctccccacac atgaccccag ccctctacag cggtacagtg aggaccccac agtacccctg 3360
ccctctgaga ctgatggcta cgttgccccc ctgacctgca gcccccagcc tgaatatgtg 3420
aaccagccag atgttcggcc ccagccccct tcgccccgag agggccctct gcctgctgcc 3480
cgacctgctg gtgccactct ggaaagggcc aagactctct ccccagggaa gaatggggtc 3540
gtcaaagacg tttttgcctt tgggggtgcc gtggagaacc ccgagtactt gacaccccag 3600
ggaggagctg cccctcagcc ccaccctcct cctgccttca gcccagcctt cgacaacctc 3660
tattactggg accaggaccc accagagcgg ggggctccac ccagcacctt caaagggaca 3720
cctacggcag agaacccaga gtacctgggt ctggacgtgc cagtgtga 3768
<210> 13
<211> 235
<212> PRT
<213> 人工序列
<220>
<223> FC
<400> 13
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 Phe 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 Ile Leu Gln Ile Ser Ile Thr Leu
225 230 235
<210> 14
<211> 705
<212> DNA
<213> 人工序列
<220>
<223> FC
<400> 14
gacaaaactc acacatgccc accgtgccca gcacctgaac tcctgggggg accgtcagtc 60
ttcctcttcc ccccaaaacc caaggacacc ctcatgatct cccggacccc tgaggtcaca 120
tgcgtggtgg tggacgtgag ccacgaagac cctgaggtca agttcaactg gtacgtggac 180
ggcgtggagg tgcataatgc caagacaaag cggcgggagg agcagtacaa cagcacgtac 240
cgtgtggtca gcgtcctcac cgtcctgcac caggactggc tgaatggcaa ggagtacaag 300
tgcaaggtct ccaacaaagc cctcccagcc cccatcgaga aaaccatctc caaagccaaa 360
gggcagcccc gagaaccaca ggtgtacacc ctgcccccat cccgggatga gctgaccaag 420
aaccaggtca gcctgacctg cctggtcaaa ggcttctatc ccagcgacat cgccgtggag 480
tgggagagca atgggcagcc ggagaacaac tacaagacca cgcctcccgt gctggactcc 540
gacggctcct tcttcttcta cagcaagctc accgtggaca agagcaggtg gcagcagggg 600
aacgtcttct catgctccgt gatgcatgag gctctgcaca accactacac gcagaagagc 660
ctctccctgt ctccgggtaa aattctgcag atatccatca cactg 705
<210> 15
<211> 4
<212> PRT
<213> 人工序列
<220>
<223> 弗林蛋白酶
<400> 15
Arg Val Lys Arg
1
<210> 16
<211> 13
<212> DNA
<213> 人工序列
<220>
<223> 弗林蛋白酶
<400> 16
acgggtgaag cgg 13
<210> 17
<211> 89
<212> PRT
<213> 人工序列
<220>
<223> CXCL16
<400> 17
Asn Glu Gly Ser Val Thr Gly Ser Cys Tyr Cys Gly Lys Arg Ile Ser
1 5 10 15
Ser Asp Ser Pro Pro Ser Val Gln Phe Met Asn Arg Leu Arg Lys His
20 25 30
Leu Arg Ala Tyr His Arg Cys Leu Tyr Tyr Thr Arg Phe Gln Leu Leu
35 40 45
Ser Trp Ser Val Cys Gly Gly Asn Lys Asp Pro Trp Val Gln Glu Leu
50 55 60
Met Ser Cys Leu Asp Leu Lys Glu Cys Gly His Ala Tyr Ser Gly Ile
65 70 75 80
Val Ala His Gln Lys His Leu Leu Pro
85
<210> 18
<211> 270
<212> DNA
<213> 人工序列
<220>
<223> CXCL16
<400> 18
aacgagggca gcgtcactgg aagttgttat tgtggtaaaa gaatttcttc cgactccccg 60
ccatcggttc agttcatgaa tcgtctccgg aaacacctga gagcttacca tcggtgtcta 120
tactacacga ggttccagct cctttcctgg agcgtgtgtg gaggcaacaa ggacccatgg 180
gttcaggaat tgatgagctg tcttgatctc aaagaatgtg gacatgctta ctcggggatt 240
gtggcccacc agaagcattt acttccttag 270
<210> 19
<211> 8748
<212> DNA
<213> 人工序列
<220>
<223> 融合蛋白表达载体
<400> 19
gacggatcgg gagatctccc gatcccctat ggtcgactct cagtacaatc tgctctgatg 60
ccgcatagtt aagccagtat ctgctccctg cttgtgtgtt ggaggtcgct gagtagtgcg 120
cgagcaaaat ttaagctaca acaaggcaag gcttgaccga caattgcatg aagaatctgc 180
ttagggttag gcgttttgcg ctgcttcgcg atgtacgggc cagatatacg cgttgacatt 240
gattattgac tagttattaa tagtaatcaa ttacggggtc attagttcat agcccatata 300
tggagttccg cgttacataa cttacggtaa atggcccgcc tggctgaccg cccaacgacc 360
cccgcccatt gacgtcaata atgacgtatg ttcccatagt aacgccaata gggactttcc 420
attgacgtca atgggtggac tatttacggt aaactgccca cttggcagta catcaagtgt 480
atcatatgcc aagtacgccc cctattgacg tcaatgacgg taaatggccc gcctggcatt 540
atgcccagta catgacctta tgggactttc ctacttggca gtacatctac gtattagtca 600
tcgctattac catggtgatg cggttttggc agtacatcaa tgggcgtgga tagcggtttg 660
actcacgggg atttccaagt ctccacccca ttgacgtcaa tgggagtttg ttttggcacc 720
aaaatcaacg ggactttcca aaatgtcgta acaactccgc cccattgacg caaatgggcg 780
gtaggcgtgt acggtgggag gtctatataa gcagagctct ctggctaact agagaaccca 840
ctgcttactg gcttatcgaa attaatacga ctcactatag ggagacccaa gcttggtacc 900
gagctcggat ccatgggatg gagctatatc atcctctttt tggtagcaac agctacagat 960
gtccactcgg cccagccggc catggccgac caggtacaga tgcagctggt agagtctggg 1020
gctgaagtga agaagcctgg ggcttcagtg aagctgtcct gcaaggcttc tggctacacc 1080
ttcagcagct actggatgca ctgggtgcgc caggcccctg gacaacgcct tgagtggatg 1140
ggagagatta atcctggcaa cggtcatact aactacaacg agaagttcaa gtcacgcgtg 1200
acaatcactg tagacaaatc cgcgagcaca gcctacatgg agctcagcag cctgagatct 1260
gagaacacgg cggtctatta ctgtgcaaga tcttttacta cggcacgggc gtttgcttac 1320
tggggccaag ggactctggt caccgtctcc tcaggcctcg gatgcaggta caactgcagc 1380
agtctgggcc tgagctggag aagcctggcg cttcagtgaa gatatcctgc aaggcttctg 1440
gttactcatt cactggctac accatgaact gggtgaagca gagccatgga aagagccttg 1500
agtggattgg acttattact ccttacaatg gtgcttctag ctacaaccag aagttcaggg 1560
gcaaggccac attaactgta gacaagtcat ccagcacagc ctacatggac ctcctcagtc 1620
tgacatctga agactctgca gtctatttct gtgcaagggg gggttacgac gggaggggtt 1680
ttgactactg gggccaaggg accacggtca ccgtctcctc aggtgtaggc ggttcaggcg 1740
gcggtggctc tggcggtggc ggatcggaca tcgagctcac tcagtctcca gcaatcatgt 1800
ctgcatctcc aggggagaag gtcaccatga cctgcagtgc cagctcaagt gtaagttaca 1860
tgcactggta ccagcagaag tcaggcacct cccccaaaag atggatttat gacacatcca 1920
aactggcttc tggagtccca ggtcgcttca gtggcagtgg gtctggaaac tcttactctc 1980
tcacaatcag cagcgtggag gctgaagatg atgcaactta ttactgccag cagtggagtg 2040
gttaccctct cacgttcggt gctgggacaa agttggaaat aaaagggccc atcggccggt 2100
gggccctggt gccgcgcggc agcgctagcg acaaaactca cacatgccca ccgtgcccag 2160
cacctgaact cctgggggga ccgtcagtct tcctcttccc cccaaaaccc aaggacaccc 2220
tcatgatctc ccggacccct gaggtcacat gcgtggtggt ggacgtgagc cacgaagacc 2280
ctgaggtcaa gttcaactgg tacgtggacg gcgtggaggt gcataatgcc aagacaaagc 2340
ggcgggagga gcagtacaac agcacgtacc gtgtggtcag cgtcctcacc gtcctgcacc 2400
aggactggct gaatggcaag gagtacaagt gcaaggtctc caacaaagcc ctcccagccc 2460
ccatcgagaa aaccatctcc aaagccaaag ggcagccccg agaaccacag gtgtacaccc 2520
tgcccccatc ccgggatgag ctgaccaaga accaggtcag cctgacctgc ctggtcaaag 2580
gcttctatcc cagcgacatc gccgtggagt gggagagcaa tgggcagccg gagaacaact 2640
acaagaccac gcctcccgtg ctggactccg acggctcctt cttcttctac agcaagctca 2700
ccgtggacaa gagcaggtgg cagcagggga acgtcttctc atgctccgtg atgcatgagg 2760
ctctgcacaa ccactacacg cagaagagcc tctccctgtc tccgggtaaa attctgcaga 2820
tatccatcac actggcggcc gcacgggtga agcggaacga gggcagcgtc actggaagtt 2880
gttattgtgg taaaagaatt tcttccgact ccccgccatc ggttcagttc atgaatcgtc 2940
tccggaaaca cctgagagct taccatcggt gtctatacta cacgaggttc cagctccttt 3000
cctggagcgt gtgtggaggc aacaaggacc catgggttca ggaattgatg agctgtcttg 3060
atctcaaaga atgtggacat gcttactcgg ggattgtggc ccaccagaag catttacttc 3120
cttaggcggc cgctcgagat tccgcccctc tccctccccc ccccctaacg ttactggccg 3180
aagccgcttg gaataaggcc ggtgtgcgtt tgtctatatg tgattttcca ccatattgcc 3240
gtcttttggc aatgtgaggg cccggaaacc tggccctgtc ttcttgacga gcattcctag 3300
gggtctttcc cctctcgcca aaggaatgca aggtctgttg aatgtcgtga aggaagcagt 3360
tcctctggaa gcttcttgaa gacaaacaac gtctgtagcg accctttgca ggcagcggaa 3420
ccccccacct ggcgacaggt gcctctgcgg ccaaaagcca cgtgtataag atacacctgc 3480
aaaggcggca caaccccagt gccacgttgt gagttggata gttgtggaaa gagtcaaatg 3540
gctctcctca agcgtattca acaaggggct gaaggatgcc cagaaggtac cccattgtat 3600
gggatctgat ctggggcctc ggtgcacatg ctttacatgt gtttagtcga ggttaaaaaa 3660
acgtctaggc cccccgaacc acggggacgt ggttttcctt tgaaaaacat cgatgataat 3720
atggttcgac cattgaactg catcgtcgcc gtgtcccaaa atatggggat tggcaagaac 3780
ggagacctac cctggcctcc gctcaggaac gagttcaagt acttccaaag aatgaccaca 3840
acctcttcag tggaaggtaa acagaatctg gtgattatgg gtaggaaaac ctggttctcc 3900
attcctgaga agaatcgacc tttaaaggac agaatcaata tagttctcag tagagaactc 3960
aaagaaccac cacgaggagc tcattttctt gccaaaagtt tggatgatgc cttaagactt 4020
attgaacaac cggaattggc aagtaaagta gacatggttt ggatagtcgg aggcagttct 4080
gtttaccagg aagccatgaa tcaaccaggc cacctcagac tctttgtgac aaggatcatg 4140
caggaatttg aaagtgacac gtttttccca gaaattgatt tggggaaata taaacttctc 4200
ccagaatacc caggcgtcct ctctgaggtc caggaggaaa aaggcatcaa gtataagttt 4260
gaagtctacg agaagaaaga ctaatctaga gggccctatt ctatagtgtc acctaaatgc 4320
tagagctcgc tgatcagcct cgactgtgcc ttctagttgc cagccatctg ttgtttgccc 4380
ctcccccgtg ccttccttga ccctggaagg tgccactccc actgtccttt cctaataaaa 4440
tgaggaaatt gcatcgcatt gtctgagtag gtgtcattct attctggggg gtggggtggg 4500
gcaggacagc aagggggagg attgggaaga caatagcagg catgctgggg atgcggtggg 4560
ctctatggct tctgaggcgg aaagaaccag ctggggctct agggggtatc cccacgcgcc 4620
ctgtagcggc gcattaagcg cggcgggtgt ggtggttacg cgcagcgtga ccgctacact 4680
tgccagcgcc ctagcgcccg ctcctttcgc tttcttccct tcctttctcg ccacgttcgc 4740
cggctttccc cgtcaagctc taaatcgggg catcccttta gggttccgat ttagtgcttt 4800
acggcacctc gaccccaaaa aacttgatta gggtgatggt tcacgtagtg ggccatcgcc 4860
ctgatagacg gtttttcgcc ctttgacgtt ggagtccacg ttctttaata gtggactctt 4920
gttccaaact ggaacaacac tcaaccctat ctcggtctat tcttttgatt tataagggat 4980
tttggggatt tcggcctatt ggttaaaaaa tgagctgatt taacaaaaat ttaacgcgaa 5040
ttaattctgt ggaatgtgtg tcagttaggg tgtggaaagt ccccaggctc cccaggcagg 5100
cagaagtatg caaagcatgc atctcaatta gtcagcaacc aggtgtggaa agtccccagg 5160
ctccccagca ggcagaagta tgcaaagcat gcatctcaat tagtcagcaa ccatagtccc 5220
gcccctaact ccgcccatcc cgcccctaac tccgcccagt tccgcccatt ctccgcccca 5280
tggctgacta atttttttta tttatgcaga ggccgaggcc gcctctgcct ctgagctatt 5340
ccagaagtag tgaggaggct tttttggagg cctaggcttt tgcaaaaagc tcccgggagc 5400
ttgtatatcc attttcggat ctgatcaaga gacaggatga ggatcgtttc gcatgattga 5460
acaagatgga ttgcacgcag gttctccggc cgcttgggtg gagaggctat tcggctatga 5520
ctgggcacaa cagacaatcg gctgctctga tgccgccgtg ttccggctgt cagcgcaggg 5580
gcgcccggtt ctttttgtca agaccgacct gtccggtgcc ctgaatgaac tgcaggacga 5640
ggcagcgcgg ctatcgtggc tggccacgac gggcgttcct tgcgcagctg tgctcgacgt 5700
tgtcactgaa gcgggaaggg actggctgct attgggcgaa gtgccggggc aggatctcct 5760
gtcatctcac cttgctcctg ccgagaaagt atccatcatg gctgatgcaa tgcggcggct 5820
gcatacgctt gatccggcta cctgcccatt cgaccaccaa gcgaaacatc gcatcgagcg 5880
agcacgtact cggatggaag ccggtcttgt cgatcaggat gatctggacg aagagcatca 5940
ggggctcgcg ccagccgaac tgttcgccag gctcaaggcg cgcatgcccg acggcgagga 6000
tctcgtcgtg acccatggcg atgcctgctt gccgaatatc atggtggaaa atggccgctt 6060
ttctggattc atcgactgtg gccggctggg tgtggcggac cgctatcagg acatagcgtt 6120
ggctacccgt gatattgctg aagagcttgg cggcgaatgg gctgaccgct tcctcgtgct 6180
ttacggtatc gccgctcccg attcgcagcg catcgccttc tatcgccttc ttgacgagtt 6240
cttctgagcg ggactctggg gttcgaaatg accgaccaag cgacgcccaa cctgccatca 6300
cgagatttcg attccaccgc cgccttctat gaaaggttgg gcttcggaat cgttttccgg 6360
gacgccggct ggatgatcct ccagcgcggg gatctcatgc tggagttctt cgcccacccc 6420
aacttgttta ttgcagctta taatggttac aaataaagca atagcatcac aaatttcaca 6480
aataaagcat ttttttcact gcattctagt tgtggtttgt ccaaactcat caatgtatct 6540
tatcatgtct gtataccgtc gacctctagc tagagcttgg cgtaatcatg gtcatagctg 6600
tttcctgtgt gaaattgtta tccgctcaca attccacaca acatacgagc cggaagcata 6660
aagtgtaaag cctggggtgc ctaatgagtg agctaactca cattaattgc gttgcgctca 6720
ctgcccgctt tccagtcggg aaacctgtcg tgccagctgc attaatgaat cggccaacgc 6780
gcggggagag gcggtttgcg tattgggcgc tcttccgctt cctcgctcac tgactcgctg 6840
cgctcggtcg ttcggctgcg gcgagcggta tcagctcact caaaggcggt aatacggtta 6900
tccacagaat caggggataa cgcaggaaag aacatgtgag caaaaggcca gcaaaaggcc 6960
aggaaccgta aaaaggccgc gttgctggcg tttttccata ggctccgccc ccctgacgag 7020
catcacaaaa atcgacgctc aagtcagagg tggcgaaacc cgacaggact ataaagatac 7080
caggcgtttc cccctggaag ctccctcgtg cgctctcctg ttccgaccct gccgcttacc 7140
ggatacctgt ccgcctttct cccttcggga agcgtggcgc tttctcaatg ctcacgctgt 7200
aggtatctca gttcggtgta ggtcgttcgc tccaagctgg gctgtgtgca cgaacccccc 7260
gttcagcccg accgctgcgc cttatccggt aactatcgtc ttgagtccaa cccggtaaga 7320
cacgacttat cgccactggc agcagccact ggtaacagga ttagcagagc gaggtatgta 7380
ggcggtgcta cagagttctt gaagtggtgg cctaactacg gctacactag aaggacagta 7440
tttggtatct gcgctctgct gaagccagtt accttcggaa aaagagttgg tagctcttga 7500
tccggcaaac aaaccaccgc tggtagcggt ggtttttttg tttgcaagca gcagattacg 7560
cgcagaaaaa aaggatctca agaagatcct ttgatctttt ctacggggtc tgacgctcag 7620
tggaacgaaa actcacgtta agggattttg gtcatgagat tatcaaaaag gatcttcacc 7680
tagatccttt taaattaaaa atgaagtttt aaatcaatct aaagtatata tgagtaaact 7740
tggtctgaca gttaccaatg cttaatcagt gaggcaccta tctcagcgat ctgtctattt 7800
cgttcatcca tagttgcctg actccccgtc gtgtagataa ctacgatacg ggagggctta 7860
ccatctggcc ccagtgctgc aatgataccg cgagacccac gctcaccggc tccagattta 7920
tcagcaataa accagccagc cggaagggcc gagcgcagaa gtggtcctgc aactttatcc 7980
gcctccatcc agtctattaa ttgttgccgg gaagctagag taagtagttc gccagttaat 8040
agtttgcgca acgttgttgc cattgctaca ggcatcgtgg tgtcacgctc gtcgtttggt 8100
atggcttcat tcagctccgg ttcccaacga tcaaggcgag ttacatgatc ccccatgttg 8160
tgcaaaaaag cggttagctc cttcggtcct ccgatcgttg tcagaagtaa gttggccgca 8220
gtgttatcac tcatggttat ggcagcactg cataattctc ttactgtcat gccatccgta 8280
agatgctttt ctgtgactgg tgagtactca accaagtcat tctgagaata gtgtatgcgg 8340
cgaccgagtt gctcttgccc ggcgtcaata cgggataata ccgcgccaca tagcagaact 8400
ttaaaagtgc tcatcattgg aaaacgttct tcggggcgaa aactctcaag gatcttaccg 8460
ctgttgagat ccagttcgat gtaacccact cgtgcaccca actgatcttc agcatctttt 8520
actttcacca gcgtttctgg gtgagcaaaa acaggaaggc aaaatgccgc aaaaaaggga 8580
ataagggcga cacggaaatg ttgaatactc atactcttcc tttttcaata ttattgaagc 8640
atttatcagg gttattgtct catgagcgga tacatatttg aatgtattta gaaaaataaa 8700
caaatagggg ttccgcgcac atttccccga aaagtgccac ctgacgtc 8748
<210> 20
<211> 34
<212> DNA
<213> 人工序列
<220>
<223> 间皮素scFV正向引物
<400> 20
ggcccagccg gccatgcagg tacaactgca gcag 34
<210> 21
<211> 39
<212> DNA
<213> 人工序列
<220>
<223> 间皮素scFV反向引物
<400> 21
ggcccttggt ggaggcactc gagacggtga ccagggttc 39
<210> 22
<211> 36
<212> DNA
<213> 人工序列
<220>
<223> PD-L1scFV正向引物
<400> 22
ggcccagccg gccatgcagg tccaacttgt gcagtc 36
<210> 23
<211> 30
<212> DNA
<213> 人工序列
<220>
<223> PD-L1scFV反向引物
<400> 23
ggcccttggt ggaccaagct ggagatcaaa 30
<210> 24
<211> 33
<212> DNA
<213> 人工序列
<220>
<223> Her2scFV正向引物
<400> 24
ggcccagccg gccatggagg ttcagctggt gga 33
<210> 25
<211> 28
<212> DNA
<213> 人工序列
<220>
<223> Her2scFV反向引物
<400> 25
ggcccttggt accaaggtgg agatcaaa 28
<210> 26
<211> 39
<212> DNA
<213> 人工序列
<220>
<223> CXCL16,弗林蛋白酶切割位点正向引物
<400> 26
cacactggcg gccgcacggg tgaagcggaa cgagggcag 39
<210> 27
<211> 40
<212> DNA
<213> 人工序列
<220>
<223> CXCL16,弗林蛋白酶切割位点反向引物
<400> 27
aatctcgagc ggccgcctaa ggaagtaaat gcttctggtg 40
<210> 28
<211> 119
<212> PRT
<213> 人工序列
<220>
<223> CD19scFV重链
<400> 28
Gln Val Gln Leu Gln Gln Ser Gly Pro Glu Leu Val Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Ile Ser Cys Lys Ala Ser Gly Tyr Ala Phe Ser Ser Ser
20 25 30
Trp Met Asn Trp Val Lys Gln Arg Pro Gly Lys Gly Leu Glu Trp Ile
35 40 45
Gly Arg Ile Tyr Pro Gly Asp Glu Asp Thr Asn Tyr Ser Gly Lys Phe
50 55 60
Lys Asp Lys Ala Thr Leu Thr Ala Asp Lys Ser Ser Thr Thr Ala Tyr
65 70 75 80
Met Gln Leu Ser Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Phe Cys
85 90 95
Ala Arg Ser Leu Leu Tyr Gly Asp Tyr Leu Asp Tyr Trp Gly Gln Gly
100 105 110
Thr Thr Leu Thr Val Ser Ser
115
<210> 29
<211> 357
<212> DNA
<213> 人工序列
<220>
<223> CD19scFV重链
<400> 29
caggtgcagc tgcagcagag cggcccggaa ctggtgaaac cgggcgcgag cgtgaaaatt 60
agctgcaaag cgagcggcta tgcgtttagc agcagctgga tgaactgggt gaaacagcgc 120
ccgggcaaag gcctggaatg gattggccgc atttatccgg gcgatgaaga taccaactat 180
agcggcaaat ttaaagataa agcgaccctg accgcggata aaagcagcac caccgcgtat 240
atgcagctga gcagcctgac cagcgaagat agcgcggtgt atttttgcgc gcgcagcctg 300
ctgtatggcg attatctgga ttattggggc cagggcacca ccctgaccgt gagcagc 357
<210> 30
<211> 107
<212> PRT
<213> 人工序列
<220>
<223> CD19scFV轻链
<400> 30
Gln Ile Val Leu Thr Gln Ser Pro Ala Ile Met Ser Ala Ser Pro Gly
1 5 10 15
Glu Lys Val Thr Met Thr Cys Ser Ala Ser Ser Ser Val Ser Tyr Met
20 25 30
His Trp Tyr Gln Gln Lys Ser Gly Thr Ser Pro Lys Arg Trp Ile Tyr
35 40 45
Asp Thr Ser Lys Leu Ala Ser Gly Val Pro Asp Arg Phe Ser Gly Ser
50 55 60
Gly Ser Gly Thr Ser Tyr Phe Leu Thr Ile Asn Asn Met Glu Ala Glu
65 70 75 80
Asp Ala Ala Thr Tyr Tyr Cys Gln Gln Trp Asn Ile Asn Pro Leu Thr
85 90 95
Phe Gly Ala Gly Thr Lys Leu Glu Leu Lys Arg
100 105
<210> 31
<211> 321
<212> DNA
<213> 人工序列
<220>
<223> CD19scFV轻链
<400> 31
cagattgtgc tgacccagag cccggcgatt atgagcgcga gcccgggcga aaaagtgacc 60
atgacctgca gcgcgagcag cagcgtgagc tatatgcatt ggtatcagca gaaaagcggc 120
accagcccga aacgctggat ttatgatacc agcaaactgg cgagcggcgt gccggatcgc 180
tttagcggca gcggcagcgg caccagctat tttctgacca ttaacaacat ggaagcggaa 240
gatgcggcga cctattattg ccagcagtgg aacattaacc cgctgacctt tggcgcgggc 300
accaaactgg aactgaaacg c 321
<210> 32
<211> 118
<212> PRT
<213> 人工序列
<220>
<223> MCU-1scFV重链
<400> 32
Gln Val Lys Leu Gln Gln Ser Gly Thr Glu Val Val Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Leu Ser Cys Lys Ala Ser Gly Tyr Ile Phe Thr Ser Tyr
20 25 30
Asp Ile Asp Trp Val Arg Gln Thr Pro Glu Gln Gly Leu Glu Trp Ile
35 40 45
Gly Trp Ile Phe Pro Gly Glu Gly Ser Thr Glu Tyr Asn Glu Lys Phe
50 55 60
Lys Gly Arg Ala Thr Leu Ser Val Asp Lys Ser Ser Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Thr Arg Leu Thr Ser Glu Asp Ser Ala Val Tyr Phe Cys
85 90 95
Ala Arg Gly Asp Tyr Tyr Arg Arg Tyr Phe Asp Leu Trp Gly Gln Gly
100 105 110
Thr Thr Val Thr Val Ser
115
<210> 33
<211> 353
<212> DNA
<213> 人工序列
<220>
<223> MCU-1scFV重链
<400> 33
caggtgaaac tgcagcagag cggcaccgaa gtggtgaaac cgggcgcgag cgtgaaactg 60
agctgcaaag cgagcggcta tatttttacc agctatgata ttgattgggt gcgccagacc 120
ccggaacagg gcctggatgg attggctgga tttttccggg cgaaggcagc accgaatata 180
acgaaaaatt taaaggccgc gcgaccctga gcgtggataa aagcagcagc accgcgtata 240
tggaactgac ccgcctgacc agcgaagata gcgcggtgta tttttgcgcg cgcggcgatt 300
attatcgccg ctattttgat ctgtggggcc agggcaccac cgtgaccgtg agc 353
<210> 34
<211> 109
<212> PRT
<213> 人工序列
<220>
<223> MCU-1scFV轻链
<400> 34
Asp Ile Glu Leu Thr Gln Ser Pro Ala Ile Met Ser Ala Ser Pro Gly
1 5 10 15
Glu Arg Val Thr Met Thr Cys Ser Ala Ser Ser Ser Ile Arg Tyr Ile
20 25 30
Tyr Trp Tyr Gln Gln Lys Pro Gly Ser Ser Pro Arg Leu Leu Tyr Asp
35 40 45
Thr Ser Asn Val Ala Pro Gly Val Pro Phe Arg Phe Ser Gly Ser Gly
50 55 60
Ser Gly Thr Ser Tyr Ser Leu Thr Ile Asn Arg Met Glu Ala Glu Asp
65 70 75 80
Ala Ala Thr Tyr Tyr Cys Gln Glu Trp Ser Gly Tyr Pro Tyr Thr Phe
85 90 95
Gly Gly Gly Thr Lys Leu Glu Leu Lys Arg Ala Ala Ala
100 105
<210> 35
<211> 327
<212> DNA
<213> 人工序列
<220>
<223> MCU-1scFV轻链
<400> 35
gatattgaac tgacccagag cccggcgatt atgagcgcga gcccgggcga acgcgtgacc 60
atgacctgca gcgcgagcag cagcattcgc tatatttatt ggtatcagca gaaaccgggc 120
agcagcccgc gcctgctgta tgataccagc aacgtggcgc cgggcgtgcc gtttcgcttt 180
agcggcagcg gcagcggcac cagctatagc ctgaccatta accgcatgga agcggaagat 240
gcggcgacct attattgcca ggaatggagc ggctatccgt atacctttgg cggcggcacc 300
aaactggaac tgaaacgcgc ggcggcg 327
<210> 36
<211> 129
<212> PRT
<213> 人工序列
<220>
<223> EGFRscFV重链
<400> 36
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Glu
1 5 10 15
Ser Leu Lys Ile Ser Cys Lys Gly Ser Gly Tyr Ser Phe Thr Ser Tyr
20 25 30
Trp Leu Ala Trp Val Arg Gln Met Pro Gly Lys Gly Leu Glu Tyr Met
35 40 45
Gly Leu Ile Tyr Pro Gly Asp Ser Asp Thr Lys Tyr Ser Pro Ser Phe
50 55 60
Gln Gly Gln Val Thr Ile Ser Val Asp Lys Ser Val Ser Thr Ala Tyr
65 70 75 80
Leu Gln Trp Ser Ser Leu Lys Pro Ser Asp Ser Ala Val Tyr Phe Cys
85 90 95
Ala Arg His Asp Val Gly Tyr Cys Ser Ser Ser Asn Cys Ala Lys Trp
100 105 110
Pro Glu Tyr Phe Gln His Trp Gly Gln Gly Thr Leu Val Thr Val Ser
115 120 125
Ser
<210> 37
<211> 387
<212> DNA
<213> 人工序列
<220>
<223> EGFRscFV重链
<400> 37
caggtgcagc tggtgcagag cggcgcggaa gtgaaaaaac cgggcgaaag cctgaaaatt 60
agctgcaaag gcagcggcta tagctttacc agctattggc tggcgtgggt gcgccagatg 120
ccgggcaaag gcctggaata tatgggcctg atttatccgg gcgatagcga taccaaatat 180
agcccgagct ttcagggcca ggtgaccatt agcgtggata aaagcgtgag caccgcgtat 240
ctgcagtgga gcagcctgaa accgagcgat agcgcggtgt atttttgcgc gcgccatgat 300
gtgggctatt gcagcagcag caactgcgcg aaatggccgg aatattttca gcattggggc 360
cagggcaccc tggtgaccgt gagcagc 387
<210> 38
<211> 111
<212> PRT
<213> 人工序列
<220>
<223> EGFRscFV轻链
<400> 38
Gln Ser Val Leu Thr Gln Pro Pro Ser Val Ser Ala Ala Pro Gly Gln
1 5 10 15
Lys Val Thr Ile Ser Cys Ser Gly Ser Ser Ser Asn Ile Gly Asn Asn
20 25 30
Tyr Val Ser Trp Tyr Gln Gln Leu Pro Gly Thr Ala Pro Lys Leu Leu
35 40 45
Ile Tyr Gly His Thr Asn Arg Pro Ala Gly Val Pro Asp Arg Phe Ser
50 55 60
Gly Ser Lys Ser Gly Thr Ser Ala Ser Leu Ala Ile Ser Gly Phe Arg
65 70 75 80
Ser Glu Asp Glu Ala Asp Tyr Tyr Cys Ala Ala Trp Asp Asp Ser Leu
85 90 95
Ser Gly Trp Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu Gly
100 105 110
<210> 39
<211> 333
<212> DNA
<213> 人工序列
<220>
<223> EGFRscFV轻链
<400> 39
cagagcgtgc tgacccagcc gccgagcgtg agcgcggcgc cgggccagaa agtgaccatt 60
agctgcagcg gcagcagcag caacattggc aacaactatg tgagctggta tcagcagctg 120
ccgggcaccg cgccgaaact gctgatttat ggccatacca accgcccggc gggcgtgccg 180
gatcgcttta gcggcagcaa aagcggcacc agcgcgagcc tggcgattag cggctttcgc 240
agcgaagatg aagcggatta ttattgcgcg gcgtgggatg atagcctgag cggctgggtg 300
tttggcggcg gcaccaaact gaccgtgctg ggc 333
<210> 40
<211> 227
<212> PRT
<213> 人工序列
<220>
<223> VEGFRscFV重链
<400> 40
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Ile Ser Asp Tyr
20 25 30
Trp Ile His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Gly Ile Thr Pro Ala Gly Gly Tyr Thr Tyr Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Ala Asp Thr Ser Lys Asn Thr Ala Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Phe Val Phe Phe Leu Pro Tyr Ala Met Asp Tyr Trp Gly Gln
100 105 110
Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val
115 120 125
Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala
130 135 140
Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser
145 150 155 160
Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val
165 170 175
Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro
180 185 190
Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys
195 200 205
Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp
210 215 220
Lys Thr His
225
<210> 41
<211> 681
<212> DNA
<213> 人工序列
<220>
<223> VEGFRscFV重链
<400> 41
gaagtgcagc tggtggaaag cggcggcggc ctggtgcagc cgggcggcag cctgcgcctg 60
agctgcgcgg cgagcggctt taccattagc gattattgga ttcattgggt gcgccaggcg 120
ccgggcaaag gcctggaatg ggtggcgggc attaccccgg cgggcggcta tacctattat 180
gcggatagcg tgaaaggccg ctttaccatt agcgcggata ccagcaaaaa caccgcgtat 240
ctgcagatga acagcctgcg cgcggaagat accgcggtgt attattgcgc gcgctttgtg 300
ttttttctgc cgtatgcgat ggattattgg ggccagggca ccctggtgac cgtgagcagc 360
gcgagcacca aaggcccgag cgtgtttccg ctggcgccga gcagcaaaag caccagcggc 420
ggcaccgcgg cgctgggctg cctggtgaaa gattattttc cggaaccggt gaccgtgagc 480
tggaacagcg gcgcgctgac cagcggcgtg catacctttc cggcggtgct gcagagcagc 540
ggcctgtata gcctgagcag cgtggtgacc gtgccgagca gcagcctggg cacccagacc 600
tatatttgca acgtgaacca taaaccgagc aacaccaaag tggataaaaa agtggaaccg 660
aaaagctgcg ataaaaccca t 681
<210> 42
<211> 214
<212> PRT
<213> 人工序列
<220>
<223> VEGFRscFV轻链
<400> 42
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Thr Thr Cys Arg Ala Ser Gln Asp Val Ser Thr Ala
20 25 30
Val Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Ser Ala Ser Phe Leu Tyr Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Ser Tyr Thr Thr Pro Pro
85 90 95
Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg Thr Val Ala Ala
100 105 110
Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly
115 120 125
Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala
130 135 140
Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln
145 150 155 160
Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser
165 170 175
Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr
180 185 190
Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser
195 200 205
Phe Asn Arg Gly Glu Cys
210
<210> 43
<211> 642
<212> DNA
<213> 人工序列
<220>
<223> VEGFRscFV轻链
<400> 43
gatattcaga tgacccagag cccgagcagc ctgagcgcga gcgtgggcga tcgcgtgacc 60
accacctgcc gcgcgagcca ggatgtgagc accgcggtgg cgtggtatca gcagaaaccg 120
ggcaaagcgc cgaaactgct gatttatagc gcgagctttc tgtatagcgg cgtgccgagc 180
cgctttagcg gcagcggcag cggcaccgat tttaccctga ccattagcag cctgcagccg 240
gaagattttg cgacctatta ttgccagcag agctatacca ccccgccgac ctttggccag 300
ggcaccaaag tggaaattaa acgcaccgtg gcggcgccga gcgtgtttat ttttccgccg 360
agcgatgaac agctgaaaag cggcaccgcg agcgtggtgt gcctgctgaa caacttttat 420
ccgcgcgaag cgaaagtgca gtggaaagtg gataacgcgc tgcagagcgg caacagccag 480
gaaagcgtga ccgaacagga tagcaaagat agcacctata gcctgagcag caccctgacc 540
ctgagcaaag cggattatga aaaacataaa gtgtatgcgt gcgaagtgac ccatcagggc 600
ctgagcagcc cggtgaccaa aagctttaac cgcggcgaat gc 642
Claims (16)
1.一种融合多肽,其包含:
结合肿瘤相关抗原的抗体或其片段;
接头;和
自然杀伤(NK)细胞诱导蛋白CXCL16。
2.根据权利要求1所述的融合多肽,其中所述肿瘤相关抗原选自间皮素、PD-L1(程序性死亡配体1)、Her2(人EGFR相关的2)、CD19、MUC1、EGFR、VEGFR、B7H1、B7H2、B7H3、BT-062、BTLA、CAIX、4-1BB、5T4、AGS-5或AGS-16中的至少一种。
3.根据权利要求1所述的融合多肽,其中所述抗体是单链Fv片段(scFv)。
4.根据权利要求1所述的融合多肽,其中所述接头包含弗林蛋白酶切割位点。
5.根据权利要求4所述的融合多肽,其中所述弗林蛋白酶切割位点包含SEQ ID NO:15的氨基酸序列。
6.根据权利要求1所述的融合多肽,其中所述CXCL16包含SEQ ID NO:17的氨基酸序列。
7.一种核酸,其编码根据权利要求1至9中任一项所述的融合多肽。
8.一种表达载体,其包含权利要求7所述的编码融合多肽的核酸。
9.一种宿主细胞,其包含权利要求8所述的表达载体。
10.根据权利要求9所述的宿主细胞,其中所述宿主细胞选自COS、CHO、HeLa和骨髓瘤细胞系之一。
11.一种用于预防或治疗癌症的药物组合物,其包含融合多肽,其中所述融合多肽包含:
结合肿瘤相关抗原的抗体或其片段;
接头;和
自然杀伤细胞诱导蛋白CXCL16。
12.根据权利要求11所述的用于预防或治疗癌症的药物组合物,其中所述抗原选自间皮素、PD-L1、Her2、CD19、MUC1、EGFR、VEGFR、B7H1、B7H2、B7H3、BT-062、BTLA、CAIX、4-1BB、5T4、AGS-5或AGS-16中的至少一种。
13.根据权利要求11所述的用于预防或治疗癌症的药物组合物,其中所述癌症选自胰腺癌、乳腺癌、前列腺癌、胃癌、肝癌或肺癌中的一种。
14.根据权利要求11所述的用于预防或治疗癌症的药物组合物,其中所述接头包含弗林蛋白酶切割位点。
15.根据权利要求11所述的用于预防或治疗癌症的药物组合物,其中所述CXCL16包含SEQ ID NO:17的氨基酸序列。
16.一种用于预防或治疗癌症的药物组合物,其包含融合多肽和自然杀伤细胞,其中所述融合多肽包含:结合肿瘤相关抗原的抗体或其片段;接头;和自然杀伤细胞诱导蛋白CXCL16。
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KR20170043988 | 2017-04-05 | ||
PCT/KR2018/004043 WO2018186706A1 (ko) | 2017-04-05 | 2018-04-05 | Nk 세포 활성화 융합 단백질, nk 세포 및 이들을 포함하는 약제학적 조성물 |
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US (1) | US11655306B2 (zh) |
EP (1) | EP3594242A4 (zh) |
JP (1) | JP6933724B2 (zh) |
KR (1) | KR102009040B1 (zh) |
CN (1) | CN110573529A (zh) |
AU (1) | AU2018248672B2 (zh) |
BR (1) | BR112019020909A2 (zh) |
CA (1) | CA3057989C (zh) |
IL (1) | IL269801B2 (zh) |
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CN114887080A (zh) * | 2020-12-08 | 2022-08-12 | 深圳市瑞吉生物科技有限公司 | 一种mRNA剂型的免疫抑制剂及其在制备肿瘤治疗药物中的应用 |
CN116790616A (zh) * | 2023-07-07 | 2023-09-22 | 佛山科学技术学院 | 编码sCXCL16的基因及表达载体、制备方法和应用 |
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CN114588258B (zh) * | 2022-05-10 | 2023-04-25 | 中山大学 | Bmp9联合nk细胞和pd-l1抗体在制备肝癌药物方面的应用 |
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AU2018248672B2 (en) | 2021-09-30 |
KR20180113183A (ko) | 2018-10-15 |
IL269801B2 (en) | 2024-02-01 |
MX2019011958A (es) | 2019-12-11 |
EP3594242A4 (en) | 2020-12-09 |
IL269801B1 (en) | 2023-10-01 |
IL269801A (zh) | 2020-02-27 |
US11655306B2 (en) | 2023-05-23 |
EP3594242A1 (en) | 2020-01-15 |
KR102009040B1 (ko) | 2019-08-08 |
CA3057989C (en) | 2023-03-21 |
CA3057989A1 (en) | 2018-10-11 |
BR112019020909A2 (pt) | 2020-05-12 |
US20200148786A1 (en) | 2020-05-14 |
RU2740438C1 (ru) | 2021-01-14 |
JP2020515624A (ja) | 2020-05-28 |
WO2018186706A1 (ko) | 2018-10-11 |
AU2018248672A1 (en) | 2019-11-14 |
JP6933724B2 (ja) | 2021-09-08 |
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