CN114621353B - 一种重组融合蛋白及其应用 - Google Patents
一种重组融合蛋白及其应用 Download PDFInfo
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Abstract
本发明涉及生物医药领域,具体而言,涉及一种重组融合蛋白及其应用。本发明提供了一种重组IL‑10‑Fc融合蛋白,该融合蛋白能够有效降低异质性、降低了因糖基化导致的免疫原性,提高了安全性,延长了IL‑10的血浆半衰期;该融合蛋白及其相关核酸、载体、细胞或药物组合物能够广泛用于制备预防和/或治疗肿瘤的药物。
Description
技术领域
本发明属于生物医药技术领域。更具体地,涉及一种重组融合蛋白及其应用。
背景技术
人白细胞介素-10(Interleukin-10,IL-10)是由Vieira于1991年从破伤风毒性特异性T细胞克隆和表达,其基因位于1号染色体1q32区域,DNA全长4.7kb,包含5个外显子,其功能蛋白是由二硫键非共价结合而成的同源二聚体,分子量35kD,每个亚基含有178个氨基酸,包括18个氨基酸的信号肽,和鼠类IL-10的同源性约为75%。人IL-10受体是IL-10R1和IL-10R2异源二聚体,属于II类细胞因子受体。IL-10及其受体相互作用是首先高亲和力与IL-10R1结合,而后通过空间构象改变再与IL-10R2结合,进而介导JAK-STAT途径的信号转导。
几乎所有淋巴细胞均能合成IL-10,主要来源是由单核巨噬细胞和T辅助细胞分泌,在多种类型的免疫细胞中具有免疫抑制或免疫刺激双向调节功能:一方面抑制Th1细胞应答及细胞因子的合成,抑制Th2细胞产生IL-4和IL-5,抑制巨噬细胞的抗原递呈功能及免疫介质的释放,但不能抑制Th17细胞产生IL-17,也似乎对CD8+T细胞没有直接抑制作用;另一方面促进B细胞增殖分化及抗体产生,NK细胞的细胞毒活性、肥大细胞和T细胞活性。
目前,以IL-10为靶点的药物仍然没有被批准上市,且处于研究阶段的药物绝大多数是用于治疗自身免疫疾病和慢性炎症,而用于治疗肿瘤的产品仅有聚乙二醇(PEG)化的IL-10,例如Pegilodecakin和IL-10Synthorin。然而,天然IL-10的半衰期仅有几个小时,即使表面被PEG化后其半衰期也仅有几天,且高剂量会产生毒副作用。因此,开发抗肿瘤活性显著、无毒副作用的以IL-10为靶点的抗肿瘤药物具有重要意义。
发明内容
本发明旨在至少在一定程度上解决以下技术问题之一:
(1)IL-10融合蛋白在生产过程中易发生降解或截短,产生异质性;
(2)IL-10融合蛋白中IgG Fc片段的铰链区存在的游离半胱氨酸容易导致产品聚集;
(3)部分N-糖基化位点会造成免疫原性,导致产品的安全性降低;
(4)人IL-10作为药物治疗相关疾病时的血浆半衰期很短。
本发明的目的是提供一种重组融合蛋白,包括IL-10、连接肽和IgG Fc片段,所述IL-10的C末端通过连接肽连接至IgG Fc片段的N末端,所述IL-10与野生型IL-10相比缺失N末端的Ser和Pro。
在一些实施方式中,所述连接肽的序列如SEQ ID NO:6或SEQ ID NO:10所示。
在一些实施方式中,所述IgG Fc片段的铰链区依照EU编号在第220位的Cys被Ser取代。
在一些实施方式中,所述IgG Fc片段依照EU编号在第235位的Leu被Ala取代、第237位的Gly被Gln取代或第327位的Ala被Gln取代。
本发明还提供了所述融合蛋白相关核酸、载体、细胞或药物组合物。
本发明还涉及所述融合蛋白、所述核酸、所述载体、所述细胞或所述药物组合物在制备预防和/或治疗肿瘤的药物中的应用。
附图说明
图1是构建得到的含有目的基因的pCDNA3.4A-R0356载体示意图。
图2是构建得到的含有目的基因的pCDNA3.1-M1载体示意图。
图3是构建得到的含有目的基因的pCDNA3.1-M2载体示意图。
图4是构建得到的含有目的基因的pCDNA3.1-M3载体示意图。
图5是R0356的SEC检测结果图。
图6是M1的SEC检测结果图。
图7是M2的SEC检测结果图。
图8是M3的SEC检测结果图。
图9是R0356的质谱检测结果图。
图10是重组IL-10-Fc融合蛋白在细胞水平与IL-10的受体IL-10R1的结合情况测定结果图;图中,“Isotype”代表未融合IL-10的IgG1蛋白;“HillSlope”代表EC50处曲线的斜率,“Span”代表EC50处曲线的上平台值。
图11是报告基因检测生物活性结果图;“HillSlope”代表EC50处的斜率。
图12是肿瘤生长曲线图。
具体实施方式
以下结合具体实施例来进一步说明本发明,但实施例并不对本发明做任何形式的限定。除非特别说明,本发明采用的试剂、方法和设备为本技术领域常规试剂、方法和设备。
除非特别说明,以下实施例所用试剂和材料均为市购。
本发明涉及一种重组融合蛋白,包括IL-10、连接肽和IgG Fc片段,所述IL-10的C末端通过连接肽连接至IgG Fc片段的N末端,所述IL-10与野生型IL-10相比缺失N末端的Ser和Pro。
本发明通过截短IL-10的N末端的Ser和Pro两个氨基酸,降低或消除了由于IL-10融合蛋白降解或截短而导致的产品异质性。
在一些实施方式中,所述Fc选自IgG1 Fc,IgG2 Fc,IgG3Fc或IgG4 Fc中的任一种。
在优选实施方式中,所述Fc是IgG1 Fc。
在本发明中,IgG Fc包含IgG CH2和IgG CH3域。IgG1 Fc,IgG2 Fc,IgG3Fc,IgG4Fc分别表示IgG1、IgG2、IgG3和IgG4的Fc。
在本发明中,术语“Fc”用于定义抗体重链中至少含有恒定区的一部分的C端区域。
在一些实施方式中,所述连接肽的序列如SEQ ID NO:6或SEQ ID NO:10所示。
本发明通过修饰连接肽去除了产生的非预期的N-糖基化位点,降低了因为糖基化导致的免疫原性,提高了安全性。
在一些实施方式中,所述IgG Fc片段的铰链区依照EU编号在第220位的Cys被Ser取代。
在一些实施方式中,所述IgG Fc片段依照EU编号在第235位的Leu被Ala取代、第237位的Gly被Gln取代或第327位的Ala被Gln取代。从而降低了产品的聚集。
除非本文中另外指定,IgG Fc片段氨基酸残基的编号方式依照EU编号系统,也称为EU索引如记载于Kabat et al.,Sequences of Proteins of ImmunologicalInterest,5th Ed.Public Health Service,National Institutes of Health,Bethesda,MD,1991。
在一些实施方式中,所述融合蛋白的氨基酸序列如SEQ ID NO:2、SEQ ID NO:3或SEQ ID NO:4所示。
在本发明中,R0356的氨基酸序列如SEQ ID NO:1所示;R0356中,IL-10(野生型IL-10)的氨基酸序列如SEQ ID NO:5所示;连接肽的氨基酸序列如SEQ ID NO:6所示;IgG Fc片段的氨基酸序列如SEQ ID NO:7所示。
在一些实施方式中,所述融合蛋白为M1、M2或M3。
在一些实施方式中,M1的氨基酸序列如SEQ ID NO:2所示;M1中,IL-10的氨基酸序列如SEQ ID NO:9所示;连接肽的氨基酸序列如SEQ ID NO:6所示;IgG Fc片段的氨基酸序列如SEQ ID NO:7所示。
在一些实施方式中,M2的氨基酸序列如SEQ ID NO:3所示;M2中,IL-10的氨基酸序列如SEQ ID NO:9所示;连接肽的氨基酸序列如SEQ ID NO:6所示;IgG Fc片段的氨基酸序列如SEQ ID NO:8所示。
在一些实施方式中,M3的氨基酸序列如SEQ ID NO:4所示;M3中,IL-10的氨基酸序列如SEQ ID NO:9所示;连接肽的氨基酸序列如SEQ ID NO:10所示;IgG Fc片段的氨基酸序列如SEQ ID NO:8所示。
在本发明中,“野生型IL-10”是指天然存在的IL-10,是由两个α-螺旋单体域构成的同源二聚体,与“经修饰IL-10”相反,后者是天然存在的IL-10经过修饰后得到,例如为了改变它的一项或多项特性,诸如稳定性、亲和力。经修饰IL-10分子可以例如包含氨基酸序列中的修饰,例如氨基酸替代、删除或插入。
在本发明中,“连接肽”包含一个或多个氨基酸,通常约为2-20个氨基酸的肽,是本领域中已知的或本文中记载的。合适的、非免疫原性的连接肽包括例如(GS)n接头,其中n为1-10的整数。
在本发明中,氨基酸“取代”指多肽中一个氨基酸用另一种氨基酸替换。在一个实施方案中,氨基酸用具有相似结构和/或化学特性的另一种氨基酸替换,例如保守氨基酸替换。“保守”氨基酸取代可以在所涉及残基的极性、电荷、溶解性、疏水性、亲水性、和/或两亲性性质的相似性基础上进行。例如,非极性(疏水性)氨基酸包括丙氨酸、亮氨酸、异亮氨酸、缬氨酸、脯氨酸、苯丙氨酸、色氨酸、和甲硫氨酸;极性中性氨基酸包括甘氨酸、丝氨酸、苏氨酸、半胱氨酸、酪氨酸、天冬酰胺、和谷氨酰胺;带正电荷(碱性)氨基酸包括精氨酸、赖氨酸、和组氨酸;而带负电荷(酸性)氨基酸包括天冬氨酸和谷氨酸。非保守取代会需要用这些类别之一的成员交换另一个类别的成员。例如,氨基酸取代还可导致将一个氨基酸用具有不同结构和/或化学特性的另一种氨基酸替换,例如将来自一个组(例如极性)的氨基酸用来自一个不同组(例如碱性)的另一种氨基酸替换。可以使用本领域公知的遗传或化学方法来生成氨基酸取代。
在本发明中,术语“修饰”指对肽主链(例如氨基酸序列)的任何操作或对多肽的翻译后修饰(例如糖基化)。修饰也包括氨基酸序列中氨基酸的取代、缺失或插入。
本发明还涉及一种核酸,所述核酸编码所述融合蛋白。
本发明还涉及一种载体,所述载体携带所述核酸。
在本发明中,术语“载体”是能够增殖与其连接的另一种核酸的核酸分子。该术语包括作为自身复制型核酸结构的载体及整合入接受其导入的宿主细胞的基因组中的载体。
本发明还涉及一种细胞,所述细胞含有所述核酸或所述载体。
本发明还涉及一种药物组合物,所述药物组合物含有所述融合蛋白、所述核酸、所述载体或所述细胞。
在优选实施方式中,所述药物组合物还包括药学可接受的载体。
在本发明中,术语“药物组合物”是以允许活性成分的生物学活性有效的形式存在,并且不包含对将施用所述组合物的对象具有不可接受的毒性的另外的成分。
在本发明中,术语“药学可接受的载体”可以包括生理学上相容的任何和所有溶剂、分散介质、包衣、抗细菌剂和抗真菌剂、等渗剂和延迟吸收剂等,用来延长抗体的保存限期或效力。
本发明还涉及所述融合蛋白、所述核酸、所述载体、所述细胞或所述药物组合物在制备预防和/或治疗肿瘤的药物中的应用。
在本发明中,术语“治疗”是指给予有效量的治疗活性物质,其目的在于减轻、改善、抑制或根除(治愈)症状或疾病状态。为了预防或治疗疾病,本发明的融合蛋白的合适剂量(当单独或与一种或多种其它另外的治疗剂组合使用时)将取决于待治疗疾病的类型、施用路径、患者的体重、融合蛋白的类型、疾病的严重程度和进程、施用融合蛋白是为了预防还是治疗目的、先前或同时的治疗干预、患者的临床史和对融合蛋白的响应、以及主治医师的判断。负责施用的从业人员将在任何事件中确定组合物中活性成分的浓度和用于个体受试者的合适剂量。本文中涵盖各种给药方案,包括但不限于在各个时间点的单次或多次施用、推注施用和脉冲输注。
本发明具有以下有益效果:
本发明构建了一种IL-10与IgG抗体的Fc片段的基因重组融合蛋白IL-10-Fc,该融合蛋白通过对IL-10进行改造,例如,截短处理,降低了产品异质性;进一步地,通过修饰连接肽去除了非有益的N-糖基化位点,降低了因糖基化导致的免疫原性,更进一步的,对Fc片段定点突变,降低了高聚体,降低了ADCC效应,提高了安全性,并通过Fc融合IL-10延长了血浆半衰期,能够减少给药频率,提高药物安全性的疗效。
实施例1重组IL-10-Fc融合蛋白的基因构建
将表1中R0356、M1、M2、M3和M4的氨基酸序列翻译成DNA序列,并根据Expi CHO或Expi 293F细胞的密码子优化并常规合成基因,之后在5'端依次添加HindIII酶切位点和5'UTR保护碱基([CCGC]);在3'端依次添加3'UTR终止密码子([TGATGA])、EcoRI酶切位点和3'UTR保护碱基([CGG]),将常规条件PCR扩增后的目的基因通过5'EcoRI and 3'HindIII克隆至载体pCDNA3.1A或pCDNA3.4A,构建得到的含有目的基因的载体(pCDNA3.4A-R0356、pCDNA3.1-M1、pCDNA3.1-M2、pCDNA3.1-M3)示意图如图1-图4所示。
将目的DNA分子和载体分子进行Hind III(NEB)和EcoRI(NEB)双酶切,并用T4DNA连接酶(TAKARA)连接后转导至DH5α感受态细菌(NEB)。选用氨苄青霉素的LB培养液培养,挑选克隆进行测序,选择测序正确的菌体进行保种并进行菌体的扩大培养,扩大的菌体用于质粒的提取。
表1 R0356、M1、M2、M3和M4的氨基酸序列
融合蛋白 | IL-10 | 连接肽 | IgG Fc片段 |
R0356(SEQ ID NO:1) | SEQ ID NO:5 | SEQ ID NO:6 | SEQ ID NO:7 |
M1(SEQ ID NO:2) | SEQ ID NO:9 | SEQ ID NO:6 | SEQ ID NO:7 |
M2(SEQ ID NO:3) | SEQ ID NO:9 | SEQ ID NO:6 | SEQ ID NO:8 |
M3(SEQ ID NO:4) | SEQ ID NO:9 | SEQ ID NO:10 | SEQ ID NO:8 |
M4(SEQ ID NO:11) | SEQ ID NO:5 | SEQ ID NO:6 | SEQ ID NO:8 |
其中,R0356、M1、M2和M3的结构为IL-10-连接肽-IgG Fc;M4的结构为IgG Fc-连接肽-IL-10。
实施例2重组IL-10-Fc融合蛋白的表达和纯化
1、实验方法
本实施例选用实施例1提取后的质粒,以Expi293F细胞作为表达系统为例进行细胞转染和瞬转表达技术方案的描述,其他常规技术工艺也应视为本发明的保护范围。
选择状态良好、活力大于95%的Expi293F(Thermo)细胞,用Dynamis培养基(GIBCO)调整密度至3×106细胞/mL,轻轻摇匀并分装细胞(转染体系90%),摇瓶中细胞体积不超过摇瓶规格的1/3,放入摇床待用。根据转染细胞体积计算转染缓冲液opti-MEM的体积,为转染体系的1/10;计算转染试剂PEI的量,其比例为3μL/mL转染细胞;计算转染DNA的总量,其比例为1μg/mL转染细胞。具体转染的操作过程如下:
取1支50mL离心管,加入转染体系10%的转染缓冲液opti-MEM,加入质粒,混匀后过滤,静置5min,向DNA混悬液中加入PEI,轻柔混匀(轻轻颠倒混匀2-3次)后静置15-20min。随后将复合物轻柔加入分装好的细胞中,边加入边轻轻晃动摇瓶,完成细胞转染。将转染完成的细胞放入37℃、8%CO2摇床以120rpm速度进行培养24小时后,按5%转染细胞体积加补料培养基,第15天收集培养上清。
然后将培养上清进行亲和层析纯化,亲和层析步骤如下:
在层析系统(GE Healthcare,AKTA pure150)中对装有层析填料1(GEHealthcare,MabSelect SuRe LX)的层析柱1(GE Healthcare,XK16/20,柱体积(CV),53ml)再生后用20mM PBS平衡2CV,重设紫外检测器(UV Monitor),以气泡感应方式载入Expi293细胞发酵上清液。上样结束后用20mM PBS洗涤层析柱3CV,接着用100%缓冲液20mM NaAc,pH3.4步阶洗脱3CV,收集40mAu~40mAu 280nm紫外吸收组分,并在收集管中预先加入1.8%中和缓冲液使最终pH在6.0-7.0范围,接着在位清洗4CV,保持5min,然后缓冲液A向下流动清洗5CV后,使用20%乙醇缓冲液保存。
采用预装PG200填料的层析柱对层析柱洗脱后的样品进行分子筛作用精纯样品,其步骤如下:
将捕获后的洗脱样品进一步进行分子筛精纯,使用0.22um滤膜对亲和洗脱样品进行除菌、过滤,备用。在层析系统(GE Healthcare,AKTA avant150)中对装有层析填料2(博格隆,PG200)的层析柱2(博格隆,BXK50/100,柱体积(CV),1825ml)使用20mM PBS平衡2CV,重设紫外检测器(UV Monitor),以气泡感应方式载入R0673亲和洗脱后的样品,上样结束后用20mM PBS洗涤层析柱2CV,收集20mAu~20mAu280nm紫外吸收组分,并用质谱分析分子完整性。在培养15天后收获样品,经体积排阻色谱(SEC)和质谱法(MS)检测纯度和完整分子量。
其中体积排阻色谱法检测纯度方法如下:用流动相A(50mM磷酸盐+300mM氯化钾,pH7.0±0.1)将标准品稀释至1.0mg/mL,混匀后装入内衬管。仪器设置参数如下表所示,按流动相A-参考品-待测样品-参考品顺序进样检测。采用峰面积归一法对结果进行定量分析,并计算单体、高聚体、低分子量杂质体的峰面积百分比。以单体峰面积百分比作为样品纯度,高聚体,低分子量杂质峰面积百分比作为样品杂质的含量。
色谱柱 | Xbridge BEH 200A SEC 7.8×300mm,3.5μm |
检测波长 | 280nm |
柱温 | 25℃ |
进样盘温度 | 2~10℃ |
流速 | 1mL/min |
进样体积 | 50μL(1mg/ml) |
流动相 | 50mM PB+0.3M KCl,pH 7.0±0.1 |
洗脱方式 | 等度洗脱 |
洗脱时间 | 20min |
2、实验结果
R0356、M1、M2和M3的SEC检测结果依次如图5-图8和表2所示,结果显示,与R0356和M1相比,M2和M3的高聚体显著降低,说明M2和M3有效降低了聚体的产生。
表2 M1、M2和M3的SEC高聚体检测结果
R0356的质谱检测结果如图9所示,结果显示R0356中大约50%的分子发生了截短;M1、M2和M3的质谱检测结果如表3所示,结果显示M1、M2和M3保持完整状态,均未观察到降解或截短,有效降低了异质性。
表3 M1、M2和M3的质谱检测结果
样品名称 | 说明 | 理论分子量 | 实测分子量 | 差值(Da) | 差值(ppm) |
M1 | 半抗体分子 | 45009.56 | 45013.34 | 3.78 | 83.98 |
M2 | 半抗体分子 | 44993.50 | 44997.21 | 3.71 | 82.46 |
M3 | 半抗体分子 | 45107.60 | 45110.81 | 3.21 | 71.16 |
实施例3糖基化位点的检测
1、实验方法
检测氨基酸序列依次为SEQ ID NO:1-4的R0356、M1、M2和M3的糖基化位点情况,选用ExPASy中的NetNGlyc 1.0Server模块检测糖基化。
2、实验结果
糖基化位点检测结果显示,R0356、M1和M2除了IL-10和IgG Fc天然存在的2个糖基化位点外,均还有一个由IL-10末端和Linker序列形成异常的糖基化位点NGSG;而M3仅有IL-10和IgG Fc天然存在的2个糖基化位点,未检测到糖基化位点NGSG,进而降低了因为糖基化导致的免疫原性,提高了安全性。
实施例4重组IL-10-Fc融合蛋白在细胞水平与IL-10的受体IL-10R1的结合情况测定
1、实验方法
本实施例中选用实施例1和2生产和纯化的重组IL-10-Fc融合蛋白,并采用基于过表达IL-10R1细胞的检测重组IL-10-Fc融合蛋白在细胞水平与IL-10的受体IL-10R1的结合情况。
将2×105cells/well的CHO-IL10R细胞铺VU底96孔板孵育过夜;用200μL PBS洗板,离心后弃上清后,加上200μL预冷的3%BSA-PBS封闭液,2-8℃封闭1h;弃液洗板后,依次加入用分析缓冲液稀释R0356(图10中标注R0356(plate1)和R0356(plate2))M1(图10中M1-E1和M1-E2)、M2(图10中M2-E1和M2-E2)M3、M4、isotype(未融合IL-10的IgG1蛋白,即同型IgG1对照)和blank(未添加任何蛋白,即空白对照)从15μg/mL起始3倍序列稀释的样品,含零点共11个稀释点,100μl/孔,复孔,2-8℃孵育2h;弃液洗板后,加入用分析缓冲液进行1:15000稀释Goat Anti-Human IgG Fc(HRP)二抗,100μl/孔,2-8℃孵育1h;弃液洗板后,加入按照1:15000稀释的Goat Anti-Human IgG Fc(HRP)二抗,100μl/孔,2-8℃孵育1h;弃液洗板后,每孔加入100μl/孔的TMB,37℃避光显色10~20min,用100μL/孔的终止液(1M的H2SO4)终止显色。用酶标仪采集A450nm的吸光值,并GraphPad Prism 5.0软件计算EC50。
2、实验结果
重组IL-10-Fc融合蛋白在细胞水平与IL-10的受体IL-10R1的结合情况测定结果如图10所示,结果显示R0356、M1、M2和M3的EC50相当。
实施例5报告基因检测生物活性
1、实验方法
本实施例中选用实施例1和2生产和纯化的重组IL-10-Fc融合蛋白,以串联IL-10R和STAT3信号通路的报告基因系统H_IL10 receptor 293 cell line(Genomeditech)作为检测系统,当含有IL-10的样品与该体系表面IL-10R结合时,能够刺激细胞荧光素酶表达上升。具体检测步骤如下:
首先将2×105cells/well的H_IL10 receptor 293 cell line细胞50μl/孔,铺96孔板;紧接着依次加入用分析缓冲液稀释R0356、M1(图11中M1-E2)、M2(图11中M2-E2)、M3(图中M3-E2)和M4(图11中M4-E2)从10μg/mL起始2倍序列稀释的样品,含零点共10个稀释点,50μl/孔,混匀后置于CO2培养箱中,37℃条件下孵育16h;每孔加入100μl荧光素酶报告基因检测试剂(Cat#RG051M,Beyotime)孵育10min,用酶标仪采集荧光强度值,并GraphPadPrism 5.0软件计算EC50。
2、实验结果
报告基因检测生物活性结果如图11所示,结果显示R0356、M1、M2和M3的EC50相当,M3的生物活性比R0356好,其相对生物学活性为106.5%。
实施例6重组IL-10-Fc融合蛋白的体内抗肿瘤评价
1、实验方法
取对数生长期的小鼠结肠癌CT26细胞,调节细胞浓度为1×106/mL。取雌性BALB/C小鼠,皮下接种CT26细胞,接种体积为0.1mL/小鼠。接种当天记为第0天(D0),第9天,将小鼠按瘤体积随机分为3组,每组8只,开始给药(给药方案如表4所示)。其中本实施例中M1、M2和M3分别为M1、M2和M3,R0511是同型IgG1对照。
表4给药方案
给药当天开始测量肿瘤体积并记录,之后每周2次用游标卡尺测量肿瘤长径和短径。以公式计算肿瘤体积肿瘤生长抑制TGI(%)=[1-(Ti-T0)/(Vi-V0)]×100,Ti为第i天治疗组的平均瘤体积,T0为治疗开始时治疗组的平均瘤体积,Vi为第i天溶剂对照组的平均瘤体积,V0为治疗开始时溶剂对照组的平均瘤体积。每只小鼠达到实验终点时(肿瘤体积超过2000mm3达到仁慈终点),颈椎脱臼法处死小鼠,记录生存曲线。
2、实验结果
给药M1、M2、M3、R0511和R0356的平均瘤体积如表5所示,结果显示M3的平均瘤体积显著小于R0356,说明M3具有抑制肿瘤细胞生长的效果。
表5给药M1、M2、M3、R0511和R0356的平均瘤体积结果
肿瘤生长曲线如图12所示,结果显示M3的抗肿瘤效果强于R0356,M2和R0356的抗肿瘤效果相当,而M1的抗肿瘤效果最弱。
上述实施例为本发明较佳的实施方式,但本发明的实施方式并不受上述实施例的限制,其他的任何未背离本发明的精神实质与原理下所作的改变、修饰、替代、组合、简化,均应为等效的置换方式,都包含在本发明的保护范围之内。
SEQUENCE LISTING
<110> 广东菲鹏生物制药股份有限公司
<120> 一种重组融合蛋白及其应用
<130> 2020
<160> 11
<170> PatentIn version 3.5
<210> 1
<211> 400
<212> PRT
<213> 人工序列
<400> 1
Ser Pro Gly Gln Gly Thr Gln Ser Glu Asn Ser Cys Thr His Phe Pro
1 5 10 15
Gly Asn Leu Pro Asn Met Leu Arg Asp Leu Arg Asp Ala Phe Ser Arg
20 25 30
Val Lys Thr Phe Phe Gln Met Lys Asp Gln Leu Asp Asn Leu Leu Leu
35 40 45
Lys Glu Ser Leu Leu Glu Asp Phe Lys Gly Tyr Leu Gly Cys Gln Ala
50 55 60
Leu Ser Glu Met Ile Gln Phe Tyr Leu Glu Glu Val Met Pro Gln Ala
65 70 75 80
Glu Asn Gln Asp Pro Asp Ile Lys Ala His Val Asn Ser Leu Gly Glu
85 90 95
Asn Leu Lys Thr Leu Arg Leu Arg Leu Arg Arg Cys His Arg Phe Leu
100 105 110
Pro Cys Glu Asn Lys Ser Lys Ala Val Glu Gln Val Lys Asn Ala Phe
115 120 125
Asn Lys Leu Gln Glu Lys Gly Ile Tyr Lys Ala Met Ser Glu Phe Asp
130 135 140
Ile Phe Ile Asn Tyr Ile Glu Ala Tyr Met Thr Met Lys Ile Arg Asn
145 150 155 160
Gly Ser Gly Ser Gly Ser Gly Ser Glu Pro Lys Ser Cys Asp Lys Thr
165 170 175
His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Ala Gly Ala Pro Ser
180 185 190
Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg
195 200 205
Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro
210 215 220
Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala
225 230 235 240
Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val
245 250 255
Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr
260 265 270
Lys Cys Lys Val Ser Asn Lys Gln Leu Pro Ala Pro Ile Glu Lys Thr
275 280 285
Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu
290 295 300
Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr Cys
305 310 315 320
Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser
325 330 335
Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp
340 345 350
Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser
355 360 365
Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala
370 375 380
Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
385 390 395 400
<210> 2
<211> 398
<212> PRT
<213> 人工序列
<400> 2
Gly Gln Gly Thr Gln Ser Glu Asn Ser Cys Thr His Phe Pro Gly Asn
1 5 10 15
Leu Pro Asn Met Leu Arg Asp Leu Arg Asp Ala Phe Ser Arg Val Lys
20 25 30
Thr Phe Phe Gln Met Lys Asp Gln Leu Asp Asn Leu Leu Leu Lys Glu
35 40 45
Ser Leu Leu Glu Asp Phe Lys Gly Tyr Leu Gly Cys Gln Ala Leu Ser
50 55 60
Glu Met Ile Gln Phe Tyr Leu Glu Glu Val Met Pro Gln Ala Glu Asn
65 70 75 80
Gln Asp Pro Asp Ile Lys Ala His Val Asn Ser Leu Gly Glu Asn Leu
85 90 95
Lys Thr Leu Arg Leu Arg Leu Arg Arg Cys His Arg Phe Leu Pro Cys
100 105 110
Glu Asn Lys Ser Lys Ala Val Glu Gln Val Lys Asn Ala Phe Asn Lys
115 120 125
Leu Gln Glu Lys Gly Ile Tyr Lys Ala Met Ser Glu Phe Asp Ile Phe
130 135 140
Ile Asn Tyr Ile Glu Ala Tyr Met Thr Met Lys Ile Arg Asn Gly Ser
145 150 155 160
Gly Ser Gly Ser Gly Ser Glu Pro Lys Ser Cys Asp Lys Thr His Thr
165 170 175
Cys Pro Pro Cys Pro Ala Pro Glu Leu Ala Gly Ala Pro Ser Val Phe
180 185 190
Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro
195 200 205
Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val
210 215 220
Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr
225 230 235 240
Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val
245 250 255
Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys
260 265 270
Lys Val Ser Asn Lys Gln Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser
275 280 285
Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro
290 295 300
Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val
305 310 315 320
Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly
325 330 335
Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp
340 345 350
Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp
355 360 365
Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His
370 375 380
Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
385 390 395
<210> 3
<211> 398
<212> PRT
<213> 人工序列
<400> 3
Gly Gln Gly Thr Gln Ser Glu Asn Ser Cys Thr His Phe Pro Gly Asn
1 5 10 15
Leu Pro Asn Met Leu Arg Asp Leu Arg Asp Ala Phe Ser Arg Val Lys
20 25 30
Thr Phe Phe Gln Met Lys Asp Gln Leu Asp Asn Leu Leu Leu Lys Glu
35 40 45
Ser Leu Leu Glu Asp Phe Lys Gly Tyr Leu Gly Cys Gln Ala Leu Ser
50 55 60
Glu Met Ile Gln Phe Tyr Leu Glu Glu Val Met Pro Gln Ala Glu Asn
65 70 75 80
Gln Asp Pro Asp Ile Lys Ala His Val Asn Ser Leu Gly Glu Asn Leu
85 90 95
Lys Thr Leu Arg Leu Arg Leu Arg Arg Cys His Arg Phe Leu Pro Cys
100 105 110
Glu Asn Lys Ser Lys Ala Val Glu Gln Val Lys Asn Ala Phe Asn Lys
115 120 125
Leu Gln Glu Lys Gly Ile Tyr Lys Ala Met Ser Glu Phe Asp Ile Phe
130 135 140
Ile Asn Tyr Ile Glu Ala Tyr Met Thr Met Lys Ile Arg Asn Gly Ser
145 150 155 160
Gly Ser Gly Ser Gly Ser Glu Pro Lys Ser Ser Asp Lys Thr His Thr
165 170 175
Cys Pro Pro Cys Pro Ala Pro Glu Leu Ala Gly Ala Pro Ser Val Phe
180 185 190
Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro
195 200 205
Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val
210 215 220
Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr
225 230 235 240
Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val
245 250 255
Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys
260 265 270
Lys Val Ser Asn Lys Gln Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser
275 280 285
Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro
290 295 300
Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val
305 310 315 320
Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly
325 330 335
Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp
340 345 350
Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp
355 360 365
Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His
370 375 380
Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
385 390 395
<210> 4
<211> 400
<212> PRT
<213> 人工序列
<400> 4
Gly Gln Gly Thr Gln Ser Glu Asn Ser Cys Thr His Phe Pro Gly Asn
1 5 10 15
Leu Pro Asn Met Leu Arg Asp Leu Arg Asp Ala Phe Ser Arg Val Lys
20 25 30
Thr Phe Phe Gln Met Lys Asp Gln Leu Asp Asn Leu Leu Leu Lys Glu
35 40 45
Ser Leu Leu Glu Asp Phe Lys Gly Tyr Leu Gly Cys Gln Ala Leu Ser
50 55 60
Glu Met Ile Gln Phe Tyr Leu Glu Glu Val Met Pro Gln Ala Glu Asn
65 70 75 80
Gln Asp Pro Asp Ile Lys Ala His Val Asn Ser Leu Gly Glu Asn Leu
85 90 95
Lys Thr Leu Arg Leu Arg Leu Arg Arg Cys His Arg Phe Leu Pro Cys
100 105 110
Glu Asn Lys Ser Lys Ala Val Glu Gln Val Lys Asn Ala Phe Asn Lys
115 120 125
Leu Gln Glu Lys Gly Ile Tyr Lys Ala Met Ser Glu Phe Asp Ile Phe
130 135 140
Ile Asn Tyr Ile Glu Ala Tyr Met Thr Met Lys Ile Arg Asn Gly Gly
145 150 155 160
Gly Ser Gly Ser Gly Ser Gly Ser Glu Pro Lys Ser Ser Asp Lys Thr
165 170 175
His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Ala Gly Ala Pro Ser
180 185 190
Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg
195 200 205
Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro
210 215 220
Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala
225 230 235 240
Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val
245 250 255
Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr
260 265 270
Lys Cys Lys Val Ser Asn Lys Gln Leu Pro Ala Pro Ile Glu Lys Thr
275 280 285
Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu
290 295 300
Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr Cys
305 310 315 320
Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser
325 330 335
Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp
340 345 350
Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser
355 360 365
Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala
370 375 380
Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
385 390 395 400
<210> 5
<211> 160
<212> PRT
<213> 人工序列
<400> 5
Ser Pro Gly Gln Gly Thr Gln Ser Glu Asn Ser Cys Thr His Phe Pro
1 5 10 15
Gly Asn Leu Pro Asn Met Leu Arg Asp Leu Arg Asp Ala Phe Ser Arg
20 25 30
Val Lys Thr Phe Phe Gln Met Lys Asp Gln Leu Asp Asn Leu Leu Leu
35 40 45
Lys Glu Ser Leu Leu Glu Asp Phe Lys Gly Tyr Leu Gly Cys Gln Ala
50 55 60
Leu Ser Glu Met Ile Gln Phe Tyr Leu Glu Glu Val Met Pro Gln Ala
65 70 75 80
Glu Asn Gln Asp Pro Asp Ile Lys Ala His Val Asn Ser Leu Gly Glu
85 90 95
Asn Leu Lys Thr Leu Arg Leu Arg Leu Arg Arg Cys His Arg Phe Leu
100 105 110
Pro Cys Glu Asn Lys Ser Lys Ala Val Glu Gln Val Lys Asn Ala Phe
115 120 125
Asn Lys Leu Gln Glu Lys Gly Ile Tyr Lys Ala Met Ser Glu Phe Asp
130 135 140
Ile Phe Ile Asn Tyr Ile Glu Ala Tyr Met Thr Met Lys Ile Arg Asn
145 150 155 160
<210> 6
<211> 8
<212> PRT
<213> 人工序列
<400> 6
Gly Ser Gly Ser Gly Ser Gly Ser
1 5
<210> 7
<211> 232
<212> PRT
<213> 人工序列
<400> 7
Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala
1 5 10 15
Pro Glu Leu Ala Gly Ala Pro Ser Val Phe Leu Phe Pro Pro Lys Pro
20 25 30
Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val
35 40 45
Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val
50 55 60
Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln
65 70 75 80
Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln
85 90 95
Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gln
100 105 110
Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro
115 120 125
Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr
130 135 140
Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser
145 150 155 160
Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr
165 170 175
Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr
180 185 190
Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe
195 200 205
Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys
210 215 220
Ser Leu Ser Leu Ser Pro Gly Lys
225 230
<210> 8
<211> 232
<212> PRT
<213> 人工序列
<400> 8
Glu Pro Lys Ser Ser Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala
1 5 10 15
Pro Glu Leu Ala Gly Ala Pro Ser Val Phe Leu Phe Pro Pro Lys Pro
20 25 30
Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val
35 40 45
Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val
50 55 60
Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln
65 70 75 80
Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln
85 90 95
Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gln
100 105 110
Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro
115 120 125
Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr
130 135 140
Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser
145 150 155 160
Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr
165 170 175
Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr
180 185 190
Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe
195 200 205
Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys
210 215 220
Ser Leu Ser Leu Ser Pro Gly Lys
225 230
<210> 9
<211> 158
<212> PRT
<213> 人工序列
<400> 9
Gly Gln Gly Thr Gln Ser Glu Asn Ser Cys Thr His Phe Pro Gly Asn
1 5 10 15
Leu Pro Asn Met Leu Arg Asp Leu Arg Asp Ala Phe Ser Arg Val Lys
20 25 30
Thr Phe Phe Gln Met Lys Asp Gln Leu Asp Asn Leu Leu Leu Lys Glu
35 40 45
Ser Leu Leu Glu Asp Phe Lys Gly Tyr Leu Gly Cys Gln Ala Leu Ser
50 55 60
Glu Met Ile Gln Phe Tyr Leu Glu Glu Val Met Pro Gln Ala Glu Asn
65 70 75 80
Gln Asp Pro Asp Ile Lys Ala His Val Asn Ser Leu Gly Glu Asn Leu
85 90 95
Lys Thr Leu Arg Leu Arg Leu Arg Arg Cys His Arg Phe Leu Pro Cys
100 105 110
Glu Asn Lys Ser Lys Ala Val Glu Gln Val Lys Asn Ala Phe Asn Lys
115 120 125
Leu Gln Glu Lys Gly Ile Tyr Lys Ala Met Ser Glu Phe Asp Ile Phe
130 135 140
Ile Asn Tyr Ile Glu Ala Tyr Met Thr Met Lys Ile Arg Asn
145 150 155
<210> 10
<211> 10
<212> PRT
<213> 人工序列
<400> 10
Gly Gly Gly Ser Gly Ser Gly Ser Gly Ser
1 5 10
<210> 11
<211> 400
<212> PRT
<213> 人工序列
<400> 11
Glu Pro Lys Ser Ser Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala
1 5 10 15
Pro Glu Leu Ala Gly Ala Pro Ser Val Phe Leu Phe Pro Pro Lys Pro
20 25 30
Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val
35 40 45
Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val
50 55 60
Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln
65 70 75 80
Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln
85 90 95
Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gln
100 105 110
Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro
115 120 125
Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr
130 135 140
Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser
145 150 155 160
Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr
165 170 175
Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr
180 185 190
Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe
195 200 205
Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys
210 215 220
Ser Leu Ser Leu Ser Pro Gly Lys Gly Ser Gly Ser Gly Ser Gly Ser
225 230 235 240
Ser Pro Gly Gln Gly Thr Gln Ser Glu Asn Ser Cys Thr His Phe Pro
245 250 255
Gly Asn Leu Pro Asn Met Leu Arg Asp Leu Arg Asp Ala Phe Ser Arg
260 265 270
Val Lys Thr Phe Phe Gln Met Lys Asp Gln Leu Asp Asn Leu Leu Leu
275 280 285
Lys Glu Ser Leu Leu Glu Asp Phe Lys Gly Tyr Leu Gly Cys Gln Ala
290 295 300
Leu Ser Glu Met Ile Gln Phe Tyr Leu Glu Glu Val Met Pro Gln Ala
305 310 315 320
Glu Asn Gln Asp Pro Asp Ile Lys Ala His Val Asn Ser Leu Gly Glu
325 330 335
Asn Leu Lys Thr Leu Arg Leu Arg Leu Arg Arg Cys His Arg Phe Leu
340 345 350
Pro Cys Glu Asn Lys Ser Lys Ala Val Glu Gln Val Lys Asn Ala Phe
355 360 365
Asn Lys Leu Gln Glu Lys Gly Ile Tyr Lys Ala Met Ser Glu Phe Asp
370 375 380
Ile Phe Ile Asn Tyr Ile Glu Ala Tyr Met Thr Met Lys Ile Arg Asn
385 390 395 400
Claims (8)
1.一种重组融合蛋白,由IL-10、连接肽和IgG Fc片段组成,其特征在于,所述IL-10的C末端通过连接肽连接至所述IgG Fc片段的N末端,所述IL-10与野生型IL-10相比缺失N末端的Ser和Pro;
所述野生型IL-10的氨基酸序列如SEQ ID NO:5所示;
所述连接肽的序列如SEQ ID NO:6或SEQ ID NO:10所示;
所述IgG Fc片段的氨基酸序列如SEQ ID NO:7或SEQ ID NO:8所示。
2.根据权利要求1所述融合蛋白,其特征在于,所述IgG Fc片段的铰链区依照EU编号在第220位的Cys被Ser取代。
3.根据权利要求1或2所述融合蛋白,其特征在于,所述融合蛋白的氨基酸序列如SEQID NO:2、SEQ ID NO:3或SEQ ID NO:4所示。
4.一种核酸,其特征在于,所述核酸编码权利要求1-3任一所述融合蛋白。
5.一种载体,其特征在于,所述载体携带权利要求4所述核酸。
6.一种细胞,其特征在于,所述细胞含有权利要求4所述核酸或权利要求5所述载体。
7.一种药物组合物,其特征在于,所述药物组合物含有权利要求1-3任一所述融合蛋白、权利要求4所述核酸、权利要求5所述载体或权利要求6所述细胞。
8.权利要求1-3任一所述融合蛋白、权利要求4所述核酸、权利要求5所述载体、权利要求6所述细胞或权利要求7所述药物组合物在制备治疗结肠癌的药物中的应用。
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CN101948543A (zh) * | 2010-08-30 | 2011-01-19 | 中国科学技术大学 | 一种融合蛋白及其编码基因与应用 |
CN101962413A (zh) * | 2010-09-21 | 2011-02-02 | 中国科学技术大学 | 具有透皮能力和白细胞介素-10活性的融合蛋白及其编码基因与应用 |
CN108948207A (zh) * | 2017-05-22 | 2018-12-07 | 杭州博虎生物科技有限公司 | 一种人白细胞介素10-Fc融合蛋白及其编码基因与应用 |
CN111989340A (zh) * | 2018-11-18 | 2020-11-24 | 杭州博虎生物科技有限公司 | 一种重组人白细胞介素10融合蛋白及其应用 |
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CN101948543A (zh) * | 2010-08-30 | 2011-01-19 | 中国科学技术大学 | 一种融合蛋白及其编码基因与应用 |
CN101962413A (zh) * | 2010-09-21 | 2011-02-02 | 中国科学技术大学 | 具有透皮能力和白细胞介素-10活性的融合蛋白及其编码基因与应用 |
CN108948207A (zh) * | 2017-05-22 | 2018-12-07 | 杭州博虎生物科技有限公司 | 一种人白细胞介素10-Fc融合蛋白及其编码基因与应用 |
CN111989340A (zh) * | 2018-11-18 | 2020-11-24 | 杭州博虎生物科技有限公司 | 一种重组人白细胞介素10融合蛋白及其应用 |
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