CN111100211B - 一种Fc融合蛋白及其应用 - Google Patents
一种Fc融合蛋白及其应用 Download PDFInfo
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- CN111100211B CN111100211B CN202010071809.9A CN202010071809A CN111100211B CN 111100211 B CN111100211 B CN 111100211B CN 202010071809 A CN202010071809 A CN 202010071809A CN 111100211 B CN111100211 B CN 111100211B
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Abstract
本发明公开了一种Fc融合蛋白及其应用。所述的融合蛋白包含第一抗原结合功能区、第二抗原结合功能区以及连接的第一Fc链和第二Fc链；其中，所述的第一抗原结合功能区包含TNFαR2和IL‑17RA，所述的第二抗原结合功能区包含TNFαR2和IL‑17RC。本发明的Fc融合蛋白可以在不增加毒副作用的同时，协同治疗效果。
Description
技术领域
本发明属于生物医药领域，具体涉及一种Fc融合蛋白及其应用。
背景技术
针对类风湿关节炎、结肠炎、Crohn’s(克罗恩)病、白癜风以及强直性脊柱炎等自身免疫性疾病，目前生物药治疗手段是使用单克隆抗体或者融合蛋白。其中，在阻断TNFα分子上，目前主要是使用针对该分子的抗体，如阿达木单抗(adalimumab)或Fc融合蛋白(etanercept)。后者是TNFα受体部分p75TNFR2融合Fc部分IgG1。这个融合蛋白已申请了专利并被FDA批准上市。其主要作用机理及副作用与阿达木单抗类似。还有部分上市药物以单克隆抗体阻断IL-17的p19或者IL-17R，其主要作用是阻断自身免疫性疾病的一些炎性反应，达到改善症状的作用。但以类风湿关节炎为代表的自身免疫性疾病发病机理复杂，单纯阻断TNF或者IL-17的作用，只是部分减轻病人的症状，而若是两种药物同时使用则会大幅增加治疗费用，并有可能产生超过人体耐受限度的毒副作用。尽管现有的Fc融合蛋白，其商业化的表达、生产以及纯化已相对比较成熟。例如Etanercept就是在CHO细胞进行表达生产；其为融合蛋白，是两部分蛋白的融合，即及IgG单克隆抗体的Fc片段的CH2-CH3，融合TNFα受体p75。而目前药物领域尚无能够既能够阻断TNF、又能够阻断IL-17的融合蛋白或治疗方式出现。
发明内容
本发明所要解决的技术问题是针对现有技术中缺乏能够同时阻断TNF和IL-17的融合蛋白缺陷，提供一种Fc融合蛋白及其应用。本发明最终获得的Fc融合蛋白可以在不增加毒副作用的同时，协同治疗效果。
本发明主要通过以下技术方案解决上述技术问题。
本发明提供一种异源二聚体形式的Fc融合蛋白，所述的Fc融合蛋白包含第一抗原结合功能区、第二抗原结合功能区以及连接的第一Fc链和第二Fc链；其中，所述的第一抗原结合功能区包含TNFαR2(TNFαII型受体)和IL-17RA，所述的第二抗原结合功能区包含TNFαR2(TNFαII型受体)和IL-17RC。
所述第一Fc链和所述第二Fc链之间的所述连接可为本领域常规的连接，例如通过二硫键所形成的连接。所述的连接可为人工的或者天然形成的，本发明中的所述第一Fc链和所述第二Fc链之间的所述连接为自连接。另外，本发明中所述的第一Fc链和所述的第二Fc链可根据本领域的常规理解，即两者构成人源IgG1的CH2-CH3。
较佳地，所述第一抗原结合功能区从N端到C端依次为TNFαR2和IL-17RA，所述第二抗原结合功能区从N端到C端依次为IL-17RC和TNFαR2。
为保证两部分的空间结构得以维持，并维持与原融合蛋白前的各部生物学功能，所述的第一抗原结合功能区中的所述TNFαR2和所述IL-17RA之间较佳地通过连接子1连接。同理，所述的第二抗原结合功能区中的所述IL-17RC和所述TNFαR2之间较佳地通过连接子2连接。
较佳地，所述的连接子1或者所述的连接子2的氨基酸个数可为5～46个，优选46个；更佳地，所述的连接子1和/或所述的连接子2的氨基酸序列如序列表中SEQ ID NO.1所示；进一步更佳地，编码所述连接子1或所述连接子2的核苷酸序列如序列表中SEQ ID NO.2所示。
如上所述的Fc融合蛋白，较佳地，所述的第一抗原结合功能区的C端连接于所述第一Fc链的N端，所述第二抗原结合功能区的C端连接于所述第二Fc链的N端；更佳地，所述第一抗原结合功能区的氨基酸序列如序列表中SEQ ID NO.3所示，所述第二抗原结合功能区的氨基酸序列如序列表中SEQ ID NO.4所示。
本发明还提供一种编码如上所述的Fc融合蛋白的核苷酸。
本发明还提供一种包含上述的核苷酸的表达载体。
本发明还提供一种包含上述的核苷酸或如上所述的表达载体的宿主细胞，所述的宿主细胞较佳地为真核细胞，例如CHO、HEK293或者NS0等，优选CHO细胞。
本发明还提供一种药物组合物，其包含如上所述的Fc融合蛋白、如上所述的核苷酸、如上所述的表达载体或者如上所述的宿主细胞，以及药学上可接受的载体。
本发明还提供一种如上所述的Fc融合蛋白或者如上所述的药物组合物在制备治疗与TNFα受体和/或IL-17受体表达或者功能异常相关的疾病的药物中的应用；较佳地，所述与TNFα受体和/或IL-17受体表达或者功能异常相关的疾病为类风湿关节炎、结肠炎、克罗恩病、白癜风以及强直性脊柱炎。
本发明中所提及的“连接子1”、“第一抗原结合功能区”以及“第一Fc链”中的数字仅为区分相同的术语，并无实际意义；该情况说明也同样适用于“连接子2”、“第二抗原结合功能区”以及“第二Fc链”中的数字。
如本发明所述，除非另外说明，Fc是指人免疫球蛋白的Fc片段。术语“免疫球蛋白Fc区”指免疫球蛋白链恒定区，特别是免疫球蛋白重链恒定区的羧基端或其中的一部分，例如免疫球蛋白Fc区可包括重链CH1、CH2、CH3的两个或更多结构域与免疫球蛋白铰链区的组合，在优选例中，所用的免疫球蛋白的Fc区包括至少一个免疫球蛋白绞链区，一个CH2结构域和一个CH3结构域，优选缺少CH1结构域。
已知人免疫球蛋白有多种类别，如IgA、IgD、IgE、IgM及IgG(包括IgG1、IgG2、IgG3、IgG4四个亚类)，从特定的免疫球蛋白类别和亚类中选择特定的免疫球蛋白Fc区是在本领域技术人员所掌握的范围之内的，在一个优选的实例中，免疫球蛋白Fc区可选择包含有人免疫球蛋白IgG4亚类Fc区的编码序列，其中缺失一个免疫球蛋白重链1结构域(CH1)，但包括了铰链区以及CH2、CH3、二个结构域的编码序列。
如本发明所用，所述的“含有”、“具有”或“包括”包括了“包含”、“主要由……构成”、“基本上由……构成”、和“由……构成”；“主要由……构成”、“基本上由……构成”和“由……构成”属于“含有”、“具有”或“包括”的下位概念。
如本发明所用，除非另外说明，所述的融合蛋白是一种分离的蛋白，与其它蛋白、多肽或分子无联系，是重组宿主细胞培养的纯化产物或作为一种纯化的提取物。
根据本发明提供的氨基酸序列，本技术领域人员可方便地用各种已知方法制得本发明的融合蛋白。这些方法例如但不限于：重组DNA法、人工合成等，参见Murray KM,DahlSLAnn；Pharmacother 1997Nov；31(11):1335-8。
在得知了本发明的融合蛋白的氨基酸序列后，本领域人员可以方便地根据所述的氨基酸序列获得编码本发明的融合蛋白的基因序列。
在符合本领域常识的基础上，上述各优选条件，可任意组合，即得本发明各较佳实例。
本发明所用试剂和原料均市售可得。
本发明的积极进步效果在于：
本发明中的Fc融合蛋白的每一单元亲和力和与之相应的单个单元的亲和力几乎一致，因此用一个单位的融合蛋白可以达到合用二个单位的单元蛋白的作用。故使用剂量会减半，从而达到减轻药物副作用的目的。另外，Fc融合蛋白的各功能区均为人体本身的蛋白成分，特异性专一且几乎没有免疫源性，不具有单抗药物可能存在的非特异性组织结合能力及免疫源性，因而其毒副作用低于单抗药物，适用于类风湿关节炎、结肠炎、Crohn’s(克罗恩)病、白癜风以及强直性脊柱炎等自身免疫性疾病。综上，本发明的Fc融合蛋白可以在不增加毒副作用的同时，协同治疗效果。
附图说明
图1为融合蛋白的组成结构示意图。
图2及表1为ELISA检测的融合蛋白产量。
图3及表2为MTT检测的L929细胞成活率。
图4及表3为MTT检测的BJF细胞成活率。
具体实施方式
下面通过实施例的方式进一步说明本发明，但并不因此将本发明限制在所述的实施例范围之中。下列实施例中未注明具体条件的实验方法，按照常规方法和条件，或按照商品说明书选择。
实施例1合成DNA
将蛋白质TNFαR2(NCBI Reference Sequence:NM_001066.3)分别与IL17RA(GenBank:BC011624.2)和IL17RC(GenBank:AF458065.1)连接[所用连接子的氨基酸序列如序列表中SEQ ID NO.1所示，编码该氨基酸序列的核苷酸序列如序列表中SEQ ID NO.2所示；另外尝试了其他种类的连接子，例如(GSSSS)n(n为1～10)，最终所得的融合蛋白的生物学功能差于利用氨基酸序列如SEQ ID NO.1所示的连接子制备得到的Fc融合蛋白]，作为Fc(人的IgG1的CH2和CH3)的双臂。连接后的蛋白的名称分别为TNFαR2-IL17RA(氨基酸序列详见序列表中SEQ ID NO.3)和IL17RC-TNFαR2(氨基酸序列详见序列表中SEQ ID NO.4)。生物公司合成蛋白TNFαR2-IL17RA和IL17RC-TNFαR2的基因。
合成的DNA经过PCR扩增(引物带有酶切位点)、纯化、酶切，再度纯化，将该酶切的片段与表达载体pGKpuro-EF(购自生物风，http://www.biofeng.com/)进行连接。该表达载体含有人的IgG1片段(其中，IgG1通过铰链与TNFαR2-IL17RA以及IL17RC-TNFαR2连接。插入的片段已经设计为连接片段与IgG1位于同一阅读框架。连接反应的产物经纯化后，转入DH5α细菌(市售可得)，选择抗生素抵抗菌落、扩增，提取DNA质粒，酶切证实插入片段的长度及方向正确。进一步测序证实每个核酸及阅读框架均正确。扩增含该表达载体的细菌，制备maxiPrep高纯度质粒备用。
实施例2蛋白表达
使用Fugene将实施例1制备得到的表达质粒，转入CHO细胞(市售可得)。24小时后开始用5μg/ml Puromycin(嘌呤霉素)选择(操作为本领域常规，具体为每隔2～3天置换含5μg/ml puromycin细胞培养液)，直至明显克隆形成。挑取大约8～10个克隆，进一步扩增。在细胞数量大约达到1×106时，使用5×105细胞，培养在10ml不含抗生素的培养液，24小时后，收集培养液，检查相关蛋白质的产量。选取2～3个高表达克隆株，在含有puromycin培养液中继续选择1个月，无puromycin选择1个月，最后选择最高表达株作为稳定细胞株。
表达Fc融合蛋白(其示意图如图1所示，其中的hinge为常规抗体的一部分)的细胞培养液，其蛋白以protein A柱纯化，检查含量后备用。
实施例3Fc融合蛋白的性能测定
以ELISA检测Fc融合蛋白产量。对TNFαR2的检测，采用Abcam公司的Human SolubleTNF Receptor ELISA Kit(ab100642)。操作步骤按其试剂盒要求执行。对IL17RA的检测，采用Abcam公司的Human IL-17A Receptor ELISA Kit(ab100558)。操作步骤按其试剂盒的要求执行。对IL17RC的检测，采用Abcam公司的Human IL-17RC ELISA Kit(ab213794)。操作步骤按其试剂盒要求执行。
检测结果如表1及图2所示，根据表1及图2可知：稳定细胞株培养液经Protein A柱纯化后，含有的融合蛋白成分经ELISA检测，含有TNFαR2、IL17RA及IL17RC的活性。说明该细胞株产生的融合蛋白的各蛋白组成部分，保留了原来各自蛋白的结构及功能。
表1 Fc融合蛋白三种含量的检测(mg/ml)
| TNFαR2 | IL-17RA | IL-17RC | |
| 第一次检测 | 0.87 | 0.56 | 0.68 |
| 第二次检测 | 0.69 | 0.53 | 0.6 |
| 第三次检测 | 0.85 | 0.61 | 0.65 |
2、以bioassay检测其生物学功能
具体步骤，以BJ human foreskin fibroblast cells(BJF；市售可得)检测IL-17RA/RC阻断IL-17对该细胞生长的影响。BJF细胞需要IL17作为其生长的必需条件。BJF细胞以5×105/孔的密度置于在96孔盘中，每孔均加入15ng/ml的hIL17(人IL17；购自Abcam)作为生长因子。Protein A纯化的细胞株培养液，以1:2连续稀释，然后再将同等体积的稀释液加入到每个孔中。24小时后，每孔中加入等量的MTT(四甲基偶氮唑盐)，测量OD值，换算出细胞成活率。
TNFαR2 bioassay则以L929细胞(购自ATCC)检测TNFαR2阻断TNFα对该细胞的毒性作用。TNFα对L929细胞生长具有毒性杀灭作用。L929细胞以5×105/孔的密度置于在96孔盘中，每孔均加入20ng/ml的TNFα。Protein A纯化的细胞株培养液，以1:2连续稀释，然后再将同等体积的稀释液加入到每个孔中。24小时后，每孔中加入等量的MTT，测量OD值，换算出细胞成活率。
图3和表2利用融合蛋白中的TNFαR2结合TNFα，以中和TNFα对L929细胞的毒性作用。融合蛋白被稀释的倍数越低，融合蛋白的浓度越高，融合蛋白结合的TNFα越多，BJF细胞成活率越高。其中，表2及图3中的“TNFR2-Fc”为测试对象，即融合蛋白中的TNFRα2；“TNFR2-ST”，意指单独的TNFαR2标准蛋白(Recombinant human TNF Receptor II protein，购自Abcam，商品号为ab168884)。
表2 L929细胞在TNFα+TNFα-Fc融合蛋白中的成活率(MTT测量)
| 浓度ng/ml | 1000 | 250 | 62.5 | 15.63 | 3.91 | 0.98 | 0.24 | 0.06 |
| TNFRα2-Fc | 100 | 100 | 98.34 | 92.11 | 55.73 | 15.33 | 10.01 | 1.25 |
| TNFαR2-ST | 98.73 | 97.64 | 96.23 | 98.35 | 50.38 | 10.95 | 4.41 | 0.49 |
图4和表3利用融合蛋白中的IL17RA及IL17RC结合IL17，以减少IL17对BJF细胞的生长作用。融合蛋白被稀释的倍数越高，融合蛋白的浓度越低，融合蛋白结合的IL17越少，BJF细胞成活率越高。其中，表3及图4中的“IL17R-Fc”为测试对象，即融合蛋白中的IL17R；“IL17RC-ST”为单独的IL17RC标准蛋白(Recombinant Human IL-17RC protein，购自Abcam，商品号为ab164665)；“IL17RA-ST”为单独的IL17RA标准蛋白(Recombinant HumanIL-17RA Receptor protein，购自Abcam，商品号为ab161762)。
表3 BJF细胞在hIL17R融合蛋白中的成活率
| 浓度ng/ml | 1000 | 250 | 62.5 | 15.63 | 3.91 | 0.98 | 0.24 | 0.06 |
| IL17R-Fc | 98.12 | 96.23 | 99.73 | 94.51 | 38.76 | 13.21 | 4.32 | 1.34 |
| IL17RC-ST | 98.45 | 100 | 96.37 | 84.26 | 30.16 | 8.42 | 5.39 | 0.15 |
| IL17RA-ST | 100 | 99.48 | 100 | 76.31 | 27.19 | 3.69 | 3.16 | 0.18 |
表2及图3、以及表3及图4结果表明，融合蛋白中含有的TNFαR2及IL17R具有结合各自TNFα及IL17的生物活性；分别中和了TNFα和IL17对BJF细胞的细胞毒性作用和生长作用。
SEQUENCE LISTING
<110> 武汉九州钰民医药科技有限公司
<120> 一种Fc融合蛋白及其应用
<130> P20010273C
<150> CN2019100935219
<151> 2019-01-30
<160> 4
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Claims (15)
1.一种异源二聚体形式的Fc融合蛋白，其特征在于，其由第一抗原结合功能区、第二抗原结合功能区以及连接的第一Fc链和第二Fc链组成；其中，所述的第一抗原结合功能区由TNFαR2和IL-17RA组成，所述的第二抗原结合功能区由TNFαR2和IL-17RC组成；
所述第一抗原结合功能区从N端到C端依次为TNFαR2和IL-17RA，所述第二抗原结合功能区从N端到C端依次为IL-17RC和TNFαR2。
2.如权利要求1所述的Fc融合蛋白，其特征在于，所述的第一抗原结合功能区中的所述TNFαR2和所述IL-17RA之间通过连接子1连接；
和/或，所述的第二抗原结合功能区中的所述IL-17RC和所述TNFαR2之间通过连接子2连接。
3.如权利要求2所述的Fc融合蛋白，其特征在于，所述的连接子1或者所述的连接子2的氨基酸个数为5～46个。
4.如权利要求3所述的Fc融合蛋白，其特征在于，所述的连接子1或者所述的连接子2的氨基酸个数为46个。
5.如权利要求4所述的Fc融合蛋白，其特征在于，所述的连接子1和/或所述的连接子2的氨基酸序列如序列表中SEQ ID NO:1所示。
6.如权利要求5所述的Fc融合蛋白，其特征在于，编码所述连接子1或所述连接子2的核苷酸序列如序列表中SEQ ID NO.2所示。
7.如权利要求1～6任一项所述的Fc融合蛋白，其特征在于，所述的第一抗原结合功能区的C端连接于所述第一Fc链的N端，所述第二抗原结合功能区的C端连接于所述第二Fc链的N端。
8.如权利要求7所述的Fc融合蛋白，其特征在于，所述第一抗原结合功能区的氨基酸序列如序列表中SEQ ID NO:3所示，所述第二抗原结合功能区的氨基酸序列如序列表中SEQID NO:4所示。
9.一种编码如权利要求1～8任一项所述的Fc融合蛋白的核苷酸。
10.一种包含如权利要求9所述的核苷酸的表达载体。
11.一种包含如权利要求9所述的核苷酸或如权利要求10所述的表达载体的宿主细胞。
12.如权利要求11所述的宿主细胞，其特征在于，所述的宿主细胞为真核细胞。
13.如权利要求12所述的宿主细胞，其特征在于，所述的宿主细胞为CHO细胞。
14.一种药物组合物，其包含如权利要求1～8任一项所述的Fc融合蛋白、如权利要求9所述的核苷酸、如权利要求10所述的表达载体或者如权利要求11～13任一项所述的宿主细胞，以及药学上可接受的载体。
15.一种如权利要求1～8任一项所述的Fc融合蛋白或者如权利要求14所述的药物组合物在制备治疗与TNFα受体和/或IL-17受体表达或者功能异常相关的疾病的药物中的应用；
所述与TNFα受体和/或IL-17受体表达或者功能异常相关的疾病为类风湿关节炎、结肠炎、克罗恩病、白癜风以及强直性脊柱炎。
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Denomination of invention: A Fc Fusion Protein and Its Application Granted publication date: 20220408 Pledgee: Agricultural Bank of China Co.,Ltd. Wuhan Branch Business Department Pledgor: Wuhan Jiuzhou Yumin Medical Technology Co.,Ltd. Registration number: Y2024980025475 |