CN116410328A - 重组犬pd-l1融合蛋白及其制备方法与应用 - Google Patents
重组犬pd-l1融合蛋白及其制备方法与应用 Download PDFInfo
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Abstract
本发明涉及生物医药技术领域,具体涉及重组犬PD‑L1融合蛋白及其制备方法与应用。本发明提供的重组犬PD‑L1融合蛋白包含犬PD‑L1蛋白胞外区以及与所述犬PD‑L1蛋白胞外区直接或间接相连的Fc片段。该融合蛋白与野生型PD‑L1相比,具有更高的PD‑1亲和力以及更长的半衰期,且具有良好的生物学活性,能够有效减少犬T细胞的过度活化增殖,减少细胞因子的分泌,为犬自身免疫病的免疫治疗提供了新的治疗药物。
Description
技术领域
本发明涉及生物医药技术领域,具体涉及一种重组犬PD-L1融合蛋白及其制备方法与应用。
背景技术
免疫系统是机体对自身进行防御、自稳和监视的重要体系,它能发现并清除异物、外来病原微生物等引起内环境波动的因素。免疫功能的实现主要包括对于“异己”成分的识别以及产生免疫应答将其清除,而对“自己”成分则不产生应答,维持耐受。正常情况下,免疫系统保持稳定状态,但在免疫系统紊乱时会导致多种疾病的发生,自身免疫病就是其中一种,常见自身免疫病包括类风湿关节炎(RA)、系统性红斑狼疮(SLE)等。自身免疫病是免疫系统过度激活,将正常的组织作为入侵者而进行攻击,自身反应性T细胞和自身反应性B细胞被激活,攻击并破坏自身组织细胞,导致机体出现病理改变和相应临床表现。自身免疫病主要的发病机制是免疫紊乱导致的T细胞过度活化和免疫病理损伤,常用激素、免疫抑制剂等药物进行治疗,但是这些药物不仅抑制自身免疫反应,同时还会抑制机体自身抵御异物(包括导致感染的微生物和恶性肿瘤细胞等)侵袭的能力,长期使用毒副作用较大。如何有针对性地阻断患者机体细胞攻击自身的健康组织是治疗自身免疫性疾病的关键。目前,随着抗肿瘤靶向药的大量研发,免疫靶向治疗研究不断深入,已有一些自身免疫性疾病的免疫治疗药物的报道,免疫靶向治疗生物制剂通过阻断关键炎症细胞因子或细胞表面分子而发挥治疗作用。但由于自身免疫病发病机制复杂,针对单一细胞因子或信号分子为靶点难以达到长期、稳定的疗效。因此,需要开发不同的治疗药物和治疗方法。
程序性细胞死亡受体1(PD-1,又称为PDCD1)是大小为50~55KD的I型膜糖蛋白,属于CD28超家族受体,是一种重要的免疫抑制分子。PD-1蛋白主要在T细胞(包括抗原刺激活化的T细胞)、B淋巴细胞和活化的巨噬细胞表面表达,骨髓细胞也表达PD-1。PD-1具有两个配体,即PD-L1和PD-L2。在正常生理状态下,PD-1与PD-L1/PD-L2结合抑制T细胞的活化及细胞因子的产生,保护机体免受自身免疫系统攻击,从而防止过度免疫损伤和自身免疫病的发生,是T细胞活化的重要调节信号通道。PD-1/PD-L1通路是目前自身免疫病治疗的靶点之一,以过度活化的T细胞PD-1受体为靶点,引入外源PD-L1分子增强机体自身反应性T细胞的抑制性信号,有望对自身免疫病产生良好的治疗效果。
PD-L1融合蛋白是针对PD-1/PD-L1信号通路的一种新的自身免疫病治疗药物,可竞争性的结合T细胞的PD-1受体,激活T细胞的活化抑制通路,从而减弱T细胞的活化以及降低细胞因子分泌水平,减弱免疫应答。PD-L1融合蛋白相关药物在人上的应用及研究鲜有报道,在犬自身免疫病上的研究仍处于空白阶段。
与人类类似,犬也会发生自身免疫疾病,涉及多个系统及器官,例如:内分泌自身免疫性疾病(如自身免疫性甲状腺炎、糖尿病、阿狄森氏病)、皮肤自身免疫性疾病(如寻常性天疱疮、系统性红斑狼疮)、眼睛自身免疫性疾病(如干眼症、葡萄膜炎)、消化系统自身免疫性疾病(如犬炎症性肠病)、关节疾病(如类风湿性关节炎)、过敏(高度敏感的免疫系统)等,目前针对犬的自身免疫疾病的研究极少,也尚未有相关的治疗药物,因此患病犬临床治疗存在较大困难。
发明内容
本发明的目的是提供一种重组犬PD-L1融合蛋白及其制备方法与应用。
具体地,本发明提供以下技术方案:
第一方面,本发明提供一种重组犬PD-L1融合蛋白,所述融合蛋白包含犬PD-L1蛋白胞外区以及与所述犬PD-L1蛋白胞外区直接或间接相连的Fc片段;
其中,所述犬PD-L1蛋白胞外区具有如下氨基酸序列:
(a)如SEQ ID NO:3所示的氨基酸序列;或,
(b)如SEQ ID NO:3所示的氨基酸序列经取代、缺失或添加一个或几个氨基酸且具有同等功能的由(a)衍生的氨基酸序列。
以上所述的Fc片段包含犬IgG1免疫球蛋白的铰链区、CH2和CH3区。
优选地,所述融合蛋白由犬PD-L1蛋白胞外区直接或间接与Fc片段之间通过Linker连接而成;所述Linker为由2-20个柔性氨基酸组成的柔性多肽,所述柔性氨基酸选自Gly、Ser、Ala、Thr中的至少一种。
进一步优选地,所述Linker为(Gly-Gly-Gly-Gly-Ser)n,其中n为2-5之间的整数。更优选n为2。
具体地,所述融合蛋白为cPD-L1-Fc,具有如下氨基酸序列:
(c)如SEQ ID NO:1所示的氨基酸序列;或,
(d)与如SEQ ID NO:1所示的氨基酸序列具有90%以上同源性且具有相同功能的由(c)衍生的氨基酸序列。
本领域技术人员应理解的是,犬cPD-L1-Fc融合蛋白经突变或与其他蛋白融合构成的不改变蛋白活性的融合蛋白,均属于本发明的保护范围。
经过修饰的蛋白,包括融合蛋白cPD-L1-Fc经糖基化、聚乙二醇化、乙酰化或与BSA结合等得到的蛋白,均属于本发明的保护范围。
第二方面,本发明提供一种核酸分子,其编码以上所述的重组犬PD-L1融合蛋白。
优选地,所述核酸分子的核苷酸序列如SEQ ID NO:2所示。如SEQ ID NO:2所示的序列为经密码子优化得到的适于在真核细胞中表达的序列。
第三方面,本发明提供含有所述融合蛋白或所述核酸分子的生物材料,所述生物材料为表达盒、转座子、质粒载体、噬菌体载体、病毒载体、工程菌或转基因细胞系。
第四方面,本发明提供所述重组犬PD-L1融合蛋白的制备方法,所述方法包括:将编码重组犬PD-L1融合蛋白的核酸分子与表达载体连接得到重组表达载体,将所述重组表达载体导入宿主细胞中,培养宿主细胞使其表达所述融合蛋白,经分离纯化得到所述融合蛋白。
优选地,所述表达载体为pcDNA3.1,所述宿主细胞为CHO细胞。
第五方面,本发明提供所述融合蛋白或所述核酸分子或所述生物材料在制备用于抑制犬免疫细胞过度活化的药物中的应用。
优选地,所述的药物通过PD-1/PD-L1信号通路抑制免疫细胞过度活化。
第六方面,本发明提供所述融合蛋白或所述核酸分子或所述生物材料在制备用于治疗犬自身免疫病的药物中的应用。
优选地,所述自身免疫疾病包括自身免疫性甲状腺炎、糖尿病、阿狄森氏病、类风湿关节炎、寻常性天疱疮、系统性红斑狼疮、犬炎症性肠病、干眼症或葡萄膜炎。
第七方面,本发明提供所述融合蛋白或所述核酸分子或所述生物材料在治疗犬免疫细胞过度活化、减少细胞因子产生,或治疗犬自身免疫性疾病中的应用。
第八方面,本发明提供一种药物,所述药物包含以上所述的重组犬PD-L1融合蛋白。
以上所述的药物优选以所述重组犬PD-L1融合蛋白作为有效成分。
除包含所述重组犬PD-L1融合蛋白以外,所述药物还可包含药学领域允许的辅料或其它有效成分。
以上所述的药物可用于抑制犬免疫细胞过度活化或治疗犬自身免疫病。
本发明的有益效果至少包括:本发明提供的重组犬PD-L1融合蛋白与野生型PD-L1相比,具有更高的PD-1亲和力以及更长的半衰期,具有良好的生物学活性,能够有效减少犬T细胞的过度活化增殖,减少细胞因子的分泌,为犬自身免疫病的免疫治疗提供了新的治疗药物。
本发明提供的重组犬PD-L1融合蛋白,特异性地针对犬自身免疫疾病,通过抑制T细胞的活化,有望应用于治疗以T细胞过度活化和免疫病理损伤为特征的疾病。
附图说明
图1为本发明实施例2中cPD-L1-Fc的SDS-PAGE电泳图;其中,A:cPD-L1-Fc的非还原电泳图;B:cPD-L1-Fc的还原电泳图。MK:蛋白Marker;1、5:细胞培养上清液;2、6:复合模式层析收集液;3、7:阴离子层析收集液;4、8:疏水层析收集液。
图2为本发明实施例5中cPD-L1-Fc的生物学活性验证结果;其中,PBMC代表阴性对照组,Act PBMC代表空白对照组(激活PBMC且未添加任何蛋白或受试药),Act PBMC+Fc代表Fc同型对照组,Act PBMC+cPD-L1-Fc代表cPD-L1-Fc融合蛋白组。
具体实施方式
本发明的技术方案如下:犬PD-L1胞外区的氨基酸序列直接或间接通过连接元件融合至Fc片段合成重组犬PD-L1融合蛋白cPD-L1-Fc。
所述cPD-L1-Fc融合蛋白是犬PD-L1胞外区的融合蛋白,是由SEQ ID NO:1所示的氨基酸序列构成的蛋白;或者与SEQ ID NO:1所示的氨基酸序列的同源性在90%以上,且具有同等功能的蛋白。
所述融合蛋白包括Fc片段,所述Fc片段包含免疫球蛋白铰链区以及CH2和CH3区;所述免疫球蛋白来自犬。
所述犬PD-L1胞外区与Fc的连接关系为直接连接或通过Linker连接,优选通过Linker连接;其中所述Linker是由2-20个柔性氨基酸组成的柔性多肽,所述柔性氨基酸选自Gly、Ser、Ala和Thr中的至少一种;优选地,所述Linker为(Gly-Gly-Gly-Gly-Ser)n,其中n为2-5之间的整数,更优选n为2。
进一步地,本发明还提供一种编码所述融合蛋白的核酸分子以及含有所述融合蛋白或所述核酸分子的生物材料,所述生物材料为表达盒、转座子、质粒载体、噬菌体载体、病毒载体、工程菌或转基因细胞系。
进一步地,本发明提供一种重组犬PD-L1融合蛋白的制备方法,所述方法包括:将编码重组犬PD-L1融合蛋白的核酸分子与表达载体连接得到重组表达载体,将所述重组表达载体导入宿主细胞中,培养宿主细胞使其表达所述融合蛋白,经分离纯化得到所述融合蛋白。优选地,所述表达载体为pcDNA3.1,所述宿主细胞为CHO细胞。
以下实施例用于说明本发明,但不用来限制本发明的范围。若未特别指明,实施例均按照常规实验条件,如Sambrook等分子克隆实验手册(Sambrook J&Russell DW,Molecular Cloning:a Laboratory Manual,2001),或按照制造厂商说明书建议的条件。
实施例1犬cPD-L1-Fc融合蛋白真核表达载体的构建
在UniProt库和GenBank库中搜索犬PD-L1(UniProtKB:E2RKZ5)和犬Fc(GenBank:AF354264)的氨基酸序列。在犬PD-L1和犬Fc的基础上设计融合蛋白。经不断筛选和优化,获得由犬PD-L1蛋白胞外区与犬Fc片段通过linker相连的融合蛋白cPD-L1-Fc,融合蛋白cPD-L1-Fc的氨基酸序列如SEQ ID NO:1所示,其中,犬PD-L1蛋白胞外区的氨基酸序列如SEQ IDNO:3所示。
对融合蛋白cPD-L1-Fc的编码基因进行密码子优化,得到优化后的cPD-L1-Fc的编码基因的核苷酸序列如SEQ ID NO:2所示。人工合成上述基因,并构建于pcDNA3.1载体中,得到重组表达载体pcDNA3.1-cPD-L1-Fc。将pcDNA3.1-cPD-L1-Fc重组载体线性化后电转转入CHO细胞中获得cPD-L1-Fc的稳转细胞系。
实施例2犬cPD-L1-Fc融合蛋白的表达和纯化
将表达犬PD-L1-Fc的稳转细胞在发酵罐中进行发酵培养,发酵液先经过两级深层过滤膜包去除细胞和细胞碎片,然后用0.22μm滤膜过滤,获得澄清的细胞培养液。获得的细胞培养液首先用阴离子交换纯化(Uni-Gel30Q):先用平衡液(10mM Tris-HCl 0.05M NaClpH7.5)平衡,平衡好后开始上样,上样后用平衡液再平衡层析柱至基线后用洗脱液(10mMTris-HCl,0.17M NaCl,pH7.5)洗脱,收集洗脱液。然后进行疏水层析(Phenyl SepharoseCL-4B):阴离子层析洗脱收集液用(10mM Tris-HCl 1.6M硫酸铵pH7.5)稀释至样品电导率与疏水层析平衡液一致,再用疏水层析进行纯化,用平衡液(10mM Tris-HCl1.2M硫酸铵pH7.5)平衡后上样,上样结束后用平衡液再平衡至基线,之后用洗脱液(10mM Tris-HCl,0.22M硫酸铵,pH7.5)洗脱,收集目的蛋白。最后进行复合模式层析(Capto MMC):疏水层析收集液用水稀释至电导率与复合模式层析平衡液(10mM柠檬酸三钠-柠檬酸,0.1M NaCl,pH5.0)一致,pH调至5.0,层析柱先用平衡液平衡然后上样,后用平衡液再平衡至基线,之后用洗杂液(10mM柠檬酸三钠-柠檬酸,0.25M NaCl,pH5.0)洗杂蛋白,最后用洗脱液(10mM柠檬酸三钠-柠檬酸,0.55M NaCl,pH5.0)洗脱蛋白并收集目的蛋白。对纯化的目的蛋白进行SDS-PAGE凝胶电泳(图1)。
实施例3犬cPD-L1-Fc融合蛋白亲和力常数检测
使用BIAcore 3000仪器进行亲和力分析。试验设置2个样品组:cPD-L1组(野生型犬PD-L1的胞外区)以及cPD-L1-Fc融合蛋白组(cPD-L1-Fc),首先将重组犬PD-1(重组犬PD-1的制备方法参考实施例2,其氨基酸序列如SEQ ID NO:4所示)偶联到通道2,再对通道1进行封闭处理,作为对照通道。将分析物(cPD-L1、cPD-L1-Fc)梯度稀释(1000nM、500nM、250nM、125nM、62.5nM、31.3nM)后流入,测定对芯片表面偶联的PD-1的结合曲线,使用软件Wizard程序记录信号Fc2-1。以1:1结合模型分析,测定亲和力常数KD。测定结果显示:cPD-L1对重组犬PD-1的结合常数(Ka)为2.14×105,解离常数(Kd)为5.88×10-1,亲和力常数(KD)为2.7×10-6M;融合蛋白cPD-L1-Fc对重组犬PD-1的Ka为5.31×105,Kd为2.05×10-1,KD为3.9×10-7M。以上结果说明犬cPD-L1-Fc融合蛋白的亲和力显著高于cPD-L1。
实施例4犬cPD-L1-Fc融合蛋白的药代动力学研究
选取10只40g左右的SD雌性大鼠,随机分成两组:cPD-L1-Fc融合蛋白组和cPD-L1组。静脉注射15mg/kg体重的相应药品,分别在给药0、1、2、4、8、12、24、48、72、96、120、144h后采集血液,3000rpm离心分离血清-80℃冻存。使用ELISA法检测血清中cPD-L1-Fc、cPD-L1的含量。使用Pksolver软件计算cPD-L1-Fc半衰期为53.2h,cPD-L1半衰期为4.5h,表明cPD-L1-Fc融合蛋白的半衰期较cPD-L1显著延长。
实施例5犬cPD-L1-Fc融合蛋白的生物学活性检测
分离犬PBMC,按照4×105cells/孔的密度接种至96孔板,分别设置阴性对照组(PBMC)、空白对照组(Act PBMC)、Fc同型对照组(Act PBMC+Fc)、cPD-L1-Fc融合蛋白组(ActPBMC+cPD-L1-Fc),除阴性对照组外,其余各组均添加适量浓度的SEB(金黄色葡萄球菌肠毒素B,100ng/ml)刺激犬外周血T细胞活化增殖;然后Fc同型对照组和cPD-L1-Fc融合蛋白组分别添加cFc(犬Fc片段)和cPD-L1-Fc融合蛋白,添加的蛋白浓度为1000nM,阴性对照组添加等体积完全培养基,各组于37℃,5%CO2培养箱中孵育72h,收集上清,ELISA检测犬IFN-γ的浓度。
实验结果如图2所示,cPD-L1-Fc融合蛋白可以降低SEB刺激的犬PBMC中T细胞的活化增殖,减少犬IFN-γ的分泌,具有良好的生物学活性。
虽然,上文中已经用一般性说明及具体实施方案对本发明作了详尽的描述,但在本发明基础上,可以对之作一些修改或改进,这对本领域技术人员而言是显而易见的。因此,在不偏离本发明精神的基础上所做的这些修改或改进,均属于本发明要求保护的范围。
序列表
<110> 北京伟杰信生物科技有限公司
<120> 重组犬PD-L1融合蛋白及其制备方法与应用
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Claims (10)
1.重组犬PD-L1融合蛋白,其特征在于,所述融合蛋白包含犬PD-L1蛋白胞外区以及与所述犬PD-L1蛋白胞外区直接或间接相连的Fc片段;
其中,所述犬PD-L1蛋白胞外区具有如下氨基酸序列:
(a)如SEQ ID NO:3所示的氨基酸序列;或,
(b)如SEQ ID NO:3所示的氨基酸序列经取代、缺失或添加一个或几个氨基酸且具有同等功能的由(a)衍生的氨基酸序列。
2.根据权利要求1所述的融合蛋白,其特征在于,所述Fc片段包含犬IgG1免疫球蛋白的铰链区、CH2和CH3区。
3.根据权利要求1或2所述的融合蛋白,其特征在于,所述融合蛋白由犬PD-L1蛋白胞外区直接或间接与Fc片段之间通过Linker连接而成;
所述Linker为由2-20个柔性氨基酸组成的柔性多肽,所述柔性氨基酸选自Gly、Ser、Ala、Thr中的至少一种;
优选地,所述Linker为(Gly-Gly-Gly-Gly-Ser)n,其中n为2-5之间的整数,更优选n为2。
4.根据权利要求1~3任一项所述的融合蛋白,其特征在于,所述融合蛋白为cPD-L1-Fc,具有如下氨基酸序列:
(c)如SEQ ID NO:1所示的氨基酸序列;或,
(d)与如SEQ ID NO:1所示的氨基酸序列具有90%以上同源性且具有相同功能的由(c)衍生的氨基酸序列。
5.一种核酸分子,其特征在于,其编码权利要求1~4任一项所述的融合蛋白。
6.含有权利要求1-4任一项所述的融合蛋白或权利要求5所述的核酸分子的生物材料,其特征在于,所述生物材料为表达盒、转座子、质粒载体、噬菌体载体、病毒载体、工程菌或转基因细胞系。
7.权利要求1-4任一项所述的融合蛋白的制备方法,其特征在于,所述方法包括:将权利要求5所述的核酸分子与表达载体连接得到重组表达载体,将所述重组表达载体导入宿主细胞中,培养宿主细胞使其表达所述融合蛋白,经分离纯化得到所述融合蛋白。
8.权利要求1-4任一项所述的融合蛋白或权利要求5所述的核酸分子或权利要求6所述的生物材料在制备用于抑制犬免疫细胞过度活化的药物中的应用;
优选地,所述的药物通过PD-1/PD-L1信号通路抑制免疫细胞过度活化。
9.权利要求1-4任一项所述的融合蛋白或权利要求5所述的核酸分子或权利要求6所述的生物材料在制备用于治疗犬自身免疫病的药物中的应用;
优选地,所述自身免疫病包括自身免疫性甲状腺炎、糖尿病、阿狄森氏病、类风湿关节炎、寻常性天疱疮、系统性红斑狼疮、犬炎症性肠病、干眼症或葡萄膜炎。
10.一种药物,其特征在于,所述药物包含权利要求1-4任一项所述的融合蛋白。
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