CN110964118A - 一种双特异性融合抗体及其在肿瘤免疫治疗中的应用 - Google Patents
一种双特异性融合抗体及其在肿瘤免疫治疗中的应用 Download PDFInfo
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Abstract
本发明公开了一种一种双特异性融合抗体及其在肿瘤免疫治疗中的应用,属于基因工程抗体技术领域。本发明利用基因工程技术将抗CD24人源化嵌合抗体cG7与人类基因来源的转化生长因子‑β的II型受体胞外区基因通过柔性肽连接,并利用HEK293细胞进行瞬时转染表达,生产的融合抗体能够通过cG7的靶向作用将融合的TGFBR2携带至肿瘤微环境中,TGFBR2通过捕获游离的TGF‑β,从而抑制活化的TGF‑β与肿瘤细胞表面的TGF‑βII型受体结合,可以有效抑制肝癌细胞Huh‑7、BEL‑7402的增殖;同时可以改善上皮‑间充质转化,减缓肝癌细胞Huh‑7、BEL‑7402迁移及侵袭。
Description
技术领域
本发明属于生物工程领域,具体涉及一种新的可同时与白细胞分化抗原CD24(cluster of differentiation 24)和转化生长因子-β(Transforming growth factor-β,TGF-β)特异性结合的抗CD24人源化嵌合抗体cG7融合人源转化生长因子-βII型受体(TGFBR2)胞外区的双特异性抗体——cG7-sTGFBR2。
背景技术
癌症是全世界首要致死疾病之一,癌症的治疗一直是我们需要面对的难题。目前,治疗癌症的主要手段有手术切除、放射介入、化学疗法和免疫疗法等。但是化疗和手术治疗对机体损伤大、预后差,肿瘤免疫疗法成为当代肿瘤治疗的热点。肿瘤免疫疗法可以重塑机体自身的特异性免疫反应,增强机体对肿瘤的免疫排斥能力,抑制和杀伤肿瘤细胞,从而降低肿瘤复发和转移可能性,其具有高特异性和低毒副作用的优势。
一、肝癌与人转化生长因子-βII型受体
原发性肝癌(Hepatocellular carcinoma;HCC)是一种高发病率、高致死率的全球性难治性恶性肿瘤,是最常见的恶性肿瘤之一。在全球位于癌症发病率的第6位,死亡率高达第3位。HCC相对于其他人类固态恶性肿瘤具有高侵袭性和转移力。目前肝癌获批的一线药物仅有索拉菲尼和乐伐替尼两种小分子抑制剂,但两者都存在着毒副作用大、具有耐药性、作用有限等缺点。
转化生长因子-β(TGF-β,Transforming growth factor-β)是一组能调节细胞生长和分化的细胞因子,TGF-β超家族存在着I、II、III型三种形式的受体。其中人TGF-βII型受体(TGFBR2)是一种单次跨膜丝氨酸/苏氨酸激酶受体,由一个富含半胱氨酸的胞外域、一个跨膜域和一个富含丝氨酸/苏氨酸的胞内区域三部分组成。TGFBR2胞外区可与配体结合并被激活,再与I型受体形成异源二聚体,将信号向细胞内传导,从而激活下游信号通路,调控基因表达。其中最典型的通路是TGF-β-Smads信号转导通路,可调节多种靶基因的转录。
在肝脏的情况下,在HCC患者中可以测出TGF-β1mRNA的高表达,TGF-β信号传导参与疾病进展的所有阶段。虽然在早期有一定的抑癌作用,但是在肝癌晚期,TGF-β诱导上皮-间充质转化(EMT,Epithelial mesenchymal transition)进而促进肿瘤的迁移和侵袭;还可抑制肝癌微环境中的免疫细胞发挥免疫作用,促进肝癌侵袭转移;在促进肝癌血管生成方面也发挥一定的作用。以上证据都显示,TGF-β可能是一个免疫治疗肝癌的一个重要因子或靶点。基于此我们提出一种假设:将TGFBR2胞外区与抗体融合,借助于靶向肿瘤细胞表面抗原的抗体对肿瘤细胞的识别与结合,将TGFBR2胞外区蛋白携带至肿瘤微环境中,捕获游离的TGF-β,可以有效阻断TGF-β-Smads信号转导通路,抑制肿瘤迁移与侵袭,延缓肿瘤发生发展。
二、肿瘤标志物CD24分子
肿瘤相关性抗原CD24(cluster of differentiation 24)分子是一种高度糖基化的粘蛋白样细胞表面蛋白,其通过糖基磷脂酰肌醇(GPI,Glycosylphosphatidylinositol)连接锚定在细胞表面。经文献调研发现,CD24在包括肝癌等多种肿瘤组织中过表达,但在正常组织中不表达或低表达。在肿瘤细胞中,CD24通过GPI锚定于细胞膜上的脂筏结构。该结构是Src家族酪氨酸激酶信号途径的重要平台。CD24与Src相互作用并增强Src激酶活性,进而使STAT3分子(signal transducers and activators of transcription)形成活化态;活化的STAT3形成二聚体进入细胞核内,发挥转录因子的作用。表明CD24的表达与肿瘤细胞的分化、侵袭、转移和肿瘤的复发等密切相关。基于CD24分子肿瘤细胞标记物的特点,我们提出抗CD24人源化嵌合抗体cG7作为有效的载体连接TGFBR2胞外区蛋白,增强了受体靶向性,同时保留抗体Fc段可发挥抗体依赖的细胞介导的细胞毒性作用(ADCC,antibody-dependent cell-mediated cytotoxicity)和补体依赖的细胞毒作用(CDC,complementdependent cytoxicity)效应等发挥杀伤肿瘤细胞的功能。
基于上述理论基础与科研实践,本发明在实验室自主开发的抗CD24人源化嵌合抗体cG7的基础上进行基因改造,利用基因重组技术在其Fc段C端与人源TGF-βII型受体胞外区通过柔性肽(Gly-Gly-Gly-Ser)连接,设计一种新型双特异性融合抗体cG7-sTGFBR2。cG7-sTGFBR2的设计将cG7作为有效载体,特异性地把TGFBR2带到肝癌细胞的表面,提高了TGFBR2的靶向性,降低了其系统毒副作用,使其发挥抗肿瘤活性。因此,具有自主知识产权的双特异性融合抗体cG7-sTGFBR2的开发,为肿瘤免疫治疗体系提供可能的临床用药方案。
发明内容
发明目的:本发明要解决的技术问题是提供一种具有抗肿瘤疗效的靶向CD24的双特异性融合抗体。本发明双特异性融合抗体的特征为特异性结合人CD24及人TGF-β,在体外能够有效抑制人肝癌细胞Huh-7和BEL-7402的增殖,同时减缓肝癌细胞的迁移和浸润。
技术方案:一种双特异性融合抗体,包括抗CD24人源化嵌合抗体和TGFBR2蛋白,所述TGFBR2蛋白的氨基酸序列如SEQ NO:1所示。
一种双特异性融合抗体,所述抗CD24人源化嵌合抗体重链的氨基酸序列如SEQNO:2所示,所述CD24人源化嵌合抗体轻链链的氨基酸序列如SEQ NO:3所示。
其中,所述TGFBR2蛋白的核苷酸序列如SEQ NO:4所示。
其中,所述的抗CD24人源化嵌合抗体的核苷酸序列如SEQ NO:5所示;所述的TGFBR2蛋白的核苷酸序列如SEQ NO:6所示。
其中,所述抗CD24人源化嵌合抗体与TGFBR2蛋白之间通过柔性肽连接(柔性肽氨基酸序列:GGGGS)。
作为优选,所述双特异性融合抗体重链的氨基酸序列如SEQ NO:7所示,所述双特异性融合抗体轻链链的氨基酸序列如SEQ NO:8所示。
作为优选,所述双特异性融合抗体重链的核苷酸序列如SEQ NO:9所示,所述双特异性融合抗体轻链的核苷酸序列如SEQ NO:10所示。
一种重组载体,包含SEQ NO:4、SEQ NO:9、SEQ NO:10任一所示序列。
一种重组细胞,包含SEQ NO:4、SEQ NO:9、SEQ NO:10任一所示序列。
一种双特异性融合抗体的制备方法,包括如下步骤:
(1)将SEQ NO:9、SEQ NO:10所示核苷酸序列克隆至pcDNA3.1载体中,得到两种重组质粒;
(2)将步骤(1)得到的两种重组质粒转染至HEK293细胞中,表达cG7-sTGFBR2蛋白;
(3)纯化cG7-sTGFBR2蛋白,得到双特异性融合抗体。
上述述双特异性融合抗体在制备治疗肝癌药物中的应用。
靶向CD24的双特异性融合抗体cG7-sTGFBR2的应用方式:人源化嵌合抗体cG7发挥靶向性作用将融合的TGFBR2携带至肿瘤微环境中,通过捕获肿瘤微环境中富集的游离TGF-β,从而抑制活化的TGFβ与细胞表面的TGF-βII型受体结合,从而抑制肿瘤的发生、发展。
所述双特异性融合抗体cG7-sTGFBR2在制备肿瘤靶向药物和肿瘤治疗中的应用在本发明的保护范围之内。
发明进一步说明:
本发明中靶向CD24的双特异性融合抗体cG7-sTGFBR2由两条链组成,其中一条链由抗CD24人源化嵌合抗体重链、柔性肽(Gly4Ser)和TGFBR2蛋白胞外区组成;另一条链为抗CD24人源化嵌合抗体轻链。
本发明的目的是构建靶向CD24的双特异性融合抗体cG7-sTGFBR2的表达载体并批量纯化上述靶向CD24的双特异性融合抗体cG7-sTGFBR2,用以一定的体外药效学实验,评估靶向CD24的双特异性融合抗体cG7-sTGFBR2的用于肿瘤靶向治疗的可行性。
本发明利用overlap PCR(polymerase chain reaction)技术将本实验室专利融合抗体rG7s-MICA(专利号:ZL2015106263749)基础上构建的靶向CD24人源化嵌合抗体cG7的重链恒定区C端与人源TGFBR2的胞外区(Thr23-Asp159)基因相连接,轻链保持不变,分别进行克隆重组,构建靶向CD24的双特异性融合抗体cG7-sTGFBR2的重组载体。利用PEI瞬时转染HEK293细胞,可得到分泌表达cG7-sTGFBR2的工程细胞株;收集已瞬时转染目的重组载体的细胞株上清,低温离心,将上清过Protein A柱进行分离纯化;SDS-PAGE(sodiumdodecyl sulphate polyacrylamide gel electrophoresis)和WB(Western Blot)鉴定表达产物表达及装配是否正确;SPR(surface plasmon resonance)实验分析抗体与抗原的亲和能力;FCM(flow cytometry)进一步揭示融合双特异性抗体与CD24+肝癌细胞Huh-7和BEL-7402的结合情况;MTT验证融合抗体相对于单独的靶向CD24人源化嵌合抗体cG7或者TGFBR2对肝癌细胞更优越的增殖抑制作用;划痕实验和细胞侵袭试验(Transwell)进一步验证融合抗体具有抑制肝癌细胞迁移和侵袭的作用,且在TGF-β1诱导的条件下能有效捕获TGF-β1从而抑制肝癌细胞迁移和侵袭。
有益效果:
本发明公开了一种双特异性融合抗体,由靶向CD24的双特异性融合抗体cG7-sTGFBR2的两条链组成,其中一条链由抗CD24人源化嵌合抗体重链、柔性肽(Gly4Ser)和TGFBR2蛋白胞外区组成;另一条链为抗CD24人源化嵌合抗体轻链。本发明cG7-sTGFBR2可以有效捕获TGF-β1,并特异性靶向CD24。在体外实验中,cG7-sTGFBR2可以有效抑制肝癌细胞的增殖。同时相对于cG7,cG7-sTGFBR2可以显著抑制肝癌细胞的迁移和侵袭。
附图说明
图1是基于融合蛋白结构示意图。图中重链重组基因大小约为1827bp、轻链基因大小约为720bp。VH和VL分别代表cG7-sTGFBR2的重链可变区与轻链可变区序列,CH和CL分别代表cG7-sTGFBR2的重链恒定区与轻链恒定区;序列G4S Linker为柔性连接肽序列。该蛋白由两条链组成,其中重链由抗CD24人源化嵌合抗体重链通过柔性肽(GGGGS)和TGFBR2蛋白胞外区组成,而重链和轻链及重链之间是在表达细胞中自行通过二硫键结合组装在一起。
图2是SDS-PAGE蛋白质电泳图和Western Blot鉴定融合蛋白图。图2A描述发酵表达的cG7-sTGFBR2通过Protein A柱进行分离纯化的SDS-PAGE结果;图2B和图2C描述纯化后cG7与cG7-sTGFBR2的还原和非还原Western Blot结果,其中泳道1为cG7,泳道2为cG7-sTGFBR2,说明cG7-sTGFBR2的装配正确;图2B和图2C中孵育的一抗为羊抗人IgG(H+L);M为蛋白Marker。
图3是cG7-sTGFBR2与CD24及TGF-β1利用SPR技术的结合测试实验(Biacore)。图3A测定融合双特异性抗体cG7-sTGFBR2与抗原CD24的亲和力常数为ka(1/Ms):9.37E+04;kd(1/s):1.14E-05,KD(M):1.22E-10;图3B测定融合双特异性抗体cG7-sTGFBR2与TGFβ1的亲和力常数为ka(1/Ms):1.15E+06;kd(1/s):0.06363;KD(M):5.55E-08。
图4是cG7-sTGFBR2与人源CD24+肝癌细胞株Huh-7和BEL-7402流式结合测定图,图4A显示cG7,cG7-sTGFBR2与Huh-7细胞表面CD24分子的结合率,分别为91.1%和86.9%;图4B显示cG7,cG7-sTGFBR2与BEL-7402细胞表面CD24分子的结合率,分别为47.0%和44.0%;图4C显示cG7,cG7-sTGFBR2与CD24敲低的Huh-7(shCD24 Huh-7)细胞表面CD24分子的结合率,分别为30.3%和28.6%。
图5是cG7-sTGFBR2对人源CD24+肝癌细胞株Huh-7和BEL-7402增殖抑制测试图,显示在200nM药物的作用下,cG7-sTGFBR2相对单独的抗体cG7或者单独的受体蛋白sTGFBR2-Fc具有更明显的抑制肿瘤细胞增殖的作用。
图6是cG7-sTGFBR2对人源CD24+肝癌细胞株Huh-7和BEL-7402划痕实验结果图,图6A及图6B显示cG7-sTGFBR2可以抑制肿瘤细胞的迁移。图6C是图6A的显著性分析图;图6D是图6B的显著性分析图。
图7是cG7-sTGFBR2对人源CD24+肝癌细胞株Huh-7侵袭抑制试验结果图。图7A显示cG7-sTGFBR2可以抑制肿瘤细胞的侵袭。图7B是图7A的显著性分析图。
具体实施方式
实施例1靶向CD24的双特异性融合抗体cG7-sTGFBR2的构建
首先对TGFBR2胞外区基因进行人源种属偏爱密码子优化,再以cG7重链基因及优化的TGFBR2胞外区基因为模板,设计引物进行PCR扩增。再通过Overlap PCR通过柔性肽(Gly4Ser)将这两段基因连接起来构成cG7-sTGFBR2的重链(H-chain),cG7-sTGFBR2的轻链(L-chain)与cG7的轻链一致。以H-chain和L-chain为模板进行PCR,在H-chain和L-chain基因前分别加入人IgG的信号肽基因。PCR产物与pcDNA3.1分别双酶切,酶切后回收目的基因与质粒片段。T4连接酶16℃过夜连接,连接产物转化至感受态大肠杆菌DH5α中,涂布平板,次日挑取单克隆测序鉴定。
实施例2靶向CD24的双特异性融合抗体cG7-sTGFBR2的表达、纯化与鉴定
首先将两种重组质粒H-pcDNA3.1与L-pcDNA3.1以等比例方式与PEI混匀加入到培养有HEK293细胞的细胞培养瓶中进行瞬时转染。转染之后HEK293细胞将在3-5代内携带重组质粒并分泌表达cG7-sTGFBR2蛋白。培养瞬时转染的HEK293细胞3-5代,并收集细胞培养液,低温离心后上清用0.22μm滤膜过滤,再用Protein A柱进行亲和层析纯化,最终获得纯化后的目的蛋白。A.8%SDS-PAGE蛋白电泳鉴定cG7-sTGFBR2分子量和纯度,蛋白分子量正确,且达到了电泳纯。B.通过Western blot对目的蛋白进行初步验证是否装配正确。低温,200mA恒流转膜100min,将蛋白转印到PVDF膜上;结束后,在5%脱脂牛奶中封闭膜2h;然后将膜转移至稀释的带有HRP标签的羊抗人IgG(H+L)二抗中,37℃孵育1.5h;TBST(含有0.05%吐温20的TBS)洗膜3遍,TBS洗膜3遍后,滴加ECL发光显色液,凝胶成像仪曝光拍照。C.利用β-巯基乙醇对cG7与cG7-sTGFBR2抗体蛋白轻重链之间的二硫键进行还原,再利用Western blot对目的蛋白进行结构验证。结果表明cG7-sTGFBR2的装配正确。
实施例3靶向CD24的双特异性融合抗体cG7-sTGFBR2的SPR实验
该实验中cG7-sTGFBR2与抗原CD24及TGFBR2配体TGF-β1的相互作用的测定使用BiacoreX100作为SPR依赖的生物传感器来检测。利用Human Antibody捕获试剂盒将25μg/mL抗人IgG(Fc)抗体偶联至活化的CM5芯片表面(偶联仅限二号通道)。调整cG7-sTGFBR2的浓度为25μg/mL,利用CM5芯片上的抗人IgG(Fc)抗体特异性捕获cG7-sTGFBR2。之后利用缓冲液倍比稀释CD24裸肽(从500nM至0.39nM)或者TGF-β1(100nM至0.195nM)。在25℃、流速30μL/min工作环境下,进样检测cG7-sTGFBR2与CD24或TGFβ1的结合/解离能力。同时,一号通道作为参比通道没有偶联或捕获任何蛋白。因此一号通道检测的信号将作为参比数据。cG7-sTGFBR2与CD24、TGF-β1间的自然解离达到预设时间后,利用3M MgCl2再生缓冲液洗脱芯片表面的抗原抗体复合物,洗脱目标为基线响应值回归偶联后的初始响应值水平。获得传感图数据后利用Biacore X100 Evaluation软件分析结合常数(ka)与解离常数(Kd),拟合理想的结合解离曲线,计算获得抗体抗原间的平衡解离常数KD(Kd/Ka)。双特异性抗体cG7-sTGFBR2与抗原CD24的平衡解离常数KD(M):1.22E-10,与TGF-β1的平衡解离常数KD(M):5.55E-08。
实施例4流式细胞术检测靶向CD24的双特异性融合抗体cG7-sTGFBR2与CD24+肝癌细胞株Huh-7和BEL-7402的结合能力
该实验中首先将2×105个CD24+肝癌细胞株Huh-7和BEL-7402的重悬于250μL PBS中,制备单细胞悬液。1500rpm离心5min后,弃去上清,随后向各细胞悬液中加入等体积浓度250nmol/L的cG7或cG7-sTGFBR2蛋白,冰上共孵育1h。再通过2次离心洗涤除去未结合的cG7或cG7-sTGFBR2后,利用带有FITC标签的抗人IgG(H+L)抗体与肿瘤细胞避光孵育1h。之后离心,并利用PBS洗涤细胞2次,最后加入适量的PBS重悬细胞并利用流式细胞仪检测结合于细胞表面的抗体,用软件计算得到cG7-sTGFBR2与Huh-7,shCD24 Huh-7和BEL-7402细胞的结合率。最终cG7,cG7-sTGFBR2与Huh-7细胞表面CD24分子的结合率,分别为91.1%和86.9%;与BEL-7402细胞表面CD24分子的结合率,分别为47.0%和44.0%;与CD24敲低的Huh-7(shCD24 Huh-7)细胞表面CD24分子的结合率,分别为30.3%和28.6%。
实施例5MTT检测靶向CD24的双特异性融合抗体cG7-sTGFBR2对CD24+肝癌细胞株Huh-7和BEL-7402的生长抑制作用
该实验中将融合蛋白cG7-sTGFBR2与高表达CD24的肝癌细胞株Huh-7和BEL-7402相互作用,并利用GraphPad软件对实验数据进行分析处理,以评估该蛋白的抗肿瘤活性。将3×103~5×103个Huh-7或BEL-7402细胞接种到96孔细胞培养板,100μL每孔,37℃在5%CO2培养箱中培养24h。用含2%血清浓度的培养基将样品组cG7-sTGFBR2、cG7、sTGFBR2-Fc,分别稀释至7个浓度梯度(0、0.02、0.2、2、20、100、200nmol/L).弃96孔板原培养液后每孔加100μL梯度稀释的抗体,每个浓度设置三个平行孔,继续培养72h。观察细胞生长状况后每孔加11μL的MTT,37℃在5%CO2培养箱中培养4h,小心倾去上清,每孔加入150μL DMSO,在震荡仪上振摇10分钟后在酶标仪570nm/630nm波长处测定光吸收值(OD值),计算细胞增殖。融合蛋白的生物活性由细胞生长的抑制率评价,抑制率=(1-实验组OD值/对照组OD值)×100%。
实施例6划痕实验检测靶向CD24的双特异性融合抗体cG7-sTGFBR2对CD24+肝癌细胞株Huh-7和BEL-7402的迁移抑制作用
将处于对数生长期的2×105个Huh-7或BEL-7402细胞用5%血清培养基稀释,接种至十二孔板,37℃在5%CO2培养箱中培养至细胞长至汇合度约90%。用1%血清培养基稀释cG7-sTGFBR2、cG7、sTGFBR2-Fc至100nM。PBS洗涤两遍后再加入稀释好的蛋白溶液,并在加药0h、12h、24h、36h后在倒置荧光显微镜下拍照。利用Image-J软件对划痕面积进行分析,计算迁移抑制率=(1-当前面积/0h面积)×100%。结果显示相对于cG7,cG7-sTGFBR2可以显著抑制肿瘤细胞的迁移,且作用与sTGFBR2-Fc相当。
实施例7Transwell侵袭实验检测靶向CD24的双特异性融合抗体cG7-sTGFBR2抑制CD24+肝癌细胞株Huh-7的侵袭的作用
将Transwell小室置于24孔板中,每个小室均匀铺上1:2稀释的Matrigel基质胶,37℃静置1h待胶凝上后,缓慢滴加50μL用1%血清的培养基稀释的200nmol/L的cG7-sTGFBR2、cG7或sTGFBR2-Fc,再加入等体积的2×105个Huh-7细胞悬液。37℃在5%CO2培养箱中培养30min后,在下室每孔加入600μL含5%血清的培养基,37℃在5%CO2培养箱中培养。12h后,用4℃预冷的4%多聚甲醛固定20分钟后,再用0.1%结晶紫染色,拍照。利用Image-J软件对划痕面积进行分析,计算迁移抑制率=(1-给药组侵袭细胞数/对照组侵袭细胞数)×100%。结果显示,cG7-sTGFBR2相对于cG7可以显著抑制肿瘤细胞的侵袭,且作用与sTGFBR2-Fc相当,并且在TGF-β1的作用下仍能发挥一定的作用。
序列表
<110> 中国药科大学
<120> 一种双特异性融合抗体及其在肿瘤免疫治疗中的应用
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Ser Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr
180 185 190
Glu Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser
195 200 205
Ser Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys
210 215 220
<210> 4
<211> 417
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 4
ggatccacaa tcccccctca cgtgcagaag agcgtgaaca atgacatgat cgtgaccgat 60
aacaatggcg ccgtgaagtt cccccagctg tgcaagttct gtgacgtgag gtttagcacc 120
tgcgataacc agaagtcttg catgagcaat tgttccatca catctatctg cgagaagcct 180
caggaggtgt gcgtggccgt gtggcgcaag aacgacgaga atatcaccct ggagacagtg 240
tgccacgatc caaagctgcc ctaccacgac tttatcctgg aggatgccgc ctcccctaag 300
tgtatcatga aggagaagaa gaagccaggc gagaccttct ttatgtgctc ttgtagctcc 360
gacgagtgta acgataatat catcttcagc gaggagtata acacatccaa tcccgac 417
<210> 5
<211> 1335
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 5
caggtgaaac tggaagagag cggaggtggg ctggtgcagc caggcggatc actgaaaatc 60
tcctgcgccg cctccggttt cgacttttct aggtactgga tgagttgggt ccgacaggcc 120
cctggcaagg gtctggagtg gatcggcgaa attaaccccg attccagcac tattaattat 180
accccttcac tgagagacaa gttcatcatt tcccgcgata acgcaaaaaa tacactgtac 240
ctccagatga gcaaggtgcg atatgaggac acctctctgt actattgtgc caggcaggga 300
gattactggg gccagggaac cagtgtgaca gtctctagtg ctagcgcctc caccaagggc 360
ccatcggtct tccccctggc accctcctcc aagagcacct ctgggggcac agcggccctg 420
ggctgcctgg tcaaggacta cttccccgaa ccggtgacgg tgtcgtggaa ctcaggcgcc 480
ctgaccagcg gcgtgcacac cttcccggct gtcctacagt cctcaggact ctactccctc 540
agcagcgtgg tgaccgtgcc ctccagcagc ttgggcaccc agacctacat ctgcaacgtg 600
aatcacaagc ccagcaacac caaggtggac aagagagttg agcccaaatc ttgtgacaaa 660
actcacacat gcccaccgtg cccagcacct gaactcctgg ggggaccgtc agtcttcctc 720
ttccccccaa aacccaagga caccctcatg atctcccgga cccctgaggt cacatgcgtg 780
gtggtggacg tgagccacga agaccctgag gtcaagttca actggtacgt ggacggcgtg 840
gaggtgcata atgccaagac aaagccgcgg gaggagcagt acaacagcac gtaccgtgtg 900
gtcagcgtcc tcaccgtcct gcaccaggac tggctgaatg gcaaggagta caagtgcaag 960
gtctccaaca aagccctccc agcccccatc gagaaaacca tctccaaagc caaagggcag 1020
ccccgagaac cacaggtgta caccctgccc ccatcccggg aggagatgac caagaaccag 1080
gtcagcctga cctgcctggt caaaggcttc tatcccagcg acatcgccgt ggagtgggag 1140
agcaatgggc agccggagaa caactacaag accacgcctc ccgtgctgga ctccgacggc 1200
tccttcttcc tctatagcaa gctcaccgtg gacaagagca ggtggcagca ggggaacgtc 1260
ttctcatgct ccgtgatgca tgaggctctg cacaaccact acacgcagaa gagcctctcc 1320
ctgtctccgg gtaaa 1335
<210> 6
<211> 660
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 6
gatattgtga tgactcagac tcctctgtca ctgtccgtga caatcggcca gcccgcatct 60
attagttgca agtccagcca gagcctgctg cactctgacg gcaaaactta cctgaactgg 120
ctgctccaga ggcccggaca gtctcctaag cggctgatct atcttgtgag taaactggac 180
tcaggggtcc cagatagatt caccggttca ggctccggaa ccgactttac actgaaggtg 240
tccagggtcg aggcagagga cctgggggtc tactattgtt ggcagggtgc tcatttcccc 300
tacacttttg gcggagggac caagctggag attaaagtcg acaccgtggc cgctccatcc 360
gtgttcatct ttccccctag cgacgagcag ctgaagagcg gcacagcctc tgtggtgtgc 420
ctgctgaaca atttctaccc cagggaggcc aaggtgcagt ggaaggtgga taacgctctg 480
cagagcggca attctcagga gtccgtgacc gagcaggaca gcaaggattc tacatattcc 540
ctgtccagca ccctgacact gtctaaggcc gactacgaga agcacaaggt gtatgcttgt 600
gaggtgaccc atcagggcct gtcttccccc gtcacaaagt cctttaaccg gggcgagtgt 660
<210> 7
<211> 589
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 7
Gln Val Lys Leu Glu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Lys Ile Ser Cys Ala Ala Ser Gly Phe Asp Phe Ser Arg Tyr
20 25 30
Trp Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Ile
35 40 45
Gly Glu Ile Asn Pro Asp Ser Ser Thr Ile Asn Tyr Thr Pro Ser Leu
50 55 60
Arg Asp Lys Phe Ile Ile Ser Arg Asp Asn Ala Lys Asn Thr Leu Tyr
65 70 75 80
Leu Gln Met Ser Lys Val Arg Tyr Glu Asp Thr Ser Leu Tyr Tyr Cys
85 90 95
Ala Arg Gln Gly Asp Tyr Trp Gly Gln Gly Thr Ser Val Thr Val Ser
100 105 110
Ser Ala Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro
115 120 125
Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val
130 135 140
Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala
145 150 155 160
Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly
165 170 175
Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly
180 185 190
Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys
195 200 205
Val Asp Lys Arg Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys
210 215 220
Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu
225 230 235 240
Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu
245 250 255
Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys
260 265 270
Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys
275 280 285
Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu
290 295 300
Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys
305 310 315 320
Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys
325 330 335
Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser
340 345 350
Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys
355 360 365
Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln
370 375 380
Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly
385 390 395 400
Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln
405 410 415
Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn
420 425 430
His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys Gly Gly Gly
435 440 445
Gly Ser Gly Ser Thr Ile Pro Pro His Val Gln Lys Ser Val Asn Asn
450 455 460
Asp Met Ile Val Thr Asp Asn Asn Gly Ala Val Lys Phe Pro Gln Leu
465 470 475 480
Cys Lys Phe Cys Asp Val Arg Phe Ser Thr Cys Asp Asn Gln Lys Ser
485 490 495
Cys Met Ser Asn Cys Ser Ile Thr Ser Ile Cys Glu Lys Pro Gln Glu
500 505 510
Val Cys Val Ala Val Trp Arg Lys Asn Asp Glu Asn Ile Thr Leu Glu
515 520 525
Thr Val Cys His Asp Pro Lys Leu Pro Tyr His Asp Phe Ile Leu Glu
530 535 540
Asp Ala Ala Ser Pro Lys Cys Ile Met Lys Glu Lys Lys Lys Pro Gly
545 550 555 560
Glu Thr Phe Phe Met Cys Ser Cys Ser Ser Asp Glu Cys Asn Asp Asn
565 570 575
Ile Ile Phe Ser Glu Glu Tyr Asn Thr Ser Asn Pro Asp
580 585
<210> 8
<211> 220
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 8
Asp Ile Val Met Thr Gln Thr Pro Leu Ser Leu Ser Val Thr Ile Gly
1 5 10 15
Gln Pro Ala Ser Ile Ser Cys Lys Ser Ser Gln Ser Leu Leu His Ser
20 25 30
Asp Gly Lys Thr Tyr Leu Asn Trp Leu Leu Gln Arg Pro Gly Gln Ser
35 40 45
Pro Lys Arg Leu Ile Tyr Leu Val Ser Lys Leu Asp Ser Gly Val Pro
50 55 60
Asp Arg Phe Thr Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys Val
65 70 75 80
Ser Arg Val Glu Ala Glu Asp Leu Gly Val Tyr Tyr Cys Trp Gln Gly
85 90 95
Ala His Phe Pro Tyr Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys
100 105 110
Val Asp Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp
115 120 125
Glu Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn
130 135 140
Phe Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu
145 150 155 160
Gln Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp
165 170 175
Ser Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr
180 185 190
Glu Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser
195 200 205
Ser Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys
210 215 220
<210> 9
<211> 1767
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 9
caggtgaaac tggaagagag cggaggtggg ctggtgcagc caggcggatc actgaaaatc 60
tcctgcgccg cctccggttt cgacttttct aggtactgga tgagttgggt ccgacaggcc 120
cctggcaagg gtctggagtg gatcggcgaa attaaccccg attccagcac tattaattat 180
accccttcac tgagagacaa gttcatcatt tcccgcgata acgcaaaaaa tacactgtac 240
ctccagatga gcaaggtgcg atatgaggac acctctctgt actattgtgc caggcaggga 300
gattactggg gccagggaac cagtgtgaca gtctctagtg ctagcgcctc caccaagggc 360
ccatcggtct tccccctggc accctcctcc aagagcacct ctgggggcac agcggccctg 420
ggctgcctgg tcaaggacta cttccccgaa ccggtgacgg tgtcgtggaa ctcaggcgcc 480
ctgaccagcg gcgtgcacac cttcccggct gtcctacagt cctcaggact ctactccctc 540
agcagcgtgg tgaccgtgcc ctccagcagc ttgggcaccc agacctacat ctgcaacgtg 600
aatcacaagc ccagcaacac caaggtggac aagagagttg agcccaaatc ttgtgacaaa 660
actcacacat gcccaccgtg cccagcacct gaactcctgg ggggaccgtc agtcttcctc 720
ttccccccaa aacccaagga caccctcatg atctcccgga cccctgaggt cacatgcgtg 780
gtggtggacg tgagccacga agaccctgag gtcaagttca actggtacgt ggacggcgtg 840
gaggtgcata atgccaagac aaagccgcgg gaggagcagt acaacagcac gtaccgtgtg 900
gtcagcgtcc tcaccgtcct gcaccaggac tggctgaatg gcaaggagta caagtgcaag 960
gtctccaaca aagccctccc agcccccatc gagaaaacca tctccaaagc caaagggcag 1020
ccccgagaac cacaggtgta caccctgccc ccatcccggg aggagatgac caagaaccag 1080
gtcagcctga cctgcctggt caaaggcttc tatcccagcg acatcgccgt ggagtgggag 1140
agcaatgggc agccggagaa caactacaag accacgcctc ccgtgctgga ctccgacggc 1200
tccttcttcc tctatagcaa gctcaccgtg gacaagagca ggtggcagca ggggaacgtc 1260
ttctcatgct ccgtgatgca tgaggctctg cacaaccact acacgcagaa gagcctctcc 1320
ctgtctccgg gtaaaggagg tggtggaagt ggatccacaa tcccccctca cgtgcagaag 1380
agcgtgaaca atgacatgat cgtgaccgat aacaatggcg ccgtgaagtt cccccagctg 1440
tgcaagttct gtgacgtgag gtttagcacc tgcgataacc agaagtcttg catgagcaat 1500
tgttccatca catctatctg cgagaagcct caggaggtgt gcgtggccgt gtggcgcaag 1560
aacgacgaga atatcaccct ggagacagtg tgccacgatc caaagctgcc ctaccacgac 1620
tttatcctgg aggatgccgc ctcccctaag tgtatcatga aggagaagaa gaagccaggc 1680
gagaccttct ttatgtgctc ttgtagctcc gacgagtgta acgataatat catcttcagc 1740
gaggagtata acacatccaa tcccgac 1767
<210> 10
<211> 660
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 10
gatattgtga tgactcagac tcctctgtca ctgtccgtga caatcggcca gcccgcatct 60
attagttgca agtccagcca gagcctgctg cactctgacg gcaaaactta cctgaactgg 120
ctgctccaga ggcccggaca gtctcctaag cggctgatct atcttgtgag taaactggac 180
tcaggggtcc cagatagatt caccggttca ggctccggaa ccgactttac actgaaggtg 240
tccagggtcg aggcagagga cctgggggtc tactattgtt ggcagggtgc tcatttcccc 300
tacacttttg gcggagggac caagctggag attaaagtcg acaccgtggc cgctccatcc 360
gtgttcatct ttccccctag cgacgagcag ctgaagagcg gcacagcctc tgtggtgtgc 420
ctgctgaaca atttctaccc cagggaggcc aaggtgcagt ggaaggtgga taacgctctg 480
cagagcggca attctcagga gtccgtgacc gagcaggaca gcaaggattc tacatattcc 540
ctgtccagca ccctgacact gtctaaggcc gactacgaga agcacaaggt gtatgcttgt 600
gaggtgaccc atcagggcct gtcttccccc gtcacaaagt cctttaaccg gggcgagtgt 660
Claims (9)
1.一种双特异性融合抗体,其特征在于,包括抗CD24人源化嵌合抗体和TGFBR2蛋白,所述TGFBR2蛋白的氨基酸序列如SEQ NO:1所示。
2.根据权利要求1所述的双特异性融合抗体,其特征在于,所述抗CD24人源化嵌合抗体重链的氨基酸序列如SEQ NO:2所示,所述抗CD24人源化嵌合抗体轻链的氨基酸序列如SEQNO:3所示。
3.根据权利要求1所述的双特异性融合抗体,其特征在于,所述TGFBR2蛋白的核苷酸序列如SEQ NO:4所示。
4.根据权利要求2所述的双特异性融合抗体,其特征在于,所述的抗CD24人源化嵌合抗体重链的核苷酸序列如SEQ NO:5所示;所述的抗CD24人源化嵌合抗体轻链的核苷酸序列如SEQ NO:6所示。
5.根据权利要求1所述的双特异性融合抗体,其特征在于,所述抗CD24人源化嵌合抗体与TGFBR2蛋白之间通过柔性肽连接。
6.根据权利要求1所述的双特异性融合抗体,其特征在于,所述双特异性融合抗体重链的氨基酸序列如SEQ NO:7所示,所述双特异性融合抗体轻链的氨基酸序列如SEQ NO:8所示。
7.一种重组载体,其特征在于,包含SEQ NO:4、SEQ NO:9、SEQ NO:10任一所示序列。
8.一种重组细胞,其特征在于,包含SEQ NO:4、SEQ NO:9、SEQ NO:10任一所示序列。
9.权利要求1~6任一所述双特异性融合抗体在制备治疗肝癌药物中的应用。
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