CN114573705A - 特异性启动抗乙型肝炎病毒t细胞免疫的双特异性抗体及其应用 - Google Patents
特异性启动抗乙型肝炎病毒t细胞免疫的双特异性抗体及其应用 Download PDFInfo
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- CN114573705A CN114573705A CN202210265723.9A CN202210265723A CN114573705A CN 114573705 A CN114573705 A CN 114573705A CN 202210265723 A CN202210265723 A CN 202210265723A CN 114573705 A CN114573705 A CN 114573705A
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- C07K16/08—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from viruses
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Abstract
本发明公开特异性启动抗乙型肝炎病毒T细胞免疫的双特异性抗体及其应用。本发明抗体包括抗HBs单链可变区和抗CD3ε的单链可变区，从N端到C端依次包含SP‑VH(anti‑HBs)‑Linker1‑VL(anti‑HBs)‑Linker2‑VH(anti‑CD3ε)‑Linker1‑VL(anti‑CD3ε)；本发明双特异性抗体可特异结合T细胞及HBV感染的肝细胞，促使T细胞定向结合至HBV感染肝细胞，并激活T细胞的免疫功能，从而克服慢乙肝感染者中已经发生功能耗竭的特异性抗HBV细胞免疫，重建抗HBV的特异性T细胞免疫应答。
Description
技术领域
本发明属于生物技术领域，涉及一种特异性启动抗乙型肝炎病毒T细胞免疫的双特异性抗体及其应用。
背景技术
乙型肝炎病毒(HBV)的感染是全球卫生问题。
根据中国的慢乙肝诊疗指南，目前对慢乙肝提出3种不同层面的治疗目标，包括：(1)完全清除治愈：即血清HBsAg检测不到，同时肝细胞内HBV DNA包括肝内共价闭合环状DNA(cccDNA)和整合HBV DNA完全清除；(2)功能性治愈：即有限疗程结束后HBsAg和HBV DNA持续检测不到，伴或不伴HBsAb产生，肝组织病变改善，但肝内仍存在HBV DNA，仍有再激活和肝癌发生风险，是治疗的理想目标；(3)部分治愈：即有限疗程结束后血清HBV DNA持续检测不到，但血清HBsAg仍可检出。现已批准应用于慢乙肝临床治疗的抗病毒药物主要是干扰素和核苷(酸)类似物，这些药物仅可使约 1/3慢乙肝患者在治疗后达到部分治愈，多数患者停药后病毒反弹。HBV cccDNA在肝内的持续存在，免疫系统不能对其进行清除或有效抑制其转录活性是停药后反弹的根本原因。
一般认为，HBV感染后，患者体内的特异性抗病毒免疫强度决定疾病的发展方向。数量充足和功能健全的HBV特异性T细胞免疫可有效清除感染，而其数量不足和功能耗竭可使得感染持续而发展为慢性感染。鉴于上述共识，近年发展了若干增强慢乙肝患者抗HBV特异性细胞免疫的研究策略，包括：(1)免疫检查点抑制剂：大量病毒抗原刺激导致的特异性T细胞耗竭被认为是免疫耐受发生的机制之一，其中PD-1及其配体在抗原介导的免疫细胞耗竭中起关键作用。目前有处于临床试验II期的ASC22(KN035或 Envafolimab)和I期的GS4224，均为PDL1抑制剂。(2)治疗性疫苗：包括蛋白质疫苗，DNA疫苗及嵌合表位疫苗等。GS4774(Gilead Sciences)为表达4个HBV主要基因型表面抗原的融合蛋白，已进入II期临床，此外，NASVAC(CIGB)已进入临床III 期等。(3)工程化免疫细胞，通过基因工程技术将HBV特异性T细胞受体(TCR)或嵌合抗原受体(CARs)在T细胞上表达，以重建慢乙肝患者的抗HBV特异性T细胞免疫。 TCR-T细胞识别靶细胞为HLA限制性，而CAR-T则可以突破HLA限制性，因此其应用人群更具普适性，目前处于临床II期的IMC-I109V采用TCR-T技术。但对于已经发生功能和数量耗竭的HBV特异性免疫细胞，上述免疫检查点抑制剂或治疗性疫苗对免疫系统的刺激对促进其功能恢复的作用有限。而工程化免疫细胞涉及对患者个体的T细胞提取，基因改造和回输等，难以形成标准化生产；且细胞治疗的生产工艺对生产车间，无菌操作，保存运输等有很高的要求，限制了其在临床的开展和应用。
双特异性抗体(Bispecific antibody，BsAb)是近年发展的一种可以同时结合两种特异性表位的人工工程化抗体。相对于普通单抗的2个Fab臂相同特异性，只能结合单一靶点；BsAb拥有两个不同的抗原结合位点，可以同时和两个靶抗原或一个抗原两个不同表位结合。根据结构不同，可将BsAb总体上分为2大类：含Fc片段的IgG样 BsAb与不含Fc片段的非IgG样BsAb。(1)IgG样BsAb有Fc部分，因此具有Fc介导的效应功能：如抗体依赖性细胞介导的细胞毒作用、补体依赖的细胞毒作用和抗体依赖的细胞介导的细胞吞噬作用。IgG样BsAb相对分子量较大，且Fc部分与受体FcRn结合，增加了抗体血清半衰期。Fc部分亦有助于抗体后期的纯化并提高其溶解性、稳定性。(2)非IgG样BsAb：缺乏Fc片段，仅通过抗原结合力发挥治疗作用，具有较低的免疫原性、分子量小等特点。因分子量小，其在肿瘤组织的渗透性较高，因此具有更强的治疗效果。作为新兴的抗体种类，双特异性抗体已纳入临床药物研究，目前主要集中于介导免疫细胞对肿瘤细胞的杀伤研究，但尚未在慢性感染性疾病中临床应用。
发明内容
本发明的第一个目的是针对现有技术的不足，提出一种抗HBs×CD3ε的双特异性抗体(BsAb)。
本发明抗HBs×CD3ε的双特异性抗体包括抗HBs单链可变区和抗CD3ε的单链可变区，从N端到C端依次包含SP-VH(anti-HBs)-Linker1-VL(anti-HBs)-Linker2- VH(anti-CD3ε)-Linker1-VL(anti-CD3ε)；
上述anti-HBs单链抗体结构域包括重链VH(anti-HBs)和轻链VL(anti-HBs)，其靶向位点为HBV的表面抗原表位结合，靶向表位可为表面抗原前S1区的第36-43位氨基酸(PreS1)，或为表面抗原小蛋白区的第265-336位氨基酸的抗原环(antigen loop)。
上述抗T细胞CD3ε分子的单链抗体结构域VH(anti-CD3ε)和VL(anti-CD3ε)序列来源于OKT3或UCTH1。
上述抗体结构域之间使用linker进行柔性连接，其中Linker1为3个G4S，Linker2为1个G4S。
作为优选，在抗体的N端添加信号肽SP可促进其分泌，且在分泌后该序列自动切除，其氨基酸序列为MDMRAPAQIFGFLLLLFPGTRCD。
作为优选，抗HBs×CD3ε的双特异性抗体中HBs单链可变区VH(anti-HBs)和轻链 VL(anti-HBs)靶向HBV的S蛋白的36-43氨基酸(5a19)，抗CD3ε的单链可变区 VH(anti-CD3ε)和VL(anti-CD3ε)来自CD3单克隆抗体OKT3，其核苷酸序列和氨基酸序列分别如SEQ IDNO.1和SEQ ID NO.2。
作为优选，抗HBs×CD3ε的双特异性抗体中HBs单链可变区VH(anti-HBs)和轻链 VL(anti-HBs)靶向HBV的S蛋白的265-336氨基酸(XTL19)，抗CD3ε的单链可变区 VH(anti-CD3ε)和VL(anti-CD3ε)来自CD3单克隆抗体UCTH1，其核苷酸序列和氨基酸序列分别如SEQ IDNO.3和SEQ ID NO.4。
本发明的第二个目的是提供双特异性抗体(BsAb)在制备抗乙型肝炎药物中的应用。
本发明的第三个目的是提供一种药物组合物，包括双特异性抗体(BsAb)和药学上可接受的载体。
本发明的第四个目的是提供一种用于治疗乙型肝炎疾病和/或治疗由乙型肝炎病毒感染引起的肝癌药物，包括活性成分双特异性抗体(BsAb)。
本发明的有益效果是：
(1)、本发明双特异性抗体可特异结合T细胞及HBV感染的肝细胞，促使T细胞定向结合至HBV感染肝细胞，并激活T细胞的免疫功能，从而克服慢乙肝感染者中已经发生功能耗竭的特异性抗HBV细胞免疫，重建抗HBV的特异性T细胞免疫应答。
(2)、本发明可有效抑制肝细胞内HBV复制及病毒蛋白表达，并靶向清除HBV感染细胞，从而可能实现慢乙肝的功能性治愈甚至完全治愈。
(3)、本发明能靶向清除HBV复制的肝细胞，从而可能用于HBV感染相关肝癌的治疗，靶向清除肝癌细胞。
(4)、本发明双特异性抗体无Fc段(可结晶片段fragment crystallizable)，分子量相对较小，半衰期短，有较低的潜在毒性和副作用。
(5)、本发明抗体N端添加了分泌信号肽，使得此抗体也可以通过表达载体(如腺病毒，慢病毒等)进入体内后表达分泌，发挥其生物学效应。
(6)、本发明采用5a19和UCHT1的scFv作为双抗结构域在动物模型中有较高生物学效应。此外添加了分泌序列，使得其可通过基因载体的在体表达以启动T细胞介导的抗病毒免疫应答。
(7)、本发明在抗体药物注射之后，其所激活抗HBV特异性T细胞免疫功能可以持续维持3-4周。
附图说明
图1(A)-(B)分别是Anti-HBs-CD3ε双特异性抗体的靶向序列及结构示意图；
图2是使用所制备的anti-HBs-CD3双特异性抗体对CEM-C7细胞进行免疫荧光染色；其中A为细胞膜表面CD3表达，B为DAPI细胞核染色，C为二者叠加图像；
图3是对转染了pUC18-HBV1.3的HepG2细胞进行染色；其中A为细胞内HBsAg表达，B为DAPI细胞核染色，C为二者叠加图像；
图4：HepG2细胞转染pUC18-HBV1.2质粒2天后，加入0到10nM的anti-HBs-CD3 BiTE及外周血单个核细胞(靶效细胞比1：10)3天后检测培养上清中病毒学指标；其中A为HBsAg，B为HBeAg。加入0nm BiTE为对照组，各组间差异采用配对T检验。*P<0.05； **P<0.01。
图5：CD3人源化C57BL/6小鼠注射AAV-HBV1.3建立HBV复制模型后，水动力注射BiTEs 表达质粒pCDNA3.1-5a19-OKT3或pCDNA3.1-XTL19-UCHT1.在随后1个月内持续监测血清中HBsAg病毒学指标。箭头指示为质粒水动力注射时间0天和第3天。0天为对照组，各组间差异采用配对T检验。*P<0.05；**P<0.01。
图6：CD3人源化C57BL/6小鼠注射AAV-HBV1.3建立HBV复制模型后，水动力注射BiTEs 表达质粒pCDNA3.1-5a19-OKT3或pCDNA3.1-XTL19-UCHT1.在随后1个月内持续监测血清中HBeAg病毒学指标。箭头指示为质粒水动力注射时间0天和第3天。0天为对照组，各组间差异采用配对T检验。*P<0.05；**P<0.01。
具体实施方式
下面结合附图对本发明做进一步的分析。
实施例1：BiTE-5a19-OKT3和BiTE-XTL19-UCTH1的构建
采用基因合成和重组的方法构建双特异性T细胞衔接子(BiTE)表达质粒 anti-HBs-CD3，表达载体为pCDNA3.1(+)。其表达蛋白的近N端为anti-sHBs抗体的单链可变区(scFv)，靶向HBV的S蛋白的37-43氨基酸(5a19)或265-336氨基酸(XTL19)， VH和VL链之间用3个G4S(即Linker1)进行连接。C端为anti-CD3ε(OKT3或UCTH1) 的scFV，靶向CD3分子ε结构域，VH和VL链之间用3个G4S(即Linker1)进行连接。两种抗体之间使用G4S(即Linker2)柔性肽进行连接。此anti-HBs-CD3双特异性抗体的N端添加信号肽(SP)，可促使其表达后分泌至细胞外，并在C端添加6×His标签以便检测其表达及纯化。表达质粒分别命名为BiTE-5a19-OKT3和BiTE-XTL19-UCTH1。
质粒转染293F细胞以表达抗体，收集上清及细胞进行蛋白纯化，以干粉形式冻存。应用此抗体对表达CD3的CEM-C7细胞系及转染pUC18-HBV1.3质粒的HepG2细胞进行免疫荧光检测，以验证抗体的结合能力及特异性，检测结果如图2-3。
抗HBs×CD3ε的双特异性抗体BiTE，其包括抗HBs单链可变区和抗CD3ε的单链可变区，其靶向序列及结构如图1所示。
实施例2：在细胞培养模型中抑制HBV复制
以HepG2细胞系作为研究平台。适量HepG2细胞接种于24孔板后，转染pUC18-HBV1.2 质粒以支持病毒复制和病毒蛋白表达。3天后加入10倍数量的健康人外周血单个核细胞(PBMCs)，并同时加入不同浓度的anti-HBs-CD3εBiTE(0-10nm)。3天后取细胞培养上清检测HBsAg及HBeAg，可见各指标显著下降，并呈剂量依赖性。结果显示： BiTE-XTL19-UCTH1和BiTE-5a19-OKT3均可实现抑制HBV蛋白，但BiTE-XTL19-UCTH1 抑制HBV蛋白表达效果优于BiTE-5a19-OKT3分子(图4)。
实施例3：在动物模型中抑制HBV复制
以AAV-HBV感染小鼠动物模型为研究对象，采用CD3人源化C57BL/6小鼠。4-6周龄小鼠注射3.0×1010的AAV-HBV1.3病毒，建立HBV复制模型。模型建立后第0和第3 天，水动力注射基于pCDNA3.1载体的BiTE-5a19-OKT3或BiTE-XTL19-UCTH1质粒50μg/ 只。采血检测其血清中HBsAg及HBeAg水平，可见各病毒指标随时间在1个月内持续下降(图5-6)。
上述实施例并非是对于本发明的限制，本发明并非仅限于上述实施例，只要符合本发明要求，均属于本发明的保护范围。
序列表
<110> 杭州师范大学
<120> 特异性启动抗乙型肝炎病毒T细胞免疫的双特异性抗体及其应用
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tgtcttgtaa ggcctctgga tatacattca cacgatatac aatgcattgg gtgaagcagc 840
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Ser Ser Val Gln Ala Glu Asp Leu Ala Val Tyr Tyr Cys Lys Gln Ser
100 105 110
Tyr Ser Leu Tyr Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys Gly
115 120 125
Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Leu
130 135 140
Val Lys Pro Gly Gly Ser Leu Lys Leu Ser Cys Ala Ala Ser Gly Phe
145 150 155 160
Thr Phe Ser Ser Tyr Ala Met Ser Trp Val Arg Gln Ser Pro Glu Lys
165 170 175
Arg Leu Glu Trp Val Ala Glu Val Ser Ser Asp Gly Ser Tyr Ala Tyr
180 185 190
Tyr Pro Asp Thr Leu Thr Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala
195 200 205
Lys Asn Thr Leu Tyr Leu Glu Met Thr Ser Leu Arg Ser Glu Asp Thr
210 215 220
Ala Met Tyr Tyr Cys Ala Ser Phe Asn Trp Asp Val Ala Tyr Trp Gly
225 230 235 240
Gln Gly Thr Leu Val Thr Val Ser Ala Ala Gly Gly Gly Gly Ser Met
245 250 255
Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Arg Tyr Thr Met His Trp
260 265 270
Val Lys Gln Arg Pro Gly Gln Gly Leu Glu Trp Ile Gly Tyr Ile Asn
275 280 285
Pro Ser Arg Gly Tyr Thr Asn Tyr Asn Gln Lys Phe Lys Asp Lys Ala
290 295 300
Thr Leu Thr Thr Asp Lys Ser Ser Ser Thr Ala Tyr Met Gln Leu Ser
305 310 315 320
Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys Ala Arg Tyr Tyr
325 330 335
Asp Asp His Tyr Cys Leu Asp Tyr Trp Gly Gln Gly Thr Thr Leu Thr
340 345 350
Val Ser Ser Ala Lys Thr Thr Ala Pro Ser Val Tyr Pro Leu Ala Pro
355 360 365
Val Cys Gly Gly Thr Thr Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
370 375 380
Gly Gly Gly Gly Ser Cys Ser Ala Ser Ser Ser Val Ser Tyr Met Asn
385 390 395 400
Trp Tyr Gln Gln Lys Ser Gly Thr Ser Pro Lys Arg Trp Ile Tyr Asp
405 410 415
Thr Ser Lys Leu Ala Ser Gly Val Pro Ala His Phe Arg Gly Ser Gly
420 425 430
Ser Gly Thr Ser Tyr Ser Leu Thr Ile Ser Gly Met Glu Ala Glu Asp
435 440 445
Ala Ala Thr Tyr Tyr Cys Gln Gln Trp Ser Ser Asn Pro Phe Thr Phe
450 455 460
Gly Ser Gly Thr Lys Leu Glu Ile Asn Arg Ala Asp Thr Ala Pro Thr
465 470 475 480
Val Ser Ile Phe Pro Pro Ser Ser Glu Gln Leu Thr Ser Gly Gly His
485 490 495
His His His His His
500
<210> 3
<211> 1597
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 3
cggaattcgg taccatggat atgcgagccc ctgcccagat cttcggattc ctgctgctgc 60
tgttccctgg aacacgatgt gattcttatg tgctgacaca gcctccttct gtgtctgtgg 120
cccctggaaa gacagcccga atctcttgtg gaggaaataa tatcggcaca aagaatgtgc 180
attggtatca gcagaagcct ggacaggccc ctgtgctggt ggtgtatgcc gattctgatc 240
gaccttctgg aatacctgag cgattctctg gctctaattc tggaaataca gccacactga 300
caatctctcg agtggaggtg ggagatgagg ccgattatta ttgtcaggtg tgggattctg 360
tgtcttatca tgtggtgttc ggaggaggca caacactgac agtgctggga ggaggtggcg 420
gaagtggtgg aggcggttca ggaggtggcg gtagtcaggt gcagctggtg gagtctggag 480
gaggagtggt gcagcctgga ggctctctgc gactgtcttg tgccccttct ggattcgtgt 540
tccgatctta tggaatgcat tgggtgcgac agacacctgg aaagggactg gagtgggtgt 600
ctctgatctg gcatgatggc tctaatcgat tctatgccga ttctgtgaag ggacgattca 660
caatctctcg agataattct gagaatacac tgtatctgca gatgaactct ctgcgagccg 720
aggatacagc catgtatttc tgtgcccgag agcgactgat cgccgcccct gccgccttcg 780
atctgtgggg acagggcaca ctggtgacag tgtcttctgg aggtggcgga tccgaggtgc 840
agctgcagca gtctggacct gagctggtga agcctggagc ctctatgaag atctcttgta 900
aggcctctgg atattctttc acaggatata caatgaattg ggtgaagcag tctcatggaa 960
agaacctgga gtggatggga ctgatcaatc cttataaggg agtgtctaca tataatcaga 1020
agttcaagga taaggccaca ctgacagtgg ataagtcttc ttctacagcc tatatggagc 1080
tgctgtctct gacatctgag gattctgccg tgtattattg tgcccgatct ggatattatg 1140
gagattctga ttggtatttc gatgtgtggg gacagggcac aacactgaca gtgttctctg 1200
gaggtggcgg aagtggtgga ggcggttcag gaggtggcgg tagtatggat atccagatga 1260
cacagacaac atcttctctg tctgcctctc tgggagatcg agtgacaatc tcttgtcgag 1320
cctctcagga tatccgaaat tatctgaatt ggtatcagca gaagcctgat ggcacagtga 1380
agctgctgat ctattataca tctcgactgc attctggagt gccttctaag ttctctggct 1440
ctggctctgg cacagattat tctctgacaa tctctaacct ggagcaggag gatatcgcca 1500
catatttctg tcagcaggga aatacactgc cttggacatt cgccggaggc acaaagctgg 1560
agatcaagca tcatcatcat catcattagt ctagagc 1597
<210> 4
<211> 524
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 4
Met Asp Met Arg Ala Pro Ala Gln Ile Phe Gly Phe Leu Leu Leu Leu
1 5 10 15
Phe Pro Gly Thr Arg Cys Asp Ser Tyr Val Leu Thr Gln Pro Pro Ser
20 25 30
Val Ser Val Ala Pro Gly Lys Thr Ala Arg Ile Ser Cys Gly Gly Asn
35 40 45
Asn Ile Gly Thr Lys Asn Val His Trp Tyr Gln Gln Lys Pro Gly Gln
50 55 60
Ala Pro Val Leu Val Val Tyr Ala Asp Ser Asp Arg Pro Ser Gly Ile
65 70 75 80
Pro Glu Arg Phe Ser Gly Ser Asn Ser Gly Asn Thr Ala Thr Leu Thr
85 90 95
Ile Ser Arg Val Glu Val Gly Asp Glu Ala Asp Tyr Tyr Cys Gln Val
100 105 110
Trp Asp Ser Val Ser Tyr His Val Val Phe Gly Gly Gly Thr Thr Leu
115 120 125
Thr Val Leu Gly Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly
130 135 140
Gly Gly Ser Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln
145 150 155 160
Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Pro Ser Gly Phe Val Phe
165 170 175
Arg Ser Tyr Gly Met His Trp Val Arg Gln Thr Pro Gly Lys Gly Leu
180 185 190
Glu Trp Val Ser Leu Ile Trp His Asp Gly Ser Asn Arg Phe Tyr Ala
195 200 205
Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Glu Asn
210 215 220
Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Met
225 230 235 240
Tyr Phe Cys Ala Arg Glu Arg Leu Ile Ala Ala Pro Ala Ala Phe Asp
245 250 255
Leu Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly
260 265 270
Ser Glu Val Gln Leu Gln Gln Ser Gly Pro Glu Leu Val Lys Pro Gly
275 280 285
Ala Ser Met Lys Ile Ser Cys Lys Ala Ser Gly Tyr Ser Phe Thr Gly
290 295 300
Tyr Thr Met Asn Trp Val Lys Gln Ser His Gly Lys Asn Leu Glu Trp
305 310 315 320
Met Gly Leu Ile Asn Pro Tyr Lys Gly Val Ser Thr Tyr Asn Gln Lys
325 330 335
Phe Lys Asp Lys Ala Thr Leu Thr Val Asp Lys Ser Ser Ser Thr Ala
340 345 350
Tyr Met Glu Leu Leu Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr
355 360 365
Cys Ala Arg Ser Gly Tyr Tyr Gly Asp Ser Asp Trp Tyr Phe Asp Val
370 375 380
Trp Gly Gln Gly Thr Thr Leu Thr Val Phe Ser Gly Gly Gly Gly Ser
385 390 395 400
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Met Asp Ile Gln Met Thr
405 410 415
Gln Thr Thr Ser Ser Leu Ser Ala Ser Leu Gly Asp Arg Val Thr Ile
420 425 430
Ser Cys Arg Ala Ser Gln Asp Ile Arg Asn Tyr Leu Asn Trp Tyr Gln
435 440 445
Gln Lys Pro Asp Gly Thr Val Lys Leu Leu Ile Tyr Tyr Thr Ser Arg
450 455 460
Leu His Ser Gly Val Pro Ser Lys Phe Ser Gly Ser Gly Ser Gly Thr
465 470 475 480
Asp Tyr Ser Leu Thr Ile Ser Asn Leu Glu Gln Glu Asp Ile Ala Thr
485 490 495
Tyr Phe Cys Gln Gln Gly Asn Thr Leu Pro Trp Thr Phe Ala Gly Gly
500 505 510
Thr Lys Leu Glu Ile Lys His His His His His His
515 520
Claims (8)
1.一种抗HBs×CD3ε的双特异性抗体，其特征在于包括抗HBs单链可变区和抗CD3ε的单链可变区，从N端到C端依次包含SP-VH(anti-HBs)-Linker1-VL(anti-HBs)-Linker2-VH(anti-CD3ε)-Linker1-VL(anti-CD3ε)；
上述anti-HBs单链抗体结构域包括重链VH(anti-HBs)和轻链VL(anti-HBs)，其靶向位点为HBV的表面抗原表位结合，靶向表位可为表面抗原前S1区的第36-43位氨基酸，或为表面抗原小蛋白区的第265-336位氨基酸的抗原环。
上述抗T细胞CD3ε分子的单链抗体结构域包括重链VH(anti-CD3ε)和轻链VL(anti-CD3ε)序列来源于CD3单克隆抗体OKT3或UCTH1。
2.如权利要求1所述的一种抗HBs×CD3ε的双特异性抗体，其特征在于Linker1为3个G4S，Linker2为1个G4S。
3.如权利要求1或2所述的一种抗HBs×CD3ε的双特异性抗体，其特征在于信号肽SP的氨基酸序列为MDMRAPAQIFGFLLLLFPGTRCD。
4.如权利要求1所述的一种抗HBs×CD3ε的双特异性抗体，其特征在于抗HBs×CD3ε的双特异性抗体中HBs单链可变区VH(anti-HBs)和轻链VL(anti-HBs)靶向HBV的S蛋白的37-43氨基酸(5a19)，抗CD3ε的单链可变区VH(anti-CD3ε)和VL(anti-CD3ε)来自CD3单克隆抗体OKT3，其核苷酸序列和氨基酸序列分别如SEQ ID NO.1和SEQ ID NO.2。
5.如权利要求1所述的一种抗HBs×CD3ε的双特异性抗体，其特征在于抗HBs×CD3ε的双特异性抗体中HBs单链可变区VH(anti-HBs)和轻链VL(anti-HBs)靶向HBV的S蛋白的265-336氨基酸(XTL19)，抗CD3ε的单链可变区VH(anti-CD3ε)和VL(anti-CD3ε)来自CD3单克隆抗体UCTH1，其核苷酸序列和氨基酸序列分别如SEQ ID NO.3和SEQ ID NO.4。
6.如权利要求1-5任一项所述的一种抗HBs×CD3ε的双特异性抗体在制备抗乙型肝炎药物中的应用。
7.一种药物组合物，其特征在于包括权利要求1-5任一项所述的一种抗HBs×CD3ε的双特异性抗体和药学上可接受的载体。
8.一种用于治疗乙型肝炎疾病和/或治疗由乙型肝炎病毒感染引起的肝癌药物，其特征在于权利要求1-5任一项所述的一种抗HBs×CD3ε的双特异性抗体作为活性成分。
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