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CN105384825B - 一种基于单域抗体的双特异性嵌合抗原受体及其应用 - Google Patents

一种基于单域抗体的双特异性嵌合抗原受体及其应用 Download PDF

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Publication number
CN105384825B
CN105384825B CN201510733585.2A CN201510733585A CN105384825B CN 105384825 B CN105384825 B CN 105384825B CN 201510733585 A CN201510733585 A CN 201510733585A CN 105384825 B CN105384825 B CN 105384825B
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CN
China
Prior art keywords
single domain
car
antigen receptor
domain antibody
cell
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CN201510733585.2A
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CN105384825A (zh
Inventor
范晓虎
周传初
庄秋传
王平艳
王林
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Nanjing Legend Biotechnology Co Ltd
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Nanjing Legend Biotechnology Co Ltd
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Application filed by Nanjing Legend Biotechnology Co Ltd filed Critical Nanjing Legend Biotechnology Co Ltd
Priority to CN201510733585.2A priority Critical patent/CN105384825B/zh
Publication of CN105384825A publication Critical patent/CN105384825A/zh
Priority to LTEP22168161.2T priority patent/LT4063397T/lt
Priority to JP2018526984A priority patent/JP6859347B2/ja
Priority to IL294683A priority patent/IL294683A/en
Priority to EP24174651.0A priority patent/EP4424376A2/en
Priority to UAA201802367A priority patent/UA125818C2/uk
Priority to AU2016305075A priority patent/AU2016305075B2/en
Priority to CA2994579A priority patent/CA2994579C/en
Priority to PCT/CN2016/094408 priority patent/WO2017025038A1/en
Priority to CR20210225A priority patent/CR20210225A/es
Priority to IL257297A priority patent/IL257297B/en
Priority to EP16834662.5A priority patent/EP3334765A4/en
Priority to EP22168161.2A priority patent/EP4063397B1/en
Priority to EA201890302A priority patent/EA201890302A1/ru
Priority to CR20180153A priority patent/CR20180153A/es
Priority to MYPI2018000199A priority patent/MY188362A/en
Priority to SG10201913485QA priority patent/SG10201913485QA/en
Priority to RS20240831A priority patent/RS65866B1/sr
Priority to MX2018001739A priority patent/MX2018001739A/es
Priority to BR112018002844-4A priority patent/BR112018002844A2/pt
Priority to FIEP22168161.2T priority patent/FI4063397T3/fi
Priority to KR1020187006996A priority patent/KR20180035918A/ko
Priority to PT221681612T priority patent/PT4063397T/pt
Priority to US15/751,609 priority patent/US10934363B2/en
Priority to DK22168161.2T priority patent/DK4063397T3/da
Priority to NZ758571A priority patent/NZ758571A/en
Priority to ZA2018/00703A priority patent/ZA201800703B/en
Priority to CL2018000378A priority patent/CL2018000378A1/es
Priority to MX2022015823A priority patent/MX2022015823A/es
Priority to PH12018500295A priority patent/PH12018500295A1/en
Priority to SA518390904A priority patent/SA518390904B1/ar
Priority to CONC2018/0001405A priority patent/CO2018001405A2/es
Application granted granted Critical
Publication of CN105384825B publication Critical patent/CN105384825B/zh
Priority to AU2020200151A priority patent/AU2020200151C1/en
Priority to US17/164,125 priority patent/US20210261675A1/en
Priority to JP2021052453A priority patent/JP7168173B2/ja
Priority to CL2021001686A priority patent/CL2021001686A1/es
Priority to AU2022204180A priority patent/AU2022204180A1/en
Priority to JP2022167222A priority patent/JP2022183283A/ja
Priority to JP2024014929A priority patent/JP2024032975A/ja
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Abstract

本发明公开了一种基于单域抗体的双特异性嵌合抗原受体及其应用。所述的双特异性单域抗体嵌合抗原受体由CD8信号肽、CD19及CD20抗原特异性的两个单域抗体和CD28跨膜区以及CD28、CD3胞内信号传导结构域依次串联组成。本发明通过优化设计CD19、CD20特异的单域抗体，提供了一种CD19、CD20双靶点修饰的CAR‐T细胞，能够特异地与CD19及CD20抗原结合。在B淋巴细胞系恶性肿瘤杀伤试验中，采用CD19、CD20双靶点修饰的CAR‐T细胞进行CAR‐T疗法与单独的CD19或CD20CAR‐T相比，明显加强了免疫细胞靶向识别肿瘤细胞的能力，也增强了对肿瘤细胞的杀伤活性。

Description

一种基于单域抗体的双特异性嵌合抗原受体及其应用
技术领域
本发明属于生物医学或生物制药技术领域，涉及一种基于单域抗体的双特异性嵌合抗原受体及其应用。
背景技术
随着肿瘤免疫学理论和临床技术的发展，嵌合抗原受体T细胞疗法(Chimericantigen receptor T-cell immunotherapy，CAR-T)成为目前最有发展前景的肿瘤免疫疗法之一。一般，嵌合抗原受体CAR由一个肿瘤相关抗原结合区、胞外铰链区、跨膜区域以及胞内信号转导区组成。CAR-T细胞疗法通过外源基因转染技术，把识别肿瘤相关抗原的单链抗体(Single chain fragment variable，scFv)和T细胞活化序列的融合蛋白表达到T细胞表面，使可以特异识别肿瘤相关抗原的scFv通过跨膜区与T细胞胞内的活化增殖信号域偶联。表达CAR的T细胞以抗原依赖、但非MHC限制的方式结合肿瘤抗原，启动并活化特异性杀伤肿瘤反应。
CD19、CD20分子是治疗B淋巴细胞系肿瘤潜在的靶点，也是CAR研究中的热点。靶向CD19分子的嵌合抗原受体基因修饰的T细胞(CD19 CAR-T)在治疗多发性、难治性的急性B淋巴细胞白血病上取得巨大成功，而在难治性、复发性慢性B淋巴细胞白血病和B淋巴细胞系淋巴瘤的治疗中疗效明显较差。CD20分子也是B淋巴细胞系淋巴瘤，尤其是慢性、套细胞淋巴瘤表面的靶标分子。一般在CD19阳性的B细胞表面都会表达CD20。所以理论上如果能实现针对CD19和CD20的双靶标的双特异性CAR-T技术，其对B淋巴细胞白血病和B淋巴细胞系淋巴瘤的疗效应该可以明显改善。
另外，目前针对CD19的CAR-T细胞疗法在治疗急性B淋巴细胞白血病的临床试验中虽然可以在短期内实现90％左右的完全缓解疗效，但在治疗后数月后发现有约10％的患者发生远期复发，主要原因是残存肿瘤细胞产生了CD19缺失的变异株。因而同时设计针对肿瘤表面CD19及CD20抗原进行协同CAR-T疗法，将不仅有效提高T细胞加强杀伤信号并且可以利用像抗生素联用一样的原理，有效地避免发生靶点逃逸现象引起的远期白血病复发。
CAR-T细胞的有效激活均严重依赖识别肿瘤相关抗原的抗体的特异性以及抗原结合的亲和力高低等性质。所以在目前CAR-T细胞胞内信号转导区的设计已经趋于成熟的现状下，抗原结合区的设计成为新型CAR-T技术开发的重点和关键。从骆驼源重链抗体(Heavychain antibody,HCAb)中克隆出仅由一个重链可变区组成的单链抗体，其大小仅为2.4×4nm，是能够结合抗原的最小片段，称为单域抗体(Variable domain of heavy chain ofheavy-chain antibody,VHH)或纳米抗体。与传统抗体相比，VHH单域抗体分子量小且表达量高，化学稳定性好，亲和力高并且与人源抗体同源性高，免疫原性低。分子量小易于进行基因工程改造，构建双重或多重特异性的单域抗体组合，达到一个分子多靶点或多种功能的效果。VHH组织渗透性好，在进行肿瘤治疗时，具有接触到不能被常规抗体接触的较为隐蔽的靶点的可能性。正由于这些优点，利用单域抗体作为CAR的抗原结合区进行CAR修饰及CAR-T细胞疗法是CAR疗法的创新性的发展。
发明内容
本发明的目的是针对现有技术的上述不足，提供一种应用于高效拮抗包括血液病在内的各种癌症的多靶点的CAR-T细胞疗法中的双特异性单域抗体嵌合抗原受体。
本发明的另一目的是提供含有该双特异性单域抗体嵌合抗原受体的T淋巴细胞或其他免疫效应细胞。
本发明的又一目的是提供该双特异性单域抗体嵌合抗原受体的应用。
本发明的目的可通过以下技术方案实现：一种基于单域抗体的双特异性嵌合抗原受体，胞外信号肽，由两个不同单域抗体构成的抗原结合结构域，跨膜结构域和胞内信号传导结构域共同组成。
所述基于单域抗体的双特异性嵌合抗原受体,其抗原与恶性肿瘤相关联，可以选自CD19、CD20、CD22、CD33/IL3Rα、CD38、BCMA、CS1、CD138、c-Met、EGFRvIII、GD-2、NY-ESO-1、MAGE A3、糖脂F77中任意二者的组合；优选CD19与CD20的组合；进一步优选的包括CD19及CD20抗原特异性的两个单域抗体VHH链组成的抗原结合结构域，并由一个Linker连接。
其中，所述的CD19抗原特异性的单域抗体VHH链包括框架区FR和互补决定区CDR，所述框架区FR包括FR1～FR4的氨基酸序列：SEQ ID NO:4所示的FR1，SEQ ID NO:5所示的FR2，SEQ ID NO:6所示的FR3，SEQ ID NO:7所示的FR4；所述互补决定区CDR包括CDR1～CDR3的氨基酸序列：SEQ ID NO:8所示的CDR1，SEQ ID NO:9所示的CDR2，SEQ ID NO:10所示的CDR3。
所述的CD19抗原特异性的单域抗体VHH链优选具有SEQ ID NO:3所示的氨基酸序列。
编码所述的CD19抗原特异性的单域抗体VHH链的核苷酸序列优选如SEQ ID NO:11所示。
所述的CD20抗原特异性的单域抗体VHH链包括框架区FR和互补决定区CDR，所述框架区FR包括FR1～FR4的氨基酸序列：SEQ ID NO:13所示的FR1，SEQ ID NO:14所示的FR2，SEQ ID NO:15所示的FR3，SEQ ID NO:16所示的FR4；所述互补决定区CDR包括CDR1～CDR3的氨基酸序列：SEQ ID NO:17所示的CDR1，SEQ ID NO:18所示的CDR2，SEQ ID NO:19所示的CDR3。
所述的CD20抗原特异性的单域抗体VHH链优选具有SEQ ID NO:12所示的氨基酸序列。
编码所述的CD20抗原特异性的单域抗体VHH链的核苷酸序列如SEQ ID NO:20所示。
所述基于单域抗体的双特异性嵌合抗原受体优选进一步包括共刺激信号传导区，包括选自下列的共刺激分子的细胞内结构域：CD27、CD28、4-1BB、OX40、CD30、CD40、CD3、淋巴细胞功能相关抗原-1(LFA-1)、CD2、CD7、LIGHT、NKG2C、B7-H3与CD83特异性结合的配体和其任意组合。
所述基于单域抗体的双特异性嵌合抗原受体优选地由CD8信号肽、CD19及CD20抗原特异性的两个单域抗体、CD28跨膜区以及CD28、CD3胞内信号传导结构域依次串联组成。
所述基于单域抗体的双特异性嵌合抗原受体更进一步优选具有SEQ ID NO:1所示的氨基酸序列，其编码基因序列如SEQ ID NO:2所示。
一种基因工程改造的免疫效应细胞，包括编码本发明所述的双特异性嵌合抗原受体的核苷酸序列。所述的免疫效应细胞选自T淋巴细胞、NK细胞，造血干细胞、多能干细胞或胚胎干细胞培养分化的免疫细胞，优选T淋巴细胞。
其中，所述嵌合抗原受体优选由CD8信号肽、CD19及CD20抗原特异性的两个单域抗体、CD28跨膜区以及CD28、CD3胞内信号传导结构域依次串联组成。
所述嵌合抗原受体进一步优选具有SEQ ID NO:1所示的氨基酸序列，其编码基因序列如SEQ ID NO:2所示。
本发明所述的双特异性嵌合抗原受体在制备抗肿瘤药物中的应用；优选在制备抗血液恶性肿瘤的药物中的应用。
本发明所述的免疫效应细胞在制备抗肿瘤药物中的应用；优选在制备抗血液恶性肿瘤的药物中的应用。
有益效果：
我们利用基因工程手段设计双特异性单域抗体作为CAR的抗原结合区进行CAR修饰及CAR-T细胞疗法是CAR疗法的创新性的发展。例如，将两个单域抗体结合起来(两个重链串联)蛋白质结构上和一个重链与轻链串联的scFv其实非常相似，我们的研究也证实双特异性单域抗体完全可以作为CAR技术的抗原结合域使用，从而成功地实现了双靶点双特异性的CAR技术，也在疗效试验中验证了前述双特异性CAR技术相对于传统CAR-T技术的多种理论优势。同时我们发现此发明还得以避免了以scFv为基础设计的CAR-T所常有的表达困难、稳定性差等缺陷。我们的CD19x CD20双特异性单域抗体-CAR技术在体外高效地转导了健康人T淋巴细胞，对于CD19和CD20阳性的靶细胞产生了强力的杀伤效果，在基于NOG小鼠的高质量人淋巴瘤模式动物体内起到了比单特异性CAR-T更好的治疗效果。
本发明通过优化设计CD19、CD20特异的单域抗体，提供了一种CD19、CD20双靶点修饰的CAR-T细胞，能够特异地与CD19及CD20抗原结合。此外，在B淋巴细胞系恶性肿瘤治疗中，采用CD19、CD20双靶点修饰的CAR-T细胞进行CAR-T疗法与单独的CD19或CD20CAR-T相比，明显增强了免疫细胞靶向识别肿瘤抗原的能力，加强了对肿瘤细胞的杀伤活性。
附图说明
图1为基于CD19xCD20单域抗体的嵌合抗原受体结构图。
图2为基于CD19xCD20单域抗体双特异性CAR-T体外杀伤效果图。其中，Raji细胞为靶细胞，A)只加入未转导的T细胞，B)加入CD19 CAR-T细胞，C)加入CD19 CAR-T细胞，D)加入CD19xCD20 CAR-T细胞。根据Raji细胞占总细胞的比例结果显示，与未加入CAR-T细胞的对照组相比，B)、C)与D)组对Raji肿瘤细胞均有杀伤作用，而CD19xCD20 CAR-T细胞的杀伤效果最好。
图3为小鼠生存曲线；分别对24只NOG小鼠尾静脉注射Raji细胞。10天以后，将注射Raji细胞的小鼠随机分成四组，分别注射等量(400万细胞)的T细胞、CD19 CAR-T细胞、CD20CAR-T细胞以及CD19xCD20 CAR-T细胞。连续观察动物5周，记录小鼠死亡时间。注射未转导T细胞的小鼠基本上在20天内全部死亡，注射CD19 CAR-T细胞的小鼠在40天时发生1例死亡，注射CD20 CAR-T细胞的小鼠在42天时发生1例死亡，而注射CD19xCD20 CAR-T细胞的小鼠在观察期间均未发生死亡。
具体实施方式
本发明利用多个各自特异的单域抗体进行CAR设计修饰，涉及识别多个靶点的CAR-T技术，协同杀伤包括血液系肿瘤的肿瘤，防止免疫逃逸及肿瘤复发。下面结合具体实施例，进一步阐述本发明。
实施例1 CD19与CD20单域抗体制备
(一)CD19与CD20单域抗体文库构建
利用购自R&D SYSTEMS公司的CD19及CD20抗原对美洲驼进行定期免疫。第一次免疫时，分别将200μg重组CD19或CD20蛋白与等体积弗氏佐剂混合，其后用弗氏不完全佐剂与抗原混合，进行免疫，每周一次。经多次免疫加强美洲驼对靶抗原的免疫应激反应，刺激B细胞表达针对靶抗原的重链抗体。
免疫期间对免疫动物取血采样，评估免疫反应效果。免疫结束后，取100mL美洲驼外周血淋巴细胞并提取Total RNA，并反转录成cDNA，通过二次PCR扩增美洲驼重链抗体的可变区片段VHH。将VHH片段构建入噬菌体展示载体中，并通过电转化将携带有单域抗体基因片段的产物转入感受态大肠杆菌中，从而获得单域抗体免疫文库。
第一次PCR模板：cDNA；
上游引物CALL001，如SEQ ID NO:21所示：5’-GTCCTGGCTGCTCTTCTACAAGG-3’；
下游引物CALLOO2，如SEQ ID NO:22所示：5’-GGTACGTGCTGTTGAACTGTTCC-3’；
第二次PCR模板：第一次PCR割胶回收产物；
上游引物BACK-1，如SEQ ID NO:23所示：5’-GATGTGCAGCTGCAGGAGTCTGGAGGAGG-3’；BACK-2，如SEQ ID NO:24所示：5’-GATGTGCAGCTGCAGGAGTCTGGGGGAGG-3’；
下游引物PMCF，如SEQ ID NO:25所示：5’-CTAGTGCGGCCGCTGAGGAGACGGTGACCTGGGT-3’；
两次PCR程序均为：预变性94℃、7min，变性94℃、1min，退火55℃、1min，延伸72℃、7min。
(二)CD19与CD20单域抗体筛选及表达
利用噬菌体展示技术将单域抗体分子展示于噬菌体表面，进而筛选出抗原特异性的单域抗体。通过噬菌体酶联免疫吸附ELISA方法，将抗原用100mM NaHCO3(pH 8.0)稀释至终浓度为100μg/mL,包被100μL至96孔板中，4℃过夜。经过PBS冲洗、1％脱脂牛奶封闭后，加入噬菌体孵育1～2h，然后将抗原特异性的噬菌体洗脱并侵染TG1细胞，在含有氨苄青霉素的LB培养板上涂布培养，经过多轮筛选逐步达到富集。挑选大量阳性克隆进行ELISA检测并对阳性克隆进行测序，根据序列比对，确定独特的的克隆并将其序列分为框架区FR和互补决定区CDR。
将测序正确的克隆接种在5mL含有氨苄青霉素的LB培养液中，37℃摇床培养过夜；接种1mL的菌液至300mL TB培养液中，37℃摇床培养至OD600nm＝0.6～0.9时，加入1M IPTG，28℃摇床培养过夜；离心，收菌；利用渗透法，获得抗体粗提液；通过Protein L标记并利用亲和层析法纯化出单域抗体，其产量均在10mg/L以上。利用SPR技术检测抗体的亲和力，进一步筛选出特异性高的单域抗体。通过以上实施方式，共获得6株CD19单域抗体、5株CD20单域抗体。选择亲和力较高的单域抗体，其中一株CD19单域抗体具有SEQ ID NO:11所示的核甘酸序列，一株CD20单域抗体具有SEQ ID NO:20所示的核甘酸序列。
实施例2 CD19与CD20双特异性嵌合抗原受体修饰的T细胞的制备
(一)嵌合抗原受体基因片段制备
本发明按以下编码基因的顺序设计融合基因片段：CD8信号肽、CD19 VHH-linker-CD20 VHH、CD28跨膜区以及CD28和CD3ζ胞内信号结构域，通过基因合成技术直接合成该融合基因，使表达的嵌合抗原受体具有CD8α-VHH(CD19-linker-CD20)-CD28 TM-CD28-CD3ζ的氨基酸结构。将购自Clontech公司的pLVX-Puro载体的CMV启动子改造为人EF1a启动子从而获得pLVX-hEF1α载体，将合成的基因片段构建在pLVX-hEF1α载体上，形成重组质粒，命名为pLVX-CD8α-VHH(CD19-linker-CD20)-CD28 TM-CD28-CD3ζ。
CD8信号肽的核酸序列如SEQ ID NO:26所示；
Linker的核酸序列如SEQ ID NO:27所示；
CD28 TM及CD28-CD3ζ胞内信号结构域的核酸序列如SEQ ID NO:28所示；
(二)嵌合抗原受体慢病毒表达载体的构建
在本发明中，CAR-T细胞通过基因修饰的CAR、慢病毒表达载体构建，转导T细胞而获得。提取pLVX-CD8α-VHH(CD19-linker-CD20)-CD28 TM-CD28-CD3ζ表达质粒和pRRE、pRSV-rev及pMD2.G辅助质粒，按一定比例混合，共转染293T细胞。转染48h、96h后，收集含有病毒的细胞培养上清，4℃、3000rpm离心5min。上清经0.45μm滤器过滤后，与PEG8000/NaCl按4:1体积混匀，4℃静置2～3h后高速离心30min。弃上清，沉淀用预冷的PBS重悬溶解，即获得病毒浓缩液，-80℃保存备用。
(三)T淋巴细胞的制备
取50mL健康人新鲜血液，通过淋巴细胞分离液、密度梯度离心方法分离外周血单核细胞(PBMC)。利用Pan T Cell Isolation Kit(购自Miltenyi Biotech)对细胞进行磁珠标记，并分离纯化出T淋巴细胞。纯化后的T细胞，再利用CD3/CD28磁珠进行T淋巴细胞激活及增殖。
(四)慢病毒转导T淋巴细胞
收集激活的T淋巴细胞，重悬在含有终浓度为100IU/mL IL-2的R10培养基中。用相同培养基将慢病毒稀释至MOI＝5，感染1x106个活化的T淋巴细胞，并加入终浓度为7μg/mL的聚凝胺，32℃、1000g离心1h。将细胞悬液加在24孔板中，置37℃、5％CO2培养箱中孵育过夜。第二天，再次离心并换新鲜培养基，每隔2天检测一次细胞浓度。当细胞浓度达到2x106个/mL时，离心吸取1mL细胞悬液到另一个孔中，并分别加入新鲜培养基，继续扩大培养。
实施例3 CD19与CD20双特异性CAR-T细胞对肿瘤的杀伤试验
(一)体外杀伤试验
离心收集实施例2中制备的CD19xCD20 CAR-T细胞，用含10％人AB血清的DPBS调节浓度，洗涤三次后接种在96孔板中，用Protein L进行标记。Raji肿瘤细胞用Calcein-AM标记，标记后的CAR-T与肿瘤细胞按1:1、5:1、10:1及20:1比率在37℃条件下共培养4h，利用流式细胞技术FACS进行检测。每种细胞设置三个阴性对照，分别为只加CD19 CAR-T或CD20CAR-T及非CAR修饰的T细胞的肿瘤细胞。试验结果显示与未注射CAR-T细胞的对照组相比，B)、C)与D)组对Raji肿瘤细胞均有杀伤作用，而CD19xCD20 CAR-T细胞的杀伤效果最好。
(二)动物模型试验
扩增Raji细胞，按4x106细胞量/只小鼠，分别进行24只高度免疫缺陷NOG小鼠尾静脉注射，建立模型。10天后将注射Raji细胞的小鼠分成四组，每组6只，分别注射等量的Tcell、CD19 CAR-T cell、CD20 CAR-T cell、CD19xCD20 CAR-T cell。连续饲养5周，观察小鼠状态，若有小鼠死亡，及时记录死亡时间，绘制小鼠生存曲线。小鼠模型试验表明，注射T细胞的小鼠基本上在20天内死亡，注射单一CD19 CAR-T cell或CD20 CAR-T cell的小鼠有少量死亡，而注射CD19xCD20 CAR-T细胞的小鼠均未发生死亡，说明本发明设计的CD19xCD20 CAR-T细胞在模式动物体内同样对肿瘤细胞具有杀伤作用。

Claims (7)

1.一种基于单域抗体的双特异性嵌合抗原受体，其特征在于包括胞外信号肽，由两个不同单域抗体构成的抗原结合结构域，跨膜结构域和胞内信号传导结构域;所述嵌合抗原受体具有SEQ ID NO: 1所示的氨基酸序列，其编码基因序列如SEQ ID NO: 2所示。
2.一种基因工程改造的免疫效应细胞，其特征在于包括编码权利要求1所述的双特异性嵌合抗原受体的核苷酸序列；所述的免疫效应细胞选自T淋巴细胞、NK细胞，多能干细胞或胚胎干细胞培养分化的免疫细胞。
3.根据权利要求2所述的基因工程改造的免疫效应细胞，其特征在于所述的免疫效应细胞为T淋巴细胞。
4.权利要求1所述基于单域抗体的双特异性嵌合抗原受体在制备抗肿瘤药物中的应用。
5.根据权利要求4所述的应用，其特征在于权利要求1所述基于单域抗体的双特异性嵌合抗原受体在制备抗血液恶性肿瘤的药物中的应用。
6.权利要求2所述的免疫效应细胞在制备抗肿瘤药物中的应用。
7.根据权利要求6所述的应用，其特征在于权利要求2所述的免疫效应细胞在制备抗恶性肿瘤的药物中的应用。
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