CN112062851B - 靶向bcma嵌合抗原受体的抗体及其应用 - Google Patents
靶向bcma嵌合抗原受体的抗体及其应用 Download PDFInfo
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Abstract
本发明公开了一种抗体或其scFv或片段，该抗体可特异结合一种靶向BCMA的嵌合抗原受体(CAR)的胞外结合结构域scFv，而不与其它scFv或抗体序列有交叉反应。本发明还公开了该抗体在检测所述CAR中的应用。
Description
技术领域
本发明涉及靶向BCMA嵌合抗原受体的抗体，还涉及该抗体的编码核酸分子和其应用。
背景技术
多发性骨髓瘤(multiple myeloma，MM)是仅次于非霍奇金淋巴瘤的第二常见恶性血液病，其肿瘤细胞起源于骨髓中的浆细胞，目前用传统方法不可治愈，疾病进展较为迅速，中位生存时间仅3至4年[1-2]。嵌合抗原受体(Chimeric Antigen Receptor,CAR)T细胞的过继疗法对于血液恶性肿瘤是一种突破性的新疗法。B细胞成熟抗原(BCMA)，又名CD269或TNFRSF17，是肿瘤坏死因子受体家族成员，被鉴定为嵌合抗原受体(CAR)T细胞疗法的重要多发性骨髓瘤(MM)特异性靶标[3]。此前，我公司发明了一种靶向BCMA的嵌合抗原受体(RD103A CAR，其胞外结构域称为RD103A CAR scFv或RD103A scFv)，利用患者自身的T细胞，通过体外基因修饰后，将表达全人源103A scFv的CAR-T细胞回输到患者体内。103ACAR-T在临床前和临床研究中，效果非常显著。此产品正在准备在中国申报一期临床试验。鉴于其优秀的临床治疗效果，RD103 CAR-T有望得到更广的应用，临床应用和市场价值巨大。
在临床应用中，CAR基因能否表达、表达效率的高低、CAR-T细胞的活性和纯度都会直接影响CAR-T细胞对癌细胞的清除效率。临床研究证明，CAR-T细胞回输后在患者外周血中的增殖能力与疗效具有很强的相关性[4]。
目前，主流的临床试验采用实时荧光定量PCR的方法检测外周血基因组中的CAR基因拷贝数，进而间接估算CAR-T细胞数量。qPCR的方法存在以下几个方面的问题：1)qPCR检测的是外周血PBMC基因组DNA中的CAR基因数量，而CAR的表达水平与基因组中的CAR基因含量与并不直接相关，甚至有可能发生基因沉默而导致的基因不表达；2)CAR在基因组中的拷贝数会因为不同CAR-T细胞克隆的增殖或凋亡而处于动态变化的过程，进一步导致通过检测外周血基因组中的CAR含量估算CAR-T细胞的误差；3)qPCR的方法难以对CAR-T细胞在体内的状态，如T细胞亚型进行进一步的分析，为CAR-T的深入研究带来困难。
用带荧光标记的靶抗原(如FITC-BCMA)来估计CAR-T细胞数量也存在很大不确定性。主要原因是患者外周血中可能存在的拮抗BCMA抗原的抗体，或者细胞上表达BCMA的天然配体而产生假阳性信号。这些因素都会严重影响实验结果。还有一种情况是，当患者因疾病情况复杂而输注过多种CAR-T后，就无法用荧光标记的抗原去区分不同的CAR-T细胞数量了。因此，开发一种准确、快速的检测CAR表达情况的技术，对于该疗法的实施、监测以及深入研究具有重要意义。
另一方面，CAR-T治疗完全缓解后一年内再次复发的比例很高，文献[5]中统计，不同的CD19CAR-T疗法，复发率为(4.6％至33.9％)。复发主要分为靶抗原阴性的复发和靶抗原阳性的复发。前者的原因是肿瘤细胞发生了抗原调低或丢失导致的CAR-T治疗失效；后者通常与CAR-T细胞在体内扩增和存续时间短相关。目前认为除了病人T细胞本身有缺陷之外，患者体内产生针对CAR-T细胞的抗体(Anti-Drug Antibody，ADA)和杀伤性的T细胞(Cytotoxic T Lymphocyte，CTL)是导致CAR-T快速失效的主要可能原因[5]。因此，检测回输病人体内是否产生了针对CAR-T scFv的ADA，并定量ADA浓度，可以分析ADA的浓度与CAR-T细胞存续之间的相关性，对于CAR-T产品的研究有重要意义。目前ADA检测主要是基于酶联免疫吸附测定(ELISA)。定量检测ADA的ELISA需要有标准参比品，也就是一个特异结合待检抗原的对照抗体。根据不同浓度对照抗体的ELISA读数制作标准曲线，我们才可以定量评估样品中的ADA浓度。
发明内容
在一方面，本文提供了一种抗体或其scFv或片段，该抗体的重链可变区包括HCDR1、HCDR2和HCDR3，轻链可变区包括LCDR1、LCDR2和LCDR3，其中HCDR1、HCDR2和HCDR3的氨基酸序列分别为：GFTFSSYA、ISGSGGST和ARGYMHAEHEKMEKSSRSDP，LCDR1、LCDR2和LCDR3的氨基酸序列分别为：SLRSTY、GKT和SSRDSSGYHYV。
在一些实施方案中，所述抗体的轻链可变区包括SEQ ID NO：5所示的氨基酸序列，所述抗体的重链可变区包括SEQ ID NO：6所示的氨基酸序列。
在一些实施方案中，所述scFv包括SEQ ID NO：4所示的氨基酸序列。
另一方面，本文提供了所述抗体或其scFv或片段在抗原检测中的应用，其中所述抗原包括SEQ ID NO：12所示的氨基酸序列。
在一些实施方案中，所述抗原为融合蛋白的一部分。
在一些实施方案中，所述融合蛋白为靶向BCMA的嵌合抗原受体，所述抗原为所述嵌合抗原受体的胞外结合结构域或其一部分。
在一些实施方案中，所述应用包括：
1)对表达所述嵌合抗原受体的培养T细胞进行定性和定量检测；
2)在患者中检测表达所述嵌合抗原受体的T细胞的浓度，其中所述患者在所述检测前经表达所述嵌合抗原受体的T细胞输注治疗；或
3)作为标准品用于在患者中检测所述患者体内针对所述嵌合抗原受体产生的抗体，其中所述患者在所述检测前经表达所述嵌合抗原受体的T细胞输注治疗。
另一方面，本文提供了编码抗体或其scFv或片段的核酸分子，其中所述抗体的重链可变区包括HCDR1、HCDR2和HCDR3，轻链可变区包括LCDR1、LCDR2和LCDR3，其中HCDR1、HCDR2和HCDR3的氨基酸序列分别为：GFTFSSYA、ISGSGGST、和ARGYMHAEHEKMEKSSRSDP，LCDR1、LCDR2和LCDR3的氨基酸序列分别为：SLRSTY、GKT和SSRDSSGYHYV。
在一些实施方案中，编码所述抗体的轻链可变区的序列包括SEQ ID NO：2所示的核苷酸序列，编码所述抗体的重链可变区的序列包括SEQ ID NO：3所示的核苷酸序列。
在一些实施方案中，编码所述scFv的序列包括SEQ ID NO：1所示的核苷酸序列。
另一方面，本文提供了包括上述核酸分子的表达载体。
本文提供的抗体作为独特型抗体特异靶向RD103A scFv，而不与其它scFv或抗体序列有交叉反应，有益于对RD103A CAR-T产品的药学研究。
附图说明
图1显示了本发明的大体研究流程图。
图2显示了对富集的噬菌体抗体克隆进行ELISA初筛的结果。
图3显示了噬菌体抗体克隆与细胞表面靶抗原(Jurkat-103A scFv)结合的FACS测定结果。
图4显示了蛋白形式的抗体分子与靶抗原和无关抗原结合的ELISA测定结果。
图5显示了蛋白形式的抗体分子与细胞表面靶抗原(Jurkat-103A scFv)结合的FACS测定结果。
图6显示了蛋白形式的抗体分子与CAR T细胞表面靶抗原(RD103A CAR)结合的FACS测定结果。
具体实施方式
除非另有说明，本文使用的所有技术和科学术语具有本领域普通技术人员所通常理解的含义。
抗体指由浆细胞(效应B细胞)分泌、被机体免疫系统用来中和外来物质(多肽、病毒、细菌等)的免疫球蛋白。该外来物质相应地称作抗原。抗体分子的基本结构是由2个相同重链和2个相同轻链组成的4聚体。根据氨基酸序列的保守性差异，将重链和轻链分为位于氨基端的可变区(V)和位于羧基端的恒定区(C)。一条重链和一条轻链的可变区相互作用形成了抗原结合部位(Fv)。在可变区中，某些区域氨基酸残基的组成和排列次序比可变区内的其它区域(骨架区，FR)更易变化，称为高变区(HVR)，高变区实际上是抗体与抗原结合的关键部位。由于这些高变区序列与抗原决定簇互补，故又称为互补决定区(complementarity-determining region,CDR)。重链和轻链均具有三个互补决定区，分别称为HCDR1、HCDR2、HCDR3和LCDR1、LCDR2、LCDR3。抗体片段指经酶学、化学、或基因工程等手段处理而获得的抗体部分，其可以具有或不具有抗原结合能力。
单链抗体(single chain fragment variable,scFv)，是由抗体重链可变区和轻链可变区通过短肽连接成一条肽链而构成。通过正确折叠，来自重链和轻链的可变区通过非共价键相互作用形成Fv段，因而scFv能较好地保留其对抗原的亲和活性。
嵌合抗原受体(CAR)，也称为嵌合T细胞受体、嵌合免疫受体，为一种工程化的蛋白受体分子，其可将期望的特异性赋予免疫效应细胞，例如与特定肿瘤抗原结合的能力。嵌合抗原受体通常由胞外抗原结合结构域、跨膜结构域和胞内信号结构域构成。多数情况下，抗原结合结构域为一段scFv序列，负责识别和结合特定的抗原。胞内信号结构域通常包括免疫受体酪氨酸活化基序(ITAM)，例如来源于CD3ζ分子的信号传导结构域，负责激活免疫效应细胞，产生杀伤作用。另外，嵌合抗原受体还可在氨基端包括负责新生蛋白在细胞内定位的信号肽，以及在抗原结合结构域和跨膜结构域之间包括铰链区。除了信号传导结构域，胞内信号结构域还可包括例如来源于4-1BB分子的共刺激结构域。RD103A CAR为申请人之前开发的靶向BCMA的CAR，其scFv具有SEQ ID NO：12所示的氨基酸序列。
CAR-T细胞指表达CAR的T细胞，通常采用编码CAR的表达载体转导T细胞获得。常用的表达载体为病毒载体，例如慢病毒表达载体。经嵌合抗原受体修饰的T细胞(CAR-T)不受主要组织相容性复合体的限制，具有特异性靶向杀伤活性和持久扩增的能力。
研究过程概述
1.淘选：使用噬菌体抗体库，通过RD103A scFv-rFc蛋白进行正淘，RD103B scFv-rFc蛋白(另一全人源scFv克隆)和B53 scFv-rFc(鼠源scFv克隆)进行负淘，富集与RD103AscFv蛋白特异结合的抗体克隆。这里，RD103B scFv-rFc是CDR序列和103A不同的另一个靶向BCMA的全人源单链抗体，B53 scFv则是框架区和CDR都差异比较大的一个鼠源BCMA单链抗体，其中RD103A scFv的氨基酸序列如SEQ ID NO：12所示，RD103B scFv的氨基酸序列如SEQ ID NO：13所示。同时，在每一轮的正淘的步骤中，我们加入了终浓度5％的人血清(Human serum)作为竞争负淘。人血清中含有大量的IgG、IgM类抗体蛋白，可以进一步减少与不相关人IgG结合的抗体，更好地富集RD103A scFv特异型抗体。
2.单克隆初筛：从富集后的抗体库中分离单克隆，包装成单克隆噬菌体，用ELISA法筛选能与RD103A scFv-rFc蛋白结合，但不与RD103B scFv-rFc蛋白结合的克隆；DNA测序确定这些初筛特异克隆包含的抗体可变区序列；
3.噬菌体水平的单克隆流式细胞术(FACS)鉴定：把测序获得的单克隆包装成噬菌体，通过FACS鉴定这些克隆与Jurkat-RD103A以及Jurkat(阴性对照细胞系)的结合情况，筛选能与细胞表面RD103A-scFv特异结合的克隆。其中，Jurkat-RD103A是用RD103A CAR慢病毒转染的Jurkat细胞系，其细胞表面高表达RD103A scFv，可作为代表细胞表面状态RD103AscFv的很好的模式细胞系，鉴定我们筛选到的特异型抗体能否与细胞表面状态天然构象的RD103A scFv结合。
4.IgG水平的单克隆鉴定：
4.1 ELISA鉴定：挑选了3个特异性克隆，构建到哺乳动物细胞表达载体中，以scFv-rFc的形式，在293F细胞系里进行蛋白表达。表达的蛋白通过AKTA蛋白纯化系统(Protein A亲和纯化)纯化后，ELISA检测这些类IgG蛋白与RD103A scFv,RD103B scFv蛋白,以及6个健康人血清(含有大量的无关IgG蛋白)的结合，在IgG水平分析比较这些克隆的特异性；
4.2 FACS鉴定：这些克隆表达成scFv-rFc蛋白的形式，并经protein A亲和纯化后，通过流式细胞术鉴定这些克隆与Jurkat-103A(高表达RD103A scFv的阳性细胞系)，Jurkat(阴性对照细胞系)；RD103A CAR-T(阳性样品)/Mock-T(阴性对照)的结合情况，并评估其与荧光标记的抗原FITC-BCMA检测CAR-T阳性细胞比例的一致性。大体研究流程如图1所示。
以下通过具体实施例详细说明本发明。
实施例1.噬菌体抗体库淘选以富集RD103A scFv特异噬菌体克隆
利用负淘选抗原RD103B scFv-rFc、B53scFv-rFc和正淘选靶抗原RD103A scFv-rFc交替淘选，同时在正淘的步骤中，加入终浓度为5％的人血清作为竞争负淘，以富集靶向RD103B scFv的特异噬菌体克隆。表1列出了淘选过程。
简要实验步骤：
1)将带Fc标签的靶抗原RD103A scFv-rFc或者对照抗原RD103B scFv-rFc、B53scFv-rFc包被高结合96孔ELISA板(Corning Incorporated 96well EIA/RIA plate,Costar,3590)上，用封闭液封闭ELISA板；
2)让噬菌体抗体库与包被好的负抗原RD103B scFv-rFc或B53 scFv-rFc孵育，扣除非特异结合Fc标签或者封闭液成分的噬菌体抗体克隆；
3)将上一步孵育后的上清转移到包被好靶抗原RD103A scFv-rFc的板中，加入终浓度为5％的人血清(含大量人抗体类蛋白)继续孵育，使噬菌体和靶抗原结合；
4)用洗涤液洗涤固体载体的表面，将未结合的噬菌体洗去；
5)用洗脱液将阳性噬菌体从靶抗原上洗脱下来；
6)用洗脱后的噬菌体重新感染宿主菌XL1-blue，扩增回收的噬菌体；
7)重复步骤1)至6)，通常需要进行2至3轮淘选，直到观察到噬菌体的回收率(洗脱噬菌体数/投入噬菌体数)有明显上升。
富集好的噬菌体池(Pool)可进行下一步的单克隆挑选及ELISA/FACS鉴定。
主要材料和试剂：
全人源噬菌体抗体库，包含天然库与半合成库；
辅助噬菌体KO7，Thermo/Invitrogen,18311019；
RD103A scFv-rFc蛋白；
RD103B scFv-rFc蛋白；
B53scFv-rFc蛋白；
High binding ELSIA plate,Costar，#3590；
封闭液：PBS+3％BSA；
漂洗液：PBS+0.1％Tween20；
洗脱液：1mg/mL Trypsin in PBS。
表1噬菌体淘选过程。
实验结果：
表2展示不同抗体库3轮淘选的回收率(回收噬菌体/投入噬菌体)和富集倍数(本轮回收率/前一轮回收率)。可以看到抗体库XL-N1-3、XL-N4-6和XL-SS1第3轮淘选回收率都明显提高，说明富集了特异噬菌体克隆；而XL-SS2的第3轮淘选回收率没有提高反而下降，说明尚未富集到特异克隆。
表2不同抗体库3轮淘选的回收率和富集倍数
实施例2.噬菌体单克隆的ELISA初筛
从实施例1富集后的噬菌体抗体池随机挑选单克隆，包装成噬菌体后，通过噬菌体ELISA检测单克隆噬菌体与RD103A scFv-rFc蛋白、103B scFv-rFc蛋白的结合，找到特异性结合103A scFv的噬菌体抗体克隆。对这些克隆测序以确定其scFv序列。
简要实验步骤：
1)将富集后的噬菌体溶液进行梯度稀释，感染宿主菌XL1-blue，涂含Amp与Tet的平板；
2)挑单克隆在96孔板中，在37℃，250rpm培养至对数生长期，并加入辅助噬菌体KO7，继续培养，扩增得到单克隆的噬菌体溶液；
3)将靶抗原和对照抗原直接或者间接地固定在96孔板中；
4)将单克隆噬菌体上清加入包被好抗原的96孔板中孵育；
5)用洗涤液洗涤ELISA板6次，将未结合噬菌体洗去；
6)加入鼠抗噬菌体衣壳蛋白PIII的抗体[Anti-M13Bacteriophage Coat Proteing8p antibody(clone:RL-ph2),abcam,ab9225]，室温孵育45min；
7)用洗涤液洗涤ELISA板6次，将未结合噬菌体洗去；
8)加入HRP偶联山羊抗鼠抗体[HRP Goat anti-mouse IgG(minimal x-reactivity)Antibody,BioLegend]，室温孵育45min；
9)用洗涤液洗涤ELISA板6次，加入TMB(可溶性单组分TMB底物溶液,TIANGEN,PA107-02)，显色后读数；
10)挑选103A scFv-rFc特异的单克隆进行测序，并编号。
主要材料和试剂：
辅助噬菌体KO7，Thermo/Invitrogen,18311019；
High binding ELSIA plate,Costa，#3590；
封闭液：PBS+3％BSA；
漂洗液：PBS+0.1％Tween20；
可溶型单组分TMB底物溶液，Tiangen,PA-107-02；
Anti-M13Bacteriophage Coat Protein g8p antibody,abcam,ab9225；
HRP Goat anti-mouse IgG(minimal x-reactivity)Antibody,Biolegend,405306。
实验结果：
部分克隆的ELISA结果如图2所示。Control 1为HRP Donkey anti rabbit IgG。Control 2为阴性对照噬菌体KO7。#1至#10号克隆与103A scFv-rFc结合良好，且不与103BscFv-rFc结合，特异性良好。ITRD103-43及辅助噬菌体KO7与103A scFv-rFc及103B scFv-rFc都不结合，为阴性克隆。ITRD103-21能与103A scFv-rFc结合，但与103B scFv-rFc也可结合，为非特异性克隆。
实施例3.噬菌体单克隆的FACS鉴定
通过实施例2的ELISA初筛，我们已经证明了#1至#10号克隆可与103A scFv-rFc蛋白特异性的结合，但在实际检测中，我们需要保证其可以有效地结合在CAR分子的scFv结构域上，才可起到检测CAR-T细胞的作用。所以我们通过流式细胞术(FACS)测定了这些克隆与Jurkat-103A scFv及Jurkat细胞的结合情况。
简要实验步骤：
1.将待测单克隆噬菌体抗体与分别与Jurkat-103A scFv及Jurkat细胞于4℃孵育1h，离心得到第一沉淀物；
2.将第一沉淀物洗涤后结合一抗[Anti-M13Bacteriophage Coat Protein g8pantibody,abcam，ab9225]孵育30min，洗涤后结合二抗[FITC horse anti mouse-IgG(H+L),vector,FI2000]孵育30min，离心得到第二沉淀物；
3.将第二沉淀物洗涤后流式缓冲液重悬流式上机，分析其与Jurkat-103A scFv及Jurkat细胞的结合情况，并判断所测CAR阳性率百分比与CAR实际阳性率(通过阳性对照FITC-BCMA抗原所测得的阳性率)是否相符。
主要材料和试剂：
辅助噬菌体KO7,Thermo/Invitrogen,18311019
Jurkat细胞系和Jurkat-103A细胞系；
漂洗液：PBS+0.1％Tween20；
FITC horse anti mouse-IgG(H+L),Vector,FI2000；
Anti-M13Bacteriophage Coat Protein g8p antibody,abcam,ab9225
FITC-BCMA抗原，ACRObiosystems,BCA-HF254。
实验结果：
如图3所示，初筛获得的10个能与103A scFv-rFc蛋白结合的单克隆，都能与Jurkat-103A scFv细胞结合，同时不与Jurkat细胞结合，并且所测CAR阳性率百分比与CAR实际阳性率接近。Control 1为辅助噬菌体KO7(阴性对照)。Control 2为FITC-BCMA抗原(阳性对照)。
实施例4.IgG水平的单克隆鉴定
单克隆抗体ELISA验证：
为了验证以上实施例获得的克隆表达为抗体分子形式后仍能与103A CAR分子结合，且不受人血清的干扰，我们将前期特异性较好的#4、#9、和#10号3个单克隆，构建成scFv-rFc结构，在293F细胞中进行蛋白表达，并通过protein A亲和纯化获得纯度较高的抗体蛋白。然后，我们通过ELISA检测这些克隆的scFv-rFc蛋白形式，与RD103A scFv(靶抗原)、RD103B scFv(对照抗原)、以及6个健康人血清(含有大量的抗体类蛋白)的结合情况。
简要实验步骤：
1)将scFv形式的靶抗原RD103A scFv-StrepTag蛋白(2μg/mL)、对照抗原RD103BscFv-StrepTag蛋白(2μg/mL)、以及来自不同健康供者的血清Human serum(5％inPBS)包被高结合96孔ELISA板上(室温包被2h)，100μL/孔；
2)250μL封闭液封闭ELISA板，4℃封闭2h；
3)用200μL洗涤液洗涤5次后，分别加入100μL#4、#9、#10单克隆抗体及阳性对照和阴性对照孵育(5μg/mL)。阳性对照孔：RD103A scFv和RD103B scFv的阳性对照为在此步骤中加入BCMA-hFc，血清样品为加入漂洗液；阴性对照加入PBST，室温孵育30min；
4)用200μL洗涤液洗涤5次后，检测样品孔和阴性对照孔加入100μL二抗Anti-Rabbit IgG-HRP(1:2000)；阳性对照孔加入二抗Anti-Human IgG-HRP(1:2000)，室温孵育30min；
5)用200μL洗涤液洗涤ELISA板6次，加入TMB底物，显色，终止后读数。
主要材料和试剂：
RD103A scFv-Strep tag蛋白和RD103B scFv-Strep tag蛋白；
健康捐献者血清；
High binding ELSIA plate,Costar,#3590；
封闭液：PBS+3％BSA；
漂洗液：PBS+0.1％Tween20；
可溶型单组分TMB底物溶液，Tiangen，PA-107-02；
BCMA-hFC-Biotin,ACRObiosystems,BC7-H82FO；
Anti-Rabbit IgG-HRP,Biolegend,406401；
Anti-Human IgG-HRP,Biolegend,410902。
实验结果：
结果如图4所示。#4、#9、#10scFv-rFc蛋白都能与靶抗原RD103A scFv-strep tag结合，同时不与对照抗原RD103B scFv-strep tag以及6个健康人的血清成分结合。结果表明这3个克隆转化成scFv-rFc蛋白形式之后，都能识别RD103scFv蛋白，且特异性较好。Control 1为阳性对照，对于103A scFv和103B scFv孔添加的是BCMA-hFc+anti humanIgG-HRP，血清样品只添加了anti human-HRP；阴性对照孔添加的是PBST+anti rabbitIgG-HRP。
单克隆抗体与Jurkat-103A/Jurkat细胞的FACS验证：
为了进一步验证上述克隆表达为抗体后仍能与细胞上天然构象的RD103A CAR分子结合，我们用慢病毒感染的方法构建了高表达RD103CAR的Jurkat-103A CAR细胞系，将Jurkat本身作为阴性细胞。然后，我们通过FACS检验这3个克隆scFv-rFc蛋白与细胞上103ACAR分子的结合能力。
简要实验步骤：
1)将Jurkat-103A scFv和Jurkat细胞用PBS洗2次，用PBS重悬成1x107/mL浓度，以50μL分装到管中；
2)实验组中每管入50μL待测抗体#4、#9、#10(10μg/ml)，其他组补充等体积PBS，混匀后，4℃结合1h；
3)200μL PBS洗涤2次；
4)实验组中加入1:400稀释的Goat Anti-Rabbit IgG，100μL/孔，阳性对照中加入1：100稀释的FITC-BCMA，100μL/孔，空白对照Cell Only补充等体积PBS，吹打混匀后，4℃结合30min；
5)200μL PBS洗涤2次；最后用200μL PBS重悬细胞；
6)流式细胞仪上检测样品Vioblue及FITC通道的荧光强度，分析结果。
主要材料和试剂：
漂洗液：PBS+0.1％Tween20；
#4，#9，#10的scFv-rFc蛋白；
DyLight 405-AffiniPure F(ab)2Fragment Goat Anti-Rabbit IgG；
FITC-BCMA抗原，ACRObiosystems，BCA-HF254。
实验结果：
表3和图5显示了#4、#9和#10号克隆的scFv-rFc蛋白的细胞流式分析结果。#4和#9号单克隆抗体与Jurkat-103A scFv和Jurkat细胞均无明显结合，说明其不结合细胞上天然构象的103A CAR分子。#10单克隆抗体可特异性结合Jurkat-103A scFv细胞上的103A CAR分子，所测103A CAR阳性百分率(％)与阳性对照FITC-BCMA所测103A CAR阳性百分率(％)相符(相差<5％)，且不结合Jurkat细胞，所以#10单克隆抗体在本实验中特异性良好，满足实验需要，可进一步在103A CAR-T细胞上验证其检测效果。
表3 scFv-rFc蛋白与Jurkat-103A/Jurkat细胞结合的流式检测结果(阳性百分率)
实施例5.单克隆抗体与实际CAR-T样品结合的FACS验证
为了验证#10单克隆抗体(scFv-rFc蛋白)与103A CAR-T细胞上103A CAR分子的结合能力，我们采用了同一健康捐献者T细胞经慢病毒转染后第6天的103A CAR-T细胞及未转染的阴性对照细胞(Mock T)对#10单克隆抗体进行FACS分析。
主要实验步骤与试剂与实施例4中单克隆抗体的细胞系FACS验证类似。
判定标准：待测抗体所测103A CAR阳性百分率(％)与阳性对照FITC-BCMA所测103A CAR阳性百分率(％)是否相符(相差<5％)。
实验结果：
结果显示在表4和图6中。#10单克隆抗体可特异性结合103A CAR-T细胞上的103ACAR分子，所测103A CAR阳性百分率(％)与阳性对照FITC-BCMA所测103ACAR阳性百分率(％)相符(相差<5％)，且与Mock T无非特异性结合，所以#10单克隆抗体在该实验中特异性良好，可满足在实验及临床中的检测需要。
表4 scFv-rFc蛋白与CAR-T细胞结合的流式检测结果((阳性百分率))
本发明筛选出的单克隆抗体为特异识别RD103A scFv的独特型抗体，可特异性结合103A scFv蛋白及103A CAR-T细胞，不与其它不相干抗体以及膜蛋白有非特异结合，可用于流式细胞术检测CAR-T细胞，或者ELISA检测RD103scFv蛋白，对于对RD103A CAR-T产品的药学研究有重要价值。
本发明所获得的特异性抗体的具体应用可以包括但不限于以下3个方面：1)用于流式细胞术(FACS)对RD103A CAR-T产品细胞进行定量的分析和检测，如检测CAR-T的产品的阳性率；2)用于流式细胞术(FACS)检测回输后病人血液中RD103A CAR-T细胞浓度。相对于用荧光标记的BCMA蛋白检测RD103A scFv，此独特型抗体有更好的特异性和更低的背景，因而也有更高的灵敏度；3)在检测病人回输血液中针对RD103scFv的抗抗体(ADA)浓度ELISA实验中，此特异型抗体可作为标准参比品。
本文中提及的一些序列如下：
SEQ ID NO：1#10scFv DNA序列：771bp
TCTTCTGAGCTGACTCAGGACCCTGCTGTGTCTGTGGCCTTGGGACAGACAGTCAAGATCACATGCCGAGGAGACAGCCTCAGAAGCACTTACGCAAGCTGGTACCAGCAGAAGCCAGGACAGGCCCCTGTACTTGTCATCTATGGTAAAACCAACCGGCCCTCAGGGATCCCAGACCGATTCTATGGTTCCAGCTCAGGAAACACAGCTTCCTTGACCATCACTGGGGCTCAGGCGGAAGATGAGGCTGACTATTACTGTAGCTCCCGCGACAGCAGTGGTTACCATTATGTCTTCGGAAGTGGGACCAAGCTGACCGTCCTAGGTTCTAGAGGTGGTGGTGGTAGCGGCGGCGGCGGCTCTGGTGGTGGTGGATCCCTCGAGATGGCCCAGGTGCAGCTGGTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGGGGGTCCCTGAGACTCTCCTGTGCAGCCTCTGGATTCACCTTTAGCAGCTATGCCATGAGCTGGGTCCGCCAGGCTCCAGGGAAGGGGCTGGAGTGGGTCTCAGCTATTAGTGGTAGTGGTGGTAGCACATACTACGCAGACTCCGTGAAGGGCCGGTTCACCATCTCCAGAGACAATTCCAAGAACACGCTGTATCTGCAAATGAACAGCCTGAGAGCCGAGGACACGGCCGTATATTACTGTGCGCGCGGTTACATGCATGCAGAACATGAAAAAATGGAAAAATCTTCTCGTTCTGATCCATGGGGTCAAGGTACTCTGGTGACCGTCTCCTCA
SEQ ID NO：2#10VL DNA序列：327bp
TCTTCTGAGCTGACTCAGGACCCTGCTGTGTCTGTGGCCTTGGGACAGACAGTCAAGATCACATGCCGAGGAGACAGCCTCAGAAGCACTTACGCAAGCTGGTACCAGCAGAAGCCAGGACAGGCCCCTGTACTTGTCATCTATGGTAAAACCAACCGGCCCTCAGGGATCCCAGACCGATTCTATGGTTCCAGCTCAGGAAACACAGCTTCCTTGACCATCACTGGGGCTCAGGCGGAAGATGAGGCTGACTATTACTGTAGCTCCCGCGACAGCAGTGGTTACCATTATGTCTTCGGAAGTGGGACCAAGCTGACCGTCCTAGGT
SEQ ID NO：3#10VH DNA序列：387bp
ATGGCCCAGGTGCAGCTGGTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGGGGGTCCCTGAGACTCTCCTGTGCAGCCTCTGGATTCACCTTTAGCAGCTATGCCATGAGCTGGGTCCGCCAGGCTCCAGGGAAGGGGCTGGAGTGGGTCTCAGCTATTAGTGGTAGTGGTGGTAGCACATACTACGCAGACTCCGTGAAGGGCCGGTTCACCATCTCCAGAGACAATTCCAAGAACACGCTGTATCTGCAAATGAACAGCCTGAGAGCCGAGGACACGGCCGTATATTACTGTGCGCGCGGTTACATGCATGCAGAACATGAAAAAATGGAAAAATCTTCTCGTTCTGATCCATGGGGTCAAGGTACTCTGGTGACCGTCTCCTCA
SEQ ID NO：4#10scFv氨基酸序列：256aa
SSELTQDPAVSVALGQTVKITCRGDSLRSTYASWYQQKPGQAPVLVIYGKTNRPSGIPDRFYGSSSGNTASLTITGAQAEDEADYYCSSRDSSGYHYVFGSGTKLTVLGSRGGGGSGGGGSGGGGSLEMAQVQLVESGGGLVQPGGSLRLSCAASGFTFSSYAMSWVRQAPGKGLEWVSAISGSGGSTYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARGYMHAEHEKMEKSSRSDPWGQGTLVTVS
SEQ ID NO：5#10VL氨基酸序列：109aa
SSELTQDPAVSVALGQTVKITCRGDSLRSTYASWYQQKPGQAPVLVIYGKTNRPSGIPDRFYGSSSGNTASLTITGAQAEDEADYYCSSRDSSGYHYVFGSGTKLTVLG
SEQ ID NO：6#10VH氨基酸序列：130aa
LEMAQVQLVESGGGLVQPGGSLRLSCAASGFTFSSYAMSWVRQAPGKGLEWVSAISGSGGSTYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARGYMHAEHEKMEKSSRSDPWGQGTLVTVS
#10单克隆抗原决定簇(CDR)氨基酸序列：
SEQ ID NO：12RD103A scFv氨基酸序列：
DIQMTQSPSSLSASVGDRVTITCRASQSISSYLNWYQQKPGKAPKLLIYAASSLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQKYDLLTFGGGTKVEIKGSTSGSGKPGSGEGSTKGQLQLQESGPGLVKPSETLSLTCTVSGGSISSSSYYWGWIRQPPGKGLEWIGSISYSGSTYYNPSLKSRVTISVDTSKNQFSLKLSSVTAADTAVYYCARDRGDTILDVWGQGT
SEQ ID NO：13RD103B scFv氨基酸序列：
EIVLTQSPATLSLSPGERATLSCRASQSVSSYLAWYQQKPGQAPRLLIYDASKRATGIPARFSGSGSGTDFTLTISSLEPEDFAVYYCQQASALPLTFGGGTKVEIKGSTSGSGKPGSGEGSTKGEVQLVESGGGLVQPGRSLRLSCAASGFTFDDYAMHWVRQAPGKGLEWVSGISWSSGSIGYADSVKGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCAKDSPRRDSFGSIAFDIWGQGT
参考文献：
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2.Shely R N,Ratliff P D.Carfilzomib-Associated Tumor Lysis Syndrome[J].Pharmacotherapy:The Journal of Human Pharmacology and Drug Therapy,2014,34(5).
3.Carpenter R O,Evbuomwan M O,Pittaluga S,et al.B-cell maturationantigen is apromising target for adoptive T-cell therapy of multiple myeloma[J].Clinical cancer research,2013,19(8):2048-2060.
4.Porter D L,Hwang W T,Frey N V,et al.Chimeric antigen receptor Tcells persist and induce sustained remissions in relapsed refractory chroniclymphocytic leukemia[J].Science translational medicine,2015,7(303):303ra139-303ra139.
5.Jiasheng Wang,Yongxian Hu,and He Huang，Acute lymphoblastic leukemiarelapse after CD19-targeted chimeric antigen receptor T cell therapy，PP1-11，Volume 102,December 2017,Journal of Leukocyte Biology.
SEQUENCE LISTING
<110> 南京驯鹿医疗技术有限公司
<120> 靶向BCMA嵌合抗原受体的抗体及其应用
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Claims (12)
1.靶向BCMA嵌合抗原受体的抗体，所述抗体的重链可变区包括HCDR1、HCDR2和HCDR3，轻链可变区包括LCDR1、LCDR2和LCDR3，其中HCDR1、HCDR2、和HCDR3的氨基酸序列分别为：GFTFSSYA、ISGSGGST和ARGYMHAEHEKMEKSSRSDP， LCDR1、LCDR2和LCDR3的氨基酸序列分别为：SLRSTY、GKT和SSRDSSGYHYV。
2.如权利要求1所述的抗体，其中所述抗体的轻链可变区包括SEQ ID NO：5所示的氨基酸序列，所述抗体的重链可变区包括SEQ ID NO：6所示的氨基酸序列。
3.如权利要求1或2所述的抗体，其中所述抗体是scFv。
4.如权利要求3所述的抗体，其中所述scFv包括SEQ ID NO：4所示的氨基酸序列。
5.权利要求1至4任一项所述的抗体在制备用于抗原检测的试剂中的应用，其中所述抗原包括SEQ ID NO：12所示的氨基酸序列。
6.如权利要求5所述的应用，其中所述抗原为融合蛋白的一部分。
7.如权利要求6所述的应用，其中所述融合蛋白为靶向BCMA的嵌合抗原受体，所述抗原为所述嵌合抗原受体的胞外结合结构域或其一部分。
8.编码靶向BCMA嵌合抗原受体的抗体的核酸分子，其中所述抗体的重链可变区包括HCDR1、HCDR2和HCDR3，轻链可变区包括LCDR1、LCDR2和LCDR3，其中HCDR1、HCDR2和HCDR3的氨基酸序列分别为：GFTFSSYA、ISGSGGST和ARGYMHAEHEKMEKSSRSDP， LCDR1、LCDR2和LCDR3的氨基酸序列分别为：SLRSTY、GKT和SSRDSSGYHYV。
9.如权利要求8所述的核酸分子，其中编码所述抗体的轻链可变区的序列包括SEQ IDNO：2所示的核苷酸序列，编码所述抗体的重链可变区的序列包括SEQ ID NO：3所示的核苷酸序列。
10.如权利要求8或9所述的核酸分子，其中所述抗体是scFv。
11.如权利要求10所述的核酸分子，其中编码所述scFv的序列包括SEQ ID NO：1所示的核苷酸序列。
12.包括权利要求8至11任一项的核酸分子的表达载体。
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| WO2023044633A1 (zh) * | 2021-09-22 | 2023-03-30 | 南京驯鹿医疗技术有限公司 | Bcma car-t在制备用于治疗自身免疫病的药物中的应用 |
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