CN115028734A - 一种靶向bcma的嵌合抗原受体及其用途 - Google Patents
一种靶向bcma的嵌合抗原受体及其用途 Download PDFInfo
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- CN115028734A CN115028734A CN202210750475.7A CN202210750475A CN115028734A CN 115028734 A CN115028734 A CN 115028734A CN 202210750475 A CN202210750475 A CN 202210750475A CN 115028734 A CN115028734 A CN 115028734A
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Abstract
本发明提出了一种靶向BCMA的嵌合抗原受体及其用途，获得的BCMA抗体与人IgG抗体Fc片段融合，通过引物设计构建原核表达载体BCMA‑IgGFc‑pCZN1，可有效抑制Daudi细胞的增殖活性，对Daudi细胞毒性具有一定的浓度依赖性，效果随着浓度的增加而提高，通过抗体IgG的Fc段，能够与效应细胞相结合，可快速诱导ADCC效应，有助于效应细胞攻击靶细胞，发挥杀伤肿瘤细胞的作用，细胞死亡率达到19.7％。
Description
技术领域
本发明涉及肿瘤治疗技术领域，特别涉及一种靶向BCMA的嵌合抗原受体及其用途。
背景技术
B细胞成熟抗原(B cell maturation antigen，BCMA)是一种表达在浆细胞，浆母细胞和骨髓浆细胞的抗原，其不在B细胞或者造血干细胞上表达。BCMA的表达与许多癌症，自身免疫性疾病和感染性疾病相关。具有增加的BCMA表达的癌症包括一些血液癌症，例如多发性骨髓瘤，霍奇金淋巴瘤和非霍奇金淋巴瘤等。其中，非霍奇金淋巴瘤是最常见的恶性淋巴瘤，有85％左右来源于B细胞系。
传统抗体含有两条轻链(L)和两条重链(H)，而在骆驼科和软骨鱼的血清中，仅含有重链可变区的特殊抗，为单域抗体，分子量约为12-15KD。单域抗体更易于携带靶向药物进入传统抗体难以进图的结合部位，同时具有更好的溶解度和表达性。近年来，更多热点集中于对对骆驼或者羊驼来源的抗体的研究。但单域抗体半衰期较短，开发一种含有靶向BCMA抗体与IgG抗体Fc片段融合的嵌合抗原受体，对治疗肿瘤，尤其是B细胞非霍奇金淋巴瘤，具有一定的临床意义。
发明内容
鉴于此，本发明的目的在于提出一种靶向BCMA的嵌合抗原受体及其用途，为BCMA融合抗体在临床的靶向治疗药物、疾病诊断等研发方面提供一定的指导方法和理论依据。
本发明的技术方案是这样实现的：
一种靶向BCMA的嵌合抗原受体，包括靶向BCMA抗体与人抗体融合获得的靶向BCMA融合抗体。
根据权利要求1的一种靶向BCMA的嵌合抗原受体，其特征在于，所述人抗体为人IgG抗体。
进一步的，所述靶向BCMA融合抗体为人BCMA蛋白免疫单峰驼获得的靶向BCMA抗体与人IgG抗体的Fc片段融合。
进一步的，所述靶向BCMA融合抗体的氨基酸序列如SEQ ID NO.1所示。
本发明还构建了靶向BCMA融合抗体的表达载体，其特征在于，所述表达载体靶向BCMA融合抗体的编码基因。
本发明的嵌合抗原受体和/或构建的靶向BCMA融合抗体表达载体在制备抗肿瘤制剂中的应用。
优选的，本发明的嵌合抗原受体和/或构建的靶向BCMA融合抗体表达载体在抗非霍奇金淋巴瘤制剂中的应用。
与现有技术相比，本发明的有益效果为：
本发明使用人BCMA蛋白免疫单峰驼，采用ELISA鉴定阳性克隆，将获得的BCMA抗体与人IgG抗体Fc片段融合，通过引物设计构建原核表达载体BCMA-IgG Fc-pCZN1，可有效抑制Daudi细胞的增殖活性，对Daudi细胞毒性具有一定的浓度依赖性，效果随着浓度的增加而提高，通过抗体IgG的Fc段，能够与效应细胞相结合，可快速诱导ADCC效应，有助于效应细胞攻击靶细胞，发挥杀伤肿瘤细胞的作用，细胞死亡率达到19.7％。
本发明获得的靶向BCMA融合抗体，可为该融合抗体在临床的靶向治疗药物、疾病诊断等研发方面提供一定的指导方法和理论依据。
附图说明
图1为本发明对Daudi细胞增殖的抑制效果图；
图2为本发明对Daudi细胞毒性结果图。
具体实施方式
为了更好理解本发明技术内容，下面提供具体实施例，对本发明做进一步的说明。
本发明实施例所用的实验方法如无特殊说明，均为常规方法。
本发明实施例所用的材料、试剂等，如无特殊说明，均可从商业途径得到。
实施例1-靶向BCMA抗体的筛选
(1)BCMA体外免疫骆驼
选取三岁健康无疾病的单峰驼，免疫前进行颈静脉采血5mL，常温放置凝固后，以1000r/min离心10min，取血清，置于-20℃储存备用。等比例将人BCMA蛋白与弗氏完全佐剂混合，振荡，充分乳化，进行免疫接种；加强免疫时选用弗氏不完全佐剂，免疫间隔周期为2周，免疫6次。
(2)采用ELISA检测血清抗体效价
将人BCMA蛋白包被至浓度为5μg/mL，每孔加入100uL至96孔酶标板，，4℃包被过夜。弃去酶标板内的液体，每孔加入300uL的PBST(PBS+1mL/LTween-20)进行清洗，清洗3-5次，每次5min。每孔加入300uL的PBSM封闭液(PBS+3％milk)，于25℃、5％CO条件下封闭2h。弃去酶标板内的液体，每孔加入300uL PBST进行清洗，清洗3-5次，每次5min。每孔加入100uL稀释1万倍的抗血清，37℃培育1h。每孔加入300uL PBST进行清洗，清洗3-5次，每次5min。每孔加入100uL稀释5000倍的HRP标记的山羊抗骆驼的二抗，37℃孵育1h，每孔加入300uL PBST进行清洗，清洗3-5次，每次5min。每孔加入100uL TMB显色液，37℃避光10min，每孔加入50uL ELISA终止液，于波长450nm处记录OD值，当样品OD值大于阴性对照OD值两倍以上时，视为阳性抗体。
选取阳性抗体进行测序，其中，选取亲水性较好的阳性克隆作为获得的免疫骆驼的靶向BCMA抗体，氨基酸序列如SEQ ID NO.1：
GVGVLGAGGSVGMAAGSGPGLVTPSGITHSSLAASAAAGVLLISGLASGAGAATTCMAAVPGGALIGMAVGVGVLGAGGSVGMAAGSGPG LVTPSGITHSSLAASAAAGVLLISGLASGAGAATTCMAAVPGGALIGMAVGPAGLGGSAGTGCAGLGLAPIGAPTRVTVSFTISRDYQPKYADSVANHILSLRLSCRGSATFNNYVCASS。
实施例2-BCMA融合抗体的构建
(1)构建BCMA-IgG Fc-pCZN1载体
使用NdeⅠ，XbaⅠ限制性内切酶对pCZN1质粒进行双酶切，将筛选获得的阳性抗体与人IgG Fc片段偶联在聚合酶链反应下接入pCZN1双酶切位点，采用Nimble Cloning试剂盒进行NC克隆反应，并转化DH5a感受态细胞，而后进行PCR菌落筛选阳性克隆，获得载体BCMA-IgG Fc-pCZN1；以接入阳性抗体为对照，获得载体BCMA-pCZN1。
(2)BCMA融合抗体的表达、纯化
挑取单克隆菌落接种至5mL LB液体培养基(含有50μg/mL卡那霉素)，37℃，220r/min过夜培养。取1mL培养菌液接种至100mL的LB液体培养基(含有50μg/mL卡那霉素)，37℃，220r/min培养至OD600值为0.6～0.8。以4000r/min离心5min，弃去上清液，收集菌体，超声破碎，经Ni柱亲和纯化后，进行Westem blot验证，纯化蛋白的大小约为50000。
实施例3-BCMA融合抗体的抗肿瘤作用
(1)BCMA融合抗体对Daudi细胞增殖的抑制作用
细胞株选用Burkit's lymphoma Daudi细胞，复苏Daudi细胞，采用RPMI培养基重悬细胞，加入至T25培养瓶中，37℃、5％CO培养，经2次传代后，取Daudi细胞，加入细胞密度为1×105个至流式管，使用PBS清洗细胞，去除上清，吹打细胞分散，将Daudi细胞加入至96孔酶标板，每孔细胞密度为1×103个，使用RPMI培养基将BCMA融合抗体稀释成不同浓度，加入至酶标板，37℃、5％CO培养36h。去除上清液，每孔快速加入CCK-8试剂，37℃、5％CO培养2h，未加入CCK-8试剂的为空白组。于波长450nm处记录OD值，以未加入BCMA融合抗体为对照组。
由图1可知，单独使用BCMA抗体作用Daudi细胞36h，细胞的存活率仍较高，而BCMA融合抗体在相同作用浓度下，则对Daudi细胞具有显著的增殖抑制效果，使Daudi细胞增殖效率降低，IgG抗体协同增效BCMA抗体，使BCMA融合抗体具有较高的生物学活性。
(2)BCMA融合抗体对Daudi细胞毒性的作用
采用含5％FBS的RPIM培养基将BCMA融合抗体稀释成不同浓度，加入至96孔酶标板，采用含5％FBS的RPIM培养基将Daudi细胞稀释成细胞密度为1×105个，加入至96孔酶标板，复苏PBMC细胞(PB009C-2)，30min后加入PBMC细胞培养液，其中靶细胞和效应细胞的比值为1：10，以未加入Daudi细胞、加入PBMC细胞培养液的为效应细胞释放值，以加入Daudi细胞、未加入PBMC细胞培养液的为靶细胞最大释放值，37℃、5％CO培养5。以1000r/min离心4min，取上清液50uL至96孔酶标板，根据CytoTox96试剂盒测定靶细胞和效应细胞释放乳酸脱氢酶的OD值，于波长492nm处记录OD值，细胞毒性计算公式：细胞毒性(％)＝(A样品-A效应)/A靶×100，式中，A样品为测得的样品OD值，A效应为效应细胞释放值的OD值，A靶为靶细胞最大释放值，
由图2可知，BCMA融合抗体对Daudi细胞的死亡率效果显著，并具有一定的浓度依赖性，效果随着浓度的增加而提高，通过抗体IgG的Fc段，能够与效应细胞相结合，可快速诱导ADCC效应，有助于效应细胞攻击靶细胞，发挥杀伤肿瘤细胞的作用，细胞死亡率达到19.7％。
以上所述仅为本发明的较佳实施例而已，并不用以限制本发明，凡在本发明的精神和原则之内，所作的任何修改、等同替换、改进等，均应包含在本发明的保护范围之内。
序列表
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Claims (7)
1.一种靶向BCMA的嵌合抗原受体，其特征在于，包括靶向BCMA抗体与人抗体融合获得的靶向BCMA融合抗体。
2.根据权利要求1的一种靶向BCMA的嵌合抗原受体，其特征在于，所述人抗体为人IgG抗体。
3.根据权利要求1或2的种靶向BCMA的嵌合抗原受体，其特征在于，所述靶向BCMA融合抗体为人BCMA蛋白免疫单峰驼获得的靶向BCMA抗体与人IgG抗体的Fc片段融合。
4.根据权利要求3的一种靶向BCMA的嵌合抗原受体，其特征在于，所述靶向BCMA抗体的氨基酸序列如SEQ ID NO.1所示。
5.一种表达载体，其特征在于，所述表达载体含有权利要求1所述的靶向BCMA融合抗体的编码基因。
6.根据权利要求1所述的嵌合抗原受体和/或权利要求3所述的表达载体在制备抗肿瘤制剂中的应用。
7.根据权利要求6所述的应用，其特征在于，所述肿瘤为非霍奇金淋巴瘤。
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| WO2021068761A1 (zh) * | 2019-10-10 | 2021-04-15 | 苏州亲为药业有限公司 | 靶向bcma的具有人猴交叉的人源化单克隆抗体 |
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| WO2021043169A1 (zh) * | 2019-09-02 | 2021-03-11 | 成都盛世君联生物技术有限公司 | 特异性结合b细胞成熟抗原的抗体及其用途 |
| WO2021068761A1 (zh) * | 2019-10-10 | 2021-04-15 | 苏州亲为药业有限公司 | 靶向bcma的具有人猴交叉的人源化单克隆抗体 |
| CN112028996A (zh) * | 2020-10-30 | 2020-12-04 | 南京北恒生物科技有限公司 | 靶向bcma的单域抗体及其用途 |
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