CN114057880A - 一种dll3单克隆抗体 - Google Patents
一种dll3单克隆抗体 Download PDFInfo
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- CN114057880A CN114057880A CN202111327597.7A CN202111327597A CN114057880A CN 114057880 A CN114057880 A CN 114057880A CN 202111327597 A CN202111327597 A CN 202111327597A CN 114057880 A CN114057880 A CN 114057880A
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- seq
- amino acid
- acid sequence
- dll3
- monoclonal antibody
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Abstract
本发明提供了一种DLL3单克隆抗体，属于肿瘤免疫治疗药物领域。所述DLL3单克隆抗体包含片段CDR1、CDR2和CDR3，其中，CDR1的氨基酸序列为SEQ ID NO.9、CDR2的氨基酸序列为SEQ ID NO.10、CDR3的氨基酸序列为SEQ ID NO.11；或者，CDR1的氨基酸序列为SEQ ID NO.12、CDR2的氨基酸序列为SEQ ID NO.13、CDR3的氨基酸序列为SEQ ID NO.14；或者，CDR1的氨基酸序列为SEQ ID NO.15、CDR2的氨基酸序列为SEQ ID NO.16、CDR3的氨基酸序列为SEQ ID NO.17。该DLL3单克隆抗体序列短，可以很好地识别DLL3，并且对DLL3结合能力强，将其用于抗肿瘤免疫治疗药物的制备，能够识别肿瘤细胞中表达的DLL3，与肿瘤细胞良好结合，进一步起到良好的靶向抗肿瘤效果。本发明为临床上抗肿瘤提供一种新选择，具有良好的应用前景。
Description
技术领域
本发明属于肿瘤免疫治疗药物领域，尤其涉及一种抗DLL3单克隆重组单域抗体。
背景技术
肺癌是我国发病率和死亡率最高的恶性肿瘤，其中小细胞肺癌(Small Cell LungCancer,SCLC)为肺癌一种重要亚型，占整体比例15％-20％。由于小细胞肺癌具有生长快、远处转移早、恶性程度高的特点，小细胞肺癌预后极差，且既往诸多化疗方案均未获得成功，中位总生存期(Overall Survival,OS)<10个月。近年来，免疫疗法在肿瘤治疗领域取得了巨大的突破，在小细胞肺癌治疗中的地位也日趋重要。但目前主流免疫治疗药物，免疫检查点抑制剂仍难以克服SCLC免疫耐药问题，患者OS获益仍有限(延长2-2.4月)。因此继续开发SCLC新型免疫治疗策略具有较大临床前景及转化价值。
DLL3(Delta-like ligand 3)是一种抑制性的Notch通路配体，在小细胞肺癌和其他高级神经内分泌肿瘤表面异常高表达。文献记载83％小细胞肺癌患者肿瘤组织DLL3表达阳性，且均匀地表达于细胞质与细胞膜。大部分正常组织细胞不表达DLL3，只有少数几种正常细胞(神经元，胰岛细胞和垂体细胞)存在低丰度的DLL3表达，且仅表达于细胞质。DLL3在小细胞肺癌中高水平、均匀的表达于细胞膜，而在正常组织低水平、表达于细胞胞质的特点，表明DLL3可能是小细胞肺癌治疗的一个潜在靶点。
研究一种靶向DLL3小细胞肺癌的单克隆抗体，特异性识别DLL3+的小细胞肺癌肿瘤细胞，可以为进一步制备抗肿瘤免疫药物提供基础，为临床上治疗小细胞肺癌提供一种新选择。
发明内容
本发明的目的是提供一种DLL3单克隆抗体。该抗DLL3单克隆重组单域抗体能特异性识别DLL3+的肿瘤细胞，为临床上***提供一种新选择。
本发明的技术方法如下：
本发明提供了一种DLL3单克隆抗体，它包含片段CDR1、CDR2和CDR3，其中，
CDR1的氨基酸序列为SEQ ID NO.9、CDR2的氨基酸序列为SEQ ID NO.10、CDR3的氨基酸序列为SEQ ID NO.11；
或者，CDR1的氨基酸序列为SEQ ID NO.12、CDR2的氨基酸序列为SEQ ID NO.13、CDR3的氨基酸序列为SEQ ID NO.14；
或者，CDR1的氨基酸序列为SEQ ID NO.15、CDR2的氨基酸序列为SEQ ID NO.16、CDR3的氨基酸序列为SEQ ID NO.17。
进一步地，所述单克隆抗体的氨基酸序列为SEQ ID NO.6、SEQ ID NO.7或SEQ IDNO.8。
本发明还提供了编码前述的DLL3单克隆抗体的核酸。
本发明还提供了一种重组核酸载体，所述载体包括前述的核酸；
优选地，所述核酸载体是真核表达载体。
本发明还提供了一种重组细胞，所述重组细胞内含有前述的核酸载体。
本发明还提供了前述的DLL3单克隆抗体在制备靶向识别肿瘤的药物中的用途。
进一步地，所述肿瘤为DLL3表达呈阳性的肿瘤。
进一步地，所述肿瘤为肺癌、神经内分泌肿瘤。
进一步地，所述肺癌为小细胞肺癌；
和/或，所述神经内分泌肿瘤为胃肠神经内分泌肿瘤、膀胱小细胞癌、神经内分泌***癌。
本发明还提供了一种药物，它是以前述DLL3单克隆抗体为活性成分，加上药学上可接受的辅料或辅助性成分制备而成的制剂。
与现有技术相比，本发明的有益效果为：
本发明提供了一种DLL3单克隆抗体，该DLL3单克隆抗体序列短，可以很好地识别DLL3，并且对DLL3结合能力强，将其用于抗肿瘤免疫治疗药物的制备，能够识别肿瘤细胞中表达的DLL3，与肿瘤细胞良好结合，进一步起到良好的靶向抗肿瘤效果。本发明为临床上抗肿瘤提供一种新选择，具有良好的应用前景。
本申请中，针对的肿瘤为DLL3表达呈阳性的肿瘤，如小细胞肺癌以及一系列神经内分泌肿瘤，包括胃肠神经内分泌肿瘤、膀胱小细胞癌、神经内分泌***癌等。
显然，根据本发明的上述内容，按照本领域的普通技术知识和惯用手段，在不脱离本发明上述基本技术思想前提下，还可以做出其它多种形式的修改、替换或变更。
以下通过实施例形式的具体实施方式，对本发明的上述内容再作进一步的详细说明。但不应将此理解为本发明上述主题的范围仅限于以下的实例。凡基于本发明上述内容所实现的技术均属于本发明的范围。
附图说明
图1为RNA电泳图；其中，M：DNA marker；泳道1：NB229A；泳道2：NB229B。
图2是菌落PCR鉴定图：其中，上方：NB229A；下方：NB229B；左侧第一泳道均为DNAmarker，DNA marker大小同图1。
图3为Binding ELISA数据图。
图4为抗体结合DLL3表达阳性细胞流式图。
具体实施方式
本发明具体实施方式中使用的原料、设备均为已知产品，通过购买市售产品获得。
实施例1、本发明DLL3抗体HP-92、HP-98和HP-208的制备
DLL3单克隆重组单域抗体制备的主要步骤如下：
1、文库构建，获得免疫抗体蛋白
为保证免疫结果可靠，免疫两只羊驼(编号：NB229A和NB229B)，经过4次免疫后，采集50mL外周血，分离PBMC(外周血单个核细胞)。然后用TRIzol试剂提取PBMC总RNA。取1μgRNA电泳，检测RNA纯度，结果表明RNA纯度良好(图1)。参见
III First-Strand Synthesis System for RT-PCR说明书将提取的RNA反转录为cDNA。用巢式PCR扩增编码重链抗体的可变区的核酸片段：
第一轮PCR：
上游引物F1：CTTGGTGGTCCTGGCTGC(SEQ ID NO.1)；
下游引物R1：GGTACGTGCTGTTGAACTGTTCC(SEQ ID NO.2)。
第二轮PCR：
以第一轮PCR产物作模板，
上游引物F2：
GATGCCATGACTGTGGCCCAGGCGGCCCAGKTGCAGCTCGTGGAGTC(SEQ ID NO.3)；
下游引物R2：
CATGCCATGACTCGCGGCCGGCCTGGCCATGGGGGTCTTCGCTGTGGTGCG(SEQ ID NO.4)；
下游引物R3：
CATGCCATGACTCGCGGCCGGCCTGGCCGTCTTGTGGTTTTGGTGTCTTGGG(SEQ ID NO.5)。
使用引物F1和R1进行第一轮PCR扩增，得到大小约为750bp的产物，纯化，使用引物F2和R2、R3(R2与R3混在一起，因为抗体有2个亚型，所以用到了2个反向引物)进行第二轮PCR扩增，得到大小约为450bp的VHH目的片段。
将载体pocomb3Xss(NBbiolab，P001)与目的片段分别用SfiI进行酶切，50℃过夜酶切。酶切后，使用T4连接酶连接载体与目的片段，电泳，然后割胶回收目的片段。连接摩尔比例为pocomb3Xss：VHH＝1:3。
接下来进行电击转化，共进行了10次电击转化，电击之后立即向电击杯中加入1mL2YT培养基(37℃预热)复苏，吸出电击产物并用2YT培养基洗净电击杯，共计获得100ml复苏产物，37℃，180rpm复苏45min，取100μL梯度稀释至10-3和10-4测定库转化子数目，涂布于90mm的平板上，其余离心，加入8mL 2YT重悬，涂布于8块200mm的平板上。第二天在测定库转化子数目的平板上NB229-A项目10-4共有428个克隆，同时在该平板上挑取48个单克隆进行***率鉴定，电泳结果发现库***率为100％(图2)；NB229-B项目10-4共有472个克隆，同时在该平板上挑取48个单克隆进行***率鉴定，电泳结果发现库***率为100％(图2)。
2、DLL3重链单域抗体筛选
将靶分子DLL3抗原用PH值为9.6的碳酸盐缓冲液稀释至终浓度为5μg/mL，按100μL/孔加入酶标孔中，每个靶分子包被8孔(第二轮筛选包被4孔，第三轮和第四轮筛选各包被2孔)，4℃包被过夜。弃包被液，每孔加入300μL 3％BSA-PBS封闭液，37℃封闭1h后，加入100μL噬菌体文库，37℃孵育1h后，加入100μL Gly-HCl洗脱液，将该洗脱液转移至1.5mL无菌离心管中，迅速用15μL Tris-HCl中和缓冲液中和。取10μL进行梯度稀释，测定滴度，计算淘选回收率，其余洗脱物混合后进行扩增和纯化，用于下一轮亲和淘选，改变淘选条件，每一轮淘选条件如表1，共计三轮。
表1.亲和淘选条件
将淘选洗脱物与处于对数生长前期的E.coli TG1培养物20mL混匀，37℃，静置30min。加入1mL 20％葡萄糖，37℃，180r/min振荡培养30min。按cell：phage＝1：20的比例加入M13K07噬菌体，并加入4μL Amp+(100mg/mL)，37℃，静置30min后，180r/min振荡培养30min。将培养物分装于离心管中，细胞沉淀重悬，过夜，将沉淀悬浮于200μL PBS中，得到带有阳性载体的噬菌体，测定滴度。
3、特异性噬菌体克隆的鉴定及分析
将淘选洗脱物滴度的平板上，用灭菌牙签随机挑取96个单克隆接种于1mL 2×YT-A培养基中，37℃振荡培养8h。然后取200μL上述培养物，按cell：phage＝1：20的比例加入M13K07噬菌体，37℃，静置15min，220r/min振荡培养45min。第二天离心取上清，用于ELISA鉴定阳性噬菌体克隆。根据阳性噬菌体克隆的序列分析等得到HP-92、HP-98和HP-208重组单域抗体。其氨基酸序列如下：
HP-92：
HP-98：
HP-208：
上述氨基酸序列中，起关键作用的片段如表2所示。
表2.本发明重组单域抗体的关键片段
以下用实验例的方式对本发明的有益效果做进一步说明。
实验例1、抗体HP-92、HP-98和HP-208与DLL3抗原结合力的效果验证
1、实验步骤
(1)包被板：96孔一次性微孔用指定抗原(2μg/mL，100μL/孔)在4℃下包被16小时；
(2)用200μL/孔的缓冲液2洗板3次；
(3)用150μL/孔的缓冲液3在37℃下封闭包被板1小时；
(4)将抗体稀释至30nM，四倍连续稀释，共7个梯度浓度；
(5)在相应孔中加入100μL抗体，稀释缓冲液作为空白对照，在37℃下孵育1小时；
(6)用200μL/孔的缓冲液2洗板5次；
(7)用100μL抗人IgG，HRP在37℃下每孔转移0.5小时；
(8)用200μL/孔的缓冲液2洗板3次；
(9)室温下每孔加入100μL TMB底物；
(10)每孔加入50μL 1M HCl终止反应；
(11)在450nm的读板机上读板。
2、结果
如图3所示，抗体HP-92、HP-98和HP-208与DLL3抗原具有良好的结合能力。
实验例2、抗体HP-92、HP-98和HP-208与小细胞肺癌细胞系表达DLL3的结合实验
1、实验原理
流式细胞术是一种从细胞分子水平上通过单克隆抗体对单个细胞表面抗原进行定量分析的高通量检测技术。当加入DLL3抗体时，单克隆抗体会结合肿瘤细胞表面的DLL3蛋白分子，进一步加入携带荧光标记的结合人抗体IgG Fc端二抗，通过流式细胞仪检测细胞表面的荧光强度，从而评价抗DLL3单抗对肿瘤细胞表达DLL3的识别能力。
本实验例构建过表达人源DLL3和绿色荧光蛋白的H446小细胞肺癌细胞，同时选择DLL3中度表达的H524小细胞肺癌细胞系。以H446-DLL3和H524作为效应细胞。以Rovalpituzumab(货号：CSB-RA882142A1HU)的生物类似药作为阳性对照，用以评估抗体HP-92、HP-98、HP-208的细胞膜DLL3蛋白识别能力。
2、实验步骤
(1)构建H446-DLL3小细胞肺癌细胞系
H446细胞接种于6孔细胞培养板中，接种密度1×106个/孔，加入hDLL3-ZsGreen-puroR质粒(购自汉恒生物)，并加入促感试剂HitransG A(上海吉凯基因医学科技股份有限公司，货号genechem REVG004)，混匀后，置于37℃培养箱中培养。48h后换液，加入puromycin筛选构建H446-DLL3细胞系。
(2)离心收集H446-DLL3以及H524细胞，使用100μL洗涤缓冲液重悬细胞(5×105)并制备单细胞悬液。
(3)分别向细胞悬液样本中加入1μL抗DLL3抗体，冰上避光孵育30分钟后，用洗涤缓冲液洗涤两次，以300g离心5分钟，去除上清，然后加入100μL PBS缓冲液重悬细胞。
(4)再次向细胞悬液样本加入1μL Goat anti-Human IgG Fc二抗(eBioscience，货号12-4998-82)，冰上避光孵育30分钟后，用洗涤缓冲液洗涤两次，以300g离心5分钟，去除上清，然后加入200μL PBS缓冲液重悬细胞。用流式细胞仪分别对各样本进行检测分析。
3、结果
如图4所示，抗体HP-92、HP-98、HP-208可有效识别小细胞肺癌细胞系表达的DLL3，其识别亲和力与阳性对照Rovalpituzumab相当。
上述试验结果表明：本发明抗体HP-92、HP-98、HP-208能够有效识别DLL3，并能与DLL3有效结合，因此可以用于识别肿瘤细胞中表达的DLL3，与肿瘤细胞良好结合，起到优异的靶向作用，进一步用于制备抗肿瘤的免疫药物。
综上，本发明提供了一种DLL3单克隆抗体，该DLL3单克隆抗体序列短，可以很好地识别DLL3，并且对DLL3结合能力强，将其用于抗肿瘤免疫治疗药物的制备，能够识别肿瘤细胞中表达的DLL3，与肿瘤细胞良好结合，进一步起到良好的靶向抗肿瘤效果。本发明为临床上抗肿瘤提供一种新选择，具有良好的应用前景。
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Claims (10)
1.一种DLL3单克隆抗体，其特征在于：它包含片段CDR1、CDR2和CDR3，其中，
CDR1的氨基酸序列为SEQ ID NO.9、CDR2的氨基酸序列为SEQ ID NO.10、CDR3的氨基酸序列为SEQ ID NO.11；
或者，CDR1的氨基酸序列为SEQ ID NO.12、CDR2的氨基酸序列为SEQ ID NO.13、CDR3的氨基酸序列为SEQ ID NO.14；
或者，CDR1的氨基酸序列为SEQ ID NO.15、CDR2的氨基酸序列为SEQ ID NO.16、CDR3的氨基酸序列为SEQ ID NO.17。
2.根据权利要求1所述的DLL3单克隆抗体，其特征在于：所述单克隆抗体的氨基酸序列为SEQ ID NO.6、SEQ ID NO.7或SEQ ID NO.8。
3.编码权利要求1或2所述的DLL3单克隆抗体的核酸。
4.一种重组核酸载体，其特征在于：所述载体包括权利要求3所述的核酸；
优选地，所述核酸载体是真核表达载体。
5.一种重组细胞，其特征在于：所述重组细胞内含有权利要求4所述的核酸载体。
6.权利要求1或2所述的DLL3单克隆抗体在制备靶向识别肿瘤的药物中的用途。
7.根据权利要求6所述的用途，其特征在于：所述肿瘤为DLL3表达呈阳性的肿瘤。
8.根据权利要求7所述的用途，其特征在于：所述肿瘤为肺癌、神经内分泌肿瘤。
9.根据权利要求8所述的用途，其特征在于：所述肺癌为小细胞肺癌；
和/或，所述神经内分泌肿瘤为胃肠神经内分泌肿瘤、膀胱小细胞癌、神经内分泌***癌。
10.一种药物，其特征在于：它是以权利要求1或2所述DLL3单克隆抗体为活性成分，加上药学上可接受的辅料或辅助性成分制备而成的制剂。
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| CN107540747A (zh) * | 2017-08-09 | 2018-01-05 | 苏州大学附属儿童医院 | 抗人dll4单克隆抗体6f12 |
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| CN110981958A (zh) * | 2019-08-23 | 2020-04-10 | 四川大学华西医院 | 一种pd-l1抗体 |
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| CN107698681A (zh) * | 2016-12-28 | 2018-02-16 | 天津天锐生物科技有限公司 | 一种识别hla‑a2/rmfpnapyl的单域抗体 |
| CN107540747A (zh) * | 2017-08-09 | 2018-01-05 | 苏州大学附属儿童医院 | 抗人dll4单克隆抗体6f12 |
| CN108586614A (zh) * | 2018-04-24 | 2018-09-28 | 南京市妇幼保健院 | EpCAM单域抗体D7 |
| CN110981958A (zh) * | 2019-08-23 | 2020-04-10 | 四川大学华西医院 | 一种pd-l1抗体 |
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| CN116789836A (zh) * | 2023-08-14 | 2023-09-22 | 浙江时迈药业有限公司 | 针对dll3的抗体及其用途 |
| CN116789836B (zh) * | 2023-08-14 | 2024-01-05 | 浙江时迈药业有限公司 | 针对dll3的抗体及其用途 |
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