CN109939230A - 关于cd3×b7h3双特异性抗体定向杀伤耐顺铂膀胱癌细胞t24/ddp的应用 - Google Patents
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Abstract
本发明的目的在于提供一种偶联CD3×B7H3双特异性抗体定向杀伤耐顺铂人膀胱癌细胞T24/DDP的应用，具体为偶联CD3×B7H3双特异性抗体可增强活化T细胞（ATC）对T24/DDP耐顺铂膀胱癌细胞的杀伤作用，为膀胱癌耐药的靶向治疗提供新的免疫治疗靶点。本发明通过研究证实B7H3在T24/DDP耐顺铂膀胱癌细胞中高表达；与未偶联CD3×B7H3双特异性抗体的ATC相比，结合CD3×B7H3双特异性抗体的ATC定向杀伤T24/DDP耐顺铂膀胱癌细胞的能力增强，对T24/DDP耐顺铂膀胱癌细胞具有显著细胞毒活性。当结合CD3×B7H3双特异性抗体的ATC与肿瘤细胞在效靶比为10:1条件下共培养时杀伤效果明显增加。同时，结合CD3×B7H3双特异性抗体的ATC分泌γ‑干扰素（IFN‑γ）和α‑肿瘤坏死因子（TNF‑α）水平增加。
Description
技术领域
本发明的目的在于提供一种偶联CD3×B7H3双特异性抗体定向杀伤耐顺铂膀胱癌细胞T24/DDP的应用，具体为偶联CD3×B7H3双特异性抗体可增强活化T细胞（ATC）对T24/DDP耐顺铂膀胱癌细胞的杀伤作用，为膀胱癌耐药的靶向治疗提供新的免疫治疗靶点。
背景技术
膀胱癌是男性中第四常见的癌症，女性中第11常见的癌症。2017年在美国估计有79030例新发膀胱癌病例和19870例死亡病例，其中男性发病率和死亡率高于女性4倍。最初，约85%的膀胱癌患者被诊断为浅表性膀胱癌，超过50%的浅表性膀胱癌会复发，并且，仅有46%的三期患者和15%的4期患者可以达到五年生存。因此，膀胱癌患者所面临的形式非常严峻。尽管存在多种治疗方法，比如说手术，放疗，化疗，膀胱癌的术后生存率依旧很不理想。这些治疗方法可以限制肿瘤的发展及生长，但它们无法遏制肿瘤的复发和耐药的产生。因此，发展新的疗法对膀胱癌患者是至关重要的。
随着免疫学的研究进展，免疫治疗被公认为二十一世纪肿瘤综合治疗模式中第四种治疗方法。例如，靶向CTLA-4（细胞毒性T淋巴细胞抗原4）和PD-1/PD-L（程序化细胞死亡1/ PD-1配体）的免疫检查点抑制剂已经促进了癌症的治疗，另一个有效的方法是靶向T细胞抗原受体T细胞（TCR）和肿瘤相关抗原（TAA）的双特异性抗体（BiAb）的运用。
在过去两年里，双特异性抗体靶向不同的肿瘤相关抗原，包括EGFR,Her2,CD19,CD20,CD30,CEA,CA125,PSA等已在实验和临床研究中取得令人鼓舞的成果。B7H3，也称为CD276，与B7家族有着高达30%相同的氨基酸。它高度表达在多种类型的癌症中，并已被证明能促进肿瘤的进展和癌细胞的转移，包括急性白血病，胶质瘤，肝细胞癌，肺癌，乳腺癌，前列腺癌，骨肉瘤，皮肤黑色素瘤和胰腺癌。Luo等人证明了小鼠B7H3的基因转移产生了有效的抗肿瘤免疫反应，Lupu等在小鼠原位结肠癌模型中注射含B7H3的腺病毒，发现可抑制肿瘤的转移，MJ18，一种抗B7H3鼠抗，在胰腺癌模型中被证明可抑制肿瘤的生长。研究结果表明B7H3有望用于基于免疫的抗肿瘤治疗。
发明内容
内容
本发明的目的在于提供一种偶联CD3×B7H3双特异性抗体定向杀伤耐顺铂膀胱癌细胞T24/DDP的应用。
优选地，所述膀胱癌耐药细胞为T24/DDP耐顺铂膀胱癌细胞。
优选地，所述偶联CD3×B7H3双特异性抗体的结构如图1。
优选地，所述双特异性抗体可增强活化T细胞对T24/DDP耐顺铂膀胱癌细胞的杀伤作用。
优选地，所述活化T细胞分泌γ-干扰素和α-肿瘤坏死因子水平增加。
优选地，所述结合CD3×B7H3双特异性抗体的活化T细胞与肿瘤细胞在效靶比为10:1时，杀伤作用明显增加。
发明人首先培养耐顺铂膀胱癌T24/DDP细胞株。使用Ficoll密度梯度离心法分离北京血库提供的健康捐赠者的外周血获得外周血单核细胞（PBMCs）。在补充有10%FBS和5ug/ml抗CD3mAb（eBioscience，San Diego，CA，USA）和100IU/ml重组人IL-2的RPMI-1640培养基中以1×10 6 / ml培养PBMC。使抗B7-H3单克隆抗体（R＆D System，Minneapolis，MN，USA）与磺基-SMCC反应，抗CD3（OKT3，eBioscience）与Traut's试剂反应。解冻冷冻保存的ATC，并与B7-H3Bi-Ab结合，计算偶联率。利用乳酸脱氢酶活性试剂盒测定细胞毒性，ELISA检测细胞因子，Beckman流式细胞仪检测细胞周期，CCK-8检测细胞增殖。结果表明，与单独ATC和未偶联双特异性抗体的ATC相比，偶联双抗的ATC对人类耐顺铂膀胱癌细胞有着显著的细胞毒活性，并且，偶联双抗的ATC分泌更高水平的IFN-γ，TNF-α。结果表明，T细胞的细胞毒活性是通过CD3-B7H3的桥梁靶向B7H3阳性的耐顺铂膀胱癌细胞，从而发挥杀伤作用的。
本发明通过研究证实CD3XB7H3双特异性抗体可增强ATC杀伤耐顺铂膀胱癌细胞的能力，可能为膀胱癌耐药的靶向治疗提供新的免疫治疗靶点。
本发明将为膀胱癌耐药的免疫治疗及精准医学的发展提供新的策略和实验依据。
为让本发明的上述和其它目的、特征和优点能更明显易懂，下文特举较佳实施例，并配合附图，作详细说明如下。
附图说明
图1 是偶联CD3XB3H7双特异性抗体的结构图。
图2 是B7H3在耐顺铂膀胱癌T24/DDP细胞中高表达。
图3是扩增的ATC 中CD3的表达及ATC 增殖图。
图4是利用LDH检测偶联双特异性抗体的ATC对耐顺铂膀胱癌细胞的杀伤作用。
图5是偶联双特异性抗体的ATC分泌细胞因子增加。
具体实施方式
实施例1 细胞培养
耐顺铂膀胱癌细胞株T24/DDP通过其亲本细胞株T24逐渐增加顺铂的剂量建立，顺铂的最终浓度为1.0μg/ ml。20%胎牛血清培养。细胞在37℃含有5％的二氧化碳的孵育箱中培养。
实施例2 外周血单个核细胞的分离以及制备冷冻保存活化的T淋巴细胞（ATC）
使用Ficoll密度梯度离心分离北京血库提供的健康捐赠者的外周血获得外周血单核细胞（PBMCs）。在补充有10％FBS和5μg/ ml抗CD3mAb（eBioscience，San Diego，CA，USA）和100IU /ml重组人IL-2的RPMI-1640培养基中以1×10 6 / ml培养PBMC。 细胞培养所需的新鲜培养基含有100IU / ml重组人IL-2。第13天，平均有扩增的ATC表达CD3 +（的CD4 +和％CD8 +），冷冻保存以便进一步使用。
实施例3 合成抗CD3×抗B7-H3双特异性抗体（B7-H3Bi-Ab）并偶联到活化的T细胞
抗B7-H3单克隆抗体（R＆D System，Minneapolis，MN，USA）与磺基-SMCC反应，抗CD3（OKT3，eBioscience）与Traut's试剂反应。解冻冷冻保存的ATC，并与B7-H3Bi-Ab以50ng /106细胞的浓度在室温下30分钟，随后洗涤细胞以消除未结合的抗体。利用ImagJ对westernblot条带进行灰度分析计算偶联率。
实施例4 细胞毒性的检测
将靶细胞接种在96孔U底微板中，分别加入偶联双抗的ATC，未偶联双抗的ATC或单独的ATC。每种做3个复孔。效应细胞和肿瘤细胞效靶比为和10：1，在37℃下相互作用24个小时后收集上清。细胞毒性主要用由乳酸脱氢酶活性试剂盒进行测定（Sigma-Aldrich，St.Louis，MO，USA）
实施例5 ELISA检测细胞因子
靶细胞接种于96孔U底微孔板，浓度为1×104 /孔，37℃过夜。然后以10：1的E / T比加入偶联双抗的ATC，未偶联双抗的ATC或单独的ATC孵育24小时。 收集细胞上清液，并根据制造商的说明使用特异性人类ELISA试剂盒（eBioscience）测定IFN-γ，TNF-α。
实施例6 流式细胞术分析
抗人B7-H3-PE mAb和小鼠IgG1-PE isotpye抗体，抗人CD3-FITC，抗小鼠IgG1-FITC，和抗小鼠IgG2a-FITC二抗购自eBioscience。 细胞测定用Beckman流式细胞仪检测，并用cytExpert软件进行数据分析。
虽然本发明已以较佳实施例披露如上，然其并非用以限定本发明，任何所属技术领域的技术人员，在不脱离本发明的精神和范围内，当可作些许的更动与改进，因此本发明的保护范围当视权利要求所界定者为准。
Claims (6)
1.偶联CD3×B7H3双特异性抗体定向杀伤人膀胱癌耐药细胞的应用。
2.根据权利要求1所述的应用，其特征在于，所述膀胱癌耐药细胞为T24/DDP耐顺铂膀胱癌细胞。
3.根据权利要求1所述的应用，其特征在于，偶联CD3×B7H3双特异性抗体的结构如图1。
4.根据权利要求3所示的应用，其特征在于，双特异性抗体可增强活化T细胞对T24/DDP耐顺铂膀胱癌细胞的杀伤作用。
5.根据权利要求4所示的应用，其特征在于，活化T细胞分泌γ-干扰素和α-肿瘤坏死因子水平增加。
6.根据权利要求4所示的应用，其特征在于，结合CD3×B7H3双特异性抗体的活化T细胞与肿瘤细胞在效靶比为10:1时，杀伤作用明显增强。
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| CN114164176A (zh) * | 2021-12-13 | 2022-03-11 | 深圳市第二人民医院(深圳市转化医学研究院) | 人膀胱癌顺铂耐药细胞株及其用途 |
| WO2023273913A1 (zh) * | 2021-07-02 | 2023-01-05 | 安源医药科技（上海）有限公司 | 抗b7-h3单克隆抗体及其用途 |
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| CN113402610A (zh) * | 2021-06-09 | 2021-09-17 | 东大生物技术(苏州)有限公司 | 一组b7h3单克隆抗体及其医药用途 |
| CN113402610B (zh) * | 2021-06-09 | 2023-02-24 | 英诺湖医药(杭州)有限公司 | 一组b7h3单克隆抗体及其医药用途 |
| WO2023273913A1 (zh) * | 2021-07-02 | 2023-01-05 | 安源医药科技（上海）有限公司 | 抗b7-h3单克隆抗体及其用途 |
| CN114164176A (zh) * | 2021-12-13 | 2022-03-11 | 深圳市第二人民医院(深圳市转化医学研究院) | 人膀胱癌顺铂耐药细胞株及其用途 |
| CN114164176B (zh) * | 2021-12-13 | 2023-10-13 | 深圳市第二人民医院(深圳市转化医学研究院) | 人膀胱癌顺铂耐药细胞株及其用途 |
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