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当代肿瘤药物靶点

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ISSN (Print): 1568-0096
ISSN (Online): 1873-5576

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Research Article

CT109-SN-38，一种具有CEACAM5和6双重特异性的新型抗体-药物偶联物，诱导胰腺癌细胞的有效杀伤

卷 24, 期 7, 2024

发表于: 04 January, 2024

页: [720 - 732] 页: 13

弟呕挨: 10.2174/0115680096260614231115192343

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摘要

背景：CEACAM5和CEACAM6是癌胚抗原相关细胞粘附分子(CEACAM)家族中与糖基磷脂酰肌醇(GPI)相关的成员，在上皮性癌症中经常上调，参与侵袭、转移、免疫逃避和对肿瘤的抵抗。CT109是一种对CEACAM5和CEACAM6具有双重特异性的新型抗体 目的：在本研究中，我们旨在对CT109及其抗体-药物偶联衍生物进行临床前表征，重点是CT109-SN-38。 方法：用扫描诱变法对CT109的同源表位进行了鉴定。采用免疫印迹和流式细胞术分别评价CT109的特异性和内化动力学。采用免疫组化方法测定同源抗原在结直肠癌和正常组织阵列中的表达率。CT109缀合物是由还原的CT109半胱氨酸与马来酰亚胺功能化的负载连接物反应而产生的。采用荧光活力测定法对抗原阳性和阴性胰腺导管腺癌细胞(PDAC)细胞系进行体外细胞毒活性研究。以10和25 mg/kg浓度的CT109-SN-38在PDAC肿瘤异种移植模型上的体内疗效进行了评估。 结果：CT109与以N309为中心的糖表位结合。CT109内化于CEACAM5+/CEACAM6+双阳性PDAC线BxPC-3, t1/2为2.3小时。CT109 ADC可引起剂量依赖性和抗原依赖性的细胞毒性作用，CT109-SN-38对BxPC-3细胞的IC50值为21 nM。在BxPC-3肿瘤异种移植模型中，CT109-SN-38在25 mg/kg浓度下可抑制3/10小鼠的肿瘤生长并诱导肿瘤消退。 结论：这些数据表明CT109-SN-38的进一步临床前和临床开发是有必要的。

关键词: CEACAM6, CEACAM5，胰腺导管腺癌，抗体-药物偶联物，ADC, cn -38。

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