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基于DARPins修饰的轻链费里丁的双特异向系统用于癌症化疗

A Yu Frolova¹, E I Shramova², D L Kakuev¹

¹Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Moscow, Russian Academy of Science, 16/10 Miklukho-Maklaya Street, Moscow, 117997, Russia.

|October 9, 2025

概括

这项研究开发了一种针对人类表皮生长因子受体2 (HER2) 和上皮细胞粘附分子 (EpCAM) 的新型双特异性癌症疗法. 该疗法在体内显示了特定的瘤细胞结合,内部化和显著的瘤减少.

科学领域:

在瘤学瘤学.
生物技术是生物技术.
分子生物学分子生物学

背景情况:

癌症的异质性对向治疗提出了挑战.
双受体向可以提高治疗疗效.
人类表皮生长因子受体2 (HER2) 和上皮细胞粘附分子 (EpCAM) 在上皮癌中过度表达.

研究的目的:

创建一个双特异的融合蛋白质,同时准HER2和EpCAM.
开发一种强大的蛋白质药物联合体,用于增强癌症治疗.
评估新型治疗剂的疗效和特异性.

主要方法:

使用截断的费里L子单元支架和设计的安基林重复蛋白 (DARPins) 构建了一个混合蛋白 (DARP_9-29-FTLsh-EC1).
将混合蛋白与单甲基奥里斯塔丁E (MMAE) 结合,形成一种蛋白质药物结合物 (DARP_9-29-FTLsh-EC1/MMAE).
使用流式细胞计,共聚焦显微镜,体外细胞毒性测定和小鼠异种移植模型进行评估.

主要成果:

DARP_9-29-FTLsh-EC1融合蛋白显示出特定的结合和内化到表达HER2/EpCAM的细胞中.
蛋白质药物合物在体外表现出HER2/EpCAM特异性细胞毒性,与受体密度相关.
在体内研究证实了选择性瘤积累和显著的瘤减少在老鼠异种移植模型.

结论:

使用DARPins和费里基架的双特异向提供了精确抗癌治疗的有希望的策略.
开发的蛋白质药物结合物显示出克服瘤异质性和改善治疗结果的潜力.
这种方法为开发有效的向癌症治疗开辟了新的途径.

关键词:

主动准活动的目标.癌症癌症癌症癌症在DARP中,insins是DARP.在 EpCAM 中使用 EpCAM.费里丁L亚单元 (Ferritin L-subunit) 是一种铁素的亚单元.在HER2中,HER2是HER2.

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