针对癌症治疗的TROP2向免疫毒素的模块化组装和评估
Yajie Deng1, Zi Hui1, Lu Liu1
1Engineering Research Center of Cell & Therapeutic Antibody, Ministry of Education, School of Pharmacy, Shanghai Jiao Tong University, Shanghai 200240, China.
International journal of biological macromolecules
|April 19, 2025
概括
研究人员开发了一种新的TROP2向免疫毒素Fab-PE24,以克服抗体与药物合物的局限性. 这种新疗法在临床前模型中显示出强大的抗癌活性,并有可能克服化疗耐药性.
科学领域:
- 在瘤学瘤学.
- 分子生物学分子生物学
- 免疫治疗是一种免疫疗法.
背景情况:
- 热囊细胞表面抗原2 (TROP2) 在许多癌症中过度表达,与预后不佳相关.
- 针对TROP2的抗体-药物合物 (ADC) 是有前途的,但面临着高分子量和制造复杂性等挑战.
研究的目的:
- 开发一种针对TROP2的新型免疫毒素,以克服ADC的限制.
- 在临床前癌症模型中评估新型免疫毒素Fab-PE24的疗效和安全性.
主要方法:
- 使用SpyCatcher-SpyTag技术,将一个人性化的抗TROP2抗体Fab片段与一个截断的Pseudomonas aeruginosa外毒素A (PE24KDEL) 结合在一起.
- 在TROP2阳性癌细胞中评估Fab-PE24结合亲和力,内化,细胞毒性和亡诱导.
- 在胃癌和肺癌异种移植模型中对体内抗瘤疗效的评估以及与西斯普拉丁的联合治疗.
主要成果:
- Fab-PE24对TROP2具有很高的结合亲和力,对TROP2阳性癌细胞具有强大的细胞毒性.
- 在体内研究表明,在异种移植模型中显著抑制瘤生长.
- Fab-PE24与西斯普拉丁具有协同效应,表明有可能克服化疗耐药性.
结论:
- 模块化SpyCatcher-SpyTag方法可以有效地构建基于Pseudomonas aeruginosa外毒素A的免疫毒素.
- Fab-PE24是TROP2阳性恶性瘤的有希望的治疗候选者,为ADCs提供了替代方案.
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