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化学控制抗体和蛋白质治疗药物的合理设计

Anthony Marchand¹, Lucia Bonati^1,2, Sailan Shui¹

¹Laboratory of Protein Design and Immunoengineering, Institute of Bioengineering, Ecole Polytechnique Fédérale de Lausanne (EPFL), CH-1015 Lausanne, Switzerland.

ACS chemical biology

|May 30, 2023

概括

科学家们开发了可切换的蛋白质疗法,以更好地控制. 添加特定药物很快就会使这些生物药物失活,减少副作用,并在瘤学和自身免疫性疾病中扩大治疗潜力.

科学领域:

生物技术是生物技术.
蛋白质工程是指蛋白质工程.
药物开发药物开发

背景情况:

抗体和细胞因子等蛋白质疗法对于治疗癌症,自身免疫性疾病和感染至关重要.
它们的临床使用受到诸如细胞因子风暴综合征和器官衰竭等毒性的限制.
对蛋白质活性的时空控制对于更广泛的治疗应用至关重要.

研究的目的:

设计和验证小分子控制,可切换的蛋白质疗法.
设计一种药物诱导的OFF开关系统,以提高安全性和有效性.
为了证明使用竞争药物控制生物制剂的可行性.

主要方法:

使用Rosetta微调蛋白质与蛋白质相互作用 (Bcl-2和LD3) 的计算优化.
设计了一个关闭开关系统,用于快速异构体中断,由Venetoclax触发.
将开关系统纳入抗CTLA4抗体,抗HER2抗体和Fc融合IL-15细胞因子.

主要成果:

在药物添加后,证明了工程蛋白疗法的有效体外破坏.
在施用Venetoclax后,表现出可切换生物制剂的快速体内清除.
在不同基于蛋白质的治疗方式中验证了OFF开关系统的功能.

结论:

这项研究为合理设计可控制的生物制剂提供了概念验证.
在蛋白质疗法中引入药物诱导的OFF开关可以提高安全性和控制性.
这种方法有望扩大基于蛋白质的药物的治疗窗口.

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