iScience ( IF 5.8 ) Pub Date : 2020-11-20 , DOI: 10.1016/j.isci.2020.101835 Zhaoqian Su , Bo Wang , Steven C. Almo , Yinghao Wu
Immunotherapeutics are frequently associated with adverse side effects due to the elicitation of global immune modulation. To lower the risk of these side effects, recombinant DNA technology is employed to enhance the selectivity of cell targeting by genetically fusing different biomolecules, yielding new species referred to as multi-specific biologics. The design of new multi-specific biologics is a central challenge for the realization of new immunotherapies. To understand the molecular determinants responsible for regulating the binding between multi-specific biologics and surface-bound membrane receptors, we developed a multiscale computational framework that integrates various simulation approaches covering different timescales and spatial resolutions. Our model system of multi-specific biologics contains two natural ligands of immune receptors, which are covalently tethered by a peptide linker. Using this method, a number of interesting features of multi-specific biologics were identified. Our study therefore provides an important strategy to design the next-generation biologics for immunotherapy.
中文翻译:
通过多尺度建模了解免疫疗法中多种生物制剂的靶向机制
由于引起整体免疫调节,免疫治疗常与不良副作用有关。为了降低这些副作用的风险,采用重组DNA技术通过遗传融合不同的生物分子来增强细胞靶向的选择性,从而产生称为多特异性生物制剂的新物种。新的多特异性生物制剂的设计是实现新的免疫疗法的主要挑战。为了了解负责调节多特异性生物制剂和表面结合膜受体之间结合的分子决定因素,我们开发了一种多尺度计算框架,该框架整合了涵盖不同时标和空间分辨率的各种模拟方法。我们的多特异性生物制剂模型系统包含两种天然的免疫受体配体,它们通过肽接头共价连接。使用这种方法,鉴定了多特异性生物制剂的许多有趣特征。因此,我们的研究为设计用于免疫疗法的下一代生物制剂提供了重要的策略。