Click and link: a chemistry-driven approach to bispecific antibodies

点击链接：化学驱动的双特异性抗体方法

• 批准号: 493006134
• 负责人: Dr. Aldrin Vasco Vidal
• 金额: --
• 依托单位: Yusuf Hamied Department of Chemistry
• 依托单位国家: 德国
• 项目类别: WBP Fellowship
• 财政年份: 2021
• 资助国家: 德国
• 起止时间: 2020-12-31 至 2022-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/493006134?language=en
• 关键词: Click; link; chemistry; driven; approach

The development of new therapeutic agents which specifically target malignant over healthy tissues has become a paradigm of modern cancer therapy. Bispecific antibodies (bsAbs) combine two monospecific antibodies onto a common scaffold, triggering the bridging of a target (e.g. cancerous) cell to an effector (eg. immune) cell which will effectively kill it. Despite their modular nature, a major drawback of bsAbs is that the current development process is slow due to their tedious and linear production process, which relies on genetic approaches. The present project constitutes a chemistry-driven effort to exploit site-specifically click reactions for the ligation of two different proteins, and its application to explore the structural and functional space of bsAbs. The main objective is to develop an integrated approach for combinatorial construction of bsAbs libraries through the design of linkers that site-specifically bridge two different proteins under biocompatible conditions and in a stoichiometric manner. The methodology will be applied for the generation of a small library of bsAbs capable of triggering immunomodulatory responses towards cancerous cells. The immunomodulatory potential of the bsAbs library will be determined using cell-cell interaction profiling through high-content imaging methods, and the best candidates will be further analyzed using classical cancer immune biology and cutting-edge -omics approaches.

专门针对健康组织恶性肿瘤的新治疗剂的发展已成为现代癌症治疗的范式。双特异性抗体（BSABS）将两种单特异性抗体结合在一个共同的支架上，从而触发靶细胞的桥接（例如癌细胞）细胞与效应子（例如免疫）细胞有效地杀死它。尽管具有模块化的性质，但BSAB的主要缺点是，由于其乏味和线性生产过程，当前的开发过程却很慢，这依赖于遗传方法。本项目构成了化学驱动的努力，以针对两种不同蛋白质的连接进行特定的点击反应，并应用其用于探索BSABS的结构和功能空间的应用。主要目的是通过设计在生物相容性条件下并以化学计量方式设计站点特定于站点特定桥接两个不同蛋白质的接头，开发一种集成方法来组合BSABS库的组合。该方法将用于生成一个小型BSAB库，能够触发对癌细胞的免疫调节反应。 BSABS文库的免疫调节潜力将通过高素质成像方法确定，并使用经典的癌症免疫生物学和尖端 - 组方法进一步分析最好的候选者。