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.

开发专门针对健康组织的恶性组织的新治疗剂已成为现代癌症治疗的范例。双特异性抗体 (bsAb) 将两种单特异性抗体结合到一个共同的支架上，触发目标细胞（例如癌细胞）与效应细胞（例如免疫细胞）的桥接，从而有效杀死它。尽管具有模块化性质，但双特异性抗体的一个主要缺点是，由于其依赖于遗传方法的繁琐且线性的生产过程，目前的开发过程很缓慢。本项目是一项化学驱动的工作，旨在利用位点特异性点击反应来连接两种不同的蛋白质，并将其应用于探索双特异性抗体的结构和功能空间。主要目标是通过设计连接子来开发一种组合构建双特异性抗体文库的综合方法，该连接子在生物相容性条件下以化学计量方式位点特异性地桥接两种不同的蛋白质。该方法将用于生成能够触发针对癌细胞的免疫调节反应的小型双抗体库。 bsAb 库的免疫调节潜力将通过高内涵成像方法使用细胞间相互作用分析来确定，并且将使用经典癌症免疫生物学和尖端组学方法进一步分析最佳候选者。