基于二硫键桥接的定点修饰抗体偶联药物研究

Antibody-drug conjugates or ADCs are a new class of highly potent biopharmaceutical drugs designed as a targeted therapy for the treatment of people with cancer, it is clear that this is becoming an important and viable approach for selectively delivering highly cytotoxic agents to tumor cells while sparing normal tissue. However, the cytotoxic drugs or payloads used to make ADCs are typically conjugated to the antibody through cysteine or lysine residues, which lead to less heterogeneous. In order to generate ADC with high heterogeneous, in this project we designed disulphide bonds rebridging groups to build a new generation of ADCs, the research might effectively improve the stability of the ADC drugs, and it is very helpful to establish reliable ADCs drug quality control system with independent intellectual property rights.

以单克隆抗体为载体的抗肿瘤导向药物因同时实现了对肿瘤细胞的靶向性、定点释放和强细胞杀伤而被称为真正的"生物导弹"。随着FDA对抗体交联药物（ADC）的优先审定、加速批准，ADC已成为国际抗体药物和小分子药物化学研发共同关注的新热点。然而，目前上市及在研的ADC 中，偶联方式均是通过抗体上的赖氨酸或半胱氨酸偶联，联接链基本为随机交联所设计，存在均一性差、产品质量难以控制、分析方法复杂等问题。本项目通过利用化学手段，构建新一代均一性好、稳定性好的"连接基团"，将有效提高ADC药物的稳定性，有利于建立可靠的ADCs药物质控体系，将为目前ADCs药物产业化开发所解决很多实际的基础性问题，也为开发具有自主知识产权的ADC药物打下基础。

目前处于临床研究的ADC所采用的Linker大多与上市药物相同，大多为国际上通用的第一代、第二代ADC偶联技术，即Lys-SMCC、Cys-mc-VC、SPDB等，得到的ADC是非均一性的，其中高载药组分（非最佳DAR值）常常影响化学稳定性和代谢稳定性，且易发生聚集，导致治疗指数较低。本项目通过基于抗体二硫键桥接技术，通过优化连接子从而构建新一代均一性、稳定性、水溶性好的“连接基团”，有效提高了ADC 药物的体内药效和血浆稳定性，并建立了可靠的 ADCs 药物质控体系，该连接子与多个抗体偶联获得相关ADC分子均显示出将传统偶联方式更高的体内外抗肿瘤作用。