TACSTD2 是一个在很多外胚层来源的人体肿瘤细胞表面都有高表达的一个一型跨膜糖蛋白。最近，sacituzumab govitecan，一个以TACSTD2为靶点的抗体与药物偶联体（ADC）候选药物分子，在治疗多种晚期恶性实体肿瘤的临床研究中都显示了显著的疗效。但是该分子采用的载荷SN38的细胞杀伤效力较弱，而且整体分子在血浆中的半衰期短，预计将极大地限制它的临床应用。造成该分子半衰期短的可能原因有：1）连接链CL2A不够稳定；2）抗体hSR7的人源化不充分；3）药物与抗体的比率 (DAR)值偏高等。我们设想采用更强效的载荷分子，更稳定的连接链，人源化更充分的抗体，以及较低DAR值可以增强原ADC分子的肿瘤细胞杀伤效力。本课题拟对以上几个因素与ADC分子的药效、血浆半衰期和毒副作用之间的结构功能关系进行研究，为最终产生一个更为安全有效的抗癌ADC药物分子奠定基础。

Tumor-Associated Calcium Signal Transducer 2 (TACSTD2) is a type I transmembrane glycoprotein that is highly expressed on many epithelial human tumors. Recently, sacituzumab govitecan, an antibody-drug conjugate (ADC) molecule that targets TACSTD2, has demonstrated strong anti-tumor activity in patients with a variety of late-stage solid tumors. However, this molecule’s payload SN38 is relatively weak and its half-life in plasma is short, which may greatly limits its clinical application. The short half-life may be caused by three reasons: 1) unstable linker CL2A; 2) insufficiently-humanized antibody hSR7; 3) relatively high drug-to-antibody ratio (DAR). We hypothesize that adoption of more potent payload, more stable linker, an antibody with greater degree of humanization, and low DAR number would improve the ADC molecule’s anti-tumor effect. Therefore, we would conduct structure-activity relationship studies to evaluate the contribution of these factors to the potency and efficacy of TACSTD2-based ADC molecule. If successful, it would provide the necessary foundation for continued preclinical testing of an ADC molecule with potential to treat multiple advanced epithelial cancers.