尽管靶向单一靶点的抗体与药物偶联体(ADC)分子在多种恶性肿瘤的治疗中显示了不俗的疗效，但是它们难以避免对表达同一靶点的健康人体组织产生“中靶毒性”。由不同的抗原结合臂组成的双特异性抗体（BsAb）分子可以在保持对双抗原的高协同亲和力(avidity)的同时，丧失或降低对各自单独抗原的协同亲和力。通过生物信息学工具，我们发现TROP2和EPCAM在多数健康人体组织中的表达基本不重合，而在多种恶性实体肿瘤组织中的表达高度重合。因此，我们设想TROP-2和EPCAM双靶向的异源臂BsAb引导的ADC分子可以在保持对表达双靶点的肿瘤组织杀伤的同时，减轻对表达单靶点的健康组织的损伤。我们把这类分子具有组织选择性的分子称为“智慧型”双靶向ADC分子。我们已经设计出一个概念验证型分子，并计划开展蛋白、细胞及动物模型实验来证明其“智慧性”。如果成功，本研究可以为恶性实体肿瘤的精准治疗提供一个新的思路。

Although antibody-drug conjugate (ADC) molecules that target solo targets have demonstrated strong anti-tumor activities in a variety of solid tumors, they are limited by “on-target” toxicities due to the presence of their targets in human healthy tissues. Bispecific antibodies (BsAb) that bind to duo targets with heterodimmeric arms can lose avidities to solo antigen, while maintain avidity to the duo if they are present in close proximity. Interestingly, co-expression of TROP2 and EPCAM is found in many human solid tumor tissues, but not in healthy tissues. We hypothesize that TACSTD2 and EPCAM duo-targeting heterodimmeric BsAb-based ADC molecules may alleviate “on-target” toxicity to healthy TROP2 or EPCAM –expressing tissues, while maintain their therapeutical effectiveness. We thus called this type of molecues with tissue-selectiveness “intelligent” bispecific ADC molecules. To test our hypothesis, we have constructed a proof-of-concept type molecule and propose a sequence of in vitro and in vivo biological studies. If successful, this project may point to a new direction to precisely treat solid tumors.