胰腺癌是一种高度侵袭性的恶性肿瘤，治疗选择有限且预后不良。滋养层细胞表面抗原 2 (TROP2) 是一种在一半以上胰腺癌患者的肿瘤中过度表达的细胞表面抗原，已被确定为抗体药物偶联物 (ADC) 的潜在靶点。几乎所有报道的 TROP2 靶向 ADC 都是 IgG 类型，并且在胰腺癌中的研究很少。在此，我们的目标是开发一种新型靶向TROP2的纳米抗体-药物偶联物（NDC），用于治疗胰腺癌。在本研究中，我们开发了一种新型靶向TROP2的NDC，HuNbTROP2-HSA-MMAE，用于治疗TROP2阳性的胰腺癌。胰腺癌。 HuNbTROP2-HSA-MMAE的特点是使用针对TROP2和人血清白蛋白（HSA）的纳米抗体，药物抗体比为1。HuNbTROP2-HSA-MMAE表现出与TROP2的特异性结合，并以高胞吞作用内化到肿瘤细胞中5 小时内发挥效率，然后在细胞内易位至溶酶体并释放 MMAE，通过 caspase-3/9 途径诱导 TROP2 阳性胰腺癌细胞凋亡。在胰腺癌异种移植模型中，0.2 mg/kg 和 1 mg/kg 剂量的 HuNbTROP2-HSA-MMAE 显示出显着的抗肿瘤作用，5 mg/kg 剂量甚至可以根除肿瘤。HuNbTROP2-HSA-MMAE 具有理想的亲和力、内化效率和抗肿瘤活性。它作为治疗 TROP2 阳性胰腺癌的潜在治疗选择具有重大前景。© 2023。作者。

Pancreatic cancer is a highly aggressive malignancy with limited treatment options and a poor prognosis. Trophoblast cell surface antigen 2 (TROP2), a cell surface antigen overexpressed in the tumors of more than half of pancreatic cancer patients, has been identified as a potential target for antibody-drug conjugates (ADCs). Almost all reported TROP2-targeted ADCs are of the IgG type and have been poorly studied in pancreatic cancer. Here, we aimed to develop a novel nanobody-drug conjugate (NDC) targeting TROP2 for the treatment of pancreatic cancer.In this study, we developed a novel TROP2-targeted NDC, HuNbTROP2-HSA-MMAE, for the treatment of TROP2-positive pancreatic cancer. HuNbTROP2-HSA-MMAE is characterized by the use of nanobodies against TROP2 and human serum albumin (HSA) and has a drug-antibody ratio of 1. HuNbTROP2-HSA-MMAE exhibited specific binding to TROP2 and was internalized into tumor cells with high endocytosis efficiency within 5 h, followed by intracellular translocation to lysosomes and release of MMAE to induce cell apoptosis in TROP2-positive pancreatic cancer cells through the caspase-3/9 pathway. In a xenograft model of pancreatic cancer, doses of 0.2 mg/kg and 1 mg/kg HuNbTROP2-HSA-MMAE demonstrated significant antitumor effects, and a dose of 5 mg/kg even eradicated the tumor.HuNbTROP2-HSA-MMAE has desirable affinity, internalization efficiency and antitumor activity. It holds significant promise as a potential therapeutic option for the treatment of TROP2-positive pancreatic cancer.© 2023. The Author(s).