Pancreatic cancer (PC) is among the most aggressive malignancies associated with a 5-year survival rate of <9%, and the treatment options remain limited. Antibody–drug conjugates (ADCs) are a new class of anticancer agents with superior efficacy and safety profiles. We studied the antitumor activity of Oba01 ADC and the mechanism underlying the targeting of death receptor 5 (DR5) in preclinical PC models. Our data revealed that DR5 was highly expressed on the plasma membrane of PC cells and Oba01 showed potent in vitro antitumor activity in a panel of human DR5-positive PC cell lines. DR5 was readily cleaved by lysosomal proteases after receptor-mediated internalization. Monomethyl auristatin E (MMAE) was then released into the cytosol to induce G2/M-phase growth arrest, cell death via apoptosis induction, and the bystander effect. Furthermore, Oba01 mediated cell death via antibody-dependent cell-mediated cytotoxicity and complement-dependent cytotoxicity. For improved potency, we investigated the synergetic effect of Oba01 in combination with approved drugs. Oba01 combined with gemcitabine showed better antiproliferative activity than either standalone treatment. In cell- and patient-derived xenografts, Oba01 showed excellent tumoricidal activity in mono- or combinational therapy. Thus, Oba01 may provide a novel biotherapeutic approach and a scientific basis for clinical trials in DR5-expressing patients with PC.

胰腺癌 (PC) 是最具侵袭性的恶性肿瘤之一，5 年生存率 <9%，且治疗选择仍然有限。抗体药物偶联物（ADC）是一类新型抗癌药物，具有卓越的功效和安全性。我们在临床前 PC 模型中研究了 Oba01 ADC 的抗肿瘤活性以及靶向死亡受体 5 (DR5) 的机制。我们的数据显示，DR5 在 PC 细胞的质膜上高度表达，并且 Oba01 在一组人类 DR5 阳性 PC 细胞系中显示出有效的体外抗肿瘤活性。受体介导的内化后，DR5 很容易被溶酶体蛋白酶切割。然后将单甲基 auristatin E (MMAE) 释放到细胞质中，诱导 G2/M 期生长停滞、通过细胞凋亡诱导导致细胞死亡以及旁观者效应。此外，Oba01 通过抗体依赖性细胞介导的细胞毒性和补体依赖性细胞毒性介导细胞死亡。为了提高效力，我们研究了 Oba01 与已批准药物联合使用的协同效应。 Oba01 与吉西他滨联合显示出比任一单独治疗更好的抗增殖活性。在细胞来源和患者来源的异种移植物中，Oba01 在单一或联合治疗中表现出优异的杀肿瘤活性。因此，Oba01可能为表达DR5的PC患者的临床试验提供一种新的生物治疗方法和科学基础。