Delta 样配体 3 (DLL3) 在小细胞肺癌 (SCLC) 的细胞表面高度表达，小细胞肺癌是最致命的恶性肿瘤之一，但在正常组织中表达极少或不表达，使其成为 SCLC 有吸引力的靶点。然而，目前尚未批准用于 SCLC 治疗的 DLL3 靶向抗体药物偶联物 (ADC)。我们开发了 DB-1314，这是一种新型抗 DLL3 ADC，由新型人源化抗 DLL3 单克隆抗体 (DB131401) 与 8 分子 P1021（拓扑异构酶 I 抑制剂）缀合组成，并描述了其临床前概况。 DB131401 和 Rovalpituzumab 的结合表位通过生物层干涉测量法进行测试。通过表面等离振子共振和酶联免疫吸附试验分别测量DB-1314与DLL3和其他同源蛋白的结合亲和力和特异性。通过各自的测定评估内化、旁观者效应和抗体依赖性细胞介导的细胞毒性（ADCC）。通过每个细胞结合的抗体测定和免疫组织化学对 DLL3 进行定量。在 SCLC 细胞系和细胞系/患者来源的异种移植模型中评估了体外和体内生长抑制研究。安全性是在食蟹猴中测量的。DB-1314 在体外细胞和体内细胞/患者来源的异种移植模型中诱导有效、持久和剂量依赖性的抗肿瘤作用。 DB-1314 的杀伤活性机械地源自 P1021 诱导的 DNA 损伤，由此 P1021 通过 DLL3 特异性结合和有效内化在肿瘤细胞内传递和释放。旁观者效应和 ADCC 也有助于 DB-1314 的抗肿瘤活性。 DB-1314 在大鼠和食蟹猴中显示出良好的药代动力学和毒代动力学特征；此外，DB-1314 在猴子中的耐受性良好，剂量高达 60 mg/kg。这些结果表明，DB-1314 可能是一种靶向 DLL3 的候选 ADC，用于治疗 DLL3 阳性 SCLC，支持在临床环境。© 2024。作者。

Delta-like ligand 3 (DLL3) is highly expressed on the cell surface of small cell lung cancer (SCLC), one of the most lethal malignancies, but minimally or not in normal tissues, making it an attractive target for SCLC. However, none of the DLL3-targeting antibody-drug conjugates (ADCs) have been approved for SCLC therapy yet. We developed DB-1314, the new anti-DLL3 ADC composed of a novel humanized anti-DLL3 monoclonal antibody (DB131401) conjugated with eight molecules of P1021 (topoisomerase I inhibitor), and described its preclinical profiles.The binding epitope for DB131401 and Rovalpituzumab was tested by biolayer interferometry. The binding affinity and specificity of DB-1314 to DLL3 and other homologous proteins were respectively measured by surface plasmon resonance and enzyme-linked immunosorbent assay. Internalization, bystander effects, and antibody-dependent cell-mediated cytotoxicity (ADCC) were assessed by respective assay. DLL3 was quantified by antibodies bound per cell assay and immunohistochemistry. In vitro and in vivo growth inhibition studies were evaluated in SCLC cell lines, and cell line/patient-derived xenograft models. The safety profile was measured in cynomolgus monkeys.DB-1314 induces potent, durable, and dose-dependent antitumor effects in cells in vitro and in cell/patient-derived xenograft models in vivo. The killing activity of DB-1314 mechanically arises from P1021-induced DNA damage, whereby P1021 is delivered and released within tumor cells through DLL3-specific binding and efficient internalization. Bystander effects and ADCC also contribute to the antitumor activity of DB-1314. DB-1314 displays favorable pharmacokinetic and toxicokinetic profiles in rats and cynomolgus monkeys; besides, DB-1314 is well-tolerated at a dose of up to 60 mg/kg in monkeys.These results suggest that DB-1314 may be a candidate ADC targeting DLL3 for the treatment of DLL3-positive SCLC, supporting further evaluation in the clinical setting.© 2024. The Author(s).