Li Chenggang, Yao Jun, Yang Junjie, Zhang Yu, Qiu Yang, Zhu Zhongyuan, Hua Haiqing
Department of Research and Development, Duality Biologics, LTD, Shanghai, P.R. China.
Clin Cancer Res. 2025 Aug 14;31(16):3581-3593. doi: 10.1158/1078-0432.CCR-25-0634.
We developed a bifunctional B7-H3 × PD-L1-targeting bispecific antibody-drug conjugate (named DB-1419) conjugated with a novel topoisomerase I inhibitor, P1003 (drug-to-antibody ratio, 8), and assessed its preclinical profiles.
The pharmacologic activities of DB-1419 were assessed in multiple cancer cell lines and immunodeficient and immunocompetent cell line-/patient-derived xenograft (PDX) models. The mechanisms of action behind the efficacy, pharmacokinetics in cynomolgus monkeys, and the safety profiles in vitro and in cynomolgus monkeys were also explored.
With high stability in circulation, DB-1419 displayed efficient cellular internalization and trafficked to the lysosome within 48 hours to release the payload P1003. In vitro, we observed inhibitory effects on the proliferation of lung cancer cell lines and beyond, mechanically by P1003-mediated direct cytotoxicity, antibody-mediated antibody-dependent cellular cytotoxicity, and bystander effects. Excellent tumor growth inhibition of DB-1419 was revealed in liver cancer cell line-derived xenografts and lung cancer PDX, along with the verification of DNA damage and apoptosis induced by P1003 using tumor tissues. Furthermore, DB-1419 has driven a robust antitumor response in immunocompetent PDX; the blockade of the interaction between PD-1 and PD-L1 and significant induction of markers of immunogenic cell death were also found, suggesting the activation of tumor-specific immunity. DB-1419 was well tolerated in cynomolgus monkeys (highest nonseverely toxic dose, 120 mg/kg) and did not elicit the production of inflammatory cytokines in vitro.
DB-1419 demonstrated potent antitumor activity against multiple tumors, with favorable pharmacokinetic and safety profiles. These preclinical data potentially position DB-1419 as a promising treatment approach, currently in the ongoing phase I/IIa study in advanced tumors (NCT06554795).
我们研发了一种双功能的靶向B7-H3和PD-L1的双特异性抗体药物偶联物（命名为DB-1419），其与一种新型拓扑异构酶I抑制剂P1003偶联（药物与抗体比例为8），并评估了其临床前特性。
在多种癌细胞系以及免疫缺陷和免疫健全的细胞系/患者来源的异种移植（PDX）模型中评估DB-1419的药理活性。还探究了其疗效背后的作用机制、食蟹猴的药代动力学以及体外和食蟹猴体内的安全性。
DB-1419在循环中具有高稳定性，表现出高效的细胞内化，并在48小时内转运至溶酶体以释放有效载荷P1003。在体外，我们观察到其对肺癌细胞系及其他细胞系的增殖具有抑制作用，机制上是通过P1003介导的直接细胞毒性、抗体介导的抗体依赖性细胞毒性以及旁观者效应。在肝癌细胞系来源的异种移植瘤和肺癌PDX模型中，DB-1419显示出优异的肿瘤生长抑制作用，同时利用肿瘤组织验证了P1003诱导的DNA损伤和凋亡。此外，DB-1419在免疫健全的PDX模型中引发了强烈的抗肿瘤反应；还发现其阻断了PD-1与PD-LI之间的相互作用，并显著诱导了免疫原性细胞死亡标志物，提示激活了肿瘤特异性免疫。DB-1419在食蟹猴中耐受性良好（最高非严重毒性剂量为120mg/kg），且在体外未引发炎性细胞因子的产生。
DB-1419对多种肿瘤显示出强大的抗肿瘤活性，具有良好的药代动力学和安全性。这些临床前数据可能使DB-1419成为一种有前景的治疗方法，目前正在进行晚期肿瘤的I/IIa期研究（NCT06554795）。
