Wang Yang, Xia Bing, Cao Lixia, Yang Jianfeng, Feng Cui, Jiang Fangdun, Li Chen, Gu Lixia, Yang Yifan, Tian Jing, Cheng Xin, Furuuchi Keiji, Fulmer James, Verdi Arielle, Rybinski Katherine, Soto Allis, Albone Earl, Uenaka Toshimitsu, Gong Likun, Liu Tingting, Qin Qiuping, Wei Ziping, Zhou Yuhong
Bliss Biopharmaceutical (Hangzhou) Co., Ltd, Hexiang Technology Center, Hangzhou 310018, China.
Epochal Precision Anti-Cancer Therapeutics (EPAT), Cell Lineage and Differentiation (CLD) Domain, Eisai Inc., Exton, PA 19341, United States.
Antib Ther. 2024 Jun 25;7(3):221-232. doi: 10.1093/abt/tbae019. eCollection 2024 Jul.
Several HER2-targeting antibody-drug conjugates (ADC) have gained market approval for the treatment of HER2-expressing metastasis. Promising responses have been reported with the new generation of ADCs in patients who do not respond well to other HER2-targeting therapeutics. However, these ADCs still face challenges of resistance and/or severe adverse effects associated with their particular payload toxins. Eribulin, a therapeutic agent for the treatment of metastatic breast cancer and liposarcoma, is a new choice of ADC payload with a distinct mechanism of action and safety profile.
We've generated a novel HER2-tageting eribulin-containing ADC, BB-1701. The potency of BB-1701 was tested and against cancer cells where HER2-expressing levels vary in a large range. Bystander killing effect and toxin-induced immunogenic cell death (ICD) of BB-1701 were also tested.
In comparison with HER2-targeting ADCs with DM1 and Dxd payload, eribulin-containing ADC demonstrated higher cytotoxicity in HER2-low cancer cell lines. BB-1701 also effectively suppressed tumors in models resistant to DM1 or Dxd containing ADCs. Mode of action studies showed that BB-1701 had a significant bystander effect on HER2-null cells adjacent to HER2-high cells. In addition, BB-1701 treatment induced ICD. Repeated doses of BB-1701 in nonhuman primates showed favorable pharmacokinetics and safety profiles at the intended clinical dosage, route of administration, and schedule.
The preclinical data support the test of BB-1701 in patients with various HER2-expressing cancers, including those resistant to other HER2-targeting ADCs. A phase I clinical trial of BB-1701 (NCT04257110) in patients is currently underway.
几种靶向HER2的抗体药物偶联物（ADC）已获得市场批准，用于治疗HER2表达的转移瘤。新一代ADC在对其他HER2靶向治疗反应不佳的患者中已报告有良好疗效。然而，这些ADC仍面临耐药性挑战和/或与其特定有效载荷毒素相关的严重不良反应。艾日布林是一种用于治疗转移性乳腺癌和脂肪肉瘤的治疗药物，是一种具有独特作用机制和安全性的ADC有效载荷新选择。
我们制备了一种新型的含艾日布林的靶向HER2的ADC，即BB-1701。测试了BB-1701对HER2表达水平在很大范围内变化的癌细胞的效力。还测试了BB-1701的旁观者杀伤效应和毒素诱导的免疫原性细胞死亡（ICD）。
与含DM1和Dxd有效载荷的靶向HER2的ADC相比，含艾日布林的ADC在HER2低表达癌细胞系中表现出更高的细胞毒性。BB-1701在对含DM1或Dxd的ADC耐药的模型中也有效抑制了肿瘤。作用机制研究表明，BB-1701对HER2高表达细胞附近的HER2阴性细胞有显著的旁观者效应。此外，BB-1701治疗诱导了ICD。在非人类灵长类动物中重复给予BB-1701，在预期的临床剂量、给药途径和给药方案下显示出良好的药代动力学和安全性。
临床前数据支持在各种HER2表达癌症患者中对BB-1701进行测试，包括那些对其他HER2靶向ADC耐药的患者。目前正在进行BB-1701（NCT04257110）在患者中的I期临床试验。
