背景:几种HER2靶向抗体-药物偶联物(ADC)已获得市场批准用于治疗HER2表达转移。已经报道了新一代ADC对其他HER2靶向疗法反应不佳的患者的有希望的反应。然而,这些ADC仍然面临与其特定有效负载毒素相关的抗性和/或严重副作用的挑战。Eribulin,一种治疗转移性乳腺癌和脂肪肉瘤的治疗剂,是ADC有效载荷的新选择,具有独特的作用机制和安全性。
方法:我们已经生成了一种新型的HER2标记含有eribulin的ADC,BB-1701.在体外和体内测试BB-1701对抗其中HER2表达水平在大范围内变化的癌细胞的效力。还测试了BB-1701的旁观者杀伤作用和毒素诱导的免疫原性细胞死亡(ICD)。
结果:与具有DM1和Dxd有效载荷的靶向HER2的ADC相比,含有艾瑞布林的ADC在HER2低癌细胞系中显示出更高的体外细胞毒性。BB-1701还有效抑制对含有DM1或Dxd的ADC具有抗性的模型中的肿瘤。作用模式研究表明,BB-1701对与HER2高细胞相邻的HER2无效细胞具有显著的旁观者效应。此外,BB-1701处理诱导ICD。在非人类灵长类动物中重复剂量的BB-1701在预期的临床剂量下显示出良好的药代动力学和安全性,给药途径,和时间表。
结论:临床前数据支持BB-1701在各种HER2表达癌症患者中的测试,包括对其他HER2靶向ADC耐药的患者。BB-1701(NCT04257110)在患者中的I期临床试验目前正在进行中。
BACKGROUND: 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.
METHODS: We\'ve generated a novel HER2-tageting eribulin-containing ADC, BB-1701. The potency of BB-1701 was tested in vitro and in vivo 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.
RESULTS: In comparison with HER2-targeting ADCs with DM1 and Dxd payload, eribulin-containing ADC demonstrated higher in vitro 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.
CONCLUSIONS: 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.