Preclinical studies of BB-1701, a HER2-targeting eribulin-containing ADC with potent bystander effect and ICD activity

• Published in: Antibody therapeutics 2024-07, Vol.7 (3), p.221-232
• Main Authors: 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
• Format: Article
• Language: English
• ISSN: 2516-4236; 2516-4236
• DOI: 10.1093/abt/tbae019

Abstract 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. Statement of Significance: A HER2-targeting eribulin-containing ADC had exhibited good plasma stability; BB-1701 had potent antitumor activities against multiple HER2-expressing cancers, especially those insensitive to other HER2-targeting ADCs; BB-1701 had bystander killing effect and induced immunogenic cell death; BB-1701 also showed favorable pharmacokinetics and safety profiles in nonhuman primates.