Abstract
Several HER2-targeting antibody-drug conjugates (ADC) have gained market approval for the treatment of HER2-expressing metastasis. However, these ADC drugs still face challenges of acquired resistance and/or severe adverse effects associate with their payload toxins. Eribulin, a market approval agent for the treatment of metastatic breast cancer and liposarcoma , is a new choice of ADC payload with distinct mechanism of action (MOA). Here we report preclinical studies of BB-1701, a novel HER2-tageting eribulin-containing ADC. BB-1701 exhibited potent and specific cytotoxicity activities to various types of cancer cells where HER2-exprssing levels vary in large ranges. BB-1701 induced tumor-growth suppression, even regression in in vivo models with a single dose of 1-5 mg/kg dosage. In comparison with other HER2-targeting ADCs with different toxin payloads (DM1, MMAE and Dxd), eribulin-containing ADC demonstrated higher potency to cancer cell lines with low HER2 expressing levels (with lower IC50). BB-1701 also showed effective tumor suppression in models insensitive to T-DM1 or T-Dxd. Mode of action studies revealed significant bystander cytotoxicity of BB-1701 to HER2-low cells when co-cultured with HER2-high cells. Additionally, BB-1701 treatment increased ATP releasing and Calreticulin expression, both were deemed immunogenic cell death (ICD) markers. Lastly, repeat dose pharmacokinetic and toxicology studies in nonhuman primates revealed favorable PK and safety profiles of BB-1701 in the clinical intend dosage route and schedule. In conclusion, these comprehensive preclinical data have strongly supported BB-1701 as a potent antitumor agent to cancers including HER2-low expressing and/or cancers insensitive to other HER2-targeting ADCs. A phase I clinical study of BB-1701 in those patients is ongoing.
Citation Format: Yang Wang, Bing Xia, Lixia Cao, Jianfeng Yang, Cui Feng, Fangdun Jiang, Chen Li, Lixia Gu, Yifan Yang, Jing Tian, Cindy Cheng, Keiji Furuuchi, James Fulmer, Arielle Verdi, Katherine Rybinski, Allis Soto, Earl Albone, Toshimitsu Uenaka, Likun Gong, Tingting Liu, Qiuping Qin, Ziping Wei, Yuhong Zhou. Preclinical development of BB-1701, a HER2-tageting eribulin-containing ADC with potent bystander effect and ICD activity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1887.
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