Abstract 4779: Preclinical studies of BB-1705: An EGFR-targeting eribulin-containing ADC with an affinity optimized antibody to minimize potential toxicities to normal tissues

Abstract Epidermal Growth Factor Receptor (EGFR) is a type I receptor tyrosine kinase critical for the development and normal function of epithelial cells. However, its overexpression or hyperactivity in certain cancers can lead to tumor growth and metastasis. While existing EGFR-targeting therapies can effectively inhibit tumor progression, they often cause significant toxicity due to EGFR expression in normal tissues. To mitigate these side effects, we have developed BB-1705, an antibody-drug conjugate (ADC) that utilizes eribulin as its cytotoxic agent. Eribulin is an FDA-approved treatment for metastatic breast cancer and advanced liposarcoma. BB-1705 employs an affinity-optimized anti-EGFR antibody to selectively deliver eribulin to tumor cells, sparing normal tissues by not effectively blocking the EGFR signaling pathway in those areas. This strategy aims to enhance the therapeutic index of EGFR-targeted treatments while minimizing adverse effects on normal tissues. In vitro studies demonstrated that BB-1705 exhibits potent cytotoxicity against a range of cancer cell lines with medium to high levels of EGFR expression, while showing reduced efficacy against normal human keratinocytes, likely due to their lower EGFR expression and the antibody's affinity profile. Notably, BB-1705 also induced a significant bystander effect on EGFR-low/null cells when co-cultured or co-inoculated with EGFR-high cells. In vivo experiments using xenograft models revealed that a single dose of BB-1705 resulted in substantial antitumor activity. When administered repeatedly via a clinically relevant route and schedule, BB-1705 demonstrated a favorable pharmacokinetic profile and safety in cynomolgus monkeys with manageable hematological side effects and minimal skin toxicity observed even at the highest tested dose (12 mg/kg, Q3W x 3). In summary, our preclinical findings suggest that BB-1705 has the potential to optimize the efficacy and safety profile of EGFR-targeting therapies for cancers characterized by medium to high EGFR expression levels. A clinical trial evaluating BB-1705 is currently underway, aiming to assess its therapeutic potential in treatment of EGFR-expressing human cancers including TNBC, NSCLC and head and neck cancers. Citation Format: Bing Xia, Lixia Cao, Jianfeng Yang, Cui Feng, Fangdun Jiang, Chen Li, Lixia Gu, Yifan Yang, Jing Tian, Jiasheng Geng, Likun Gong, Tingting Liu, Qiuping Qin, Ziping Wei, Yuhong Zhou. Preclinical studies of BB-1705: An EGFR-targeting eribulin-containing ADC with an affinity optimized antibody to minimize potential toxicities to normal tissues [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 4779.