Abstract 2243: Preclinical studies of BB-1709, a CD73-targeting ADC potentially suppresses tumor growth through dual mechanisms

Abstract CD73, also known as ecto-5'-nucleotidase, is a cell surface enzyme that catalyzes the conversion of AMP to adenosine. It is highly expressed in various types of cancers, including gastric, glioblastoma, non-small cell lung, and colorectal cancers. Elevated CD73 expression is highly correlated with poor prognosis, increased metastasis, and resistance to chemotherapy. In the tumor microenvironment, CD73-derived adenosine exerts multiple immunosuppressive effects, promoting tumor growth and metastasis. Currently, there are no approved antibody-drug conjugates (ADCs) targeting CD73. In this study, we introduce BB-1709, a CD73-targeting ADC that incorporates MMAE as its cytotoxic payload, demonstrating its antitumor activity through direct cytotoxicity against CD73-expressing tumor cells and its ability to inhibit CD73 enzyme activity. A comprehensive set of studies was conducted to assess its in vitro cytotoxicity, in vivo antitumor activity as well as its ability to inhibit CD73 enzyme activity. In vitro studies demonstrated that BB-1709 exhibited potent and selective cytotoxicity against various CD73-positive cancer cells and significantly inhibited CD73 enzyme activity, effectively blocking the conversion of AMP into adenosine. In vivo studies using xenograft models showed that a single dose of BB-1709 resulted in substantial antitumor activity. Pharmacokinetic and toxicology assessments in non-human primates revealed a favorable safety profile for BB-1709 at clinically relevant dosages and administration schedules. In summary, these results suggest that BB-1709 not only exhibits good preclinical efficacy and safety, but also has the potential to promote anti-tumor immune responses by inhibiting CD73 enzymatic activity. A phase I clinical trial of BB-1709 is currently underway to further explore its therapeutic potential in cancer treatment. Citation Format: Bing Xia, Lixia Cao, Jianfeng Yang, Cui Feng, Fangdun Jiang, Chen Li, Lixia Gu, Yifan Yang, Jing Tian, Jiasheng Geng, Ziping Wei, Yuhong Zhou. Preclinical studies of BB-1709, a CD73-targeting ADC potentially suppresses tumor growth through dual mechanisms. [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 2243.