Abstract 6742: High-affinity human IgG1 antibody against GUCY2C for ADC development: Identification, characterization, and efficacy

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Abstract Colorectal cancer (CRC) is the third most common cancer and the second most common cause of cancer mortality worldwide. Despite the early disease screening techniques could reduce the number of deaths, the treatments for metastatic CRC still remains limited. GUCY2C, a receptor predominantly found in the intestinal epithelium, is a tumor-associated antigen that is overexpressed in gastrointestinal malignancies, particularly colorectal cancer (CRC). GUCY2C offers a super clean therapeutic target, due to restricted expression in normal tissues and high expression in CRC cells, with significantly reduced the on-target-off-tumor toxicities. A high-affinity, high-specificity human IgG1 monoclonal antibody against GUCY2C was obtained from a 100 billion-capacity human Fab phage display library. This antibody, after recombinant expression in CHO cells, was extensively validated both in vitro and in vivo for its suitability in antibody-drug conjugate (ADC) development. The recombinant antibody demonstrated high affinity for its specific antigen, as confirmed by Bio-Layer Interferometry (BLI) and Enzyme-Linked Immunosorbent Assay (ELISA) methods. Flow cytometry further confirmed that the antibody had picomolar (pM) affinity for gastric and colorectal cancer cell lines expressing high levels of GUCY2C. Cellular internalization experiments indicated that the antibody possesses excellent endocytic capabilities, making it particularly suitable for ADC development. The antibody was then conjugated with a linker-payload complex containing a topoisomerase I inhibitor and an antimetabolite moiety, and subjected to a series of in vitro and in vivo evaluations. The ADC achieved in vitro proliferation inhibition in the picomolar range of IC50. Several in vivo CDX model experiments also demonstrated significant tumor suppression efficacy. Moreover, acute toxicity evaluation of the GUCY2C-ADC in diverse preclinical models indicated favorable safety profiles and tolerability. Overall, these compelling preclinical data supports the promising therapeutic potential of this ADC in targeted treatment of CRC. Citation Format: Yunxia Zheng, Xiafen Wu, Junxiang Jia, Huihui Guo, Xiangfei Kong, Gengxiang Zhao, Yuanyuan Huang, Hangbo Ye, Xiaolei Liu, Yi Luo, Xiaoqiang Xie, Xia Zhou, Lu Bai, Wenjun Li, Binbin Chen, Qingliang Yang, Robert Yongxin Zhao. High-affinity human IgG1 antibody against GUCY2C for ADC development: Identification, characterization, and efficacy [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 6742.