Abstract A137: GS24-B025, a highly differentiated CDH17- and CEA-directed bispecific antibody-drug conjugate (bsADC), for the treatment of colorectal cancer

Abstract Background: Colorectal cancer (CRC) is the third most common cancer worldwide and the second leading cause of cancer deaths. Often diagnosed at advanced stages with limited treatment options, substantial unmet need remains in the metastatic setting of CRC (mCRC). Both CDH17 and CEA are highly expressed tumor-associated antigens (TAAs) in CRC, representing promising therapeutic targets. GS24-B025, a dual CDH17- and CEA-targeting ADC comprising topoisomerase 1 inhibitor payloads site-specifically conjugated to a CDH17 x CEA bsAb by a proprietary peptide-based cleavable linker with a drug-to-antibody ratio (DAR) of 8, is currently in development as a potential therapy for mCRC. Methods: Membrane expression of CDH17 and CEA was assessed in CRC tissue microarrays (TMAs) by immunohistochemistry (IHC). Binding affinity and activity of GS24-B025 to CDH17 and CEA were determined by Biacore and flow cytometry, respectively. In vitro cytotoxicity and bystander killing effect of GS24-B025 were examined in a Cell Titer-Glo assay in CRC cell lines. In vivo anti-tumor efficacy of GS24-B025 was investigated in the CRC xenograft models in mice. Results: CDH17 and CEA were found to be highly co-expressed in CRC tissues (N=209), and thus, dual targeting of CDH17 and CEA may enable broader patient coverage across and provide benefit to the entire CRC population. GS24-B025 showed single digital nanomolar affinity to both CDH17 and CEA and potent binding to CDH17+ and CEA+ tumor cells. Compared to the parental ADCs, GS24-B025 exhibited more efficient internalization in the CDH17+, CEA+, and CDH17+ CEA+ tumor cell lines, and displayed robust cytotoxicity and bystander killing activity against CRC cell lines in vitro (with an EC50 in the sub-nanomolar range). Furthermore, GS24-B025 effectively induced tumor regression across different levels of CDH17 and/or CEA expression and demonstrated superior in vivo efficacy versus benchmark ADCs, including the M9140, TORL-3-600, and HS-20110 analogs. Conclusion: These preclinical data suggest the potential of GS24-B025 as an effective treatment option for CRC patients and support its further evaluation in IND-enabling studies. Citation Format: Zeng Qi, Fu Li, Liping Shao, Yuting Lu, Chong Ding, Nan Li, Huan Wang, Weiming He, Wenqiang Zhai, Fanglong Yang, Siqin Wang, Lei Jin, John Liuzhong Xu. GS24-B025, a highly differentiated CDH17- and CEA-directed bispecific antibody-drug conjugate (bsADC), for the treatment of colorectal cancer [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2025 Oct 22-26; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2025;24(10 Suppl):Abstract nr A137.