Abstract 4417: GS24-B025, a novel CDH17- and CEA-directed bispecific antibody-drug conjugate, 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. Pharmacokinetics was studied in cynomolgus monkeys. 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-digit nanomolar affinity to both CDH17 and CEA and potent binding to CDH17+ and CEA+ tumor cells, resulting in efficient internalization, 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 in-house generated M9140 and TORL-3-600. Furthermore, GS24-B025 featured a favorable pharmacokinetic profile in cynomolgus monkeys. Conclusion: These 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, Qiangqiang Deng, Peng Qi, Wenqiang Zhai, Yihui Lin, Xiaozhen Wang, Fanglong Yang, Siqin Wang, Lei Jin, John L. Xu. GS24-B025, a novel CDH17- and CEA-directed bispecific antibody-drug conjugate, for the treatment of colorectal cancer abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 4417.