Abstract 3500: LBL-054-CD3: An anti-CDH17 and CD3 bispecific antibody for the treatment of CDH17-positive gastrointestinal cancer

Abstract Background: CDH17 is a member of the cadherin superfamily, a group of calcium-dependent cell adhesion molecules critical for organ development, tissue integrity, and cancer progression. In normal tissues, CDH17 is highly restricted to the lateral membrane and concealed within intestinal tight junctions, making it inaccessible and blocking immune cell infiltration. In contrast, it is overexpressed and redistributed in 50% to 90% of gastrointestinal cancers, leading to its exposure on the cancer cell surface, therefore becoming more accessible to target. This unique feature makes CDH17 a promising target for T cell engager based immunotherapy for GI cancer. Here, we have developed a novel bispecific antibody, LBL-054-CD3, targeting CDH17 and CD3 to selectively kill CDH17-positive tumor cells by engaging T cells. Methods: LBL-054-CD3 was developed using our proprietary LeadsBody™ T-cell engager platform, comprising high-affinity arms targeting CDH17 and one finely tuned arm targeting CD3, engineered to balance efficacy and safety characteristics. The binding affinity of LBL-054-CD3 to CDH17 and CD3 was assessed using Fortebio, while its biological activity was evaluated through several cell-based assays, including reporter gene assay, TDCC to various levels of CDH17 expressing tumor cells, and T cell activation. The anti-tumor activity of LBL-054-CD3 antibody was evaluated in PBMC-humanized mice bearing GI tumor cell line xenograft models. Results: LBL-054-CD3 was shown potent binding affinity for CDH17 with no cross-reactivity to other family proteins. In vitro cytotoxicity assays revealed that LBL-054-CD3 mediated tumor cell killing was dependent on CDH17 expression level, inducing moderate cytokine release and cell proliferation while exhibiting no cytotoxic effects on CDH17-negative cells. In a PBMC-humanized mouse CDX model, LBL-054-CD3 demonstrated significant antitumor activity. Conclusions: The study demonstrates that LBL-054-CD3 has potent binding affinity to the membrane-proximal region of CDH17 and mediates T-cell cytotoxicity against various levels of CDH17 expressing tumor cells. Further, the bispecific antibody is shown excellent antitumor activity in both in vitro and in vivo experiments. Citation Format: Xingxing Fang, Yurong Qin, Xiaoya Liu, Chengze Ni, Tingtng Li, Peng Zhang, Chao Chu, Mi Ye, Guojin Wu, Jianming Sun, Yue Zhao, Xiao Huang, Jordan Zhu, Shoupeng Lai, Xiaoqiang Kang, Hong Ling. LBL-054-CD3: An anti-CDH17 and CD3 bispecific antibody for the treatment of CDH17-positive gastrointestinal cancer [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 3500.