Abstract 2934: Novel hydrophilic CDH17-targeting antibody-drug conjugate exhibits anti-tumor efficacy in preclinical xenograft models

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 hidden within intestinal tight junctions which is inaccessible. 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. This unique feature makes CDH17 a promising target for antibody-based therapies. Here, we describe the preclinical development of LBL-054, a novel CDH17-targeting antibody drug conjugate (ADC) that is developed from a humanized CDH17 IgG1 monoclonal antibody conjugated with our proprietary linker-payload platform. Methods: LBL-054 targeting CDH17 monoclonal antibody was generated using mouse hybridoma technology. The binding affinity of mAb to CDH17 was determined using Fortebio and flow cytometry. The mAb internalization was assessed with anti-Fc-MMAE method. The internalization of both the mAb itself and LBL-054 was assessed by FACS method. Binding of LBL-054 to CDH17 was confirmed in human cancer cell lines and cells engineered to overexpress CDH17. Furthermore, plasma stability of LBL-054 was assessed with LC-MS methods. The killing activity of cancer cells was evaluated on CDH17 positive, negative and the mixed cancer cells. Finally, the anti-tumor effects of LBL-054 were evaluated in xenograft mouse tumor models with pharmacokinetics studies. Results: LBL-054 exhibited proper affinity, and rapid internalization. In the killing assays with CDH17 positive cancer cells LBL-054 was more potent than LBL-054-Dxd conjugate while LBL-054 was less prone than LBL-054-Dxd conjugate to kill CDH17 negative cells. And also, LBL-054 exhibited stronger bystander effect than LBL-054-Dxd conjugate. LBL-054 was highly stable in plasma stability test. A single dose of LBL-054, which induced tumor regression, was more potent than LBL-054-Dxd conjugate in the xenograft models, and better PK than LBL-054-Dxd conjugate as well. Conclusions: By conjugating with high potent/bystander/non-pgp substrate TOP1i payload exatecan with a cleavable/hydrophilic linker, LBL-054 targeting CDH17 demonstrates high stability in plasma, robust anti-tumor activity and good tolerability in the xenograft models, supporting clinical development of LBL-054 for patients with CDH17-expressing tumors. Citation Format: Yang Ye, Yurong Qin, Xingxing Fang, Xiaoya Liu, Wanting Wang, Tingting Li, Chengze Ni, Chao Chu, Mi Ye, Guojin Wu, Jianming Sun, Yue Zhao, Xiao Huang, Jordan Zhu, Shoupeng Lai, Xiaoqiang Kang, Hong Ling. Novel hydrophilic CDH17-targeting antibody-drug conjugate exhibits anti-tumor efficacy in preclinical xenograft models [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 2934.