Abstract 4328: Preclinical development of SCR-A008: A CDH17-targeted ADC for gastrointestinal cancer

Abstract Background: Cadherin is a superfamily of cell adhesion molecules that depend on Ca2+ and play an important role in maintaining tissue architecture. Abnormal expression of Cadherins is often associated with malformation of tissues, tumor formation, and metastasis. Cadherin-17 (CDH17) also known as hepatocyte-enterocyte cadherin, is a non-classical member of the calcium-dependent cadherin superfamily. Unlike classical cadherins, the CDH17 sequence is formed by seven extracellular calcium-dependent cadherin domains and a very short cytoplasmic domain. CDH17 is a calcium-dependent transmembrane glycoprotein that mediates cell-cell adhesion in intestinal epithelial cells. Studies have found that CDH17 expression is limited to the intestinal and pancreatic duct epithelial cells in human normal tissues. However, in tumor tissues, CDH17 is highly expressed in various digestive tract tumors, such as gastric cancer (73%), colorectal cancer (100%) and pancreatic cancer (31%). Some studies have also reported positive staining for CDH17 in about 6% of lung cancer patients, 11% of ovarian cancer patients, and 2% of liver cancer patients. These results suggest that CDH17 may be a potential therapeutic target in related tumors, especially digestive tract tumors. Methods & Results: We developed a novel CDH17-targeting antibody-drug conjugate (ADC) called SCR-A008, which is comprised of an anti-CDH17 humanized monoclonal antibody conjugated with novel topoisomerase 1 inhibitor (CPT116) via a hydrophilic cleavable linker at DAR 8. SCR-A008 specifically recognizes human and cyno CDH17 with high affinity. In vitro cytotoxicity experiment demonstrated that SCR-A008 induced tumor cell lysis in various tumor cell type. Compared to MMAE-based CDH17-ADC, SCR-A008 exhibits significantly stronger anti-tumor activity in colorectal cancer cells. Additionally, we utilized CDX and PDX model to evaluate the in vivo efficacy of SCR-A008. The results showed that SCR-A008 inhibited tumor growth of various tumors in a dose dependent manner. SCR-A008 also have good stability and favorable developability. Pharmacokinetics and tolerability were assessed in mouse and cynomolgus monkey. The pharmacokinetics experiment in mice showed better PK characteristic than the reference ADC. Conclusion: These findings suggest that SCR-A008 is a potential Best-in-Class therapeutic drug for CDH17-positive solid tumor. Citation Format: Guangcun Cheng, Hui Zheng, Zhiyong Yu, Chunlei Xia, Huipeng Guo, Xiyuan Wang, Yayuan Fu, Renhong Tang. Preclinical development of SCR-A008: A CDH17-targeted ADC for 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 4328.