Abstract 341: VBC108: a first-in-class CDH17/CLDN18.2 targeted bispecific antibody drug conjugate (ADC) to overcome tumor heterogeneity of gastrointestinal cancers (GC, PADC, CRC, etc.)

Abstract CLDN18.2 is a promising target for GI cancer therapy, with various modalities under clinical evaluation. However, these therapies face challenges due to the heterogeneous expression of CLDN18.2, leading to inconsistent efficacy and the need of patient stratification, as observed with Zolbetuximab, AZD0901 and IBI343. Besides, these treatments may induce drug resistance by downregulating CLDN18.2. Recently, CDH17 (Cadherin 17) has emerged as a novel target for biologics, often overexpressed in GI cancers. But in normal tissues, it remains inaccessible as it is hidden within the tight junctions of intestinal epithelial cells, which makes it a favorable target for cancer therapy. More importantly, systematic analysis of expression data reveals high co-expression or complementary expression of CDH17 with CLDN18.2 in GI cancers, with no co-expression in other major organs. This discovery presents an opportunity for a bispecific anti-CDH17/CLDN18.2 therapy, potentially addressing the limitation of targeting CLDN18.2 alone. VBC108 is a bispecific ADC designed to target both CDH17 and CLDN18.2 with TOPO1i payload. The unique design maximizes efficacy while minimizing safety risks. VBC108 distinguishes itself from other CLDN18.2-targeting therapies through the following features. VBC108 targets both CDH17 and CLDN18.2, potentially overcoming tumor heterogeneity and covering over 80% of gastric and 50% of pancreatic cancers without CLDN18.2 IHC selection. It has high affinity to CDH17 and CLDN18.2, enhanced binding avidity, internalization and cytotoxicity. Moreover, it has a strong bystander effect to help further overcome the heterogeneity of tumor antigen expression. In CDH17 single-positive CDX models, which represent clinical scenarios lacking targeted therapies, VBC108 exhibited strong efficacy, whereas AZD0901 did not inhibit tumor growth at all. In CDH17/CLDN18.2 double-positive CDX models, representing clinical scenarios with target expression heterogeneity, VBC108 further showed its superiority. In CLDN18.2 single-positive CDX models, reflecting clinical scenarios with available CLDN18.2-targeted therapies, VBC108 demonstrated comparable efficacy with different payload mechanisms. In the PDX (GC, PADC, CRC) studies, especially in the GC model with low to medium expression of CDH17/CLDN18.2, it achieved a 100% CR. Furthermore, preliminary toxicity studies in Cyno-monkeys showed good tolerability with repeated doses. VBC108 also exhibited excellent developability in a comprehensive developability assessment (DA) test, making it a strong candidate for further CMC development. In summary, VBC108, with its unique design, shows the potential as a first-in-class ADC for GI cancer and supports the advancement to clinical trials. Citation Format: Wei (Vivian) Wang, Lingyu Guan, Man Xu, Qun Yin, Chen Dong, Jing Li. VBC108: a first-in-class CDH17/CLDN18.2 targeted bispecific antibody drug conjugate (ADC) to overcome tumor heterogeneity of gastrointestinal cancers (GC, PADC, CRC, etc.) [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 341.