Abstract 3213: A novel CDH17/PD-1 bispecific antibody for treatment of advanced gastrointestinal cancers

Abstract

Targeting immune checkpoints like programmed death receptor 1 (PD-1) with monoclonal antibodies has achieved durable responses in a range of cancers, however, immune-related adverse events may occur in a subset of patients. As such, we developed a bispecific antibody targeting cadherin-17 (CDH17) and PD-1 with a hope to rejuvenate specifically the exhausted T cells within tumor microenvironment. In healthy individuals, CDH17 is expressed at a restricted level in intestinal epithelial junction that is not accessible to biologics, however, in gastrointestinal cancers, CDH17 is overexpressed and can be targeted by antibodies. Our new CDH17/PD-1 bispecific antibody would reactivate anti-tumor immunity with reduced risk of on-target off-tumor toxicity. Different bispecific antibody formats were designed, cloned, and expressed. Strong binders were first identified using CDH17 and PD-1 ELISA. The binding affinities to CDH17 and PD-1 of the selected candidate were examined using biolayer interferometry. The effect of these bispecific antibodies on blocking PD-1/PD-L1 axis in T cells was demonstrated in a cell-based reporter assay. T-cell mediated killing on CDH17-positive GI cancer cells and induction of T cell activation markers upon antibody treatment were also studied. A total of 7 CDH17/PD-1 bispecific antibodies of different formats were screened. Of these candidates, one, named ARB204, was selected because of its potent binding to both antigens in ELISA (i.e., EC50 values: CDH17, 1.6nM; PD-1, 0.4nM) and biolayer interferometry (i.e., KD values: CDH17, 2.4E-09M; PD-1, 6.02E-11M). ARB204 blocked PD-1/PD-L1 axis in the reporter assay with EC50 value 4.4nM. Notably, ARB204 redirected T cells to eradicate CDH17-positive pancreatic AsPC1 cells with an EC50 value of 3.5nM. No cytotoxicity against CDH17-negative cancer cells were seen. ARB204 effectively bound CDH17 on GI cancer cells and PD-1 on T cells. This bispecific design allowed selective T-cell mediated killing on cancer cells expressing CDH17, mitigating the risk of off-tumor toxicity. ARB204 warrants further studies on its immune checkpoint inhibition in animal models. Citation Format: Kwan Wa Wong, Po Yee Wong, Kronos Chow, Chui Yee O, Dennis Wong, John Moon Luk, Kwong Fai Wong. A novel CDH17/PD-1 bispecific antibody for treatment of advanced gastrointestinal cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 3213.