Abstract 1568: Humanized PD1 mouse with MC38-hCLDN18.2 cell line provide powerful syngeneic model platform for evaluating Claudin18.2-targeted therapies

Abstract Claudin18.2 is a highly specific tight junction protein that is minimally expressed in normal tissues but aberrantly activated and overexpressed in various malignancies, particularly digestive system tumors such as gastric cancer (approximately 70%) and pancreatic cancer (around 50%). In these tumors, the loss of cell polarity exposes Claudin18.2 on the cell surface, making it accessible to biologics and effector cells. Innovative therapeutic strategies, including monoclonal antibodies, bispecific antibodies, ADCs, and CAR-T cells, leverage this accessibility to enhance tumor-targeting precision and immune activation. Combining Claudin18.2-targeted therapies with immune checkpoint inhibitors, such as PD-1 blockade, holds promising therapeutic potential.To evaluate the efficacy of antibody drugs and ADCs, tumor cell lines overexpressing tumor-associated antigens are critical. We generated MC38-CLDN18.2 murine colon cancer cell lines by overexpressing human CLDN18.2 in MC38 cells. Human CLDN18.2 protein expression was confirmed by flow cytometry. The tumorigenic potential of MC38-CLDN18.2 cells was further validated in vivo.To investigate novel combination therapies or bispecific antibodies targeting CLDN18.2 and PD-1 in an immunocompetent model, we developed a humanized PD-1 (hPD1) mouse model on a C57BL/6 (C57) background. Using CRISPR/Cas9-based gene engineering, the murine Pdcd1 gene was replaced with the human PDCD1 gene, ensuring full-length human PD-1 protein expression in the knock-in model. Human PD-1 protein expression was validated by FACS analysis after in vivo anti-CD3 stimulation.The tumor growth inhibition of two CLDN18.2 monoclonal antibodies (IMAB362 and ASKB589) was evaluated in hPD1 mice engrafted with MC38-CLDN18.2 syngeneic tumors. The therapeutic effects of these antibodies were also investigated in combination with anti-PD-1 treatment. Both anti-CLDN18.2 monotherapies demonstrated moderate antitumor efficacy, while their combination with PD-1/PD-L1 immune checkpoint blockade produced significant synergistic effects, resulting in enhanced tumor suppression and increased antitumor immunity with robust T-cell infiltration.In summary, the humanized PD-1 mouse model and MC38-CLDN18.2 cell line provide robust in vivo platforms to evaluate novel therapeutic candidates targeting CLDN18.2. Citation Format: Jane Hong, Shuang Li, Xiaolei Qiu, Hechun Ma, Yi Li, Ruilin Sun. Humanized PD1 mouse with MC38-hCLDN18.2 cell line provide powerful syngeneic model platform for evaluating Claudin18.2-targeted therapies [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 1568.