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Background BDC-4182 is a clinical stage molecule, consisting of a CLDN18.2-targeting antibody covalently attached to a novel next generation toll-like receptor (TLR)7/8 agonist via a non-cleavable linker. In preclinical models, systemic delivery of ISACs has been shown to broadly activate the innate and adaptive immune system, leading to complete tumor regression, immunologic memory and epitope spreading to eliminate tumors cells that no longer express the target antigen. Herein, we further characterize activity of CLDN18.2 ISAC in multiple tumor models.Methods In vivo assessment of anti-tumor activity was performed with a mouse active surrogate of BDC-4182 (BDC-4182.S) or other CLDN18.2 cytotoxic ADCs in xenograft and syngeneic tumor models with different levels of CLDN18.2 expression.Results BDC-4182.S led to significant tumor regression in both xenograft and syngeneic mouse models and elicited T cell-dependent immunological memory with epitope spreading. BDC-4182.S also outperformed cytotoxic CLDN18.2 ADCs, exhibiting a greater ability to inhibit growth of low CLDN18.2 expressing tumors. Furthermore, we observed pharmacodynamic changes associated with the BDC-4182.S mechanism of action. Lastly, we provide supporting preclinical data supporting the use of BDC-4182 in combination with CPI in gastric cancer patients.Conclusions As the BDC-4182 clinical trial is enrolling patients ( NCT06921837), we used preclinical models to help understand the activity across a range of CLDN18.2 expressing models, induction of immunologic memory with epitope spreading, favorable activity compared to cytotoxic CLDN18.2 ADCs, pharmacodynamic changes related to its mechanism and activity in combination with approved agents in gastric cancer.