Abstract 5206: ADC efficacy and safety evaluation based on organoid models

Abstract Introduction: Antibody-drug conjugates (ADCs) are effective cancer therapies that selectively deliver cytotoxic payloads to tumors. For the discovery of new ADCs, in vitro efficacy testing with organoids is crucial, as they replicate the 3D structure of tumors, providing a more accurate model for assessing the complex mechanism of action of ADCs. In this poster, we present an organoid-based ADC testing platform suitable for high-throughput screening. We demonstrate its application through a case study targeting human epidermal growth factor receptor 2 (HER2) to predict ADC efficacy and safety. Method: We established multiple PDX-derived organoid (PDXO) models from different cancer types with low, medium or high expression levels of HER2, which we verified by RNA-seq and immunohistochemistry. Responses to four groups of HER2-targeted ADC drugs were evaluated in these models by assessing cell viability, including Trastuzumab deruxtecan, Trastuzumab duocarmazine, Trastuzumab emtansine, Trastuzumab MMAE, and their corresponding payloads (with or without linker). Furthermore, we conducted additional safety studies to assess the intestinal toxicity of these drugs using human intestinal organoids (HIO) derived from normal intestinal tissues. Results: The HER2 expression levels in the in vitro cultured PDXO models were almost consistent at both RNA and protein levels, and they accurately reflected the expression status of the original tissues. The ADC screening revealed a differential sensitivity of organoids based on HER2 expression levels, with high HER2 expression correlating with increased sensitivity to ADC treatment, while low expression indicated resistance. Interestingly, normal organoid models were insensitive to ADC treatment, suggesting a potential for minimal side effects. However, the payloads alone demonstrated strong, unbiased cytotoxic activity against all models. In addition, the cytotoxic efficacy of payloads connected to linkers was significantly reduced, likely because the linkers hindered the payloads from entering the cells. Summary: Our organoid-based ADC screening platform offers a rapid and reliable method for early high-throughput screening, pharmacology, and efficacy research that help bridge the gap between in vitro and in vivo studies. The translational results enhance the development process of ADCs through more accurate assessments of their potential effectiveness and safety. Citation Format: Yuhui Wang, Junwen Zhang, Jiawen Xu, Lin Feng, Junjie Zhu, Pengwei Pan, Fang He. ADC efficacy and safety evaluation based on organoid models [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 5206.