Abstract 6743: Patient-derived organoids: an <i>in vitro</i> platform for evaluating ADC efficacy, potency, and specificity

Abstract Antibody-drug conjugates (ADCs) are pharmaceutical drugs that selectively deliver cytotoxic agents to cells expressing a specific target antigen (TA). Structurally, ADC consists of a highly specific monoclonal antibody linked to a cytotoxic payload. HUB patient-derived organoids (PDOs) are a unique in vitro 3D adult stem cell-based model. They closely resemble the architecture and physiology of the tissue of origin, maintaining the patient-specific genetic and phenotypic characteristics, including surface marker expression. This unique feature makes them a patient-relevant in vitro model for ADC screenings. The work presented here demonstrates the potential of the HUB PDO platform in an in vitro basket trial. Organoids derived from 7 different tissue origins were used for ADC screening, showcasing the platform's reliability and ability to assess ADC specificity, potency, and efficacy. ADCs directed to different TAs, such as Tissue Factor (F3) or trophoblast antigen 2 (TROP2), were tested, and organoid viability was assessed with CellTiter Glo® 3D after 7 days of treatment. Further parameters, such as TA expression and the percentage of the cell population expressing TA in each organoid, were evaluated by flow cytometry. The analysis of ADCs targeting F3 revealed an ADC-dependent organoid-killing correlation with F3 expression for a subset of PDOs across all different tumor tissue types. However, as observed in clinical trials, the impact of ADC on the viability of some PDOs was unrelated to F3 expression. The lack of correlation between ADC efficacy and target antigen expression was more evident for the TROP2 ADC. These findings underscore the importance of the study in understanding the differential activity between ADCs. Altogether, these results highlight the value of the PDO platform in assessing ADC target specificity and as a patient-relevant model to study the mechanism behind differential activity between ADCs such as antibody internalization dynamics or bystander effects. Citation Format: Daniele Mori, Claudia Beaurivage, Eider Valle Encinas, Yara Hendriksen, Anna Schepers, Foteini Gkogkou, Joris Maas, Ka Wai Lai, Mariana Silva, Sumeyra Mucuk, Vineeta Adegbenro, Ricardo Korporaal, Merel Derksen, Sylvia F. Boj. Patient-derived organoids: an in vitro platform for evaluating ADC efficacy, potency, and specificity [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 6743.