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Poster

SITC 2025 Poster #992

Development of a Clinically Relevant Organoid-Based ADCC Co-Culture Platform for Preclinical Evaluation of Fc-Competent Antibody Therapeutics

Summary

ADCC is central to the activity of many antibody therapeutics, it depends on Fcγ receptor engagement on effector cells. Traditional 2D models fall short for predicting this biology. This study introduces a translational co-culture built on PDX-derived organoids, with mouse stroma depleted to preserve human tumor complexity, and primary human NK cells added at optimized E:T ratios in 96-well format. We luciferase-label organoids to quantify killing, test intact HER2-targeting antibodies, isotypes, free payloads, and ADC controls, and report strong Z′ performance and dynamic range. The platform captures differences driven by Fc engagement and antibody format, and extends to immune-modulating regimens in additional tumor types.

Using CTG3D PDXOs from HER2-positive breast cancer and other indications, we profile NK-mediated cytotoxicity and antibody format effects. Readouts include luminescence viability, IC50 in monoculture, and ADCC deltas in co-culture, supported by high-content imaging and flow panels that quantify immune activation and tumor susceptibility. The result is a scalable, physiologically relevant system for Fc-competent antibody and ADC optimization before in vivo.

Learning outcomes:

  • Understand how CTG3D organoids plus primary human NK cells in 96-well format deliver reproducible ADCC measurements with robust Z′ and dynamic range.

  • See HER2 case data, Enhertu shows an IC50 of ~5.2 nM by Day 6 in monoculture, while co-culture reveals NK-dependent killing, trastuzumab ~31% and Enhertu ~38% at 25 nM versus vehicle.

  • Recognize how antibody format and Fc engagement drive differential activity that simple 2D assays can miss.

  • Learn how immune-modulating regimens translate in this system, PD-1/PD-L1 blockade ~51% ADCC and CD38 blockade ~24% in LUAD PDXO-PBMC co-culture.

  • Identify workflow extensions, target validation by IHC or flow, high-content imaging, and high-throughput flow cytometry to map immune activation and refine construct selection.

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