AACR 2026 Poster 2161

Paired PDX-PDXO Models Serve an Integrated Preclinical Platform for High-Throughput Payload Screening and ADC drugs development

Jinxi Wang, Leilei Chen, Qingzhi Liu, Jiawen Gao, Jun Zhou, Chengcheng Wang, Wubin Qian, Likun Zhang, Ludovic Bourre, Jessie J.J. Wang

Discover how paired patient-derived xenograft and organoid models accelerate ADC payload selection and overcome clinical resistance mechanisms through integrated preclinical screening.

Antibody-drug conjugates (ADCs) deliver potent cytotoxic payloads directly to tumor cells, but payload selection is critical for efficacy and overcoming resistance. This study demonstrates an integrated strategy using patient-derived xenograft (PDX) models paired with PDX-derived organoids (PDXOs) to streamline ADC development. Focusing on a triple-negative breast cancer patient who progressed on Sacituzumab Govitecan, this approach enabled high-throughput payload screening that predicted in vivo efficacy and identified alternative payloads capable of overcoming topoisomerase I inhibitor resistance—demonstrating how paired models accelerate data-driven ADC optimization.

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• Streamline payload selection with high-throughput screening: Evaluate multiple ADC payloads (DM4, MMAE, PBD, DXd, SN-38) across patient-derived organoid models to rapidly identify optimal cytotoxic agents before in vivo studies.
  
  
• Model clinical resistance mechanisms: Study PDX/PDXO models derived from a patient with acquired resistance to Sacituzumab Govitecan to understand topoisomerase I inhibitor resistance and identify alternative strategies.
  
  
• Validate in vitro predictions in vivo: Demonstrate strong correlation between organoid payload screening results and subsequent PDX efficacy studies, confirming the predictive value of the platform.
  
  
• Compare TROP2-targeted ADCs with different payloads: Assess Sacituzumab Govitecan, Dato-DXd, SKB264, and custom Dato-MMAE constructs to identify which payload classes overcome resistance in specific patient contexts.
  
  
• Characterize payload-specific mechanisms: Distinguish between target-dependent responses and payload-level resistance using matched genomic profiling, protein expression analysis, and pharmacokinetic assessment.
  
  
• Accelerate patient-tailored ADC development: Learn how integrated PDX/PDXO platforms enable efficient, biology-driven decision-making to develop more effective ADC therapies and overcome clinical resistance.

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