Integrated multi-omics analysis reveals conserved tumor-associated antigens (TAAs) profiles in PDX and organoid models for advancing ADC development

Introduction The development of antibody-drug conjugates (ADCs) requires reliable tumor-associated antigens (TAAs) expression for efficacy, necessitating predictive preclinical models. Patient-derived xenografts (PDXs) preserve patient tumor characteristics, which serve as a mainstay in translational oncology research, while patient-derived organoids (PDOs) and PDX-derived organoids (PDXOs) have recently emerged as powerful in vitro 3D systems that offer enhanced scalability while retaining key biological features of the original tissue. However, their fidelity in maintaining TAA profiles requires multi-omics validation. This study evaluates TAA consistency across platforms and between PDXs and matched organoids. Methods We analyzed 18 clinically relevant TAAs using IHC on ~1000 PDX models across 18 cancer types. IHC quantification was analyzed using HALO AI platform to generate H-Score, this data was integrated with RNA-seq and MS-mass spectra-proteomics from Crown Bioscience's database to determine the correlation coefficients. To assess model translatability, a focused panel of 10 key TAAs was selected for IHC assessment between a subset of ~400 characterized PDXs and their paired PDOs/PDXOs, enabling a cross-model comparison. Results Our integrated multi-omics analysis within the extensive PDXs cohort demonstrated a high degree of concordance between protein expression (H-Score) and both transcriptomics and proteomics data for the 18 investigated TAAs, including HER2(R RNAseq =0.871,R Proteomics =0.765), TROP2(R RNAseq =0.852, R Proteomics =0.775), Nectin-4(R RNAseq =0.679, R Proteomics =0.861), DLL3(R RNAseq =0.75, R Proteomics =0.698), CEACAM5(R RNAseq =0.799, R Proteomics =0.743). Critically, a remarkably high degree of concordance was observed in TAAs protein expression patterns between PDXs and their paired PDOs/PDXOs models, including TROP2(R=0.946, P<0.0001), Nectin-4(R=0.772, P<0.0001), DLL3(R=0.819, P<0.0001), HER3(R=0.659, P<0.0001), Claudin 18.2(R=0.775, P<0.0001). The consistency of IHC intensity and heterogeneity characteristics between organoids and their in vivo counterparts further supports this molecular fidelity. Conclusion This study validated TAAs expression concordance across multi-omics platforms in a large PDX cohort. More significantly, we deliver compelling evidence that PDOs/PDXOs models exhibit exceptional fidelity in maintaining the TAA expression landscape of their corresponding PDX tumors, demonstrating PDOs/PDXOs as highly reliable and invaluable tools from initial target validation and lead antibody characterization to the formulation of biomarker-driven patient selection strategies in clinical trials.