A rapid patient-derived organoids platform guides the evaluation of ERBB-targeting bispecific T-cell engagers
Presenter: Yuhong Liu, PhD Session: Redefining Targeted Therapy: Bispecific T-Cell Engagers and Antibody-Drug Conjugates 1 Time: 4/20/2026 9:00:00 AM → 4/20/2026 12:00:00 PM
Authors
Yuhong Liu 1 , Chen Wang 2 , Jing Zhao 3 , Leli Zeng 4 1 Centre for Virology, Vaccinology and Therapeutics, The University of Hong Kong, Hong Kong, China, 2 Digestive Diseases Center, The Seventh Affiliated Hospital of Sun Yat-Sen University, Shen Zhen, China, 3 Scientific research centre, The Seventh Affiliated Hospital of Sun Yat-Sen University, Shen Zhen, China, 4 The Biobank, Scientific Research Center, The Seventh Affiliated Hospital of Sun Yat-Sen University, Shenzhen, China
Abstract
Background: The ERBB receptor family (EGFR/HER1, HER2, HER3, HER4) are well-validated oncogenic drivers. The clinical translation of ERBB-targeted bispecific antibodies (e.g., EGFRxCD3, HER2xCD3,HER2 degrading BsAbs) is bottlenecked by the lack of models that can rapidly and concurrently predict patient-specific efficacy and on-target, off-tumor toxicity. Optimizing these drugs including fine-tuning parameters like affinity, valency, and epitope to maximize the therapeutic window, which requires a predictive platform that provides integrated feedback on both anti-tumor activity and on-target toxicity in a clinically relevant timeframe. Methods: We established a comprehensive biobank of patient-derived organoids (PDOs) from breast, gastric, and non-small cell lung cancers, alongside matched normal organoids. We developed a high-throughput, standardized co-culture assay with PBMCs or T cells to evaluate a panel of ERBB-targeting bispecific antibodies with varying molecular formats. The entire workflow was designed for speed, generating parallel data on tumor organoid killing and normal organoid toxicity within days. Results: Our platform delivered robust, quantitative data on the therapeutic index for a series of BsAb candidates within a 3-week window. We demonstrated that affinity-tuning towards tumor-associated antigen levels could preferentially spare normal organoids with low ERBB expression while maintaining potent tumor killing. Furthermore, comparing different BsAbs revealed that certain molecular formats or epitope choices were associated with reduced cytokine release and less severe toxicity in normal organoids, without compromising efficacy in target-positive tumors. This provides a direct, rapid strategy for lead candidate selection and optimization. Conclusion: We have developed a rapid, reproducible PDO-based platform that not only predicts the therapeutic window of ERBB-targeting BsAbs but also provides critical insights for their molecular optimization. This “fast-feedback” system can significantly de-risk and accelerate the translation of BsAbs by enabling data-driven decisions on affinity, format, and epitope selection early in the drug development process. The ability to rapidly profile multiple candidates against a backdrop of human tumor and normal tissues makes this an invaluable tool for designing safer and more effective bispecific antibodies. This study presents a transformative preclinical optimization tool. By generating predictive safety and efficacy data in weeks, our platform moves beyond mere prediction to active guidance, empowering the rational design of next-generation BsAbs with an inherently improved therapeutic profile for clinical trials.
Disclosure
Y. Liu, None.. C. Wang, None.. J. Zhao, None.. L. Zeng, None.
Cited in
Control: 2361 · Presentation Id: 9650 · Meeting 21436