Abstract C088: Intelligent Hit Discovery Platform for Accelerated Cyclic Peptide Radiopharmaceutical Development

Abstract We present an integrated hit discovery platform for radiopharmaceutical drug conjugates (RDCs) that synergizes high-throughput biophysical screening (SPR, MST) with phage display technology to rapidly identify and optimize high-affinity cyclic peptide binders against oncology targets. This platform addresses critical challenges in RDC development by providing a streamlined solution for hit discovery, optimization, and validation. Our methodology employs parallel in vitro biophysical characterization, phage display library screening, and AI-driven computational modeling to optimize radioligand properties. Target validation was achieved through engineered recombinant protein constructs (including PSMA and SSTR) and isogenic cell lines with uniform target expression. Comprehensive evaluation was performed using modular functional assays measuring binding affinity and cellular internalization kinetics. We successfully established a cyclic peptide evaluation system incorporating recombinant proteins and engineered cell lines for both validated RDC targets (PSMA, SSTR) and novel tumor-associated antigens. For several emerging RDC targets, primary screening identified cyclic peptide hits demonstrating high affinity (SPR Kd < 100 nM), with subsequent optimization improving target retention while reducing off-target interactions. Preliminary evaluations confirmed these candidates possess favorable pharmacokinetic properties. This platform significantly accelerates the RDC development pipeline—from hit discovery to preclinical candidate selection—while ensuring optimal tumor targeting and minimized off-target effects. Our methodology demonstrates robust applicability across multiple radiotherapy targets, offering a versatile solution for next-generation radiopharmaceuticals with superior therapeutic efficacy and clinical translatability. Citation Format: Xinyu Bai, Tiejun Bing. Intelligent Hit Discovery Platform for Accelerated Cyclic Peptide Radiopharmaceutical Development [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2025 Oct 22-26; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2025;24(10 Suppl):Abstract nr C088.