PRISM AIR: High-Throughput Platform for Validating ADC Targets and Prioritizing Antibody Candidates

The development of antibody-drug conjugates (ADCs) remains a resource-intensive process, often hampered by the lack of scalable, early functional assays for validating new tumor targets and prioritizing candidate antibodies with therapeutic potential. To address this technological innovation gap, we developed PRISM AIR (Antibody Internalization Reporter), an assay designed to facilitate discovery of novel cell surface targets and accelerate development of ADCs through integration of large-scale functional cell viability screening with comprehensive molecular data. PRISM AIR utilizes a universal secondary Fab-MMAF conjugate targeting the Fc domain of primary human IgGs. By coupling a secondary drug conjugate with a primary antibody, we hypothesized that we could achieve selective drug delivery mimicking the mechanism of an ADC. This approach would enable early functional screening of candidate antibodies without the need for resource-intensive conjugation of individual antibodies. We screened a panel of antibody and ADC test agents across the entire PRISM cell set of 957 genomically characterized cancer cell lines, validating the platform against several targets including HER2, TROP2, tissue factor and transferrin receptor. Results showed consistent potent, target-selective killing that correlated with antigen expression and analogous conventional ADC efficacy, confirming the assay’s ability to functionally prioritize lead candidates. Integration of viability data with comprehensive baseline genomic and perturbational profiles allowed us to disentangle antibody versus linker and payload activity and identify predictive biomarkers. Notably, comparative profiling of AIR against ADCs with distinct payloads revealed differential activity, identifying GPX2 and AKR1C3 as resistance biomarkers specific to deruxtecan versus MMAF. We also identified the lysosomal transporter SLC46A3 as a critical sensitivity biomarker for non-cleavable linkers, a role previously unreported for MMAF conjugates. In conclusion, PRISM AIR represents a significant technological innovation for the antibody field. It is a robust, high-throughput platform that empowers researchers to identify novel ADC targets, prioritize lead candidates based on optimal internalization and functional cytotoxicity, and discover biomarkers predictive of response or resistance. By enabling these critical assessments early in the discovery pipeline, this next-gen tool for ADC development has the potential to significantly streamline the translation of new cancer immunotherapies from bench to clinic. Citation Format: Jillian Eskra, Alvin Kalathungal, Aydin Golabi, Bailey Porter, Ursula Widocki, Ashish Bino George, Mustafa Kocak, Melissa Ronan, Matthew Rees, Jennifer Roth. PRISM AIR: A high-throughput platform for functional validation of ADC targets and antibody candidate prioritization [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 1326.