Abstract LB009: Safety profile assessment for IND-enabling studies: Bispecific antibodies and antibody-drug conjugates (ADCs)

Abstract Developing antibody-based therapeutics requires balancing potency and safety. Off-target effects can cause adverse events, necessitating precise target engagement and comprehensive safety profiling during early development. The work presented outlines a systematic approach to identify and mitigate off-target interactions for antibodies and ADCs. This de-risking roadmap which spans 12-16 weeks, evaluates on-target and off-target interactions, ensuring thorough vetting before IND-enabling studies. The de-risking platform uses two primary approaches: (1) Off-target analysis via Retrogenix® Cell Microarray Technology (2) Off-target liability evaluation in human primary tissue cells. The Retrogenix® Cell Microarray Platform is a unique platform that screens over 6,500 human plasma membrane and secreted proteins expressed in HEK cells, providing comprehensive primary and off-target binding analysis. Widely used in regulatory submissions, it helps identify suitable leads and derisk biologics. Analysis of screens from over 300 molecules showed ∼50% had at least one off-target binding, highlighting the importance of early screening. In vitro safety profiling in human primary tissue cells, comprise of robust assays to evaluate off-target liabilities, where the biologics are tested for effects on cell viability and cytokine release using over 70 optimized human primary and iPSC-derived cell types. These assays investigate: (1) Off-target liabilities from Retrogenix® screens in relevant primary cells (2) On-target liabilities from target antigen expression in normal tissues (3) Safety profiles using human tissue cells when animal models are unavailable. The integrated approach to off-target analysis and safety profiling presented provides crucial insights for IND-enabling studies, facilitating safer, more effective antibody-based therapeutics development. Citation Format: Laura Ratcliffe, Sophie Vermond, Sophie Hill, Sabrina de Munnik, Gijs van Puijvelde, Benita Quist, Rachel Pooley, Katherine Carr, Nick Brown, Mark Aspinall-O'Dea, Ludovico Buti, Namrata Jayanth. Safety profile assessment for IND-enabling studies: Bispecific antibodies and antibody-drug conjugates (ADCs) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_2):Abstract nr LB009.