Abstract LB140: Preclinical development of therapeutic antibodies using humanized immune system mice

Abstract The development of therapeutic antibodies, which improve specificity and efficacy over existing standards of care by engaging the patient’s own immune system, is expanding across various cancer indications but fraught by a high attrition rate in clinical trials. The availability and versatility of robust animal models containing human immune systems is poised to increase preclinical predictiveness and improve clinical success. To address this need, we present a modular design framework for the customization of preclinical oncology studies. The first module in this framework is the selection of mouse model with a complete humanized immune system. Such mice are generated by engrafting of human CD34+ hematopoietic stem cells into a variety of initially immunodeficient strains thus leading to the expansion of T, B, NK, and myeloid cells (which can be further enhanced through the hydrodynamic boost technique). From a variety of strains that can be humanized and are available (e.g. NSG, NCG, NCG-X, NOG-EXL, etc), we highlight certain advantages and limitations to facilitate tailoring of preclinical study designs. Subsequent modules in the framework include tumor model (e.g. melanoma, lymphoma, lung, ovarian, breast, pancreatic, prostate, etc), engraftment site (liver, mammary gland, lung, pancreas, subcutaneous), and molecular and cellular readouts (e.g. flow cytometry, histology, qPCR, ELISA, ELISpot, etc). We then describe a set of case studies whereby this framework has been successfully applied to assess the safety, PK/PD, efficacy, and mechanisms of action of clinically-approved antibodies and preclinical candidates. These include checkpoint inhibitors (e.g., PD-1, PD-L1, OX40), T-cell engagers, and tumor-targeting antibodies (e.g., EGFR, Her2, CD47) across diverse cancer types. This framework illustrates the flexibility of mouse model humanization for drug-specific preclinical assessment and highlights the potential in across cancer types and in diseases beyond oncology. Citation Format: Emilie Bayon, Pierre Wallet, Joséphine Zangari, Sébastien Tabruyn, Dan Georgess. Preclinical development of therapeutic antibodies using humanized immune system mice [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 LB140.