Abstract 1296: Development of a novel NCG-hIL15-FcγR-KO model for precise drug efficacy evaluation

Abstract Humanized mice, particularly immunodeficiency mice reconstituted with human immune systems by the transplantation of human hematopoietic stem cells (HSCs) or human peripheral blood mononuclear cells (PBMCs), have been widely used in tumor immunology. The NCG-hIL15 model has been developed to reconstitute both human T and natural killer (NK) cells, which allows the study of immune checkpoint inhibitors (ICIs) and antibody-dependent cellular cytotoxicity (ADCC)-dependent drugs. However, the remaining murine cells from the myeloid compartment can interfere with the mAb-based drug clearance and efficacy. To precisely evaluate the function of mAb-based drugs, we have successfully developed the NCG-hIL15-FcγR-KO model by disrupting the murine FcγRI, FcγRII, FcγRIII, and FcγRIV genes in NCG-hIL15 mice, resulting in the absence of murine FcγRs. In this model, the interference from mouse FcγRs to induce ADCC was minimal. Compared to the parental NCG-hIL15 mice, NCG-hIL15-FcγR-KO mice can reconstitute comparable levels of human NK and T cells post-HSC transplantation. Both NCG-hIL15-FcγR-KO and NCG-hIL15 mice showed stable body weight changes with a long survival period. In our study, we found that rituximab could inhibit tumor growth through murine innate cells in the absence of human NK cells in NCG-hIL15 mice bearing Raji tumors, obscuring the interpretation of the results, while it had no inhibitory effect on tumors in NCG-hIL15-FcγR-KO mice bearing Raji tumors. Therefore it was suggested that the NCG-hIL15-FcγR-KO model was able to avoid false positives of ADCC drugs and was able to accurately evaluate the true drug efficacy. Furthermore, compared with the PBMC-NCG-hIL15 mice, nivolumab was able to significantly inhibit the growth of tumors in PBMC-NCG-hIL15-FcγR-KO mice bearing NCI-H1975 tumors. This demonstrated that NCG-hIL15-FcγR-KO mice may provide a good platform to study anti-tumor T cell responses in the absence of murine FcγRs. Taken together, the NCG-hIL15-FcγR-KO model is the ideal model to accurately reflect the true efficacy. We present this model as a valuable addition to the preclinical research toolkit, promising a deeper understanding of efficacy evaluation for clinical applications. Citation Format: Hongyan Sun, Jun Xing, Jianming Xu, Shiying Guo, Xiang Gao, Jun Wang. Development of a novel NCG-hIL15-FcγR-KO model for precise drug efficacy evaluation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 1296.