Development of a Novel NCG-hIL15-FcγR-KO Model for Precise Drug Efficacy Evaluation

Humanized mice, particularly immunodeficient mice reconstituted with human immune systems via 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 residual murine cells from the myeloid compartment can interfere with the monoclonal antibody (mAb)-based drug clearance and efficacy. To 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. 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.