Abstract 7256: Development of a human immune system reconstituted mouse model without the function of FcγRs expressed on mouse innate immune cells
Authors: Jay Zhang, Yanhui Nie, Dexuan Huang, Xiao Liu, Qingqing Xu, Qiang Liu, Shuangshi Liu, Xiaofei Zhou
Journal: Cancer Research (2025)

Abstract Severe immunodeficient mice have been widely used in xenotransplantation research and for validating various immunotherapy methods. We utilized gene editing techniques to knock out the IL2rg gene in NOD scid mice, resulting in a severe immunodeficient mouse model that lacks mature T, B and NK cells, but retains most of the myeloid cells, which we named B-NDG mice (#110586). Human immune cells can be successfully reconstituted in B-NDG mice (#110586). However, due to the lack of effective support from human cytokines, only human T cells can be reconstituted in B-NDG mice (#110586). IL15 is a key cytokine in the development and maturation of NK cells and also promotes the survival of memory CD8+ T cells. When validating the in vivo efficacy of therapeutic IgG antibodies using a mouse model with a reconstituted human immune system, the antibodies may not only bind to the reconstituted human immune cells to exert pharmacodynamic activity but also bind to various Fcγ receptors expressed on mouse innate immune cells, such as macrophages and neutrophils. This interaction may lead to antibody neutralization or antibody-dependent cellular phagocytosis (ADCP), affecting the accuracy of the efficacy validation.Biocytogen developed B-NDG hIL15, FcγR KO mice (#112653) in which the mouse IL15 gene was replaced by human IL15 gene. Then the mouse genes Fcgr1, Fcgr2b, Fcgr3 and Fcgr4 were knocked out. Mouse FcγRI, FcγRIIb, FcγRIII and FcγRIV were not detectable in B-NDG hIL15, FcγR KO mice (#112653). Human IL15 was detectable in homozygous B-NDG hIL15, FcγR KO mice (#112653). The concentration of human IL15 in the serum was 112 pg/mL, similar to that in B-NDG hIL15 mice (#110600). The frequency of mouse granulocytes, monocytes, macrophages and DCs in the blood and spleen of B-NDG hIL15, FcγR KO mice (#112653) are similar to that in B-NDG hIL15 mice (#110600). Binding analysis of rituximab analog (in-house) showed that rituximab-bound cells were not detectable in B-NDG hIL15, FcγR KO mice (#112653). B-luc Daudi cells (#310677) were intravenously injected into B-NDG hIL-15, FcγR KO mice (#112653). After 3 days, mice were grouped when the intensity of the imaging signal reached approximately 1.2×106 p/sec, at which time human NK cells expanded in vitro were engrafted into the mice and the mice were treated with anti-human CD20 antibody rituximab. The results showed that rituximab was efficacious in controlling B-luc Daudi growth in human NK cells engrafted B-NDG hIL15, FcγR KO mice (#112653). Citation Format: Jay Zhang, Yanhui Nie, Dexuan Huang, Xiao Liu, Qingqing Xu, Qiang Liu, Shuangshi Liu, Xiaofei Zhou. Development of a human immune system reconstituted mouse model without the function of FcγRs expressed on mouse innate immune cells [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 7256.