Abstract 2584: Development of an Fc gamma receptor fully-humanized mouse model to support the accurate preclinical study of therapeutic antibodies

Abstract The Fc gamma receptor (FcγR), a member of the immunoglobulin superfamily, binds the IgG Fc segment of antibodies and is mainly expressed on the surface of immune cell. The FcγR binds to the Fc region of an antibody that is attached to target cells, transmitting an activation or inhibition signal to the FcγR expressing cells, resulting in various biological responses and functions. Many therapeutic antibodies are developed based on the engineering of the Fc region to fine-tune the FcγR mediated effects. There are four subtypes of mouse FcγRs, including Fcgr1, Fcgr2b, Fcgr3, and Fcgr4. In contrast, human FcγRs consist of at least seven members, including FCGR1A, FCGR1B, FCGR2A, FCGR2B, FCGR2C, FCGR3A, and FCGR3B. Additionally, the expression pattern of even the orthologous FcγR genes varies between humans and mice. e.g., the distribution of mouse FCGR3 and FCGR2. Therefore, animals harboring the murine FcγRs are not ideal models for the accurate preclinical evaluation of human therapeutic antibodies. To address this problem, we established an FcγRs fully humanized mouse model by injecting an engineered human bacterial artificial chromosome construct carrying all seven human FcγR genes into mouse zygotes. The transgene carriers were mated with another strain in which all mouse FcγR genes were knocked out to establish the colony. Unlike the endogenous mouse FcγR genes expression profiles, the transgenic human FcγR genes regulated under the control of the human control elements retain the human expression pattern. For example, the transgenic human FCGR3A was observed on mouse NK cells and macrophages, whereas the FCGR3B was detected on mouse neutrophils only, which were consistent with their expression patterns in humans. Antibody-dependent cellular cytotoxicity (ADCC) experiment indicated that a human therapeutic antibody could direct NK cells derived from the FcγRs fully-humanized mice to kill target tumor cells. Moreover, a significant anti-tumor effect could also be achieved by an ADCC based human antibody in tumor-bearing FcγRs humanized mice. Taken together, the FcγR gene fully-humanized model established in this study demonstrates a human FcγR expression pattern and functionality, thus providing a valuable tool for accurate preclinical evaluation of human therapeutic antibodies. Citation Format: Mingkun Zhang, Cunxiang Ju, Ying Li, Yunlong Jiang, Weiwei Yu, Shuai Li, Hongyan Sun, Zhiying Li, Jing Zhao, Xiang Gao. Development of an Fc gamma receptor fully-humanized mouse model to support the accurate preclinical study of therapeutic antibodies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2584.