Abstract 5201: TNFR2 humanized mice: an ideal model for studying anti-TNFR2 antibodies

Abstract

Abstract Tumor necrosis factor (TNF) receptor 2 (TNFR2) is mainly expressed on the surface of regulatory T cells (Tregs) and CD8+ T cells, which can stimulate the proliferation of these cells through NF-kB activation. TNFR2 is also highly expressed on the surface of various human tumors, such as colorectal cancer and lung cancer. Therefore, a TNFR2 antagonist blocking the binding of TNFR2 to its ligand that targets TNFR2+ tumor-infiltrating Tregs can directly enhance the killing ability of effector T cells (Teff) against TNFR2-expressing tumors. Many pharmaceutical and biotech companies have lined up TNFR2-targeting drugs, and most TNFR2 antibodies related research is in the early preclinical/clinical stage. We established a humanized TNFR2 (hTNFR2) genetically engineered mouse model on the BALB/c background, in which the extracellular domain of the mouse TNFR2 was replaced with its human counterpart, and the murine transmembrane and cytoplasmic domain kept intact. The hTNFR2 chimeric protein is mainly expressed on Teff and Treg cells in BALB/c-hTNFR2 and BALB/c-hPD1/hPDL1/hTNFR2 mice, which is similar to mouse TNFR2 protein expression profiles in wild-type mice. Our data showed that anti-TNFR2 antibodies could significantly inhibit tumor growth in BALB/c-hTNFR2 mice bearing CT26 tumor cells or BALB/c-hTNFR2 mice bearing CT26-hTNFR2 tumors. Furthermore, within the tumor-infiltrating lymphocytes, there was a reduction in Tregs cells and an increase in cytotoxic CD8 T cells, which accurately mimics the mechanism of action of anti-TNFR2 antibodies. In conclusion, BALB/c-hTNFR2 and BALB/c-hPD1/hPDL1/hTNFR2 mice are ideal models for studying the efficacy and pharmacodynamics of anti-TNFR2 antibodies as a single agent or in combination with anti-PD-1/PD-L1 therapies. Citation Format: Huiyi Wang, Ying Li, Mingkun Zhang, Xu Su, Santi Suryani Chen, Zhiying Li, Mark Wade Moore, Jing Zhao, Xiang Gao, Cunxiang Ju. TNFR2 humanized mice: an ideal model for studying anti-TNFR2 antibodies. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5201.