IO Summit #2: Novel TNFR2 humanized mouse model for in vivo validation of human TNFR2 antibody targeting hTNF /hTNFR2 signaling pathways

IO Summit #2: Novel TNFR2 humanized mouse model for in vivo validation of human TNFR2 antibody targeting hTNF /hTNFR2 signaling pathways

Author: Yanan Guo, Yanan Li, Xiaofei Zhou, Youhong Su, Qingcong Lin

Abstract:

In recent years, immune checkpoint inhibitors (ICIs) have revolutionized cancer treatment. Tumor necrosis factor receptor 2 (TNFR2), also known as tumor necrosis factor receptor superfamily member 1B (TNFRSF1B), is a transmembrane receptor that plays an essential role in immune modulation and tissue regeneration (Chen et al., 2008). TNFR2 is mainly expressed on the surface of immune cells in particular CD8 and CD4 T cells, including regulatory T cells in inflammatory and tumor-microenvironment (Wu et al, 2013, Azizi et al, 2018). TNFR2 promotes the proliferation of Tregs through nuclear factor kappa B (NF-κB) signaling (Rodriguez et al., 2011). TNFR2 also provided early costimulatory signals during CD4 and CD8 T cell activation (Kim et al, 2006). Both antagonistic and agonistic anti-TNFR2 antibodies have been developed to modify T cell functions and shown to inhibit tumor growth (Torrey et al, 2019, Tam et al, 2019).  Therefore, TNFR2 has become an enthusiastically pursuit therapeutic target for both immuno-oncology and autoimmune disease field.

To investigate the role of TNFR2, Biocytogen generated TNFR2 humanized mouse for both in vitro function validation of signaling pathway and in vivo efficacy evaluation of TNFR2 antibodies. In this model, the exons 2~6 of mouse Tnfrsf1b gene which encode the extracellular domain were replaced by human TNFRSF1B counterparts. Human extracellular domain of TNFR2 was detectable on the Tregs in spleen and the anti-human TNFR2 antibodies associated well to the splenocytes of the TNFR2 humanized mice. Basal leukocyte subpopulations of TNFR2 humanized mice were comparable to those of wild-type mice, including T/B cells, NK cells, DC, granulocytes and monocytes/macrophages. Anti-human TNFR2 antibodies bound with CD3+ T cells and inhibited tumor growth in TNFR2 humanized mice. Taken together, TNFR2 humanized mouse is a valuable tool for in vivo efficacy assessment of therapeutics that target human TNFR2.

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