AACR 2020: Immune biomarker profiling and safety evaluation response to 4-1BB antibody (Urelumab) in humanized 4-1BB mice
4-1BB (CD137) belongs to the TNFR superfamily and is expressed by activated CD4 helper T cells, B cells, natural killer cells, natural killer T cells, dendritic cells and Treg cells. 4-1BB is a potential therapeutic target as it enhances tumor rejection by upregulating T cells following activation and its engagement increases T cell proliferation and pro-inflammatory cytokine production. However, the liver toxicity associated with over immune activation has obstructed the clinical development of 4-1BB targeting therapies. To address the issue, Biocytogen has developed humanized B-h4-1BB mice as an efficient platform of both in vivo MOA and safety studies of 4-1BB antibody.
In B-h4-1BB mice, murine colon cancer MC38 cells were subcutaneously implanted. Biomarkers, such as, mCD45, mCD3, mCD4, mCD8, mNK, mFoxp3, mCD11b, and etc., were profiled after the treatment with an 4-1BB antibody (Urelumab). FACS, IHC, and IF data showed that Urelumab have increased the ratio of CD8+ T cell, but on the other hand decreased Treg cell, the PD-1 and Tim3 (T cell exhausted marker) upon treatment. Toxicity have also been with the treatment of Urelumab using this model. The blood chemistry assays showed that the high dose Urelumab had toxicity effects compared with the control group and WT C57BL/6 mice. Based on these findings, we conclude that the B-h4-1BB humanized mouse model is a powerful platform for both MOA (biomarker) discovery and safety evaluation of 4-1BB antibody.