Host: The Japanese Society of Toxicology
Name : The 49th Annual Meeting of the Japanese Society of Toxicology
Date : June 30, 2022 - July 02, 2022
CD3 bispecific antibodies (CD3BiAbs) show promising therapeutic potential for cancer, but they concurrently cause difficult-to-manage cytokine release syndrome (CRS) in clinical contexts. CRS frequently occurs after the first dose, and the severity of CRS is known to decrease with each subsequent dose. Although repeated administration of CD3BiAbs has been shown to reduce CRS, the mechanism behind this effect remains unclear. The purpose of this study is to elucidate the mechanism underlying the reduced cytokine induction after repeated treatment with ERY974, a CD3BiAb against GPC3.
In this study, human peripheral blood mononuclear cells (PBMCs) and GPC3 expressing cells were treated with ERY974 or negative control. PBMCs were then cultured for one week before being treated again with ERT974 or negative control. We examined cytokine concentrations, mRNA expression of cytokines, CD3 expression, CD3-mediated signal transduction, T-cell activation markers, cytotoxic activity, and T-cell chromatin state.
The repeated ERY974 treatment showed lower cytokine levels (mRNA and protein) than the first treatment, and ATAC-seq analysis revealed that the priming treatment changed chromatin accessibility in T cells. CD3 expression, CD3-mediated signal transduction, T cell activation markers, and cytotoxic activity were similar between ERY974 priming treatment and negative control. These results suggest that epigenetic changes to T cells after the priming treatment play an important role in the mitigation of cytokine release after the second ERY974 treatment.
