Computational simulations of bispecific T cell engagers by a multiscale model

The use of bispecific antibodies as T cell engagers can bypass the normal T cell receptor -major histocompatibility class interaction, redirect the cytotoxic activity of T cells, and lead to highly efficient tumor cell killing. However, this immunotherapy also causes significant on -target off -tumor toxicologic effects, especially when it is used to treat solid tumors. To avoid these adverse events, it is necessary to understand the fundamental mechanisms involved in the physical process of T cell engagement. We developed a multiscale computational framework to reach this goal. The framework combines simulations on the intercellular and multicellular levels. On the intercellular level, we simulated the spatial -temporal dynamics of threebody interactions among bispecific antibodies, CD3 and tumor -associated antigens (TAAs). The derived number of intercellular bonds formed between CD3 and TAAs was further transferred to the multicellular simulations as the input parameter of adhesive density between cells. Through the simulations under various molecular and cellular conditions, we were able to gain new insights into how to adopt the most appropriate strategy to maximize the drug efficacy and avoid the off -target effect. For instance, we discovered that the low antibody -binding affinity resulted in the formation of large clusters at the cell -cell interface, which could be important to control the downstream signaling pathways. We also tested different molecular architectures of the bispecific antibody and suggested the existence of an optimal length in regulating the T cell engagement. Overall, the current multiscale simulations serve as a proof -of -concept study to help in the future design of new biological therapeutics. SIGNIFICANCE T cell engagers (TCEs) are a class of anticancer drugs that can directly kill tumor cells by bringing T cells next to them. However, current treatments using TCEs can cause serious side effects. To reduce these effects, it is necessary to understand how T cells and tumor cells interact together through the connection of TCEs. Unfortunately, this process is not well studied due to the limitations in current experimental techniques. We developed computational models on two different scales to simulate the physical process of T cell engagement. Our simulation results provide new insights into the general properties of TCEs. The new simulation methods can therefore serve as a useful tool for the design of novel antibodies for cancer immunotherapy.