Computational simulations of Bispecific T-Cell Engagers by a Multiscale Model

Biophys J. 2023 Dec 14:S0006-3495(23)04150-4. doi: 10.1016/j.bpj.2023.12.012. Online ahead of print.ABSTRACTThe use of bispecific antibodies as T cell engagers can bypass the normal TCR-MHC 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. In order 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 three-body interactions among bispecific antibodies, CD3 and TAA. The derived number of intercellular bonds formed between CD3 and TAA was further transferred into 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 ...
Source: Biophysical Journal - Category: Physics Authors: Source Type: research