| Abstract: | Targeted T-cell redirection is a promising field in cancer immunotherapy. T-cell bispecific antibodies (TCB) are novel antibody
constructs capable of binding simultaneously to T cells and tumor
cells, allowing cross-linking and the formation of immunologic
synapses. This in turn results in T-cell activation, expansion, and
tumor killing. TCB activity depends on system-related properties
such as tumor target antigen expression as well as antibody properties such as binding affinities to target and T cells. Here, we
developed a systems model integrating in vitro data to elucidate
further the mechanism of action and to quantify the cytotoxic effects
as the relationship between targeted antigen expression and corresponding TCB activity. In the proposed model, we capture relevant
processes, linking immune synapse formation to T-cell activation,
expansion, and tumor killing for TCBs in vitro to differentiate the
effect between tumor cells expressing high or low levels of the
tumor antigen. We used cibisatamab, a TCB binding to carcinoembryonic antigen (CEA), to target different tumor cell lines
with high and low CEA expression in vitro. We developed a
model to capture and predict our observations, as a learn-andconfirm cycle. Although full tumor killing and substantial T-cell
activation was observed in high expressing tumor cells, the model
correctly predicted partial tumor killing and minimal T-cell
activation in low expressing tumor cells when exposed to cibisatamab. Furthermore, the model successfully predicted cytotoxicity across a wide range of tumor cell lines, spanning from very
low to high CEA expression. |
