Novel Platform Design for Screening of Optimal Immune Receptors for Antibody Circuits

Abstract

In recent years, cancer immunotherapy has acquired a central role in the combat of cancer, an example being the use of T-cell engaging bispecific antibodies which offer a relatively simple approach to engaging patients’ T cells to target cancer cells in an HLA-independent manner. Unfortunately, trials of bispecific T-cell engaging antibodies (BiTE) have shown either severe adverse events or death that remains a major barrier to broad implementation. T cell engaging antibody circuits (TEACs) is a novel immune cell engaging platform that allows for exquisite targeting of cancer cells with minimal targeting of healthy cells. Beyond T-cells, our interest is to use this platform to engage the innate compartment. For the effective design of TEAC molecules that can redirect innate immune responses, we developed a platform that allows for dynamic screening of potential immunoreceptor targets called adaptor bispecific antibody circuits (ABA-C). It accomplishes this by using an adaptor bispecific antibody (ABA) to differentially recognize and bridge antibodies against target antigens on a cancer cell and a target immunoreceptor, emulating the synapse created by TEACs. As a model to investigate the potential of ABA-C in activating immune cells, we chose prostate adenocarcinoma as studies have linked innate immunity with its progression. Data shows that ABA-C can activate T-cells in vitro at comparable levels with TEACs in a highly specific manner at micromolar concentrations of target antigen antibody, independent of target antigen identity or cell line used. Further studies will look to use ABA-C to screen optimal activating immunoreceptors on macrophages, as their inflammatory subsets have been associated to better prognoses on prostate cancer patients.