Enhancing the anti-tumor efficacy of Bispecific T cell engagers via cell surface glycocalyx editing

Bispecific T-cell engager (BiTE)-based cancer therapies that activate the cytotoxic T cells of a patient’s own immune system have gained momentum with the recent FDA approval of Blinatumomab for treating B cell malignancies. However, this approach has had limited success in targeting solid tumors. Here, we report the development of BiTE-sialidase fusion proteins that enhance tumor cell susceptibility to BiTE-mediated cytolysis by T cells via targeted desialylation at the BiTE-induced T cell-tumor cell interface. Targeted desialylation results in better immunological synapse formation, T-cell activation and effector function. As a result, BiTE-sialidase fusion proteins show remarkably increased efficacy in inducing T-cell-dependent tumor cell cytolysis in response to target antigens compared to the parent BiTE molecules alone. This enhanced function is seen bothin vitroand inin vivoxenograft and syngeneic solid tumor mouse models. Our findings highlight BiTE-sialidase fusion proteins as promising candidates for the development of next-generation bispecific T-cell engaging molecules for cancer immunotherapy.