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. We have reported 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 both in vitro and in in vivo xenograft 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. This transcriptomic dataset documents the effect of BiTE-sialidase vs uncojugated BiTE on T cells including the upregulation of effector associated genes. Overall design: 1.2 million hPBMCs and 0.1 million MDA-MB-231 cells were incubated together under the treatment of either 4 nM 4D5 BiTE or 4 nM 4D5 BiTE-sialidase (three biological replicates for each condition). After 48 hours of incubation, the mixture was stained with DAPI and anti-CD3 antibody to sort CD3+ T cells by flow cytometry and subjected to RNA isolation and library preparation for bulk RNA-sequencing.