Targeted desialylation and cytolysis of tumour cells by fusing a sialidase to a bispecific T-cell engager

Abstract

Bispecific T-cell engagers (BiTEs) bring together tumour cells and cytotoxic T cells by binding to specific cell-surface tumour antigens and T-cell receptors, and have been clinically successful for the treatment of B-cell malignancies. Here we show that a BiTE–sialidase fusion protein enhances the susceptibility of solid tumours to BiTE-mediated cytolysis of tumour cells via targeted desialylation—that is, the removal of terminal sialic acid residues on glycans—at the BiTE-induced T-cell–tumour-cell interface. In xenograft and syngeneic mouse models of leukaemia and of melanoma and breast cancer, and compared with the parental BiTE molecules, targeted desialylation via the BiTE–sialidase fusion proteins enhanced the formation of immunological synapses, T-cell activation and T-cell-mediated tumour-cell cytolysis in the presence of the target antigen. The targeted desialylation of tumour cells may enhance the potency of therapies relying on T-cell engagers. The removal of terminal sialic acid residues on glycans at the T-cell–tumour-cell interface via a sialidase fused to a bispecific T-cell engager enhances the susceptibility of solid cancers to T-cell-mediated cytolysis.