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

Abstract

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 selective desialylation at the T cell-tumor cell interface that results in better immunological synapse formation. We show that a BiTE-sialidase fusion protein targeting human epidermal growth factor receptor 2 (HER2) exhibits remarkably increased efficacy in terms of killing HER2 positive tumor cells when compared to the BiTE alone. This enhanced function is seen both in vitro and in an in vivo xenograft solid tumor model. We feel that BiTE-sialidase fusion proteins have great potential as candidates for the development of next generation bispecific T-cell engaging molecules for cancer immunotherapy.