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.

Bringing enzymes to the proximity party

“…5a). 23 There have been multiple approaches to target sialidases to the tumor microenvironment, including antibody-enzyme conjugates, 5,68 bispecific T-cell engagers (BiTEs), 69,70 and chimeric antigen receptor (CAR) T-cells. 71…”

“…In all three models, the BiTE-sialidase reduced tumor burden as compared to vehicle control and the BiTE alone. 69 In an orthogonal approach, Durgin et al engineered CAR T-cells to secrete sialidase when activated by tumor cells. In multiple mouse tumor models, sialidase secreting CAR T-cells extended mouse survival and reduced tumor burden as compared to non-sialidase secreting CAR T-cells.…”

“…5a). 23 There have been multiple approaches to target sialidases to the tumor microenvironment, including antibody-enzyme conjugates, 5,68 bispecific T-cell engagers (BiTEs), 69,70 and chimeric antigen receptor (CAR) T-cells. 71 Antibody-sialidase conjugates were designed to cleave the immune inhibitory sialic acids specifically from cancer cells, thus promoting immune cell killing of the desialylated cancer cells.…”

“…Yang et al and Szijj et al both demonstrated that conjugation of sialidases to BiTEs enhanced T-cell killing of the target cancer cells as compared to unconjugated BiTEs. 69,70 Yang et al further evaluated the efficiency of BiTE-sialidases in controlling tumor burden in two cancer xenograft mouse models in immune deficient mice injected with human peripheral blood mononuclear cells and one syngeneic mouse model of melanoma. In all three models, the BiTEsialidase reduced tumor burden as compared to vehicle control and the BiTE alone.…”