Yang et al. investigated targeted removal of cell surface sialyoglycans at the T cell–tumor interface to improve the efficacy of bispecific T cell engagers (BiTEs). In xenograft and syngeneic mouse models of solid (melanoma and breast cancer) and hematological (leukemia) tumors, a BiTE–sialidase fusion protein enhanced BiTE-induced antigen-specific T cell cytotoxicity and activation, and promoted stronger immunological synapse formation compared to unmodified BiTEs. BiTE-sialidase treatment delayed tumor growth significantly and resulted in a more permissive TME with increased CD8+ T cells, effector CD3+ T cells, and NK cells, and fewer myeloid cells.
Contributed by Katherine Turner
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.
Author Info: (1) Department of Molecular and Cellular Biology, The Scripps Research Institute, La Jolla, CA, USA. Department of Chemistry, The Scripps Research Institute, La Jolla, CA, USA. (2)
Author Info: (1) Department of Molecular and Cellular Biology, The Scripps Research Institute, La Jolla, CA, USA. Department of Chemistry, The Scripps Research Institute, La Jolla, CA, USA. (2) Department of Molecular and Cellular Biology, The Scripps Research Institute, La Jolla, CA, USA. (3) Department of Chemistry, The Scripps Research Institute, La Jolla, CA, USA. (4) Department of Pathology, Immunology and Laboratory Medicine, Rutgers University-New Jersey Medical School, Newark, NJ, USA. (5) Department of Molecular and Cellular Biology, The Scripps Research Institute, La Jolla, CA, USA. (6) Department of Molecular and Cellular Biology, The Scripps Research Institute, La Jolla, CA, USA. (7) Department of Immunology and Microbiology, The Scripps Research Institute, La Jolla, CA, USA. (8) Department of Chemistry, The Scripps Research Institute, La Jolla, CA, USA. (9) Department of Molecular and Cellular Biology, The Scripps Research Institute, La Jolla, CA, USA. (10) Department of Pathology, Immunology and Laboratory Medicine, Rutgers University-New Jersey Medical School, Newark, NJ, USA. (11) Department of Immunology and Microbiology, The Scripps Research Institute, La Jolla, CA, USA. (12) Department of Chemistry, The Scripps Research Institute, La Jolla, CA, USA. (13) Department of Molecular and Cellular Biology, The Scripps Research Institute, La Jolla, CA, USA. pengwu@scripps.edu.
