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.
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Data availability
The main data supporting the results in this study are available within the paper and its Supplementary Information. Gene-expression data obtained by RNA-seq are available from the NCBI Gene Expression Omnibus, via the accession number GSE245991. The raw and analysed datasets generated during the study are available for research purposes from the corresponding author on reasonable request. Source data are provided with this paper.
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Acknowledgements
This work was supported by the NIH (to P.W. R01AI154138, to J.R.T. R01AI143884 and to D.L. R01AI130197). J.Z. is a recipient of the Cancer Research Institute/Irvington postdoctoral fellowship. We thank N. Lerner and J. R. Cappiello for their critical comments on the paper and L. Liu and Y. Fu for providing the B16-E5 cell line.
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Z.Y., R.A.L. and P.W. conceived and designed research studies. Z.Y. and P.W. wrote the paper and analysed the data and prepared the figures. J.Z. and J.R.T. performed analysis on the transcriptome sequencing results. J.H.C. and D.L. performed immunological synapse formation and confocal imaging for BiTE–sialidase fusion protein and analysed the data. Z.Y., Y.H., G.G., C.W., Y.W., K.Q. and Y.S. performed all experiments described in the paper. All authors reviewed and edited the paper. P.W. finalized the paper.
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P.W., Z.Y. and K.Q. were listed as inventors of Sialidase Fusion Molecules and Use, a US patent application no. 63/338,134 filed in May 2022. The other authors declare no competing interests.
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Yang, Z., Hou, Y., Grande, G. et al. Targeted desialylation and cytolysis of tumour cells by fusing a sialidase to a bispecific T-cell engager. Nat. Biomed. Eng (2024). https://doi.org/10.1038/s41551-024-01202-w
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DOI: https://doi.org/10.1038/s41551-024-01202-w
