On March 26, 2024, the team of Peng Wu from the Scripps Research Institute published an article entitled "Targeted desialylation and cytolysis of tumour cells by fusing a sialidase to a bispecific T-cell engager" in nature biomedical engineering.

Brief

• The association between sialic acid removal on the surface of tumor cells and the efficacy of bispecific T cell engagers (BiTEs)

In this study, the authors demonstrated that targeted removal of Sialic Acid on the surface of tumor cells can enhance the therapeutic effect of BiTEs.

• The relationship between enhanced cytotoxicity induced by sialic acid removal and sialic acid-binding immunoglobulin-like lectin (Siglec) signaling

The study found that within a short period of 24 hours, the enhanced Cytotoxicity induced by sialic acid removal on the surface of tumor cells was not related to the Siglec signaling pathway.

• Treatment strategies and clinical significance

In preclinical models of several solid tumors, it was found that BiTE-sialidase fusion proteins showed superior efficacy in controlling tumor proliferation and prolonging in vivo survival compared with parent BiTE molecules. In the future, they can be used in combination with other anticancer drugs to improve anti-tumor efficacy.

Fig. 1 Removal of sialic acid enhances BiTE-induced T cell cytotoxicity. (Yang, et al., 2024)

Background

• BiTE development and status

BiTEs can recruit endogenous CD8⁺ and CD4⁺ T cells and can eradicate tumor cells in a manner independent of the major histocompatibility complex. A BiTE molecule consists of two single-chain variable fragments, one targeting Tumor-associated Antigens and the other binding to CD3 on T cells.

• Immune escape of tumor cells

During the formation of tumor cells, the ends of surface protein glycans abnormally express sialic acid glycans as a physical barrier to prevent T cells from infiltrating tumor cells. These terminal sialic acid upregulated glycoforms can inhibit the activation of immune cells.

• Immunosuppression involving sialic acid

Sialic acid weakens immune cell activation and effector function by recruiting immune checkpoints on most leukocytes to immune synapses and transmitting inhibitory signals.

Sialic acid expressed on antigen-presenting cells interacts with CD28 on T cells, causing competition with CD80 on antigen-presenting cells, thereby inhibiting the co-stimulation required for T cell activation and survival.

Main Conclusions

• Efficacy of BiTE-sialidase fusion protein

The study demonstrated that the therapeutic effect of Sialidase on solid tumors can be enhanced by fusing it to BiTEs. This fusion protein enhanced T cell-mediated tumor cell lysis by targeted desialylation.

• Effect of targeted desialylation

The study confirmed that targeted desialylation of BiTE-sialidase fusion protein can enhance T cell-mediated tumor cell lysis in the short term, and this effect is independent of the inhibitory Siglec signaling pathway.

• Universality of efficacy

BiTE-sialidase fusion protein is not only effective against HER2-positive breast cancer cells, but also applied to tumor models such as leukemia and melanoma in this article.

Prospects

• Innovative therapeutic strategies

The idea of combining Enzymes (sialidase) with BiTEs provides a new direction for the development of new cancer immunotherapy strategies, especially for solid tumors where traditional BiTEs have limited efficacy.

• In-depth preclinical research

The study provides in-depth research from molecular mechanisms to preclinical models, laying the foundation for subsequent Siglec research.

• Applicability to Multiple Tumor Types

The study is not limited to one tumor type, but demonstrates potential applications in multiple tumor types (such as breast cancer, melanoma, and leukemia), which increases the breadth of its clinical applications.

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Reference

1. Yang, Z., et al. (2024). Targeted desialylation and cytolysis of tumour cells by fusing a sialidase to a bispecific T-cell engager. Nature biomedical engineering, 8(5), 499-512. DOI: 1038/s41551-024-01202-w.