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Updated: Dec 11, 2025
Author Spotlight: Dendritic Cells Maturation Using Sialidases-Based Enzymatic Treatment of the Cell Surface
Published on: October 20, 2023
Targeted glycan degradation potentiates the anticancer immune response in vivo
Melissa A Gray1, Michal A Stanczak2,3, Natália R Mantuano2,3
1Department of Chemistry, Stanford University, Stanford, CA, USA.
Abstract:
Currently approved immune checkpoint inhibitor therapies targeting the PD-1 and CTLA-4 receptor pathways are powerful treatment options for certain cancers; however, most patients across cancer types still fail to respond. Consequently, there is interest in discovering and blocking alternative pathways that mediate immune suppression. One such mechanism is an upregulation of sialoglycans in malignancy, which has been recently shown to inhibit immune cell activation through multiple mechanisms and therefore represents a targetable glycoimmune checkpoint. Since these glycans are not canonically druggable, we designed an αHER2 antibody-sialidase conjugate that potently and selectively strips diverse sialoglycans from breast cancer cells. In syngeneic breast cancer models, desialylation enhanced immune cell infiltration and activation and prolonged the survival of mice, an effect that was dependent on expression of the Siglec-E checkpoint receptor found on tumor-infiltrating myeloid cells. Thus, antibody-sialidase conjugates represent a promising modality for glycoimmune checkpoint therapy.
Insights
Researchers developed a novel antibody-sialidase conjugate to target sialoglycans, a newly identified glycoimmune checkpoint. This approach enhances anti-tumor immunity and improves survival in breast cancer models.
Area of Science:
- Oncology
- Immunology
- Glycobiology
Background:
- Approved immune checkpoint inhibitors (e.g., PD-1, CTLA-4) show limited efficacy in many cancer patients.
- Sialoglycans on cancer cells can suppress immune responses, representing a potential glycoimmune checkpoint.
- Current methods are insufficient for targeting these sialoglycans directly.
Purpose of the Study:
- To investigate sialoglycans as a targetable glycoimmune checkpoint.
- To develop a novel therapeutic strategy for overcoming resistance to current immunotherapies.
- To evaluate the efficacy of an antibody-sialidase conjugate in preclinical cancer models.
Main Methods:
- Design and synthesis of an alpha-HER2 antibody conjugated with a sialidase enzyme.
- Treatment of syngeneic breast cancer models with the antibody-sialidase conjugate.
- Assessment of immune cell infiltration, activation, and overall survival.
- Analysis of the role of Siglec-E receptor in mediating the therapeutic effect.
Main Results:
- The antibody-sialidase conjugate effectively removed sialoglycans from breast cancer cells.
- Desialylation led to increased immune cell infiltration and activation within tumors.
- Therapeutic intervention significantly prolonged mouse survival.
- The observed survival benefit was dependent on the Siglec-E receptor expressed on myeloid cells.
Conclusions:
- Antibody-sialidase conjugates are a promising new therapeutic modality for targeting glycoimmune checkpoints.
- This approach can enhance anti-tumor immunity and overcome resistance to existing immunotherapies.
- Targeting sialoglycans offers a novel strategy for cancer treatment.
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