Targeting Sialylation Enhances the Therapeutic Efficacy of the Nectin-4–Targeted Antibody–Drug Conjugate Enfortumab Vedotin in Bladder Cancer

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More than half of patients with advanced or metastatic bladder cancer are ineligible for cisplatin chemotherapy or have poor response to cisplatin. Recently, the combination therapy of enfortumab vedotin (EV), a Nectin-4-targeted antibody-drug conjugate (ADC), with the anti-PD-1 antibody pembrolizumab (EV + pembrolizumab) has shown high and durable response rates, as well as survival benefits, for these patients with bladder cancer. Identifying factors that affect the response to single-agent EV or EV + pembrolizumab therapy could help to further improve response rates. In this study, we showed that Nectin-4 expression is negatively correlated with sialylation and complex type N-glycans levels and positively correlated with high-mannose type N-glycans levels in bladder cancer. Pharmacologic inhibition of sialylation sensitized bladder cancer to EV monotherapy and its combination with immunotherapy both in vitro and in vivo. Mechanistically, α-2,6-sialylation mediated the downregulation of Nectin-4. Furthermore, the removal of sialylation increased the endocytosis of EV by bladder cancer cells and enhanced EV-mediated immunogenic cell death. Collectively, these findings suggest that sialylation is a promising therapeutic target to improve EV sensitivity and provide a rational basis for clinical application of sialylation inhibitors in bladder cancer. SIGNIFICANCE: Suppressed enfortumab vedotin endocytosis and elevated degradation of its target Nectin-4 is mediated by sialylation, which can be targeted to improve the therapeutic efficacy of the antibody-drug conjugate in bladder cancer.

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