Engineered human sialidase as a novel cancer therapeutic targeting immune-suppressive sialoglycans in tumors

Immune checkpoint blockade has revolutionized cancer therapy, but resistance in many patients highlights the need for new approaches. Sialoglycans, recognized as novel immune checkpoints, can be therapeutically targeted to enhance anti-tumor immunity. Tumor-targeted antibody-bacterial sialidase conjugates have shown antitumor activity preclinically, but immunogenicity risks limit their clinical use. To address this, we engineered a human sialidase, E-602 (eNeu2), with improved stability, developability, and a production titer of ~3 g/L, a major advance over the near-zero yield of the wild-type enzyme. E-602’s higher Km compared to bacterial sialidases enables selective desialylation of tumor and immune cells with abundant surface sialoglycans, while sparing healthy cells, achieving a favorable safety profile without a tumor-targeting moiety. E-602 alleviated sialoglycan-mediated immunosuppression and enhanced immune effector functions in human immune assays. In syngeneic mouse models, it showed single-agent anti-tumor activity and was well tolerated at doses up to 100 mg/kg in non-human primates, supporting its clinical potential.