A lectin-directed antibody-recruiting molecule against Tn antigen for cancer immunotherapy

The Tn antigen, an abnormally glycosylated structure on the cell surface, is a key target for cancer immunotherapy. However, the intrinsically weak immunogenicity of glycans and the resulting complex immune tolerance constitute the primary challenges in the clinical translation of Tn-targeted immunotherapies. Native human macrophage galactose lectin (MGL) exhibits a strong binding preference for Tn antigen. Here, we report a Tn-targeting, bifunctional antibody-like molecule ZZ-MGL comprised of an antibody-recruiting domain and a lectin domain. It was demonstrated that ZZ-MGL can target the Tn antigen with high avidity while potently recruiting circulating IgGs in situ. Furthermore, ZZ-MGL could effectively enhance anti-tumor immune responses, by triggering Fc-mediated effector pathways, ultimately translating into significant tumor growth inhibition in a colorectal cancer xenograft mouse model. This chimera platform can potentially be adapted to target other tumor-associated carbohydrate antigens by simply substituting with suitable lectins, highlighting its wide application in cancer immunotherapy.