MGL‐Based Drug Conjugate: A Novel Glycan‐Targeting Strategy for Potential Precision Cancer Therapy

Cancer remains a major cause of mortality, especially in advanced stages where current therapies are less effective. Antibody‐drug conjugates offer targeted treatment, but their efficacy is limited by on‐target/off‐tumor toxicity since most protein receptors are also present in healthy tissues. Abnormal glycosylation is a hallmark of cancer, with Thomsen‐nouveau (Tn) and Sialyl‐Tn (STn) antigens driving tumor progression. The human macrophage galactose‐type lectin (MGL) binds αGalNAc within these antigens through its carbohydrate recognition domain (CRD), distinguishing Tn/STn‐expressing cancer cells from healthy ones. This specificity positions the MGL‐CRD as a promising vehicle for safer drug delivery. Herein, an MGL‐based drug conjugate was engineered by introducing an exposed cysteine (mMGL) to allow chemical linkage to monomethyl auristatin E derivative (vcMMAE). The resulting conjugate (mMGL‐vcMMAE) is stable and preserves the thermal stability, the αGalNAc binding profile and, the affinity of the native MGL‐CRD, including its selectivity toward glycoengineered cancer models expressing Tn/STn antigens. Tissue validation confirmed selective binding to colorectal cancer (CRC) tissues. Metabolism and apoptosis analysis demonstrated that mMGL‐vcMMAE impacts glycoengineered cancer cells expressing Tn/STn O ‐glycans compared to free vcMMAE, improving targeting precision. This strategy offers a novel glycan‐guided approach to potentially minimize off‐target effects, advancing in safer and more effective cancer therapies.