Mucin-domain glycoproteins (MUCs)

Mucin-domain glycoproteins, such as MUC1 and MUC4, are heavily O-glycosylated proteins that are frequently overexpressed on the surface of HER2-positive cancer cells. These molecules contribute to tumor progression by forming a dense, rigid glycocalyx that provides physical protection to the tumor cell. In HER2-positive cancers, high levels of mucins like MUC4 can sterically mask the HER2 receptor, preventing the binding of therapeutic antibodies such as Trastuzumab and leading to drug resistance (Price-Schiavi et al., 2002, J Biol Chem). Additionally, the terminal sialic acids on these mucins act as an 'immune checkpoint' by binding to Siglec receptors (e.g., Siglec-7 and Siglec-9) on natural killer cells and myeloid cells, thereby suppressing the anti-tumor immune response (Gray et al., 2020, Nat Chem Biol). Therapeutic strategies targeting these glycoproteins often involve the use of sialidase enzymes, either as standalone agents (like E-602) or conjugated to HER2-targeting antibodies (Antibody-Sialidase Conjugates). By stripping the sialic acids from the mucin domains, these therapies 'unmask' the cancer cell, making the HER2 epitope more accessible to standard-of-care antibodies and eliminating the inhibitory signals sent to immune cells. This dual action enhances antibody-dependent cellular cytotoxicity (ADCC) and promotes a more robust immune-mediated clearance of the tumor (Palleon Pharmaceuticals, 2024). This approach is particularly relevant for patients who have developed resistance to traditional HER2-targeted therapies due to mucin-mediated shielding.

Other names

Cancer-associated mucinsSialoglycansMUC1MUC4MUC16Cell surface mucinsO-linked glycoproteins

Enzymatic desialylation to remove immunosuppressive sialic acids and unmask HER2 epitopes; inhibition of Siglec-mediated immune suppression; reduction of steric hindrance to enhance antibody-dependent cellular cytotoxicity (ADCC).