Cell-surface terminal galactose–containing glycans (Terminal Gal glycans)

Cell-surface terminal galactose–containing glycans are carbohydrate structures found on the exterior of cell membranes, characterized by a galactose residue at the non-reducing end of the glycan chain. These glycans play critical roles in biological processes such as cell-cell recognition, immune system modulation, and the regulation of glycoprotein half-life via the asialoglycoprotein receptor (ASGPR) in the liver (Ashwell and Harford, 1982; Stockert, 1995). In healthy tissues, terminal galactose is frequently masked by terminal sialic acid; however, in many cancers, aberrant glycosylation leads to the exposure of these residues, such as the Thomsen-Friedenreich (TF) antigen, which serves as a prominent tumor-associated carbohydrate antigen (Kim and Varki, 1997; Picard and Feizi, 1983). These glycans are targeted by various therapeutic and diagnostic agents, including plant-derived lectins like mistletoe lectin and monoclonal antibodies such as JAA-F11, which are designed to recognize specific terminal galactose motifs on malignant cells (Park et al., 2001; Heimburg-Molinaro et al., 2011). Furthermore, the interaction between terminal galactose and endogenous galectins is a major focus in the development of anti-fibrotic and anti-cancer drugs, as these interactions facilitate immune evasion and metastasis (Hernandez and Baum, 2002). In the context of biotherapeutics, the degree of terminal galactosylation on the Fc region of antibodies is a critical quality attribute, as it significantly influences complement-dependent cytotoxicity (CDC) and overall therapeutic efficacy (Hodoniczky et al., 2005; Zhang et al., 2020).

Other names

Terminal galactose residuesGalactose-terminated glycansAsialoglycansThomsen-Friedenreich antigenTF antigenT-antigenAlpha-GalCD176Gal-beta-1,3-GalNAcGal-alpha-1,3-Gal

Drugs targeting these glycans typically function by binding to the terminal galactose residue to induce apoptosis, trigger antibody-dependent cellular cytotoxicity (ADCC), or block pathogen attachment. In the case of therapeutic antibodies, terminal galactosylation of the Fc region enhances complement-dependent cytotoxicity (CDC) by increasing C1q binding. Additionally, these glycans serve as recognition signals for the asialoglycoprotein receptor (ASGPR), mediating the clearance of desialylated proteins from the circulation.