Figure 1.

Schematic representation of the anti-GRP78 IgG molecular structure and its associated N-glycan structures identified in cancer patients. It consists of two interconnected heavy (H) and two light chains (L) with two domains that infer different properties, the fragment antigen-binding (Fab) and fragment crystallizable (Fc) domains. The Fab domain is responsible for recognizing and binding the antigen. The Fc domain contains two glycans attached to Asn²⁹⁷ in conserved regions of the C_H2 domain. The Fc domain binds to the FcR on natural killers and other inflammatory cells. In cancer, the Fab region is asymmetrically glycosylated with one additional N-glycan that converts the anti-GRP78 IgG into a univalent molecule that binds the antigen with a decreased affinity, preventing it from triggering some IgG-linked functions of the immune response such as complement fixation, phagocytic activity and antigen clearance. Moreover, the N-glycans of the Fc region are aberrantly glycosylated, mainly at the levels of D-mannosylation and galactosylation with a reduction in the affinity of the antibody for the FcR and its activation, thus inhibiting the inflammatory effects of the IgG.