Therapeutic
monoclonal antibodies (mAbs) have high efficacy in treating TNF α-related
immunological diseases. Other than neutralizing TNF α, these
IgG1 antibodies exert
Fc receptor-mediated effector functions such as the
complement-dependent cytotoxicity (CDC) and antibody-dependent cell cytotoxicity (ADCC). The crystallizable
fragment (Fc) of these
IgG1 contains a single glycosylation site at Asn 297/300 that is essential for the CDC and ADCC. Glycosylated
antibodies lacking core fucosylation showed an improved ADCC. However, no structural data are available concerning the
ligand-binding interaction of these mAbs used in TNF α-related diseases and the role of the fucosylation. We therefore used comparative modeling for generating complete 3D mAb models that include the
antigen-binding
fragment (Fab) portions of
infliximab, complexed with TNF α (4G3Y.pdb), the Fc region of the human IGHG1 fucosylated (3SGJ) and afucosylated (3SGK) complexed with the
Fc receptor subtype Fcγ RIIIA, and the Fc region of a murine
immunoglobulin (1IGT). After few thousand steps of energy minimization on the resulting 3D mAb models, minimized final models were used to quantify interactions occurring between Fcγ RIIIA and the fucosylated/afucosylated
Fc fragments. While fucosylation does not affect Fab-TNF α interactions, we found that in the absence of fucosylation the Fc-mAb domain and Fcγ RIIIA are closer and new strong interactions are established between G129 of the receptor and S301 of the Chimera 2 Fc mAb; new polar interactions are also established between the Chimera 2 Fc residues Y299, N300, and S301 and the Fcγ RIIIA residues K128, G129, R130, and R155. These data help to explain the reduced ADCC observed in the fucosylated mAbs suggesting the specific AA residues involved in binding interactions.