Molecular modeling of antibodies for the treatment of TNFα‐related immunological diseases. Issue 1 (15th January 2016)

• Record Type: Journal Article
• Authors: Pierri, Ciro Leonardo; Bossis, Fabrizio; Punzi, Giuseppe; De Grassi, Anna; Cetrone, Michela; Parisi, Giovanni; Tricarico, Domenico
• Is Part Of: Pharmacology research & perspectives. Volume 4:Issue 1(2016:Feb.)
• Page Start: n/a
• Page End: n/a
• Publication Date: 2016-01-15
• Subjects: TNFalpha modeling -- antibody‐receptor docking -- antibody‐receptor complex stability -- anti‐TNF alpha antibody biosimilar -- Fc glycosylation; Pharmacology -- Periodicals; Drug development -- Periodicals; 615.105
• DOI: 10.1002/prp2.197
• Languages: English
• ISSNs: 2052-1707

Abstract

Abstract: 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 Fc γ 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 Fc γ 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 Fc γ 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 Fc γ 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.