Therapeutic Anti‐TNF alpha Antibodies : Structure‐Activity Investigations

Abstract

Therapeutic mAbs have high efficacy in treating TNFalpha‐related immunological diseases such as ankylosing spondylitis, psoriatic‐rheumatoid arthritis, and skin diseases. Three mAbs are available:Etanercept(Enbrel®), Infliximab(Remicade®), and Adalimumab(Humira®). Biosimilars(Inflectra® and Remsima®) of Infliximab have been recently approved. These IgG1 antibodies contain a single asn 297 glycosylation site that is essential for the Fc effector functions. Glycosylated antibodies lacking fucosylation show an increase in the affinity for FcγRIIIa, with an improved ADCC. However, no structural data on the Infliximab‐FcγRIII complex are available. For investigating the role of Fc fucosylation in the response to Infliximab we built a 3D mAb model that included the FAB portions of Infliximab complexed with TNFalpha(coordinates from 4G3Y.pdb), the Fc region of IGHG1 fucosylated(3SGJ) and afucosylated(3SGK) with FcγRIIIa. A few hundred steps of energy minimization were performed on the resulting 3D mAb‐model and on the minimized model we quantified interactions occurring between FcγRIII and the fucosylated/afucosylated Fc. While fucosylation does not affect FAB‐TNFalpha interactions, the superimposition of the 3D‐mAb models revealed a change in the number/quality of interactions at the carbo.‐carbo. interface between FcγRIIIa glycans and the fucosylated/afucosylated Fc. In the fucosylated Fc‐FcγRIIIa, these interactions are weakened/nonexistent supporting the reduced Fc‐FcγRIIIa affinity and ADCC activity also described in Infliximab biosimilars but not in the originator showing low fucosylation level of the Fc‐FcγRIIIa.