Structural Basis for Treating Tumor Necrosis Factor α (TNFα)-associated Diseases with the Therapeutic Antibody Infliximab

Monoclonal antibody (mAb) drugs have been widely used for treating tumor necrosis factor alpha (TNF alpha)-related diseases for over 10 years. Although their action has been hypothesized to depend in part on their ability to bind precursor cell surface TNF alpha, the precise mechanism and the epitope bound on TNF alpha remain unclear. In the present work, we report the crystal structure of the infliximab Fab fragment in complex with TNF alpha at a resolution of 2.6 angstrom. The key features of the TNF alpha E-F loop region in this complex distinguish the interaction between infliximab and TNF alpha from other TNF-receptor structures, revealing the mechanism of TNF alpha inhibition by overlapping with the TNF alpha-receptor interface and indicating the crucial role of the E-F loop in the action of this therapeutic antibody. This structure also indicates the formation of an aggregated network for the activation of complement-dependent cytolysis and antibody-dependent cell-mediated cytotoxicity, which result in development of granulomatous infections through TNF alpha blockage. These results provide the first experimental model for the interaction of TNF alpha with therapeutic antibodies and offer useful information for antibody optimization by understanding the precise molecular mechanism of TNF alpha inhibition.