Molecular Basis for the Neutralization of Tumor Necrosis Factor α by Certolizumab Pegol in the Treatment of Inflammatory Autoimmune Diseases
Open Access
- 23 January 2017
- journal article
- research article
- Published by MDPI AG in International Journal of Molecular Sciences
- Vol. 18 (1), 228
- https://doi.org/10.3390/ijms18010228
Abstract
Monoclonal antibodies against TNFα, including infliximab, adalimumab, golimumab, and certolizumab pegol, are widely used for the treatment of the inflammatory diseases such as rheumatoid arthritis and inflammatory bowel disease. Recently, the crystal structures of TNFα, in complex with the Fab fragments of infliximab and adalimumab, have revealed the molecular mechanisms of these antibody drugs. Here, we report the crystal structure of TNFα in complex with the Fab fragment of certolizumab pegol to clarify the precise antigen-antibody interactions and the structural basis for the neutralization of TNFα by this therapeutic antibody. The structural analysis and the mutagenesis study revealed that the epitope is limited to a single protomer of the TNFα trimer. Additionally, the DE loop and the GH loop of TNFα play critical roles in the interaction with certolizumab, suggesting that this drug exerts its effects by partially occupying the receptor binding site of TNFα. In addition, a conformational change of the DE loop was induced by certolizumab binding, thereby interrupting the TNFα-receptor interaction. A comprehensive comparison of the interactions of TNFα blockers with TNFα revealed the epitope diversity on the surface of TNFα, providing a better understanding of the molecular mechanism of TNFα blockers. The accumulation of these structural studies can provide a basis for the improvement of therapeutic antibodies against TNFα.This publication has 52 references indexed in Scilit:
- Placental Transfer of Anti–Tumor Necrosis Factor Agents in Pregnant Patients With Inflammatory Bowel DiseaseClinical Gastroenterology and Hepatology, 2013
- Recognition of Human Tumor Necrosis Factor α (TNF-α) by Therapeutic Antibody FragmentOnline Journal of Public Health Informatics, 2012
- Historical perspectives on tumor necrosis factor and its superfamily: 25 years later, a golden journeyBlood, 2012
- PHENIX: a comprehensive Python-based system for macromolecular structure solutionActa crystallographica. Section D, Structural biology, 2010
- Phasercrystallographic softwareJournal of Applied Crystallography, 2007
- Coot: model-building tools for molecular graphicsActa crystallographica. Section D, Structural biology, 2004
- TNF-R1 Signaling: A Beautiful PathwayScience, 2002
- TNF? and the TNF receptor superfamily: Structure-function relationship(s)Microscopy Research and Technique, 2000
- Biochemical characterization of the extracellular domain of the 75-kilodalton tumor necrosis factor receptorBiochemistry, 1993
- Dissociation of recombinant tumor necrosis factor-α studied by gel permeation chromatographyBiochemical and Biophysical Research Communications, 1987