Next Article in Journal
Evolutionary Conservation of pou5f3 Genomic Organization and Its Dynamic Distribution during Embryogenesis and in Adult Gonads in Japanese Flounder Paralichthys olivaceus
Next Article in Special Issue
Serum-Infliximab Trough Levels in 45 Children with Inflammatory Bowel Disease on  Maintenance Treatment
Previous Article in Journal
Surface Modification of Titanium with BMP-2/GDF-5 by a Heparin Linker and Its Efficacy as a Dental Implant
Article Menu
Issue 1 (January) cover image

Export Article

Open AccessArticle
Int. J. Mol. Sci. 2017, 18(1), 228; doi:10.3390/ijms18010228

Molecular Basis for the Neutralization of Tumor Necrosis Factor α by Certolizumab Pegol in the Treatment of Inflammatory Autoimmune Diseases

Department of Chemistry, Konkuk University, 120 Neungdong-ro, Gwangjin-gu, Seoul 05029, Korea
*
Author to whom correspondence should be addressed.
Academic Editors: Silvio Danese and Laurent Peyrin-Biroulet
Received: 28 December 2016 / Revised: 17 January 2017 / Accepted: 17 January 2017 / Published: 23 January 2017
View Full-Text   |   Download PDF [2962 KB, uploaded 23 January 2017]   |  

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. View Full-Text
Keywords: certolizumab pegol; TNFα; inflammatory bowel diseases; rheumatoid arthritis; therapeutic antibody; crystal structure certolizumab pegol; TNFα; inflammatory bowel diseases; rheumatoid arthritis; therapeutic antibody; crystal structure
Figures

This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. (CC BY 4.0).

Scifeed alert for new publications

Never miss any articles matching your research from any publisher
  • Get alerts for new papers matching your research
  • Find out the new papers from selected authors
  • Updated daily for 49'000+ journals and 6000+ publishers
  • Define your Scifeed now

SciFeed Share & Cite This Article

MDPI and ACS Style

Lee, J.U.; Shin, W.; Son, J.Y.; Yoo, K.-Y.; Heo, Y.-S. Molecular Basis for the Neutralization of Tumor Necrosis Factor α by Certolizumab Pegol in the Treatment of Inflammatory Autoimmune Diseases. Int. J. Mol. Sci. 2017, 18, 228.

Show more citation formats Show less citations formats

Note that from the first issue of 2016, MDPI journals use article numbers instead of page numbers. See further details here.

Related Articles

Article Metrics

Article Access Statistics

1

Comments

[Return to top]
Int. J. Mol. Sci. EISSN 1422-0067 Published by MDPI AG, Basel, Switzerland RSS E-Mail Table of Contents Alert
Back to Top