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Structural basis for treating tumor necrosis factor ? (TNF?)-associated diseases with the therapeutic antibody infliximab.

ABSTRACT: BACKGROUND: Although infliximab has high efficacy in treating TNF?-associated diseases, the epitope on TNF? remains unclear. RESULTS: The crystal structure of the TNF? in complex with the infliximab Fab is reported at a resolution of 2.6 Å. CONCLUSION: TNF? E-F loop plays a crucial role in the interaction. SIGNIFICANCE: The structure may lead to understanding the mechanism of mAb anti-TNF? Monoclonal antibody (mAb) drugs have been widely used for treating tumor necrosis factor ? (TNF?)-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?, the precise mechanism and the epitope bound on TNF? remain unclear. In the present work, we report the crystal structure of the infliximab Fab fragment in complex with TNF? at a resolution of 2.6 ?. The key features of the TNF? E-F loop region in this complex distinguish the interaction between infliximab and TNF? from other TNF-receptor structures, revealing the mechanism of TNF? inhibition by overlapping with the TNF?-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? blockage. These results provide the first experimental model for the interaction of TNF? with therapeutic antibodies and offer useful information for antibody optimization by understanding the precise molecular mechanism of TNF? inhibition.

SUBMITTER: Liang S

PROVIDER: S-EPMC3650416 | biostudies-literature | 2013 May

REPOSITORIES: biostudies-literature

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Structural basis for treating tumor necrosis factor α (TNFα)-associated diseases with the therapeutic antibody infliximab.

Liang Shuaiyi S Dai Jianxin J Hou Sheng S Su Lishu L Zhang Dapeng D Guo Huaizu H Hu Shi S Wang Hao H Rao Zihe Z Guo Yajun Y Lou Zhiyong Z

The Journal of biological chemistry 20130315 19

<h4>Background</h4>Although infliximab has high efficacy in treating TNFα-associated diseases, the epitope on TNFα remains unclear.<h4>Results</h4>The crystal structure of the TNFα in complex with the infliximab Fab is reported at a resolution of 2.6 Å.<h4>Conclusion</h4>TNFα E-F loop plays a crucial role in the interaction.<h4>Significance</h4>The structure may lead to understanding the mechanism of mAb anti-TNFα Monoclonal antibody (mAb) drugs have been widely used for treating tumor necrosis ...[more]

PMID: 23504311

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Dataset Information

Structural basis for treating tumor necrosis factor ? (TNF?)-associated diseases with the therapeutic antibody infliximab.

Publications

Structural basis for treating tumor necrosis factor α (TNFα)-associated diseases with the therapeutic antibody infliximab.

Similar Datasets

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