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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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Project description:Renal fibrosis is the hallmark of virtually all progressive kidney diseases and strongly correlates with the deterioration of kidney function. The renin-angiotensin-aldosterone system blockade is central to the current treatment of patients with chronic kidney disease (CKD) for the renoprotective effects aimed to prevent or slow progression to end-stage renal disease (ESRD). However, the incidence of CKD is still increasing, and there is a critical need for new therapeutics. Here, we review novel strategies targeting various components implicated in the fibrogenic pathway to inhibit or retard the loss of kidney function. We focus, in particular, on antifibrotic approaches that target transforming growth factor (TGF)-?1, a key mediator of kidney fibrosis, and exciting new data on the role of autophagy. Bone morphogenetic protein (BMP)-7 and connective tissue growth factor (CTGF) are highlighted as modulators of profibrotic TGF-? activity. BMP-7 has a protective role against TGF-?1 in kidney fibrosis, whereas CTGF enhances TGF-?-mediated fibrosis. We also discuss recent advances in the development of additional strategies for antifibrotic therapy. These include strategies targeting chemokine pathways via CC chemokine receptors 1 and 2 to modulate the inflammatory response, inhibition of phosphodiesterase to restore nitric oxide-cyclic 3',5'-guanosine monophosphate function, inhibition of nicotinamide adenine dinucleotide phosphate oxidase 1 and 4 to suppress reactive oxygen species production, and inhibition of endothelin 1 or tumor necrosis factor ? to ameliorate progressive renal fibrosis. Furthermore, a brief overview of some of the biomarkers of kidney fibrosis is currently being explored that may improve the ability to monitor antifibrotic therapies. It is hoped that evidence based on the preclinical and clinical data discussed in this review leads to novel antifibrotic therapies effective in patients with CKD to prevent or delay progression to ESRD.

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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