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Structure and characterization of a high affinity C5a monoclonal antibody that blocks binding to C5aR1 and C5aR2 receptors
C5a is a potent anaphylatoxin that modulates inflammation through the C5aR1 and C5aR2 receptors. The molecular interactions between C5a–C5aR1 receptor are well defined, whereas C5a–C5aR2 receptor interactions are poorly understood. Here, we describe the generation of a human antibody, MEDI7814, that...
Autores principales: | , , , , , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Taylor & Francis
2017
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5800367/ https://www.ncbi.nlm.nih.gov/pubmed/28952876 http://dx.doi.org/10.1080/19420862.2017.1384892 |
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author | Colley, Caroline S. Popovic, Bojana Sridharan, Sudharsan Debreczeni, Judit E. Hargeaves, David Fung, Michael An, Ling–Ling Edwards, Bryan Arnold, Joanne England, Elizabeth Eghobamien, Laura Sivars, Ulf Flavell, Liz Renshaw, Jonathan Wickson, Kate Warrener, Paul Zha, Jingying Bonnell, Jessica Woods, Rob Wilkinson, Trevor Dobson, Claire Vaughan, Tristan J. |
author_facet | Colley, Caroline S. Popovic, Bojana Sridharan, Sudharsan Debreczeni, Judit E. Hargeaves, David Fung, Michael An, Ling–Ling Edwards, Bryan Arnold, Joanne England, Elizabeth Eghobamien, Laura Sivars, Ulf Flavell, Liz Renshaw, Jonathan Wickson, Kate Warrener, Paul Zha, Jingying Bonnell, Jessica Woods, Rob Wilkinson, Trevor Dobson, Claire Vaughan, Tristan J. |
author_sort | Colley, Caroline S. |
collection | PubMed |
description | C5a is a potent anaphylatoxin that modulates inflammation through the C5aR1 and C5aR2 receptors. The molecular interactions between C5a–C5aR1 receptor are well defined, whereas C5a–C5aR2 receptor interactions are poorly understood. Here, we describe the generation of a human antibody, MEDI7814, that neutralizes C5a and C5adesArg binding to the C5aR1 and C5aR2 receptors, without affecting complement–mediated bacterial cell killing. Unlike other anti–C5a mAbs described, this antibody has been shown to inhibit the effects of C5a by blocking C5a binding to both C5aR1 and C5aR2 receptors. The crystal structure of the antibody in complex with human C5a reveals a discontinuous epitope of 22 amino acids. This is the first time the epitope for an antibody that blocks C5aR1 and C5aR2 receptors has been described, and this work provides a basis for molecular studies aimed at further understanding the C5a–C5aR2 receptor interaction. MEDI7814 has therapeutic potential for the treatment of acute inflammatory conditions in which both C5a receptors may mediate inflammation, such as sepsis or renal ischemia–reperfusion injury. |
format | Online Article Text |
id | pubmed-5800367 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2017 |
publisher | Taylor & Francis |
record_format | MEDLINE/PubMed |
spelling | pubmed-58003672018-02-12 Structure and characterization of a high affinity C5a monoclonal antibody that blocks binding to C5aR1 and C5aR2 receptors Colley, Caroline S. Popovic, Bojana Sridharan, Sudharsan Debreczeni, Judit E. Hargeaves, David Fung, Michael An, Ling–Ling Edwards, Bryan Arnold, Joanne England, Elizabeth Eghobamien, Laura Sivars, Ulf Flavell, Liz Renshaw, Jonathan Wickson, Kate Warrener, Paul Zha, Jingying Bonnell, Jessica Woods, Rob Wilkinson, Trevor Dobson, Claire Vaughan, Tristan J. MAbs Report C5a is a potent anaphylatoxin that modulates inflammation through the C5aR1 and C5aR2 receptors. The molecular interactions between C5a–C5aR1 receptor are well defined, whereas C5a–C5aR2 receptor interactions are poorly understood. Here, we describe the generation of a human antibody, MEDI7814, that neutralizes C5a and C5adesArg binding to the C5aR1 and C5aR2 receptors, without affecting complement–mediated bacterial cell killing. Unlike other anti–C5a mAbs described, this antibody has been shown to inhibit the effects of C5a by blocking C5a binding to both C5aR1 and C5aR2 receptors. The crystal structure of the antibody in complex with human C5a reveals a discontinuous epitope of 22 amino acids. This is the first time the epitope for an antibody that blocks C5aR1 and C5aR2 receptors has been described, and this work provides a basis for molecular studies aimed at further understanding the C5a–C5aR2 receptor interaction. MEDI7814 has therapeutic potential for the treatment of acute inflammatory conditions in which both C5a receptors may mediate inflammation, such as sepsis or renal ischemia–reperfusion injury. Taylor & Francis 2017-10-24 /pmc/articles/PMC5800367/ /pubmed/28952876 http://dx.doi.org/10.1080/19420862.2017.1384892 Text en © 2018 The Author(s). Published with license by Taylor & Francis Group, LLC http://creativecommons.org/licenses/by-nc-nd/4.0/ This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives License (http://creativecommons.org/licenses/by-nc-nd/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited, and is not altered, transformed, or built upon in any way. |
spellingShingle | Report Colley, Caroline S. Popovic, Bojana Sridharan, Sudharsan Debreczeni, Judit E. Hargeaves, David Fung, Michael An, Ling–Ling Edwards, Bryan Arnold, Joanne England, Elizabeth Eghobamien, Laura Sivars, Ulf Flavell, Liz Renshaw, Jonathan Wickson, Kate Warrener, Paul Zha, Jingying Bonnell, Jessica Woods, Rob Wilkinson, Trevor Dobson, Claire Vaughan, Tristan J. Structure and characterization of a high affinity C5a monoclonal antibody that blocks binding to C5aR1 and C5aR2 receptors |
title | Structure and characterization of a high affinity C5a monoclonal antibody that blocks binding to C5aR1 and C5aR2 receptors |
title_full | Structure and characterization of a high affinity C5a monoclonal antibody that blocks binding to C5aR1 and C5aR2 receptors |
title_fullStr | Structure and characterization of a high affinity C5a monoclonal antibody that blocks binding to C5aR1 and C5aR2 receptors |
title_full_unstemmed | Structure and characterization of a high affinity C5a monoclonal antibody that blocks binding to C5aR1 and C5aR2 receptors |
title_short | Structure and characterization of a high affinity C5a monoclonal antibody that blocks binding to C5aR1 and C5aR2 receptors |
title_sort | structure and characterization of a high affinity c5a monoclonal antibody that blocks binding to c5ar1 and c5ar2 receptors |
topic | Report |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5800367/ https://www.ncbi.nlm.nih.gov/pubmed/28952876 http://dx.doi.org/10.1080/19420862.2017.1384892 |
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