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Stratification of responders towards eculizumab using a structural epitope mapping strategy
The complement component 5 (C5)-binding antibody eculizumab is used to treat patients with paroxysmal nocturnal hemoglobinuria (PNH) and atypical haemolytic uremic syndrome (aHUS). As recently reported there is a need for a precise classification of eculizumab responsive patients to allow for a safe...
Autores principales: | , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group
2016
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4980765/ https://www.ncbi.nlm.nih.gov/pubmed/27509843 http://dx.doi.org/10.1038/srep31365 |
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author | Volk, Anna-Luisa Hu, Francis Jingxin Berglund, Magnus M. Nordling, Erik Strömberg, Patrik Uhlen, Mathias Rockberg, Johan |
author_facet | Volk, Anna-Luisa Hu, Francis Jingxin Berglund, Magnus M. Nordling, Erik Strömberg, Patrik Uhlen, Mathias Rockberg, Johan |
author_sort | Volk, Anna-Luisa |
collection | PubMed |
description | The complement component 5 (C5)-binding antibody eculizumab is used to treat patients with paroxysmal nocturnal hemoglobinuria (PNH) and atypical haemolytic uremic syndrome (aHUS). As recently reported there is a need for a precise classification of eculizumab responsive patients to allow for a safe and cost-effective treatment. To allow for such stratification, knowledge of the precise binding site of the drug on its target is crucial. Using a structural epitope mapping strategy based on bacterial surface display, flow cytometric sorting and validation via haemolytic activity testing, we identified six residues essential for binding of eculizumab to C5. This epitope co-localizes with the contact area recently identified by crystallography and includes positions in C5 mutated in non-responders. The identified epitope also includes residue W917, which is unique for human C5 and explains the observed lack of cross-reactivity for eculizumab with other primates. We could demonstrate that Ornithodorus moubata complement inhibitor (OmCI), in contrast to eculizumab, maintained anti-haemolytic function for mutations in any of the six epitope residues, thus representing a possible alternative treatment for patients non-responsive to eculizumab. The method for stratification of patients described here allows for precision medicine and should be applicable to several other diseases and therapeutics. |
format | Online Article Text |
id | pubmed-4980765 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2016 |
publisher | Nature Publishing Group |
record_format | MEDLINE/PubMed |
spelling | pubmed-49807652016-08-19 Stratification of responders towards eculizumab using a structural epitope mapping strategy Volk, Anna-Luisa Hu, Francis Jingxin Berglund, Magnus M. Nordling, Erik Strömberg, Patrik Uhlen, Mathias Rockberg, Johan Sci Rep Article The complement component 5 (C5)-binding antibody eculizumab is used to treat patients with paroxysmal nocturnal hemoglobinuria (PNH) and atypical haemolytic uremic syndrome (aHUS). As recently reported there is a need for a precise classification of eculizumab responsive patients to allow for a safe and cost-effective treatment. To allow for such stratification, knowledge of the precise binding site of the drug on its target is crucial. Using a structural epitope mapping strategy based on bacterial surface display, flow cytometric sorting and validation via haemolytic activity testing, we identified six residues essential for binding of eculizumab to C5. This epitope co-localizes with the contact area recently identified by crystallography and includes positions in C5 mutated in non-responders. The identified epitope also includes residue W917, which is unique for human C5 and explains the observed lack of cross-reactivity for eculizumab with other primates. We could demonstrate that Ornithodorus moubata complement inhibitor (OmCI), in contrast to eculizumab, maintained anti-haemolytic function for mutations in any of the six epitope residues, thus representing a possible alternative treatment for patients non-responsive to eculizumab. The method for stratification of patients described here allows for precision medicine and should be applicable to several other diseases and therapeutics. Nature Publishing Group 2016-08-11 /pmc/articles/PMC4980765/ /pubmed/27509843 http://dx.doi.org/10.1038/srep31365 Text en Copyright © 2016, The Author(s) http://creativecommons.org/licenses/by/4.0/ This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ |
spellingShingle | Article Volk, Anna-Luisa Hu, Francis Jingxin Berglund, Magnus M. Nordling, Erik Strömberg, Patrik Uhlen, Mathias Rockberg, Johan Stratification of responders towards eculizumab using a structural epitope mapping strategy |
title | Stratification of responders towards eculizumab using a structural epitope mapping strategy |
title_full | Stratification of responders towards eculizumab using a structural epitope mapping strategy |
title_fullStr | Stratification of responders towards eculizumab using a structural epitope mapping strategy |
title_full_unstemmed | Stratification of responders towards eculizumab using a structural epitope mapping strategy |
title_short | Stratification of responders towards eculizumab using a structural epitope mapping strategy |
title_sort | stratification of responders towards eculizumab using a structural epitope mapping strategy |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4980765/ https://www.ncbi.nlm.nih.gov/pubmed/27509843 http://dx.doi.org/10.1038/srep31365 |
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