Stratification of responders towards eculizumab using a structural epitope mapping strategy
| Autor: | Patrik Strömberg, Magnus Berglund, Erik Nordling, Johan Rockberg, Anna-Luisa Volk, Mathias Uhlén, Francis Jingxin Hu |
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| Rok vydání: | 2016 |
| Předmět: |
Models
Molecular 0301 basic medicine Molecular biology CHO Cells Biology Antibodies Monoclonal Humanized Crystallography X-Ray Article Epitope 03 medical and health sciences Complement inhibitor Cricetulus 0302 clinical medicine Protein Domains SDG 3 - Good Health and Well-being medicine Animals Humans Amino Acid Sequence Complement component 5 Binding Sites Multidisciplinary Molecular medicine Complement C5 Eculizumab medicine.disease Complement Inactivating Agents 030104 developmental biology Epitope mapping Mutation Monoclonal Immunology Paroxysmal nocturnal hemoglobinuria biology.protein Immunotherapy Antibody Epitope Mapping 030217 neurology & neurosurgery medicine.drug |
| Zdroj: | Volk, A-L, Hu, F J, Berglund, M M, Nordling, E, Strömberg, P, Uhlén, M & Rockberg, J 2016, ' Stratification of responders towards eculizumab using a structural epitope mapping strategy ', Scientific Reports, vol. 6, 31365 . https://doi.org/10.1038/srep31365 Scientific Reports |
| ISSN: | 2045-2322 |
| DOI: | 10.1038/srep31365 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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