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Stratification of r...
Stratification of responders towards eculizumab using a structural epitope mapping strategy
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- Volk, Anna-Luisa (författare)
- KTH,Proteomik och nanobioteknologi,KTH Centrum för tillämpad proteomik (KCAP)
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- Hu, Francis Jingxin (författare)
- KTH,Proteomik och nanobioteknologi,KTH Centrum för tillämpad proteomik (KCAP)
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Berglund, Magnus M. (författare)
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Nordling, Erik (författare)
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Strömberg, Patrik (författare)
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- Uhlén, Mathias (författare)
- KTH,Proteomik och nanobioteknologi,Science for Life Laboratory, SciLifeLab,Denmark
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- Rockberg, Johan (författare)
- KTH,Proteomik och nanobioteknologi
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(creator_code:org_t)
- 2016-08-11
- 2016
- Engelska.
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Ingår i: Scientific Reports. - : Nature Publishing Group. - 2045-2322. ; 6
- Relaterad länk:
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https://www.nature.c...
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https://urn.kb.se/re...
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https://doi.org/10.1...
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Abstract
Ämnesord
Stäng
- 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.
Ämnesord
- NATURVETENSKAP -- Biologi (hsv//swe)
- NATURAL SCIENCES -- Biological Sciences (hsv//eng)
Nyckelord
- Paroxysmal-Nocturnal Hemoglobinuria
- Hemolytic-Uremic Syndrome
- Catastrophic Antiphospholipid Syndrome
- Antibody-Mediated Rejection
- Bacterial Surface Display
- Tick Ornithodoros-Moubata
- Optica Spectrum Disorders
- Complement Inhibitor
- Transplant Recipients
- Renal-Transplantation
Publikations- och innehållstyp
- ref (ämneskategori)
- art (ämneskategori)
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