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Stratification of responders towards eculizumab using a structural epitope mapping strategy
KTH, School of Biotechnology (BIO), Proteomics and Nanobiotechnology. KTH, School of Biotechnology (BIO), Centres, Science for Life Laboratory, SciLifeLab, KTH Center for Applied Proteomics (KCAP).
KTH, School of Biotechnology (BIO), Proteomics and Nanobiotechnology. KTH, School of Biotechnology (BIO), Centres, Science for Life Laboratory, SciLifeLab, KTH Center for Applied Proteomics (KCAP).
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2016 (English)In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 6, 31365Article in journal (Refereed) Published
Abstract [en]

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.

Place, publisher, year, edition, pages
Nature Publishing Group, 2016. Vol. 6, 31365
Keyword [en]
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
National Category
Biological Sciences
Identifiers
URN: urn:nbn:se:kth:diva-191745DOI: 10.1038/srep31365ISI: 000381185300001PubMedID: 27509843ScopusID: 2-s2.0-84982176744OAI: oai:DiVA.org:kth-191745DiVA: diva2:970945
Funder
Novo NordiskScience for Life Laboratory - a national resource center for high-throughput molecular bioscience
Note

QC 20160915

Available from: 2016-09-15 Created: 2016-09-02 Last updated: 2016-09-15Bibliographically approved

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Volk, Anna-LuisaHu, Francis JingxinUhlén, MathiasRockberg, Johan
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Proteomics and NanobiotechnologyKTH Center for Applied Proteomics (KCAP)Science for Life Laboratory, SciLifeLab
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