{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,5]],"date-time":"2026-10-05T10:56:51Z","timestamp":1791197811639,"version":"4.1.0"},"reference-count":37,"publisher":"Wiley","issue":"3","license":[{"start":{"date-parts":[[2026,7,27]],"date-time":"2026-07-27T00:00:00Z","timestamp":1785110400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2026,7,27]],"date-time":"2026-07-27T00:00:00Z","timestamp":1785110400000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/100014013","name":"UK Research and Innovation","doi-asserted-by":"publisher","award":["526567"],"award-info":[{"award-number":["526567"]}],"id":[{"id":"10.13039\/100014013","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100017510","name":"UK Dementia Research Institute","doi-asserted-by":"publisher","award":["UK DRI\u20103002"],"award-info":[{"award-number":["UK DRI\u20103002"]}],"id":[{"id":"10.13039\/501100017510","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Immunology"],"published-print":{"date-parts":[[2026,11]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>C5 inhibition is a proven therapeutic target with several monoclonal antibody (mAb) and small molecule drugs in the clinic. To explore alternative modes of inhibition, novel C5\u2010blocking mAbs were generated and compared to therapeutic mAbs eculizumab and crovalimab. Blocking mAbs were selected using complement inhibition in haemolysis assays. C5 binding and competition between mAbs were tested by ELISA and surface plasmon resonance. Impact on C5 cleavage by CVF and native convertases was tested by western blotting of C5 fragments and ELISA for C5a release. Four novel C5\u2010blocking mAbs were identified and shown to inhibit haemolysis with comparable efficacy to crovalimab and eculizumab. Competition assays identified four distinct function\u2010blocking epitopes; mAb 7D4 and eculizumab competed for an \u03b1\u2010chain epitope (epitope 1), while 10B6 and crovalimab competed for a \u03b2\u2010chain epitope (epitope 2). mAbs 2B11 and 4G2 were not competitive with epitope 1\/2 binders or each other, marking two distinct blocking \u03b1\u2010chain epitopes (epitopes 3 and 4). Epitope 1 and epitope 2 binders blocked C5 convertase\u2010mediated C5 cleavage and C5a release, while epitope 3 and epitope 4 binders permitted C5 cleavage, demonstrating distinct modes of inhibition. We identified four distinct C5 blocking epitopes; epitope 1 targeted by eculizumab and 7D4, epitope 2 targeted by crovalimab and 10B6 and epitopes 3 and 4 targeted by 2B11 and 4G2 respectively. Although all efficiently blocked haemolysis, epitope 3 and 4 binders permitted C5a release. We reveal (at least) four blocking epitopes on C5 and (at least) two distinct mechanisms of inhibition.<\/jats:p>","DOI":"10.1111\/imm.70180","type":"journal-article","created":{"date-parts":[[2026,7,28]],"date-time":"2026-07-28T02:25:11Z","timestamp":1785205511000},"page":"444-456","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Mapping of\n                    <scp>C5<\/scp>\n                    \u2010Blocking Monoclonal Antibodies Reveals New\n                    <scp>C5<\/scp>\n                    Inhibitory Epitopes and Novel Modes of\n                    <scp>C5<\/scp>\n                    Inhibition"],"prefix":"10.1111","volume":"179","author":[{"ORCID":"https:\/\/orcid.org\/0009-0008-0890-9565","authenticated-orcid":false,"given":"Rebekah Sian","family":"Cooke","sequence":"first","affiliation":[{"name":"UK Dementia Research Institute Cardiff, School of Medicine Cardiff University  Cardiff UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1014-0827","authenticated-orcid":false,"given":"Kok Yung","family":"Lee","sequence":"additional","affiliation":[{"name":"UK Dementia Research Institute Cardiff, School of Medicine Cardiff University  Cardiff UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6600-6507","authenticated-orcid":false,"given":"Georgina Elizabeth","family":"Menzies","sequence":"additional","affiliation":[{"name":"Molecular Biosciences Division, School of Biosciences Cardiff University  Cardiff UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Masashi","family":"Mizuno","sequence":"additional","affiliation":[{"name":"Department of Renal Replacement Therapy Nagoya University Graduate School of Medicine  Nagoya Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4075-7676","authenticated-orcid":false,"given":"Bryan Paul","family":"Morgan","sequence":"additional","affiliation":[{"name":"UK Dementia Research Institute Cardiff, School of Medicine Cardiff University  Cardiff UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2230-3550","authenticated-orcid":false,"given":"Wioleta Milena","family":"Zelek","sequence":"additional","affiliation":[{"name":"UK Dementia Research Institute Cardiff, School of Medicine Cardiff University  Cardiff UK"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,7,27]]},"reference":[{"key":"e_1_2_10_2_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.molimm.2019.07.030"},{"issue":"5","key":"e_1_2_10_3_1","first-page":"328","article-title":"Inhibition of Terminal Complement Complex Formation and Cell Lysis by Monoclonal Antibodies","volume":"8","author":"W\u00fcrzner R.","year":"1991","journal-title":"Complement and Inflammation"},{"key":"e_1_2_10_4_1","doi-asserted-by":"publisher","DOI":"10.1016\/0161-5890(95)00099-2"},{"key":"e_1_2_10_5_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jaci.2025.04.006"},{"key":"e_1_2_10_6_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(23)01524-6"},{"key":"e_1_2_10_7_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.imbio.2025.153089"},{"key":"e_1_2_10_8_1","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.1600280"},{"key":"e_1_2_10_9_1","doi-asserted-by":"publisher","DOI":"10.3390\/ijms252111679"},{"key":"e_1_2_10_10_1","doi-asserted-by":"publisher","DOI":"10.1111\/imm.12982"},{"key":"e_1_2_10_11_1","doi-asserted-by":"publisher","DOI":"10.1111\/imm.13083"},{"key":"e_1_2_10_12_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1311084"},{"key":"e_1_2_10_13_1","doi-asserted-by":"publisher","DOI":"10.1111\/imm.70008"},{"key":"e_1_2_10_14_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.imbio.2018.07.016"},{"key":"e_1_2_10_15_1","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2020.612402"},{"key":"e_1_2_10_16_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbi.2025.03.026"},{"key":"e_1_2_10_17_1","volume-title":"Complement Methods and Protocols","author":"Morgan B. 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