{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,16]],"date-time":"2026-09-16T06:35:02Z","timestamp":1789540502612,"version":"build-2803163510"},"update-to":[{"DOI":"10.1371\/journal.ppat.1014523","type":"new_version","label":"New version","source":"publisher","updated":{"date-parts":[[2026,8,21]],"date-time":"2026-08-21T00:00:00Z","timestamp":1787270400000}}],"reference-count":53,"publisher":"Public Library of Science (PLoS)","issue":"8","license":[{"start":{"date-parts":[[2026,8,14]],"date-time":"2026-08-14T00:00:00Z","timestamp":1786665600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["www.plospathogens.org"],"crossmark-restriction":false},"short-container-title":["PLoS Pathog"],"abstract":"<jats:p>\n                    Anthrax lethal toxin is a key virulence factor of\n                    <jats:italic>Bacillus anthracis<\/jats:italic>\n                    . However, non-canonical epitopes of protective antigen (PA) and alternative neutralization mechanisms beyond receptor blockade or prevention of proteolytic cleavage remain underexplored. Here, we characterize a fully human monoclonal antibody, 22F1, with ultrapotent toxin neutralization in vitro (IC\n                    <jats:sub>50<\/jats:sub>\n                    \u2009=\u20090.027 nM) and in vivo (molar ratio 1:7.5\u201315). Unlike known PA antibodies, 22F1 selectively binds the post-cleavage form PA63, not full-length PA83, due to shielding of the epitope by PA20. Cryo-EM reveals a novel conformational epitope spanning domains D1\u2032, D2, and D3. 22F1 does not block receptor engagement, PA proteolytic activation, or lethal factor binding. Instead, its epitope lies near the inter-protomer interface; binding of a single 22F1 Fab to any PA63 protomer exerts a dual steric hindrance effect, simultaneously preventing additional Fab binding to adjacent protomers and blocking PA63 oligomerization. This \u201csingle-hit\u201d mechanism enables one antibody molecule to efficiently block prepore formation, achieving high potency. Our findings advance anthrax antitoxin research and provide a paradigm for targeting other proteins with similar activation\u2013oligomerization\u2013pore formation mechanisms.\n                  <\/jats:p>","DOI":"10.1371\/journal.ppat.1014523","type":"journal-article","created":{"date-parts":[[2026,8,14]],"date-time":"2026-08-14T17:55:27Z","timestamp":1786730127000},"page":"e1014523","update-policy":"https:\/\/doi.org\/10.1371\/journal.ppat.corrections_policy","source":"Crossref","is-referenced-by-count":1,"title":["Ultrapotent neutralization of Bacillus anthracis toxin by a human antibody via blockade of PA oligomerization"],"prefix":"10.1371","volume":"22","author":[{"given":"Qi","family":"Wang","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ting","family":"Fang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhenwei","family":"Song","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaoyan","family":"Huang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sijun","family":"He","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tianfu","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jianmin","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiangyang","family":"Chi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7212-231X","authenticated-orcid":true,"given":"Pengfei","family":"Fan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Changming","family":"Yu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2026,8,14]]},"reference":[{"issue":"1","key":"ppat.1014523.ref001","doi-asserted-by":"crossref","first-page":"32","DOI":"10.1111\/zph.13181","article-title":"Evaluation 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Peterson","year":"2007","journal-title":"Infect Immun"},{"issue":"1","key":"ppat.1014523.ref011","doi-asserted-by":"crossref","first-page":"5","DOI":"10.1186\/1476-8518-2-5","article-title":"Human anti-anthrax protective antigen neutralizing monoclonal antibodies derived from donors vaccinated with anthrax vaccine adsorbed","volume":"2","author":"R Sawada-Hirai","year":"2004","journal-title":"J Immune Based Ther Vaccines"},{"issue":"10","key":"ppat.1014523.ref012","doi-asserted-by":"crossref","first-page":"5840","DOI":"10.1128\/IAI.00712-06","article-title":"Prophylaxis and therapy of inhalational anthrax by a novel monoclonal antibody to protective antigen that mimics vaccine-induced immunity","volume":"74","author":"L Vitale","year":"2006","journal-title":"Infect Immun"},{"issue":"5","key":"ppat.1014523.ref013","doi-asserted-by":"crossref","first-page":"625","DOI":"10.1086\/500148","article-title":"Efficient neutralization of anthrax toxin by chimpanzee monoclonal antibodies against 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inhibits anthrax toxin cell binding linked to a VHH antibody that blocks oligomer formation is highly protective in an anthrax spore challenge model","volume":"290","author":"M Moayeri","year":"2015","journal-title":"J Biol Chem"},{"issue":"8","key":"ppat.1014523.ref034","article-title":"A systematic review and meta-analysis of preclinical trials testing anti-toxin therapies for B. anthracis infection: A need for more robust study designs and results","volume":"12","author":"W Xu","year":"2017","journal-title":"PLoS One"},{"issue":"1","key":"ppat.1014523.ref035","doi-asserted-by":"crossref","first-page":"56","DOI":"10.3201\/eid2301.160608","article-title":"Analysis of Anthrax Immune Globulin Intravenous with Antimicrobial Treatment in Injection Drug Users, Scotland, 2009-2010","volume":"23","author":"X Cui","year":"2017","journal-title":"Emerg Infect Dis"},{"issue":"3","key":"ppat.1014523.ref036","article-title":"Questionable Efficacy of Therapeutic Antibodies in the Treatment of Anthrax","volume":"4","author":"J-N Tournier","year":"2019","journal-title":"mSphere"},{"issue":"1","key":"ppat.1014523.ref037","doi-asserted-by":"crossref","first-page":"53","DOI":"10.3390\/toxins13010053","article-title":"A Review of the Efficacy of FDA-Approved B. anthracis Anti-Toxin Agents When Combined with Antibiotic or Hemodynamic Support in Infection- or Toxin-Challenged Preclinical Models","volume":"13","author":"Z Couse","year":"2021","journal-title":"Toxins (Basel)"},{"issue":"23","key":"ppat.1014523.ref038","doi-asserted-by":"crossref","first-page":"4602","DOI":"10.1111\/j.1742-4658.2011.08145.x","article-title":"Epsilon toxin: a fascinating pore-forming toxin","volume":"278","author":"MR Popoff","year":"2011","journal-title":"FEBS J"},{"issue":"8","key":"ppat.1014523.ref039","doi-asserted-by":"crossref","first-page":"3344","DOI":"10.3390\/toxins7083344","article-title":"Signaling beyond Punching Holes: Modulation of Cellular Responses by Vibrio cholerae 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Abboud","year":"2010","journal-title":"J Exp Med"},{"issue":"4","key":"ppat.1014523.ref046","doi-asserted-by":"crossref","first-page":"331","DOI":"10.1038\/nmeth.4193","article-title":"MotionCor2: anisotropic correction of beam-induced motion for improved cryo-electron microscopy","volume":"14","author":"SQ Zheng","year":"2017","journal-title":"Nat Methods"},{"issue":"2","key":"ppat.1014523.ref047","doi-asserted-by":"crossref","first-page":"216","DOI":"10.1016\/j.jsb.2015.08.008","article-title":"CTFFIND4: Fast and accurate defocus estimation from electron micrographs","volume":"192","author":"A Rohou","year":"2015","journal-title":"J Struct Biol"},{"issue":"1","key":"ppat.1014523.ref048","doi-asserted-by":"crossref","first-page":"1265","DOI":"10.1038\/s41467-022-28865-w","article-title":"Improved prediction of protein-protein interactions using AlphaFold2","volume":"13","author":"P Bryant","year":"2022","journal-title":"Nat 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