Repurposing a Detrimental Antibody Epitope as Targeted Therapeutics for Sepsis and Rheumatoid Arthritis.

Repurposing a Detrimental Antibody Epitope as Targeted Therapeutics for Sepsis and Rheumatoid Arthritis. | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Article Repurposing a Detrimental Antibody Epitope as Targeted Therapeutics for Sepsis and Rheumatoid Arthritis. Haichao Wang, Weiqiang Chen, Li Lou, Xiaoling Qiang, Cassie Zhu, and 6 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-7633404/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 16 Feb, 2026 Read the published version in Military Medical Research → Version 1 posted You are reading this latest preprint version Abstract Sepsis and rheumatoid arthritis (RA) are distinct yet mechanistically related conditions commonly driven by dysregulated inflammatory responses. Here, we explored the counterintuitive hypothesis that an epitope from a deleterious anti-tetranectin (TN) antibody (mAb9) could hold unforeseen therapeutic potential. By mapping mAb9's epitope to P2 (residue 55–70), a region crucial for TN's protective functions, we developed P2-1, a water-soluble derivative as a targeted therapy. P2-1 significantly improved survival and reduced systemic inflammation in a sepsis model, and attenuated arthritis severity and pain sensitivity in a RA model, even with therapeutic administration after disease onset. Mechanistically, P2-1 exhibited high-affinity binding to high mobility group box 1 (HMGB1) and selectively suppressed HMGB1-induced Ctsl mRNA up-regulation and procathepsin L (pCTS-L) secretion from human immune cells, crucially without perturbing other HMGB1-induced cytokines and chemokines. We further validated pCTS-L as a therapeutic target by demonstrating that a neutralizing antibody conferred potent anti-arthritic effects, reducing joint inflammation, pain, and structural damage. Our findings introduce a paradigm-shifting drug discovery strategy that transforms insights from paradoxical antibody action into targeted therapeutics for the HMGB1-pCTS-L axis, not only delivering P2-1 as a potent therapy but also establishing pCTS-L as crucial mediator of inflammatory diseases like sepsis and RA. Health sciences/Molecular medicine Health sciences/Rheumatology/Rheumatic diseases Health sciences/Pathogenesis/Inflammation Biological sciences/Drug discovery/Target validation HMGB1 Procathepsin L Tetranectin Sepsis Arthritis Peptide Antibody Epitope Innate Immune Cells Full Text Additional Declarations There is a conflict of interest J.L., K.J.T., and H.W. are co-inventors on US Patent 11,124,558 (“Use of tetranectin and peptide agonists to treat inflammatory diseases”, issued September 21, 2021) and a provisional patent application (“Therapeutic use of a tetranectin-derived peptide P2-1 for Rheumatoid Arthritis”, filed September 15, 2025). C.S.Z. and H.W. are co-inventors on US Patent Application (“Use of procathepsin L-neutralizing monoclonal antibodies to treat sepsis, rheumatoid arthritis, and other inflammatory diseases”, filed April 18, 2024). All other authors do not have any conflict of interest to declare. Supplementary Files DataFileS2.txt Data File S2 DataFileS3.txt Data File S3 DataFileS19252025.xlsx Data File S1 Cite Share Download PDF Status: Published Journal Publication published 16 Feb, 2026 Read the published version in Military Medical Research → Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-7633404","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":516900211,"identity":"14d38fc5-1de6-434d-aaa3-89e579b3adf9","order_by":0,"name":"Haichao Wang","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA10lEQVRIiWNgGAWjYBACAzBZASJ4gLjAAkgkEKPlDBCzgbQYSBCphbGNFC3mEsnPHn6dd0fOfH7vMYkPQC387DkGeLVYzkgzN5bd9sxY5hhfmuQMoBbJnjf4tRjcTjCTltx2OHEGG4/ZbR6gFoMbBGwxuJ3+TVpyDlTLH6AWe8JacswkPzZAtYC8byBBSMv9N2XSDMcOG0uw5Zj/7DGQ4JE486wAv5Yzx7dJ/qg5LCfBfMbY4EeFjRx/e/IGvFpAgJkHicODUxkyYPxBlLJRMApGwSgYsQAA+CBBOKnudOIAAAAASUVORK5CYII=","orcid":"https://orcid.org/0000-0002-0211-9000","institution":"Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, 500 Hofstra Blvd, Hempstead, NY, 11549, USA","correspondingAuthor":true,"prefix":"","firstName":"Haichao","middleName":"","lastName":"Wang","suffix":""},{"id":516900212,"identity":"ecbf1feb-c54a-471b-b812-8263ce9d5950","order_by":1,"name":"Weiqiang Chen","email":"","orcid":"","institution":"The Feinstein Institutes for Medical Research","correspondingAuthor":false,"prefix":"","firstName":"Weiqiang","middleName":"","lastName":"Chen","suffix":""},{"id":516900213,"identity":"361c8deb-adb0-4aed-b95c-e169de8faaa9","order_by":2,"name":"Li Lou","email":"","orcid":"","institution":"The Feinstein Institutes for Medical Research","correspondingAuthor":false,"prefix":"","firstName":"Li","middleName":"","lastName":"Lou","suffix":""},{"id":516900214,"identity":"441bcd25-0e5f-4c49-b3e9-21edf08dd580","order_by":3,"name":"Xiaoling Qiang","email":"","orcid":"","institution":"The Feinstein Institutes for Medical Research","correspondingAuthor":false,"prefix":"","firstName":"Xiaoling","middleName":"","lastName":"Qiang","suffix":""},{"id":516900215,"identity":"d9a99ef4-6db9-4ce7-a683-95df39f393be","order_by":4,"name":"Cassie Zhu","email":"","orcid":"","institution":"The Feinstein Institutes for Medical Research","correspondingAuthor":false,"prefix":"","firstName":"Cassie","middleName":"","lastName":"Zhu","suffix":""},{"id":516900216,"identity":"779b6f73-7ce9-45f4-8961-1be2bacfa8b3","order_by":5,"name":"Jianhua Li","email":"","orcid":"","institution":"The Feinstein Institutes for Medical Research","correspondingAuthor":false,"prefix":"","firstName":"Jianhua","middleName":"","lastName":"Li","suffix":""},{"id":516900217,"identity":"b85601a4-2d8e-4d8d-9bbc-ac366bd5ab93","order_by":6,"name":"Shujin Chen","email":"","orcid":"","institution":"The Feinstein Institutes for Medical Research","correspondingAuthor":false,"prefix":"","firstName":"Shujin","middleName":"","lastName":"Chen","suffix":""},{"id":516900218,"identity":"e65293a2-0ee8-4fff-9ee3-03163e02a7c1","order_by":7,"name":"Brian Xiong","email":"","orcid":"","institution":"The Feinstein Institutes for Medical Research","correspondingAuthor":false,"prefix":"","firstName":"Brian","middleName":"","lastName":"Xiong","suffix":""},{"id":516900219,"identity":"405032f3-176e-4dce-871e-c8e4d3eb47b3","order_by":8,"name":"Huan Yang","email":"","orcid":"","institution":"The Feinstein Institutes for Medical Researchu","correspondingAuthor":false,"prefix":"","firstName":"Huan","middleName":"","lastName":"Yang","suffix":""},{"id":516900220,"identity":"4b2e5171-9de3-4800-8efa-6f7d3b29c16a","order_by":9,"name":"Ping Wang","email":"","orcid":"https://orcid.org/0000-0002-1557-0394","institution":"The Feinstein Institutes for Medical Research","correspondingAuthor":false,"prefix":"","firstName":"Ping","middleName":"","lastName":"Wang","suffix":""},{"id":516900221,"identity":"45af953a-77a2-4236-a1cf-a879903181f5","order_by":10,"name":"Kevin Tracey","email":"","orcid":"","institution":"The Feinstein Institutes for Medical Research","correspondingAuthor":false,"prefix":"","firstName":"Kevin","middleName":"","lastName":"Tracey","suffix":""}],"badges":[],"createdAt":"2025-09-16 19:11:13","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-7633404/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-7633404/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1186/s40779-026-00686-8","type":"published","date":"2026-02-17T00:00:00+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":105066018,"identity":"9a6070d2-ec72-49e7-b05f-7ee72da2e538","added_by":"auto","created_at":"2026-03-20 14:00:20","extension":"pdf","order_by":1,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":2051476,"visible":true,"origin":"","legend":"Article File","description":"","filename":"P21MS9162025.pdf","url":"https://assets-eu.researchsquare.com/files/rs-7633404/v1_covered_f42f5698-6cea-49bf-8344-01888acd8c6c.pdf"},{"id":91678936,"identity":"f597b715-e3ba-45e2-a7af-5fd97b4d8967","added_by":"auto","created_at":"2025-09-19 06:09:51","extension":"txt","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":10939,"visible":true,"origin":"","legend":"Data File S2","description":"","filename":"DataFileS2.txt","url":"https://assets-eu.researchsquare.com/files/rs-7633404/v1/544184d90df6bb7d9d521c4e.txt"},{"id":91679387,"identity":"c2b17b56-af08-4735-bfa8-3355761ac92c","added_by":"auto","created_at":"2025-09-19 06:17:51","extension":"txt","order_by":2,"title":"","display":"","copyAsset":false,"role":"supplement","size":73482,"visible":true,"origin":"","legend":"Data File S3","description":"","filename":"DataFileS3.txt","url":"https://assets-eu.researchsquare.com/files/rs-7633404/v1/ccaaafff95789bcb1aa80d59.txt"},{"id":91678939,"identity":"2877ab61-1da6-4d36-9753-b05023eb257c","added_by":"auto","created_at":"2025-09-19 06:09:51","extension":"xlsx","order_by":3,"title":"","display":"","copyAsset":false,"role":"supplement","size":1505435,"visible":true,"origin":"","legend":"Data File S1","description":"","filename":"DataFileS19252025.xlsx","url":"https://assets-eu.researchsquare.com/files/rs-7633404/v1/e71a3fdf41b98457a1f5b3ce.xlsx"}],"financialInterests":"There is a conflict of interest\nJ.L., K.J.T., and H.W. are co-inventors on US Patent 11,124,558 (“Use of tetranectin and peptide agonists to treat inflammatory diseases”, issued September 21, 2021) and a provisional patent application (“Therapeutic use of a tetranectin-derived peptide P2-1 for Rheumatoid Arthritis”, filed September 15, 2025). C.S.Z. and H.W. are co-inventors on US Patent Application (“Use of procathepsin L-neutralizing monoclonal antibodies to treat sepsis, rheumatoid arthritis, and other inflammatory diseases”, filed April 18, 2024). All other authors do not have any conflict of interest to declare.","formattedTitle":"Repurposing a Detrimental Antibody Epitope as Targeted Therapeutics \r\nfor Sepsis and Rheumatoid Arthritis.","fulltext":[],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":false,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":true,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":true,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":true,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"HMGB1, Procathepsin L, Tetranectin, Sepsis, Arthritis, Peptide, Antibody, Epitope, Innate Immune Cells","lastPublishedDoi":"10.21203/rs.3.rs-7633404/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-7633404/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eSepsis and rheumatoid arthritis (RA) are distinct yet mechanistically related conditions commonly driven by dysregulated inflammatory responses. Here, we explored the counterintuitive hypothesis that an epitope from a deleterious anti-tetranectin (TN) antibody (mAb9) could hold unforeseen therapeutic potential. By mapping mAb9's epitope to P2 (residue 55\u0026ndash;70), a region crucial for TN's protective functions, we developed P2-1, a water-soluble derivative as a targeted therapy. P2-1 significantly improved survival and reduced systemic inflammation in a sepsis model, and attenuated arthritis severity and pain sensitivity in a RA model, even with therapeutic administration after disease onset. Mechanistically, P2-1 exhibited high-affinity binding to high mobility group box 1 (HMGB1) and selectively suppressed HMGB1-induced \u003cem\u003eCtsl\u003c/em\u003e mRNA up-regulation and procathepsin L (pCTS-L) secretion from human immune cells, crucially without perturbing other HMGB1-induced cytokines and chemokines. We further validated pCTS-L as a therapeutic target by demonstrating that a neutralizing antibody conferred potent anti-arthritic effects, reducing joint inflammation, pain, and structural damage. Our findings introduce a paradigm-shifting drug discovery strategy that transforms insights from paradoxical antibody action into targeted therapeutics for the HMGB1-pCTS-L axis, not only delivering P2-1 as a potent therapy but also establishing pCTS-L as crucial mediator of inflammatory diseases like sepsis and RA.\u003c/p\u003e","manuscriptTitle":"Repurposing a Detrimental Antibody Epitope as Targeted Therapeutics \nfor Sepsis and Rheumatoid Arthritis.","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-09-19 06:01:46","doi":"10.21203/rs.3.rs-7633404/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"2e8221df-9bec-4f40-ae4c-e2ef4a32f85d","owner":[],"postedDate":"September 19th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[{"id":54922163,"name":"Health sciences/Molecular medicine"},{"id":54922164,"name":"Health sciences/Rheumatology/Rheumatic diseases"},{"id":54922165,"name":"Health sciences/Pathogenesis/Inflammation"},{"id":54922166,"name":"Biological sciences/Drug discovery/Target validation"}],"tags":[],"updatedAt":"2026-03-20T14:00:08+00:00","versionOfRecord":{"articleIdentity":"rs-7633404","link":"https://doi.org/10.1186/s40779-026-00686-8","journal":{"identity":"military-medical-research","isVorOnly":false,"title":"Military Medical Research"},"publishedOn":"2026-02-17 00:00:00","publishedOnDateReadable":"February 17th, 2026"},"versionCreatedAt":"2025-09-19 06:01:46","video":"","vorDoi":"10.1186/s40779-026-00686-8","vorDoiUrl":"https://doi.org/10.1186/s40779-026-00686-8","workflowStages":[]},"version":"v1","identity":"rs-7633404","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-7633404","identity":"rs-7633404","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}