{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,6,24]],"date-time":"2026-06-24T05:56:33Z","timestamp":1782280593701,"version":"3.54.5"},"posted":{"date-parts":[[2024,3,6]]},"group-title":"Bioengineering","reference-count":43,"publisher":"openRxiv","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2024,3,6]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                <jats:p>Atherosclerosis is a chronic inflammatory disease associated with the accumulation of low-density lipoprotein (LDL) in arterial walls. Higher levels of the anti-inflammatory cytokine IL-10 in serum are correlated with reduced plaque burden. However, cytokine therapies have not translated well to the clinic, partially due to their rapid clearance and pleiotropic nature. Here, we engineered IL-10 to overcome these challenges by hitchhiking on LDL to atherosclerotic plaques. Specifically, we constructed fusion proteins in which one domain is IL-10 and the other is an antibody fragment (Fab) that binds to protein epitopes of LDL. In murine models of atherosclerosis, we show that systemically administered Fab-IL-10 constructs bind circulating LDL and traffic to atherosclerotic plaques. One such construct, 2D03-IL-10, significantly reduces aortic immune cell infiltration to levels comparable to healthy mice, whereas non-targeted IL-10 has no therapeutic effect. Mechanistically, we demonstrate that 2D03-IL-10 preferentially associates with foamy macrophages and reduces pro-inflammatory activation markers. This platform technology can be applied to a variety of therapeutics and shows promise as a potential targeted anti-inflammatory therapy in atherosclerosis.<\/jats:p>","DOI":"10.1101\/2024.03.04.582839","type":"posted-content","created":{"date-parts":[[2024,3,6]],"date-time":"2024-03-06T19:19:21Z","timestamp":1709752761000},"source":"Crossref","is-referenced-by-count":5,"title":["LDL-Binding IL-10 Reduces Vascular Inflammation in Atherosclerotic Mice"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6197-0703","authenticated-orcid":false,"given":"Lisa R.","family":"Volpatti","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6507-3361","authenticated-orcid":false,"given":"Salvador Norton","family":"de Matos","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8857-0299","authenticated-orcid":false,"given":"Gustavo","family":"Borjas","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9413-5111","authenticated-orcid":false,"given":"Joseph","family":"Reda","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2691-5930","authenticated-orcid":false,"given":"Elyse A.","family":"Watkins","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8329-6086","authenticated-orcid":false,"given":"Zhengjie","family":"Zhou","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mindy","family":"Nguyen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ani","family":"Solanki","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yun","family":"Fang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0276-5456","authenticated-orcid":false,"given":"Jeffrey A.","family":"Hubbell","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"54368","reference":[{"key":"2024030907050793000_2024.03.04.582839v1.1","doi-asserted-by":"crossref","first-page":"154461","DOI":"10.1016\/j.metabol.2020.154461","article-title":"Advances in biological therapies for dyslipidemias and atherosclerosis","volume":"116","year":"2021","journal-title":"Metabolism"},{"key":"2024030907050793000_2024.03.04.582839v1.2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ymthe.2022.08.024"},{"key":"2024030907050793000_2024.03.04.582839v1.3","first-page":"430","article-title":"Statin intolerance management: a systematic review","volume":"79","year":"2023","journal-title":"Endocrine"},{"key":"2024030907050793000_2024.03.04.582839v1.4","doi-asserted-by":"crossref","first-page":"184","DOI":"10.1016\/j.ijcard.2016.09.075","article-title":"Statin non-adherence and residual cardiovascular risk: there is need for substantial improvement","volume":"225","year":"2016","journal-title":"Int. J. Cardiol"},{"key":"2024030907050793000_2024.03.04.582839v1.5","doi-asserted-by":"crossref","first-page":"1829","DOI":"10.1001\/jama.2021.5469","article-title":"The leading causes of death in the US for 2020","volume":"325","year":"2021","journal-title":"J. Am. Med. Assoc"},{"key":"2024030907050793000_2024.03.04.582839v1.6","doi-asserted-by":"crossref","first-page":"101622","DOI":"10.1016\/j.cpcardiol.2023.101622","article-title":"Global cardiovascular diseases death rate prediction","volume":"48","year":"2023","journal-title":"Curr. Probl. Cardiol"},{"key":"2024030907050793000_2024.03.04.582839v1.7","doi-asserted-by":"crossref","first-page":"368","DOI":"10.1038\/nrneph.2017.51","article-title":"The immunology of atherosclerosis","volume":"13","year":"2017","journal-title":"Nat. Rev. Nephrol"},{"key":"2024030907050793000_2024.03.04.582839v1.8","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCRESAHA.118.313591"},{"key":"2024030907050793000_2024.03.04.582839v1.9","doi-asserted-by":"publisher","DOI":"10.1093\/clinchem\/hvaa275"},{"key":"2024030907050793000_2024.03.04.582839v1.10","doi-asserted-by":"publisher","DOI":"10.1097\/MOL.0000000000000525"},{"key":"2024030907050793000_2024.03.04.582839v1.11","doi-asserted-by":"publisher","DOI":"10.1007\/s13238-012-2025-6"},{"key":"2024030907050793000_2024.03.04.582839v1.12","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1707914"},{"key":"2024030907050793000_2024.03.04.582839v1.13","doi-asserted-by":"crossref","first-page":"522","DOI":"10.1038\/s41569-021-00668-4","article-title":"Therapeutic strategies targeting inflammation and immunity in atherosclerosis: how to proceed?","volume":"19","year":"2022","journal-title":"Nat. Rev. Cardiol"},{"key":"2024030907050793000_2024.03.04.582839v1.14","doi-asserted-by":"crossref","first-page":"101822","DOI":"10.1016\/j.nantod.2023.101822","article-title":"Two decades of vaccine development against atherosclerosis","volume":"50","year":"2023","journal-title":"Nano Today"},{"key":"2024030907050793000_2024.03.04.582839v1.15","doi-asserted-by":"publisher","DOI":"10.1161\/01.ATV.19.12.2847"},{"key":"2024030907050793000_2024.03.04.582839v1.16","doi-asserted-by":"publisher","DOI":"10.1161\/01.RES.85.8.e17"},{"key":"2024030907050793000_2024.03.04.582839v1.17","doi-asserted-by":"crossref","first-page":"10","DOI":"10.1007\/BF03402102","article-title":"Interleukin-10 deficiency increases atherosclerosis, thrombosis, and low-density lipoproteins in apolipoprotein E knockout mice","volume":"9","year":"2003","journal-title":"Mol. Med"},{"key":"2024030907050793000_2024.03.04.582839v1.18","doi-asserted-by":"publisher","DOI":"10.1016\/j.atherosclerosis.2003.08.032"},{"key":"2024030907050793000_2024.03.04.582839v1.19","doi-asserted-by":"publisher","DOI":"10.1038\/sj.gt.3302348"},{"key":"2024030907050793000_2024.03.04.582839v1.20","doi-asserted-by":"publisher","DOI":"10.1021\/acsnano.6b01114"},{"key":"2024030907050793000_2024.03.04.582839v1.21","doi-asserted-by":"crossref","first-page":"119550","DOI":"10.1016\/j.biomaterials.2019.119550","article-title":"Targeted delivery of anti-inflammatory cytokine by nanocarrier reduces atherosclerosis in Apo E\u2212\/-mice","volume":"226","year":"2020","journal-title":"Biomaterials"},{"key":"2024030907050793000_2024.03.04.582839v1.22","doi-asserted-by":"crossref","first-page":"1064","DOI":"10.1016\/j.tips.2021.09.009","article-title":"Engineered antibody fusion proteins for targeted disease therapy","volume":"42","year":"2021","journal-title":"Trends Pharmacol. Sci"},{"key":"2024030907050793000_2024.03.04.582839v1.23","doi-asserted-by":"publisher","DOI":"10.1111\/j.1749-6632.2001.tb11378.x"},{"key":"2024030907050793000_2024.03.04.582839v1.24","doi-asserted-by":"publisher","DOI":"10.1161\/01.CIR.0000143162.56057.B5"},{"key":"2024030907050793000_2024.03.04.582839v1.25","doi-asserted-by":"publisher","DOI":"10.1016\/j.jacc.2007.07.081"},{"key":"2024030907050793000_2024.03.04.582839v1.26","unstructured":"Nilsson, J. & Carlsson, R. Oxidized ldl and antibodies thereto for the treatment of atherosclerotic plaques. World Intellectual Property Organization Publication No. WO 2008\/104194 A1 (2007)."},{"key":"2024030907050793000_2024.03.04.582839v1.27","doi-asserted-by":"publisher","DOI":"10.1172\/JCI28549"},{"key":"2024030907050793000_2024.03.04.582839v1.28","doi-asserted-by":"publisher","DOI":"10.1161\/ATVBAHA.108.180505"},{"key":"2024030907050793000_2024.03.04.582839v1.29","doi-asserted-by":"publisher","DOI":"10.1093\/eurheartj\/ehac094"},{"key":"2024030907050793000_2024.03.04.582839v1.30","doi-asserted-by":"publisher","DOI":"10.1172\/JCI29950"},{"key":"2024030907050793000_2024.03.04.582839v1.31","doi-asserted-by":"publisher","DOI":"10.1016\/j.it.2004.09.015"},{"key":"2024030907050793000_2024.03.04.582839v1.32","doi-asserted-by":"publisher","DOI":"10.1038\/ncpcardio0195"},{"key":"2024030907050793000_2024.03.04.582839v1.33","doi-asserted-by":"crossref","first-page":"54","DOI":"10.1016\/j.vph.2018.08.002","article-title":"Foam cell formation: A new target for fighting atherosclerosis and cardiovascular disease","volume":"112","year":"2019","journal-title":"Vascu. Pharmacol"},{"key":"2024030907050793000_2024.03.04.582839v1.34","doi-asserted-by":"publisher","DOI":"10.1097\/00041433-200104000-00010"},{"key":"2024030907050793000_2024.03.04.582839v1.35","doi-asserted-by":"publisher","DOI":"10.1016\/j.autrev.2008.04.018"},{"key":"2024030907050793000_2024.03.04.582839v1.36","doi-asserted-by":"publisher","DOI":"10.1161\/01.ATV.20.10.2243"},{"key":"2024030907050793000_2024.03.04.582839v1.37","doi-asserted-by":"publisher","DOI":"10.1111\/j.1749-6632.2001.tb03943.x"},{"key":"2024030907050793000_2024.03.04.582839v1.38","doi-asserted-by":"publisher","DOI":"10.1161\/ATVBAHA.116.306874"},{"key":"2024030907050793000_2024.03.04.582839v1.39","doi-asserted-by":"crossref","first-page":"117279","DOI":"10.1016\/j.atherosclerosis.2023.117279","article-title":"Sex differences in the genetic and molecular mechanisms of coronary artery disease","volume":"384","year":"2023","journal-title":"Atherosclerosis"},{"key":"2024030907050793000_2024.03.04.582839v1.40","doi-asserted-by":"publisher","DOI":"10.1016\/j.atherosclerosis.2008.11.020"},{"key":"2024030907050793000_2024.03.04.582839v1.41","doi-asserted-by":"publisher","DOI":"10.1110\/ps.062246706"},{"key":"2024030907050793000_2024.03.04.582839v1.42","doi-asserted-by":"publisher","DOI":"10.1126\/sciimmunol.abe1801"},{"key":"2024030907050793000_2024.03.04.582839v1.43","first-page":"e2848","article-title":"Flow cytometry analysis of immune cells within murine aortas","volume":"53","year":"2011","journal-title":"J. Vis. Exp"}],"container-title":[],"original-title":[],"link":[{"URL":"https:\/\/syndication.highwire.org\/content\/doi\/10.1101\/2024.03.04.582839","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,6,24]],"date-time":"2026-06-24T05:03:02Z","timestamp":1782277382000},"score":1,"resource":{"primary":{"URL":"http:\/\/biorxiv.org\/lookup\/doi\/10.1101\/2024.03.04.582839"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,3,6]]},"references-count":43,"URL":"https:\/\/doi.org\/10.1101\/2024.03.04.582839","relation":{"is-preprint-of":[{"id-type":"doi","id":"10.1038\/s41551-025-01573-8","asserted-by":"subject"}]},"subject":[],"published":{"date-parts":[[2024,3,6]]},"subtype":"preprint"}}