{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T16:34:17Z","timestamp":1785429257132,"version":"3.56.0"},"reference-count":83,"publisher":"American Society for Microbiology","issue":"5","license":[{"start":{"date-parts":[[2026,5,13]],"date-time":"2026-05-13T00:00:00Z","timestamp":1778630400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2026,5,13]],"date-time":"2026-05-13T00:00:00Z","timestamp":1778630400000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/journals.asm.org\/non-commercial-tdm-license"}],"funder":[{"DOI":"10.13039\/100000060","name":"National Institute of Allergy and Infectious Diseases","doi-asserted-by":"publisher","award":["R01 AI157155"],"award-info":[{"award-number":["R01 AI157155"]}],"id":[{"id":"10.13039\/100000060","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000060","name":"National Institute of Allergy and Infectious Diseases","doi-asserted-by":"publisher","award":["U19 AI181103"],"award-info":[{"award-number":["U19 AI181103"]}],"id":[{"id":"10.13039\/100000060","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["journals.asm.org"],"crossmark-restriction":true},"short-container-title":["mBio"],"published-print":{"date-parts":[[2026,5,13]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:sec>\n                    <jats:title\/>\n                    <jats:p>\n                      As the SARS-CoV-2 pandemic progressed, many monoclonal antibodies (mAbs) that neutralized infection against initial strains lost potency against later variants due to the accumulation of mutations in the spike protein. Nonetheless, some mAbs, including the parent of the therapeutically used sotrovimab, S309, remained protective in animals against Omicron variants despite reduced neutralizing potential, with inhibitory activity likely sustained by Fc-mediated effector functions. Here, we identify Fc variants of S309 that confer enhanced protection against SARS-CoV-2 infection in a humanized Fc\u03b3 receptor transgenic (Hu-Fc\u03b3R Tg) mouse model of infection. Versions of S309 that are afucosylated (AFUC) and contain a G236A (GA) mutation in the Fc region showed increased binding to Fc\u03b3Rs IIA, IIIA, and IIIB and enhanced phagocytic activity in cell culture-based assays. Treatment with S309-GA-AFUC resulted in less viral burden, inflammation, and pulmonary ventilatory dysfunction in the lungs of Hu-Fc\u03b3R Tg mice challenged with SARS-CoV-2 strains compared to the parental S309 mAb or a variant lacking Fc effector functions (S309-GRLR). The enhanced protection in the lung conferred by S309-GA-AFUC required trafficking of CCR2-expressing monocytes to reduce SARS-CoV-2 viral burden and lung injury. Flow cytometry and RNA sequencing analyses showed that compared to the parental S309 mAb, S309-GA-AFUC treatment reduced the inflammatory state and induced a reparative transcriptional signature in monocytes and interstitial macrophages. Overall, our findings demonstrate that Fc engineering to increase antibody binding to activating Fc\u03b3Rs can strengthen effector functions, shape myeloid transcriptional profiles, and enhance protection against SARS-CoV-2 infection\n                      <jats:italic toggle=\"yes\">in vivo<\/jats:italic>\n                      .\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>IMPORTANCE<\/jats:title>\n                    <jats:p>Although therapeutic antibodies had success in protecting vulnerable individuals from severe COVID-19 during the early stages of the pandemic, many lost effectiveness as SARS-CoV-2 accumulated mutations that compromised neutralizing activity. Our experiments show that antibody protection against SARS-CoV-2 strains can be enhanced by genetically engineering the Fc region or altering its N-linked glycosylation to improve interactions with Fc\u03b3Rs on host immune cells. Modified versions of S309, the parent of the clinically used sotrovimab antibody, more effectively reduce viral burden and inflammation in the lung and shape protective transcriptional responses, which, together, result in improved lung ventilatory function and outcome after SARS-CoV-2 infection. Thus, antibody engineering can serve as a strategy to enhance therapeutic activity against rapidly evolving viruses with the potential to escape neutralization.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1128\/mbio.00557-26","type":"journal-article","created":{"date-parts":[[2026,4,13]],"date-time":"2026-04-13T13:01:12Z","timestamp":1776085272000},"update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":0,"title":["Fc-engineered antibodies enhance protection against SARS-CoV-2 lung infection and inflammation"],"prefix":"10.1128","volume":"17","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4518-1274","authenticated-orcid":false,"given":"Samantha R.","family":"Mackin","sequence":"first","affiliation":[{"name":"Department of Medicine, Washington University School of Medicine","place":["St. Louis, USA"]},{"name":"Department of Pathology & Immunology, Washington University School of Medicine","place":["St. Louis, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4624-7212","authenticated-orcid":false,"given":"Chieh-Yu","family":"Liang","sequence":"additional","affiliation":[{"name":"Department of Medicine, Washington University School of Medicine","place":["St. Louis, USA"]},{"name":"Department of Pathology & Immunology, Washington University School of Medicine","place":["St. Louis, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Courtney E.","family":"Karl","sequence":"additional","affiliation":[{"name":"Department of Medicine, Washington University School of Medicine","place":["St. Louis, USA"]},{"name":"Department of Molecular Microbiology, Washington University School of Medicine","place":["St. Louis, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maksim","family":"Kleverov","sequence":"additional","affiliation":[{"name":"Department of Pathology & Immunology, Washington University School of Medicine","place":["St. Louis, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2780-4119","authenticated-orcid":true,"given":"Mehak Z.","family":"Khan","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/053r20n13","id-type":"ROR","asserted-by":"publisher"}],"name":"Ragon Institute of MGH, MIT and Harvard","place":["Cambridge, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thendral","family":"Selvam","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/053r20n13","id-type":"ROR","asserted-by":"publisher"}],"name":"Ragon Institute of MGH, MIT and Harvard","place":["Cambridge, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matthias","family":"Mack","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/01226dv09","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Nephrology, University Hospital Regensburg","place":["Regensburg, Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Galit","family":"Alter","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/053r20n13","id-type":"ROR","asserted-by":"publisher"}],"name":"Ragon Institute of MGH, MIT and Harvard","place":["Cambridge, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Barbara","family":"Guarino","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/01ew95g57","id-type":"ROR","asserted-by":"publisher"}],"name":"Vir Biotechnology","place":["Bellinzona, Switzerland"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5797-1364","authenticated-orcid":true,"given":"Davide","family":"Corti","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/01ew95g57","id-type":"ROR","asserted-by":"publisher"}],"name":"Vir Biotechnology","place":["Bellinzona, Switzerland"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1137-9322","authenticated-orcid":false,"given":"Michael A.","family":"Schmid","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/01ew95g57","id-type":"ROR","asserted-by":"publisher"}],"name":"Vir Biotechnology","place":["Bellinzona, Switzerland"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8791-3165","authenticated-orcid":true,"given":"Michael S.","family":"Diamond","sequence":"additional","affiliation":[{"name":"Department of Medicine, Washington University School of Medicine","place":["St. Louis, USA"]},{"name":"Department of Pathology & Immunology, Washington University School of Medicine","place":["St. Louis, USA"]},{"name":"Department of Molecular Microbiology, Washington University School of Medicine","place":["St. Louis, USA"]},{"name":"Andrew M. and Jane M. Bursky the Center for Human Immunology and Immunotherapy Programs, Washington University School of Medicine","place":["St. Louis, USA"]},{"name":"Center for Vaccines and Immunity to Microbial Pathogens, Washington University School of Medicine","place":["St. Louis, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"235","reference":[{"key":"e_1_3_6_2_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-020-2349-y"},{"key":"e_1_3_6_3_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa2107934"},{"key":"e_1_3_6_4_2","doi-asserted-by":"publisher","DOI":"10.1001\/jama.2022.2832"},{"key":"e_1_3_6_5_2","doi-asserted-by":"publisher","DOI":"10.1016\/S1473-3099(22)00365-6"},{"key":"e_1_3_6_6_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-022-04594-4"},{"key":"e_1_3_6_7_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-022-31615-7"},{"key":"e_1_3_6_8_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-023-06487-6"},{"key":"e_1_3_6_9_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.antiviral.2023.105638"},{"key":"e_1_3_6_10_2","doi-asserted-by":"publisher","DOI":"10.1007\/s15010-024-02245-6"},{"key":"e_1_3_6_11_2","volume-title":"Fundamental immunology","author":"Greenberg S","year":"1993","unstructured":"Greenberg S, Silverstein S, Paul W. 1993. Fundamental immunology. Vol. 509."},{"key":"e_1_3_6_12_2","first-page":"1","volume-title":"Antibody Fc","author":"Ra\u00fal V","year":"2014","unstructured":"Ra\u00fal V, Rom\u00e1n G, Murray JC, Weiner LM. 2014. Antibody-dependent cellular cytotoxicity (ADCC), p 1\u201327. In Margaret E (ed), Antibody Fc. Academic Press, Boston."},{"key":"e_1_3_6_13_2","doi-asserted-by":"publisher","DOI":"10.1038\/cr.2009.139"},{"key":"e_1_3_6_14_2","doi-asserted-by":"publisher","DOI":"10.1111\/imr.12350"},{"key":"e_1_3_6_15_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0810163105"},{"key":"e_1_3_6_16_2","doi-asserted-by":"publisher","DOI":"10.1038\/srep25629"},{"key":"e_1_3_6_17_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1203954109"},{"key":"e_1_3_6_18_2","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2019.01296"},{"key":"e_1_3_6_19_2","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20201993"},{"key":"e_1_3_6_20_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0253487"},{"key":"e_1_3_6_21_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2021.03.029"},{"key":"e_1_3_6_22_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2021.02.026"},{"key":"e_1_3_6_23_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-021-04017-w"},{"key":"e_1_3_6_24_2","doi-asserted-by":"publisher","DOI":"10.1172\/JCI84428"},{"key":"e_1_3_6_25_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41564-019-0401-1"},{"key":"e_1_3_6_26_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-020-2838-z"},{"key":"e_1_3_6_27_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.chom.2020.03.025"},{"key":"e_1_3_6_28_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1911842116"},{"key":"e_1_3_6_29_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1108360108"},{"key":"e_1_3_6_30_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2020.10.052"},{"key":"e_1_3_6_31_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.xcrm.2022.100540"},{"key":"e_1_3_6_32_2","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2010-01-265280"},{"key":"e_1_3_6_33_2","doi-asserted-by":"publisher","DOI":"10.1158\/1535-7163.MCT-08-0201"},{"key":"e_1_3_6_34_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1108455108"},{"key":"e_1_3_6_35_2","doi-asserted-by":"publisher","DOI":"10.1080\/19420862.2017.1323159"},{"key":"e_1_3_6_36_2","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2008-09-179754"},{"key":"e_1_3_6_37_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41392-021-00704-2"},{"key":"e_1_3_6_38_2","doi-asserted-by":"publisher","DOI":"10.1111\/imr.12503"},{"key":"e_1_3_6_39_2","doi-asserted-by":"publisher","DOI":"10.1128\/mBio.02749-21"},{"key":"e_1_3_6_40_2","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.166.7.4697"},{"key":"e_1_3_6_41_2","doi-asserted-by":"publisher","DOI":"10.3390\/vaccines10081172"},{"key":"e_1_3_6_42_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.isci.2024.111727"},{"key":"e_1_3_6_43_2","doi-asserted-by":"publisher","DOI":"10.1097\/RLI.0000000000000672"},{"key":"e_1_3_6_44_2","doi-asserted-by":"publisher","DOI":"10.1007\/s00330-020-06801-0"},{"key":"e_1_3_6_45_2","doi-asserted-by":"publisher","DOI":"10.1038\/nm.3443"},{"key":"e_1_3_6_46_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.ppat.1011569"},{"key":"e_1_3_6_47_2","doi-asserted-by":"publisher","DOI":"10.1172\/jci.insight.92750"},{"key":"e_1_3_6_48_2","doi-asserted-by":"publisher","DOI":"10.1093\/infdis\/jiw262"},{"key":"e_1_3_6_49_2","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2018.02322"},{"key":"e_1_3_6_50_2","doi-asserted-by":"publisher","DOI":"10.1089\/vim.2019.0137"},{"key":"e_1_3_6_51_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41591-021-01488-2"},{"key":"e_1_3_6_52_2","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2021.682120"},{"key":"e_1_3_6_53_2","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20190736"},{"key":"e_1_3_6_54_2","doi-asserted-by":"publisher","DOI":"10.1126\/sciimmunol.aav5062"},{"key":"e_1_3_6_55_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.ppat.1003312"},{"key":"e_1_3_6_56_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.chom.2016.05.014"},{"key":"e_1_3_6_57_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.xcrm.2023.101305"},{"key":"e_1_3_6_58_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41590-021-01068-z"},{"key":"e_1_3_6_59_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-021-03777-9"},{"key":"e_1_3_6_60_2","doi-asserted-by":"publisher","DOI":"10.1001\/jama.2022.0470"},{"key":"e_1_3_6_61_2","doi-asserted-by":"publisher","DOI":"10.1136\/bmjopen-2023-076892"},{"key":"e_1_3_6_62_2","doi-asserted-by":"publisher","DOI":"10.1126\/scitranslmed.ado1941"},{"key":"e_1_3_6_63_2","doi-asserted-by":"publisher","DOI":"10.1172\/jci.insight.176359"},{"key":"e_1_3_6_64_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41564-023-01359-1"},{"key":"e_1_3_6_65_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.xcrm.2022.100893"},{"key":"e_1_3_6_66_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2024.114922"},{"key":"e_1_3_6_67_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2022.110368"},{"key":"e_1_3_6_68_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-017-00928-3"},{"key":"e_1_3_6_69_2","doi-asserted-by":"publisher","DOI":"10.1084\/jem.186.10.1757"},{"key":"e_1_3_6_70_2","doi-asserted-by":"publisher","DOI":"10.1038\/nri.2017.28"},{"key":"e_1_3_6_71_2","doi-asserted-by":"publisher","DOI":"10.1038\/nri2206"},{"key":"e_1_3_6_72_2","doi-asserted-by":"publisher","DOI":"10.1080\/19420862.2024.2402701"},{"key":"e_1_3_6_73_2","doi-asserted-by":"publisher","DOI":"10.1126\/sciimmunol.abc3582"},{"key":"e_1_3_6_74_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41591-021-01294-w"},{"key":"e_1_3_6_75_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-022-04630-3"},{"key":"e_1_3_6_76_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jim.2017.01.010"},{"key":"e_1_3_6_77_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2022.111216"},{"key":"e_1_3_6_78_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41591-019-0441-3"},{"key":"e_1_3_6_79_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-023-40699-8"},{"key":"e_1_3_6_80_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.aaf8505"},{"key":"e_1_3_6_81_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jbc.2022.102676"},{"key":"e_1_3_6_82_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2021.08.016"},{"key":"e_1_3_6_83_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.virol.2020.05.015"},{"key":"e_1_3_6_84_2","doi-asserted-by":"publisher","DOI":"10.3791\/50172"}],"container-title":["mBio"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/journals.asm.org\/doi\/pdf\/10.1128\/mbio.00557-26","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/journals.asm.org\/doi\/pdf\/10.1128\/mbio.00557-26","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,5,13]],"date-time":"2026-05-13T13:06:11Z","timestamp":1778677571000},"score":1,"resource":{"primary":{"URL":"https:\/\/journals.asm.org\/doi\/10.1128\/mbio.00557-26"}},"subtitle":[],"editor":[{"given":"Gong","family":"Cheng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"editor"}]}],"short-title":[],"issued":{"date-parts":[[2026,5,13]]},"references-count":83,"journal-issue":{"issue":"5","published-print":{"date-parts":[[2026,5,13]]}},"alternative-id":["10.1128\/mbio.00557-26"],"URL":"https:\/\/doi.org\/10.1128\/mbio.00557-26","relation":{},"ISSN":["2150-7511"],"issn-type":[{"value":"2150-7511","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,5,13]]},"assertion":[{"value":"2026-03-02","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-03-10","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-04-13","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e00557-26"}}