{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,26]],"date-time":"2026-09-26T06:00:11Z","timestamp":1790402411753,"version":"4.1.0"},"reference-count":28,"publisher":"Wiley","issue":"3","license":[{"start":{"date-parts":[[2026,7,12]],"date-time":"2026-07-12T00:00:00Z","timestamp":1783814400000},"content-version":"vor","delay-in-days":11,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"},{"start":{"date-parts":[[2026,7,1]],"date-time":"2026-07-01T00:00:00Z","timestamp":1782864000000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/100012513","name":"Coins for Alzheimer's Research Trust","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100012513","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100007625","name":"Cure Alzheimer's Fund","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100007625","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100007306","name":"Arizona Department of Health Services","doi-asserted-by":"publisher","award":["CTR057001"],"award-info":[{"award-number":["CTR057001"]}],"id":[{"id":"10.13039\/100007306","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100017803","name":"Translational Genomics Research Institute","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100017803","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["alz-journals.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["A&amp;D Transl Res &amp; Clin Interv"],"published-print":{"date-parts":[[2026,7]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>INTRODUCTION<\/jats:title>\n                    <jats:p>Anti\u2010amyloid beta (A\u03b2) monoclonal antibodies are effective at lowering amyloid in Alzheimer's disease (AD). However, whether Fc\u2010mediated effector function is absolutely required for efficacy is not completely understood. This is important for optimizing therapeutic efficacy and mitigating side effects such as amyloid\u2010related imaging abnormalities (ARIA). Antibodies lacking Fc effector function, like single\u2010domain antibodies (nanobodies), offer a unique tool to dissect these mechanisms, as their small size facilitates blood\u2013brain barrier (BBB) penetration and allows Fc\u2010mediated functions to be studied independently.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>METHODS<\/jats:title>\n                    <jats:p>We immunized a llama with A\u03b2 aggregates and constructed a phage display library to screen for aggregate\u2010specific nanobodies. Lead candidates were characterized by epitope mapping and binding affinity to amyloid plaques in both murine and human AD brain tissues. We further assessed their BBB permeability and evaluated their efficacy in clearing pre\u2010existing plaques in amyloid precursor protein (APP)\/presenilin 1 (PS1) mice.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>RESULTS<\/jats:title>\n                    <jats:p>We identified two lead nanobodies, 3A11 and 2D10, that bind distinct epitopes and specifically bind A\u03b2 plaques in murine and human AD brain tissues. Following systemic administration, the monovalent, unmodified (Fc\u2010less) 2D10 nanobody, but not 3A11, successfully crossed the BBB and engaged amyloid plaques in APP\/PS1 mice. However, despite robust target engagement, the Fc\u2010less 2D10 failed to recruit microglia or reduce plaque burden. In contrast, an engineered 2D10\u2010Fc fusion antibody potently cleared amyloid plaques, achieving a reduction in pathology comparable to aducanumab treatment. This efficacy was directly correlated with Fc\u2010mediated microglial recruitment and activation, demonstrating that the Fc domain is essential for phagocytic plaque removal.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>DISCUSSION<\/jats:title>\n                    <jats:p>Our findings demonstrate that Fc effector function is indispensable for microglial\u2010mediated amyloid clearance in vivo. By clarifying this fundamental mechanism, this study provides a framework for the rational design of next\u2010generation immunotherapies. Furthermore, 2D10\u2010Fc represents a promising therapeutic candidate, combining the high\u2010affinity targeting of nanobodies with the effector power necessary for robust plaque clearance.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/trc2.70269","type":"journal-article","created":{"date-parts":[[2026,7,13]],"date-time":"2026-07-13T03:45:25Z","timestamp":1783914325000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Anti\u2010amyloid nanobody\u2010Fc fusion protein drives potent amyloid clearance through microglial recruitment"],"prefix":"10.1002","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9291-6435","authenticated-orcid":false,"given":"Zonghui","family":"Ding","sequence":"first","affiliation":[{"name":"Immunology and Microbial Genomics Division The Translational Genomics Research Institute  Phoenix Arizona USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Katelin A.","family":"Gibson","sequence":"additional","affiliation":[{"name":"Immunology and Microbial Genomics Division The Translational Genomics Research Institute  Phoenix Arizona USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David G.","family":"Nascari","sequence":"additional","affiliation":[{"name":"Immunology and Microbial Genomics Division The Translational Genomics Research Institute  Phoenix Arizona USA"},{"name":"Alix School of Medicine Arizona Mayo Clinic  Phoenix Arizona USA"},{"name":"Graduate School of Biomedical Science Arizona Mayo Clinic  Phoenix Arizona USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lauren E.","family":"Tallant","sequence":"additional","affiliation":[{"name":"Immunology and Microbial Genomics Division The Translational Genomics Research Institute  Phoenix Arizona USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Samantha M.","family":"Bouchal","sequence":"additional","affiliation":[{"name":"Immunology and Microbial Genomics Division The Translational Genomics Research Institute  Phoenix Arizona USA"},{"name":"Alix School of Medicine Arizona Mayo Clinic  Phoenix Arizona USA"},{"name":"Graduate School of Biomedical Science Arizona Mayo Clinic  Phoenix Arizona USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dennis W.","family":"Dickson","sequence":"additional","affiliation":[{"name":"Department of Neuroscience Mayo Clinic  Jacksonville Florida USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John D.","family":"Fryer","sequence":"additional","affiliation":[{"name":"Immunology and Microbial Genomics Division The Translational Genomics Research Institute  Phoenix Arizona USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,7,12]]},"reference":[{"key":"e_1_2_8_2_1","doi-asserted-by":"publisher","DOI":"10.1002\/alz.70235"},{"key":"e_1_2_8_3_1","doi-asserted-by":"publisher","DOI":"10.1186\/s13024-019-0333-5"},{"key":"e_1_2_8_4_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMra0909142"},{"key":"e_1_2_8_5_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41573-022-00391-w"},{"key":"e_1_2_8_6_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.1072994"},{"key":"e_1_2_8_7_1","doi-asserted-by":"publisher","DOI":"10.1038\/d41573-024-00116-1"},{"key":"e_1_2_8_8_1","doi-asserted-by":"publisher","DOI":"10.3233\/ADR-230025"},{"key":"e_1_2_8_9_1","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.23-24-08532.2003"},{"key":"e_1_2_8_10_1","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.22-18-07873.2002"},{"key":"e_1_2_8_11_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.brainres.2016.01.028"},{"key":"e_1_2_8_12_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0018296"},{"key":"e_1_2_8_13_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.91.12.5705"},{"key":"e_1_2_8_14_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.ads3204"},{"key":"e_1_2_8_15_1","doi-asserted-by":"publisher","DOI":"10.1146\/annurev-biochem-063011-092449"},{"key":"e_1_2_8_16_1","doi-asserted-by":"publisher","DOI":"10.1038\/d41573-019-00104-w"},{"key":"e_1_2_8_17_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neurobiolaging.2009.11.012"},{"key":"e_1_2_8_18_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuroscience.2011.05.076"},{"key":"e_1_2_8_19_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0038284"},{"key":"e_1_2_8_20_1","doi-asserted-by":"publisher","DOI":"10.1038\/nprot.2014.039"},{"key":"e_1_2_8_21_1","doi-asserted-by":"publisher","DOI":"10.1007\/978-1-4939-7447-4_9"},{"key":"e_1_2_8_22_1","doi-asserted-by":"publisher","DOI":"10.1186\/s12974-015-0379-4"},{"key":"e_1_2_8_23_1","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20231363"},{"key":"e_1_2_8_24_1","doi-asserted-by":"publisher","DOI":"10.1038\/78682"},{"key":"e_1_2_8_25_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-024-61691-2"},{"key":"e_1_2_8_26_1","doi-asserted-by":"publisher","DOI":"10.1186\/s40035-025-00465-w"},{"key":"e_1_2_8_27_1","doi-asserted-by":"publisher","DOI":"10.7554\/eLife.106156"},{"key":"e_1_2_8_28_1","doi-asserted-by":"publisher","DOI":"10.1096\/fj.11-201384"},{"key":"e_1_2_8_29_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41593-025-02125-8"}],"container-title":["Alzheimer's 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