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However, dual strategies combining virus neutralization and immune response stimulation to enhance specific cytotoxic T cell responses, such as dendritic cell (DC) cross\u2010priming, represent a promising field but have not yet been explored. Here, a broadly nAb, TN<jats:sup>T<\/jats:sup>, are first generated by grafting an anti\u2010RBD biparatopic tandem nanobody onto a trimerbody scaffold. Cryo\u2010EM data show that the TN<jats:sup>T<\/jats:sup> structure allows simultaneous binding to all six RBD epitopes, demonstrating a high\u2010avidity neutralizing interaction. Then, by C\u2010terminal fusion of an anti\u2010DNGR\u20101 scFv to TN<jats:sup>T<\/jats:sup>, the bispecific trimerbody TN<jats:sup>T<\/jats:sup>DNGR\u20101 is generated to target neutralized virions to type 1 conventional DCs (cDC1s) and promote T cell cross\u2010priming. Therapeutic administration of TN<jats:sup>T<\/jats:sup>DNGR\u20101, but not TN<jats:sup>T<\/jats:sup>, protects K18\u2010hACE2 mice from a lethal SARS\u2010CoV\u20102 infection, boosting virus\u2010specific humoral responses and CD8<jats:sup>+<\/jats:sup> T cell responses. These results further strengthen the central role of interactions with immune cells in the virus\u2010neutralizing antibody activity and demonstrate the therapeutic potential of the Fc\u2010free strategy that can be used advantageously to provide both immediate and long\u2010term protection against SARS\u2010CoV\u20102 and other viral infections.<\/jats:p>","DOI":"10.1002\/advs.202304818","type":"journal-article","created":{"date-parts":[[2023,10,20]],"date-time":"2023-10-20T21:55:32Z","timestamp":1697838932000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Dendritic Cell\u2010Mediated Cross\u2010Priming by a Bispecific Neutralizing Antibody Boosts Cytotoxic T Cell Responses and Protects Mice against SARS\u2010CoV\u20102"],"prefix":"10.1002","volume":"10","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6885-3486","authenticated-orcid":false,"given":"Rodrigo","family":"L\u00e1zaro\u2010Gorines","sequence":"first","affiliation":[{"name":"Cancer Immunotherapy Unit (UNICA) Department of Immunology Hospital Universitario 12 de Octubre  Madrid 28041 Spain"},{"name":"Immuno\u2010Oncology and Immunotherapy Group Instituto de Investigaci\u00f3n Sanitaria 12 de Octubre (imas12)  Madrid 28041 Spain"},{"name":"H12O\u2010CNIO Cancer Immunotherapy Clinical Research Unit Centro Nacional de Investigaciones Oncol\u00f3gicas (CNIO)  Madrid 28029 Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8983-6784","authenticated-orcid":false,"given":"Patricia","family":"P\u00e9rez","sequence":"additional","affiliation":[{"name":"Department of Molecular and Cellular Biology Centro Nacional de Biotecnolog\u00eda (CNB) Consejo Superior de Investigaciones 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