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Here, we tested a two-tier approach for selecting non-cross-reactive mAbs combined with modulating Fc glycosylation as a strategy to doubly secure the elimination of ADE while preserving Fc effector functions. To this end, we selected a ZIKV-specific mAb (ZV54) and generated three ZV54 variants using Chinese hamster ovary cells and wild-type (WT) and glycoengineered \u0394XF Nicotiana benthamiana plants as production hosts (ZV54CHO, ZV54WT, and ZV54\u0394XF). The three ZV54 variants shared an identical polypeptide backbone, but each exhibited a distinct Fc N-glycosylation profile. All three ZV54 variants showed similar neutralization potency against ZIKV but no ADE activity for DENV infection, validating the importance of selecting the virus\/serotype-specific mAbs for avoiding ADE by related flaviviruses. For ZIKV infection, however, ZV54CHO and ZV54\u0394XF showed significant ADE activity while ZV54WT completely forwent ADE, suggesting that Fc glycan modulation may yield mAb glycoforms that abrogate ADE even for homologous viruses. In contrast to the current strategies for Fc mutations that abrogate all effector functions along with ADE, our approach allowed the preservation of effector functions as all ZV54 glycovariants retained antibody-dependent cellular cytotoxicity (ADCC) against the ZIKV-infected cells. Furthermore, the ADE-free ZV54WT demonstrated in vivo efficacy in a ZIKV-infection mouse model. Collectively, our study provides further support for the hypothesis that antibody\u2013viral surface antigen and Fc-mediated host cell interactions are both prerequisites for ADE, and that a dual-approach strategy, as shown herein, contributes to the development of highly safe and efficacious anti-ZIKV mAb therapeutics. Our findings may be impactful to other ADE-prone viruses, including SARS-CoV-2.<\/jats:p>","DOI":"10.3390\/v15051156","type":"journal-article","created":{"date-parts":[[2023,5,12]],"date-time":"2023-05-12T01:05:10Z","timestamp":1683853510000},"page":"1156","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":11,"title":["A Dual-Approach Strategy to Optimize the Safety and Efficacy of Anti-Zika Virus Monoclonal Antibody Therapeutics"],"prefix":"10.3390","volume":"15","author":[{"given":"Haiyan","family":"Sun","sequence":"first","affiliation":[{"name":"The Biodesign Institute and School of Life Sciences, Arizona State University, Tempe, AZ 85287, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1617-9960","authenticated-orcid":false,"given":"Ming","family":"Yang","sequence":"additional","affiliation":[{"name":"The Biodesign Institute and School of Life Sciences, Arizona State University, Tempe, AZ 85287, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Huafang","family":"Lai","sequence":"additional","affiliation":[{"name":"The Biodesign Institute and School of Life Sciences, Arizona State University, Tempe, AZ 85287, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Biswas","family":"Neupane","sequence":"additional","affiliation":[{"name":"Department of Cell and Molecular Biology, University of Southern Mississippi, Hattiesburg, MS 39406, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Audrey Y.-H.","family":"Teh","sequence":"additional","affiliation":[{"name":"Institute for Infection and Immunity, St. George\u2019s, University of London, London SW17 0RE, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9207-7539","authenticated-orcid":false,"given":"Collin","family":"Jugler","sequence":"additional","affiliation":[{"name":"The Biodesign Institute and School of Life Sciences, Arizona State University, Tempe, AZ 85287, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Julian K.-C.","family":"Ma","sequence":"additional","affiliation":[{"name":"Institute for Infection and Immunity, St. George\u2019s, University of London, London SW17 0RE, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4823-1505","authenticated-orcid":false,"given":"Herta","family":"Steinkellner","sequence":"additional","affiliation":[{"name":"Department of Applied Genetics and Cell Biology, University of Natural Resources and Life Sciences, 1180 Vienna, Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fengwei","family":"Bai","sequence":"additional","affiliation":[{"name":"Department of Cell and Molecular Biology, University of Southern Mississippi, Hattiesburg, MS 39406, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1498-7013","authenticated-orcid":false,"given":"Qiang","family":"Chen","sequence":"additional","affiliation":[{"name":"The Biodesign Institute and School of Life Sciences, Arizona State University, Tempe, AZ 85287, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,5,11]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"4864","DOI":"10.1128\/JVI.00252-16","article-title":"Zika Virus: New Clinical Syndromes and Its Emergence in the Western Hemisphere","volume":"90","author":"Lazear","year":"2016","journal-title":"J. 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