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Fc-engineered antibody therapeutics with improved anti-SARS-CoV-2 efficacy

Author

Listed:
  • Rachel Yamin

    (The Rockefeller University)

  • Andrew T. Jones

    (The Rockefeller University)

  • Hans-Heinrich Hoffmann

    (The Rockefeller University)

  • Alexandra Schäfer

    (University of North Carolina at Chapel Hill)

  • Kevin S. Kao

    (The Rockefeller University)

  • Rebecca L. Francis

    (The Rockefeller University)

  • Timothy P. Sheahan

    (University of North Carolina at Chapel Hill)

  • Ralph S. Baric

    (University of North Carolina at Chapel Hill
    University of North Carolina at Chapel Hill)

  • Charles M. Rice

    (The Rockefeller University)

  • Jeffrey V. Ravetch

    (The Rockefeller University)

  • Stylianos Bournazos

    (The Rockefeller University)

Abstract

Monoclonal antibodies with neutralizing activity against SARS-CoV-2 have demonstrated clinical benefits in cases of mild-to-moderate SARS-CoV-2 infection, substantially reducing the risk for hospitalization and severe disease1–4. Treatment generally requires the administration of high doses of these monoclonal antibodies and has limited efficacy in preventing disease complications or mortality among hospitalized patients with COVID-195. Here we report the development and evaluation of anti-SARS-CoV-2 monoclonal antibodies with optimized Fc domains that show superior potency for prevention or treatment of COVID-19. Using several animal disease models of COVID-196,7, we demonstrate that selective engagement of activating Fcγ receptors results in improved efficacy in both preventing and treating disease-induced weight loss and mortality, significantly reducing the dose required to confer full protection against SARS-CoV-2 challenge and for treatment of pre-infected animals. Our results highlight the importance of Fcγ receptor pathways in driving antibody-mediated antiviral immunity and exclude the possibility of pathogenic or disease-enhancing effects of Fcγ receptor engagement of anti-SARS-CoV-2 antibodies upon infection. These findings have important implications for the development of Fc-engineered monoclonal antibodies with optimal Fc-effector function and improved clinical efficacy against COVID-19 disease.

Suggested Citation

  • Rachel Yamin & Andrew T. Jones & Hans-Heinrich Hoffmann & Alexandra Schäfer & Kevin S. Kao & Rebecca L. Francis & Timothy P. Sheahan & Ralph S. Baric & Charles M. Rice & Jeffrey V. Ravetch & Stylianos, 2021. "Fc-engineered antibody therapeutics with improved anti-SARS-CoV-2 efficacy," Nature, Nature, vol. 599(7885), pages 465-470, November.
  • Handle: RePEc:nat:nature:v:599:y:2021:i:7885:d:10.1038_s41586-021-04017-w
    DOI: 10.1038/s41586-021-04017-w
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    Cited by:

    1. Jaime S. Rosa Duque & Xiwei Wang & Daniel Leung & Samuel M. S. Cheng & Carolyn A. Cohen & Xiaofeng Mu & Asmaa Hachim & Yanmei Zhang & Sau Man Chan & Sara Chaothai & Kelvin K. H. Kwan & Karl C. K. Chan, 2022. "Immunogenicity and reactogenicity of SARS-CoV-2 vaccines BNT162b2 and CoronaVac in healthy adolescents," Nature Communications, Nature, vol. 13(1), pages 1-15, December.
    2. James Brett Case & Samantha Mackin & John M. Errico & Zhenlu Chong & Emily A. Madden & Bradley Whitener & Barbara Guarino & Michael A. Schmid & Kim Rosenthal & Kuishu Ren & Ha V. Dang & Gyorgy Snell &, 2022. "Resilience of S309 and AZD7442 monoclonal antibody treatments against infection by SARS-CoV-2 Omicron lineage strains," Nature Communications, Nature, vol. 13(1), pages 1-11, December.
    3. Franziska K. Kaiser & Mariana Gonzalez Hernandez & Nadine Krüger & Ellinor Englund & Wenjuan Du & Anna Z. Mykytyn & Mathijs P. Raadsen & Mart M. Lamers & Francine Rodrigues Ianiski & Tatiana M. Shamor, 2024. "Filamentous fungus-produced human monoclonal antibody provides protection against SARS-CoV-2 in hamster and non-human primate models," Nature Communications, Nature, vol. 15(1), pages 1-14, December.
    4. Andrew P. Hederman & Harini Natarajan & Leo Heyndrickx & Kevin K. Ariën & Joshua A. Wiener & Peter F. Wright & Evan M. Bloch & Aaron A. R. Tobian & Andrew D. Redd & Joel N. Blankson & Amihai Rottenstr, 2023. "SARS-CoV-2 vaccination elicits broad and potent antibody effector functions to variants of concern in vulnerable populations," Nature Communications, Nature, vol. 14(1), pages 1-11, December.
    5. Yingdan Wang & Aihua Hao & Ping Ji & Yunping Ma & Zhaoyong Zhang & Jiali Chen & Qiyu Mao & Xinyi Xiong & Palizhati Rehati & Yajie Wang & Yanqun Wang & Yumei Wen & Lu Lu & Zhenguo Chen & Jincun Zhao & , 2024. "A bispecific antibody exhibits broad neutralization against SARS-CoV-2 Omicron variants XBB.1.16, BQ.1.1 and sarbecoviruses," Nature Communications, Nature, vol. 15(1), pages 1-13, December.

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