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Bispecific IgG neutralizes SARS-CoV-2 variants and prevents escape in mice

Author

Listed:
  • Raoul Gasparo

    (Università della Svizzera italiana (USI))

  • Mattia Pedotti

    (Università della Svizzera italiana (USI))

  • Luca Simonelli

    (Università della Svizzera italiana (USI))

  • Petr Nickl

    (Institute of Molecular Genetics of the Czech Academy of Sciences)

  • Frauke Muecksch

    (The Rockefeller University)

  • Irene Cassaniti

    (Fondazione IRCCS Policlinico San Matteo)

  • Elena Percivalle

    (Fondazione IRCCS Policlinico San Matteo)

  • Julio C. C. Lorenzi

    (The Rockefeller University)

  • Federica Mazzola

    (Università della Svizzera italiana (USI))

  • Davide Magrì

    (Joint Research Centre)

  • Tereza Michalcikova

    (Institute of Molecular Genetics of the Czech Academy of Sciences)

  • Jan Haviernik

    (Veterinary Research Institute)

  • Vaclav Honig

    (Veterinary Research Institute
    Biology Centre of the Czech Academy of Sciences)

  • Blanka Mrazkova

    (Institute of Molecular Genetics of the Czech Academy of Sciences)

  • Natalie Polakova

    (Institute of Molecular Genetics of the Czech Academy of Sciences)

  • Andrea Fortova

    (Veterinary Research Institute)

  • Jolana Tureckova

    (Institute of Molecular Genetics of the Czech Academy of Sciences)

  • Veronika Iatsiuk

    (Institute of Molecular Genetics of the Czech Academy of Sciences)

  • Salvatore Girolamo

    (Università della Svizzera italiana (USI))

  • Martin Palus

    (Veterinary Research Institute
    Biology Centre of the Czech Academy of Sciences)

  • Dagmar Zudova

    (Institute of Molecular Genetics of the Czech Academy of Sciences)

  • Petr Bednar

    (Veterinary Research Institute
    University of South Bohemia)

  • Ivana Bukova

    (Institute of Molecular Genetics of the Czech Academy of Sciences)

  • Filippo Bianchini

    (Università della Svizzera italiana (USI))

  • Dora Mehn

    (Joint Research Centre)

  • Radim Nencka

    (Institute of Organic Chemistry and Biochemistry of the Czech Academy of Sciences)

  • Petra Strakova

    (Veterinary Research Institute)

  • Oto Pavlis

    (Military Health Institute, Military Medical Agency)

  • Jan Rozman

    (Institute of Molecular Genetics of the Czech Academy of Sciences)

  • Sabrina Gioria

    (Joint Research Centre)

  • Josè Camilla Sammartino

    (Fondazione IRCCS Policlinico San Matteo)

  • Federica Giardina

    (Fondazione IRCCS Policlinico San Matteo)

  • Stefano Gaiarsa

    (Fondazione IRCCS Policlinico San Matteo)

  • Qiang Pan-Hammarström

    (Karolinska Institutet)

  • Christopher O. Barnes

    (California Institute of Technology)

  • Pamela J. Bjorkman

    (California Institute of Technology)

  • Luigi Calzolai

    (Joint Research Centre)

  • Antonio Piralla

    (Fondazione IRCCS Policlinico San Matteo)

  • Fausto Baldanti

    (Fondazione IRCCS Policlinico San Matteo
    Università degli Studi di Pavia)

  • Michel C. Nussenzweig

    (The Rockefeller University
    The Rockefeller University)

  • Paul D. Bieniasz

    (The Rockefeller University
    The Rockefeller University)

  • Theodora Hatziioannou

    (The Rockefeller University)

  • Jan Prochazka

    (Institute of Molecular Genetics of the Czech Academy of Sciences)

  • Radislav Sedlacek

    (Institute of Molecular Genetics of the Czech Academy of Sciences)

  • Davide F. Robbiani

    (Università della Svizzera italiana (USI))

  • Daniel Ruzek

    (Veterinary Research Institute
    Biology Centre of the Czech Academy of Sciences)

  • Luca Varani

    (Università della Svizzera italiana (USI))

Abstract

Neutralizing antibodies that target the receptor-binding domain (RBD) of the SARS-CoV-2 spike protein are among the most promising approaches against COVID-191,2. A bispecific IgG1-like molecule (CoV-X2) has been developed on the basis of C121 and C135, two antibodies derived from donors who had recovered from COVID-193. Here we show that CoV-X2 simultaneously binds two independent sites on the RBD and, unlike its parental antibodies, prevents detectable spike binding to the cellular receptor of the virus, angiotensin-converting enzyme 2 (ACE2). Furthermore, CoV-X2 neutralizes wild-type SARS-CoV-2 and its variants of concern, as well as escape mutants generated by the parental monoclonal antibodies. We also found that in a mouse model of SARS-CoV-2 infection with lung inflammation, CoV-X2 protects mice from disease and suppresses viral escape. Thus, the simultaneous targeting of non-overlapping RBD epitopes by IgG-like bispecific antibodies is feasible and effective, and combines the advantages of antibody cocktails with those of single-molecule approaches.

Suggested Citation

  • Raoul Gasparo & Mattia Pedotti & Luca Simonelli & Petr Nickl & Frauke Muecksch & Irene Cassaniti & Elena Percivalle & Julio C. C. Lorenzi & Federica Mazzola & Davide Magrì & Tereza Michalcikova & Jan , 2021. "Bispecific IgG neutralizes SARS-CoV-2 variants and prevents escape in mice," Nature, Nature, vol. 593(7859), pages 424-428, May.
    • Handle: RePEc:nat:nature:v:593:y:2021:i:7859:d:10.1038_s41586-021-03461-y
    DOI: 10.1038/s41586-021-03461-y
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    Cited by:

    1. Zhiqiang Ku & Xuping Xie & Jianqing Lin & Peng Gao & Bin Wu & Abbas El Sahili & Hang Su & Yang Liu & Xiaohua Ye & Eddie Yongjun Tan & Xin Li & Xuejun Fan & Boon Chong Goh & Wei Xiong & Hannah Boyd & A, 2022. "Engineering SARS-CoV-2 specific cocktail antibodies into a bispecific format improves neutralizing potency and breadth," Nature Communications, Nature, vol. 13(1), pages 1-12, December.
    2. Yubin Liu & Ziyi Wang & Xinyu Zhuang & Shengnan Zhang & Zhicheng Chen & Yan Zou & Jie Sheng & Tianpeng Li & Wanbo Tai & Jinfang Yu & Yanqun Wang & Zhaoyong Zhang & Yunfeng Chen & Liangqin Tong & Xi Yu, 2023. "Inactivated vaccine-elicited potent antibodies can broadly neutralize SARS-CoV-2 circulating variants," Nature Communications, Nature, vol. 14(1), pages 1-17, December.

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