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

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 Haviernik, Vaclav Honig, Blanka Mrazkova, Natalie Polakova, Andrea Fortova, Jolana Tureckova, Veronika Iatsiuk, Salvatore Girolamo, Martin Palus, Dagmar Zudova, Petr Bednar, Ivana Bukova, Filippo Bianchini, Dora Mehn, Radim Nencka, Petra Strakova, Oto Pavlis, Jan Rozman, Sabrina Gioria, Josè Camilla Sammartino, Federica Giardina, Stefano Gaiarsa, Qiang Pan-Hammarström, Christopher O. Barnes, Pamela J. Bjorkman, Luigi Calzolai, Antonio Piralla, Fausto Baldanti, Michel C. Nussenzweig, Paul D. Bieniasz, Theodora Hatziioannou, Jan Prochazka, Radislav Sedlacek, Davide F. Robbiani (), Daniel Ruzek () and Luca Varani ()
Additional contact information
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
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
Dagmar Zudova: Institute of Molecular Genetics of the Czech Academy of Sciences
Petr Bednar: Veterinary Research Institute
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
Michel C. Nussenzweig: The Rockefeller University
Paul D. Bieniasz: 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
Luca Varani: Università della Svizzera italiana (USI)

Nature, 2021, vol. 593, issue 7859, 424-428

Abstract: 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.

Date: 2021
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DOI: 10.1038/s41586-021-03461-y

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