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

• Published in: Nature (London) Vol. 593; no. 7859; pp. 424 - 428
• Main Authors: De Gasparo, Raoul, Pedotti, Mattia, Simonelli, Luca, Nickl, Petr, Muecksch, Frauke, Cassaniti, Irene, Percivalle, Elena, Lorenzi, Julio C. C., Mazzola, Federica, Magrì, Davide, Michalcikova, Tereza, Haviernik, Jan, Honig, Vaclav, Mrazkova, Blanka, Polakova, Natalie, Fortova, Andrea, Tureckova, Jolana, Iatsiuk, Veronika, Di Girolamo, Salvatore, Palus, Martin, Zudova, Dagmar, Bednar, Petr, Bukova, Ivana, Bianchini, Filippo, Mehn, Dora, Nencka, Radim, Strakova, Petra, Pavlis, Oto, Rozman, Jan, Gioria, Sabrina, Sammartino, Josè Camilla, Giardina, Federica, Gaiarsa, Stefano, Pan-Hammarström, Qiang, Barnes, Christopher O., Bjorkman, Pamela J., Calzolai, Luigi, Piralla, Antonio, Baldanti, Fausto, Nussenzweig, Michel C., Bieniasz, Paul D., Hatziioannou, Theodora, Prochazka, Jan, Sedlacek, Radislav, Robbiani, Davide F., Ruzek, Daniel, Varani, Luca
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 20.05.2021; Nature Publishing Group
• Subjects: 101/1; 13/51; 45; 631/154/51/1568; 631/250/251/1567; 631/250/255/2514; 631/326/596/4130; 631/61/338/469; 64/60; 82/103; 82/16; 82/80; 82/83; ACE2; Analysis; Angiotensin; Angiotensin-converting enzyme 2; Antigenic determinants; Antigens; Binding; Binding sites; Bispecific antibodies; Coronaviruses; COVID-19; Enzymes; Epitopes; Health aspects; Humanities and Social Sciences; Identification and classification; Immunoglobulin G; Infections; Inflammation; Lungs; Medicin och hälsovetenskap; Monoclonal antibodies; multidisciplinary; Mutation; Peptidyl-dipeptidase A; Properties; Receptors; Science; Science (multidisciplinary); Severe acute respiratory syndrome coronavirus 2; Spike protein; Viral diseases; Czech Republic; United States
• ISSN: 0028-0836; 1476-4687; 1476-4687
• DOI: 10.1038/s41586-021-03461-y

Neutralizing antibodies that target the receptor-binding domain (RBD) of the SARS-CoV-2 spike protein are among the most promising approaches against COVID-19 1 , 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-19 3 . 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. The bispecific IgG1-like CoV-X2 prevents SARS-CoV-2 spike binding to ACE2, neutralizes SARS-CoV-2 and its variants of concern, protects against disease in a mouse model, whereas the parental monoclonal antibodies generate viral escape.