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. A bispecifc 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 infammation, CoV-X2 protects mice
from disease and suppresses viral escape. Thus, the simultaneous targeting of non-overlapping RBD epitopes by IgG-like bispecifc antibodies is feasible and effective, and combines the advantages of antibody cocktails with those of single-molecule approaches.
DE GASPARO Raul;
PEDOTTI Mattia;
SIMONELLI L.;
NICKL Petr;
MUECKSCH Frauke;
CASSANITI Irene;
PERCIVALLE Elena;
LORENZI Julio;
MAZZOLA Federica;
MAGRI Davide;
MICHALCIKOVA Tereza;
HAVIERNICK 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;
MĖHN Dóra;
NENCKA Radim;
STRAKOVA Petra;
PAVLIS Otto;
ROZMAN Jan;
GIORIA Sabrina;
SAMMARTINO Josè;
GIARDINA Federica;
GAIARSA Stefano;
PAN-HAMMARSTRÖM Qiang;
BARNES Christopher;
BJORKMAN Pamela;
CALZOLAI Luigi;
PIRALLA Antonio;
BALDANTI Fausto;
NUSSENZWEIG Michel;
BIENIASZ Paul;
HATZIIOANNOU Theodora;
PROCHAZKA Jan;
SEDLACEK Radislav;
ROBBIANI Davide;
RUZEK Daniel;
VARANI Luca;
2021-11-16
NATURE PUBLISHING GROUP
JRC123490
0028-0836 (online),
https://www.nature.com/articles/s41586-021-03461-y,
https://publications.jrc.ec.europa.eu/repository/handle/JRC123490,
10.1038/s41586-021-03461-y (online),
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