biostudies-literatureDe Gasparo RSwiss National Science FoundationHoward Hughes Medical InstituteNIAID NIH HHSNIH HHS424-428https://www.ebi.ac.uk/biostudies/studies/S-EPMC12910678biostudies-literatureUnknown593(7859)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-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 lungNatureBispecific IgG neutralizes SARS-CoV-2 variants and prevents escape in mice.PMC12910678P50 AI150464P01-AI138398-S1U01 AI151698R01 AI0787882U19AI111825182270R37 AI064003Nickl PRobbiani DFNussenzweig MCMehn DHaviernik JBaldanti FMazzola FBednar PRuzek DMuecksch FProchazka JSimonelli LLorenzi JCCStrakova PHonig VFortova APolakova NBarnes COBjorkman PJPiralla AVarani LTureckova JCalzolai LMichalcikova TBukova IGaiarsa SPedotti MCassaniti INencka RSammartino JCHatziioannou TDe Gasparo RPalus MMagri DMrazkova BZudova DBianchini FPercivalle EBieniasz PDGioria SRozman JGiardina FPavlis OIatsiuk VSedlacek RDi Girolamo SPan-Hammarstrom QfalseBispecific IgG neutralizes SARS-CoV-2 variants and prevents escape in mice.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-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 lung2021-01-01T00:00:00Z2021 May2026-07-16T05:15:01.209Z2026-07-09T13:09:54.138ZS-EPMC129106783376744510.1038/s41586-021-03461-y