Bispecific antibody neutralizes circulating SARS-CoV-2 variants, prevents escape and protects mice from disease

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; Girolamo, Salvatore Di; Palus, Martin; Zudova, Dagmar; Bednar, Petr; Bukova, Ivana; Bianchini, Filippo; Mehn, Dora; Nencka, Radim; Strakova, Petra; Pavlis, Oto; Rozman, Jan; Gioria, Sabrina; Camilla Sammartino, Josè; Giardina, Federica; Gaiarsa, Stefano; Hammarström, Qiang Pan; 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

Neutralizing antibodies targeting the receptor binding domain (RBD) of the SARS-CoV-2 Spike (S) are among the most promising approaches against coronavirus disease 2019 (COVID-19)1,2. We developed a bispecific, IgG1-like molecule (CoV-X2) based on two antibodies derived from COVID-19 convalescent donors, C121 and C1353. CoV-X2 simultaneously binds two independent sites on the RBD and, unlike its parental antibodies, prevents detectable S binding to Angiotensin-Converting Enzyme 2 (ACE2), the virus cellular receptor. Furthermore, CoV-X2 neutralizes SARS-CoV-2 and its variants of concern, as well as the escape mutants generated by the parental monoclonals. In a novel animal model of SARS-CoV-2 infection with lung inflammation, CoV-X2 protects mice from disease and suppresses viral escape. Thus, simultaneous targeting of non-overlapping RBD epitopes by IgG-like bispecific antibodies is feasible and effective, combining into a single molecule the advantages of antibody cocktails.