De Gasparo R, Pedotti M, Simonelli L, Nickl P, Muecksch F, Cassaniti I, Percivalle E, Lorenzi JCC, Mazzola F, Magrì D, Michalcikova T, Haviernik J, Honig V, Mrazkova B, Polakova N, Fortova A, Tureckova J, Iatsiuk V, Di Girolamo S, Palus M, Zudova D, Bednar P, Bukova I, Bianchini F, Mehn D, Nencka R, Strakova P, Pavlis O, Rozman J, Gioria S, Sammartino JC, Giardina F, Gaiarsa S, Pan-Hammarström Q, Barnes CO, Bjorkman PJ, Calzolai L, Piralla A, Baldanti F, Nussenzweig MC, Bieniasz PD, Hatziioannou T, Prochazka J, Sedlacek R, Robbiani DF, Ruzek D, Varani L
Nature 593 (7859) 424-428 [2021-05-20; online 2021-03-25]
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 based on two antibodies derived from COVID-19 convalescent donors, C121 and C135 3 . CoV-X2 simultaneously binds two independent sites on the RBD and, unlike its parental antibodies, completely prevents S binding to Angiotensin-Converting Enzyme 2 (ACE2), the virus cellular receptor. Furthermore, CoV-X2 recognizes a broad panel of RBD variants and neutralizes SARS-CoV-2 and the escape mutants generated by the single monoclonals at sub-nanomolar concentrations. In a novel 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.