Neutralizing antibodies that target the receptor-binding domain (RBD) of the SARS-CoV-2 spike protein are among the most promising approaches against COVID-191,2. 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 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.

Center of Biological Defense Military Health Institute Military Medical Agency Techonin Czech Republic

Czech Centre of Phenogenomics and Laboratory of Transgenic Models of Diseases Institute of Molecular Genetics of the Czech Academy of Sciences Vestec Czech Republic

Department of Biosciences and Nutrition Karolinska Institutet Huddinge Sweden

Department of Clinical Surgical Diagnostic and Pediatric Sciences Università degli Studi di Pavia Italy

Division of Biology and Biological Engineering California Institute of Technology Pasadena CA USA

European Commission Joint Research Centre Ispra Italy

Faculty of Science University of South Bohemia Ceske Budejovice Czech Republic

Howard Hughes Medical Institute The Rockefeller University New York NY USA

Institute for Research in Biomedicine Università della Svizzera italiana Bellinzona Switzerland

Institute of Organic Chemistry and Biochemistry of the Czech Academy of Sciences Prague Czech Republic

Institute of Parasitology Biology Centre of the Czech Academy of Sciences Ceske Budejovice Czech Republic

Laboratory of Molecular Immunology The Rockefeller University New York NY USA

Laboratory of Retrovirology The Rockefeller University New York NY USA

Molecular Virology Unit Microbiology and Virology Department Fondazione IRCCS Policlinico San Matteo Pavia Italy

Veterinary Research Institute Brno Czech Republic

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