Human neutralizing antibodies to cold linear epitopes and subdomain 1 of the SARS-CoV-2 spike glycoprotein

• Authors: BIANCHINI Filippo; CRIVELLI Virginia; ABERNATHY Morgan E.; GUERRA Concetta; PALUS Martin; MURI Jonathan; MARCOTTE Harold; PIRALLA Antonio; PEDOTTI Mattia; DE GASPARO Raoul; SIMONELLI Luca; MATKOVIC Milos; TOSCANO Chiara; BIGGIOGERO Maira; CALVARUSO Veronica; SVOBODA Pavel; CERVANTES RINCÓN Tomás; FAVA Tommaso; PODEŠVOVÁ Lucie; SHANBHAG Akanksha A.; CELORIA Andrea; SGRIGNANI Jacopo; STEFANIK Michal; HÖNIG Václav; PRANCLOVA Veronika; MICHALCIKOVA Tereza; PROCHAZKA Jan; GUERRINI Giuditta; MEHN Dora; CIABATTINI Annalisa; ABOLHASSANI Hassan; JARROSSAY David; UGUCCIONI Mariagrazia; MEDAGLINI Donata; PAN-HAMMARSTRÖM Qiang; CALZOLAI Luigi; FERNANDEZ Daniel; BALDANTI Fausto; FRANZETTI-PELLANDA Alessandra; GARZONI Christian; SEDLACEK Radislav; RŮŽEK Daniel; VARANI Luca; CAVALLI Andrea; BARNES Christopher O.; ROBBIANI Davide F.
• Year of publication: 2023
• Type: Article in Periodical
• Magazine / Source: Science Immunology
• MU Faculty or unit: Faculty of Science
• Web: https://doi.org/10.1126/sciimmunol.ade0958
• Doi: http://dx.doi.org/10.1126/sciimmunol.ade0958
• Keywords: SARS-CoV-2; coronavirus; vaccines; antiviral monoclonal antibodies
• Description: Emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants diminishes the efficacy of vaccines and antiviral monoclonal antibodies. Continued development of immunotherapies and vaccine immunogens resilient to viral evolution is therefore necessary. Using coldspot-guided antibody discovery, a screening approach that focuses on portions of the virus spike glycoprotein that are both functionally relevant and averse to change, we identified human neutralizing antibodies to highly conserved viral epitopes. Antibody fp.006 binds the fusion peptide and cross-reacts against coronaviruses of the four genera, including the nine human coronaviruses, through recognition of a conserved motif that includes the S2' site of proteolytic cleavage. Antibody hr2.016 targets the stem helix and neutralizes SARS-CoV-2 variants. Antibody sd1.040 binds to subdomain 1, synergizes with antibody rbd.042 for neutralization, and, similar to fp.006 and hr2.016, protects mice expressing human angiotensin-converting enzyme 2 against infection when present as a bispecific antibody. Thus, coldspot-guided antibody discovery reveals donor-derived neutralizing antibodies that are cross-reactive with Orthocoronavirinae, including SARS-CoV-2 variants.