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Human neutralizing antibodies to cold linear epitopes and subdomain 1 of the SARS-CoV-2 spike glycoprotein. 2023
Filippo Bianchini, and
Virginia Crivelli, and
Morgan E Abernathy, and
Concetta Guerra, and
Martin Palus, and
Jonathan Muri, and
Harold Marcotte, and
Antonio Piralla, and
Mattia Pedotti, and
Raoul De Gasparo, and
Luca Simonelli, and
Milos Matkovic, and
Chiara Toscano, and
Maira Biggiogero, and
Veronica Calvaruso, and
Pavel Svoboda, and
Tomás Cervantes Rincón, and
Tommaso Fava, and
Lucie Podešvová, and
Akanksha A Shanbhag, and
Andrea Celoria, and
Jacopo Sgrignani, and
Michal Stefanik, and
Vaclav Hönig, and
Veronika Pranclova, and
Tereza Michalcikova, and
Jan Prochazka, and
Giuditta Guerrini, and
Dora Mehn, and
Annalisa Ciabattini, and
Hassan Abolhassani, and
David Jarrossay, and
Mariagrazia Uguccioni, and
Donata Medaglini, and
Qiang Pan-Hammarström, and
Luigi Calzolai, and
Daniel Fernandez, and
Fausto Baldanti, and
Alessandra Franzetti-Pellanda, and
Christian Garzoni, and
Radislav Sedlacek, and
Daniel Ruzek, and
Luca Varani, and
Andrea Cavalli, and
Christopher O Barnes, and
Davide F Robbiani
Institute for Research in Biomedicine, Università della Svizzera italiana, Bellinzona, Switzerland.
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.
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