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Extremely potent human monoclonal antibodies from COVID-19 convalescent patients

Emanuele Andreano1, Emanuele Nicastri4, Ida Paciello1, Piero Pileri1, Noemi Manganaro1, Giulia Piccini2, Alessandro Manenti2,3, Elisa Pantano1, Anna Kabanova1,11, Marco Troisi1,9, Fabiola Vacca1,9, Dario Cardamone1,10, Concetta De Santi1, Jonathan L. Torres16, Gabriel Ozorowski16, Linda Benincasa3, Hyesun Jang13, Cecilia Di Genova15, Lorenzo Depau12, Jlenia Brunetti12, Chiara Agrati4, Maria Rosaria Capobianchi4, Concetta Castilletti4, Arianna Emiliozzi5,6, Massimiliano Fabbiani6, Francesca Montagnani5,6, Luisa Bracci12, Giuseppe Sautto13, Ted M. Ross13,14, Emanuele Montomoli2,3,7, Nigel Temperton15, Andrew B. Ward16, Claudia Sala1, Giuseppe Ippolito4, Rino Rappuoli1,8,

1Monoclonal Antibody Discovery (MAD) Lab, Fondazione Toscana Life Sciences, Siena, Italy; 2VisMederi S.r.l, Siena, Italy; 3VisMederi Research S.r.l., Siena, Italy; 4National Institute for Infectious Diseases Lazzaro Spallanzani, IRCCS, Rome, Italy; 5Department of Medical Biotechnologies, University of Siena, Siena, Italy; 6Department of Medical Sciences, Infectious and Tropical Diseases Unit, University Hospital of Siena, Siena, Italy; 7Department of Molecular and Developmental Medicine, University of Siena, Siena, Italy; 8Faculty of Medicine, Imperial College, London, United Kingdom; 9Department of Biotechnology, Chemistry and Pharmacy, University of Siena, Siena, Italy; 10University of Turin, Turin, Italy; 11Tumour Immunology Unit, Fondazione Toscana Life Sciences, Siena, Italy; 12MedBiotech Hub and Competence Center, Department of Medical Biotechnologies, University of Siena; 13Center for Vaccines and Immunology, University of Georgia, Athens, GA 30602, USA; 14Department of Infectious Diseases, University of Georgia, Athens, GA 30602, USA; 15Viral Pseudotype Unit, Medway School of Pharmacy, University of Kent, Chatham, UK; 16Department of Integrative Structural and Computational Biology, The Scripps Research Institute, La Jolla, CA 92037

Human monoclonal antibodies are safe, preventive and therapeutic tools, that can be rapidly developed to help restore the massive health and economic disruption caused by the COVID-19 pandemic. By single cell sorting 4,277 SARS-CoV-2 spike protein specific memory B cells from 14 COVID-19 survivors, 453 neutralizing antibodies were identified. The Fc portion of the three most potent antibodies was engineered to reduce the risk of antibody dependent enhancement (ADE) of disease and extend serum half-life. Despite silencing of Fc-functions, the most potent antibody was able to protect hamsters from viral challenge at very low concentrations. Since escape mutants are a major concern for the development of monoclonal antibodies for therapy and prophylaxis, we incubated the monoclonal with the authentic SARS-CoV-2 virus. Over 60 days of co-incubation were required before the first detection of a partial escape mutant. Furthermore, the antibody was able to neutralize viruses carrying the E484K mutation which are commonly selected as escape mutant by many of the described antibodies. The extreme in vitro and in vivo potency of the antibody combined with its ability to neutralize the most common natural variants of the virus and the difficulty to generate escape mutants, make this antibody a suitable candidate for affordable and accessible prophylactic and therapeutic tool against SARS-CoV-2.