SARS-CoV-2 RBD antibodies that maximize breadth and resistance to escape

• DOI: 10.1038/s41586-021-03807-6
• Publication Date: 2021-07-14T10:03:36Z
• Authors: Tyler N. Starr; Nadine Czudnochowski; Zhuoming Liu; Fabrizia Zatta; Young-Jun Park; Amin Addetia; Dora Pinto; Martina Beltramello; Patrick Hernandez; Allison J. Greaney; Roberta Marzi; William G. Glass; Ivy Zhang; Adam S. Dingens; John E. Bowen; M. Alejandra Tort...; Alexandra C. Walls; Jason A. Wojcecho...; Anna De Marco; Laura E. Rosen; Jiayi Zhou; Martin Montiel-Ruiz; Hannah Kaiser; Josh R. Dillen; Heather Tucker; Jessica Bassi; Chiara Silacci-Fr...; Michael P. Housley; Julia di Iulio; Gloria Lombardo; Maria Agostini; Nicole Sprugasci; Katja Culap; Stefano Jaconi; Marcel Meury; Exequiel Dellota Jr; Rana Abdelnabi; Shi-Yan Caroline Foo; Elisabetta Cameroni; Spencer Stumpf; Tristan I. Croll; Jay C. Nix; Colin Havenar-Dau...; Luca Piccoli; Fabio Benigni; Johan Neyts; Amalio Telenti; Florian A. Lempp; Matteo S. Pizzuto; John D. Chodera; Christy M. Hebner; Herbert W. Virgin; Sean P. J. Whelan; David Veesler; Davide Corti; Jesse D. Bloom; Gyorgy Snell
• Keywords: Male; Models, Molecular; Coronaviruses; Antibody Affinity; Antibodies, Viral; Epitopes; Coronaviruses Therapeutics and Interventions; RESPIRATORY SYNDROME CORONAVIRUS; Models; Cricetinae; Monoclonal; Viral; REFINEMENT; B-Lymphocyte; Antibodies, Monoclonal; Middle Aged; Spike Glycoprotein; 3. Good health; Multidisciplinary Sciences; Vaccinology; Infectious Diseases; Medical Microbiology; 5.1 Pharmaceuticals; Spike Glycoprotein, Coronavirus; Science & Technology - Other Topics; Epitopes, B-Lymphocyte; Female; Infection; Biotechnology; Adult; COVID-19 Vaccines; General Science & Technology; Immunology; 610; Cross Reactions; Antibodies; Cell Line; Vaccine Related; NEUTRALIZING ANTIBODY; Biodefense; Animals; Humans; Aged; Immune Evasion; Science & Technology; RECEPTOR-BINDING DOMAIN; SARS-LIKE; Biomedical and Clinical Sciences; Mesocricetus; MUTATIONS; SARS-CoV-2; Molecular; COVID-19; COVID-19 Drug Treatment; Coronavirus; Emerging Infectious Diseases; Good Health and Well Being; Immunization; Broadly Neutralizing Antibodies; RESPONSES

An ideal therapeutic anti-SARS-CoV-2 antibody would resist viral escape1-3, have activity against diverse sarbecoviruses4-7, and be highly protective through viral neutralization8-11 and effector functions12,13. Understanding how these properties relate to each other and vary across epitopes would aid the development of therapeutic antibodies and guide vaccine design. Here we comprehensively characterize escape, breadth and potency across a panel of SARS-CoV-2 antibodies targeting the receptor-binding domain (RBD). Despite a trade-off between in vitro neutralization potency and breadth of sarbecovirus binding, we identify neutralizing antibodies with exceptional sarbecovirus breadth and a corresponding resistance to SARS-CoV-2 escape. One of these antibodies, S2H97, binds with high affinity across all sarbecovirus clades to a cryptic epitope and prophylactically protects hamsters from viral challenge. Antibodies that target the angiotensin-converting enzyme 2 (ACE2) receptor-binding motif (RBM) typically have poor breadth and are readily escaped by mutations despite high neutralization potency. Nevertheless, we also characterize a potent RBM antibody (S2E128) with breadth across sarbecoviruses related to SARS-CoV-2 and a high barrier to viral escape. These data highlight principles underlying variation in escape, breadth and potency among antibodies that target the RBD, and identify epitopes and features to prioritize for therapeutic development against the current and potential future pandemics.