SARS-CoV-2 RBD antibodies that maximize breadth and resistance to escape.
СтатьяПоддержка NIH: внешняя программаПоддержка исследования: вне правительства СШАПоддержка правительства СШАНазвание и аннотация: Перевод в очереди
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Starr Tyler N, Czudnochowski Nadine, Liu Zhuoming, Zatta Fabrizia, Park Young-Jun, Addetia Amin, Pinto Dora, Beltramello Martina, Hernandez Patrick, Greaney Allison J, Marzi Roberta, Glass William G, Zhang Ivy, Dingens Adam S, Bowen John E, Tortorici M Alejandra, Walls Alexandra C, Wojcechowskyj Jason A, De Marco Anna, Rosen Laura E, Zhou Jiayi, Montiel-Ruiz Martin, Kaiser Hannah, Dillen Josh R, Tucker Heather, Bassi Jessica, Silacci-Fregni Chiara, Housley Michael P, di Iulio Julia, Lombardo Gloria, Agostini Maria, Sprugasci Nicole, Culap Katja, Jaconi Stefano, Meury Marcel, Dellota Exequiel, Abdelnabi Rana, Foo Shi-Yan Caroline, Cameroni Elisabetta, Stumpf Spencer, Croll Tristan I, Nix Jay C, Havenar-Daughton Colin, Piccoli Luca, Benigni Fabio, Neyts Johan, Telenti Amalio, Lempp Florian A, Pizzuto Matteo S, Chodera John D, Hebner Christy M, Virgin Herbert W, Whelan Sean P J, Veesler David, Corti Davide, Bloom Jesse D, Snell Gyorgy
Аннотация
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.