Cell Reports 2022 | Volume 39 | Issue 7 | 24 APR 2022

Kathryn Westendorf, Stefanie Zentelis, Lingshu Wang, Denisa Foster, Peter Vaillancourt, Matthew Wiggin, Erica Lovett, Robin van der Lee, Jorg Hendle, Anna Pustilnik, J. Michael Sauder, Lucas Kraft, Yuri Hwang, Robert W. Siegel, Jinbiao Chen, Beverly A. Heinz, Richard E. Higgs, Nicole L. Kallewaard, Kevin Jepson, Rodrigo Goya, Maia A. Smith, David W. Collins, Davide Pellacani, Ping Xiang, Valentine de Puyraimond, Marketa Ricicova, Lindsay Devorkin, Caitlin Pritchard, Aoise O’Neill, Kush Dalal, Pankaj Panwar, Harveer Dhupar, Fabian A. Garces, Courtney A. Cohen, John M. Dye, Kathleen E. Huie, Catherine V. Badger, Darwyn Kobasa, Jonathan Audet, Joshua J. Freitas, Saleema Hassanali, Ina Hughes, Luis Munoz, Holly C. Palma, Bharathi Ramamurthy, Robert W. Cross, Thomas W. Geisbert, Vineet Menachery, Kumari Lokugamage, Viktoriya Borisevich, Iliana Lanz, Lisa Anderson, Payal Sipahimalani, Kizzmekia S. Corbett, Eun Sung Yang, Yi Zhang, Wei Shi, Tongqing Zhou, Misook Choe, John Misasi, Peter D. Kwong, Nancy J. Sullivan, Barney S. Graham, Tara L. Fernandez, Carl L. Hansen, Ester Falconer, John R. Mascola, Bryan E. Jones, and Bryan C. Barnhart

Hightlights

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-neutralizing monoclonal antibodies (mAbs) can reduce the risk of hospitalization from coronavirus disease 2019 (COVID-19) when administered early. However, SARS-CoV-2 variants of concern (VOCs) have negatively affected therapeutic use of some authorized mAbs. Using a high-throughput B cell screening pipeline, we isolated LY-CoV1404 (bebtelovimab), a highly potent SARS-CoV-2 spike glycoprotein receptor binding domain (RBD)-specific antibody. LYCoV1404 potently neutralizes authentic SARS-CoV-2,B.1.1.7,B.1.351, and B.1.617.2. In pseudovirus neutralization studies, LY-CoV1404 potently neutralizes variants, including B.1.1.7, B.1.351, B.1.617.2, B.1.427/ B.1.429, P.1, B.1.526, B.1.1.529, and the BA.2 subvariant. Structural analysis reveals that the contact residues of the LY-CoV1404 epitope are highly conserved, except for N439 and N501. The binding and neutralizing activity of LY-CoV1404 is unaffected by the most common mutations at these positions (N439K and N501Y). The broad and potent neutralization activity and the relatively conserved epitope suggest that LY-CoV1404 has the potential to be an effective therapeutic agent to treat all known variants.

Introduction

Variants of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) continue to alter the trajectory of the coronavirus disease 2019 (COVID-19) pandemic, which, at the time of writing, has infected over 416 million people worldwide and is responsible for more than 5.8 million deaths (https://covid19.who.int/, accessed February 17, 2022). As predicted, SARS-CoV-2 has continued to evolve as the pandemic has progressed (). Selective pressure and viral adaptation during prolonged, suboptimally treated infections are thought to have generated numerous variants (), some significantly diminishing the effectiveness of COVID-19 clinical countermeasures (). Variants of concern (VOCs) are a closely monitored subset of the many detected SARS-CoV-2 variants because of their potential for increased transmissibility and ability to evade immunity produced by infection or vaccines while reducing the efficacy of antibody-based treatment (). The effect of VOCs continues to increase (), with emerging variants threatening to slow the pace and success of global vaccination efforts and limit the effectiveness of existing COVID-19 treatments ().

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