Kathryn Westendorf, Stefanie Žentelis, Denisa Foster, Peter Vaillancourt, Matthew Wiggin, Erica Lovett, Robin van der Lee, Jörg Hendle, Anna Pustilnik, J. Michael Sauder, Lucas Kraft, Yuri Hwang, Robert W. Siegel, Jinbiao Chen, Beverly A. Heinz, Richard E. Higgs, Nicole Kalleward, 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 Cohen, John 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 Menacherry, Kumari Lokugamage, Viktoriya Borisevich, Iliana Lanz, Lisa Anderson, Payal Sipahimalani, Kizzmekia S. Corbett, Lingshu Wang, Eun Sung Yang, Yi Zhang, Wei Shi, Barney S. Graham, John R. Mascola, Tara L. Fernandez, Carl L. Hansen, Ester Falconer, Bryan E. Jones, and Bryan C. Barnhart

In Brief

LY-CoV1404 is a potent SARS-CoV-2-binding antibody that neutralizes all known variants of concern and whose epitope is rarely mutated.

Highlights

  • LY-CoV1404 potently neutralizes SARS-CoV-2 authentic virus and all known variants of concern including the B.1.617.2 (Delta) variant
  • No loss of potency against currently circulating variants
  • Binding epitope on RBD of SARS-CoV-2 is rarely mutated in GISAID database
  • Breadth of neutralizing activity and potency supports clinical development

Abstract

LY-CoV1404 (also known as bebtelovimab) is a highly potent, neutralizing, SARS-CoV-2 spike glycoprotein receptor binding domain (RBD)-specific antibody identified from a convalescent COVID-19 patient sample, obtained approximately 60 days after symptom onset. In pseudovirus studies, LY-CoV1404 retains potent neutralizing activity against numerous variants including B.1.617.2, B.1.1.7, B.1.351, B.1.427/B.1.429, P.1, and B.1.526, binding to these variants in the presence of their underlying RBD mutations (which include K417N, L452R, E484K, and N501Y). LY-CoV1404 also neutralizes multiple isolates of the authentic SARS-CoV-2 virus in two different assays. The RBD positions comprising the LY-CoV1404 epitope are highly conserved, with the exception of N439 and N501; notably the binding and neutralizing activity of LYCoV1404 is unaffected by the most common mutations at these positions (N439K and N501Y). New variant-resistant treatments such as LY-CoV1404 are desperately needed, given that some of the existing therapeutic antibodies are less effective or ineffective against certain variants and the impact of variants on vaccine efficacy is still poorly understood. The breadth of variant binding, potent neutralizing activity and the relatively conserved epitope suggest that LYCoV1404 is one in a panel of well-characterized, clinically developable antibodies that could be deployed as potentially long-term solutions to address current and emerging variants.

Introduction

Variants of SARS-CoV-2 continue to alter the trajectory of the COVID-19 pandemic, which at the time of writing has infected over 190 million people world-wide and is responsible for more than 4 million deaths (https://covid19.who.int/). As predicted, SARS-CoV-2 has continued to evolve as the pandemic has progressed (Mercatelli and Giorgi, 2020; Pachetti et al., 2020). Selective pressures and viral adaptation during prolonged, suboptimally-treated infections are thought to have generated numerous variants (McCormick et al., 2021), some significantly diminishing the effectiveness of COVID-19 clinical countermeasures (Altmann et al., 2021; Plante et al., 2020). Variants of concern (VOC) represent a closely monitored subset of the many detected SARS-CoV-2 variants, due to their potential for increased transmissibility, and ability to evade immunity produced by infection or vaccines while reducing the efficacies of antibody-based treatments (Hoffmann et al., 2021; Kuzmina et al., 2021; McCormick et al., 2021; Thomson et al., 2021; Wang et al., 2021b). As of April 2021, the number of countries reporting VOC continues to increase (World Health Organization, 2021), with emerging variants threatening to slow the pace and success of global vaccination efforts and limit the effectiveness of existing COVID-19 treatments (Davies et al.; Munnink et al., 2021; Plante et al., 2020; Tegally et al., 2021).

 

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