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. 2022 May 17;39(7):110812.
doi: 10.1016/j.celrep.2022.110812. Epub 2022 Apr 25.

LY-CoV1404 (bebtelovimab) potently neutralizes SARS-CoV-2 variants

Kathryn Westendorf  1 , Stefanie Žentelis  1 , Lingshu Wang  2 , Denisa Foster  3 , Peter Vaillancourt  3 , Matthew Wiggin  1 , Erica Lovett  1 , Robin van der Lee  1 , Jörg Hendle  3 , Anna Pustilnik  3 , J Michael Sauder  3 , Lucas Kraft  1 , Yuri Hwang  1 , Robert W Siegel  4 , Jinbiao Chen  4 , Beverly A Heinz  4 , Richard E Higgs  4 , Nicole L Kallewaard  4 , Kevin Jepson  1 , Rodrigo Goya  1 , Maia A Smith  1 , David W Collins  1 , Davide Pellacani  1 , Ping Xiang  1 , Valentine de Puyraimond  1 , Marketa Ricicova  1 , Lindsay Devorkin  1 , Caitlin Pritchard  1 , Aoise O'Neill  1 , Kush Dalal  1 , Pankaj Panwar  1 , Harveer Dhupar  1 , Fabian A Garces  1 , Courtney A Cohen  5 , John M Dye  5 , Kathleen E Huie  5 , Catherine V Badger  5 , Darwyn Kobasa  6 , Jonathan Audet  6 , Joshua J Freitas  3 , Saleema Hassanali  3 , Ina Hughes  3 , Luis Munoz  3 , Holly C Palma  3 , Bharathi Ramamurthy  3 , Robert W Cross  7 , Thomas W Geisbert  7 , Vineet Menachery  8 , Kumari Lokugamage  8 , Viktoriya Borisevich  8 , Iliana Lanz  1 , Lisa Anderson  1 , Payal Sipahimalani  1 , Kizzmekia S Corbett  2 , Eun Sung Yang  2 , Yi Zhang  2 , Wei Shi  2 , Tongqing Zhou  2 , Misook Choe  2 , John Misasi  2 , Peter D Kwong  2 , Nancy J Sullivan  2 , Barney S Graham  2 , Tara L Fernandez  1 , Carl L Hansen  1 , Ester Falconer  1 , John R Mascola  2 , Bryan E Jones  9 , Bryan C Barnhart  10
Affiliations

LY-CoV1404 (bebtelovimab) potently neutralizes SARS-CoV-2 variants

Kathryn Westendorf et al. Cell Rep. .

Abstract

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. LY-CoV1404 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.

Keywords: COVID-19; CP: Microbiology; SARS-CoV-2; neutralizing antibody; variant of concern.

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Conflict of interest statement

Declaration of interests Eli Lilly and Company provided resources for this study. AbCellera Biologics Inc. received funding from the U.S. Department of Defense, Defense Advanced Research Projects Agency (DARPA) Pandemic Prevention Platform, agreement D18AC00002. This research was funded in part by the U.S. Government (the views and conclusions contained in this document are those of the authors and should not be interpreted as representing the official policies, either expressed or implied, of the U.S. Government). This research used resources of the Advanced Photon Source, a U.S. Department of Energy (DOE) Office of Science User Facility operated for the DOE Office of Science by Argonne National Laboratory under contract DE-AC02-06CH11357 (https://www.aps.anl.gov/Science/Publications/Acknowledgment-Statement-for-Publications). Use of the Lilly Research Laboratories Collaborative Access Team (LRL-CAT) beamline at Sector 31 of the Advanced Photon Source was provided by Eli Lilly and Company, which operates the facility (http://lrlcat.lilly.com/). This work was supported by the Intramural Program at the National Institutes of Health, National Institute of Allergy and Infectious Diseases, Vaccine Research Center (to B.S.G. and J.R.M.). Operations support of the Galveston National Laboratory was supported by NIAID/NIH grant UC7AI094660. D.F., P.V., A.P., J.H., J.M.S., R.W.S., J.C., I. H., J.J.F., S.H., H.C.P., B.R., B.A.H., R.W.S., J.C., J.M.S., R.E.H., N.K., and B.E.J. are employees and/or stockholders of Eli Lilly and Company. K.W., S.Ž., M.W., E.L., L.K., Y.H., K.J., R.G., M.A.S., D.W.C., D.P., P.X., V.d.P., R.v.d.L., M.R., L.D., C.P., I.L., L.A., P.S., T.L.F., C.L.H., E.F., and B.C.B. are employees and stockholders of AbCellera Biologics Inc. AbCellera Biologics Inc. and the National Institutes of Health have filed patent applications related to the work described herein (US patent application 17/192243 and international patent application PCT/US21/20843, both titled “Anti-Coronavirus Antibodies and Methods of Use”).

Figures

None
Graphical abstract
Figure 1
Figure 1
LY-CoV1404 discovery and binding properties (A) Timeline (top) of identification of variants of concern (VOCs) to date in the COVID-19 pandemic and milestones of discovery of antibody therapies to treat SARS-CoV-2 infection (bottom). (B) Representation of the soluble antigen assay, live cell-based screening assay, and multiplexed bead-based assay. Also shown are representative microscopic images of antibodies assessed for SARS-CoV-2 S protein specificity in each indicated assay. (C) Epitope binning and isolated subdomain binding for discovered antibodies and benchmarks. Each antibody was tested in two orientations: as a ligand on the chip, and as an analyte in solution. Individual antibodies are represented as a circle (data present in both orientations) or as a square (data present with the antibody in a single orientation). Bins are represented as envelopes (46 total) and competition between antibodies as solid (symmetric competition) or dashed (asymmetric competition) lines. Benchmark-based blocking profiles are indicated by color. (D) Single-cycle kinetics of LY-CoV1404 Fab run on the full-length S protein carrying the D614G mutation. (E) Multi-cycle kinetics of LY-CoV1404 run on the indicated full-length S protein. (F) Binding of LY-CoV1404 to the indicated S proteins expressed on Chinese hamster ovary (CHO) cells.
Figure 2
Figure 2
Anti-SARS-CoV-2 mAb authentic virus neutralization (A) Authentic virus (Italy isolate) neutralization using IFA by LY-CoV1404 and LY-CoV555 across a dose range. (B) Authentic virus (Italy isolate) neutralization using IFA by S309 across a dose range. (C) Comparison of authentic virus neutralization by antibodies in PRNT and IFA assays. Specific antibodies are indicated. Data are compiled from several different individual experiments.
Figure 3
Figure 3
Structural analysis of LY-CoV1404 binding to RBD (A) Three-dimensional structure of the Fab portion of LY-CoV1404 bound to the S protein RBD. (B) Overlay of LY-CoV1404 compared with imdevimab (REGN10987; PDB: 6DXG), bound to the S protein RBD. (C) Cryo-EM density map of the S protein-LY-CoV1404 complex (EMD-26560), shown at low threshold and docked with the atomic model of the S protein (cyan) and LY-CoV1404 (red), highlights binding of 3 Fab molecules in 1 RBD “up” and 2 “down” conformation.
See this image and copyright information in PMC

Update of

  • LY-CoV1404 (bebtelovimab) potently neutralizes SARS-CoV-2 variants.
    Westendorf K, Žentelis S, Wang L, Foster D, Vaillancourt P, Wiggin M, Lovett E, van der Lee R, Hendle J, Pustilnik A, Sauder JM, Kraft L, Hwang Y, Siegel RW, Chen J, Heinz BA, Higgs RE, Kallewaard NL, Jepson K, Goya R, Smith MA, Collins DW, Pellacani D, Xiang P, de Puyraimond V, Ricicova M, Devorkin L, Pritchard C, O'Neill A, Dalal K, Panwar P, Dhupar H, Garces FA, Cohen CA, Dye JM, Huie KE, Badger CV, Kobasa D, Audet J, Freitas JJ, Hassanali S, Hughes I, Munoz L, Palma HC, Ramamurthy B, Cross RW, Geisbert TW, Menacherry V, Lokugamage K, Borisevich V, Lanz I, Anderson L, Sipahimalani P, Corbett KS, Yang ES, Zhang Y, Shi W, Zhou T, Choe M, Misasi J, Kwong PD, Sullivan NJ, Graham BS, Fernandez TL, Hansen CL, Falconer E, Mascola JR, Jones BE, Barnhart BC. Westendorf K, et al. bioRxiv [Preprint]. 2022 Mar 24:2021.04.30.442182. doi: 10.1101/2021.04.30.442182. bioRxiv. 2022. Update in: Cell Rep. 2022 May 17;39(7):110812. doi: 10.1016/j.celrep.2022.110812. PMID: 33972947 Free PMC article. Updated. Preprint.

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