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

Kathryn Westendorf; Stefanie Žentelis; Lingshu Wang; 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 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; Bryan C. Barnhart

doi:10.1016/j.celrep.2022.110812

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

Kathryn Westendorf, Stefanie Žentelis, Lingshu Wang, 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 L. Kallewaard, Kevin Jepson, Rodrigo GoyaMaia 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, Bryan C. Barnhart

Microbiology And Immunology

Research output: Contribution to journal › Article › peer-review

90 Scopus citations

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.

Original language	English (US)
Article number	110812
Journal	Cell Reports
Volume	39
Issue number	7
DOIs	https://doi.org/10.1016/j.celrep.2022.110812
State	Published - May 17 2022

Keywords

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

ASJC Scopus subject areas

Biochemistry, Genetics and Molecular Biology(all)

Access to Document

10.1016/j.celrep.2022.110812

Cite this

Westendorf, K., Žentelis, S., Wang, L., Foster, D., Vaillancourt, P., Wiggin, M., Lovett, E., van der Lee, R., Hendle, J., Pustilnik, A., Sauder, J. M., Kraft, L., Hwang, Y., Siegel, R. W., Chen, J., Heinz, B. A., Higgs, R. E., Kallewaard, N. L., Jepson, K., ... Barnhart, B. C. (2022). LY-CoV1404 (bebtelovimab) potently neutralizes SARS-CoV-2 variants. Cell Reports, 39(7), [110812]. https://doi.org/10.1016/j.celrep.2022.110812

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 , Menachery, 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 2022, 'LY-CoV1404 (bebtelovimab) potently neutralizes SARS-CoV-2 variants', Cell Reports, vol. 39, no. 7, 110812. https://doi.org/10.1016/j.celrep.2022.110812

@article{d454b15d3a6c4c28b24523a580136db7,

title = "LY-CoV1404 (bebtelovimab) potently neutralizes SARS-CoV-2 variants",

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",

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

note = "Funding Information: 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.{\v Z}., 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”). Funding Information: We thank Kristi Huntington (Eli Lilly and Company) and Emma McCarren (AbCellera Biologics Inc.) for project leadership and coordination; Franz Trianna, Douglas Burtrum, Prabakaran Narayanasamy, Xiaomin Yang, Ricky Lieu, Dongmei He, and Henry Koo of Eli Lilly and Company for reagent and antibody cloning, expression, and purification; Craig Dickinson, Kristina Coleman, and Jeffrey Boyles of Eli Lilly and Company for initiation and reagent generation for crystallography experiments; David Driver of Eli Lilly and Company for assistance with pseudovirus genomic titering; and Natalie Thornburg, Kenneth Plante, and the University of Texas Medical Branch (UTMB) World Reference Collection for Emerging Viruses and Arboviruses (WRCEVA) for the WA-1 isolate (deposited by N. Thornburg), San Diego isolate (deposited by N. Thornburg), Maryland isolate (Mehul Suthar), and Delta isolate. The SARS-CoV-2/INMI-1-Isolate/2020/Italy used in this study was kindly provided by the European Virus Archive Goes Global project, which has received funding from the European Union's Horizon 2020 Research and Innovation Program under grant agreement 653316. We also thank Steven Widen of the NextGen Sequencing Core at UTMB for genomic sequencing of the variants used in this study; Sherie Duncan, Anders Klaus, Keith Mewis, Karine Herve, Amanda Moreira, and Emilie Lameignere of AbCellera Biologics Inc. for technical support; Chad Thiessen of AbCellera Biologics Inc. for development of features for Celium required for antibody selection; Clara Ng-Cummings of AbCellera Biologics Inc. for figure generation; and Wolfgang Glaesner of Eli Lilly and Company for management and personnel resources. We gratefully acknowledge the authors from the originating laboratories and the submitting laboratories who generated and shared, via GISAID, genetic sequence data on which this research is based. B.E.J. J.D. C.C. B.A.H. D.F. J.H. V.d.P. M.W. E.L. M.R. L.D. A.O.N. R.v.d.L. P.P. H.D. F.A.G. I.L. L.A. C.P. K.D. D.K. J.A. B.S.G. J.R.M. N.K. J.J.F. S.H. I.H. L.M. H.C.P. B.R. and R.E.H. conceived and designed experiments, data analysis, and reporting and participated in manuscript authoring and review. A.P. and J.H. conceived and designed experiments (crystallography/structure determination) and participated in manuscript authoring and review. K.S.C. P.V. L.W. E.S.Y. Y.Z. T.Z. J.M. P.D.K. N.J.S. and W.S. conceived, designed, and performed experiments/reagents (pseudovirus neutralization assay), data analysis, and reporting and participated in manuscript authoring and review. R.S. and J.C. performed yeast display experiments to identify resistance mutations and characterized ACE2 competition for variants. T.W.G. R.W.C. D.K. and J.A. conceived and designed experiments (PRNT assay), data analysis, and reporting and participated in manuscript review. C.C. J.D. K.E.H. and C.V.B. conceived and designed experiments (IFA assay), data analysis, and reporting and participated in manuscript review. R.G. participated in conception and design of bioinformatics experiments, data analysis, and reporting. M.A.S. designed and implemented software improvements to Celium for antibody selection. R.G. M.A.S. K.J. and D.W.C. assisted with acquisition, organization, and interpretability of the data and participated in manuscript review. S.{\v Z}. and K.W. participated in design, execution, data analysis and interpretation (screening and validation experiments), and drafting and review of the manuscript. K.W. participated in the interpretation of screening and validation and characterization data for downselection of antibodies for expression and characterization. L.K. and Y.H. designed and executed binding kinetics and epitope binning experiments and data analysis and reporting and participated in manuscript authoring and review. D.P. designed and implemented data analysis and reporting pipelines for binding kinetics, epitope binning, and ACE2 blocking and participated in manuscript authoring and review. P.X. conceived experiments, designed and established the fast mutant full-length S protein expression vector generation protocol for cell-based validation, performed mutant tracing and surveys, and participated in manuscript authorship. P.S. participated in design of the data acquisition pipeline (discovery, characterization, bioinformatics, and antibody lead selection). T.L.F participated in data analysis and reporting and manuscript authorship and review. B.C.B. C.L.H. and E.F. conceived and designed experiments, analyzed and reported data (discovery, characterization, bioinformatics, and antibody lead selection), and participated in manuscript authorship and review. 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.{\v Z}. 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”). Funding Information: We thank Kristi Huntington (Eli Lilly and Company) and Emma McCarren (AbCellera Biologics Inc.) for project leadership and coordination; Franz Trianna, Douglas Burtrum, Prabakaran Narayanasamy, Xiaomin Yang, Ricky Lieu, Dongmei He, and Henry Koo of Eli Lilly and Company for reagent and antibody cloning, expression, and purification; Craig Dickinson, Kristina Coleman, and Jeffrey Boyles of Eli Lilly and Company for initiation and reagent generation for crystallography experiments; David Driver of Eli Lilly and Company for assistance with pseudovirus genomic titering; and Natalie Thornburg, Kenneth Plante, and the University of Texas Medical Branch (UTMB) World Reference Collection for Emerging Viruses and Arboviruses (WRCEVA) for the WA-1 isolate (deposited by N. Thornburg), San Diego isolate (deposited by N. Thornburg), Maryland isolate (Mehul Suthar), and Delta isolate. The SARS-CoV-2/INMI-1-Isolate/2020/Italy used in this study was kindly provided by the European Virus Archive Goes Global project, which has received funding from the European Union{\textquoteright}s Horizon 2020 Research and Innovation Program under grant agreement 653316 . We also thank Steven Widen of the NextGen Sequencing Core at UTMB for genomic sequencing of the variants used in this study; Sherie Duncan, Anders Klaus, Keith Mewis, Karine Herve, Amanda Moreira, and Emilie Lameignere of AbCellera Biologics Inc. for technical support; Chad Thiessen of AbCellera Biologics Inc. for development of features for Celium required for antibody selection; Clara Ng-Cummings of AbCellera Biologics Inc. for figure generation; and Wolfgang Glaesner of Eli Lilly and Company for management and personnel resources. We gratefully acknowledge the authors from the originating laboratories and the submitting laboratories who generated and shared, via GISAID, genetic sequence data on which this research is based. Publisher Copyright: {\textcopyright} 2022 The Authors",

year = "2022",

month = may,

day = "17",

doi = "10.1016/j.celrep.2022.110812",

language = "English (US)",

volume = "39",

journal = "Cell Reports",

issn = "2211-1247",

publisher = "Cell Press",

number = "7",

}

TY - JOUR

T1 - LY-CoV1404 (bebtelovimab) potently neutralizes SARS-CoV-2 variants

AU - Westendorf, Kathryn

AU - Žentelis, Stefanie

AU - Wang, Lingshu

AU - Foster, Denisa

AU - Vaillancourt, Peter

AU - Wiggin, Matthew

AU - Lovett, Erica

AU - van der Lee, Robin

AU - Hendle, Jörg

AU - Pustilnik, Anna

AU - Sauder, J. Michael

AU - Kraft, Lucas

AU - Hwang, Yuri

AU - Siegel, Robert W.

AU - Chen, Jinbiao

AU - Heinz, Beverly A.

AU - Higgs, Richard E.

AU - Kallewaard, Nicole L.

AU - Jepson, Kevin

AU - Goya, Rodrigo

AU - Smith, Maia A.

AU - Collins, David W.

AU - Pellacani, Davide

AU - Xiang, Ping

AU - de Puyraimond, Valentine

AU - Ricicova, Marketa

AU - Devorkin, Lindsay

AU - Pritchard, Caitlin

AU - O'Neill, Aoise

AU - Dalal, Kush

AU - Panwar, Pankaj

AU - Dhupar, Harveer

AU - Garces, Fabian A.

AU - Cohen, Courtney A.

AU - Dye, John M.

AU - Huie, Kathleen E.

AU - Badger, Catherine V.

AU - Kobasa, Darwyn

AU - Audet, Jonathan

AU - Freitas, Joshua J.

AU - Hassanali, Saleema

AU - Hughes, Ina

AU - Munoz, Luis

AU - Palma, Holly C.

AU - Ramamurthy, Bharathi

AU - Cross, Robert W.

AU - Geisbert, Thomas W.

AU - Menachery, Vineet

AU - Lokugamage, Kumari

AU - Borisevich, Viktoriya

AU - Lanz, Iliana

AU - Anderson, Lisa

AU - Sipahimalani, Payal

AU - Corbett, Kizzmekia S.

AU - Yang, Eun Sung

AU - Zhang, Yi

AU - Shi, Wei

AU - Zhou, Tongqing

AU - Choe, Misook

AU - Misasi, John

AU - Kwong, Peter D.

AU - Sullivan, Nancy J.

AU - Graham, Barney S.

AU - Fernandez, Tara L.

AU - Hansen, Carl L.

AU - Falconer, Ester

AU - Mascola, John R.

AU - Jones, Bryan E.

AU - Barnhart, Bryan C.

N1 - Funding Information: 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”). Funding Information: We thank Kristi Huntington (Eli Lilly and Company) and Emma McCarren (AbCellera Biologics Inc.) for project leadership and coordination; Franz Trianna, Douglas Burtrum, Prabakaran Narayanasamy, Xiaomin Yang, Ricky Lieu, Dongmei He, and Henry Koo of Eli Lilly and Company for reagent and antibody cloning, expression, and purification; Craig Dickinson, Kristina Coleman, and Jeffrey Boyles of Eli Lilly and Company for initiation and reagent generation for crystallography experiments; David Driver of Eli Lilly and Company for assistance with pseudovirus genomic titering; and Natalie Thornburg, Kenneth Plante, and the University of Texas Medical Branch (UTMB) World Reference Collection for Emerging Viruses and Arboviruses (WRCEVA) for the WA-1 isolate (deposited by N. Thornburg), San Diego isolate (deposited by N. Thornburg), Maryland isolate (Mehul Suthar), and Delta isolate. The SARS-CoV-2/INMI-1-Isolate/2020/Italy used in this study was kindly provided by the European Virus Archive Goes Global project, which has received funding from the European Union's Horizon 2020 Research and Innovation Program under grant agreement 653316. We also thank Steven Widen of the NextGen Sequencing Core at UTMB for genomic sequencing of the variants used in this study; Sherie Duncan, Anders Klaus, Keith Mewis, Karine Herve, Amanda Moreira, and Emilie Lameignere of AbCellera Biologics Inc. for technical support; Chad Thiessen of AbCellera Biologics Inc. for development of features for Celium required for antibody selection; Clara Ng-Cummings of AbCellera Biologics Inc. for figure generation; and Wolfgang Glaesner of Eli Lilly and Company for management and personnel resources. We gratefully acknowledge the authors from the originating laboratories and the submitting laboratories who generated and shared, via GISAID, genetic sequence data on which this research is based. B.E.J. J.D. C.C. B.A.H. D.F. J.H. V.d.P. M.W. E.L. M.R. L.D. A.O.N. R.v.d.L. P.P. H.D. F.A.G. I.L. L.A. C.P. K.D. D.K. J.A. B.S.G. J.R.M. N.K. J.J.F. S.H. I.H. L.M. H.C.P. B.R. and R.E.H. conceived and designed experiments, data analysis, and reporting and participated in manuscript authoring and review. A.P. and J.H. conceived and designed experiments (crystallography/structure determination) and participated in manuscript authoring and review. K.S.C. P.V. L.W. E.S.Y. Y.Z. T.Z. J.M. P.D.K. N.J.S. and W.S. conceived, designed, and performed experiments/reagents (pseudovirus neutralization assay), data analysis, and reporting and participated in manuscript authoring and review. R.S. and J.C. performed yeast display experiments to identify resistance mutations and characterized ACE2 competition for variants. T.W.G. R.W.C. D.K. and J.A. conceived and designed experiments (PRNT assay), data analysis, and reporting and participated in manuscript review. C.C. J.D. K.E.H. and C.V.B. conceived and designed experiments (IFA assay), data analysis, and reporting and participated in manuscript review. R.G. participated in conception and design of bioinformatics experiments, data analysis, and reporting. M.A.S. designed and implemented software improvements to Celium for antibody selection. R.G. M.A.S. K.J. and D.W.C. assisted with acquisition, organization, and interpretability of the data and participated in manuscript review. S.Ž. and K.W. participated in design, execution, data analysis and interpretation (screening and validation experiments), and drafting and review of the manuscript. K.W. participated in the interpretation of screening and validation and characterization data for downselection of antibodies for expression and characterization. L.K. and Y.H. designed and executed binding kinetics and epitope binning experiments and data analysis and reporting and participated in manuscript authoring and review. D.P. designed and implemented data analysis and reporting pipelines for binding kinetics, epitope binning, and ACE2 blocking and participated in manuscript authoring and review. P.X. conceived experiments, designed and established the fast mutant full-length S protein expression vector generation protocol for cell-based validation, performed mutant tracing and surveys, and participated in manuscript authorship. P.S. participated in design of the data acquisition pipeline (discovery, characterization, bioinformatics, and antibody lead selection). T.L.F participated in data analysis and reporting and manuscript authorship and review. B.C.B. C.L.H. and E.F. conceived and designed experiments, analyzed and reported data (discovery, characterization, bioinformatics, and antibody lead selection), and participated in manuscript authorship and review. 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”). Funding Information: We thank Kristi Huntington (Eli Lilly and Company) and Emma McCarren (AbCellera Biologics Inc.) for project leadership and coordination; Franz Trianna, Douglas Burtrum, Prabakaran Narayanasamy, Xiaomin Yang, Ricky Lieu, Dongmei He, and Henry Koo of Eli Lilly and Company for reagent and antibody cloning, expression, and purification; Craig Dickinson, Kristina Coleman, and Jeffrey Boyles of Eli Lilly and Company for initiation and reagent generation for crystallography experiments; David Driver of Eli Lilly and Company for assistance with pseudovirus genomic titering; and Natalie Thornburg, Kenneth Plante, and the University of Texas Medical Branch (UTMB) World Reference Collection for Emerging Viruses and Arboviruses (WRCEVA) for the WA-1 isolate (deposited by N. Thornburg), San Diego isolate (deposited by N. Thornburg), Maryland isolate (Mehul Suthar), and Delta isolate. The SARS-CoV-2/INMI-1-Isolate/2020/Italy used in this study was kindly provided by the European Virus Archive Goes Global project, which has received funding from the European Union’s Horizon 2020 Research and Innovation Program under grant agreement 653316 . We also thank Steven Widen of the NextGen Sequencing Core at UTMB for genomic sequencing of the variants used in this study; Sherie Duncan, Anders Klaus, Keith Mewis, Karine Herve, Amanda Moreira, and Emilie Lameignere of AbCellera Biologics Inc. for technical support; Chad Thiessen of AbCellera Biologics Inc. for development of features for Celium required for antibody selection; Clara Ng-Cummings of AbCellera Biologics Inc. for figure generation; and Wolfgang Glaesner of Eli Lilly and Company for management and personnel resources. We gratefully acknowledge the authors from the originating laboratories and the submitting laboratories who generated and shared, via GISAID, genetic sequence data on which this research is based. Publisher Copyright: © 2022 The Authors

PY - 2022/5/17

Y1 - 2022/5/17

N2 - 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.

AB - 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.

KW - COVID-19

KW - CP: Microbiology

KW - SARS-CoV-2

KW - neutralizing antibody

KW - variant of concern

UR - http://www.scopus.com/inward/record.url?scp=85130359181&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85130359181&partnerID=8YFLogxK

U2 - 10.1016/j.celrep.2022.110812

DO - 10.1016/j.celrep.2022.110812

M3 - Article

C2 - 35568025

AN - SCOPUS:85130359181

SN - 2211-1247

VL - 39

JO - Cell Reports

JF - Cell Reports

IS - 7

M1 - 110812

ER -

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

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