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 | |
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)
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LY-CoV1404 (bebtelovimab) potently neutralizes SARS-CoV-2 variants. / Westendorf, Kathryn; Žentelis, Stefanie; Wang, Lingshu et al.
In: Cell Reports, Vol. 39, No. 7, 110812, 17.05.2022.Research output: Contribution to journal › Article › peer-review
}
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 -