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Genetic and structural basis for SARS-CoV-2 variant neutralization by a two-antibody cocktail
Open accessAbstract
Understanding the molecular basis for immune recognition of SARS-CoV-2 spike glycoprotein antigenic sites will inform the development of improved therapeutics. We determined the structures of two human monoclonal antibodies-AZD8895 and AZD1061-which form the basis of the investigational antibody cocktail AZD7442, in complex with the receptor-binding domain (RBD) of SARS-CoV-2 to define the genetic and structural basis of neutralization. AZD8895 forms an 'aromatic cage' at the heavy/light chain interface using germ line-encoded residues in complementarity-determining regions (CDRs) 2 and 3 of the heavy chain and CDRs 1 and 3 of the light chain. These structural features explain why highly similar antibodies (public clonotypes) have been isolated from multiple individuals. AZD1061 has an unusually long LCDR1; the HCDR3 makes interactions with the opposite face of the RBD from that of AZD8895. Using deep mutational scanning and neutralization escape selection experiments, we comprehensively mapped the crucial binding residues of both antibodies and identified positions of concern with regards to virus escape from antibody-mediated neutralization. Both AZD8895 and AZD1061 have strong neutralizing activity against SARS-CoV-2 and variants of concern with antigenic substitutions in the RBD. We conclude that germ line-encoded antibody features enable recognition of the SARS-CoV-2 spike RBD and demonstrate the utility of the cocktail AZD7442 in neutralizing emerging variant viruses.
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“Importantly, our spike did not contain R346K, which has been observed at relatively low frequency (<10%) within the Omicron lineage, but which is known to mediate escape from class 3 neutralizing monoclonal antibodies such as AZD1061/cilgavimab (Barnes et al., 2020; Dong et al., 2021; Greaney et al., 2021b).”
From mRNA-based COVID-19 vaccine boosters induce neutralizing immunity against SARS-CoV-2 Omicron variant (2022) · cites this paper as Dong et al., 2021
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Self-citationComplex Mutation Pattern of Omicron BA.2: Evading Antibodies without Losing Receptor Interactions
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BackgroundInfluentialSelf-citationEmerging variants develop total escape from potent monoclonal antibodies induced by BA.4/5 infection
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“Even though mAb REGN10933 is not effective in neutralizing the Beta variant, its efficacy was restored with its use in cocktails [19, 64, 90–92].”
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“For example, F486 or N487 residues were defined as hot spots for MAb COV2‐2196 epitope binding.(51,64) Mutagenesis analysis for MW05 revealed E484 as the hot spot residue of RBD.”
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Self-citationOmicron BA.2 specifically evades broad sarbecovirus neutralizing antibodiesPreprint
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“20,51,57,58 Notably, a set of antibodies from children showed potent neutralization of different currently circulating SARS-CoV-2 variants, including variants that have successfully escaped from the currently available mAb products.”
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“Furthermore, against BA.2/4/5, cilgavimab showed recovered efficacy, while Tixagevimab was still ineffective [59,60].”
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“Its mode of recognition is driven by a configuration of predominantly germline-encoded aromatic residues that recognize phenylalanine 486 on the RBD (100–104).”
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“Therefore, to capture positions on the RBD that led to strong antibody escape when mutated, an escape fraction threshold of >0.25 was applied.”
MethodInfluentialIn-Silico Analysis of Monoclonal Antibodies against SARS-CoV-2 Omicron
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“Of all antibodies under emergency use authorization (EUA), our database suggests that the neutralisation potential of Etesevimab (LY-CoV016) [12], Bamlanivimab (LYCoV555) [13], Casirivimab (REGN10933), Imdevimab (REGN10987) [14], Cilgavimab (AZD1061), Tixagevimab (AZD8895) [15], Sotrovimab (Vir-7831 or S309) [8,16], a…”
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“2 spike is located in the binding site of cilgavimab [9].”
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COVID-19 Therapeutics: An Update on Effective Treatments Against Infection With SARS-CoV-2 Variants
Padasas, B. T., Españo, E., Kim, S., Song, Y., Lee, C., & Kim, J.-K. (2023) · Immune Network · doi:10.4110/in.2023.23.e13 · Cited by 9
“This two-antibody cocktail showed efficacy in preventing and treating SARS-CoV-2 infections in vivo (106,107).”
BackgroundTao, K., Tzou, P. L., Pond, S. L. K., Ioannidis, J. P. A., & Shafer, R. W. (2022) · Preprints.org · doi:10.20944/preprints202203.0155.v1 · Cited by 9
Identification of antibody-resistant SARS-CoV-2 mutants via N4-Hydroxycytidine mutagenesis
Kumar, P., Zhang, X., Shaha, R., Kschischo, M., & Dobbelstein, M. (2024) · Antiviral Research · doi:10.1016/j.antiviral.2024.106006 · Cited by 7
“The PDB structure 6wps (Pinto et al., 2020) was used to depict the Sotrovimab heavy chain and the interacting residue E340 of the Spike RBD. Cilgavimab heavy chain interactions with Spike RBD residues N450 and K444 were shown on 7l7e (Dong et al., 2021).”
BackgroundMethodInfluentialSelf-citationPatel, A. R., Rosenke, K., Parzych, E. M., Feldmann, F., Bharti, S., Griffin, A. J., Schouest, B., Lewis, M., Choi, J., Chokkalingam, N., et al. (2024) · Emerging Microbes & Infections · doi:10.1080/22221751.2023.2294860 · Cited by 8
“…two RBD-binding mAbs, AZD8895 and AZD1061, which were originally isolated from a high-throughput screen of neutralizing mAbs isolated from SARS-CoV-2 convalescent individuals (parental antibodies COV2-2196 and COV2-2130, respectively) [10] and bind to non-competing epitopes on the RBD [11].”
BackgroundSelf-citationMonobodies with potent neutralizing activity against SARS-CoV-2 Delta and other variants of concern
Kondo, T., Matsuoka, K., Umemoto, S., Fujino, T., Hayashi, G., Iwatani, Y., & Murakami, H. (2022) · Life Science Alliance · doi:10.26508/lsa.202101322 · Cited by 7
Nkolola, J. P., Yu, J., Wan, H., Chang, A., McMahan, K., Anioke, T., Jacob-Dolan, C., Powers, O. C., Ye, T., Chandrashekar, A., et al. (2022) · Science Translational Medicine · doi:10.1126/scitranslmed.abo6160 · Cited by 8
Self-citationQualification of a Biolayer Interferometry Assay to Support AZD7442 Resistance Monitoring
Brady, T. M., Zhang, T., Tuffy, K. M., Haskins, N., Du, Q., Lin, J., Kaplan, G., Novick, S. J., Roe, T. L., Ren, K., et al. (2022) · Microbiology Spectrum · doi:10.1128/spectrum.01034-22 · Cited by 7
Self-citationFiedler, S., Devenish, S. R. A., Morgunov, A. S., Ilsley, A., Ricci, F., Emmenegger, M., Kosmoliaptsis, V., Theel, E. S., Mills, J. R., Sholukh, A. M., et al. (2022) · Scientific Reports · doi:10.1038/s41598-022-22214-z · Cited by 8
Prediction of antibody binding to SARS-CoV-2 RBDs
Wang, E. J. D. (2022) · Bioinformatics Advances · doi:10.1093/bioadv/vbac103 · Cited by 9
Sun, J., Yang, Z.-D., Xie, X., Li, L., Zeng, H., Gong, B., Xu, J., Wu, J., Qu, B.-B., & Song, G. (2023) · World Journal of Clinical Cases · doi:10.12998/wjcc.v11.i10.2168 · Cited by 8
Self-citationIshimaru, H., Nishimura, M., Tjan, L. H., Sutandhio, S., Marini, M. I., Effendi, G. B., Shigematsu, H., Kato, K., Hasegawa, N., Aoki, K., et al. (2023) · Journal of Virology · doi:10.1128/jvi.00286-23 · Cited by 8
“Both bebtelovimab and cilgavimab are class 2 antibodies that block the ACE2 binding by covering that footprint (16, 18) (Fig.”
BackgroundThomas, M., Masson, M., Bitoun, S., Hamroun, S., Séror, R., Dupuy, H., Lazaro, E., Richez, C., Allanore, Y., & Avouac, J. (2023) · Rheumatology · doi:10.1093/rheumatology/kead449 · Cited by 8
SARS-CoV-2 Omicron potently neutralized by a novel antibody with unique Spike binding propertiesPreprint
Fenwick, C. W., Turelli, P., Ni, D., Perez, L. H., Lau, K., Lana, E., Pellaton, C., Raclot, C., Esteves-Leuenberger, L., Campos, J., et al. (2022) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2022.03.18.484873 · Cited by 8
Ruiz, F., Foreman, W. B., Lilly, M., Baharani, V. A., Depierreux, D. M., Chohan, V., Taylor, A. L., Guenthoer, J., Ralph, D., Matsen IV, F. A., et al. (2024) · PLOS Pathogens · doi:10.1371/journal.ppat.1012650 · Cited by 7
Self-citationTixagevimab/cilgavimab for prevention and treatment of COVID-19: a review
Ustianowski, A. (2022) · Expert Review of Anti-infective Therapy · doi:10.1080/14787210.2022.2134118 · Cited by 8
Roppelt, A., Сергеевна, Л. М., Chernov, A. A., Кruglova, T. S., Mukhina, O. A., Yukhnovskaya, Y. D., Samedova, F. A., Алексеевна, М. У., Andrenova, G. V., Karaulov, A. V., et al. (2023) · Terapevticheskii arkhiv · doi:10.26442/00403660.2023.01.202088 · Cited by 7
COVID-19: A Pediatric Update in Epidemiology, Management, Prevention, and Long-term Effects
Inagaki, K., & Hobbs, C. V. (2023) · Pediatrics in Review · doi:10.1542/pir.2022-005686 · Cited by 7
Design of immunogens for eliciting antibody responses that may protect against SARS-CoV-2 variants
Wang, E. J. D., & Chakraborty, A. K. (2022) · PLoS Computational Biology · doi:10.1371/journal.pcbi.1010563 · Cited by 7
“These 224 mutations were found from various deep mutational scanning experiments over 20 225 class 1/2 antibodies (43-47) (Table S2), in which a mutation’s ability to abrogate 226 binding was quantified as an escape fraction.”
BackgroundMonoclonal Antibodies with Extended Half-Life to Prevent Covid-19
Abraham, J. (2022) · New England Journal of Medicine · doi:10.1056/nejme2205563 · Cited by 7
Functional and structural basis of Omicron BA.3.2.1 spike
Wang, Y., Hu, Y., Chen, Z., Zou, J., Zhang, K., Ren, P., Shi, P., Liang, B., & Xie, X. (2026) · Cell Reports · doi:10.1016/j.celrep.2026.117812 · Cited by 6
Self-citationVariation in structural motifs within SARS-related coronavirus spike proteins
Hills, F. R., Eruera, A.-R., Hodgkinson‐Bean, J., Jorge, F., Easingwood, R. A., Brown, S. H. J., Bouwer, J. C., Li, Y., Burga, L. N., & Bostina, M. (2024) · PLoS Pathogens · doi:10.1371/journal.ppat.1012158 · Cited by 6
“…rapid healthcare responses should 007, SZ3 or WIV1 spill over into humans, although it is possible that class I antibodies, which bind the RBM, may be less efficient at cross-neutralizing SARSr-CoV spikes by virtue of local variation in the Thr 470-Pro 491 loop i.e. Tixagevimab + Cilgavimab [56].”
BackgroundAntivirals for Coexistence with COVID-19: Brief Review for General Physicians
Yoo, J. (2021) · Journal of Korean Medical Science · doi:10.3346/jkms.2021.36.e298 · Cited by 6
Drug discovery to treat COVID-19 two years after its outbreak
Gao, J., & Sun, F. (2021) · Drug Discoveries & Therapeutics · doi:10.5582/ddt.2021.01302 · Cited by 6
Convergent evolution in SARS-CoV-2 Spike creates a variant soup that causes new COVID-19 wavesPreprint
Focosi, D., Quiroga, R., McConnell, S. A., Johnson, M. C., & Casadevall, A. (2022) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2022.12.05.518843 · Cited by 6
Poulakou, G., Royer, P., Evgeniev, N., Evanno, G., Shneiker, F., Marcelin, A., Vanhove, B., Duvaux-Miret, O., Marot, S., & Cálvez, V. (2024) · Frontiers in Immunology · doi:10.3389/fimmu.2024.1330178 · Cited by 5
Verkhivker, G. M. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms23031646 · Cited by 5
“429 (epsilon) variants in the SARS-CoV-2 S protein affect 115 conformational landscapes of the S protein and the ability to evade host immunity and incur 116 resistance to antibodies [59-69].”
BackgroundNtanasis‐Stathopoulos, I., Filippatos, C., Gavriatopoulou, M., Malandrakis, P., Eleutherakis‐Papaiakovou, E., Spiliopoulou, V., Syrigou, R., Theodorakakou, F., Fotiou, D., Migkou, M., et al. (2023) · Diseases · doi:10.3390/diseases11030123 · Cited by 5
“They work by binding to the SARS-CoV-2 spike protein receptor-binding domain in order to potentially neutralize the virus [12–15].”
BackgroundGlobal Emergence of SARS-CoV2 Infection and Scientific Interventions to Contain its Spread
Ajmera, H., Lakhawat, S. S., Malik, N., Kumar, A., Bhatti, J. S., Kumar, V., Gogoi, H., Jaswal, S. K., Chandel, S., & Sharma, P. K. (2024) · Current Protein and Peptide Science · doi:10.2174/0113892037274719231212044235 · Cited by 5
Anzai, I., Fujita, J., Ono, C., Kosaka, Y., Miyamoto, Y., Shichinohe, S., Takada, K., Torii, S., Taguwa, S., Suzuki, K., et al. (2024) · Microbiology Spectrum · doi:10.1128/spectrum.03655-23 · Cited by 5
“For AZD8895, COVOX-253H55L, XGv347, and S2E12, which had similar binding modes (Fig.”
BackgroundTang, H., Ke, Y., Wang, L., Wu, M., Sun, T., & Zhu, J. (2022) · Pharmaceuticals · doi:10.3390/ph15081002 · Cited by 4
“In fact, two studies have reported that the N487T RBD mutant has attenuated binding to the ACE2 receptor [21,25].”
BackgroundA Rapid Method for Detection of Antigen-Specific B Cells
Vakhitova, M. T., Myshkin, M. Y., Staroverov, D. B., Shagina, I. A., Izraelson, M., Tverdova, N., Britanova, O. V., & Merzlyak, E. M. (2023) · Cells · doi:10.3390/cells12050774 · Cited by 5
Yuan, M., West, B. R., Foreman, W. B., Powers, C., Feng, Z., Taylor, A. L., Yu, X., Wang, G., Walker, L. M., Starr, T. N., et al. (2025) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2025.08.28.672883 · Cited by 5
Self-citationCabanillas-Bernal, O., Valdovinos-Navarro, B. J., Cervantes-Luévano, K., Sánchez-Campos, N., & Licea-Navarro, A. F. (2023) · Frontiers in Immunology · doi:10.3389/fimmu.2023.1257042 · Cited by 4
“To address this challenge, combinations of human mAbs have been found to enhance neutralizing activity against variants of concern with antigenic substitutions in the RBD (17, 18).”
BackgroundRemesh, S. G., Merz, G. E., Brilot, A. F., Chio, U. S., Rizo, A. N., Pospiech, T. H., Lui, I., Laurie, M. T., Glasgow, J. E., Le, C. Q., et al. (2023) · Structure · doi:10.1016/j.str.2023.01.009 · Cited by 4
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“Overall, structural and rational design of the 2196 LC allowed for identi fi cation of variants with signi fi cantly improved expression, though with some reduction in binding af fi nity to WT RBD.”
InfluentialDu, W., Hurdiss, D. L., Drabek, D., Mykytyn, A. Z., Kaiser, F. K., González-Hernández, M. C., Muñoz‐Santos, D., Lamers, M. M., van Haperen, R., Li, W., et al. (2022) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2022.02.17.480751 · Cited by 4
In vitro activity of therapeutic antibodies against SARS-CoV-2 Omicron BA.1 and BA.2Preprint
Touret, F., Baronti, C., Pastorino, B. A. M., Villarroel, P. M. S., Ninove, L., Nougaırède, A., & de Lamballerie, X. N. (2022) · Research Square · doi:10.21203/rs.3.rs-1415749/v1 · Cited by 4
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“This epitope is quite similar to that of tixagevimab.(22) Interestingly, Ab803 can neutralize the BA.”
Yaghoobizadeh, F., Ardakani, M. R., Ranjbar, M. M., Khosravi, M., & Galehdari, H. (2024) · Computers in Biology and Medicine · doi:10.1016/j.compbiomed.2024.108091 · Cited by 5
Metadata
- Authors
- Dong, J., Zost, S. J., Greaney, A. J., Starr, T. N., Dingens, A. S., Chen, E. C., Chen, R. E., Case, J. B., Sutton, R. E., Gilchuk, P., Rodriguez, J., Armstrong, E., Gainza, C., Nargi, R. S., Binshtein, E., Xie, X., Zhang, X., Shi, P.-Y., Logue, J., Weston, S., McGrath, M. E., Frieman, M. B., Brady, T., Tuffy, K. M., Bright, H., Loo, Y.-M., McTamney, P. M., Esser, M. T., Carnahan, R. H., Diamond, M. S., Bloom, J. D., & Crowe, J. E.
- Affiliations
- Vanderbilt University Medical Center (US)
- University of Washington (US)
- Fred Hutch Cancer Center (US)
- Washington University in St. Louis (US)
- The University of Texas Medical Branch at Galveston (US)
- University of Maryland, College Park (US)
- AstraZeneca (United States) (US)
- Howard Hughes Medical Institute (US)
- Corresponding author
- Crowe, James E.
- ORCID
- Dong, Jinhui
- Zost, Seth J.
- Greaney, Allison J.
- Starr, Tyler N.
- Dingens, Adam S.
- Chen, Elaine C.
- Chen, Rita E.
- Case, James Brett
- Gilchuk, Pavlo
- Rodriguez, Jessica
- Binshtein, Elad
- Xie, Xuping
- Zhang, Xianwen
- Shi, Pei-Yong
- Logue, James
- Weston, Stuart
- McGrath, Marisa E.
- Frieman, Matthew B.
- Brady, Tyler
- Tuffy, Kevin M.
- Bright, Helen
- Loo, Yueh-Ming
- Esser, Mark T.
- Carnahan, Robert H.
- Diamond, Michael S.
- Bloom, Jesse D.
- Crowe, James E.
- Venue
- Nature Microbiology
- Published
- 2021-09-21
- Volume
- 6
- Issue
- 10
- Pages
- 1233-1244
- ISSN
- 2058-5276 (ISSN-L)
- PMC
- PMC8543371
- OpenAlex
- W3199394546
- Cited by
- 285
- References
- 84
- Citations by year
- 2026: 12 · 2025: 17 · 2024: 43 · 2023: 72 · 2022: 107 · 2021: 33
- FWCI
- 20.13
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Nature Microbiology (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- U.S. Department of Health & Human Services | NIH | National Institute of Allergy and Infectious Diseases (AI095202, 75N93019C00062, AI157155, AI141707, 75N93019C00074, AI150739)
- U.S. Department of Health & Human Services | NIH | National Center for Advancing Translational Sciences (UL1TR001439)
- United States Department of Defense | Defense Advanced Research Projects Agency (HR0011-18-3-0001, HR0011-18-2-0001)
- Merck KGaA (Future Insight Prize 2019)
- DOE | LDRD | Argonne National Laboratory (DE-AC02-06CH11357)
- Michigan Economic Development Corporation (085P1000817)
- Topics
- Health Sciences › Medicine › Infectious Diseases › SARS-CoV-2 and COVID-19 Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › vaccines and immunoinformatics approaches
- Life Sciences › Immunology and Microbiology › Immunology › Monoclonal and Polyclonal Antibodies Research
- Keywords
- SARS-CoV-2, spike protein, receptor binding domain, monoclonal antibodies, antibody neutralization, antibody-antigen complex structure, hypervariable region, HCDR3, neutralization escape, variants of concern, deep mutational scanning
- MeSH terms
- Protein Domains, COVID-19, SARS-CoV-2, Antibodies, Monoclonal, Antibodies, Viral, Antigenic Variation, Binding Sites, Humans, Mutation, Complementarity Determining Regions, Antibodies, Neutralizing, Spike Glycoprotein, Coronavirus
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