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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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“a1, b1, c1, d1, e1, f1 and g1 depict the 3D structures of antibody-RBD complexes of Eli Lilly LY-CoV555 (PDB ID: 7KMG [23]) and LY-CoV016 (PDB ID: 7C01 [24]), Regeneron REGN10987 and REGN10933 (PDB ID: 6XDG [25]), AstraZeneca AZD1061 and AZD8895 (PDB ID: 7L7E [26]), Celltrion CT-P59 (aka Regdanvimab, PDB ID: 7CM4), Ro…”
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“Tixagevimab, cilgavimab and tixagevimab + cilgavimab bind to the spike protein receptor binding domain with equilibrium dissociation constants (KD) of 2.76 pM, 13.0 pM and 13.7 pM, respectively; binding blocks interaction with the human ACE2 receptor, which is required for SARSCoV-2 virus attachment.”
BackgroundInfluentialIn vitro evaluation of therapeutic antibodies against a SARS-CoV-2 Omicron B.1.1.529 isolate
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A delicate balance between antibody evasion and ACE2 affinity for Omicron BA.2.75
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“The results can be explained by the structure of the ternary complex of the ancestral SARS-CoV-2 RBD/AZD1061/AZD8895.(26) G446 has contacts with CDR-L2 Y55 and W56 of AZD1061, thus the G446S mutation will induce steric clashes (Figures 6D and 6E), and while the CDR-H2 of AZD8895 sits above and makes a hydrogen bond to…”
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“Deep mutations scanning (DMS) studies have also been conducted [27,28].”
BackgroundIn vitro activity of therapeutic antibodies against SARS-CoV-2 Omicron BA.1, BA.2 and BA.5
Touret, F., Baronti, C., Pastorino, B. A. M., Villarroel, P. M. S., Ninove, L., Nougaırède, A., & de Lamballerie, X. N. (2022) · Scientific Reports · doi:10.1038/s41598-022-16964-z · Cited by 55
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Structural basis for a conserved neutralization epitope on the receptor-binding domain of SARS-CoV-2
Huang, K.-Y. A., Chen, X., Mohapatra, A., Nguyen, H. T. V., Schimanski, L. M., Tan, T. K., Rijal, P., Vester, S. K., Hills, R. A., Howarth, M. R., et al. (2023) · Nature Communications · doi:10.1038/s41467-023-35949-8 · Cited by 51
Computationally restoring the potency of a clinical antibody against Omicron
Desautels, T., Arrildt, K. T., Zemla, A. T., Lau, E. Y., Zhu, F., Ricci, D. P., Cronin, S., Zost, S. J., Binshtein, E., Scheaffer, S. M., et al. (2024) · Nature · doi:10.1038/s41586-024-07385-1 · Cited by 51
“We used co-structures that were both experimentally determined and computationally estimated, starting from co-structures including the wild-type antigen 13 .”
Self-citationDeep mutational scanning for therapeutic antibody engineering
Hanning, K. R., Minot, M., Warrender, A. K., Kelton, W., & Reddy, S. T. (2021) · Trends in Pharmacological Sciences · doi:10.1016/j.tips.2021.11.010 · Cited by 53
Human Antibodies for Viral Infections
Crowe, J. E. (2022) · Annual Review of Immunology · doi:10.1146/annurev-immunol-042718-041309 · Cited by 54
Self-citationArora, P., Zhang, L., Krüger, N., Rocha, C., Sidarovich, A., Schulz, S. R., Kempf, A. M., Graichen, L., Moldenhauer, A.-S., Cossmann, A., et al. (2022) · Cell Host & Microbe · doi:10.1016/j.chom.2022.04.017 · Cited by 45
“1pp, in keeping with the mutations’ being located in the epitopes of these antibodies (Figures 2A and 2B) (Dong et al., 2021; Hansen et al., 2020; Jones et al., 2021; Kim et al., 2021; Pinto et al., 2020; Shi et al., 2020).”
Cheng, M. H., Krieger, J., Banerjee, A., Xiang, Y., Kaynak, B., Shi, Y., Arditi, M., & Bahar, İ. (2022) · iScience · doi:10.1016/j.isci.2022.103939 · Cited by 50
Yang, W.-T., Huang, W.-H., Liao, T.-L., Hsiao, T.-H., Chuang, H.-N., & Liu, P.-Y. (2022) · Infection and Drug Resistance · doi:10.2147/idr.s344099 · Cited by 51
“Other studies also proved that AZD7442 is effective against the Beta variant.(15,55,56) Regdanvimab, a monoclonal antibody, is also known as CT-P59.”
BackgroundSARS-CoV-2 resistance to monoclonal antibodies and small-molecule drugs
Iketani, S., & Ho, D. D. (2024) · Cell chemical biology · doi:10.1016/j.chembiol.2024.03.008 · Cited by 49
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“These modifications target highly conserved S epitopes, causing conformational transitions necessary for association with the receptor angiotensin-converting enzyme 2 (ACE2) (15, 16), resulting in reduced risk of disease progression and death (13, 24).”
BackgroundTouret, F., Giraud, É., Bourret, J., Donati, F., Tran-Rajau, J., Chiaravalli, J., Lemoine, F., Agou, F., Simon‐Lorière, E., van der Werf, S., et al. (2023) · iScience · doi:10.1016/j.isci.2023.106413 · Cited by 42
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“Overall, escape profiles defined by DMS have predicted instances where the mutations that emerged in VOCs, especially mutations in the RBM, resulted in loss of activity for all authorized therapeutic mAbs (28, 31, 32, 46, 48, 64).”
Self-citationFocosi, D., Franchini, M., Maggi, F., & Shoham, S. (2024) · Clinical Microbiology Reviews · doi:10.1128/cmr.00119-23 · Cited by 51
Evolution of Anti-SARS-CoV-2 Therapeutic Antibodies
Almagro, J. C., Mellado‐Sánchez, G., Pedraza‐Escalona, M., & Pérez‐Tapia, S. M. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms23179763 · Cited by 40
“The X-ray structure (PDB ID: 7L7D) [79] shows that these cysteine residues make an intra-loop disulfide bond.”
BackgroundSARS-CoV-2 variants: biology, pathogenicity, immunity and control
Uraki, R., Korber, B., Diamond, M., & Kawaoka, Y. (2025) · Nature Reviews Microbiology · doi:10.1038/s41579-025-01255-x · Cited by 50
Self-citationThe 15-Months Clinical Experience of SARS-CoV-2: A Literature Review of Therapies and Adjuvants
Inchingolo, A. D., Dipalma, G., Inchingolo, A. M., Malcangi, G., Santacroce, L., D’Oria, M. T., Isacco, C. G., Bordea, I. R., Candrea, S., Scarano, A., et al. (2021) · Antioxidants · doi:10.3390/antiox10060881 · Cited by 54
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Treatments for COVID-19: Lessons from 2020 and new therapeutic options
Salasc, F., Lahlali, T., Laurent, E., Rosa‐Calatrava, M., & Pizzorno, A. (2021) · Current Opinion in Pharmacology · doi:10.1016/j.coph.2021.11.002 · Cited by 39
Baral, P. K., Yin, J., & James, M. N. G. (2021) · International Journal of Biological Macromolecules · doi:10.1016/j.ijbiomac.2021.07.013 · Cited by 36
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Structure-based neutralizing mechanisms for SARS-CoV-2 antibodies
Huang, Q., Han, X., & Yan, J. (2022) · Emerging Microbes & Infections · doi:10.1080/22221751.2022.2125348 · Cited by 37
“somatic hypermutation with potent neutralizing activity [44,53,59-65].”
Windsor, I. W., Tong, P., Lavidor, O., Moghaddam, A. S., McKay, L. G. A., Gautam, A. K., Chen, Y., MacDonald, E. A., Yoo, D. K., Griffths, A., et al. (2022) · Science Immunology · doi:10.1126/sciimmunol.abo3425 · Cited by 37
Monoclonal Antibodies against SARS-CoV-2: Current Scenario and Future Perspectives
Quirós-Roldán, E., Amadasi, S., Zanella, I., Antoni, M. D., Storti, S., Tiecco, G., & Castelli, F. (2021) · Pharmaceuticals · doi:10.3390/ph14121272 · Cited by 36
“Several phase 3 clinical trials are ongoing to study this association for post-exposure prophylaxis (NCT04625972), prevention (NCT04625725), outpatient (NCT04723394 and NCT04518410) and inpatient (NCT04501978) treatment of COVID-19 [42].”
BackgroundAn antibody targeting the N-terminal domain of SARS-CoV-2 disrupts the spike trimer
Suryadevara, N., Shiakolas, A. R., VanBlargan, L. A., Binshtein, E., Chen, R. E., Case, J. B., Kramer, K. J., Armstrong, E., Myers, L., Trivette, A., et al. (2022) · Journal of Clinical Investigation · doi:10.1172/jci159062 · Cited by 31
“…both in terms of their potency and structure (Barnes et al., 2020; Baum et al., 2020; Cerutti et al., 2021b; Chen et al., 2021b; Chi et al., 2020; Dong et al., 2021; Hansen et al., 2020; McCallum et al., 2021; Pinto et al., 2020; Rogers et al., 2020; Shi et al., 2020; Suryadevara et al., 2021;…”
BackgroundInfluentialSelf-citationA broadly neutralizing antibody protects Syrian hamsters against SARS-CoV-2 Omicron challenge
Zhou, B., Zhou, R., Tang, B., Chan, J. F., Luo, M., Peng, Q., Yuan, S., Liu, H., Mok, B. W.-Y., Chen, B., et al. (2022) · Nature Communications · doi:10.1038/s41467-022-31259-7 · Cited by 32
Levin, M. J., Ustianowski, A., Thomas, S., Templeton, A., Yuan, Y., Seegobin, S., Houlihan, C. F., Menendez-Perez, I., Pollett, S. D., Arends, R. H., et al. (2022) · Clinical Infectious Diseases · doi:10.1093/cid/ciac899 · Cited by 33
Self-citationWang, S., Sun, H., Zhang, Y., Yuan, L., Wang, Y., Zhang, T., Wang, S., Zhang, J., Yu, H. J., Xiong, H., et al. (2022) · Cell Reports · doi:10.1016/j.celrep.2022.110862 · Cited by 30
“…sequences (the heavy chain: IGHV1-58 and IGHJ3, and the light chain: IGKV3-20 and IGKJ1), such as S2E12, target the similar antigenic site as XMA01 (Dong et al., 2021; Tortorici et al., 2020), their relatively weaker affinities with conserved F486 and higher overlapping with Omicron mutation sites…”
BackgroundInfluentialKelley, B. D., Moor, P. D., Douglas, K., Renshaw, T., & Traviglia, S. L. (2022) · Current Opinion in Biotechnology · doi:10.1016/j.copbio.2022.102798 · Cited by 34
Paredes-Santos, T. C., Bitew, M. A., Swale, C., Rodriguez, F., Krishnamurthy, S., Wang, Y., Maru, P., Sangaré, L. O., & Saeij, J. P. J. (2023) · PLoS Pathogens · doi:10.1371/journal.ppat.1011543 · Cited by 30
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Forte-Soto, P., Albayaty, M., Brooks, D. A., Arends, R. H., Tillinghast, J. S., Aksyuk, A. A., Bouquet, J., Chen, C., Gebre, A., Kubiak, R. J., et al. (2023) · The Journal of Infectious Diseases · doi:10.1093/infdis/jiad014 · Cited by 32
Self-citationCaì, Y., Diallo, S., Rosenthal, K., Ren, K., Flores, D. J., Dippel, A. B., Oganesyan, V., van Dyk, N., Chen, X., Cantu, E. N., et al. (2024) · Science Translational Medicine · doi:10.1126/scitranslmed.ado2817 · Cited by 31
Self-citationParzych, E. M., Du, J., Ali, A., Schultheis, K., Frase, D. M., Smith, T. R. F., Cui, J., Chokkalingam, N., Tursi, N. J., Andrade, V. M., et al. (2022) · Nature Communications · doi:10.1038/s41467-022-33309-6 · Cited by 30
Self-citationMolecular analysis of a public cross-neutralizing antibody response to SARS-CoV-2
Yuan, M., Wang, Y., Lv, H., Tan, T. J. C., Wilson, I. A., & Wu, N. C. (2022) · Cell Reports · doi:10.1016/j.celrep.2022.111650 · Cited by 27
An update on the anti-spike monoclonal antibody pipeline for SARS-CoV-2
Focosi, D., Franchini, M., Casadevall, A., & Maggi, F. (2024) · Clinical Microbiology and Infection · doi:10.1016/j.cmi.2024.04.012 · Cited by 31
Brady, D. K., Gurijala, A. R., Huang, L., Hussain, A. A., Lingan, A. L., Pembridge, O. G., Ratangee, B. A., Sealy, T. T., Vallone, K. T., & Clements, T. P. (2022) · FEBS Journal · doi:10.1111/febs.16662 · Cited by 30
“Originating from research carried out by the Vanderbilt University Medical Center in 2020, these antibodies were isolated from patients with COVID-19 and neutralized the S protein of SARS-CoV-2 in vitro [21].”
BackgroundMethodFurther antibody escape by Omicron BA.4 and BA.5 from vaccine and BA.1 serumPreprint
Tuekprakhon, A., Huo, J., Nutalai, R., Dijokaite-Guraliuc, A., Zhou, D., Ginn, H. M., Selvaraj, M., Liu, C., Mentzer, A. J., Supasa, P., et al. (2022) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2022.05.21.492554 · Cited by 31
Structural Immunology of SARS ‐ CoV ‐2
Yuan, M., & Wilson, I. A. (2024) · Immunological Reviews · doi:10.1111/imr.13431 · Cited by 29
Designed mosaic nanoparticles enhance cross-reactive immune responses in mice
Wang, E. J. D., Cohen, A. A., Caldera, L. F., Keeffe, J. R., Rorick, A. V., Adia, Y. M., Gnanapragasam, P. N. P., Björkman, P. J., & Chakraborty, A. K. (2025) · Cell · doi:10.1016/j.cell.2024.12.015 · Cited by 29
Computationally designed proteins mimic antibody immune evasion in viral evolution
Youssef, N., Gurev, S. F., Ghantous, F., Brock, K. P., Jaimes, J. A., Thadani, N. N., Dauphin, A., Sherman, A. C., Yurkovetskiy, L., Soto, D., et al. (2025) · Immunity · doi:10.1016/j.immuni.2025.04.015 · Cited by 34
Kramer, K. J., Johnson, N. V., Shiakolas, A. R., Suryadevara, N., Periasamy, S., Raju, N., Williams, J. K., Wrapp, D., Zost, S. J., Walker, L. M., et al. (2021) · Cell Reports · doi:10.1016/j.celrep.2021.109784 · Cited by 25
Self-citation
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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