Theranostics 2022; 12(1):1-17. doi:10.7150/thno.65563 This issue Cite

Research Paper

Structures and therapeutic potential of anti-RBD human monoclonal antibodies against SARS-CoV-2

Kuan-Ying A. Huang1,2,3#✉, Daming Zhou4#, Tiong Kit Tan5#, Charles Chen6,7#, Helen M. E. Duyvesteyn4, Yuguang Zhao4, Helen M. Ginn8, Ling Qin4, Pramila Rijal5, Lisa Schimanski5, Robert Donat5, Adam Harding9, Javier Gilbert-Jaramillo9, William James9, Julia A. Tree10, Karen Buttigieg10, Miles Carroll10, Sue Charlton10, Chia-En Lien6,11, Meei-Yun Lin6, Cheng-Pin Chen12, Shu-Hsing Cheng13, Xiaorui Chen3, Tzou-Yien Lin1, Elizabeth E. Fry4, Jingshan Ren4, Che Ma3, Alain R. Townsend5✉, David I. Stuart4,8✉

1. Division of Pediatric Infectious Diseases, Department of Pediatrics, Chang Gung Memorial Hospital, Taoyuan, Taiwan
2. Research Center for Emerging Viral Infections, College of Medicine, Chang Gung University, Taoyuan, Taiwan
3. Genomics Research Center, Academia Sinica, Taipei, Taiwan
4. Division of Structural Biology, Nuffield Department of Medicine, University of Oxford, The Wellcome Centre for Human Genetics, Headington, Oxford, UK
5. MRC Human Immunology Unit, Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, Oxford, UK
6. Medigen Vaccine Biologics Corporation, Taipei, Taiwan
7. Temple University, Philadelphia, PA 19122, USA
8. Diamond Light Source Ltd, Harwell Science & Innovation Campus, Didcot, UK
9. Sir William Dunn School of Pathology, South Park Road, University of Oxford, UK
10. National Infection Service, Public Health England, Porton Down, Salisbury, UK
11. Institute of Public Health, National Yang-Ming Chiao Tung University, Taipei, Taiwan
12. Department of Infectious Diseases, Taoyuan General Hospital, Ministry of Health and Welfare, Taoyuan, and National Yang-Ming University, Taipei, Taiwan
13. Department of Infectious Diseases, Taoyuan General Hospital, Ministry of Health and Welfare, Taoyuan, and Taipei Medical University, Taipei, Taiwan
# These authors contributed equally.

Citation:
Huang KYA, Zhou D, Tan TK, Chen C, Duyvesteyn HME, Zhao Y, Ginn HM, Qin L, Rijal P, Schimanski L, Donat R, Harding A, Gilbert-Jaramillo J, James W, Tree JA, Buttigieg K, Carroll M, Charlton S, Lien CE, Lin MY, Chen CP, Cheng SH, Chen X, Lin TY, Fry EE, Ren J, Ma C, Townsend AR, Stuart DI. Structures and therapeutic potential of anti-RBD human monoclonal antibodies against SARS-CoV-2. Theranostics 2022; 12(1):1-17. doi:10.7150/thno.65563. https://www.thno.org/v12p0001.htm
Other styles

File import instruction

Abstract

Graphic abstract

Background: Administration of potent anti-receptor-binding domain (RBD) monoclonal antibodies has been shown to curtail viral shedding and reduce hospitalization in patients with SARS-CoV-2 infection. However, the structure-function analysis of potent human anti-RBD monoclonal antibodies and its links to the formulation of antibody cocktails remains largely elusive.

Methods: Previously, we isolated a panel of neutralizing anti-RBD monoclonal antibodies from convalescent patients and showed their neutralization efficacy in vitro. Here, we elucidate the mechanism of action of antibodies and dissect antibodies at the epitope level, which leads to a formation of a potent antibody cocktail.

Results: We found that representative antibodies which target non-overlapping epitopes are effective against wild type virus and recently emerging variants of concern, whilst being encoded by antibody genes with few somatic mutations. Neutralization is associated with the inhibition of binding of viral RBD to ACE2 and possibly of the subsequent fusion process. Structural analysis of representative antibodies, by cryo-electron microscopy and crystallography, reveals that they have some unique aspects that are of potential value while sharing some features in common with previously reported neutralizing monoclonal antibodies. For instance, one has a common VH 3-53 public variable region yet is unusually resilient to mutation at residue 501 of the RBD. We evaluate the in vivo efficacy of an antibody cocktail consisting of two potent non-competing anti-RBD antibodies in a Syrian hamster model. We demonstrate that the cocktail prevents weight loss, reduces lung viral load and attenuates pulmonary inflammation in hamsters in both prophylactic and therapeutic settings. Although neutralization of one of these antibodies is abrogated by the mutations of variant B.1.351, it is also possible to produce a bi-valent cocktail of antibodies both of which are resilient to variants B.1.1.7, B.1.351 and B.1.617.2.

Conclusions: These findings support the up-to-date and rational design of an anti-RBD antibody cocktail as a therapeutic candidate against COVID-19.

Keywords: SARS-CoV-2, Human monoclonal antibody, In vitro and in vivo function, Antibody-antigen complex, Receptor-binding domain epitope, Antibody cocktail


Citation styles

APA
Huang, K.Y.A., Zhou, D., Tan, T.K., Chen, C., Duyvesteyn, H.M.E., Zhao, Y., Ginn, H.M., Qin, L., Rijal, P., Schimanski, L., Donat, R., Harding, A., Gilbert-Jaramillo, J., James, W., Tree, J.A., Buttigieg, K., Carroll, M., Charlton, S., Lien, C.E., Lin, M.Y., Chen, C.P., Cheng, S.H., Chen, X., Lin, T.Y., Fry, E.E., Ren, J., Ma, C., Townsend, A.R., Stuart, D.I. (2022). Structures and therapeutic potential of anti-RBD human monoclonal antibodies against SARS-CoV-2. Theranostics, 12(1), 1-17. https://doi.org/10.7150/thno.65563.

ACS
Huang, K.Y.A.; Zhou, D.; Tan, T.K.; Chen, C.; Duyvesteyn, H.M.E.; Zhao, Y.; Ginn, H.M.; Qin, L.; Rijal, P.; Schimanski, L.; Donat, R.; Harding, A.; Gilbert-Jaramillo, J.; James, W.; Tree, J.A.; Buttigieg, K.; Carroll, M.; Charlton, S.; Lien, C.E.; Lin, M.Y.; Chen, C.P.; Cheng, S.H.; Chen, X.; Lin, T.Y.; Fry, E.E.; Ren, J.; Ma, C.; Townsend, A.R.; Stuart, D.I. Structures and therapeutic potential of anti-RBD human monoclonal antibodies against SARS-CoV-2. Theranostics 2022, 12 (1), 1-17. DOI: 10.7150/thno.65563.

NLM
Huang KYA, Zhou D, Tan TK, Chen C, Duyvesteyn HME, Zhao Y, Ginn HM, Qin L, Rijal P, Schimanski L, Donat R, Harding A, Gilbert-Jaramillo J, James W, Tree JA, Buttigieg K, Carroll M, Charlton S, Lien CE, Lin MY, Chen CP, Cheng SH, Chen X, Lin TY, Fry EE, Ren J, Ma C, Townsend AR, Stuart DI. Structures and therapeutic potential of anti-RBD human monoclonal antibodies against SARS-CoV-2. Theranostics 2022; 12(1):1-17. doi:10.7150/thno.65563. https://www.thno.org/v12p0001.htm

CSE
Huang KYA, Zhou D, Tan TK, Chen C, Duyvesteyn HME, Zhao Y, Ginn HM, Qin L, Rijal P, Schimanski L, Donat R, Harding A, Gilbert-Jaramillo J, James W, Tree JA, Buttigieg K, Carroll M, Charlton S, Lien CE, Lin MY, Chen CP, Cheng SH, Chen X, Lin TY, Fry EE, Ren J, Ma C, Townsend AR, Stuart DI. 2022. Structures and therapeutic potential of anti-RBD human monoclonal antibodies against SARS-CoV-2. Theranostics. 12(1):1-17.

This is an open access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/). See http://ivyspring.com/terms for full terms and conditions.