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

Kuan Ying A. Huang*, Daming Zhou, Tiong Kit Tan, Charles Chen, Helen M.E. Duyvesteyn, Yuguang Zhao, Helen M. Ginn, Ling Qin, Pramila Rijal, Lisa Schimanski, Robert Donat, Adam Harding, Javier Gilbert-Jaramillo, William James, Julia A. Tree, Karen Buttigieg, Miles Carroll, Sue Charlton, Chia En Lien, Meei Yun LinCheng Pin Chen, Shu Hsing Cheng, Xiaorui Chen, Tzou Yien Lin, Elizabeth E. Fry, Jingshan Ren, Che Ma, Alain R. Townsend, David I. Stuart

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish
Pages (from-to)1-17
Number of pages17
JournalTheranostics
Volume12
Issue number1
DOIs
Publication statusPublished - 1 Jan 2022

Bibliographical note

Funding Information: We acknowledge the BD FACSAria cell sorter service provided by the Core Instrument Center of Chang Gung University. This work was supported by the Chang Gung Memorial Hospital (BMRPE22) and the Ministry of Science and Technology of Taiwan (MOST 109-2628-B-182-010, MOST 110-2628-B-182-009, MOST 110-2628-B-182-013) to K.-Y.A.H. This work was partially supported by the Mercatus Fast Grant (BRD00230-CF01) awarded to A.R.T., the Chinese Academy of Medical Sciences (CAMS) Innovation Fund for Medical Science (CIFMS), China (2018-I2M-2-002) to T.K.T, P.R., L.S., D.I.S. and A.R.T., the EPA Cephalosporin Fund and The Townsend– Jeantet Charitable Trust (charity no. 1011770) to T.K.T. D.I.S. and E.E.F. were supported by the UKRI MRC (MR/N00065X/1). We thank Schmidt Futures for support of this work. D.I.S. is a Jenner Investigator. J.R. is supported by the Wellcome Trust (101122/Z/13/Z). This supported by the UK Instruct-ERIC Centre. We acknowledge Diamond Light Source for time on Beamline I03 under Proposal lb27009 for COVID-19 Rapid Access, especially Dave Hall and the staff of I03. We thank the BMRC for provision of high performance computing.

Open Access: 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.

Publisher Copyright: © The author(s).

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. Available from https://www.thno.org/v12p0001.htm

DOI: 10.7150/thno.65563

Keywords

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

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