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

DOI: 10.7150/thno.65563

Authors: Kuan-Ying A. Huang (Chang Gung Memorial Hospital; Chang Gung University; Academia Sinica) , Daming Zhou (The Wellcome Centre for Human Genetics, University of Oxford) , Tiong Kit Tan (University of Oxford) , Charles Chen (Medigen Vaccine Biologics Corporation; Temple University) , Helen M. E. Duyvesteyn (The Wellcome Centre for Human Genetics, University of Oxford) , Yuguang Zhao (The Wellcome Centre for Human Genetics, University of Oxford) , Helen M. Ginn (Diamond Light Source) , Ling Qin (The Wellcome Centre for Human Genetics, University of Oxford) , Pramila Rijal (University of Oxford) , Lisa Schimanski (University of Oxford) , Robert Donat (University of Oxford) , Adam Harding (University of Oxford) , Javier Gilbert-Jaramillo (University of Oxford) , William James (University of Oxford) , Julia A. Tree (Public Health England) , Karen Buttigieg (Public Health England) , Miles Carroll (Public Health England) , Sue Charlton (Public Health England) , Chia-En Lien (Medigen Vaccine Biologics Corporation; National Yang-Ming Chiao Tung University) , Meei-Yun Lin (Medigen Vaccine Biologics Corporation) , Cheng-Pin Chen (Taoyuan General Hospital, Ministry of Health and Welfare; National Yang-Ming University) , Shu-Hsing Cheng (Taoyuan General Hospital, Ministry of Health and Welfare; Taipei Medical University,) , Xiaorui Chen (Academia Sinica) , Tzou-Yien Lin (Chang Gung Memorial Hospital) , Elizabeth E. Fry (The Wellcome Centre for Human Genetics, University of Oxford) , Jingshan Ren (The Wellcome Centre for Human Genetics, University of Oxford) , Che Ma (Academia Sinica) , Alain R. Townsend (University of Oxford) , David I. Stuart (The Wellcome Centre for Human Genetics, University of Oxford; Diamond Light Source)
Co-authored by industrial partner: Yes

Type: Journal Paper
Journal: Theranostics

State: Published (Approved)
Published: November 2021
Diamond Proposal Number(s): 27009

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.

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

Diamond Keywords: COVID-19; Viruses

Subject Areas: Biology and Bio-materials


Instruments: I03-Macromolecular Crystallography

Added On: 05/11/2021 10:00

Documents:
v12p0001.pdf

Discipline Tags:

Pathogens Infectious Diseases Health & Wellbeing Structural biology Life Sciences & Biotech

Technical Tags:

Diffraction Macromolecular Crystallography (MX)