@article{5f3e9d49842848c6a8a58983b2b6b48d,
title = "Structures and therapeutic potential of anti-RBD human monoclonal antibodies against SARS-CoV-2",
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 = "Antibody cocktail, Antibody-antigen complex, Human monoclonal antibody, In vitro and in vivo function, Receptor-binding domain epitope, SARS-CoV-2",
author = "Huang, {Kuan Ying A.} and Daming Zhou and Tan, {Tiong Kit} and Charles Chen and Duyvesteyn, {Helen M.E.} and Yuguang Zhao and Ginn, {Helen M.} and Ling Qin and Pramila Rijal and Lisa Schimanski and Robert Donat and Adam Harding and Javier Gilbert-Jaramillo and William James and Tree, {Julia A.} and Karen Buttigieg and Miles Carroll and Sue Charlton and Lien, {Chia En} and Lin, {Meei Yun} and Chen, {Cheng Pin} and Cheng, {Shu Hsing} and Xiaorui Chen and Lin, {Tzou Yien} and Fry, {Elizabeth E.} and Jingshan Ren and Che Ma and Townsend, {Alain R.} and Stuart, {David I.}",
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. 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. Publisher Copyright: {\textcopyright} The author(s).",
year = "2022",
doi = "10.7150/THNO.65563",
language = "English",
volume = "27",
pages = "1--17",
journal = "Theranostics",
issn = "1838-7640",
publisher = "Ivyspring International Publisher",
number = "1",
}
