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      Rational development of a human antibody cocktail that deploys multiple functions to confer Pan-SARS-CoVs protection

      research-article
      Author(s): 1 , 2 , 3 , 2 , 4 , 3 , 3 , 4 , 3 , 3 , 3 , 3 , 4 , 2 , 2 , 2 , 2 , 1 , 4 , 4 , 5 , 3 , 3 , 3 , 4 , 4 , 6 , 4 , 4 , 1 , 1 , 3 , 3 , 1 , 1 , 7 , 8 , 2 , 8 , 3 , 4 , , 3 , , 1 , , 2 , 9 ,
      Publication date (Electronic):
      Journal: Cell Research
      Publisher: Springer Singapore
      Keywords: Structural biology, Immunology

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          Abstract

          Structural principles underlying the composition and synergistic mechanisms of protective monoclonal antibody cocktails are poorly defined. Here, we exploited antibody cooperativity to develop a therapeutic antibody cocktail against SARS-CoV-2. On the basis of our previously identified humanized cross-neutralizing antibody H014, we systematically analyzed a fully human naive antibody library and rationally identified a potent neutralizing antibody partner, P17, which confers effective protection in animal model. Cryo-EM studies dissected the nature of the P17 epitope, which is SARS-CoV-2 specific and distinctly different from that of H014. High-resolution structure of the SARS-CoV-2 spike in complex with H014 and P17, together with functional investigations revealed that in a two-antibody cocktail, synergistic neutralization was achieved by S1 shielding and conformational locking, thereby blocking receptor attachment and viral membrane fusion, conferring high potency as well as robustness against viral mutation escape. Furthermore, cluster analysis identified a hypothetical 3rd antibody partner for further reinforcing the cocktail as pan-SARS-CoVs therapeutics.

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          Most cited references39

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          A Novel Coronavirus from Patients with Pneumonia in China, 2019

          Na Zhu, Dingyu Zhang, Wenling Wang … (2020)
          Summary In December 2019, a cluster of patients with pneumonia of unknown cause was linked to a seafood wholesale market in Wuhan, China. A previously unknown betacoronavirus was discovered through the use of unbiased sequencing in samples from patients with pneumonia. Human airway epithelial cells were used to isolate a novel coronavirus, named 2019-nCoV, which formed a clade within the subgenus sarbecovirus, Orthocoronavirinae subfamily. Different from both MERS-CoV and SARS-CoV, 2019-nCoV is the seventh member of the family of coronaviruses that infect humans. Enhanced surveillance and further investigation are ongoing. (Funded by the National Key Research and Development Program of China and the National Major Project for Control and Prevention of Infectious Disease in China.)
          Article 0 comments Cited 13011 times – based on 0 reviews     Review now
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            A pneumonia outbreak associated with a new coronavirus of probable bat origin

            Peng Zhou, Xing-Lou Yang, Xian-Guang Wang … (2020)
            Since the outbreak of severe acute respiratory syndrome (SARS) 18 years ago, a large number of SARS-related coronaviruses (SARSr-CoVs) have been discovered in their natural reservoir host, bats 1–4 . Previous studies have shown that some bat SARSr-CoVs have the potential to infect humans 5–7 . Here we report the identification and characterization of a new coronavirus (2019-nCoV), which caused an epidemic of acute respiratory syndrome in humans in Wuhan, China. The epidemic, which started on 12 December 2019, had caused 2,794 laboratory-confirmed infections including 80 deaths by 26 January 2020. Full-length genome sequences were obtained from five patients at an early stage of the outbreak. The sequences are almost identical and share 79.6% sequence identity to SARS-CoV. Furthermore, we show that 2019-nCoV is 96% identical at the whole-genome level to a bat coronavirus. Pairwise protein sequence analysis of seven conserved non-structural proteins domains show that this virus belongs to the species of SARSr-CoV. In addition, 2019-nCoV virus isolated from the bronchoalveolar lavage fluid of a critically ill patient could be neutralized by sera from several patients. Notably, we confirmed that 2019-nCoV uses the same cell entry receptor—angiotensin converting enzyme II (ACE2)—as SARS-CoV.
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              SARS-CoV-2 Cell Entry Depends on ACE2 and TMPRSS2 and Is Blocked by a Clinically Proven Protease Inhibitor

              Markus Hoffmann, Hannah Kleine-Weber, Simon Schroeder … (2020)
              Summary The recent emergence of the novel, pathogenic SARS-coronavirus 2 (SARS-CoV-2) in China and its rapid national and international spread pose a global health emergency. Cell entry of coronaviruses depends on binding of the viral spike (S) proteins to cellular receptors and on S protein priming by host cell proteases. Unravelling which cellular factors are used by SARS-CoV-2 for entry might provide insights into viral transmission and reveal therapeutic targets. Here, we demonstrate that SARS-CoV-2 uses the SARS-CoV receptor ACE2 for entry and the serine protease TMPRSS2 for S protein priming. A TMPRSS2 inhibitor approved for clinical use blocked entry and might constitute a treatment option. Finally, we show that the sera from convalescent SARS patients cross-neutralized SARS-2-S-driven entry. Our results reveal important commonalities between SARS-CoV-2 and SARS-CoV infection and identify a potential target for antiviral intervention.
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                Author and article information

                Contributors
                Guojun Lang: guojun.lang@sunyoubio.com
                Cheng-Feng Qin:
                ORCID: http://orcid.org/0000-0002-0632-2807
                qincf@bmi.ac.cn
                Lanjuan Li: ljli@zju.edu.cn
                Xiangxi Wang:
                ORCID: http://orcid.org/0000-0003-0635-278X
                xiangxi@ibp.ac.cn
                Journal
                Journal ID (nlm-ta): Cell Res
                Journal ID (iso-abbrev): Cell Res
                Title: Cell Research
                Publisher: Springer Singapore (Singapore )
                ISSN (Print): 1001-0602
                ISSN (Electronic): 1748-7838
                Publication date (Electronic): 1 December 2020
                Publication date PMC-release: 1 December 2020
                Pages: 1-12
                Affiliations
                [1 ]GRID grid.13402.34, ISNI 0000 0004 1759 700X, State Key Laboratory for Diagnosis and Treatment of Infectious Diseases/National Clinical Research Center for Infectious Diseases, First Affiliated Hospital, , Zhejiang University School of Medicine, ; Hangzhou, Zhejiang 310003 China
                [2 ]GRID grid.9227.e, ISNI 0000000119573309, CAS Key Laboratory of Infection and Immunity, National Laboratory of Macromolecules, Institute of Biophysics, , Chinese Academy of Sciences, ; Beijing, 100101 China
                [3 ]GRID grid.410740.6, ISNI 0000 0004 1803 4911, State Key Laboratory of Pathogen and Biosecurity, , Beijing Institute of Microbiology and Epidemiology, AMMS, ; Beijing, 100071 China
                [4 ]Sanyou Biopharmaceuticals (Shanghai) Co., Ltd., Shanghai, 201114 China
                [5 ]GRID grid.413073.2, ISNI 0000 0004 1758 9341, Shulan International Medical College, , Zhejiang Shuren University, ; Hangzhou, Zhejiang 310015 China
                [6 ]GRID grid.419611.a, ISNI 0000 0004 0457 9072, State Key Laboratory of Proteomics, Beijing Proteome Research Center, National Center for Protein Sciences (Beijing), , Beijing Institute of Lifeomics, ; Beijing, 102206 China
                [7 ]Shanghai Henlius Biotech, Inc, Shanghai, 200233 China
                [8 ]Shanghai ZJ Bio-Tech Co., Ltd., Shanghai, 201114 China
                [9 ]GRID grid.508040.9, Guangzhou Regenerative Medicine and Health Guangdong Laboratory, ; Guangzhou, Guangdong 510200 China
                Author information
                http://orcid.org/0000-0001-6742-7074
                http://orcid.org/0000-0001-8764-4412
                http://orcid.org/0000-0002-0632-2807
                http://orcid.org/0000-0003-0635-278X
                Article
                Publisher ID: 444
                DOI: 10.1038/s41422-020-00444-y
                PMC ID: 7705443
                PubMed ID: 33262452
                SO-VID: 2c5332f1-fbec-4e1d-86e5-c065d2576c0e
                Copyright © © The Author(s) 2020
                License:

                Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

                History
                Date received : 6 August 2020
                Date accepted : 2 November 2020
                Categories
                Subject: Article

                ScienceOpen disciplines: Cell biology
                Keywords: structural biology,immunology
                Data availability:
                ScienceOpen disciplines: Cell biology
                Keywords: structural biology, immunology

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