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      Broad neutralization of SARS-CoV-2 variants by an inhalable bispecific single-domain antibody

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          Abstract

          The effectiveness of SARS-CoV-2 vaccines and therapeutic antibodies has been limited by the continuous emergence of viral variants, and by the restricted diffusion of antibodies from circulation into the sites of respiratory virus infection. Here, we report the identification of two highly-conserved regions on Omicron variant RBD recognized by broadly neutralizing antibodies. Furthermore, we generated a bispecific single-domain antibody that was able to simultaneously and synergistically bind these two regions on a single Omicron variant RBD as revealed by cryo-EM structures. We demonstrated that this bispecific antibody can be effectively delivered to lung via inhalation administration, and exhibited exquisite neutralization breadth and therapeutic efficacy in mouse models of SARS-CoV-2 infections. Importantly, this study also deciphered an uncommon and highly-conserved cryptic epitope within the spike trimeric interface that may have implications for the design of broadly protective SARS-CoV-2 vaccines and therapeutics.

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          Abstract

          Therapeutic effects against SARS-CoV-2 infection are seen in mice after inhalation of an engineered, bispecific, single-domain antibody that simultaneously targets two points on the spike protein receptor binding domain.

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          Author and article information

          Journal
          Cell
          Cell
          Cell
          Elsevier Inc.
          0092-8674
          1097-4172
          10 March 2022
          10 March 2022
          Affiliations
          [1 ]MOE/NHC/CAMS Key Laboratory of Medical Molecular Virology, Shanghai Institute of Infectious Disease and Biosecurity, The Fifth People's Hospital of Shanghai, Institutes of Biomedical Sciences, School of Basic Medical Sciences, Fudan University, Shanghai 200032, China
          [2 ]Shanghai Key Laboratory of Lung Inflammation and Injury, Department of Pulmonary Medicine, Zhongshan Hospital, Fudan University, Shanghai 200032, China
          [3 ]Shanghai Engineering Research Center for Synthetic Immunology, Shanghai 200032, China
          [4 ]Biomissile Corporation, Shanghai 201203, China
          Author notes
          []Corresponding author (T.Y.), (L.S.), or (Y.W.).
          [5]

          These authors contributed equally

          [6]

          Lead Contact

          Article
          S0092-8674(22)00269-0
          10.1016/j.cell.2022.03.009
          8907017
          35344711
          d5734ce1-d431-4a02-a23b-5b054a10a163
          © 2022 Elsevier Inc.

          Since January 2020 Elsevier has created a COVID-19 resource centre with free information in English and Mandarin on the novel coronavirus COVID-19. The COVID-19 resource centre is hosted on Elsevier Connect, the company's public news and information website. Elsevier hereby grants permission to make all its COVID-19-related research that is available on the COVID-19 resource centre - including this research content - immediately available in PubMed Central and other publicly funded repositories, such as the WHO COVID database with rights for unrestricted research re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for free by Elsevier for as long as the COVID-19 resource centre remains active.

          History
          : 31 December 2021
          : 28 January 2022
          : 4 March 2022
          Categories
          Article

          Cell biology
          sars-cov-2,single-domain antibody,bispecific antibody,broad neutralization,inhalation
          Cell biology
          sars-cov-2, single-domain antibody, bispecific antibody, broad neutralization, inhalation

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