Bivalent binding of a fully human IgG to the SARS-CoV-2 spike proteins reveals mechanisms of potent neutralization.

Autor:	Wang B; Singapore Immunology Network, Agency for Science, Technology and Research (A*STAR), 8A Biomedical Grove, #03-06 Immunos, Singapore 138648, Singapore., Asarnow D; Department of Biochemistry and Biophysics, University of California San Francisco (UCSF) School of Medicine, San Francisco, CA, USA.; QBI COVID-19 Research Group (QCRG), San Francisco, CA, USA., Lee WH; Singapore Immunology Network, Agency for Science, Technology and Research (A*STAR), 8A Biomedical Grove, #03-06 Immunos, Singapore 138648, Singapore., Huang CW; Singapore Immunology Network, Agency for Science, Technology and Research (A*STAR), 8A Biomedical Grove, #03-06 Immunos, Singapore 138648, Singapore., Faust B; Department of Biochemistry and Biophysics, University of California San Francisco (UCSF) School of Medicine, San Francisco, CA, USA.; QBI COVID-19 Research Group (QCRG), San Francisco, CA, USA., Ng PML; Singapore Immunology Network, Agency for Science, Technology and Research (A*STAR), 8A Biomedical Grove, #03-06 Immunos, Singapore 138648, Singapore., Ngoh EZX; Singapore Immunology Network, Agency for Science, Technology and Research (A*STAR), 8A Biomedical Grove, #03-06 Immunos, Singapore 138648, Singapore., Bohn M; QBI COVID-19 Research Group (QCRG), San Francisco, CA, USA.; Department of Pharmaceutical Chemistry, University of California San Francisco (UCSF), San Francisco, CA, USA., Bulkley D; Department of Biochemistry and Biophysics, University of California San Francisco (UCSF) School of Medicine, San Francisco, CA, USA.; QBI COVID-19 Research Group (QCRG), San Francisco, CA, USA., Pizzorno A; Virologie et Pathologie Humaine - VirPath team, Centre International de Recherche en Infectiologie (CIRI), INSERM U1111, CNRS UMR5308, ENS Lyon, Université Claude Bernard Lyon 1, Université de Lyon, Lyon, France., Tan HC; Singapore Immunology Network, Agency for Science, Technology and Research (A*STAR), 8A Biomedical Grove, #03-06 Immunos, Singapore 138648, Singapore., Lee CY; Singapore Immunology Network, Agency for Science, Technology and Research (A*STAR), 8A Biomedical Grove, #03-06 Immunos, Singapore 138648, Singapore., Minhat RA; Singapore Immunology Network, Agency for Science, Technology and Research (A*STAR), 8A Biomedical Grove, #03-06 Immunos, Singapore 138648, Singapore., Terrier O; Virologie et Pathologie Humaine - VirPath team, Centre International de Recherche en Infectiologie (CIRI), INSERM U1111, CNRS UMR5308, ENS Lyon, Université Claude Bernard Lyon 1, Université de Lyon, Lyon, France., Soh MK; Singapore Immunology Network, Agency for Science, Technology and Research (A*STAR), 8A Biomedical Grove, #03-06 Immunos, Singapore 138648, Singapore., Teo FJ; Singapore Immunology Network, Agency for Science, Technology and Research (A*STAR), 8A Biomedical Grove, #03-06 Immunos, Singapore 138648, Singapore., Yeap YYC; Singapore Immunology Network, Agency for Science, Technology and Research (A*STAR), 8A Biomedical Grove, #03-06 Immunos, Singapore 138648, Singapore., Hu Y; Singapore Immunology Network, Agency for Science, Technology and Research (A*STAR), 8A Biomedical Grove, #03-06 Immunos, Singapore 138648, Singapore., Seah SGK; Biological Defence Program, DSO National Laboratories, 27 Medical Drive, Singapore 117510, Singapore., Maurer-Stroh S; Bioinformatics Institute, Agency for Science, Technology and Research (A*STAR), 30 Biopolis Street, #07-01 Matrix, Singapore 138671, Singapore., Renia L; Singapore Immunology Network, Agency for Science, Technology and Research (A*STAR), 8A Biomedical Grove, #03-06 Immunos, Singapore 138648, Singapore.; School of Biological Sciences, Nanyang Technological University, Singapore, Singapore.; Department of Microbiology and Immunology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore., Hanson BJ; Biological Defence Program, DSO National Laboratories, 27 Medical Drive, Singapore 117510, Singapore., Rosa-Calatrava M; Virologie et Pathologie Humaine - VirPath team, Centre International de Recherche en Infectiologie (CIRI), INSERM U1111, CNRS UMR5308, ENS Lyon, Université Claude Bernard Lyon 1, Université de Lyon, Lyon, France.; VirNext, Faculté de Médecine RTH Laennec, Université Claude Bernard Lyon 1, Université de Lyon, Lyon, France., Manglik A; QBI COVID-19 Research Group (QCRG), San Francisco, CA, USA.; Department of Pharmaceutical Chemistry, University of California San Francisco (UCSF), San Francisco, CA, USA.; Department of Anesthesia and Perioperative Care, UCSF, San Francisco, CA, USA., Cheng Y; Department of Biochemistry and Biophysics, University of California San Francisco (UCSF) School of Medicine, San Francisco, CA, USA.; QBI COVID-19 Research Group (QCRG), San Francisco, CA, USA.; Howard Hughes Medical Institute, UCSF, San Francisco, CA, USA., Craik CS; QBI COVID-19 Research Group (QCRG), San Francisco, CA, USA.; Department of Pharmaceutical Chemistry, University of California San Francisco (UCSF), San Francisco, CA, USA., Wang CI; Singapore Immunology Network, Agency for Science, Technology and Research (A*STAR), 8A Biomedical Grove, #03-06 Immunos, Singapore 138648, Singapore.
Jazyk:	angličtina
Zdroj:	BioRxiv : the preprint server for biology [bioRxiv] 2020 Jul 15. Date of Electronic Publication: 2020 Jul 15.
DOI:	10.1101/2020.07.14.203414
Abstrakt:	In vitro antibody selection against pathogens from naïve combinatorial libraries can yield various classes of antigen-specific binders that are distinct from those evolved from natural infection 1-4 . Also, rapid neutralizing antibody discovery can be made possible by a strategy that selects for those interfering with pathogen and host interaction 5 . Here we report the discovery of antibodies that neutralize SARS-CoV-2, the virus responsible for the COVID-19 pandemic, from a highly diverse naïve human Fab library. Lead antibody 5A6 blocks the receptor binding domain (RBD) of the viral spike from binding to the host receptor angiotensin converting enzyme 2 (ACE2), neutralizes SARS-CoV-2 infection of Vero E6 cells, and reduces viral replication in reconstituted human nasal and bronchial epithelium models. 5A6 has a high occupancy on the viral surface and exerts its neutralization activity via a bivalent binding mode to the tip of two neighbouring RBDs at the ACE2 interaction interface, one in the "up" and the other in the "down" position, explaining its superior neutralization capacity. Furthermore, 5A6 is insensitive to several spike mutations identified in clinical isolates, including the D614G mutant that has become dominant worldwide. Our results suggest that 5A6 could be an effective prophylactic and therapeutic treatment of COVID-19. Competing Interests: Competing interests: B.W., W.H.L., C.W.H., P.M.L.N., E.Z.X.N., H.C.T., C.Y.L., R.A.M., M.K.S., F.J.T., Y.Y.C.Y., Y.H., and C.I.W. are listed as inventors of a filed patent for all 27 monoclonal antibodies mentioned in this manuscript. The other authors declare that they have no competing interests.
Databáze:	MEDLINE
Externí odkaz:	Zobrazit plný text záznamu