Highly synergistic combinations of nanobodies that target SARS-CoV-2 and are resistant to escape

eLife

Louis Herlands¹  Nicholas Dambrauskas²  Vladimir Vigdorovich²  Fred D Mast²  Jean Paul Olivier²  D Noah Sather³  John D Aitchison⁴  Elizabeth R Vanderwall⁵  Lucille M Rich⁵  Jason S Debley⁶  Tanmoy Sanyal⁷  Andrej Sali⁷  David Fenyö⁸  Sarah Keegan⁸  Peter C Fridy⁹  Milana E Stein⁹  Natalia E Ketaren⁹  Jacob B Jiler⁹  Michael P Rout⁹  Kelly R Molloy^1,10  Junjie Wang^1,10  Paul Dominic B Olinares^1,10  Brian T Chait^1,10  Erica Y Jacobs^1,11  Fabian Schmidt^1,12  Magdalena Rutkowska^1,12  Yiska Weisblum^1,12  Theodora Hatziioannou^1,12  Paul D Bieniasz^1,13 

[1] AbOde Therapeutics Inc, Woods Hole, United States;Center for Global Infectious Disease Research, Seattle Children's Research Institute, Seattle, United States;Center for Global Infectious Disease Research, Seattle Children's Research Institute, Seattle, United States;Department of Pediatrics, University of Washington, Seattle, United States;Center for Global Infectious Disease Research, Seattle Children's Research Institute, Seattle, United States;Department of Pediatrics, University of Washington, Seattle, United States;Department of Biochemistry, University of Washington, Seattle, United States;Center for Immunity and Immunotherapies, Seattle Children’s Research Institute, Seattle, United States;Center for Immunity and Immunotherapies, Seattle Children’s Research Institute, Seattle, United States;Department of Pediatrics, University of Washington, Seattle, United States;Division of Pulmonary and Sleep Medicine, Seattle Children’s Hospital, Seattle, United States;Department of Bioengineering and Therapeutic Sciences, Department of Pharmaceutical Chemistry, California Institute for Quantitative Biosciences, University of California, San Francisco, San Francisco, United States;Institute for Systems Genetics and Department of Biochemistry and Molecular Pharmacology, NYU Grossman School of Medicine, New York, United States;Laboratory of Cellular and Structural Biology, The Rockefeller University, New York, United States;Laboratory of Mass Spectrometry and Gaseous Ion Chemistry, The Rockefeller University, New York, United States;Laboratory of Mass Spectrometry and Gaseous Ion Chemistry, The Rockefeller University, New York, United States;Department of Chemistry, St. John’s University, Queens, United States;Laboratory of Retrovirology, The Rockefeller University, New York, United States;Laboratory of Retrovirology, The Rockefeller University, New York, United States;Howard Hughes Medical Institute, The Rockefeller University, New York, United States;

关键词: SARS-CoV-2;    spike glycoprotein;    nanobodies;    variants of concern;    single-domain antibodies;    synergy;    Human;   

DOI  :  10.7554/eLife.73027

来源: eLife Sciences Publications, Ltd

【 摘 要 】

The emergence of SARS-CoV-2 variants threatens current vaccines and therapeutic antibodies and urgently demands powerful new therapeutics that can resist viral escape. We therefore generated a large nanobody repertoire to saturate the distinct and highly conserved available epitope space of SARS-CoV-2 spike, including the S1 receptor binding domain, N-terminal domain, and the S2 subunit, to identify new nanobody binding sites that may reflect novel mechanisms of viral neutralization. Structural mapping and functional assays show that indeed these highly stable monovalent nanobodies potently inhibit SARS-CoV-2 infection, display numerous neutralization mechanisms, are effective against emerging variants of concern, and are resistant to mutational escape. Rational combinations of these nanobodies that bind to distinct sites within and between spike subunits exhibit extraordinary synergy and suggest multiple tailored therapeutic and prophylactic strategies.

【 授权许可】

CC BY