An Engineered Antibody with Broad Protective Efficacy in Murine Models of SARS and COVID-19

C Garrett Rappazzo; Longping V Tse; Chengzi I Kaku; Daniel Wrapp; Mrunal Sakharkar; Deli Huang; Laura M Deveau; Thomas J Yockachonis; Andrew S Herbert; Michael B Battles; Cecilia M O'Brien; Michael E Brown; James C Geoghegan; Jonathan Belk; Linghang Peng; Linlin Yang; Trevor D Scobey; Dennis R Burton; David Nemazee; John M Dye; James E Voss; Bronwyn M Gunn; Jason S McLellan; Ralph S Baric; Lisa E Gralinski; Laura M Walker

doi:10.1101/2020.11.17.385500

An Engineered Antibody with Broad Protective Efficacy in Murine Models of SARS and COVID-19

bioRxiv [Preprint]. 2020 Nov 17:2020.11.17.385500. doi: 10.1101/2020.11.17.385500.

Authors

C Garrett Rappazzo¹, Longping V Tse², Chengzi I Kaku¹, Daniel Wrapp³, Mrunal Sakharkar¹, Deli Huang⁴, Laura M Deveau¹, Thomas J Yockachonis⁵, Andrew S Herbert^{6

7}, Michael B Battles¹, Cecilia M O'Brien^{6

7}, Michael E Brown¹, James C Geoghegan¹, Jonathan Belk¹, Linghang Peng⁴, Linlin Yang⁴, Trevor D Scobey², Dennis R Burton^{4

8

9

10}, David Nemazee⁴, John M Dye⁶, James E Voss⁴, Bronwyn M Gunn⁵, Jason S McLellan³, Ralph S Baric^{2

11}, Lisa E Gralinski², Laura M Walker^{1

12}

Affiliations

¹ Adimab LLC, Lebanon, NH 03766, USA.
² Department of Epidemiology, The University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
³ Department of Molecular Biosciences, The University of Texas at Austin, Austin, TX 78712, USA.
⁴ Department of Immunology and Microbiology, The Scripps Research Institute, La Jolla, CA 92037, USA.
⁵ Paul G. Allen School of Global Animal Health, Washington State University, Pullman, WA 99164, USA.
⁶ U.S. Army Medical Research Institute of Infectious Diseases, Frederick, MD 21702, USA.
⁷ The Geneva Foundation, 917 Pacific Avenue, Tacoma, WA 98402, USA.
⁸ IAVI Neutralizing Antibody Center, The Scripps Research Institute, La Jolla, CA 92037, USA.
⁹ Consortium for HIV/AIDS Vaccine Development (CHAVD), The Scripps Research Institute, La Jolla, CA 92037, USA.
¹⁰ Ragon Institute of Massachusetts General Hospital, Massachusetts Institute of Technology, and Harvard, Cambridge, MA 02139, USA.
¹¹ Departments of Microbiology and Immunology, The University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
¹² Adagio Therapeutics, Inc., Waltham, MA 02451, USA.

Abstract

The recurrent zoonotic spillover of coronaviruses (CoVs) into the human population underscores the need for broadly active countermeasures. Here, we employed a directed evolution approach to engineer three SARS-CoV-2 antibodies for enhanced neutralization breadth and potency. One of the affinity-matured variants, ADG-2, displays strong binding activity to a large panel of sarbecovirus receptor binding domains (RBDs) and neutralizes representative epidemic sarbecoviruses with remarkable potency. Structural and biochemical studies demonstrate that ADG-2 employs a unique angle of approach to recognize a highly conserved epitope overlapping the receptor binding site. In murine models of SARS-CoV and SARS-CoV-2 infection, passive transfer of ADG-2 provided complete protection against respiratory burden, viral replication in the lungs, and lung pathology. Altogether, ADG-2 represents a promising broad-spectrum therapeutic candidate for the treatment and prevention of SARS-CoV-2 and future emerging SARS-like CoVs.

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Abstract

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