Computational design of nanomolar-binding antibodies specific to multiple SARS-CoV-2 variants by engineering a specificity switch of antibody 80R using RosettaAntibodyDesign (RAbD) results in potential generalizable therapeutic antibodies for novel SARS-CoV-2 virus

Nancy E Hernandez; Wojciech Jankowski; Rahel Frick; Simon P Kelow; Joseph H Lubin; Vijaya Simhadri; Jared Adolf-Bryfogle; Sagar D Khare; Roland L Dunbrack Jr; Jeffrey J Gray; Zuben E Sauna

doi:10.1016/j.heliyon.2023.e15032

Computational design of nanomolar-binding antibodies specific to multiple SARS-CoV-2 variants by engineering a specificity switch of antibody 80R using RosettaAntibodyDesign (RAbD) results in potential generalizable therapeutic antibodies for novel SARS-CoV-2 virus

Heliyon. 2023 Apr;9(4):e15032. doi: 10.1016/j.heliyon.2023.e15032. Epub 2023 Apr 3.

Authors

Nancy E Hernandez¹, Wojciech Jankowski¹, Rahel Frick², Simon P Kelow^{3

4}, Joseph H Lubin⁵, Vijaya Simhadri¹, Jared Adolf-Bryfogle⁶, Sagar D Khare^{5

7}, Roland L Dunbrack Jr³, Jeffrey J Gray^{2

8

9

10}, Zuben E Sauna¹

Affiliations

¹ Hemostasis Branch 1, Division of Hemostasis, Office of Plasma Protein Therapeutics, Office of Therapeutic Products, Center for Biologics Evaluation and Research U.S. FDA, Silver Spring, MD, USA.
² Chemical and Biomolecular Engineering, Johns Hopkins University, Baltimore, MD, USA.
³ Institute for Cancer Research, Fox Chase Cancer Center, Philadelphia, PA, USA.
⁴ Dept. of Biochemistry and Molecular Biophysics, University of Pennsylvania, Philadelphia, PA, USA.
⁵ Department of Chemistry and Chemical Biology, Rutgers, The State University of New Jersey, Piscataway, NJ USA.
⁶ The Institute for Protein Innovation, Boston, MA, USA.
⁷ Institute for Quantitative Biomedicine, Rutgers, The State University of New Jersey, Piscataway, NJ, USA.
⁸ Program in Molecular Biophysics, Johns Hopkins University, Baltimore, MD, USA.
⁹ Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD, USA.
¹⁰ Institute for Nanobiotechnology, Johns Hopkins University, Baltimore, MD, USA.

Abstract

The human infectious disease COVID-19 caused by the SARS-CoV-2 virus has become a major threat to global public health. Developing a vaccine is the preferred prophylactic response to epidemics and pandemics. However, for individuals who have contracted the disease, the rapid design of antibodies that can target the SARS-CoV-2 virus fulfils a critical need. Further, discovering antibodies that bind multiple variants of SARS-CoV-2 can aid in the development of rapid antigen tests (RATs) which are critical for the identification and isolation of individuals currently carrying COVID-19. Here we provide a proof-of-concept study for the computational design of high-affinity antibodies that bind to multiple variants of the SARS-CoV-2 spike protein using RosettaAntibodyDesign (RAbD). Well characterized antibodies that bind with high affinity to the SARS-CoV-1 (but not SARS-CoV-2) spike protein were used as templates and re-designed to bind the SARS-CoV-2 spike protein with high affinity, resulting in a specificity switch. A panel of designed antibodies were experimentally validated. One design bound to a broad range of variants of concern including the Omicron, Delta, Wuhan, and South African spike protein variants.

Keywords: Computational antibody design; Coronavirus Disease 2019; Diagnostic; Monoclonal antibody therapeutics; Protein engineering.

Abstract

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