Monobodies with potent neutralizing activity against SARS-CoV-2 Delta and other variants of concern

Life Sci Alliance. 2022 Mar 7;5(6):e202101322. doi: 10.26508/lsa.202101322. Print 2022 Jun.


Neutralizing antibodies against the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are useful for patients' treatment of the coronavirus disease 2019 (COVID-19). We report here affinity maturation of monobodies against the SARS-CoV-2 spike protein and their neutralizing activity against SARS-CoV-2 B.1.1 (Pango v.3.1.14) as well as four variants of concern. We selected matured monobodies from libraries with multi-site saturation mutagenesis on the recognition loops through in vitro selection. One clone, the C4-AM2 monobody, showed extremely high affinity (K D < 0.01 nM) against the receptor-binding domain of the SARS-CoV-2 B.1.1, even in monomer form. Furthermore, the C4-AM2 monobody efficiently neutralized the SARS-CoV-2 B.1.1 (IC 50 = 46 pM, 0.62 ng/ml), and the Alpha (IC 50 = 77 pM, 1.0 ng/ml), Beta (IC 50 = 0.54 nM, 7.2 ng/ml), Gamma (IC 50 = 0.55 nM, 7.4 ng/ml), and Delta (IC 50 = 0.59 nM, 8.0 ng/ml) variants. The obtained monobodies would be useful as neutralizing proteins against current and potentially hazardous future SARS-CoV-2 variants.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antibodies, Neutralizing / immunology*
  • Antibodies, Viral / immunology*
  • Antibody Affinity / immunology
  • COVID-19 / immunology
  • COVID-19 / virology
  • Humans
  • Receptors, Coronavirus / immunology
  • SARS-CoV-2 / immunology*


  • Antibodies, Neutralizing
  • Antibodies, Viral
  • Receptors, Coronavirus

Supplementary concepts

  • SARS-CoV-2 variants

Associated data

  • PDB/6M0J