The continued emergence of new SARS‐CoV‐2 variants has accentuated the growing need for fast and reliable methods for the design of potentially neutralizing antibodies (Abs) to counter immune evasion by the virus. Here, we report on the de novo computational design of high‐affinity Ab variable regions (Fv) through the recombination of VDJ genes targeting the most solvent‐exposed hACE2‐binding residues of the SARS‐CoV‐2 spike receptor binding domain (RBD) protein using the software tool
Infection with SARS‐CoV‐2 elicits robust antibody responses in some patients, with a majority of the response directed at the receptor binding domain (RBD) of the spike surface glycoprotein. Remarkably, many patient‐derived antibodies that potently inhibit viral infection harbor few to no mutations from the germline, suggesting that naïve antibody libraries are a viable means for discovery of novel SARS‐CoV‐2 neutralizing antibodies. Here, we used a yeast surface‐display library of human naïve antibodies to isolate and characterize three novel neutralizing antibodies that target the RBD: one that blocks interaction with angiotensin‐converting enzyme 2 (ACE2), the human receptor for SARS‐CoV‐2, and two that target other epitopes on the RBD. These three antibodies neutralized SARS‐CoV‐2 spike‐pseudotyped lentivirus with IC50values as low as 60 ng/ml in vitro. Using a biolayer interferometry‐based binding competition assay, we determined that these antibodies have distinct but overlapping epitopes with antibodies elicited during natural COVID‐19 infection. Taken together, these analyses highlight how in vitro selection of naïve antibodies can mimic the humoral response in vivo, yielding neutralizing antibodies and various epitopes that can be effectively targeted on the SARS‐CoV‐2 RBD.
more » « less- NSF-PAR ID:
- 10444472
- Publisher / Repository:
- Wiley Blackwell (John Wiley & Sons)
- Date Published:
- Journal Name:
- Protein Science
- Volume:
- 30
- Issue:
- 4
- ISSN:
- 0961-8368
- Page Range / eLocation ID:
- p. 716-727
- Format(s):
- Medium: X
- Sponsoring Org:
- National Science Foundation
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