Peptide-Antibody Fusions Engineered by Phage Display Exhibit an Ultrapotent and Broad Neutralization of SARS-CoV-2 Variants.

Abstract

The spread of COVID-19 has been exacerbated by the emergence of variants of concern (VoC). Many VoC contain mutations in the spike protein (S-protein) and are implicated in infection and response to therapeutics. Bivalent neutralizing antibodies (nAbs) targeting the S-protein receptor-binding domain (RBD) are promising therapeutics for COVID-19, but they are limited by low potency and vulnerability to RBD mutations in VoC. To address these issues, we used naïve phage-displayed peptide libraries to isolate and optimize 16-residue peptides that bind to the RBD or the N-terminal domain (NTD) of the S-protein. We fused these peptides to the N-terminus of a moderate-affinity nAb to generate tetravalent peptide-IgG fusions, and we showed that both classes of peptides were able to improve affinities for the S-protein trimer by >100-fold (apparent KD < 1 pM). Critically, cell-based infection assays with a panel of six SARS-CoV-2 variants demonstrated that an RBD-binding peptide was able to enhance the neutralization potency of a high-affinity nAb >100-fold. Moreover, this peptide-IgG was able to neutralize variants that were resistant to the same nAb in the bivalent IgG format, including the dominant B.1.1.529 (Omicron) variant that is resistant to most clinically approved therapeutic nAbs. To show that this approach is general, we fused the same peptide to a clinically approved nAb drug and showed that it enabled the neutralization of a resistant variant. Taken together, these results establish minimal peptide fusions as a modular means to greatly enhance affinities, potencies, and breadth of coverage of nAbs as therapeutics for SARS-CoV-2.

• Authors: Jonathan M Labriola, Shane Miersch, Gang Chen, Chao Chen, Alevtina Pavlenco, Reza Saberianfar, Francesca Caccuri, Alberto Zani, Nitin Sharma, Annie Feng, Daisy W Leung, Arnaldo Caruso, Giuseppe Novelli, Gaya K Amarasinghe, Sachdev S Sidhu
• Journal: ACS chemical biology (ACS Chem Biol) Vol. 17 Issue 7 Pg. 1978-1988 (07 15 2022) ISSN: 1554-8937 [Electronic] United States
• PMID: 35731947 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antibodies, Neutralizing
• Antibodies, Viral
• Immunoglobulin G
• Peptide Library
• Spike Glycoprotein, Coronavirus
• spike protein, SARS-CoV-2

Topics

• Antibodies, Neutralizing
• Antibodies, Viral (genetics)
• Bacteriophages (genetics)
• Humans
• Immunoglobulin G (genetics)
• Neutralization Tests
• Peptide Library
• SARS-CoV-2 (genetics)
• Spike Glycoprotein, Coronavirus (genetics)
• COVID-19 Drug Treatment