A Potent Recombinant Polyclonal Antibody Therapeutic for Protection Against New Severe Acute Respiratory Syndrome Coronavirus 2 Variants of Concern

Abstract Emerging variants of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) possess mutations that prevent antibody therapeutics from maintaining antiviral binding and neutralizing efficacy. Monoclonal antibodies (mAbs) shown to neutralize Wuhan-Hu-1 SARS-CoV-2 (ancestral) strain have...

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Bibliographic Details
Published in:The Journal of infectious diseases 2023-08, Vol.228 (5), p.555-563
Main Authors: Wayham, Nicholas P, Niedecken, Ariel R, Simons, Jan Fredrik, Chiang, Yao Y, Medina-Cucurella, Angélica V, Mizrahi, Rena A, Wagner, Ellen K, Gras, Ashley, Segal, Ilana, Witte, Peyton, Enstrom, Alexis, Bountouvas, Aristea, Nelson, Sabrina M, Weinberger, Tess, Tan, David, Asensio, Michael A, Subramanian, Alagu, Lim, Yoong Wearn, Adler, Adam S, Keating, Sheila M
Format: Article
Language:English
Subjects:
Antibody libraries
Antiviral agents
Coronaviruses
Major
Monoclonal antibodies
Polyclonal antibodies
Severe acute respiratory syndrome coronavirus 2
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Summary:Abstract Emerging variants of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) possess mutations that prevent antibody therapeutics from maintaining antiviral binding and neutralizing efficacy. Monoclonal antibodies (mAbs) shown to neutralize Wuhan-Hu-1 SARS-CoV-2 (ancestral) strain have reduced potency against newer variants. Plasma-derived polyclonal hyperimmune drugs have improved neutralization breadth compared with mAbs, but lower titers against SARS-CoV-2 require higher dosages for treatment. We previously developed a highly diverse, recombinant polyclonal antibody therapeutic anti-SARS-CoV-2 immunoglobulin hyperimmune (rCIG). rCIG was compared with plasma-derived or mAb standards and showed improved neutralization of SARS-CoV-2 across World Health Organization variants; however, its potency was reduced against some variants relative to ancestral, particularly omicron. Omicron-specific antibody sequences were enriched from yeast expressing rCIG-scFv and exhibited increased binding and neutralization to omicron BA.2 while maintaining ancestral strain binding and neutralization. Polyclonal antibody libraries such as rCIG can be utilized to develop antibody therapeutics against present and future SARS-CoV-2 threats. Emergent SARS-CoV-2 variants can evolve resistance to existing treatment modalities. A recombinant polyclonal antibody hyperimmune iteratively enriched for antiancestral and anti-omicron BA.2 receptor binding domain activity may select for neutralizing antibodies that target mutational cold spots preventing future drug resistance.
ISSN:0022-1899
1537-6613
DOI:10.1093/infdis/jiad102