Bispecific VH/Fab antibodies targeting neutralizing and non-neutralizing Spike epitopes demonstrate enhanced potency against SARS-CoV-2

• Main Authors: Shion A. Lim (Author), Josef A. Gramespacher (Author), Katarina Pance (Author), Nicholas J. Rettko (Author), Paige Solomon (Author), Jing Jin (Author), Irene Lui (Author), Susanna K. Elledge (Author), Jia Liu (Author), Colton J. Bracken (Author), Graham Simmons (Author), Xin X. Zhou (Author), Kevin K. Leung (Author), James A. Wells (Author)
• Format: Book
• Published: Taylor & Francis Group, 2021-01-01T00:00:00Z.
• Subjects: article
• Online Access: Connect to this object online.

Summary

Numerous neutralizing antibodies that target SARS-CoV-2 have been reported, and most directly block binding of the viral Spike receptor-binding domain (RBD) to angiotensin-converting enzyme II (ACE2). Here, we deliberately exploit non-neutralizing RBD antibodies, showing they can dramatically assist in neutralization when linked to neutralizing binders. We identified antigen-binding fragments (Fabs) by phage display that bind RBD, but do not block ACE2 or neutralize virus as IgGs. When these non-neutralizing Fabs were assembled into bispecific VH/Fab IgGs with a neutralizing VH domain, we observed a ~ 25-fold potency improvement in neutralizing SARS-CoV-2 compared to the mono-specific bi-valent VH-Fc alone or the cocktail of the VH-Fc and IgG. This effect was epitope-dependent, reflecting the unique geometry of the bispecific antibody toward Spike. Our results show that a bispecific antibody that combines both neutralizing and non-neutralizing epitopes on Spike-RBD is a promising and rapid engineering strategy to improve the potency of SARS-CoV-2 antibodies.

Item Description

10.1080/19420862.2021.1893426
1942-0870
1942-0862