Abstract
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.
Keywords: Bispecific; COVID-19; SARS-CoV-2; knob-in-hole; neutralizing antibody.
【저자키워드】 COVID-19, SARS-CoV-2, neutralizing antibody., bispecific, knob-in-hole, 【초록키워드】 neutralizing antibody, antibodies, IgG, ACE2, spike, antibody, neutralization, virus, SARS-CoV-2 antibodies, RBD, Neutralizing, binding, Fab, Angiotensin-converting enzyme, domain, IgGs, Fabs, neutralize, IMPROVE, reported, unique, assist, Numerous, non-neutralizing epitope, 【제목키워드】 spike, antibody, Neutralizing, epitope,