Potent Neutralization of Omicron and other SARS-CoV-2 Variants of Concern by Biparatopic Human VH Domains

Abstract

The emergence of SARS-CoV-2 variants of concern (VOCs) requires the development of next-generation biologics that are effective against a variety of strains of the virus. Herein, we characterize a human VH domain, F6, which we generated by sequentially panning large phage displayed VH libraries against receptor binding domains (RBDs) containing VOC mutations. Cryo-EM analyses reveal that F6 has a unique binding mode that spans a broad surface of the RBD and involves the antibody framework region. Attachment of an Fc region to a fusion of F6 and ab8, a previously characterized VH domain, resulted in a construct (F6-ab8-Fc) that neutralized Omicron pseudoviruses with a half-maximal neutralizing concentration (IC50) of 4.8 nM in vitro. Additionally, prophylactic treatment using F6-ab8-Fc reduced live Beta (B.1.351) variant viral titers in the lungs of a mouse model. Our results provide a new potential therapeutic against SARS-CoV-2 VOCs - including the recently emerged Omicron variant - and highlight a vulnerable epitope within the spike protein RBD that may be exploited to achieve broad protection against circulating variants.

Computational design of novel nanobodies targeting the receptor binding domain of variants of concern of SARS-CoV-2

“…The evaluation of the specificity of engineered Nbs by cross-docking with other viral RBDs/HA showed that all engineered Nbs had a higher binding affinity to their target RBDs than other viral RBDs/ Has. As expected, although all engineered Nb17.1 and Nb23.1 were multi-point mutations, This result indicated that the engineered Nbs could be applied for SARS-CoV-2 broad-specific neutralization [7][8][9]. The finding represents an exciting outcome with a usable yield however, further investigation is required in a biological system to prove their effectiveness in a real environment for the next generation of usability as SARS-CoV-2 prevention, treatment, or diagnosis applications.…”

“…Mutations in RBD, particularly in VOCs such as Alpha (B.1.1.7), Beta (B.1.351), Gamma (P.1), Delta (B.1.617.2), and Omicron (B.1.1.529); BA.1 and BA.2, have been shown to increase virus transmissibility, evade host defenses, and confer the ability to escape immune responses [4][5][6]. As a result, the development of high-specific neutralizing molecules such as nanobodies (Nbs) is critical to combat the emergence of VOCs and their impact on global public health [7][8][9].…”