Broad ultra-potent neutralization of SARS-CoV-2 variants by monoclonal antibodies specific to the tip of RBD

Abstract

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants of concern (VOCs) continue to wreak havoc across the globe. Higher transmissibility and immunologic resistance of VOCs bring unprecedented challenges to epidemic extinguishment. Here we describe a monoclonal antibody, 2G1, that neutralizes all current VOCs and has surprising tolerance to mutations adjacent to or within its interaction epitope. Cryo-electron microscopy structure showed that 2G1 bound to the tip of receptor binding domain (RBD) of spike protein with small contact interface but strong hydrophobic effect, which resulted in nanomolar to sub-nanomolar affinities to spike proteins. The epitope of 2G1 on RBD partially overlaps with angiotensin converting enzyme 2 (ACE2) interface, which enables 2G1 to block interaction between RBD and ACE2. The narrow binding epitope but high affinity bestow outstanding therapeutic efficacy upon 2G1 that neutralized VOCs with sub-nanomolar half maximal inhibitory concentration in vitro. In SARS-CoV-2, Beta or Delta variant-challenged transgenic mice and rhesus macaque models, 2G1 protected animals from clinical illness and eliminated viral burden, without serious impact to animal safety. Mutagenesis experiments suggest that 2G1 is potentially capable of dealing with emerging SARS-CoV-2 variants in the future. This report characterized the therapeutic antibodies specific to the tip of spike against SARS-CoV-2 variants and highlights the potential clinical applications as well as for developing vaccine and cocktail therapy.

A combination of potently neutralizing monoclonal antibodies isolated from an Indian convalescent donor protects against the SARS-CoV-2 Delta variant

“…As expected, a strong correlation between minimal or no loss in body weight and undetectable lung virus load in the mice that received different doses of mAb combination was observed (Figs 7G and S12F ) . Taken together our study demonstrated significant protection by a combination of these two potently neutralizing mAbs at low dose against the highly virulent Delta variant in a transgenic hACE-2 mice model and was found to be comparable with few others tested against Delta variant [ 37 , 38 ].…”

Long-term passaging of replication competent pseudo-typed SARS-CoV-2 reveals the antiviral breadth of monoclonal and bispecific antibody cocktails

“…In our previous study 21 , we identified a broad-spectrum neutralizing antibody 2G1 that targets the tip of RBD through a small contact surface from our SARS-CoV-2 antibody repertoire, which makes it less possible in epitope clash with other antibodies and thus suitable for combinational use. We performed competition ELISA to map the epitope information of antibodies.…”

“…The VSV-SARS-CoV-2 broke through the protection of monotherapy by 9E12, 10D4 and 2G1 at the 9 th , 1 st and 4 th passages, respectively (Figure 2b). The emergency use authorization (EUA) antibody REGN10933, which has a similar epitope with 2G1, was used as a control 21 . The virus broken through REGN10933 at the 3 rd passage.…”

“…The pseudovirus neutralization study was performed as described previously 21 . In brief, 293T-ACE2 cells were plated at a density of 1 × 10 4 cells per well into a 96-well white transparent bottom plate, and cultured overnight at 37 °C in 5% CO 2 .…”

“…In this study, we formulated several sets of antibody cocktails from our SARS-CoV-2 antibody repertoire and evaluated the viral escape ability from these cocktails in a replication-competent vesicular stomatitis virus model with S protein replacement (VSV-SARS-CoV-2) through long-term passaging. 21 Considering the combination of two or more antibodies may potentially complicate the product components, introduce complex manufacturing procedures, and increase production costs, we developed some of these monoclonal antibodies into a bunch of bispecific antibodies using our BAPTS bispecific antibodies development platform 22,23 .…”