LY-CoV1404 (bebtelovimab) potently neutralizes SARS-CoV-2 variants

Abstract

LY-CoV1404 is a highly potent, neutralizing, SARS-CoV-2 spike glycoprotein receptor binding domain (RBD)-specific antibody identified from a convalescent COVID-19 patient approximately 60 days after symptom onset. In pseudovirus studies, LY-CoV1404 retains potent neutralizing activity against numerous variants including B.1.1.7, B.1.351, B.1.427/B.1.429, P.1, and B.1.526 and binds to these variants in the presence of their underlying RBD mutations (which include K417N, L452R, E484K, and N501Y). LY-CoV1404 also neutralizes authentic SARS-CoV-2 in two different assays against multiple isolates. The RBD positions comprising the LY-CoV1404 epitope are highly conserved, with the exception of N439 and N501; notably the binding and neutralizing activity of LY-CoV1404 is unaffected by the most common mutations at these positions (N439K and N501Y). The breadth of variant binding, potent neutralizing activity and the relatively conserved epitope suggest that LY-CoV1404 is one in a panel of well-characterized, clinically developable antibodies that could be deployed rapidly to address current and emerging variants. New variant-resistant treatments such as LY-CoV1404 are desperately needed, given that some of the existing therapeutic antibodies are less effective or ineffective against certain variants and the impact of variants on vaccine efficacy is still poorly understood.

Potent neutralization of SARS-CoV-2 variants of concern by an antibody with an uncommon genetic signature and structural mode of spike recognition

“…well as the structure of antibody COV2-2130 in complex with the SARS-CoV-2 RBD (Table S2). The results revealed significant positive correlations with only six other antibodies: REGN10987 (Hansen et al, 2020), 2-7 (Liu et al, 2020), C119 (Barnes et al, 2020), COVOX-75 (Dejnirattisai et al, 2021), COV2-2130 (Zost et al, 2020) (in agreement with the observed binding competition with 54042-4, Figure 2D), and LY-CoV1404 (Westendorf et al, 2021) (Figure 4B). However, of these six antibodies, COVOX-75 has been reported as not a potent neutralizer (Dejnirattisai et al, 2021).…”

“…Here, we report the identification of 54042-4, an antibody that exhibited potent SARS-CoV-2 neutralization against USA-WA1 as well as the currently circulating Alpha, Beta, Gamma, and Delta VOCs. Interestingly, antibody 54042-4 neutralized virus at comparable IC 50 s to the clinical candidates LY-CoV1404 and REGN10987, despite having $10-fold lower affinity for the RBD (Hansen et al, 2020;Westendorf et al, 2021). Although the epitope of antibody 54042-4 showed partial overlap with that of several other known RBD-directed antibodies, our findings revealed a distinct mode of SARS-CoV-2 spike recognition, paired with an uncommon genetic signature that distinguishes 54042-4 from other SARS-CoV-2 antibodies.…”

Current status of therapeutic monoclonal antibodies against SARS-CoV-2

“…Currently, combination therapies comprising a cocktail of NAbs targeting distinct nonoverlapping epitopes on RBD have demonstrated exceptional potency and promising correlates of protection against SARS-CoV-2 and its variants (Fig 2B) [36,38]. Additionally, newly identified RBD core-binding NAbs SARS2-38 [39] and LY-CoV1404 [40] as monotherapy potently neutralize all SARS-CoV-2 VOCs. Therefore, several options of NAbs targeting conserved RBD epitopes are emerging as promising and attractive therapeutic candidates to tackle the disease burden caused by SARS-CoV-2 or its variants.…”

SARS-CoV-2 Spike Pseudoviruses: A Useful Tool to Study Virus Entry and Address Emerging Neutralization Escape Phenotypes

“…The inclusion of a universally acceptable robust positive control is essential in the evolving serological/neutralization assays for SARS-CoV-2. A recent report suggested potent neutralization of SARS-CoV-2 variants by an antibody, LY-CoV1404 [40]. However, as it is not commercially available to researchers for assay harmonization, we used NIBSC 20/130 reagent as a positive control.…”