Complete map of SARS-CoV-2 RBD mutations that escape the monoclonal antibody LY-CoV555 and its cocktail with LY-CoV016

Abstract

Monoclonal antibodies and antibody cocktails are a promising therapeutic and prophylaxis for coronavirus disease 2019 (COVID-19). However, ongoing evolution of severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) can render monoclonal antibodies ineffective. Here, we completely map all of the mutations to the SARS-CoV-2 spike receptor-binding domain (RBD) that escape binding by a leading monoclonal antibody, LY-CoV555, and its cocktail combination with LY-CoV016. Individual mutations that escape binding by each antibody are combined in the circulating B.1.351 and P.1 SARS-CoV-2 lineages (E484K escapes LY-CoV555, K417N/T escapes LY-CoV016). In addition, the L452R mutation in the B.1.429 lineage escapes LY-CoV555. Furthermore, we identify single amino acid changes that escape the combined LY-CoV555+LY-CoV016 cocktail. We suggest that future efforts diversify the epitopes targeted by antibodies and antibody cocktails to make them more resilient to the antigenic evolution of SARS-CoV-2.

Novel SARS-CoV-2 variants: the pandemics within the pandemic

“…Immune escape concerns : Similar to the results reported for B.1.351, the efficacy of therapeutic mAbs may be abolished/reduced, including: bamlanivimab, casirivimab, and etesivimab[ 17 , 23 , 33 ], as well as REGN10989[ 22 ]. The pervasiveness may be due to immune escape in the context of a high level of population immunity[ 49 ].…”

“…The L452R mutation is within the RBD, and thus may be relevant to transmissibility or immune escape[ 16 ], indeed, the L452R mutation has been shown to result in binding-escape from the therapeutic mAb bamlanivimab (LY-CoV555)[ 17 ].…”

“…General antibody neutralization and immune escape remarks : Studies testing specific monoclonal antibodies often report severe reductions or complete escape following mutations to S. Thus VOCs and VOIs with mutations in S are a concern for various antibody mediated therapies such as etesivimab (LY-CoV016), bamlanivimab, casirivimab(REGN10933)[ 17 , 22 ]. Resistance to specific monoclonal antibodies or resistance due to a single mutation is unlikely to significantly affect neutralizing activity of polyclonal sera, while multiple mutations may have more substantial effects; which is supported by studies using vaccine sera and pseudovirus (PsV)[ 23 ].…”

“…This effect is mostly due to the E484K mutation[ 39 ]. Notably efficacy, of mAbs approved for COVID-19 treatment may be abolished/reduced, such as: etesevimab[ 17 ], bamlanivimab, and REGN10989[ 22 ].…”

A potently neutralizing anti-SARS-CoV-2 antibody inhibits variants of concern by binding a highly conserved epitope

“…The majority of characterized potently neutralizing and protective anti-SARS-CoV-2 mAbs bind the receptor binding domain (RBD) of the viral spike protein (Barnes et al, 2020; Baum et al ., 2020a; Cao et al, 2020; Tortorici et al, 2020; Zost et al ., 2020), though some inhibitory mAbs against the N-terminal domain (NTD) of spike also have been described (Chi et al, 2020; Liu et al, 2020; Suryadevara et al, 2021). Under immune selection pressure, SARS-CoV-2 can select for mutations in the RBD and NTD that enable escape from antibody recognition and neutralization (Baum et al, 2020b; Greaney et al, 2021; Liu et al, 2021; Starr et al, 2021; Suryadevara et al ., 2021). Indeed, several emerging SARS-CoV-2 variants have mutations in the spike protein, including the RBD and NTD, that confer resistance to mAbs or polyclonal antibodies (pAbs) elicited by vaccines or natural infection (Chen et al, 2021d; Thomson et al, 2021; Weisblum et al, 2020).…”