Antibody cocktail to SARS-CoV-2 spike protein prevents rapid mutational escape seen with individual antibodies

By A. Baum, Benjamin O. Fulton, Elzbieta Wloga, R. Copin, Kristen E. Pascal, Vincenzo Russo, Stephanie Giordano, Kathryn Lanza, Nicole Negron, M. Ni and 6 more. 2020

1,270 citations recorded by the source corpus.

An antibody cocktail against SARS-CoV-2 There is an urgent focus on antibodies that target the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) viral spike and prevent the virus from entering host cells. Hansen et al. generated a large panel of antibodies against the spike protein from humanized mice and recovered patients. From this panel, they identified several neutralizing antibodies, including pairs that do not compete for binding to the receptor binding domain. Baum et al. focused in on four of these antibodies. All four are effective against known spike variants. However, by growing a pseudovirus that expresses the spike in the presence of individual antibodies, the authors were able to select for spike mutants resistant to that antibody. In contrast, escape mutants are not selected when pseudovirus is grown in the presence of pairs of antibodies that either do not compete or only partially compete for binding to the RBD. Such a pair might be used in a therapeutic antibody cocktail. Science, this issue p. 1010, p. 1014 A noncompeting antibody cocktail to SARS-CoV-2 spike protein safeguards against the ability of virus mutations to lead to antibody resistance. Antibodies targeting the spike protein of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) present a promising approach to combat the coronavirus disease 2019 (COVID-19) pandemic; however, concerns remain that mutations can yield antibody resistance. We investigated the development of resistance against four antibodies to the spike protein that potently neutralize SARS-CoV-2, individually as well as when combined into cocktails. These antibodies remain effective against spike variants that have arisen in the human population. However, novel spike mutants rapidly appeared after in vitro passaging in the presence of individual antibodies, resulting in loss of neutralization; such escape also occurred with combinations of antibodies binding diverse but overlapping regions of the spike protein. Escape mutants were not generated after treatment with a noncompeting antibody cocktail.

Subfields: Infectious Diseases, Molecular Biology, Radiology, Nuclear Medicine and Imaging

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Citations in the corpus

Complete mapping of mutations to the SARS-CoV-2 spike receptor-binding domain that escape antibody recognition (2020, positive): “We reasoned this sorting would purge the libraries of completely nonfunctional RBD mutants, but retain mutants with decreased ACE2 affinity that might enable antibody escape (Baum et al., 2020a; Rockx et al., 2010) .”
Multiple SARS-CoV-2 variants escape neutralization by vaccine-induced humoral immunity (2021, positive): “Of particular concern is an E484K mutation in RBD, which was previously identified through in vitro selection experiments to escape from monoclonal antibodies (Baum et al. 2020) and was also recently identified through deep mutational scanning as a variant with the potential to evade monoclonal and ”
Reduced neutralization of SARS-CoV-2 B.1.617 by vaccine and convalescent serum (2021, positive): “We note that although REGN10987 and mAb 75 bind at a similar site to mAb 278 and all three antibodies overlap the ACE2 binding site (Baum et al., 2020; Dejnirattisai et al., 2021a) the engagement is sufficiently different that neither REGN10987 nor mAb 75 directly contact RBD residue 452 ( Figure S2”
Deep Mutational Scanning of SARS-CoV-2 Receptor Binding Domain Reveals Constraints on Folding and ACE2 Binding (2020, positive): “These findings provide a framework that could inform the formulation of antibody cocktails aiming to limit the emergence of viral escape mutants (Baum et al., 2020; Pinto et al., 2020; Wu et al., 2020b; Zost et al., 2020), particularly if deep mutational scanning approaches like our own are extended”
SARS-CoV-2 variants B.1.351 and P.1 escape from neutralizing antibodies (2021, background): “Resistance against antibodies used for COVID-19 treatment A cocktail of monoclonal antibodies (REGN-COV2, consisting of Casirivimab and Imdevimab) and the monoclonal antibody Bam- lanivimab block SARS-CoV-2 WT infection (Figure S2) and have received EUA for COVID-19 therapy.”