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Review 1: "Antibodies with potent and broad neutralizing activity against antigenically diverse and highly transmissible SARS-CoV-2 variants"

Published onApr 14, 2022
Review 1: "Antibodies with potent and broad neutralizing activity against antigenically diverse and highly transmissible SARS-CoV-2 variants"
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Antibodies with potent and broad neutralizing activity against antigenically diverse and highly transmissible SARS-CoV-2 variants
Description

AbstractThe emergence of highly transmissible SARS-CoV-2 variants of concern (VOC) that are resistant to therapeutic antibodies highlights the need for continuing discovery of broadly reactive antibodies. We identify four receptor-binding domain targeting antibodies from three early-outbreak convalescent donors with potent neutralizing activity against 12 variants including the B.1.1.7 and B.1.351 VOCs. Two of them are ultrapotent, with sub-nanomolar neutralization titers (IC50 <0.0006 to 0.0102 μg/mL; IC80 < 0.0006 to 0.0251 μg/mL). We define the structural and functional determinants of binding for all four VOC-targeting antibodies, and show that combinations of two antibodies decrease the in vitro generation of escape mutants, suggesting potential means to mitigate resistance development. These results define the basis of therapeutic cocktails against VOCs and suggest that targeted boosting of existing immunity may increase vaccine breadth against VOCs.One Sentence SummaryUltrapotent antibodies from convalescent donors neutralize and mitigate resistance of SARS-CoV-2 variants of concern.

RR:C19 Evidence Scale rating by reviewer:

  • Reliable. The main study claims are generally justified by its methods and data. The results and conclusions are likely to be similar to the hypothetical ideal study. There are some minor caveats or limitations, but they would/do not change the major claims of the study. The study provides sufficient strength of evidence on its own that its main claims should be considered actionable, with some room for future revision.

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Review:

Recently identified SARS-CoV-2 variants of concern (VOCs) threaten to spread more rapidly than previous variants and appear to undermine the efficacy of some existing antibody therapeutics and vaccines. Antibody therapeutics and vaccines currently available or in late stages of clinical development target a spike protein based on strains circulating during the early phases of the pandemic in 2020. In this manuscript, while Wang L et al. also used ancestral SARS-CoV-2 WA-1 infected convalescent patient samples to discover potent antibodies, they focused on those maintaining efficacy against SARS-CoV-2 VOCs. Using well-established methodologies, such as antigen-based flow-sorting and live virus neutralization assays, this group identified four antibodies (A19-46.1, A19-61.1, A23-58.1, B1-182.1) which target the receptor-binding domain (RBD), block spike interaction with ACE2, and potently neutralize SARS-CoV-2 WA-1 strain. Significantly, as some antibodies currently in use like Lilly LY-CoV555 lose potency versus some VOCs, they go on to characterize these antibodies versus 11 VOCs.  While all four mAbs identified in this study retained their potency against the D614G variant, only mAbs A23-58.1 and mAb A19-46.1 maintained potency against B.1.1.7 and B.1.351 VOCs with slight reductions in IC50 values. These two potent mAbs use similar heavy and light chains genes to previously identified antibodies and are therefore considered public-clonotypes (Zost et al., 2020a, b, Baum et al 2020a, b).

Wang et al. also examined epitope interactions of their mAbs. They show that A23-58.1 and B1-182.1 exhibit similar competition binding profiles by biolayer interferometry to one another, as do A19-61.1 and A19-46.1. Surprisingly all four mAbs compete with LY-CoV555.  Further, structural studies using Cryo-Em identified that the binding mode of A23-58.1 is very similar to that of a previously reported IGHV1-58/IGKV3-20-derived antibody, S2E12. Modeling and structural mechanistic experiments revealed that REGN10933 and CB6 bind to the same side of the RBD as A23-58.1, but key contact residues differ.  Hence, REGN10933 and CB6 potentially lose neutralization, as measured by pseudotyped neutralization assays, to certain VOCs which do not impact A23-59.1 pseudoneutralization. Additional structural data shows the unique binding approaches of A23-58.1 and B1-182.1, which are derived from the same germline genes, might explain their efficacy against these VOCs.

By applying selective pressure on replication-competent vesicular stomatitis virus expressing the WA-1 SARS-CoV-2 spike (rcVSV-SARS2) with these potent mAbs (A23-58.1, B1-182.1, A19-46.1 or A19-61.1), the authors explored possible antibody-resistance mechanisms. Unlike the other three mAbs, which showed multiple potential escape mutations, only one observed mutation, F486S, allowed rcVSV-SARS2 to escape A23-58.1 mAb neutralization.  These findings agree with their structural studies and confirm this antibody has a similar escape profile to other members of this public clonotype (citations). Finally, similar to other antibody discovery efforts, the group shows that a rationally-designed antibody combination of A19-46.1 and B1-182.1 effectively mitigates the selection of escape by rcVSV-SARS2 viruses. Overall, the mAbs described above exhibit potent neutralizing activity against SARS-CoV-2 variants of concern and are public clonotypes. Remarkably, this work highlights that efforts from multiple different research groups into the identification of therapeutic antibodies against SARS-CoV-2 converged to similar outputs and, therefore, substantiate these overall research efforts.   

 

Zost, S.J., Gilchuk, P., Case, J.B., Binshtein, E., Chen, R.E., Nkolola, J.P., Schafer, A., Reidy, J.X., Trivette, A., Nargi, R.S., et al. (2020a). Potently neutralizing and protective human antibodies against SARS-CoV-2. Nature 584, 443-449.

 

Zost, S.J., Gilchuk, P., Chen, R.E., Case, J.B., Reidy, J.X., Trivette, A., Nargi, R.S., Sutton, R.E., Suryadevara, N., Chen, E.C., et al. (2020b). Rapid isolation and profiling of a diverse panel of human monoclonal antibodies targeting the SARS-CoV-2 spike protein. Nat Med 26, 1422-1427.

Baum, A., Ajithdoss, D., Copin, R., Zhou, A., Lanza, K., Negron, N., Ni, M., Wei, Y., Mohammadi, K., Musser, B., et al. (2020a). REGN-COV2 antibodies prevent and treat SARS-CoV-2 infection in rhesus macaques and hamsters. Science 370, 1110-1115.

 

Baum, A., Fulton, B.O., Wloga, E., Copin, R., Pascal, K.E., Russo, V., Giordano, S., Lanza, K., Negron, N., Ni, M., et al. (2020b). Antibody cocktail to SARS-CoV-2 spike protein prevents rapid mutational escape seen with individual antibodies. Science 369, 1014-1018.

 

 

 

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