iScience
Volume 26, Issue 4, 21 April 2023, 106323
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Article
Preclinical safety and efficacy of a therapeutic antibody that targets SARS-CoV-2 at the sotrovimab face but is escaped by Omicron

https://doi.org/10.1016/j.isci.2023.106323Get rights and content
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open access

Highlights

  • Antibody CV38-142 neutralizes wild-type SARS-CoV-2 and VOC Alpha, Beta, Gamma, Delta

  • Post-exposure and therapeutic efficacy in hamster model of VOC infection

  • No off-target binding in human protein library and tissue cross-reactivity study

  • No neutralization of Omicron led to discontinuation of clinical development

Summary

The recurrent emerging of novel viral variants of concern (VOCs) with evasion of preexisting antibody immunity upholds severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) case numbers and maintains a persistent demand for updated therapies. We selected the patient-derived antibody CV38-142 based on its potency and breadth against the VOCs Alpha, Beta, Gamma, and Delta for preclinical development into a therapeutic. CV38-142 showed in vivo efficacy in a Syrian hamster VOC infection model after post-exposure and therapeutic application and revealed a favorable safety profile in a human protein library screen and tissue cross-reactivity study. Although CV38-142 targets the same viral surface as sotrovimab, which maintains activity against Omicron, CV38-142 did not neutralize the Omicron lineages BA.1 and BA.2. These results highlight the contingencies of developing antibody therapeutics in the context of antigenic drift and reinforce the need to develop broadly neutralizing variant-proof antibodies against SARS-CoV-2.

Subject areas

Immunology
Virology

Data and code availability

Sequence information for the mAbs described in this study can be found in original publication in which they had been isolated.1 The custom software BASE used for immunoglobulin sequence analysis is available at https://github.com/automatedSequencing/BASE. The nucleotide sequences of all mAbs shown in Figure 1 have been deposited to GenBank (accession numbers MW002770 – MW002805).

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19

These authors contributed equally

20

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