Discovery and Characterization of a Pan-betacoronavirus S2-binding antibody

Johnson, Nicole V.; Wall, Steven C.; Kramer, Kevin J.; Holt, Clinton M.; Periasamy, Sivakumar; Richardson, Simone; Suryadevara, Naveenchandra; Andreano, Emanuele; Paciello, Ida; Pierleoni, Giulio; Piccini, Giulia; Huang, Ying; Ge, Pan; Allen, James D.; Uno, Naoko; Shiakolas, Andrea R.; Pilewski, Kelsey A.; Nargi, Rachel S.; Sutton, Rachel E.; Abu-Shmais, Alexandria A.; Parks, Robert; Haynes, Barton F.; Carnahan, Robert H.; Crowe, James E.; Montomoli, Emanuele; Rappuoli, Rino; Bukreyev, Alexander; Ross, Ted M.; Sautto, Giuseppe A.; McLellan, Jason S.; Georgiev, Ivelin S.

doi:10.1101/2024.01.15.575741

Cited by 2 publications

(1 citation statement)

References 94 publications

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“…Although the decision process for clinical development would likely be delayed initially, as input data may not be available, the inclusion of in silico generated data, next to classic neutralization potency, affinity, and developability, may result in longer lasting clinical efficacy. Another strategy against viral escape by new strains is to develop pan-variant reactive antibodies, although their mode of action is not necessarily neutralization [ 43 ], or several infections or vaccinations of an individual are needed to develop such an immune response [ 44 , 45 ] or the epitopes to target. Nevertheless, in an urgent pandemic setting, the question remains if such strategies would be economically viable compared to the obvious strategy of isolating neutralizing antibodies from survivors of the initial pandemic phase.…”

Section: Discussionmentioning

confidence: 99%

Fast-Track Discovery of SARS-CoV-2-Neutralizing Antibodies from Human B Cells by Direct Functional Screening

Hillenbrand,

Esslinger,

Seidenberg

et al. 2024

Viruses

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As the COVID-19 pandemic revealed, rapid development of vaccines and therapeutic antibodies are crucial to guarantee a quick return to the status quo of society. In early 2020, we deployed our droplet microfluidic single-cell-based platform DROPZYLLA® for the generation of cognate antibody repertoires of convalescent COVID-19 donors. Discovery of SARS-CoV-2-specific antibodies was performed upon display of antibodies on the surface of HEK293T cells by antigen-specific sorting using binding to the SARS-CoV-2 spike and absence of binding to huACE2 as the sort criteria. This efficiently yielded antibodies within 3–6 weeks, of which up to 100% were neutralizing. One of these, MTX-COVAB, displaying low picomolar neutralization IC50 of SARS-CoV-2 and with a neutralization potency on par with the Regeneron antibodies, was selected for GMP manufacturing and clinical development in June 2020. MTX-COVAB showed strong efficacy in vivo and neutralized all identified clinically relevant variants of SARS-CoV-2 at the time of its selection. MTX-COVAB completed GMP manufacturing by the end of 2020, but clinical development was stopped when the Omicron variant emerged, a variant that proved to be detrimental to all monoclonal antibodies already approved. The present study describes the capabilities of the DROPZYLLA® platform to identify antibodies of high virus-neutralizing capacity rapidly and directly.

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Section: Discussionmentioning

confidence: 99%

Fast-Track Discovery of SARS-CoV-2-Neutralizing Antibodies from Human B Cells by Direct Functional Screening

Hillenbrand,

Esslinger,

Seidenberg

et al. 2024

Viruses

View full text Add to dashboard Cite

show abstract

Broad Neutralization Capacity of an Engineered Thermostable Three-Helix Angiotensin-Converting Enzyme 2 Polypeptide Targeting the Receptor-Binding Domain of SARS-CoV-2

Cavazzini,

Levati,

Germani

et al. 2024

IJMS

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The mutational drift of SARS-CoV-2 and the appearance of multiple variants, including the latest Omicron variant and its sub-lineages, has significantly reduced (and in some cases abolished) the protective efficacy of Wuhan spike-antigen-based vaccines and therapeutic antibodies. One of the most functionally constrained and thus largely invariable regions of the spike protein is the one involved in the interaction with the ACE2 receptor mediating the cellular entry of SARS-CoV-2. Engineered ACE2, both as a full-length protein or as an engineered polypeptide fragment, has been shown to be capable of preventing the host-cell binding of all viral variants and to be endowed with potent SARS-CoV-2 neutralization activity both in vitro and in vivo. Here, we report on the biochemical and antiviral properties of rationally designed ACE2 N-terminal, three-helix fragments that retain a native-like conformation. One of these fragments, designated as PRP8_3H and produced in recombinant form, bears structure-stabilizing and binding-affinity enhancing mutations in α-helix-I and in both α-helix I and II, respectively. While the native-like, unmodified three α-helices ACE2 fragment proved to be thermally unstable and without any detectable pseudovirion neutralization capacity, PRP8_3H was found to be highly thermostable and capable of binding to the SARS-CoV-2 spike receptor-binding domain with nanomolar affinity and to neutralize both Wuhan and Omicron spike-expressing pseudovirions at (sub)micromolar concentrations. PRP8_3H thus lends itself as a highly promising ACE2 decoy prototype suitable for a variety of formulations and prophylactic applications.

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Discovery and Characterization of a Pan-betacoronavirus S2-binding antibody

Cited by 2 publications

References 94 publications

Fast-Track Discovery of SARS-CoV-2-Neutralizing Antibodies from Human B Cells by Direct Functional Screening

Fast-Track Discovery of SARS-CoV-2-Neutralizing Antibodies from Human B Cells by Direct Functional Screening

Broad Neutralization Capacity of an Engineered Thermostable Three-Helix Angiotensin-Converting Enzyme 2 Polypeptide Targeting the Receptor-Binding Domain of SARS-CoV-2

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