ACE2-Fc fusion protein overcomes viral escape by potently neutralizing SARS-CoV-2 variants of concern

Tsai, Tsung-I; Khalili, Jahan S.; Gilchrist, Mark; Waight, Andrew B.; Cohen, Daniella; Shi, Z.; Zhang, Yong; Ding, Muran; Zhu, Haoyu; Mak, Amanda Nga-Sze; Zhu, Yi; Goulet, Dennis R.

doi:10.1016/j.antiviral.2022.105271

Cited by 16 publications

(22 citation statements)

References 55 publications

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“…However, it seems that the use of hrsACE2 is useful only in the early stages of the disease and prevents viral infection of human blood vessels and renal organoids [136] . Despite several ACE2 and ACE-2 like molecules being developed for treatment of COVID-19, Tsai et al [152] developed an ACE2-Fc fusion protein, SI-F019, which showed a strong binding and a more potent neutralization of SARS-CoV-2 variants compared to the original strain. These findings suggested that SARS-CoV-2 cannot evolve to escape the ACE2-Fc inhibitor, in contrast to monoclonal antibodies binding to spike, which can be clearly evaded by viral escape variants.…”

Section: Strategies How To Outsmart Sars-cov-2mentioning

confidence: 99%

Molecular mechanisms involved in pathogenicity of SARS-CoV-2: Immune evasion and implications for therapeutic strategies

Latifi-Pupovci

2022

Biomedicine & Pharmacotherapy

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Section: Strategies How To Outsmart Sars-cov-2mentioning

confidence: 99%

Molecular mechanisms involved in pathogenicity of SARS-CoV-2: Immune evasion and implications for therapeutic strategies

Latifi-Pupovci

2022

Biomedicine & Pharmacotherapy

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“…The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused a global pandemic with the number of coronavirus disease (COVID-19)-related deaths exceeding 5.6 million as of February 2022 (1). Despite the unprecedented success in the SARS-CoV-2 vaccine development, this number is still growing, raising the question of multiple antiviral therapeutics development.…”

Section: Introductionmentioning

confidence: 99%

Isolation of an escape-resistant SARS-CoV-2 neutralizing nanobody from a novel synthetic nanobody library

et al. 2022

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The COVID−19 pandemic not only resulted in a global crisis, but also accelerated vaccine development and antibody discovery. Herein we report a synthetic humanized VHH library development pipeline for nanomolar-range affinity VHH binders to SARS-CoV-2 variants of concern (VoC) receptor binding domains (RBD) isolation. Trinucleotide-based randomization of CDRs by Kunkel mutagenesis with the subsequent rolling-cycle amplification resulted in more than 1011 diverse phage display library in a manageable for a single person number of electroporation reactions. We identified a number of nanomolar-range affinity VHH binders to SARS-CoV-2 variants of concern (VoC) receptor binding domains (RBD) by screening a novel synthetic humanized antibody library. In order to explore the most robust and fast method for affinity improvement, we performed affinity maturation by CDR1 and CDR2 shuffling and avidity engineering by multivalent trimeric VHH fusion protein construction. As a result, H7-Fc and G12x3-Fc binders were developed with the affinities in nM and pM range respectively. Importantly, these affinities are weakly influenced by most of SARS-CoV-2 VoC mutations and they retain moderate binding to BA.4\5. The plaque reduction neutralization test (PRNT) resulted in IC50 = 100 ng\ml and 9.6 ng\ml for H7-Fc and G12x3-Fc antibodies, respectively, for the emerging Omicron BA.1 variant. Therefore, these VHH could expand the present landscape of SARS-CoV-2 neutralization binders with the therapeutic potential for present and future SARS-CoV-2 variants.

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“…The current emerging severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes a global pandemic and the coronavirus disease (COVID-19)-related deaths had exceeded 5.6 million in February 2022 (1). Despite the unprecedented success in SARS-CoV-2 vaccine development this number is still growing, raising the question of multiple antiviral therapeutics development.…”

Section: Introductionmentioning

confidence: 99%

Development of an Escape-resistant SARS CoV-2 Neutralizing Synthetic Nanobody

Dormeshkin

Shapira

Dubovik

et al. 2022

Preprint

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An emerging COVID-19 pandemic resulted in a global crisis, but also accelerated vaccine development and antibody discovery. In this work, we identified a number of nanomolar-range affinity VHH binders to SARS-CoV-2 variants of concern (VoC) receptor binding domains (RBD), by screening synthetic humanized antibody library with more than 1e11 diversity. In order to explore the most robust and fast method for affinity improvement, we performed affinity maturation by CDR1 and CDR2 shuffling and avidity engineering by multivalent trimeric VHH fusion protein construction. As a result, H7-Fc and G12x3-Fc binders were developed with the affinities in nM and pM range respectively. Importantly, their affinities are weakly influenced by SARS-CoV-2 VoC mutations. The plaque reduction neutralization test (PRNT) resulted in IC50 = 100 ng\ml and 9.6 ng\ml for H7-Fc and G12x3-Fc antibodies respectively for emerging Omicron variant. Therefore, these VHH could expand the present landscape of SARS-CoV-2 neutralization binders with the therapeutic potential for present and future SARS-CoV-2 variants.

show abstract

ACE2-Fc fusion protein overcomes viral escape by potently neutralizing SARS-CoV-2 variants of concern

Cited by 16 publications

References 55 publications

Molecular mechanisms involved in pathogenicity of SARS-CoV-2: Immune evasion and implications for therapeutic strategies

Molecular mechanisms involved in pathogenicity of SARS-CoV-2: Immune evasion and implications for therapeutic strategies

Isolation of an escape-resistant SARS-CoV-2 neutralizing nanobody from a novel synthetic nanobody library

Development of an Escape-resistant SARS CoV-2 Neutralizing Synthetic Nanobody

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