Picomolar inhibition of SARS-CoV-2 variants of concern by an engineered ACE2-IgG4-Fc fusion protein

Svilenov, Hristo; Sacherl, Julia; Reiter, Alwin; Wolff, Lisa; Cheng, Cho-Chin; Stern, Marcel; Grass, Vincent; Feuerherd, Martin; Wachs, Frank-Peter; Simonavicius, Nicole; Pippig, Susanne; Wolschin, Florian; Keppler, Oliver T.; Büchner, Johannes; Brockmeyer, Carsten; Protzer, Ulrike

doi:10.1016/j.antiviral.2021.105197

Cited by 16 publications

(19 citation statements)

References 70 publications

(31 reference statements)

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“…This long-lasting effect was also confirmed by other scientists [3]. Further, ACE2 decoy receptor was confirmed neutralization against authentic virus [4][5][6][7][8][9] and showed promising prophylactic and therapeutic efficacy in animal models [8].…”

Section: Introductionsupporting

confidence: 66%

“…Our research studied the ACE2-Fc combination strategy with neutralizing antibodies of diverse epitopes. Taking advantage of the broad neutralizing ability of ACE2-Fc demonstrated by many previous researches [4,5,[8][9][10][11], NAb+ACE2-Fc combinations mitigated virus evasion by ACE2-Fc and NAb co-inhibiting the interaction of escaped variants with ACE2 receptor, which broadened the neutralization spectrum of individual NAbs of diverse epitopes, expanding the finding in ACE2-Fc and HLX70 combination [16].…”

Section: Discussionmentioning

confidence: 85%

“…Variants Reference ACE2-IgG4-Fc; hACE2-Fc; engineered ACE2 receptor Alpha [4]; [8]; [9] ACE2-IgG4-Fc; hACE2-Fc; engineered ACE2 receptor; S19W, T27W, and N330Y mutations in ACE2 Beta [4]; [8]; [9]; [11] engineered ACE2 receptor Gamma [9] hACE2-Fc Kappa [8] ACE2-IgG4-Fc; hACE2-Fc; S19W, T27W, and N330Y mutations in ACE2 Delta [4]; [8]; [11] ACE2-IgG4-Fc; hACE2-Fc; engineered ACE2 receptor; S19W, T27W, and N330Y mutations in ACE2; trimeric ACE2 SARS-CoV [4]; [8]; [9]; [11]; [5] hACE2-Fc HCoV-NL63 [8] trimeric ACE2 WIV1 [5] trimeric ACE2 Rs3367 [5] In clinic, antibody therapies have been used in prophylaxis and treatment of COVID-19. For example, REGN-CoV developed by Regeneron has been commonly used to treat COVID-19.…”

Section: Ace2 Decoy Receptormentioning

confidence: 99%

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Comprehensive Evaluation of ACE2-Fc Combination with Neutralization Antibody on Broad Protection against SARS-CoV-2 and Its Variants

Tang¹,

Ke²,

Ma³

et al. 2022

Preprint

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Emerging SARS-CoV-2 variants are threatening the efficacy of antibody therapies. Combination treatments including ACE2-Fc have been developed to overcome the evasion of neutralizing antibodies (NAbs) in individual cases. Here we conducted a comprehensive evaluation of this strategy by combining ACE2-Fc with NAbs of diverse epitopes on the RBD. NAb+ACE2-Fc combinations efficiently neutralized HIV-based pseudovirus carrying the spike protein of the Delta or Omicron variants, achieving a balance between efficacy and breadth. In an antibody escape assay using replication-competent VSV-SARS-CoV-2-S, all the combinations had no escape after fifteen passages. By comparison, all the NAbs without combo with ACE2-Fc had escaped within six passages. Further, the VSV-S variants escaped from NAbs were neutralized by ACE2-Fc, revealing the mechanism of NAb+ACE2-Fc combinations survived after fifteen passages. We finally examined ACE2-Fc neutralization against pseudovirus variants resistant to the therapeutic antibodies that have currently been in clinic. Our results suggest ACE2-Fc is a universal combination partner to combat SARS-CoV-2 variants including Delta and Omicron.

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Section: Introductionsupporting

confidence: 66%

Section: Discussionmentioning

confidence: 85%

Section: Ace2 Decoy Receptormentioning

confidence: 99%

See 1 more Smart Citation

Comprehensive Evaluation of ACE2-Fc Combination with Neutralization Antibody on Broad Protection against SARS-CoV-2 and Its Variants

Tang¹,

Ke²,

Ma³

et al. 2022

Preprint

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“…While preparing this manuscript, other articles reported results for similar ACE2-Fc fusion proteins to be used as Covid-19 therapeutics. In one case, a wild-type IgG1 Fc was used, while in another the IgG4 subtype was employed ( Zhang et al, 2021 ; Svilenov et al, 2021 ). However, even the more immunologically silent IgG4 version had 40–50 nM affinity for FcγRI, demonstrating the potential for immune cell activation, albeit at a much lower propensity than for more active subtypes like wild-type IgG1.…”

Section: Discussionmentioning

confidence: 99%

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

Tsai¹,

Khalili²,

Gilchrist³

et al. 2022

Antiviral Research

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“… 101 , 102 Therefore, Svilenov et al engineered IgG4-Fc-based ACE2(732)-Fc fusion constructs to avoid Fc-mediated cytotoxic side effects. 103 Nonetheless, the importance and the potential roles of Fc-associated effector functions in virus elimination should be further studied, as they could contribute to ACE2-Fc inhibitory effects against SARS-CoV-2.…”

Section: Introductionmentioning

confidence: 99%

David versus goliath: ACE2-Fc receptor traps as potential SARS-CoV-2 inhibitors

Alfaleh

Zawawi

Alamri

et al. 2022

mAbs

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Anti-SARS-CoV-2 monoclonal antibodies and vaccines have shown improvement in lowering viral burden and hospitalization. However, emerging SARS-CoV-2 variants contain neutralizing antibody-escape mutations. Therefore, several reports have suggested the administration of recombinant angiotensin-converting enzyme 2 (rACE2) as a soluble receptor trap to block SARS-CoV-2 infection and limit viral escape potential. Several strategies have been implemented to enhance the efficacy of rACE2 as a therapeutic agent. Fc fusions have been used to improve pharmacokinetics and boost the affinity and avidity of ACE2 decoys for the virus spike protein. Furthermore, the intrinsic catalytic activity of ACE2 can be eliminated by introducing point mutations on the catalytic site of ACE2 to obtain an exclusive antiviral activity. This review summarizes different evolution platforms that have been used to enhance ACE2-Fc (i.e., immunoadhesins) as potential therapeutics for the current pandemic or future outbreaks of SARS-associated betacoronaviruses.

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Picomolar inhibition of SARS-CoV-2 variants of concern by an engineered ACE2-IgG4-Fc fusion protein

Cited by 16 publications

References 70 publications

Comprehensive Evaluation of ACE2-Fc Combination with Neutralization Antibody on Broad Protection against SARS-CoV-2 and Its Variants

Comprehensive Evaluation of ACE2-Fc Combination with Neutralization Antibody on Broad Protection against SARS-CoV-2 and Its Variants

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

David versus goliath: ACE2-Fc receptor traps as potential SARS-CoV-2 inhibitors

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