Broadly Effective ACE2 Decoy Proteins Protect Mice from Lethal SARS-CoV-2 Infection

Lu, Mengjia; Yao, Weitong; Li, Yujun; Ma, Danting; Zhang, Zhaoyong; Wang, Haimin; Tang, Xiaojuan; Wang, Yanqun; Li, Chao; Cheng, De; Lin, Hua; Yin, Yandong; Zhao, Jincun; Zhong, Guocai

doi:10.1128/spectrum.01100-23

Cited by 2 publications

(1 citation statement)

References 54 publications

(102 reference statements)

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“…The advantage of the ACE2 decoy is that it is resistant to SARS-CoV-2 mutations because SARS-CoV-2 cannot mutate to the extent that it loses binding to ACE2 as this would halt its life cycle. In previous studies, engineered higher Spike affinity ACE2 decoy Fc fusions successfully improve blockade and neutralize multiple viral variants of SARS-CoV-2 in vitro and in vivo 32,35,37,39,40,42–44,46,49–52 . To our knowledge no study has assessed BiKEs employing the ACE2 decoy approach.…”

Section: Introductionmentioning

confidence: 99%

ACE2 decoy Fc-fusions and bi-specific killer engager (BiKEs) require Fc engagement forin vivoefficacy against SARS-CoV-2

Dick,

Hicks,

Krishna

et al. 2024

Preprint

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SARS-CoV-2 virus has continued to evolve over time necessitating the adaptation of vaccines to maintain efficacy. Monoclonal antibodies (mAbs) against SARS-CoV-2 were a key line of defense for unvaccinated or immunocompromised individuals. However, these mAbs are now ineffective against current SARS-CoV-2 variants. Here, we tested three aspects of αSARS-CoV-2 therapeutics. First, we tested whether Fc engagement is necessary forin vivoclearance of SARS-CoV-2. Secondly, we tested bi-specific killer engagers (BiKEs) that simultaneously engage SARS-CoV-2 and a specific Fc receptor. Benefits of these engagers include the ease of manufacturing, stability, more cell-specific targeting, and high affinity binding to Fc receptors. Using both mAbs and BiKEs, we found that both neutralization and Fc receptor engagement were necessary for effective SARS-CoV-2 clearance. Thirdly, due to ACE2 being necessary for viral entry, ACE2 will maintain binding to SARS-CoV-2 despite viral evolution. Therefore, we used an ACE2 decoy Fc-fusion or BiKE, instead of an anti-SARS-CoV-2 antibody sequence, as a potential therapeutic that would withstand viral evolution. We found that the ACE2 decoy approach also required Fc receptor engagement and, unlike traditional neutralizing antibodies against specific variants, enabled the clearance of two distinct SARS-CoV-2 variants. These data show the importance of Fc engagement for mAbs, the utility of BiKEs as therapies for infectious disease, and thein vivoeffectiveness of the ACE2 decoy approach. With further studies, we predict combining neutralization, the cellular response, and this ACE2 decoy approach will benefit individuals with ineffective antibody levels.AbbreviationsACE2, scFv, mAb, BiKE, COVID-19, Fc, CD16, CD32b, CD64, d.p.iKey pointsWith equal dosing, both neutralization and Fc engagement are necessary for the optimal efficacy ofin vivoantibodies and bi-specific killer engagers (BiKEs) against SARS-CoV-2.BiKEs can clear SARS-CoV-2 virus and protect against severe infection in the hACE2-K18 mouse model.ACE2 decoys as part of Fc-fusions or BiKEs providein vivoclearance of two disparate SARS-CoV-2 variants.

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Section: Introductionmentioning

confidence: 99%

ACE2 decoy Fc-fusions and bi-specific killer engager (BiKEs) require Fc engagement forin vivoefficacy against SARS-CoV-2

Dick,

Hicks,

Krishna

et al. 2024

Preprint

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Development of a mutant aerosolized ACE2 that neutralizes SARS-CoV-2 in vivo

Kober,

Caballero Van Dyke,

Eitson

et al. 2024

mBio

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The rapid evolution of SARS-CoV-2 variants highlights the need for new therapies to prevent disease spread. SARS-CoV-2, like SARS-CoV-1, uses the human cell surface protein angiotensin-converting enzyme 2 (ACE2) as its native receptor. Here, we design and characterize a mutant ACE2 that enables rapid affinity purification of a dimeric protein by altering the active site to prevent autoproteolytic digestion of a C-terminal His 10 epitope tag. In cultured cells, mutant ACE2 competitively inhibits lentiviral vectors pseudotyped with spikes from multiple SARS-CoV-2 variants and infectious SARS-CoV-2. Moreover, the protein can be nebulized and retains virus-binding properties. We developed a system for the delivery of aerosolized ACE2 to K18-hACE2 mice and demonstrated protection by our modified ACE2 when delivered as a prophylactic agent. These results show proof-of-concept for an aerosolized delivery method to evaluate anti-SARS-CoV-2 agents in vivo and suggest a new tool in the ongoing fight against SARS-CoV-2 and other ACE2-dependent viruses. IMPORTANCE The rapid evolution of SARS-CoV-2 variants poses a challenge for immune recognition and antibody therapies. However, the virus is constrained by the requirement that it recognizes a human host receptor protein. A recombinant ACE2 could protect against SARS-CoV-2 infection by functioning as a soluble decoy receptor. We designed a mutant version of ACE2 with impaired catalytic activity to enable the purification of the protein using a single affinity purification step. This protein can be nebulized and retains the ability to bind the relevant domains from SARS-CoV-1 and SARS-CoV-2. Moreover, this protein inhibits viral infection against a panel of coronaviruses in cells. Finally, we developed an aerosolized delivery system for animal studies and show the modified ACE2 offers protection in an animal model of COVID-19. These results show proof-of-concept for an aerosolized delivery method to evaluate anti-SARS-CoV-2 agents in vivo and suggest a new tool in the ongoing fight against SARS-CoV-2.

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Broadly Effective ACE2 Decoy Proteins Protect Mice from Lethal SARS-CoV-2 Infection

Cited by 2 publications

References 54 publications

ACE2 decoy Fc-fusions and bi-specific killer engager (BiKEs) require Fc engagement forin vivoefficacy against SARS-CoV-2

ACE2 decoy Fc-fusions and bi-specific killer engager (BiKEs) require Fc engagement forin vivoefficacy against SARS-CoV-2

Development of a mutant aerosolized ACE2 that neutralizes SARS-CoV-2 in vivo

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