Efficient inhibition of SARS-CoV-2 strains by a novel ACE2-IgG4-Fc fusion protein with a stabilized hinge region

Svilenov, Hristo; Sacherl, Julia; Reiter, Alwin; Wolff, Lisa; Chen, Cho-Chin; Stern, Marcel; Wachs, Frank-Peter; Simonavicius, Nicole; Pippig, Susanne; Wolschin, Florian; Büchner, Johannes; Brockmeyer, Carsten; Protzer, Ulrike

doi:10.1101/2020.12.06.413443

Cited by 10 publications

(11 citation statements)

References 70 publications

(114 reference statements)

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“…Although SARS‐CoV‐2 has emerged recently, the current treatments and the prophylaxis of COVID‐19 is limited, although several drugs/vaccines as candidates for treatment/prophylaxis of COVID‐19 have been tested in clinical trials. The research field is developing rapidly, and almost every day, new information and data about COVID‐19 are published, such as a report on a SARS‐CoV‐2 blocker, which has fully prevented infection of cells in vitro (Svilenov et al, 2020) or on a ribonucleoside analogue, which was able to suppress SARS‐CoV‐2 transmission in ferrets (Cox et al, 2021).…”

Section: Discussionmentioning

confidence: 99%

SARS‐CoV‐2 and hypertension

et al. 2021

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The objective of this review is to give an overview of the pathophysiological effects of the Coronavirus Disease 2019 (COVID‐19) in relation to hypertension (HT), with a focus on the Renin–Angiotensin–Aldosterone System (RAAS) and the MAS receptor. HT is a multifactorial disease and a public health burden, as it is a risk factor for diseases like stroke, coronary artery disease, and heart failure, leading to 10.4 million deaths yearly. Blood pressure is regulated by the RAAS. The system consists of two counter‐regulatory axes: ACE/ANG‐II/AT1R and ACE2/ANG‐(1‐7)/MAS. The main regulatory protein in balancing the RAAS is angiotensin‐converting enzyme 2 (ACE2). The protein also functions as the main mediator of endocytosis of the severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) into the host cell. SARS‐CoV‐2 is the cause of COVID‐19 and has caused a worldwide pandemic; however, the treatment and prophylaxis of COVID‐19 are limited. Several drugs and vaccines are currently being tested in clinical trials with a few already approved by EMA and FDA. HT is a major risk factor regarding the severity and fatality of COVID‐19, and the RAAS plays an important role in COVID‐19 infection since SARS‐CoV‐2 can lead to a dysregulation of the system by reducing the ACE2 expression. The exact mechanisms of HT in relation to COVID‐19 remain uncertain, and more research is needed for further elucidation.

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Section: Discussionmentioning

confidence: 99%

SARS‐CoV‐2 and hypertension

et al. 2021

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“…Similarly, approved monoclonal antibodies act by blocking the interaction of the cell-entry receptor ACE2 and the viral Spike protein (see https://www.covid19treatmentguidelines.nih.gov/ for further information). Thus, blocking Spike/ACE2 binding has become a central strategy of both vaccine design and multiple therapeutic approaches including ACE2 based therapeutics (8–12) . This has created an intense research focus on the molecular details of these processes thereby making the Spike/ACE2 interaction one of the best validated drug targets in biomedicine.…”

Section: Introductionmentioning

confidence: 99%

Clinical grade ACE2 as a universal agent to block SARS-CoV-2 variants

Wirnsberger

Monteil

Eaton³

et al. 2021

Preprint

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The recent emergence of multiple SARS-CoV-2 variants has caused considerable concern due to reduced vaccine efficacy and escape from neutralizing antibody therapeutics. It is therefore paramount to develop therapeutic strategies that inhibit all known and future SARS-CoV-2 variants. Here we report that all SARS-CoV-2 variants analyzed, including variants of concern (VOC) Alpha, Beta, Gamma, and Delta, exhibit enhanced binding affinity to clinical grade and phase 2 tested recombinant human soluble ACE2 (APN01). Importantly, soluble ACE2 neutralized infection of VeroE6 cells and human lung epithelial cells by multiple VOC strains with markedly enhanced potency when compared to reference SARS-CoV-2 isolates. Effective inhibition of infections with SARS-CoV-2 variants was validated and confirmed in two independent laboratories. These data show that SARS-CoV-2 variants that have emerged around the world, including current VOC and several variants of interest, can be inhibited by soluble ACE2, providing proof of principle of a pan-SARS-CoV-2 therapeutic.

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“…A version of ACE2 IgG1 Fc is currently evaluated in a Phase-I clinical trial. Developing this therapeutic candidate, it has been optimized with IgG4-Fc to facilitate Fc receptor activation and prevention of antibody-dependent disease development (48).…”

Section: Human Recombinant Soluble Ace2 (Hrsace2)mentioning

confidence: 99%

Beyond Vaccines: Clinical Status of Prospective COVID-19 Therapeutics

et al. 2021

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Since November 2019 the SARS-CoV-2 pandemic has caused nearly 200 million infection and more than 4 million deaths globally (Updated information from the World Health Organization, as on 2nd Aug 2021). Within only one year into the pandemic, several vaccines were designed and reached approval for the immunization of the world population. The remarkable protective effects of the manufactured vaccines are demonstrated in countries with high vaccination rates, such as Israel and UK. However, limited production capacities, poor distribution infrastructures and political hesitations still hamper the availability of vaccines in many countries. In addition, due to the emergency of SARS-CoV-2 variants with immune escape properties towards the vaccines the global numbers of new infections as well as patients developing severe COVID-19, remains high. New studies reported that about 8% of infected individuals develop long term symptoms with strong personal restrictions on private as well as professional level, which contributes to the long socioeconomic problems caused by this pandemic. Until today, emergency use-approved treatment options for COVID-19 are limited to the antiviral Remdesivir, a nucleoside analogue targeting the viral polymerase, the glucocorticosteroide Dexamethasone as well as neutralizing antibodies. The therapeutic benefits of these treatments are under ongoing debate and clinical studies assessing the efficiency of these treatments are still underway. To identify new therapeutic treatments for COVID-19, now and by the post-pandemic era, diverse experimental approaches are under scientific evaluation in companies and scientific research teams all over the world. To accelerate clinical translation of promising candidates, repurposing approaches of known approved drugs are specifically fostered but also novel technologies are being developed and are under investigation. This review summarizes the recent developments from the lab bench as well as the clinical status of emerging therapeutic candidates and discusses possible therapeutic entry points for the treatment strategies with regard to the biology of SARS-CoV-2 and the clinical course of COVID-19.

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Efficient inhibition of SARS-CoV-2 strains by a novel ACE2-IgG4-Fc fusion protein with a stabilized hinge region

Cited by 10 publications

References 70 publications

SARS‐CoV‐2 and hypertension

SARS‐CoV‐2 and hypertension

Clinical grade ACE2 as a universal agent to block SARS-CoV-2 variants

Beyond Vaccines: Clinical Status of Prospective COVID-19 Therapeutics

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