Credit: Juntendo
University Research Promotion Center
The surface
protein of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2),
known as the spike protein, is critical for infecting host cells. The spike
protein facilitates the infection process by binding to angiotensin-converting
enzyme 2 (ACE2) receptors on the surface of airway epithelial cells, initiating
the virus entry into the cells.
By engineering an ACE2 receptor to increase the
affinity to the spike protein, researchers demonstrated a novel method to neutralize the virus
effectively. The engineered ACE2 (3N39v4-Fc) acts as a decoy by binding to the
viral spike protein, thus preventing the binding of viruses to the ACE2
receptor on the cell surface. This inhibition by the ACE2 decoy is detrimental
to SARS-CoV-2.
The study was carried out by a team of researchers led
by Professor Toru Okamoto from the Department of Microbiology at Juntendo
University. The team, including Prof. Okamoto, Dr. Atsushi Hoshino from the
Department of Cardiovascular Medicine at Kyoto Prefectural University of
Medicine, and Prof. Junichi Takagi from the Laboratory of Protein Synthesis and
Expression at Osaka University demonstrated that 3N39v4-Fc had a 100-times
higher binding affinity to the spike protein compared to unmodified (wild-type)
ACE2.
This highlighted the potency of 3N39v4-Fc to prevent
the emergence of resistant virus and the efficacy in rodent models in 2021 and
2022.
In the latest study published in the journal Science Translational Medicine, the team demonstrated the potency of the engineered ACE2 receptor decoy (3N39v4-Fc) against the omicron variants, including BA.2.12.1, BA.2.75, and the currently spreading XBB and BQ.1.
Engineered ACE2 decoy with high affinity and an
IgG1 Fc domain demonstrated potent neutralization against Omicron subvariants,
including emerging strains. The ability to prevent escape mutants and display
therapeutic activity in a primate model was demonstrated for the first time,
which suggests its potential as a promising strategy against immune-evading
SARS-CoV-2 variants. Inhaled aerosolized decoys also improved treatment
outcomes, highlighting their potential non-invasive role in enhancing COVID-19
therapies. Credit: Toru Okamoto, Juntendo University
While several groups are working on the development of an ACE2 decoy, the
team, for the very first time, reported a therapeutic effect of the
3N39v4-Fc in a preclinical model using cynomolgus monkeys. The team
investigated several effects in the model, including the antiviral effect,
changes in CT images in the chest, inflammation, pharmacokinetics of the
3N39v4-Fc, and safety. These findings contribute to further evaluation in human trials.
First, the team tested the effectiveness of the 3N39v4-Fc in preventing the
emergence of escape mutants, 3N39v4-Fc-resistant viruses that evade the ACE2
receptor decoys. Although the team's earlier study demonstrated the ability of
an engineered ACE2 decoy to prevent the emergence of escape mutants, in the
latest study, the team validated and confirmed their results using advanced
techniques.
Their experiments revealed that the 3N39v4-Fc reduced the possibility of
the escape mutants more efficiently than wild-type ACE2, demonstrating a
minimum risk of the emergence of escape mutants by high-affinization!
Further, the team tested the feasibility of the 3N39v4-Fc administration
via the inhalation route, as compared with the administration via the
intravenous injection route used in the team's earlier study.
Through advanced imaging techniques based on positron emission
tomography (PET) imaging and zirconium (Zr)-labeling, the
team found that the distribution and clearance patterns within the body
differed between inhalation and intravenous administration route in rodents.
Intravenous administration resulted in a predominant accumulation of
3N39v4-Fc in the liver, whereas inhalation led to uptake predominantly in the
lungs. Remarkably, inhalation administration demonstrated a significant
dose-sparing benefit of up to 20-fold compared to conventional intravenous
administration. "This comparison holds immense significance, as it
achieves equivalent therapeutic results with just a twentieth of the
intravenous dose, potentially leading to substantial cost reduction in treatment
against respiratory infections," explains Prof. Okamoto.
Again, to verify the potential efficacy of these results for humans, the
researchers conducted experiments on cynomolgus monkeys infected with the delta
variant of SARS-CoV-2. The effect of 3N39v4-Fc was tested by both intravenous
and inhalation routes. The treatment led to a reduction in lung abnormalities
and a substantial reduction in infectious virus levels, showing its potential
as a therapeutic option.
"Our successful treatment of SARS-CoV-2-infected cynomolgus monkeys
emphasizes the efficacy and safety of this novel drug. The exceptional efficacy
via inhalation administration of the decoys presents a groundbreaking approach
to reduce the strain on health care systems as it enables patients to
self-administer the drug," says Prof. Okamoto.
In conclusion, the engineered ACE2 decoy exhibits potent neutralizing activity against SARS-CoV-2 variants, and the remarkable efficacy in monkeys highlights its potential for application in the treatment of humans.
by
Juntendo University Research Promotion Center
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