Efficacy of anti-SARS-CoV-2 immunoadhesins against Omicron and other emerging variants

The ongoing coronavirus disease 2019 (COVID-19) pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has claimed more than 6.5 million lives worldwide. Due to genomic variation, several SARS-CoV-2 variants have emerged, classified as variants of concern (VOC) and variants of interest (VOI). The B.1.1.529 (Omicron) variant, along with its subvariants (BA.4 and BA.5), have become predominantly circulating strains worldwide.

Background

Despite COVID-19 vaccination, numerous breakthrough infections have been reported in which both vaccinees and SARS-CoV-2 convalescent individuals were reinfected. Omicron-associated mutants can evade immune protection induced by vaccines and natural infections, resulting in a significant increase in breakthrough infections. Therefore, there is an urgent need for effective therapeutic options to combat infections caused by Omicron and other emerging mutants.

Recently, targeted immunotherapy has proven to be a potential tool against viral diseases. The main advantage of this therapy is its dual effect, including virus neutralization and elimination of infected cells by immune effector cells.

Monoclonal antibodies (mAbs) are used to treat children infected with respiratory syncytial virus. Additionally, animal models have shown efficacy in neutralizing mAbs against many viral infections, including HIV-1, Lassa, Ebola, and SARS. Several immunotherapies during the COVID-19 pandemic reagentPrescriptions were based on mAbs, including etecevimab, bammuranivimab, and sotrovimab. However, decreased efficacy of mAbs against Omicron variants was reported.

Immunoadhesins are antibody-like molecules and are a class of immunotherapeutic agents. These immune molecules consist of an engineered binding domain fused to her Fc portion of an antibody. Zoonotic viruses tend to bind to animal-derived orthologous cell receptors with higher affinity compared to human cell surface receptors, making immunoadhesins excellent antiviral agents.Previous studies have shown efficacy of Arenacept is a potent immunoadhesin that targets viruses of the Arenaviridae family.

Recent eye science A journal study demonstrated that a newly designed angiotensin-converting enzyme 2 (ACE2)-based immunoadhesin is effective against Omicron and other SARS-CoV-2 VOCs.

About research

This study demonstrated the construction of a potent ACE2-based immunoadhesin effective against the original SARS-CoV-2 strain and VOCs. A long helical segment of ACE2 at the N-terminus formed the most potential receptor-binding domain (RBD) recognition site. Based on multiple sequence alignments of over 200 of his ACE2 sequences, the scientist detected several regions containing non-conserved SARS-CoV-2 recognition sites.

A total of 68 orthologous ACE2 genes were selected for this study. Rosetta atom modeling was used to estimate the stability, shape complementarity and binding energy of the RBD. A variant was constructed containing a unique set of eight mutations, namely T27L, D30E, Q42R, E75R, L79Y, N330F, T92R and E375L. Incorporating these mutations, scientists designed a new anti-SARS-CoV-2 immunotherapeutic reagent (ACE2mod -Fc) and analyzed its efficacy against the original SARS-CoV-2 strain and VOCs.

The above design was tested against two chimeric proteins consisting of amino acids 19-615 of the human ACE2 ectodomain fused to the Fc portion of human IgG1, with or without selected mutations. ACE2-Fc and the newly designed ACE2mod -Fc were readily expressed in HEK293F cells and purified by Protein A affinity chromatography.

We evaluated the enzymatic activity of ACE2-Fc and ACE2mod-Fc. These two immunoadhesins were immobilized on a plasmon resonance sensor chip and their binding affinities were determined using purified SARS-CoV-2 RBD.

Survey results

Interestingly, a 1:1 binding model was found to fit the binding profile of ACE2mod-Fc to the SARS-CoV-2 RBD well, but not from ACE2-Fc to SARS-CoV-2 RBD. did not. Therefore, we used a more complex heterogeneous ligand model that assumes a specific heterogeneity of ACE2-Fc. The origin of heterogeneity was mainly due to partial glycosylation at Asn90 of ACE2. Importantly, higher binding affinities were observed between ACE2mod-Fc and SARS-CoV-2 RBD compared to ACE2-Fc.

ACE2mod-Fc was originally designed to bind SARS-CoV-2, but showed higher binding capacity for SARS-RBD compared to ACE2-Fc.a pseudovirus To analyze whether the enhanced affinity of ACE2mod-Fc can translate altered biological functions, we performed neutralization assays. This analysis revealed that the neutralizing capacity of ACE2mod-Fc is superior to that of ACE2-Fc. Moreover, compared to ACE2-Fc, ACE2mod-Fc showed a higher ability to detect spike complexes.

Conclusion

One of the limitations of this study is that the evaluation of newly developed ACE2-based immunoadhesins in vitro experiment.Previous in vivo Experiments demonstrate the possibility of inadequate efficacy of immunoadhesins that can surface due to various unforeseen factors. Therefore, more studies are needed to validate the clinical efficacy of newly developed immunoadhesins. Nonetheless, the efficacy of ACE2-based immunoadhesins against SARS-CoV-2 and VOCs such as alpha, beta, gamma, delta and omicron was demonstrated in this study.