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Potential of Monoclonal Antibodies as COVID-19 Therapy

The effectiveness of monoclonal antibodies in disease caused by previous coronaviruses has prompted this therapy to be reconsidered in coronavirus disease 2019 or COVID-19. Given the similarity between the severe acute respiratory syndrome (SARS) virus receptors and SARS-CoV-2, the use of monoclonal antibodies is expected to give similar results in COVID-19 patients.

Therapy with monoclonal antibodies is considered more specific, pure, and has a lower risk of bloodborne pathogen contamination than intravenous immunoglobulin therapy and serum therapy.

This article will describe the potential of monoclonal antibodies in COVID-19, the latest developments in clinical trials studying their safety and efficacy in COVID-19, and review the criteria for COVID-19 patients who may be ideal candidates for monoclonal antibody therapy.

The potential of monoclonal antibodies as a therapeutic option for COVID-19 is closely related to various developments in the isolation of SARS-CoV-2 monoclonal antibody technology. Since the discovery of SARS-CoV-2, various immunological research centers worldwide have begun to isolate monoclonal antibodies derived from B cells from patients who have recovered from SARS-CoV-2 infection.

Monoclonal antibodies can also be developed from antibodies from transgenic mice that have been immunized with SARS-CoV-2. Various modern techniques have enabled the identification of B cells capable of producing specific antibodies against certain pathogens such as SARS-CoV-2 and the collection of gene data that make specific immunoglobulin heavy and light chains that can express monoclonal antibodies (usually the IgG type).

Coronavirus infection begins when the target receptor on the host cell's surface interacts with the receptor-binding domain located on the spike glycoprotein. This interaction will trigger the fusion between the viral membrane and the plasma membrane.

Then, the cleavage of the spike protein through a proteolytic mechanism will cause the fusion of the viral and host cell membranes, then the viral infection process occurs. Furthermore, the virus will enter the host cell and replicate, thereby forming more viral genomes, envelope glycoproteins, and new nucleocapsids. The complete virus particles then enter the Golgi endoplasmic reticulum compartment, are enveloped in vesicles, and finally released into the host body.

Based on this pathogenesis, the choice of specific molecular therapy against SARS-CoV-2 needs to be directed to inhibit each viral life cycle. This can be achieved using an anti-SARS-CoV-2 neutralizing monoclonal antibody or an anti-ACE-2 monoclonal antibody.

On the other hand, the structure of the spike protein involved in the entry of the virus and the antigen components that can trigger an immune response also makes the spike protein a therapeutic target for monoclonal antibodies against SARS-CoV-2. Specifically, the receptor-binding domain (RBD) on the S1 subunit of the SARS-CoV-2 spike glycoprotein that interacts with the host cell receptor can be a target for monoclonal antibody therapy to inhibit the viral entry process into cells.

The similarity in structure and function of the spike protein of SARS-CoV-2 and SARS-CoV, which is relatively high (77%), is one of the reasons for choosing these molecules as targets for monoclonal antibodies.

Many studies have found that RBD in SARS-CoV-2 has a higher affinity than RBD for the ACE-2 receptor.

Although the structural similarity is quite significant, RBD in SARS-CoV-2 is very different from SARS-CoV in terms of residues at the end of the C chain. This difference impacts the effect of monoclonal antibodies against SARS-CoV, which turns out to have different outcomes against SARS-CoV-2.

Tian et al. investigated potent specific neutralizing antibodies against SARS-CoV such as m396 and CR3014 that target RBD in SARS-CoV. The study results showed that the neutralizing antibody specific for SARS-CoV proved ineffective in preventing the binding between the SARS-CoV-2 spike protein and the host cell receptor.

On the other hand, the SARS-CoV-specific monoclonal antibody CR3022 can bind strongly to RBD against SARS-CoV-2. The difference in response to monoclonal antibody administration to binding between SARS-CoV-2 and host cell receptors is thought to be related to the CR3022 epitope that does not overlap with the ACE-2 binding site on SARS-CoV-2 RBD.

On this basis, Tian et al. concluded that CR3022 has the potential to be developed as a candidate for therapy alone or in combination with other neutralizing antibodies for the prevention and treatment of COVID-19.

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