A team of international scientists has recently developed a bispecific antibody that can bind to two regions that do not cross the spike binding domain of acute respiratory respiratory coronavirus 2 (SARS-CoV) syndrome. -2) and prevent viral-host interaction completely. The antibody is also able to neutralize various mutated variants of SARS-CoV-2. The study is currently available on the bioRxiv* preprint server.
Background
Many studies have been conducted to find effective therapeutic interventions to prevent a progressive pathway of coronavirus disease 2019 (COVID-19). In this context, various preclinical and clinical studies have shown that monoclonal antibodies developed specifically against SARS-CoV-2 effectively treat COVID-19 patients. Furthermore, it has been observed clinically that, compared to one antibody, a combination of two or more antibodies exhibits higher efficacy and greater potency in preventing viral escape. However, this approach is not cost effective due to the complex and time consuming manufacturing process.
In the present study, the scientists have performed structural analysis and computer simulations to design a bispecific molecule-like immunoglobulin G (IgG) molecule that can simultaneously bind to two distinct, unrelated epitopes the same receptor binding domain (RBD) of SARS- Protein spike CoV-2, as well as different RBDs on spike trimer.
Study design
Using a molecular dynamics simulation approach, they have designed four molecules, of which CoV-X2 has shown the highest neutral effect against SARS-CoV-2 pseudoviruses. In particular, CoV-X2, an IgG1-like bispecific antibody, was developed by combining antigen-binding Fragment (Fab) domain of two human monoclonal antibodies, namely C121 and C135, which are known to be significantly neutralizes SARS-CoV-2. efficiency.
According to the structural prediction, CoV-X2 can bind to RBD at all condensers, spike trimmers, and several spike trimer mutants, including the D614G-containing variant and the variants UK and South African novel of SARS-CoV-2. Furthermore, CoV-X2 can bind to SARS-CoV-2 mutations that cannot be neutralized by parental monoclonal antibodies (C121 and C135).
A Plasma Resonance-based avidity assay has revealed that CoV-X2 can simultaneously bind to two distinct regions on the same RBD. Binding strength is maintained even at low antigen density. Furthermore, CoV-X2 has been found to completely inhibit the interaction between viral spike proteins and angiotensin-converting enzyme 2 (ACE2) enzyme. In contrast, only partial inhibition of spike / ACE2 interaction was achieved with both parent antibodies.
Neutral capacity of CoV-X2 was investigated using SARS-CoV-2 pseudoviruses. The results have shown that CoV-X2 is effective in neutralizing both wild-type and mutated variants of SARS-CoV-2. However, both parent antibodies have failed to neutralize SARS-CoV-2.
The clinical efficacy of CoV-X2 has been demonstrated by the induction of ACE2-induced mice with SARS-CoV-2 and subsequent treatment with the anticoagulant. The infectious mice without CoV-X2 treatment have developed lung pathologies similar to severe COVID-19 patients, as well as severe body weight loss. The viral RNA was found in the lungs and distant organs of these infected mice. In contrast, no weight loss in body weight was observed and no histopathological changes were observed in mice with CoV-X2 treatment. In addition, CoV-X2 treatment has been found to significantly reduce viral load as well as the frequency of detection of an infectious virus, demonstrating the effectiveness of CoV-X2 in reducing the disease and the disease.
To compare the anti-SARS-CoV-2 efficacy of CoV-X2 with parenteral antibodies, the scientists have treated the virus-infected mice with parenteral antibodies. Interestingly, mice treated with C121 have been found to undergo E484D mutation. The same mutation, which is pathogenic and known to reduce the virus-neutralizing efficacy of human antibodies by 10-fold, was also observed in the South African novel SARS-CoV-2. In contrast, none of the mice treated with CoV-X2 have developed pathogenic mutations, demonstrating the efficacy of CoV-X2 in the elimination of viral escape.
Natural variants of SARS-CoV-2 in the C121 and C135 epitopes. Summary of naturally occurring mutations in the C121 (a) or C135 (b) epitopes reported in the SARS-CoV-2 cycle (as of January 1, 2021). The position of the mutated remains is shown in red on the RBD structure. The variable categories C121 and C135 are in green and blue (PDB ID: 7K8X and 7K8Z respectively).
Investigate meaning
An IgG1-like bispecific antibody, CoV-X2, was developed in the study showing significant neutral efficacy against SARS-CoV-2. The antibody is able to completely inhibit spike-ACE2 interaction and prevent viral escape. Unlike parental antibodies (C121 and C135), CoV-X2 can effectively neutralize a wide range of variable variants of SARS-CoV-2, making it a potential candidate for fight against COVID-19 pandemic.
* Important message
bioRxiv publish preliminary scientific reports that are not peer-reviewed and, therefore, should not be seen as final, guiding health-related clinical practice / behavior, or be treated as information established.