Neutralizing Antibody, The New Hope of COVID-19 Therapy
Neutralizing antibody therapy is considered as the hope of treat COVID-19
Date: 1/20/2021 5:52:43 AM ( 7 mon ) ... viewed 60 times
For a long time, viruses have played a unique role in human history, affecting the progress of human civilization. The influenza virus (H1N1) that broke out globally in 1918 infected 1 billion people worldwide and at least 25 million people died; the Ebola virus that broke out in Sudan in 1976 had an average fatality rate of 50%. The case fatality rate ranges from 25% to 90%; the recent outbreak of the COVID-19 worldwide has also caused millions of patients to be infected. Although human biomedical technology is developing rapidly, it still cannot completely resist the seemingly "small" virus invasion. Therefore, it is very necessary to understand the virus invasion mechanism and develop corresponding treatment programs.
Nowadays, antiviral therapies are mainly focused on the key steps of virus replication, for example, by inhibiting the contact and fusion of virus with host cells, small molecule compounds such as maravirol and amantadine; inhibiting the replication of viral genetic material such as Cido Fovir, etc.; inhibit viral protein synthesis, such as interferon, etc.; inhibit virus aggregation and release in host cells, such as zanamivir.
However, the current antiviral treatment effect is still not satisfactory. In addition, the selectivity of antiviral drugs to the virus is quite different, and the adverse reactions are also large. With the vigorous development of human biomedicine, many new and effective antiviral therapies with less side effects have emerged. Neutralizing antibodies are one of the dazzling members.
For the prevention and treatment of major infectious diseases, neutralizing antibody therapy is one of the important strategies for effective prevention and treatment. Antibody molecules can kill and remove virus particles and infected cells by blocking the binding of virus particles to their receptors and activating immune cells such as macrophages and NK cells and complements.
Only by clearly understanding the process of virus invasion can we have a deeper understanding of the antiviral mechanism of neutralizing antibodies.
Since the virus cannot synthesize nutrients for its own survival, it must infect the host cell to survive. Take the enveloped virus as an example. In the first step of the virus infection cycle, that is, the virus invasion stage, the viral envelope protein needs to mediate the fusion of the virus with the cell membrane, thereby transferring the virus's genetic material (RNA or DNA) to the cytoplasm. Different viruses invade host cells by binding their own specific proteins to specific receptors on the surface of target cells.
Under normal circumstances, how should the body resist virus invasion?
After countless centuries of evolution, the body's immune system has also produced defensive measures against virus invasion. When a virus invades cells, the immune system activates to produce neutralizing antibodies to block the virus's invasion. First, antibodies can bind to specific proteins on the surface of the virus or receptors on the surface of susceptible cells to block the interaction between the virus and receptors on the surface of susceptible cells, thereby preventing the virus from contacting the cell membrane and blocking the adhesion process. Second, the antibody can interfere with the fusion mechanism of the virus and the cell membrane, blocking the fusion of the virus with the host cell or the release of new viruses from the host cell. Third, when the virus is internalized, the antibody can block the binding of the virus to the receptor in the endosome or block the cleavage of the protease in the endosome, preventing the release of the viral genome. Fourth, antibodies can mediate effector cells or complement to kill infected cells. Finally, antibodies can also bind to virus particles to form immune complexes that are directly eliminated by the immune system.
For example, after human rhinovirus type 14 invades the human body through the upper respiratory tract, it combines with the intercellular adhesion factor (Icam-1) of epithelial cells to invade epithelial cells, resulting in
Respiratory diseases with cold symptoms. When the virus infects the body, the B lymphocytes in the immune system are activated to produce neutralizing antibodies. On the one hand, it neutralizes the surface protein of human rhinovirus, causing it to fail to bind with intercellular adhesion factors and hinder the process of cell membrane fusion; on the other hand, The neutralizing antibody binds to the virus particle to prevent the release of its genetic material RNA.
If the body fails to resist virus invasion, what else can it do?
When the virus is highly infectious or the autoimmune system cannot be effectively mobilized to protect the body from virus infection, the development of recombinant monoclonal neutralizing antibodies becomes an effective means to treat such virus infections. According to the principle of neutralizing antibodies against viruses, antibodies often have faster onset therapeutic effects in emergency treatment of infected patients. This has been fully confirmed in the drug development of the Ebola virus epidemic.
Due to the excellent antiviral effect of neutralizing antibodies, many studies have been devoted to exploring whether neutralizing antibodies have a preventive effect to protect the body from infection before virus exposure. Some in vitro and animal experiments have confirmed the preventive function of neutralizing antibodies, and some clinical studies are also in progress. In other words, antiviral neutralizing antibodies not only have therapeutic effects, but also their potential preventive effects are worthy of attention.
SARS-CoV-2 neutralizing antibody therapy
Neutralizing antibodies can block disease. The potential of the virus to infect target cells, and the advantages of monoclonal antibodies with a clear mechanism of action and easy mass production are the key directions of research on COVID-19 therapeutic drugs.
At the same time, the "Scientists Fighting New Coronary" team composed of 12 top scientists in the United States issued a proposal to fight the new crown epidemic, which suggested that monoclonal antibody drugs are a new potential antiviral option that neutralizes COVID-19. Antibody development provides therapeutic hope in terms of speed of development, safety and effectiveness.
Current research has found that SARS-CoV-2, the pathogen of the new type of coronavirus pneumonia (COVID-19), binds to their receptor, angiotensin-converting enzyme (ACE2) through the spike protein (S protein), and undergoes cell membrane fusion. The process, enters the cell through endocytosis, replicates, processes and infects the body. In the process of SARS-CoV-2 and cell membrane fusion, cathepsin L-mediated activation of spike protein (S protein) is the key process of invasion.
SARS-CoV-2 is a type of RNA virus with an envelope and a linear single-stranded genome. The receptor domain RBD (Receptor Binding Domain) of the surface spike S protein is an important receptor binding site on the surface of the coronavirus. It can bind to the virus-specific receptor ACE2 on the cell surface, and mediate the effects of virus adsorption, virus outer membrane and cell fusion, and penetration, so it is an important target for the development of anti-virus neutralizing antibodies.
Develop a blocking neutralizing antibody against the COVID-19 S protein RBD, which can prevent the S protein RBD from binding to ACE2, thereby blocking the virus from contacting the host cell, and ultimately preventing virus infection. This is an important way for neutralizing antibodies to exert their antiviral effects, and is a different treatment strategy from other drugs that hinder the process of virus replication in cells.
Since SARS-CoV-2 has a high degree of homology with SARS-CoV virus, neutralizing antibodies targeting SARS-CoV virus may also have neutralizing activity against SARS-CoV-2 virus. For example, the team of Professor Berend-Jan Bosch from Utrecht University in the Netherlands reported a fully human monoclonal antibody 47D1115 that can neutralize both SARS-CoV-2 and SARS-CoV. David Veesler and Davide Corti also obtained two SARS-CoV-2 neutralizing antibodies from SARS-CoV neutralizing antibodies. Studies have found that although these antibodies all bind to the S protein RBD of SARS-CoV-2, they cannot block the binding of RBD to ACE2.
Recently, many biological companies and drug development companies have jointly developed this preventive and therapeutic antibody therapy for COVID-19. At present, a number of neutralizing antibodies have been engineered and completed the preclinical studies required by IND, the development and production of antibody processes for GLP toxicology studies, and the GMP production of clinical batches of antibodies. The lead antibody is scheduled to enter the clinical phase in the second quarter of this year.
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