A panacea for Covid-19?
Preclinical trials of neutralizing antibodies to SARS-CoV-2 have begun
Maria Rogovaya, Naked Science
There are no drugs for viruses — only antibodies help. Not everyone has them. It is possible to teach the human body to produce them independently, with the help of a vaccine. Or you can just make them and inject them to the patient. The first Russian antibodies to SARS-CoV-2 have already been created and are undergoing preclinical tests.
The first Russian development of neutralizing antibodies to SARS-CoV-2, created at the Institute of Molecular and Cellular Biology of the Siberian Branch of the Russian Academy of Sciences, received a grant from the Ministry of Education and Science for preclinical testing in the amount of 270 million rubles. The scientists published details of their research in the journal Cell Discovery on the website of the scientific publishing house Nature (Gorchakov et al., Isolation of a panel of ultra-potent human antibodies neutralizing SARS-CoV-2 and viral variants of concern).
"We have obtained a panel of specific human monoclonal antibodies from the B cells of recovering patients. Most of these antibodies showed high virus-neutralizing activity both in vitro (in vitro) and in vivo (in the body of a Syrian hamster. — Editor's note)," the authors of the publication said in response to a question from a Naked Science correspondent. It turned out that individual antibodies, as well as their double combinations, remain active against the SARS-CoV-2 variants circulating today. When used as prophylactic or therapeutic agents, they can strongly inhibit the replication of the virus and prevent lung pathology in infected SARS-CoV-2.
The first phase of preclinical trials and the production of two antibody producers will be completed at the end of 2022, and the life-saving antibodies to the virus, which has been killing millions of people around the world for almost two years, should be created within three years. During this time, of course, many changes can occur: on the one hand, new strains of the virus will appear, on the other, more people will be vaccinated, which, in turn, will not only prevent the spread of Covid—19 and an increase in mortality, but also the formation of mutant variants of the pathogen itself.
But one thing will not change for sure: Covid-19 will not disappear anywhere, you need to learn how to fight it and closely monitor how it mutates and what new dangers it is preparing. It is for this purpose that it is necessary to develop our own developments and conduct research at the forefront of science, without relying on the purchase of a license for the release of some promptly (timely) made foreign development.
The full official name of the grant is "A technological platform for the emergency creation of means for the prevention and therapy of viral infections on the example of SARS—CoV2-neutralizing antibodies". The history of this development began in the summer of 2020, when specialists from the Institute of Molecular and Cellular Biology of the Siberian Branch of the Russian Academy of Sciences created a panel of six antibodies to the basic epitopes of coronovirus and reported their successes in the hope of receiving funding to continue work with a view to further release of the drug into production. The development aroused the interest of foreign investors, but Siberian scientists expected that the implementation would take place in Russia, and refused the offer.
Antibodies are already used in the treatment
The very idea of treating people with neutralizing antibodies is not an innovation. The introduction of highly purified blood plasma to patients from those who have been ill with certain infectious diseases was practiced in the twentieth century, and today this method is used in some clinics for those infected with coronavirus. However, antibodies with protective or neutralizing properties make up only a small part of the total pool of antiviral antibodies that are produced by the immune system. The concentration of neutralizing antibodies in the plasma of recovered patients is insufficient for full protection against SARS-CoV-2.
Therefore, the efforts of scientists are aimed at obtaining neutralizing antibodies in the form of individual molecules, which are called monoclonal antibodies. Scientists' experiments on Syrian hamsters have shown that the effective dose is from one to 10 milligrams per kilogram of weight. There are whole classes of antibodies against inflammatory processes: in particular, some clinics today use them to prevent a cytokine storm when treating patients in covid hospitals. Antibodies are also widely used against oncological diseases.
This therapy is called targeted, because the drug is aimed at a specific target. However, antibodies for anti-cancer therapy are directed at the human body's own cells, so they are usually highly toxic and have a number of side effects, unlike antiviral antibodies, which do not bind to any receptors of human internal organs, but act only on the S-protein of the virus. Nevertheless, the first phase of preclinical testing of the drug is a test for toxicity, and then scientists will study its effectiveness in various dosages: the higher the effectiveness, the lower the dose will be needed, which is fundamental for investors and manufacturers.
More than 20 companies in the world are engaged in the development of neutralizing monoclonal antibodies to Covid-19, and most have already passed the stage of preclinical testing. The scientific group of the IMKB SB RAS received funding for such tests only at the end of September this year. The project involves co-executors from different institutes and departments, each of which will perform its part of the work: the V. A. Engelhardt Institute of Molecular Biology (IMB RAS), Imgen+ LLC, the Federal Research and Clinical Center for Specialized Types of Medical Care and Medical Technologies of the Federal Medical and Biological Agency of Russia (FSBI FNCC FMBA of the Russian Federation), FSBI "State Scientific Center "Institute of Immunology" FMBA of Russia, Federal State Budgetary Educational Institution of Higher Education "First St. Petersburg State Medical University named after Academician I. P. Pavlov" of the Ministry of Health.
In addition to preclinical testing of antiviral antibodies already obtained, the goal of the project is to obtain new variants of antibodies capable of neutralizing a wide range of SARS—CoV-2 mutants. Today, only three foreign developers have products that have reached the stage of clinical application and have proven their high effectiveness: Regeneron, Eli Lilly and Vir Biotechnology. According to published data, the introduction of neutralizing antibodies in the first days after the onset of symptoms and diagnosis can reduce the risk of hospitalization and death by 70-80%.
One of the first happy consumers of neutralizing antibodies to SARS-CoV-2 from Regeneron was former US President Donald Trump, who received eight grams (the dose was chosen with a multiple margin) of the drug at an early stage of the disease. In the later stages, the effectiveness of neutralizing antibodies is orders of magnitude lower, since almost irreversible inflammatory processes (cytokine storm) are activated in the body.
Who needs antibodies
Theoretically, antibodies should be produced by the human body itself when encountering a virus, but this process does not always occur on time and in the right volume. Vaccinated people develop their own neutralizing antibodies much faster and in greater quantities than those who have not been vaccinated. But there are quite numerous groups of people to whom the vaccine is either contraindicated, or it does not provide sufficient antibody titer to protect in any particular case (for example, patients with immunodeficiency).
In these cases, a person's life can be saved by introducing the necessary dose of neutralizing antibodies with a wide spectrum of action and high activity. It can be one or several antibodies — different manufacturers practice different approaches to choosing their products. Their common goal is that the resulting drug should neutralize the maximum number of viral particles, including all mutant variants.
"To solve the problem of mutational escape, it is enough to introduce two different antibodies or a cocktail of antibodies against two different sections of the spike—like protein of the virus," said Alexander Taranin, head of the laboratory of the IMKB SB RAS. —It is interesting that antibodies that demonstrate a high neutralizing ability in vitro may have much lower efficacy when injected into a living organism (in vivo) and vice versa, so we have yet to test all the antibodies we have created and choose the two most promising for further research."
Small antibodies of large animals
A separate promising direction in the creation of antiviral agents based on monoclonal neutralizing antibodies is the use of antibodies from camels, llamas and alpacas. Representatives of the camel family can develop antibodies that consist only of heavy chains of immunoglobulins (human antibodies consist of two heavy and two light chains). Antigen-binding sites (domains) such heavy chains are called single—domain antibodies or nanoantibodies, because they are about 10 times smaller than human ones - their size ranges from six to 10 nanometers.
On the one hand, this makes them more mobile and increases the likelihood of binding to the virus: in order to "stick" to the spike of the S-protein, the human antibody needs to turn the "right" side, and the nanoantibodies quickly "stick" it from different sides, reliably blocking it. On the other hand, the large size of the antibody is necessary so that it is retained in the bloodstream, and not instantly excreted through the kidneys. For this purpose, a fragment of the structure of human antibodies is attached to nanoantibodies, that is, they are humanized.
Experiments on mice have shown that nanoantibodies work effectively when ingested directly into the lungs: for example, using an inhaler (nebulizer). But this technique requires further testing, since these particles also quickly enter the bloodstream from the lungs. One of the works within the framework of this project is to obtain effective antibodies based on two nanoantibodies linked to each other: one is against the virus, and the second lingers well on the protein of pulmonary mucus.
It is much more convenient to work with nanoantibodies than with human ones: the features of their structure make it possible to create a variety of variants of therapeutic molecules. In addition, they are easily humanized, that is, such a sequence change that makes them very similar to human antibodies. Perhaps in the future this technology will be used in the production of therapeutic drugs, and today it is actively used for laboratory research.
Race ahead of the curve
When a new medicine is being created, which should become, if not a panacea, then at least a means of saving a huge number of people, the efforts of many scientific groups around the world are needed. The more of them there are, the higher the chances of solving the problem. Of the three antibody preparations approved for use in the United States, Sotrovimab, a product of GSK—VIR, has the widest neutralizing properties. So far, only Sotrovimab has turned out to be insensitive to all known new mutations, including the most aggressive "beta" (South African) variant with a very high lethality. The insensitivity of antibodies to strains is the preservation of the neutralizing function of antibodies, despite the variability of SARS-CoV-2.
The drug saved the lives of many patients, but today (a year later) in a cocktail of two Regeneron antibodies, one turned out to be ineffective against the beta variant. In the cocktail of Eli Lilly, "beta" is not able to neutralize both antibodies. This is a regular situation with such "rescue" antiviral operations. The experience gained by this company shows that it is impossible to count on the therapeutic effect of one type of antibodies, even actively neutralizing the virus, at the risk of the appearance of new strains. Today, scientists working on this area are trying to cover as many variants of SARS-CoV-2 as possible. It is difficult to create protection against mutations that do not exist yet, but it is possible to prepare a base for the rapid production of new antibodies.
The struggle of science with Covid-19 is a race to get ahead. Who will have time faster — scientists with widely neutralizing and highly active monoclonal antibodies and with new vaccines or a virus with the next mutation variants? Countries that do not participate in this race are forced to rely on imported achievements of pharmacology, high social responsibility and discipline of their citizens, who will be vaccinated regularly on time, wear masks, keep a distance, as well as on the domestic medical system designed to save those who could not protect themselves.
The rapid emergence of a vaccine against SARS-CoV-2 (just a year against the usual three to five years for the development and creation of new drugs) around the world, we owe only a few scientific groups that have been working with previous versions of coronaviruses - MERS and SARS—CoV-1 for many years. The key word in the name of the IMKB SB RAS grant is "emergency". Science is not able to quickly invent drugs against new diseases, but by investigating the basic principles of protective mechanisms, it is possible to create a kind of universal technological platform for their operational development.
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