Immunity for rent
Preparations based on immunoglobulins
Rostec blog, Naked Science
The creation of vaccines and antibiotics is not unreasonably considered a key event in the history of the development of modern medicine. These drugs help save millions of lives every year. Largely thanks to them, the population of the Earth has grown significantly in the XX century, the life expectancy of people has increased. However, in the arsenal of modern doctors there are other means with completely unique properties. We are talking about drugs based on human immunoglobulin. Experts of the holding "Natsibio" of Rostec State Corporation talk about the principles of operation of these drugs and the process of creating "COVID-globulin" – a unique development for the treatment of coronavirus.
The use of human immunoglobulins as medicines began after the invention of the method of plasma fractionation (separation of proteins by charge and molecular weight) by the American biochemist Edwin Cohn during World War II. By the 1950s of the century, it was already known that if the plasma of an infected or vaccinated donor was transfused into a person's blood, the disease could be successfully cured. Thanks to this discovery, such specific immunoglobulins as anti-tick, antistaphylococcal, tetanus, anti-cytomegalovirus, antiviral and others appeared in the arsenal of doctors.
In many cases, specific immunoglobulins have become the last and only means of saving patients when other treatments have proved ineffective. In 2020, with the beginning of the COVID-19 pandemic, the idea of developing a specific immunoglobulin against coronavirus also arose. Despite the appearance of the first working vaccines against SARS-CoV-2, it is possible that immunoglobulins will help save patients from severe complications and death. Even after a large-scale vaccination coverage is provided for the treatment of patients who have fallen ill for one reason or another, it will be necessary to treat, for example, those who have not had time to receive the vaccine, or those for whom vaccination is contraindicated.
How do antibodies work?
Antibodies are large proteins that are part of the human body's immune system. Each antibody has a high specificity and "works" against any one or several protein molecules or fragments of a microorganism external to the human body, called antigens.
Antibodies protect against bacteria, fungi, viruses, multicellular parasites, various poisons and foreign substances. Each antibody recognizes one or more specific antigens, binds to them, neutralizes them, and then activates other parts of the human immune system.
"The molecule of each antibody can be conditionally represented in the form of the English letter Y. Its lower "stem" consists of two "heavy chains". "On top" there are "light chains" that form "horns" – it is in this part of the antibody that amino acid sequences unique to each antibody are contained, which provide kinship with "their own" antigen for each antibody," says Technology manager of the holding "Natsibio" Mikhail Razumikhin.
There are a huge number of different antibodies in the blood and other biological fluids of a person. Their totality can be called an immunoglobulin, which carries the "memory" of all the antigens that the body has ever encountered. Among the variety of antibodies in the human body, there are five main types.
Immunoglobulins G (IgG) are the most numerous group. In the composition of blood plasma, they account for about 85 percent. They provide basic protection of the body from external pathogens, neutralize toxins, help to overcome viruses and destroy bacteria. Due to immunoglobulins G, NK cells are also activated, which destroy infected cells and provide antitumor immunity. A distinctive feature of IgG is that they penetrate through the placenta from the mother to the fetus and protect it from infections.
Immunoglobulins M (IgM) is a "rapid response group". There are only 13-15 percent of them in the blood serum, but they are the first to "fight" when "strangers" enter the body. They can bind ten antigen molecules. IgM causes agglutination – the adhesion of pathogens into larger particles, which makes it easier to remove them from the body.
Immunoglobulins E (IgE) make up only 0.002 percent of all serum antibodies, but play an important role in the immune response. They bind to the so–called mast cells and cause them to produce histamine, a regulator of many physiological processes in the body. IgE provides protection of the body from single-celled parasites, helminths. This type of immunoglobulin is involved in the development of inflammation, one of the protective reactions of the body.
Immunoglobulin A (IgA) accounts for 15 percent of all antibodies in the human body, but it accounts for only six percent in the blood serum. Most of the IgA is present in saliva, mucus, lacrimal fluid, breast milk. These "guardians" guard the most vulnerable places – the mucous membranes.
Immunoglobulin D (IgD) is a rare type of antibody. They are mainly located on the surface of B-lymphocytes and regulate their activity. Very few immunoglobulins D are present in the blood plasma. Disorders in the work of these antibodies are associated with some immune disorders.
"The point of using immunoglobulins in the fight against infections is that we use donor antibodies and artificially create immune protection in humans. This is similar to vaccination, but there are significant differences. When vaccinated, active immunization is carried out. The human body is "introduced" to a pathogen that is weakened and cannot harm the body, and then it independently develops immune protection, which, as a rule, persists for a long time.
The use of immunoglobulins is passive immunization. The patient's body does not form its own protection, it receives it temporarily from the outside, but on its basis it can accelerate the production of its own antibodies against the pathogen," explains Mikhail Razumikhin, an expert of the holding "Natsibio" of Rostec State Corporation. Passive immunity after the introduction of immunoglobulins occurs after a few hours and lasts up to two weeks. Therefore, antibodies for the prevention and treatment of infections should be administered as soon as possible after infection or the appearance of symptoms.
Usually, in order for a person to develop immune protection after vaccination, the body takes time, sometimes up to several weeks. Since doctors inoculate the patient with a weakened pathogen or some separate fragment of it, vaccination is most often carried out in several stages at certain intervals.
At the same time, not all vaccinated people develop immunity. For example, vaccination is ineffective in people with primary or secondary immunodeficiency. Such patients are currently being diagnosed and supported by the State. Usually they are shown substitution therapy – they are regularly, once every one to two weeks, injected with "normal human immunoglobulin".
In the case of infection with a pathogen to which there are no antibodies in normal immunoglobulin, as for example in the case of a new coronavirus, only an immunoglobulin specific to this pathogen can help. In summary, passive immunization with the use of specific immunoglobulins plays a key role in the fight against infectious diseases in the event that for some reason it is impossible to form immunity by vaccination.
It is noteworthy that every person receives passive immunity naturally at the very beginning of life. In women during pregnancy, especially in the third trimester, the mother's antibodies actively penetrate the placenta and protect the fetus. Colostrum is also rich in immunoglobulins, in a slightly smaller amount they are present in breast milk. Due to these factors, the child is protected by the mother's antibodies at birth and feeding, in addition to its own immunity.
Who came up with the idea of using antibodies?
In 1890, Japanese physician and bacteriologist Shibasaburo Kitasato and German bacteriologist-immunologist Emil Adolf von Behring first reported the existence of substances in the blood capable of neutralizing diphtheria toxin. They took the treated blood of animals that had suffered diphtheria and injected it into guinea pigs.
The experiment showed that after the introduction of treated blood of infected animals, guinea pigs become immune to the introduction of lethal doses of diphtheria bacillus and its toxin. Subsequently, scientists proved that the serum of immunized animals can treat already developed diphtheria, including in humans. Since 1895, the active production of diphtheria antitoxin, which was a serum of sick animals, began.
At the beginning of the XX century, when antibiotics had not yet been invented, infections claimed many human lives, so the use of serums of immunized animals and humans was a real discovery. Since 1907, human serum has been actively used for the treatment and prevention of measles, whooping cough and mumps (mumps). In the 1930s, "serum therapy" was already actively used to combat a number of bacterial and viral infections.
It has helped to significantly reduce mortality from meningitis, pneumococcal infection, diphtheria. But not everything went smoothly. Before the invention of effective methods of serum purification, serious allergic reactions were often caused, and they did not help with all infections. Nevertheless, with the help of serums, doctors managed to save many patients.
In the second half of the last century, immunoglobulins were used not only for infectious diseases. In 1952, antibodies were successfully injected for the first time to a boy suffering from agammaglobulinemia, a hereditary disease in which the body does not produce enough B-lymphocytes. Subsequently, immunoglobulins began to be used as solutions for intramuscular administration in immunodeficiency conditions as replacement therapy. And in the 1980s, thanks to the development of biochemical methods of purification of immunobiological substances, the first drugs for safe intravenous administration were created.
Finally, thanks to the development of genetic engineering methods for the targeted creation of molecules, artificial monoclonal antibodies have been created at a new stage in the development of biochemical industrial technologies, which is one of the greatest achievements of medicine and biopharaceutics in recent decades.
These antibodies bind to only one antigen and are synthesized artificially, in cells specially designed by genetic engineering methods. The use of monoclonal antibodies is of the greatest importance for oncology. Thus, it was possible to create antibodies capable of interacting with certain antigens of cancer and immune cells in a targeted manner.
Such antibodies can block the use of the necessary receptors by cancer cells, induce killer cells on cancer cells, or activate immune cells to fight tumors. Targeted therapy and immunotherapy have appeared – they help fight malignant tumors and have fewer side effects compared to classical chemotherapy. In addition, monoclonal antibodies have found wide application in the treatment of autoimmune diseases, rheumatology and can be used to fight pathogens.
Against microorganisms, toxins and allergies
Currently, drugs based on immunoglobulins are used for the prevention and treatment of infections, autoimmune diseases, immunodeficiency conditions and to neutralize toxins that have entered the human body. There are several groups of therapeutic immunoglobulins:
I. Standard immunoglobulins are produced for intravenous, subcutaneous and intramuscular administration. They are obtained from the plasma of healthy donors. To make such a drug, a plasma pool of more than a thousand people is used so that the patient receives an average set of immunoglobulins across the population, and preferably from the area in which he lives.
The spectrum of indications for the use of standard immunoglobulins is quite wide – substitution therapy for primary and secondary immunodeficiency; prevention of viral hepatitis A, measles, chickenpox (in people with immunodeficiency conditions); AIDS with recurrent infections; bone marrow transplantation from donors, and immunoglobulins are often used for neurological conditions associated with autoimmune disorders.
Immunoglobulins are also often used against various infections that are characteristic of the population. The drug is administered when infection has already occurred or the first symptoms have appeared. First of all, we are talking about dangerous infections against which there are no effective methods of treatment, or about the severe course of infections in people with a weakened immune system.
It is pointless to "vaccinate" with immunoglobulins in advance, because they create passive immunity that does not last long. But there are exceptions. For example, normal immunoglobulins are used prophylactically in the first trimester of pregnancy for women who do not have their own antibodies against the herpes virus, since a sudden outbreak of this infection can threaten serious negative consequences for the fetus.
If immunoglobulins are administered in high doses, mechanisms that provide an antiallergic effect begin to work. Thus, these drugs can be used for a number of allergic reactions and autoimmune diseases. For example, antiallergic immunoglobulin is used as part of complex therapy for pollinosis, atopic dermatitis, atopic bronchial asthma, recurrent forms of urticaria and Quincke's edema, dermorespiratory syndrome.
II. Enriched immunoglobulins contain immunoglobulin G, enriched with immunoglobulins M and A. Today, this is the "gold standard" treatment of sepsis and septic shock – a severe inflammatory process by which the body reacts to infection. Enriched immunoglobulins not only provide protection against a wide range of pathogens, but also help control inflammation.
III. Specific (hyperimmune) immunoglobulins are immunoglobulins against a specific pathogen. They are obtained from the plasma of donors with a high content of antibodies to the pathogen. The donor could have acquired these antibodies as a result of immunization or naturally. Currently, the world produces immunoglobulins against tick-borne encephalitis, tetanus, rabies, botulism, chickenpox, herpes zoster, hepatitis B, staphylococcus and many others.
IV. Monoclonal antibodies are antibodies with a given specificity obtained by biosynthesis artificially using genetically modified cells. Currently, monoclonal antibodies are actively used in various fields of medicine, but they find relatively limited use in infectious diseases.
History repeats itself
At the beginning of the last century, humanity was constantly faced with infections for which there were no vaccines or effective methods of treatment. The appearance of "serum therapy" became a life-saving straw that doctors held on to until antibiotics and vaccinations appeared. Nowadays, the situation has almost repeated itself.
The COVID-19 pandemic claimed millions of lives around the world, while doctors were not immediately able to offer patients anything other than symptomatic treatment. Today, the first effective vaccines have been created and have already been successfully tested, but their development and mass production take time. Vaccination has begun, but coronavirus vaccinations are not available in all countries and not for everyone. It will take quite some time before it will be possible to cover the main part of the world's population with vaccination and create collective immunity.
Under these conditions, given the many years of experience in the production and use of specific immunoglobulins, a logical idea arose to develop a drug capable of neutralizing the new coronavirus. To produce such an immunoglobulin, a special plasma was required – containing neutralizing SARS-CoV-2 antibodies.
The first stage of the creation of "COVID-globulin" was the work on determining the criteria for the selection of raw materials – blood plasma of sick donors, in order to make immunoglobulin effective. It became possible to accomplish such a task due to the fact that test systems were created in Russia promptly, already in the spring of 2020, to determine the presence of antibodies to coronavirus, and a number of Russian scientific institutes have already put on stream methods for determining the viral neutralizing activity of various substances on cell culture, using the real SARS-CoV virus-2. Thus, evaluation criteria have been developed that allow us to assert that immunoglobulin obtained from the plasma of donors who have had coronavirus has the ability to neutralize infection.
For the production of antikovid immunoglobulin, a previously proven technology for the production of intravenous immunoglobulin of the "fourth" generation – chromatographically purified and virus-safe - was chosen. This technology allows you to get the finished product as quickly as possible and with a good yield of the final product. The holding company "Natsibio" of Rostec State Corporation managed to obtain a series of the drug in a short time and conduct preclinical and clinical studies, especially in the field of evaluating the effectiveness of the drug to neutralize the virus, as well as the safety of its use by patients. The clinical efficacy of the drug will be revealed during the ongoing clinical trials of the second and third phases.
Already in the spring of 2020, at the very beginning of the outbreak of the disease, it was found that the plasma of COVID-19 donors with a high level of antibodies helps to reduce the viral load and improve the condition of patients with severe symptoms of infection. Currently, plasma transfusion with a high content of neutralizing antibodies is included in the recommendations for the treatment of COVID-19 of the Ministry of Health of Russia.
Food and Drug Administration (FDA) The United States has also authorized plasma transfusion of recovered patients as a method of treating severe forms of COVID-19. In April 2021, the Russian Ministry of Health approved the use of a specific immunoglobulin intended for the treatment of a new coronavirus infection. COVID-globulin has become the world's first registered drug against SASR-CoV-2. It is based on the blood plasma of people who have had a coronavirus infection.
The development of the holding "Natsibio" of the Rostec State Corporation in the course of research confirmed the safety, the absence of side effects and the ability to neutralize the virus. It is assumed that the drug will be used for the treatment of moderate and severe forms of the disease after the completion of phases II and III of clinical trials, which will be held, including on the basis of Moscow hospitals. Thus, the descendant drugs of "serum therapy" continue to play an important role in the fight against dangerous diseases. The Covid-19 pandemic has once again reminded that their potential is far from being exhausted.
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