Medicines based on immunoglobulins (or antibodies) have been known for a long time. At the beginning of the 20th century, the German scientist Emil Behring invented a drug for the treatment of diphtheria based on the blood serum of those who had recovered from the disease, and it was for this that he received the very first Nobel Prize in Physiology or Medicine. The study of antibodies has become one of the most promising areas in science for many years to come.
In practice, this made it possible to create new drugs against dangerous diseases such as hepatitis B, tick-borne encephalitis, tetanus, etc. But despite the proven benefits and virus-neutralizing effect, the first generation immunoglobulins had pronounced side effects and an inconvenient form of administration - intramuscular. It was painful and had restrictions on the volume permissible for introduction into the body. This has forced scientists to focus on innovation in the field of immunoglobulins. Further growth in production was inextricably linked with advances in purification technologies that improve drug safety.
In the 21st century, world leaders in this area use modern standards for multi-stage purification of immunoglobulins. Thanks to them, impurities that provoke adverse reactions in the drug are minimized, and the concentration of pure immunoglobulin G reaches 98%. The latest generation drugs are safe and protected from viruses. It is advanced purification methods that have made it possible to fully utilize the potential of antibodies in the fight against infectious agents.
Today, the developments of the Nacimbio holding of the Rostec State Corporation come to the rescue in the fight against coronavirus infection - its targeted drug COVID-globulin was recently officially approved in Russia. This is the world's first registered immunoglobulin preparation from blood plasma for the treatment of COVID-19.
We talk about what immunoglobulins are, the history of the study of antibodies, and their use in the fight against coronavirus.
Pharmacological properties of the drug Human immunoglobulin
Immunobiological agent, highly purified polyvalent human immunoglobulin. Immunoglobulin contains about 90% monomeric IgG and a small fraction of decomposition products, dimeric and polymeric IgG and IgA, IgM in trace concentrations. The distribution of IgG subclasses in it corresponds to their fractional distribution in human serum. It has a wide range of opsonizing and neutralizing antibodies against bacteria, viruses and other pathogens. In patients with primary or secondary immunodeficiency syndromes, it provides replenishment of missing IgG class antibodies, which reduces the risk of developing infection. In some other immune disorders, such as idiopathic (immune origin) thrombocytopenic purpura and Kawasaki syndrome, the mechanism of clinical effectiveness of immunoglobulin is not entirely clear. After IV infusion, a redistribution of immunoglobulin occurs between the blood plasma and the extravascular space, and equilibrium is achieved after approximately 7 days. Antibodies present in exogenous immunoglobulin have the same pharmacokinetic characteristics as antibodies in endogenous IgG. In individuals with normal serum IgG levels, the biological half-life of immunoglobulin averages 21 days, while in patients with primary hypogammaglobulinemia or agammaglobulinemia, the half-life of total IgG averages 32 days (however, there is significant individual variation that may be important when establishing a dosage regimen for a particular patient).
Background: How antibodies turned into a “magic bullet”
Immunoglobulins (antibodies) are special proteins that participate in the immune response. They bind to fragments of dangerous “enemies” of our body - bacteria, viruses, fungi, our own tumor cells, toxins, and trigger a mechanism to destroy the threat. Antibodies can be called an evolutionary invention of humans, like all vertebrates. Our body produces about 2-3 grams of various antibodies per day. In total, a huge number of unique variants of immunoglobulin varieties can be synthesized in the human body throughout life. Thanks to this, our body is able to select a specific antibody to any of the dangerous agents it encounters.
Scientists began studying these processes in the second half of the 19th century. It was then that immunology was born, the first data appeared on the body’s ability to recognize and defeat the causative agent of the disease when encountering it again. Of course, the foundation was laid by the English physician Edward Jenner, who at the end of the 18th century invented the first vaccine against smallpox. Later, scientists found out that such protection is possible thanks to special substances in the liquid part of the blood - serum. This means that the serum can be introduced into the body instead of vaccination and achieve temporary protection or help an already sick person cope with an infection. The first to successfully demonstrate this in practice was the German scientist Emil Behring at the end of the 19th century, when he invented a drug for the treatment of diphtheria based on the blood serum of those who had recovered from the disease.
Emil Bering with assistant
At that time, diphtheria claimed thousands of children's lives around the world - every twentieth child in Europe and the United States fell victim to this insidious disease. Doctors were powerless, so the first success of Behring's anti-diphtheria serum became a real Christmas miracle for some. On the night before Christmas 1891, dying from diphtheria, patients at the Berlin Children's Hospital received an injection of life-saving Behring serum. Then this injection turned out to be the last chance at life for many young patients, but it did not become a salvation for everyone.
His colleague and friend, immunologist Paul Ehrlich, helped Bering refine and perfect the anti-diphtheria serum. His deep knowledge of immunology helped to more accurately calculate the dosage of antitoxin and prepare purified, safer sera. In 1894, the new version was successfully administered to more than 200 young patients.
In 1901, Behring received the first ever Nobel Prize in Physiology or Medicine. In the official formulation, the serum he created was called “a victorious weapon against disease and death.” Seven years later, Paul Ehrlich was also awarded the Nobel Prize - “for the discovery of antibodies and the substantiation of the humoral theory of immunity.”
The term “immunoglobulins”, which is popular today, appeared much later - in 1959 it was proposed by the Belgian immunochemist Joseph Heremans. This name very well reflects the dual nature of antibodies - functionally they are immune factors, and in their structure they belong to the group of blood serum proteins called “globulins”.
In 1972, the chemical structure of antibodies was deciphered; for this, American immunologist Gerald Edelman and English biochemist Rodney Porter also received the Nobel Prize. The next two important discoveries in this area occurred in 1984 - the substantiation of the idiotypic chain theory and the development of a method for producing monoclonal antibodies, which also received the Nobel Prize. From the same period, the development of methods for purifying immunoglobulins began, which became a key condition for the effectiveness of therapy. Today the standard in this field is chromatography.
More than a hundred years of research and four Nobel Prizes - no other discovery in the field of physiology and medicine has received such attention and recognition.
Indications for use of the drug Human immunoglobulin
Replacement therapy for the prevention of infections in primary immunodeficiency syndrome: agammaglobulinemia, common variable immunodeficiencies caused by agammaglobulinemia or hypogammaglobulinemia, deficiency of IgG subclasses; replacement therapy to prevent infections in secondary immunodeficiency syndrome caused by chronic lymphocytic leukemia, AIDS in children, bone marrow transplantation; idiopathic (immune origin) thrombocytopenic purpura; Kawasaki syndrome (usually as an adjunct to standard treatment with acetylsalicylic acid); severe bacterial infections, including sepsis (in combination with antibiotics), and viral infections; prevention of infections in premature infants with low birth weight (less than 1500 g); Guillain-Barré syndrome and chronic inflammatory demyelinating polyneuropathy; neutropenia of autoimmune origin and autoimmune hemolytic anemia; antibody-mediated true red cell aplasia; thrombocytopenia of immune origin, for example post-infusion purpura or isoimmune thrombocytopenia of newborns; hemophilia caused by the formation of antibodies to factor P; treatment of myasthenia gravis; prevention and treatment of infections during therapy with cytostatics and immunosuppressants; prevention of recurrent miscarriage.
Use of the drug Human immunoglobulin
IV drip. The regimen of use is determined individually, taking into account the indications, severity of the disease, the state of the patient’s immune system and individual tolerance. The dosage regimens given below are advisory in nature. For primary immunodeficiency syndromes, a single dose is 200–800 mg/kg (average 400 mg/kg). Administered at intervals of 3–4 weeks to achieve and maintain a minimum level of IgG in the blood plasma of at least 5 g/l. For secondary immunodeficiency syndromes, a single dose is 200–400 mg/kg. Administer at intervals of 3–4 weeks. For the prevention of infections in patients undergoing bone marrow allotransplantation , the recommended dose is 500 mg/kg. It can be administered once 7 days before transplantation and then repeated once a week for the first 3 months after transplantation and once a month for the next 9 months. For idiopathic thrombocytopenic purpura, an initial single dose of 400 mg/kg is prescribed, administered for 5 consecutive days. It is possible to prescribe a total dose of 0.4–1 g/kg once or over 2 consecutive days. If necessary, further doses of 400 mg/kg can be administered at intervals of 1–4 weeks to maintain a sufficient platelet count. For Kawasaki syndrome, 0.6–2 g/kg is administered in several doses over 2–4 days. For bacterial infections (including sepsis) and viral infections, 0.4–1 g/kg is administered daily for 1–4 days. To prevent infection in premature infants with low birth weight, 0.5–1 g/kg is administered at intervals of 1–2 weeks. For Guillain-Barré syndrome and chronic inflammatory demyelinating polyneuropathy, 0.4 g/kg is administered for 5 consecutive days. If necessary, 5-day courses of treatment are repeated at intervals of 4 weeks. Depending on the specific situation, the lyophilized powder can be dissolved in 0.9% sodium chloride solution, water for injection or 5% glucose solution. The concentration of immunoglobulin in any of these solutions can vary from 3 to 12% depending on the volume used. For patients receiving immunoglobulin for the first time, it is recommended to administer it in the form of a 3% solution, and the initial infusion rate should be from 0.5 to 1 ml/min. If there are no side effects during the first 15 minutes, the infusion rate can be gradually increased to 2.5 ml/min. For patients who regularly receive and tolerate immunoglobulin, it can be administered in higher concentrations (up to 12%), but the initial infusion rate should be low. If there are no side effects, the infusion rate can be gradually increased.
Anticytomegalovirus
The drug is used in the treatment and prevention of cytomegalovirus infection. It has a virus-neutralizing and immunomodulatory effect. Therapy is carried out for pregnant women with cytomegaly for prophylactic purposes to prevent the development of fetal pathologies during pregnancy. It is also performed on patients with central nervous system damage. The medicine is administered to infants who were born to mothers with cytomegalovirus infection. Treatment is carried out in a course of four or five injections at intervals of two to five days. Vaccination is allowed three months after immunoglobulin therapy.
Side effects of the drug Human immunoglobulin
more likely during the first infusion; occur soon after the start of the infusion or during the first 30–60 minutes. From the side of the central nervous system: possible headache, nausea; less often - dizziness. From the digestive tract: in rare cases - vomiting, abdominal pain, diarrhea. From the cardiovascular system: rarely - arterial hypotension or hypertension (arterial hypertension), tachycardia, feeling of constriction or chest pain, cyanosis, shortness of breath. Allergic reactions: very rarely, severe arterial hypotension, collapse and loss of consciousness have been observed. Other: possible hyperthermia, chills, increased sweating and fatigue, malaise; rarely - back pain, myalgia; numbness, hot flashes, or cold sensation.
Special instructions for the use of the drug Human immunoglobulin
Immunoglobulin is obtained from the blood plasma of healthy donors who, according to clinical examination, laboratory blood tests, and medical history, do not have signs of transfusion-transmitted infections or blood-derived drugs. In case of severe side effects (severe arterial hypotension, collapse), the infusion should be stopped; IV administration of adrenaline, corticosteroids, antihistamines and plasma expanders may be indicated. Patients with agammaglobulinemia or severe hypogammaglobulinemia who have never received immunoglobulin replacement therapy or have received such therapy more than 8 weeks ago have an increased risk of developing hypersensitivity reactions (including anaphylactic shock) when administered by rapid intravenous infusion. Therefore, rapid infusion is not recommended for these patients and should be closely monitored throughout the infusion period. A transient increase in creatinine levels has been reported after the administration of immunoglobulin to patients with impaired renal function caused by an underlying disease (diabetes mellitus, systemic lupus erythematosus). In such patients, serum creatinine levels should be monitored for 3 days after infusion. After the administration of immunoglobulin, a passive increase in the level of antibodies in the patient’s blood may be observed, which can lead to an erroneous false-positive interpretation of the results of serological testing. Although there are no reports of adverse effects on the fetus or reproductive capacity, immunoglobulin should be used in pregnant women only when clearly needed.
Double immune response to Covid
In our country, one of the largest manufacturers of antibody-based drugs is Nacimbio. The pharmaceutical holding company, NPO Microgen, produces Normal Human Immunoglobulin, Albumin and other drugs based on blood plasma, including specific immunoglobulins, the line of which was recently supplemented by COVID-Globulin. Thus, Russia has the opportunity to use two types of immunization against coronavirus at once - immunoglobulin and vaccine.
Photo: Nacimbio
Nacimbio developed the drug in active collaboration with the Moscow Department of Health. Moscow doctors and experts were involved in this work, Moscow also provided centers for conducting clinical trials of the drug. Well, and the most important thing is the transfer of raw materials for the production of immunoglobulin. “COVID-globulin” is created based on the blood plasma of people who have antibodies to the SARS-CoV-2 virus. For this purpose, the capital’s Department of Health supplied Nacimbio with 2.5 tons of donor plasma. A special feature of immunoglobulin is the use of a chromatographic purification system, which ensures viral safety and the complete absence of foreign elements and proteins.
After successfully completed preclinical trials and the first phase of clinical trials, the Ministry of Health of the Russian Federation registered “COVID-globulin”. At the beginning of April, the second and third phases of clinical trials began, which will last approximately six months.
Plans for this year include processing at least 15 tons of plasma, which will help 10-15 thousand patients. Anyone who has suffered from COVID-19 can become involved in this great cause. Read more about how to become a plasma donor here
Drug interactions Human immunoglobulin
Concomitant use of immune globulin may reduce the effectiveness of active immunization against measles, rubella, mumps and varicella. In this regard, live viral vaccines for parenteral use should not be used for 6 weeks to 3 months after the use of immunoglobulin. In case of repeated administration in doses from 400 mg to 1 g/kg in children with idiopathic thrombocytopenic purpura or other pathology, vaccination against epidemic hepatitis should be postponed for 8 months. Immunoglobulin should not be mixed in the same volume with any other medications.
Contraindications
The use of immunoglobulin is contraindicated if there has been a history of an allergic reaction to injected blood products. For people prone to allergies (atopic dermatitis, bronchial asthma, urticaria, etc.), the drug is administered with the support of antihistamines. After completing the immunoglobulin course, it is recommended to continue using antihistamines for another week. Immunoglobulin should not be taken if you have IgA deficiency.
The drug is prescribed with great caution to people with diabetes, since the infusion solution may contain components that affect blood sugar levels. In patients with heart failure, kidney pathology, and pregnant women, immunoglobulins are used with regular monitoring by the attending physician.
Immunoglobulins are not combined with vaccination, since the effectiveness of immunization is reduced. It is recommended to vaccinate at least 30 days after completing the course of immunoglobulin.
The use of immunoglobulin should be carried out strictly as prescribed by a doctor. You should not take the drug on your own, as this may have negative health consequences. At the Yusupov Hospital, you can get advice on the need to use immunoglobulin from qualified specialists. The hospital operates clinics for therapy, neurology, oncology, rehabilitation, surgery and intensive care, where the patient will be provided with all the necessary information depending on the profile and condition. The Yusupov Hospital is equipped with a modern diagnostic center, where the patient can go for examination and obtain the most accurate data on his state of health. Based on diagnostic data, a specialized specialist selects an adequate treatment that will be most effective in this particular case.
You can make an appointment with a specialist and get information about the work of the diagnostic center by calling the Yusupov Hospital.
