Double capture
New generation antibodies are attacking cancer cells
Treatment of many diseases has side effects. How to minimize them? This task is solved by an employee of the Institute of Chemical Biology and Fundamental Medicine (IHBFM) SB RAS Candidate of Biological Sciences Sergey Sedykh. He is developing a universal way to create new generation antibody preparations, having received a grant from the President of the Russian Federation for young scientists for his research. Our correspondent Firyuza Yanchilina tried to find out what the new generation antibodies are and how they are better than the "old" ones.
– Sergey Evgenievich, remind me what antibodies are and what role they play in the body?
– Antibodies, or immunoglobulins, are plasma proteins that are formed in vertebrates in response to foreign compounds – antigens. Antigens can have a viral, bacterial, tumor and other nature. Antibodies bind particles (viruses, bacteria) containing the corresponding antigens and remove them from the body. According to classical concepts, natural antibodies can bind a single, specific antigen and, thus, are monospecific molecules. It is believed that for blood antibodies, monospecificity is a very important characteristic that determines their exceptional selective ability to remove foreign antigens.
Bispecific are called immunoglobulins, which can bind two different antigens. Particular interest in such molecules is caused by the possibility of their therapeutic use. In 2015, the world's leading journal in the field of biotechnology and pharmaceuticals, Nature Reviews Drug Discovery, called bispecific immunoglobulins antibodies of a new generation.
– Why is it necessary to create a new generation of antibodies?
– Monospecific antibodies have been used for the treatment of cancer for more than 15 years. Such antibodies, for example, bind a receptor on the surface of a tumor cell and trigger the natural mechanisms of its death. But not all cancer cells can be made to self-destruct in this way. Bispecific antibodies contain two antigen–binding centers, one of which interacts with the antigen of the tumor cell, and the second with the T-lymphocyte receptor (a type of white blood cells). As a result, the body's natural specific response to the tumor is enhanced, since when the T-lymphocyte and the tumor cell approach, the lymphocyte is activated, which destroys the degenerated cell.
Most drugs for the treatment of oncological diseases are directed against actively dividing tumor cells, but at the same time affect normal cells of the intestine, bone marrow, hair follicles that are in the body. Numerous undesirable side effects of anti-cancer therapy are associated with this. The use of bispecific immunoglobulins significantly reduces the occurrence of such side effects. The bispecific antibody directs the T-lymphocyte only to the tumor cells against which its antigen-binding center is designed. All other actively dividing cells do not suffer at the same time.
– Can any tumor be cured with such bispecific antibodies?
– Unfortunately, no. Like all other anticancer drugs, new generation antibodies are not universal medicines. As mentioned above, the molecules of bispecific immunoglobulins contain two different antigen-binding centers: one of them, as a rule, is directed to a special T–lymphocyte receptor, and the second is directed to the receptor of the surface of tumor cells. Each type of tumor, and there are more than two hundred of them, has different receptors on the surface. Therefore, a drug directed against a tumor of one type will have no effect on the cells of another tumor with different receptors on the surface. In addition, treatment of only blood tumors (leukemia) has now been developed. Whether there will be a possibility of new therapy for other types of cancer, it is not yet possible to say with certainty.
– How did you come to study bispecific immunoglobulins?
– Human milk antibodies have been studied in the Laboratory of repair enzymes of the IHBFM SB RAS under the leadership of Professors Georgy Alexandrovich Nevinsky and Valentina Nikolaevna Buneva for more than 25 years. It turned out that the antibody fractions of such milk have affinity for DNA and RNA, proteins and peptides, and also exhibit the properties of enzymes, hydrolyze numerous substrates of various nature.
Such catalytically active human milk immunoglobulins were the topic of my thesis and PhD thesis. In the course of research, it turned out that the reason for the extreme variety of affinity of milk antibodies to various substrates is their bispecificity. There are an order of magnitude fewer bispecific molecules among blood antibodies than in milk. This may be caused by the fact that antibodies in human blood and milk perform different functions. The first – remove the foreign antigen from the bloodstream (for example, through the kidneys), and the second – should not allow foreign molecules to get from the intestines of the child into the blood. Today we are close to knowing exactly which components of human milk and how they lead to the formation of bispecific immunoglobulins from monospecific ones.
We would like to develop a universal method for obtaining bispecific immunoglobulins from a mixture of two monospecific ones. Today there is no such method, and researchers have to re-develop an approach each time to obtain new combinations of two different antigen-binding centers as part of a single molecule. The main task is to identify the milk factor that stimulates such an exchange, and the selection of reaction conditions.
– Does anyone else in the world do such research? What is the peculiarity of your work?
– Two preparations of bispecific immunoglobulins (blinatumomab and katumaxomab) are already approved for use in the USA and Europe. More than 60 drugs are undergoing preclinical and clinical studies, two thirds of them are aimed at the treatment of oncological diseases. According to some estimates, the market for bispecific therapeutic immunoglobulins will grow to 5.8 billion per year by 2024. The advantage of our project is that we plan to develop a universal method for obtaining bispecific immunoglobulins. Most likely, this method will be most in demand in scientific and pharmaceutical laboratories, where it is required to obtain several different variants of bispecific immunoglobulins and further check their biological effect. However, before the implementation, of course, there is still a very long way to go.
This year and next, we plan to publish the results of our research on the nature of the milk factor that stimulates the formation of bispecific antibodies, as well as to develop a universal method for obtaining bispecific molecules from monospecific mixtures. We would like it to be in demand in Russia and used by domestic companies to develop new medicines.
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31.08.2017