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STRF:«Camel» antibodies «coached» on human diseases
Reporter STRF Xenia Bolokhova talks with employee Stepan Chumakov Institute of Bioorganic Chemistry of the studies conducted in the framework of the project "Development of therapeutic agents based on bifunctional single chain antibodies to eliminate cancer stem cells and preventing tumor recurrence." Here is her report.
«Camel» antibodies «coached» on human diseases
The immune system is the body's daily stravlyaetsya with a lot of internal and external «enemies», just like in a spy novel. Miscellaneous «of the armed forces» - the types of antibodies – «dragged» to the various tasks. Some are opposed to viruses, other bacteria, there are those who recognize the «fifth column» inside the body - cancer cells. Such «special forces», has already passed some training, it could significantly increase the chances of «friendly countries» - patients around the world - for success in the battle with the disease.
Scientists from the Institute of Bioorganic Chemistry. academicians MM Shemyakin-Ovchinnikov Ovchinnikov of the Russian Academy of Sciences (IBCh RAS) dealt with this problem by conducting the selection of antibodies that affects just the cancer cells, the project
«Establishment of therapeutic agents based on bifunctional single chain antibodies to eliminate cancer stem cells and preventing tumor recurrence», supported by CPF «Research and development on priority directions of scientific-technological complex of Russia for 2014-2020».
«Training of staff»
Production of therapeutic antibodies - a technically difficult task. Usually the main problem is to provide scientists the most complete set of sequences encoding the antibodies of the donor organism, and the subsequent formation of the mixture of DNA-associated antibody. The cell most logical «building block» for the formation of such complexes, is too large, so the work is carried out with ribosomes, «trapped» in the synthesis of the protein, active with respect to the tumor. This method is known as «ribosome display». Such simplified structures are needed not only for ease of study. The smaller the individual drug particles, the easier it to penetrate into the center of disease.
Another problem is related to the structure of the antibodies themselves. They usually consist of heavy and light chains of the protein. Both chains can bind to an antigen provoking the reaction of the body or other (including an immune response against cancers), but only to consume them together. Therefore, in consideration of such conventional double-stranded antibodies, scientists have great quantity of «waste» coupling reactions that can not be classified, and hence identify active antibody.
The general plan of the structure of immunoglobulins: 1) an antigen binding site; 2) the crystallizable fragment of an immunoglobulin; 3) heavy chain; 4) the light chain; 5) an antigen-binding site; 6) the hinge region. Illustration: Wikipedia
The team from the Institute of Bioorganic Chemistry, headed by the leader of the group of growth factors expression and differentiation Yelena Frolova, decided to simplify the problem, «recruit» unique antibodies having only one heavy, the protein chain. These antibodies have the members of the family camel, including the cute pets from South America - alpacas.
«It is much easier to create the desired design to us, when we work with single chain antibodies - said project participant researcher PhD Stepan Chumakov. - Another advantage of single-chain antibody is a miniature of the molecule. The smaller the molecule, the easier it to penetrate into various organs, tissues, anywhere. Increases bioavailability and simplifies the anti-cancer therapy».
Scientists working with these alpaca farm near Moscow, the one where he lives about 15 animals. They undergo a complex process of immunization, then the animals were tested and isolated biological material. We are working on the creation of libraries of antibodies that will carry out the whole cycle of works in the laboratory, but at the moment no stage in vivo can not do.
Alpaca
«Shoot» the defeat
To select antibodies brought maximum benefit, they can be «tuned» to certain categories of attack cancer cells. Despite the fact that there are a huge number of tumor types, caused by breaks in the DNA, there's quite certain «instigators» of the disease, destroying that, we actually stop its spread.
These instigators - the so-called cancer stem cells. Their existence, scientists learned relatively recently. According to this theory, a malignant tumor is relatively small population of cells that can renew its growth after resection or exposure to chemotherapy, radiation therapy and other treatments. This is due to the fact that most of the tumor cells are either not divided, or does it infrequently. In contrast, cancer stem cells possess a high proliferative potential and a high capacity for adaptation. In other words, they are responsible for the development and spread of the disease.
«Often it turns out that using a cancer therapy, we actually are conducting selection of the tumor towards the greatest malignancy. We systematically remove the cells that form the main body of the tumor, but it is not responsible for its metastasis. In their place of cancer stem cells, new cells are even more cancerous and even more stable. Based on this concept, we can say that cancer stem cells - a priority target for various types of cancer therapy», - said Chumakov.
Identify those key enemies and must be isolated from the antibody alpacas. The problem is that the «special signs» (proteins released by cells), which can calculate the «troublemakers» are not that special. «It can not be that it was quite a unique protein. He obviously for something in the body? Where else is expressed, - explains the biologist. - There are exceptions, where the fusion proteins resulting from chromosomal rearrangements, appear on the surface of tumor cells, but this occurs less frequently».
In other words, when the battle enter antibodies that destroy the cells that produce a specific protein antigen, together with the «terrorists» could be affected and "civilians" that the same protein is needed to perform their functions.
To more precisely define the parameters of the «enemy», the scientists used a set of characteristic of cancer stem cells tumor antigens. Such antibodies, «trained» to recognize stem cancer cells in several antigens isolated scientists. They are then combined in a molecule that will bind to the «enemy» cells and destroy them.
To victory
Team Elena Frolova examines stem cells specific to breast cancer. This kind of disease is well studied and highlighted the variety, but most importantly, it is one of the most common types of tumor shrine, they suffer 10% of all cancer patients.
Research Group of Elena Frolova IBCh
«In our project, we selected 4 antigen, which are characteristic of cancer stem cells. Against each of them, we obtain specific single chain antibodies. At this stage of the work we have obtained the combined library and held a primary breeding» - said the researcher.
Now the group determines which of the candidates have the best performance. And in the next stages, scientists are planning to connect them in pairs and see which of the resulting combinations of molecules has the best effect.
The project, which is designed for 3 years, the researchers plan to create a therapeutic antibody directed against breast cancer. But it is possible, their efforts will initiate a new phase of struggle and with our other internal enemies.
september 30, 2015
Source: http://strf.ru/material.aspx?CatalogId=221&d_no=106325#.Vgvde_ntmkq
