The immune system of the body copes with the huge number of external and internal "enemies" on a daily basis, just like in a spy novel. Diverse types of the "armed forces" the types of antibodies are "trained" for the various tasks. Some are opposed to viruses, the others to bacteria; there are those who recognize the "fifth column" inside the body the cancer cells. Such "special forces", has already passed some training, could significantly increase the chances of "friendly countries" patients around the world for success in the battle with the disease.
Scientists from the Academicians M.M. Shemyakin and Y.A. Ovchinnikov Institute of Bioorganic Chemistry of the Russian Academy of Sciences (RAS IBCH) deal with this problem by conducting the selection of antibodies which affect just the cancer cells, in the frameworks of
the "Creation of therapeutic bifunctional agents based on single chain antibodies to eliminate cancer stem cells and prevent tumor recurrence" project, supported by "Research and development on priority directions of scientific-technological complex of Russia for 2014-2020" FTP.
Production of therapeutic antibodies is a technically difficult task. Usually the main problem of scientists is to provide the most complete set of sequences encoding the antibodies of the donor organism, and the subsequent formation the mixture of DNA- antibody associated complexes from them. A cell, the most logical "building block" for the formation of such complexes, is too large, so the work is carried out with ribosomes, "caught" during 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 they penetrate into the site of disease.
Another problem is related to the structure of the antibodies themselves. They usually consist of a proteins heavy chain and a light one. Both chains can bind to an antigen provoking one or another reaction of the body (including an immune response to the cancer), but they can destroy them only together. Therefore, in consideration of such conventional double-stranded antibodies, scientists have a great quantity of diverse "waste" coupling reactions which cannot be classified, and hence its impossible to identify active antibodies.
The team from the RAS Institute of Bioorganic Chemistry, headed by Yelena Frolova, the leader of the group of expression of protein growth factors and differentiation, decided to simplify the problem by "recruiting" the unique antibodies having only one chain heavy, protein one. The representatives of the camel family including the cute pets from South America alpacas have these antibodies.
Scientists are working with true alpacas from one farm near Moscow, where about 15 animals live. They undergo a complex process of immunization, and then the animals are tested and isolate biological material from them. Now scientists are working on the creation of libraries of antibodies that will allow carrying out the whole cycle of works in the laboratory, but its impossible to go without in vivo stage at the moment.
To make select antibodies bring the maximum benefit, they can be "tuned" to attack the certain categories of cancer cells. Despite the fact that there are a huge number of tumor types, caused by breaks in the DNA, there are quite certain "instigators" of the disease, destroying which we actually stop its spread.
These instigators are the so-called cancer stem cells. Scientists have known about their existence relatively recently. According to this theory, a malignant tumor is relatively small population of cells which can renew its growth after resection or exposure of the chemotherapy, radiation therapy and other treatments. This is due to the fact that most of the tumor cells are either dont divide, or do 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 are not responsible for its metastasis. New cells, which are even more cancerous and even more stable, take their place, appearing from cancer stem cells. Based on this concept, we can say that cancer stem cells is a priority target for various types of cancer therapy", Stepan Chumakov, member of the project, says.
Antibodies isolated from alpacas have to identify those key enemies. The problem is that the "special signs" (proteins released by cells), thanks to which we can calculate the "troublemakers", are not that special. "It cannot be so that it was absolutely unique protein. It is obviously necessary for something in the body and is expressed somewhere else, the biologist explains. There are exceptions, but it does not happen so often".
The scientists use an entire set of tumor antigens characteristic for cancer stem cells to define the parameters of the "enemy" more precisely. Scientists isolate such "trained" to recognize stem cancer cells by several antigens. Then scientists combine the antibodies in a molecule which will bind to the "enemy" cells and destroy them.
The team of Elena Frolova examines stem cells specific to the breast cancer. This kind of the disease is well studied and its varieties are highlighted, but most importantly, it is one of the most common cancers, 10% of all cancer patients suffer from it.
"In our project, we selected 4 antigens, which are characteristic for cancer stem cells. We are receiving specific single chain antibodies against each of them. At this stage of the work we have obtained the combined libraries and held a primary breeding, the researcher said.
Now the group is trying to determine which of the candidates have the best characteristics. And scientists are planning to combine them in pairs at the next stages and see which of the resulting combinations of molecules has the best effect.
As the result of the project, which is designed for 3 years, the researchers plan to create a therapeutic antibody directed against breast cancer. But it is possible that their efforts will initiate a new phase of struggle against other internal enemies of human organism.