Cancer vaccines: incite the immune system against cancer cells

The future of pharma is behind carbohydrates
Marina Muravyeva, STRF.ruFundamental research of carbohydrates, one of the three most important classes of natural compounds, creates the basis for future blockbusters of the pharmaceutical market, Head of the Laboratory of Glycoconjugate Chemistry of the Institute of Organic Chemistry named after N.D. Zelinsky, Doctor of Chemical Sciences, Professor Nikolay Eduardovich Nifantiev is convinced.

Under his leadership, several promising drugs based on carbohydrate ligands are being developed, including vaccines against cancer and infectious diseases.

Currently, the chemistry of carbohydrates is largely developing in the interests of the pharmaceutical industry. Many cellular processes, leading, for example, to the development of cancer, occur with the participation of carbohydrate ligands. Pathogens of microbial infections also penetrate into tissues with the help of carbohydrate molecules. Therefore, what is being researched today in the field of carbohydrate chemistry may in due time find an application for the development of medicines and new diagnostic methods. At the N. D. Zelinsky Institute of Organic Chemistry of the Russian Academy of Sciences (IOH RAS), this direction began to develop intensively about 15 years ago, when the laboratory of glycoconjugate chemistry was established.

"Although the Institute is primarily engaged in classical areas of organic chemistry, but it was here that the formation of the national school of carbohydrate biochemistry took place under the leadership of our director, Academician Nikolai Kochetkov," says Nikolai Nifantiev, head of the glycoconjugate laboratory. – I started in his laboratory as a graduate student and worked up to the position of senior researcher. Then I became interested in doing biomedical applications of carbohydrate chemistry. Therefore, the idea arose to create an independent laboratory. Now it is a fairly large team that actively cooperates with leading domestic and foreign laboratories."
Help from a marine mollusk

Carbohydrate ligands have been used to create conjugated vaccines in the last 20 years (this became possible thanks to the development of preparative methods for the synthesis of complex oligosaccharides). The idea of an oncovaccine is inherently similar to an antimicrobial vaccine and is based on the fact that cancer cells have special types of carbohydrate compounds – oncoassociated antigens. These compounds are involved in various processes of intercellular interactions and are also involved in the development of diseases. If we understand their mechanisms, we can determine not only the causes of the development of diseases, but also create compounds that will selectively prevent their development. With the help of vaccination, it is possible to induce an immune protective reaction directed at oncoantigens, and with them, cancer cells.

There is a lot of research in this direction in the world. In Russia, the synthesis of these complex compounds is carried out only in the laboratory of glycoconjugate chemistry of the IOH RAS.

"The development of an oncovaccine is a rather complex interdisciplinary project involving the solution of several tasks,– says Nikolay Nifantiev. – First of all, this is the synthesis of oncoantigenic ligands, which are multifunctional structures that include special spacer groupings necessary for sewing ligands onto a carrier protein. Next is the structural analysis of the carbohydrate ligands themselves. This task is not trivial: you have to work with very small amounts of substances, the structure of which, nevertheless, must be reliably established. The IOC has a wide fleet of modern nuclear magnetic resonance spectrometers and mass spectrometers, with the help of which it is possible to study in detail the structures of complex oligosaccharide ligands and their derivatives."

A special stage in obtaining a conjugated vaccine is the attachment of many copies of carbohydrate ligands to the carrier protein. When choosing its type, it should be taken into account that oncoantigens are human autoantigens (a person produces them on cancer cells himself), therefore the immune reaction against them is very weak. To overcome this limitation, chemists have to use particularly complex carrier proteins that enhance the immune response.

"We, like colleagues from foreign laboratories, use a carrier protein with a colossal molecular weight of up to 8 million daltons when creating oncovaccines," says Nikolay Nifantiev. "This is a hemocyanin from the marine mollusk Megathura crenulata – a giant protein that has a very dense cylindrical structure with a size in the central nanoscale – 35x40 nanometers."

Scientists "sew" about 300 carbon ligands onto the carrier protein, actually creating a model of an oncocell (see figure), against which a protective immune reaction is triggered. To strengthen it during vaccination, it is also necessary to use special immune activators. Promising agents are some plant glycosides, saponins. Interesting representatives of this class of natural compounds were specially identified in the laboratory of Academician Henrikh Tolstikov at the Institute of Organic Chemistry SB RAS.

Immunological research of the developed vaccines is carried out at the Institute of Immunology under the leadership of Academician Rem Petrov, in the laboratory of Professor Rodion Stepanenko. Recently, Professor Mikhail Kiselevsky from the Cancer Research Center has joined this work.

"I think that together we will be able to create drugs with a therapeutic effect," says Nikolai Nifantiev. – The specificity of the oncovaccine is determined by the structure of the carbohydrate ligand used. Specific oncoligands with different structures are represented on different types of cancer cells. Now we are working with a model of a vaccine drug that is aimed at melanoma, but we have already synthesized other carbohydrate ligands that allow the creation of a vaccine, in particular, against breast cancer, brain cancer."

The effect is combinedThe effectiveness of the use of modern chemotherapeutic drugs is determined by the statistically confirmed result of prolonging the life of patients by at least 20 percent compared with the control (approved drugs are used as a control).

This is far from ideal. Therapeutic antibodies that have been actively introduced in recent years have approximately the same effectiveness. So far, unfortunately, in the fight against cancer, we are talking only about prolonging the lives of patients.

"The most effective is the use of oncovaccines as a preventive measure, as well as at the initial stages of the development of the disease and after surgical removal of tumors," Nikolay Nifantiev believes. – In any case, oncovaccination, as well as oncotherapy by modern methods, is an element of combined treatment using different medicines."

An integrated approach to cancer treatment is the most effective. You can't create one universal cure for cancer. This is a broad group of diseases that often have similar manifestations only externally, but proceed in different ways. For different types of cancer cells, different types of tumors and at different stages of the development of the disease, different biological processes may be critically important, for the regulation of which different types of therapy are necessary, respectively.

For example, in the formation of metastases, one of the key stages is the aggregation of cancer cells. IOH scientists have developed methods for the stereonirectional synthesis of natural oligosaccharides, which are involved in these processes, and now create effective blockers of cell aggregation. A number of carbohydrate blockers of protein-adhesives have already been synthesized, especially those belonging to the classes of galectins and selectins, which play an important role in the formation of metastases.

The laboratory of glycoconjugate chemistry is also engaged in the creation of carbohydrate blockers of angiogenesis – the formation of new blood vessels. This process is extremely important for the development of the tumor, as oxygen and nutrients are delivered through the blood vessels for its growth. The laboratory is actively conducting research on natural antiangiogenic polysaccharides and is working on the creation of their oligosaccharide synthetic analogues with the ability to block angiogenesis, which has already been shown in experiments in vitro and in vivo.

Wood MedicineAnother project of the Laboratory of glycoconjugate chemistry of the IOH RAS is associated with the creation of a completely different anti–cancer drug - not synthetic, but natural.

Based on the individual components of wood extracts, scientists are developing an estrogen receptor blocker that activates the growth of hormone-dependent cancer cells.

"The compound is isolated from coniferous wood," says Nikolai Nifantiev. – This is an individual substance with a strictly defined structure. The mechanism of its action is already known. The compound can be used to treat hormone–dependent cancers, and most of them are breast, prostate, rectum, lung and others. Blocking the estrogen receptor will prevent the development of the tumor. It is important that this compound is non-toxic and related to the components of human food. Therefore, its use in therapy should have great prospects."

The laboratory of glycoconjugate chemistry has developed an original method of preparative isolation of this substance (it was patented a few months ago) and now attempts are being made to establish production for conducting full-volume clinical trials and subsequent introduction into wide practice.

"To create a production, a number of technologies are necessary," says Nikolai Nifantiev. – In particular, sorting and grinding of wood, which is technically very difficult. Another problem is the extraction extraction of the target substance and its purification from ballast impurities. All this requires special equipment, including for filtering extracts and their rapid evaporation with subsequent regeneration of solvents. We cooperate with the "Biotechnology Corporation" (GC "Rostechnologies"), which creates a production for biotechnological processing of wood."

This is a serious project, and significant investments are required for its implementation. But if it is possible to implement it, the result will be of global importance, scientists are sure. The compound can be used both in therapy and in the prevention of cancer.

"When we were thinking about the development strategy of this project, we consulted with Russian and foreign oncologists," says Nikolay Nifantiev. – It was important to determine the target niche for the use of the drug. After surgery, radiation, and chemotherapy, the patient remains unaffected areas of the tumor. And it is necessary to continue treatment in order to suppress the remaining foci or "freeze" the situation when the tumor becomes static and does not develop. In modern oncology, the prognostication of groups of potential patients who had cancer patients in previous generations is quite good. These risk groups are quite wide. To prevent the development of tumors in patients, the possibility of using synthetic estrogen receptor blockers has been studied, but this is accompanied by significant side effects. The use of our medicinal compound seems optimal in many cases. And most importantly, it is a non-toxic natural compound, which can be considered a rare success.

The prospects for its use are not limited to oncology. No less practical potential is associated with the treatment of women's diseases caused by hormonal insufficiency and menopause. "There is a lot of talk about the Pharma 2020 program and the need for original import-substituting domestic medicines. On the basis of our compound, it is possible to create several drugs that meet these requirements," Professor Nifantiev is convinced.

Bet on carbohydratesThe Laboratory of glycoconjugate Chemistry of the IOH RAS works not only with anticancer drugs, but also with drugs for microbial infections, inflammation, autoimmune and other diseases.

"The development of drugs based on complex carbohydrates is consistently developing. There are already several such drugs on the world pharmaceutical market. These, for example, include Relentz and Tamiflu influenza virus neuraminidase blockers, as well as the synthetic pentasaccharide Arikstra, an analogue of the active link of the anticoagulant heparin. There is no doubt that the fundamental research of carbohydrates, one of the three most important classes of natural compounds, creates the basis for future blockbusters of the pharmaceutical market," says Nikolay Nifantiev. "So we keep up with the times in our work, and we were the first to synthesize a number of interesting compounds, for example, a new type of cyclic oligosaccharides, carbohydrate antigens of a number of pathogens of hospital infections, neurite growth activators, various polysulfated oligosaccharides and many others."

As for the prospects of creating innovative medicines in Russia, according to Nikolay Nifantiev, the main limitations are the lack of financial resources and problems with the molecular biological research base, which is critically important at the stage of clarifying the mechanism of action of medicinal substances. One of the solutions to these problems may be the expansion of international cooperation with specialized laboratories: "I believe that science is international. Now we have the opportunity to work closely with colleagues from other countries. Russian researchers have a choice: either to shelve their developments due to the impossibility of their independent continuation and implementation, or to establish partnerships with foreign colleagues. This can be done in different ways, for example, through joint research, to develop projects with the funds of some funds that every Western university and research institute knows how to look for appropriate scientific and organizational units. I think the strength lies in bringing together the best minds with the necessary knowledge and skills. Progress is possible only with a synergistic combination of ideas and experience of specialists in different fields of science."

Portal "Eternal youth" http://vechnayamolodost.ru/30.06.2009