Russian scientists have proposed a new method for the treatment of autoimmune diseases. The drug for ankylosing spondylitis is going through the final stage of clinical trials

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Hell pain and paralysis

The scientific international name for ankylosing spondylitis is ankylosing spondylitis or radiographic axial spondylitis. The name itself contains everything that happens to the patient. Ankylosing means stiff and inflexible, while spondylitis means inflammation of the spine. In this case, inflammation and structural changes in the spine and joints are determined on x-ray.

Typically pathology begins at the most working age – from 20 to 40 years. Some studies show that men are affected slightly more often than women. The disease is autoimmune, meaning it is caused by a malfunction of the immune system. The body “goes crazy” and begins destroying its own healthy organ cells, mistakenly considering them foreign. The main role in this process is played by autoreactive T lymphocytes.

In the case of ankylosing spondylitis, the target of attack is the connective tissue cells that form the ligaments, intervertebral discs and joint capsules. Inflammation at the points of attachment of ligaments and tendons to bones (enthesis) is called “enthesitis” and is accompanied by the development of severe pain in humans, since sensitive receptors are located there. As the disease progresses, connective tissue is replaced by bone. Ligaments and joints lose flexibility, vertebrae grow together. The person is literally twisted and mobility is lost. The most severe loss of mobility in the spine and joints is called “ankylosis”. In severe cases, disability develops to the loss of the ability to move independently.

Currently, the main treatment method is anti-inflammatory therapy. Nonsteroidal anti-inflammatory drugs (NSAIDs) are routinely prescribed. And recently biological drugs have been actively used – monoclonal antibodies that neutralize factors that cause inflammation – the so-called cytokines. Anti-cytokine drugs significantly improve the patient’s life, reduce inflammation and relieve pain. But they do not stop the disease. Tissues continue to deteriorate, albeit more slowly.

Cytokines not only play a negative role in causing and sustaining inflammation, but also have important protective functions. Anti-cytokine drugs cause suppression of the immune system (immunosuppression), resulting in an increased risk of various infections. Also, with long-term use, the body begins to “get used” to the drug, that is, it stops working. These factors significantly limit the effectiveness of modern methods of treating autoimmune diseases.

“To find a solution to the problem, we chose a fundamentally different approach; using bioinformatics approaches, we analyzed the diversity of T cells in patients and determined the structures of T cell receptors that are directly related to the development of the disease,” he explains. Rector of the Russian National Research Medical University. NI Pirogova Sergei Lukyanov. “Unlike cancer cells, which mutate very strongly, immune system cells are practically unchanged, so the structures we identified can serve as a reliable indicator of pathological cells for targeted destruction. As a result, we find that killing the specific group of T cells causing the disease but not the immune system as a whole “A monoclonal antibody was created that does not disrupt the functioning of the system.”

new approach

According to RAS Academician Sergei Lukyanov, the scientific idea of ​​​​a new approach to the treatment of ankylosing spondylitis appeared almost 20 years ago. In 2019, the “Center for Genetic Technologies for High-Precision Editing and Biomedicine” was created in Russia as part of the project to create and develop world-class scientific centers. The research consortium included scientists from the eponymous Russian National Research Medical University. NI Pirogov, Institute of Bioorganic Chemistry, Academicians MM Shemyakin and Yu.A. Ovchinnikov RAS, National Medical and Surgical Center, NI Pirogov and Russian biotechnology company BIOCAD. And from that moment on, targeted research on this topic began. The magnitude of the work done is enormous.

“We collected patients and analyzed their lymphocytes. This is an analysis of tens of millions of sequences from patients and healthy people on next-generation sequencers,” continues Sergei Lukyanov. You cannot look at such a large amount of information with your eyes. So our scientists have created computer programs that allow us to process these strings of information. After all, no one had looked at the problem from this perspective before, there were no ready-made solutions.”

As Sergei Lukyanov emphasizes, a unique, fundamentally new approach to the treatment of ankylosing spondylitis has been developed thanks to the cooperation of different groups of scientists. And based on this ideology, employees of the biotechnology company BIOCAD created a therapeutic drug – BCD-180 (the international non-proprietary name of the drug recommended by WHO is seniprutug). This is one of the most striking examples of effective cooperation between academic science and biotechnological medicine in Russia.

“To produce medicines, you need to have competencies in patent law, regulation and technology,” says the academic. — We were lucky to have an industrial partner in our genomics center; biotechnology company BIOCAD. This idea seemed promising to them, and they believed in it. After all, no one in the world has used this approach before.”

patient renewal

BCD-180 or seniprutug is a monoclonal antibody against the T cell receptor segment TRBV9. As scientists have found, in patients with ankylosing spondylitis, there are pathological cells in the group of T-lymphocytes that have this receptor, which “go crazy” and attack their own body tissues, and it is they who cause this condition. development of the disease.

“Our drug not only attacks inflammation, regardless of the cause, but also eliminates the basis of the disease,” says Pavel Yakovlev, BIOCAD’s vice president for early development and research. – This is great because all participants in inflammation are blocked. That is, when the medicine eliminates part of the inflammation, but some remains, you do not have to compromise as before. We target exactly the root cause. “We believe that the drug can be used for a very long time without becoming addicted or losing its effectiveness,” he said.

But most importantly, as Pavel Yakovlev emphasizes, under the influence of the drug it is possible not only to stop the progression of the disease, structural changes in the musculoskeletal system, but also to stop regeneration, that is, the return of the disease. No type of treatment used for ankylosing spondylitis has ever produced such results.

The scientific journal Nature Medicine details the story of a 60-year-old patient who achieved long-term recovery thanks to seniprutug. The man was diagnosed with ankylosing spondylitis in 1986. All treatment modalities available at the time were tried, including autologous hematopoietic stem cell transplantation and hip replacement. However, the disease gradually progressed.

In 2019, it was renamed the Ethics Committee of the Russian National Research Medical University. Pirogov approved the patient’s treatment with monoclonal antibodies BCD-180. Already after the first intravenous infusion, the proportion of TRBV9+ T cells in the patient’s peripheral blood dropped sharply, and T cells along with other TRBV segments were unaffected by the treatment.

The patient’s well-being has been improving all these years. The pain and stiffness decreased so much that the man started physical therapy, even though he had not previously been able to go to physical therapy due to severe pain in his joints. The man also stopped taking anti-cytokine drugs, which he had been using continuously for many years.

Currently, BCD-180 is administered to the patient every four months and no serious side effects have been detected. Remission has continued for four years. The mobility of the patient’s spine increases. It was also noted on the x-ray that one of the osteophytes in the femur, which had constantly increased before the start of BCD-180, disappeared.

The drug has already gone through two phases of clinical trials. In October, with the permission of the Russian Ministry of Health, the third and final phase of the studies involving axial spondyloarthritis patients began.

future perspective

According to Pavel Yakovlev, the new drug is expected to be primarily suitable for ankylosing spondylitis patients diagnosed with the HLA-B27 gene. According to various estimates, these cover 95-97% of ankylosing spondylitis patients. Additionally, a group of diseases associated with the HLA-B27 gene includes psoriatic arthritis, uveitis, juvenile arthritis, and some types of other diseases.

“We hope that the molecule already developed will be able to treat this entire group,” explains Yakovlev. – But the most important thing is the approach from which the colleagues at RNRMU are named. NI Pirogov managed to identify autoreactive T cells that could be extrapolated to other pathologies. That is, by analyzing blood samples from patients with various autoimmune diseases, it will be possible to similarly identify T-lymphocyte populations associated with the development of certain diseases and create drugs for their treatment. “Therefore, the scientists’ discovery could potentially be the beginning of a new platform for the treatment of autoimmune diseases.”

This approach has already been used to develop a drug against type 1 diabetes. This is a more common disease associated with impaired immune system. It almost always manifests itself in children who have become insulin dependent. The disease destroys almost all body systems – cardiovascular, metabolism, vision. A monoclonal body for the treatment of type 1 diabetes was also created by BIOCAD in collaboration with scientists from the Russian National Research Medical University. NI Pirogov. Recently, the Russian Ministry of Health gave permission to start the first phase of clinical trials.

“There is a lot of work ahead of us,” Sergei Lukyanov concludes. – I really hope that the development in Russia will encourage the world community to understand the issue in depth. Our study was published in the scientific journal Nature Medicine. Since such magazines value their reputation very much, they do not make hasty and unfounded decisions.

When the thought is expressed, active work begins, the fruits of which then begin to be seen. He cannot fail to begin because the risks are so high and the prospects so serious. We can only cope with global diseases such as autoimmune diseases as all humanity. “The efforts of individual companies and laboratories are not enough.”

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