From cancer evolution to personalized therapies
Precision Oncology is the wave of the future of cancer treatment. Cancer treatment continues to is improved from treatment based on the anatomical origin of cancer to the genetic mutations responsible for it. Our molecules «MMC-513» are specifically designed and aimed at unique form of cancer. «MMC-513» molecules form a dynamically changing antitumor response of the patient and are aimed at genetic mutations of the tumor. Depending on the new tumor antigens caused by the mutations, the molecules form a new immunological activity of the lymphocytes. Which increases the survival rate of patients.
1. MMC-513 is a «soft» agonist of receptor complex TCR/CD3, that entails the activation of genes and the formation of an adequate immune response of the patient. In addition, this is a way of activation of MAP kinase (MAPK) - serine / threonine kinases responsible for the development of inflammation.
2. A molecule is a «mixed agonist-antagonist» of CD25, a receptor for IL-2. Causing a conformational change, forming a heterodimer, which has high affinity for IL-2. This allows to regulate the activity of immune system, survival and proliferation of T-killers-cell.
3. MMC-513 is an antagonist for Fas/APO-1 (CD95). Mature Fas/APO-1 includes an extracellular domain, cysteine rich, which are «chemically attractive» for molecules Mercureid. This reduces the apoptotic death of lymphocytes induced by tumor growth, concomitant chemotherapy, radiotherapy or hormone therapy. Especially is promising to kill cancer stem cells (CSCs).
4. MMC-513 antagonist for molecules ICAM-1 (tumor angiogenesis and metastasis). Inhibition of the activity of this molecule reduces the risk of metastasis and inhibits tumor angiogenesis.
5. MMC-513 antagonist molecules CD38. CD38 is a product of the activity of cyclic ADP-ribose to the mobilization of calcium to the cytosol. An elevated level of CD38 is one of the factors in the evasion of the tumor from an antitumor response. CD38 as a novel immune checkpoint protein—one that works by inhibiting CD8+ T-cell function and that overcomes resistance to inhibition of the PD-1/PD-L1 axis in cancer. Mercureid is antagonist and reduces abnormal activity of the receptor CD38 to the physiological norm. This increases the cytotoxic potential of lymphocytes and allows the killing of tumor cells.
6. MMC-513 exhibits properties of «mixed agonist-antagonist» for molecules CD45. CD45 expression is required for signal transduction through the T-cell receptor. The protein is a member of the tyrosine protein phosphatases. Tyrosine protein phosphatases regulate the growth, differentiation, mitotic cycle, and malignant degeneration of cells. By modulating the activity of CD45, Mercureid restores the ability of lymphocyte to receive information from antigen-presenting cells through direct interaction of CD45 with the receptor C-type lectin MGL macrophage. This allows for positive selection of lymphocytes and increase the anti-tumor response of patients.
It should be noted that that a change in the activation of CD45 induces the expression of a transcriptional Bcl-6 inhibitor that regulates the expression of CTLA-4, which in turn is a protein receptor that, functioning as an immune checkpoint, downregulates immune responses. CTLA4 is constitutively expressed in regulatory T cells but only upregulated in conventional T cells after activation – a phenomenon which is particularly notable in cancers. It acts as an "off" switch when bound to CD80 or CD86 on the surface of antigen-presenting cells.
Schuette V, Embgenbroich M et al. Mannose receptor induces T-cell tolerance via inhibition of CD45 and up-regulation of CTLA-4.Proc Natl Acad Sci U S A. 2016 Sep 20;113(38):10649-54
Multitarget anti-PD-1 / PD-L1 / CD19 / CD25 / CD38 therapy using chelate nanocomplexes MSC-428 in oncopathology
Lukyanchuk O.V., Artemov A.V., Buryachkovsky E.S.
Studies of the effectiveness and tolerability of innovative molecules in 530 patients with various oncopathologies (cancer of the lung, kidney, breast, prostate, stomach, intestine, brain, etc.)
Over the past decade, there has been a deepening of ideas about the relationship between the tumor and the host’s immune system, as evidenced by the 2018 Nobel Prize in medicine and physiology for studying the role of the so-called. immune checkpoints in neoplasm care from an attack of the host’s immune system. This mechanism is associated with the appearance on the surface of tumor cells of specific proteins - PD-1 / PD-L-1, which prevent contact with the killer lymphocyte receptor.
Chelate nanocomplexes (MSC-428) target PD-1 / PD-L-1, i.e. affect the immune checkpoints directly. MSC-428 molecules attack 4 target proteins: PD-1 / PD-L1, CD19, CD25, CD38, which leads to the normalization of surface antigens - CD3, CD4, CD8, CD16, CD45, CD95 lymphocytes, phagocytosis systems and immunoglobulins of class A, M, G.
The proposed strategy of treatment against PD-1 / PD-L-1 with the use of metal-containing nanocomplex MSC-428 expands the possibilities of influencing immune checkpoints. Through conformational change in the 3-dimensional structure of the receptor proteins PD-1, the drug prevents them from binding to PD-L1 in tumor cells.
This increases the expression of CD25 on T-lymphocytes, normalizes the production of IL-2, which increases the activity of T-killers against tumor cells. The drug reduces the activity of CD19 molecules, which shield tumor antigens and prevent the attack of cytotoxic T cells.
As a result of inhibition of ZAP-70 kinase, CD38 expression is reduced, which increases the body’s antitumor response and mobilizes the cytotoxic potential of CD8 and CD16 T lymphocytes, preventing the development of tumor cell resistance.
The restoration of their activity largely predetermines the normalization of other lymphocyte subpopulations, in particular, expressing CD3, CD4, CD8, CD16, CD95, as well as the restoration of the phagocytosis system, production of immunoglobulins of class A, M, G. Such a complex effect ensures the construction of a coherent and effective strategy for immunotherapy of patients with oncopathology.
Keywords: multitarget therapy, nanocomplexes, oncopathology, Personal molecules. Targeted immunotherapy of cancer
The main results of scientific research are reported at Ukrainian and international conferences:
1. Non-toxic drug therapy of cancer: pathophysiological mechanisms and clinical features. Scientific and Practical Conference of Physicians, Kharkov, 2003.
2. A new method for the treatment of chronic apical periodontitis with the help of the drug Mercureid. Scientific and Practical Conference of Dentists. Moscow, 2011.
3. New nano-immunomodulator Mercureid in complex therapy of psoriatic disease in overweight people. Conference of Dermatologists, Kiev, 2013.
4. Immunological mechanisms of antitumor effect of innovative drugs based on chelate nanocomplexes. International scientific-practical conference. "Actual issues of development of medical sciences of the 21st century". Lviv, May 29-30, 2015.
5. Evaluation of the antitumor and antitoxic effects of the innovative chelating nanocomplex in neoadjuvant chemotherapy of breast cancer. International scientific-practical conference "Priority directions for solving urgent problems in medicine". Dnepropetrovsk, June 15-16, 2015.
6. Features of binding of new "small molecules" to lymphocyte receptors in patients with different types of malignant tumors. International scientific-practical conference "Medical science and practice of the 21st century". Kiev, 5-6 February 2016.
7. Mechanisms that determine the effectiveness of innovative chelate complexes in targeted antitumor therapy. International Scientific and Practical Conference "Peculiarities of modernization of research by representatives of medical sciences", Kiev, 3-4 June 2016.
8. Investigation of the ability of molecules "MSC-428" to carry out a multitarget effect on the basic immunological parameters for the formation of a personified immune response of the patient (Precision Immuno-Oncology). Conference, lectures to doctors of regional oncological centers of Odessa, Nikolaev. May, September 2017.
9. The role of molecules "MSC-428" in anticytokine therapy in infectious inflammatory pathologies of the eye. Lecture to doctors of ophthalmologists at the Filatov Research Institute. Odessa, May 25-27, 2018.