Immunomodulator Drug for Treatment of Tumor and Allergic Diseases
Development of Immunomodulator Drug of a Novel Generation for Treatment of Tumor and Allergic Diseases
Tech Area / Field
- MED-DRG/Drug Discovery/Medicine
3 Approved without Funding
Research Institute of Pharmacology, Siberian Branch of Russian Academy of Medical Sciences, Russia, Tomsk reg., Tomsk
- Institute of Immunological Engineering, Russia, Moscow reg., Lyubuchany
- University of Florida / College of Medicine / Department of Urology, USA, FL, Gainesville\nMontana State University / Veterinary Molecular Biology Laboratory, USA, MT, Bozeman
Project summaryThe proposal is devoted to development an immunomodulator drug of a novel generation targeted to genes responsible for macrophage activity, and permitted to switch balance М1/М2 into inflammatory M1 macrophages with strongly antitumor properties. The substance if it will be used for treatment of oncological diseases can to stimulate an antitumor immune response and to grade a haemopoiesis disturbance that accompanied a tumor growth (GM hyperactivity, accumulation of myeloid suppressor cells).
It is well known, that macrophage cells not only route differentiation of lymphocytes by Th1 or Th2, but themselves also polarize into М1/М2 and integrate in corresponding (induced its) polarization type. Dominance of M2 state under malignant neoplasm correlate with depression of antitumoral Th1 cells and is an unfavorable prognostic factor. As opposed to lymphocytes, which once polarized, do not change their orientation, macrophages are capable to change their polarized profile. Just due to this flexibility, they represent the perspective target for therapeutic intervention. Thus, effectiveness of including CpG-motif (TLR9 ligand) in therapy of melanoma and non-Hodgkin’s lymphoma had been shown. Latest years the active search of intracellular molecules, responsible for macrophage antitumoral state, has being carrying out. The first step needed for founding of an immunomodulator drug of a novel generation with targeted action regarding macrophage is a revelation of key molecules of a macrophage-signaling cascade.
Now in this direction, the authors of the project have studied certain indices of macrophage functional states (marker characteristics of classical and alternative activation); have finished screening of substances, related to derivates of glucuronic acid, in the case of their influence on marker rates of macrophage functional state and on the course of Th1 and Th2 immune response. This work allowed detecting the group of the most effective substances – hydroximethil-derivates of glucuronic acid, which stimulated Th1-depended reaction, and selectively stimulated granulomonocytopoiesis and functional activity of neutrophilic leukocyte. For identification the probable drug field of application, which may be developed on basis of these pharmacological substances, also as potential immunomodulator, it is necessary to conduct further researches. Thus, project aims are the research of immunomodulating properties of selected substances, selection of the most active substance, the detection of genes spectrum activated under it’s action and the detection of intracellular signaling key molecules, brought into macrophage activation.
During fulfillment of the project will be the received new knowledge about myeloid cell activation mechanism (it is planned to detect receptor and postreceptor events connected with classical and alternative macrophage activation). The research of influence of selected for project substances on immune response course in it’s different experimental models and the detection of genes, activating under the influence of given substances, will allow to give sufficiently complete picture of their pharmacodynamics. Such information is necessary for detection of plausible methods of application. The result of current project realization will be the receiving of the most effective pharmacological substance, and received materials may be referred to interested producers for making pharmacopeial article, testing preclinical and clinical trials. Generated in the course of project fulfillment intellectual property is planned to protect in the form of a patent. The assumed field of application of the drug, worked out on basis of selected substance, is not finally detected, but it can be firmly said, that this drug will be effective in accessory therapy of oncological diseases and it may be effective in treatment of allergic pathology and persistent infections.
Substances research methodology is based on modern view of the T-helper polarization (in Th1 or Th2), and macrophages (classically or alternatively activated). The immune response and inflammation research will be carrying out under methodological recommendations of Pharmacological Committee of Russian Federation. To realize the project, study of influence of substances on Th1/Th2 and M1/M2 balance as well as effect in vivo on inflammatory reaction in some animal models will be carry out. Substances effect will be estimated at their action on expression genes responsible for macrophage functional state, on equipped signaling cascade, on the production of inflammatory/antiinflammatory mediators.
Project fulfillment will promote the solution of important social problem, notably: providing scientists and engineers of Insitute of Immunological Engineering RAO “Biopreparat” and other specialized institutions, worked under government work in the sphere of antibiological protection formerly, with an opportunity to reorientate their scientific interest sphere and to use know-how for carrying out fundamental and applied investigations, connected with the solution of international scientific and technical problems in the sphere of biology, medicine and veterinary in peace goals, to create a long-term perspective of fruitful activity within the bounds of international scientific community. For establishing of new contacts and further integration in the network of international scientific researches the following is planned in the frames of the project: development of scientific strategy and programs of researches; exchange of information and preparations for scientific research; training of specialists in the field of partners’ competence, scientific trips of experience exchange; organization of scientific seminars with parthicipation of collaborators; development of program of help for Russian partner (consultations, recommendations, preparation of publications, information support by software for modeling of molecular structures etc.); preparation of new scientific projects and selection of potential partners with help of collaborators.
Project result aims at the supply of demand for qualitative and effective immunomodulator agent. Immunomodulator market in Russia is sufficiently broad. Thus, according to available data of Center of Medical Investigations «Pharmexpert» («Pharmacevtitcheskii Vestnik», № 37 (484), 20.11.2007), first half-year of 2007 the market volume of immunogstimulating drugs in monetary terms assembled 133 millions US dollars, in natural exponent – 11 millions of packing. The increase of sales volume in monetary terms happens since 2004 on the average 30% per half-year, and in packing only growth is observed. The expenses optimization of additional medicinal provision program (AMP) in minority extent affected the immunomodulator market, than on the markets of other groups of drugs: the sector quota of AMP insignificantly decreased. It demonstrates the importance of immunorehabilitation measures for different categories of patients. The greatest part of domestic drugs in pickings negotiates in hospital sector – about 80%. TOP10 trademark rating shows that all rating participants demonstrate stable affirmative growth of sales. Due to high efficiency and wide scope TOP10 contains 4 Russian companies - “Pheron”, “Polysan”, “Biokad” and “Petrovaks”. Among outside manufacturers, TOP10 contains “Buyer Sharing Farma” and “ROSH” corporations. The potential of immunomodulator market grows owing to the forthcoming of innovation drugs, the increase of prescription of medicine by different profile doctors, correlating immune state derangements of patient. Immunomodulator market volume in Russian Federation may reach 0.5 billions US dollars by 2010.