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Antineoplastic Medical Agent

#B-1976


Development of antineoplastic medical agent based on long acting α-2b-interferon

Tech Area / Field

  • MED-DRG/Drug Discovery/Medicine
  • CHE-POL/Polymer Chemistry/Chemistry

Status
3 Approved without Funding

Registration date
02.09.2011

Leading Institute
Belarussian State University / Institute of Physical Chemical Problems, Belarus, Minsk

Supporting institutes

  • National Research-and-Production Centre for Hematology and Transfusiology, Belarus, Minsk\nN.N. Alexandrov National Cancer Center of Belarus, Belarus, Minsk

Collaborators

  • Georgia Institute of Technology / School of Materials Science and Engineering, USA, GA, Atlanta\nAlbert-Ludwigs-Universitat Freiburg / Klinik fuer Tumorbiologie, Germany, Freiburg\nKinetic Concepts, Inc., USA, TX, San Antonio

Project summary

The Project aim: The Project aim is development of an immobilized form of α-2b-interferon ensuring enhancement of the therapeutic effect and prolongation of anti-tumor action of the bioactive substance in parallel with reduction of the drug toxicity.

Current status:

According to the data collected by WHO, malignant neoformations may be ranked among conditions with the highest mortality, causing annually about 7 million lethal outcomes worldwide. In spite of the progress in treatment of cancer achieved by means of surgery, further enhancement in survival rate of cancer patients, especially in cases of metastasis, is only possible with the use of additional medications. At the same time, toxicity of the most of anti-tumor drugs known to-date is concurrent with their therapeutic action and generally cuts down the scope of their application.

One of such medications is α-2b-interferon, an effective anti-tumor cytokine, which represents a recombinant human protein used in medicine for treatment of chronic myeloleucosis, malignant melanoma, acute hepatitis B and other diseases (Vilcek J. Immunity, 25, 343-348 (2006)). The problem of high toxicity of α-2b-interferon becomes the most evident in the treatment of metastatic melanoma, where therapeutic doses of this drug are 10-20 times those used for other oncological diseases. Toxicity of the drug used in such doses does not allow increasing survival of the patients to a significant extent, and puts a question as to advisability of using this drug (Glaspy J., et al., J. Clin. Oncol. 27 (18), 2896-2897 (2009)).

A further important disadvantage of native α-2b-interferon is its short clearance period, which prevents from achieving its maximum therapeutic action (U.S. Pat. Appl. US 2004/0136956 A1).

Therefore, the development of a macromolecular system that would ensure sustained release of α-2b-interferon and maintain its therapeutic concentration in the body for a long time while reducing toxicity of the drug and allowing a substantially smaller number of injections to be given during the course of treatment is an urgent and topical task.

By the end of 1990s, the Schering-Plough Pharmaceutical Company has developed a sustained-action form of α-2b-interferon, being a conjugate of the protein with polyethylene glycol (PegIntron®). It has been established (Rus. Pat. No. 2382048 C1) that the interferon PEGilation increases antiproliferative activity of the protein towards human tumor cells. Concurrently, it prolongs the action of the ferment and reduces its toxicity.

A benefit of this Project proposal consists in using for α-2b-interferon immobilization specially synthesized polymeric carriers, phosphorylated polysaccharides, which, unlike polyethylene glycol, possess anti-tumor activity of their own. Preliminary experiments carried out by the Project participants have proven that these carriers inhibit growth of sarcoma M-1, Jensen sarcoma and Seidel hepatoma inoculated to outbred white rats. These carriers are non-toxic, biocompatible and biodegradable. Moreover, they are characterized by high rates of interaction with α-2b-interferon, high rates of dissolution and/swelling, which makes it possible to avoid freeze-drying as an additional technological step in the manufacturing process and thereby reduce the final product cost.

The project influence on the progress in this area. The Project has social significance, since it is aimed at increasing the patients’ life span and on improving the quality of life. Preliminary studies have shown the possibility of obtaining a new sustained-action drug form of α-2b-interferon, which might have higher anti-tumor activity and be of lower cost as compared with products of other manufacturers (e.g. PegIntron® of Schering-Plough Pharmaceutical Company).

The participants’ expertise. The Project will be implemented by three teams of highly qualified scientists specialized in different research areas, the professional skills of which are complementary in solving the problems posed in the Project. The contribution of ‘weapon’ participants will amount to 3230 person*days or 71,5 % of the total effort on the Project.

The participants from RI PCP BSU (http://www.fhp.bsu.by/_private/en/labpolys.htm), NRPC HT (http://bcht.by/pay/english-page/) and NCCB (http://www.omr.med.by/index.php?lang=en) have the necessary experience in the development of ready-to-use drug forms for chemotherapy of malignant neoformations, as well as in preparation and determination of activity and analytical characteristics of recombinant human α-2b-interferon, as confirmed by publications in international scientific journals and patents.

Expected results and their application. The following results will be obtained in the course of the Project implementation:

  1. Biodegradable water-soluble and gel-forming polysaccharide esters different in composition, structure, weight-average molecular weight (MW) and molecular mass distribution (MMD) will be synthesized. Recombinant human interferon meeting up-to-date pharmacopeial requirements [Ph. Eur. 6, Ed. 2009] will be prepared and validated as to activity and analytical characteristics.
  2. Polymer-immobilized forms of α-2b-interferon, different in composition and properties, will be prepared, both as solutions and/or suspensions containing hydrogel microparticles. Physicochemical properties of the polymer-immobilized interferon forms will be characterized. Stability of the polymer-immobilized form of α-2b-interferon will be studied.
  3. Assessment of toxicity and anti-tumor activity of the new sustained-action form of α-2b-interferon will be performed in vitro and in vivo (in comparison with native α-2b-interferon and its PEGilated form – PegIntron®, as well as with the polymeric carrier). In vivo pharmacokinetics of the immobilized form of α-2b-interferon will be examined.

The Project implementation will result in obtaining a new effective sustained-action anti-tumor medication based on α-2b-interferon and biodegradable phosphates of polysaccharides. Evaluation of anti-tumor activity of the new drug form and its toxicity parameters will be performed. In vivo pharmacokinetics and stability of the new drug form will be studied.

Additional benefits from the anticipated Project results are as follows:

Scientific and practical significance: For the first time an attempt will be undertaken to prove the possibility of using water-soluble and gel-forming polysaccharide phosphates for designing the systems with controlled release of a biologically active substance. Consequently, investigations of features concerning polysaccharide esterification, including factors influencing the yields of gel- and sol-fractions, structure and physicochemical properties of the reaction products, evaluation of intermolecular interactions between polymeric carrier and the protein, as well as studies of α-2b-interferon release kinetics, are of scientific significance and may constitute a basis for the development of sustained-action forms of not only α-2b-interferon, but other therapeutic proteins as well.

Application area: The new forms of α-2b-interferon might be used for treatment of not only metastatic melanoma but also other oncological, viral or chronic inflammatory diseases, for which the high-dose chemotherapy with sustained-action medications is a critically important issue (chronic myeloleucosis, endocrine tumors of pancreas, Kaposi’s sarcoma concurrent with AIDS, chronic viral hepatitis B and C), rheumatoid arthritis, etc.).

Commercial significance: The polysaccharide esters will be prepared using relatively non-toxic and low-cost reagents, making the manufacture of the target product cost-efficient and environment-friendly.

An important additional benefit is the anticipated cost reduction of metastatic melanoma treatment.

The new anti-tumor pharmaceutical form will be of commercial value and subject to the intellectual property protection legislation.

Meeting the ISTC goals and objectives. The Project complies with the ISTC goals for the following reasons:

  • the Project allows its participants formerly involved in research work in military area to switch over to solving purely humanistic problems, i.e. the development of a new anti-tumor drug;
  • the Project participants formerly involved in ‘weapon’ research will obtain the opportunity of cooperation with colleagues from adjacent areas of science (medicine, microbiology), as well as with foreign specialists;
  • the Project results will contribute to fundamental and applied studies of water-soluble and gel-forming polyelectrolytes involving microparticles, as well as polymer-protein complexes, which could become a basis for developing sustained-action forms of not only α-2b-interferon, but other proteins as well;
  • the Project realization will enable its participants to enter the market economy due to the activities associated with the manufacturing and promotion of the final anti-tumor product on the market.

Scope of activities. Preparation and investigation of physicochemical properties of polymeric carriers and the new sustained-action drug form of recombinant human interferon, including determination of activity, conformation and stability of the interferon as a component of a polyelectrolyte complex, will be carried out by the researchers of the Leading Institution (RI PCP BSU) and those of the Participant Institution 1 (NRPC HT).

In vitro and in vivo evaluation of anti-tumor activity of all preparations, including assessment of their acute and subchronic toxicity, as well as in vivo pharmacokinetic studies, will be performed by specialists from NCCB.

The Project duration will be 30 months. The total effort will amount to 4515 person*days.

The role of foreign Collaborators:

  • Analysis of Technical Reports;
  • Discussion of the Project results and consultations;
  • Exchange of scientific information;
  • Assistance in the efforts aimed at commercialization of the Project results;
  • Other forms of cooperation are possible.

Technical approach and methodology. The development of sustained-action form of α-2b-interferon is based on the results obtained in recent investigations of physicochemical and medico-biological characteristics of polymeric carriers: the capability of forming multipoint cooperative linkage with α-2b-interferon, their own anti-tumor activity, high biocompatibility, low toxicity and biodegradability without inflammatory reactions.

Preliminary studies performed by the Project participants with an experimental sample of the gel-forming preparation of α-2b-interferon in vitro have revealed a ten-fold increase in anti-tumor activity as compared with the starting α-2b-interferon.

The following approaches will be used in the course of the Project implementation:

  1. The sustained therapeutic action of α-2b-interferon will be ensured by the protein immobilization on a polymeric carrier.
  2. The enhanced anti-tumor effect of the α-2b-interferon immobilized on a polymeric carrier as compared with the starting protein will be obtained owing to a longer dwell period of the drug in the circulatory system and the inherent anti-tumor activity of the polymeric carrier.
  3. Lower toxicity of the drug in the system will be achieved due to formation of the polymer-protein complexes ensuring sustained release of α-2b-interferon, which largely reduces the risk of overdose.
  4. The new drug form of α-2b-interferon will be developed in accordance with up-to-date pharmacopeial requirements [Ph. Eur. 6 – Ed. 2009] as regards control of composition, identity, purity, mass uniformity and other indices by performing the respective control tests.


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