Projects / Programmes
Design and preclinical development of novel drugs
January 1, 2014
- December 31, 2017
| Code |
Science |
Field |
Subfield |
| 1.09.00 |
Natural sciences and mathematics |
Pharmacy |
|
| 1.04.04 |
Natural sciences and mathematics |
Chemistry |
Organic chemistry |
| Code |
Science |
Field |
| P000 |
Natural sciences and mathematics |
|
| Code |
Science |
Field |
| 3.01 |
Medical and Health Sciences |
Basic medicine |
| 1.04 |
Natural Sciences |
Chemical sciences |
Researchers (25)
Organisations (1)
| no. |
Code |
Research organisation |
City |
Registration number |
No. of publicationsNo. of publications |
| 1. |
0258 |
Lek Pharmaceutical Company d.d. |
Ljubljana |
1732811 |
8,032 |
Abstract
Cancer cases represent currently in addition to cardiovascular disease a major cause of mortality in the developed world. Most cancers can be treated nowadays, many patients can be fully recovered, if treatment is started early enough. Despite the increasing availability of different biological therapies, the treatment of cancer is still associated with very aggressive methods. In addition to the surgical removal of tumors when possible, chemotherapy remains the first line treatment and cannot be avoided, not only because of the price of biological medicines but also because of better efficacy of the combined therapy.
Consequently, recently very intensive research and development have been started in the area of conjugation of components of biological drugs and cytotoxic agents (chemotherapeutics) in one molecule, so called antibody drug conjugates (ADC), with the goal to produce a substance that is capable of targeted delivery to the cancerous tissue enabling targeted chemotherapy for much more selective action.
Despite the recent FDA approval of the first antibody drug conjugates very intensive research continues in this area focused on the various types of cancers, as well as on the preparation of molecules with improved specificity on the basis of more specific monoclonal antibodies as well as on the basis of design of more appropriate linkers enabling more selective toxin release. The non-specificity of binding of the toxin to the antibody, resulting in the heterogeneity of the product, is one of the major challenges of preparation of antibody drug conjugates, representing major obstacle for analytical characterization. Within the proposed program, we intend to cover all aspects of development, i.e. preparation of conjugates and their physico-chemical characterization, exploring some biological effects (binding to the receptor, the behavior in in vivo models). Prepared conjugates will be characterized by a wide range of analytical methods. Due to the specifics of antibody drug conjugates the larger part of the analytical methods will be developed specifically for the purpose of their characterization, since their behavior in a variety of analytical methods differs significantly from the behavior of parent antibody.
In addition to the preparation and characterization of conjugates important objective of the program will be development of the organic synthesis pathway for the preparation of the selected toxin and its derivatives, with the long-term objective to extend our range of potentially interesting toxins, to establish procedures for their synthesis and establish a wide range of analytical methods for the characterization of toxins and linkers, since both the toxin and the linker are key elements comparably important for the selectivity and efficacy of the final conjugate as a parent antibody specificity. Considering known data on the ADCs preparation, their functioning and deficiencies, the objective of the proposed programme is to establish a solid platform for the development, characterization and production of ADCs in Lek for the purpose of later development of biosimilars, their improved variants (biobetters), as well as innovative molecules for Novartis group.
Significance for science
Despite the fact that many cancers can be cured today, cancer still leads as a cause of death in the developed world. Effective treatment of cancer comprises highly aggressive methods causing many side effects. ADCs represent the hope that cancer could be cured with significantly less side effects than is known today. Successful execution of the program means establishment of scientific and technological platform for the preparation of ADCs. It can serve for preparation of biosimilars as well as for their improved forms (biobetters) and inovators’ molecules representing important contribution to the development of science in the cancer cure field. Additionally, we have develop our processes with incorporating the latest knowledge of the engineering practice and analytical science contributing significantly to the development of engineering and analytical science in Slovenia as well as globally. Despite several years of intensive research and development work in the ADCs synthesis, the field is still quite undeveloped, and offers numerous opportunities for improvements in preparation of ADCs for a more targeted functioning. Therefore, the development in recent years has been focused on the preparation of conjugates with improved properties with a focus on linkers optimization and more defined structure, (i.e., searching and optimization of alternative processes of conjugation), where we see room for our innovative contributions, which could result in a patent protected own platform. The work is also in line with the development policy of Slovenia, as health is one of the priority themes. We are sure, that the products of the proposed research are interesting and crucial in the field of biomedicine and gained knowledge is important on a global scale.
Significance for the country
Direct importance for the economy and society Maintenance of R&D capacities in pharmaceutical industry is a national priority stated in all strategic documents of the Republic of Slovenia, where pharmaceutical industry is traditionally one of the most developed and socially economically important industries. The pharmaceutical company Lek has recognized the potential added value of research in the field of anticancer drugs and directed part of R&D funds into research connected to the establishment of the new platforms for their development. Successful establishment of a scientific and technological platform for the ADCs preparation for cancer treatment supports intensification of research and further enhancement of the advanced industrial research within Lek. All this importantly contributes to strengthening of our center for development and manufacturing of biopharmaceuticals within the Sandoz/Novartis bringing long-term competitive advantage and ensuring high-tech jobs in Slovenia. The later is especially important for Slovenia as we lag behind more developed countries in the field of technological enterprises with own research. The established platform can lead in the future to discovery of improved forms of ADCs and can thereby succeed in offering Slovenia an original drug. In view of the ever higher importance of treatment of cancer, this would be an extraordinary moral and material success. R&D in Lek are goal-orientated and supported with international cooperation, therefore the possibilities for a successful completion of development of an improved substance, at least to the phase of clinical candidate are realistic. Regarding involvement of the proposed research into trends of the global pharmacy this is an area with very intensive partnerships between pharmaceutical multinational corporations and highly innovative groups (academic and small biotech companies). Importance for the development of the profession and engineering practice. Research program group within industry is a guaranty for applicable science. It means an increase of employment for top Slovenian researchers and thus justifies significant national investments in PhD education programs. At the same time it is the driving force for academia-industry consortiums and collaborations, already proven in the past. In addition the expert knowledge and skills gained during the program can provide a great potential for high-tech spin-off companies. New knowledge and introduction of new technological platforms are vitally important for further development of pharmacy and biotechnology in Slovenia. Indirect importance for the society Publication in the international scientific journals and the patenting of the results have contribute to the strengthening of national identity. At the same time the efforts of the research group on the development of anticancer drugs can certainly contribute to the reputation and recognition of our researchers within an international scientific community.
Most important scientific results
Annual report
2014,
2015,
2016,
final report
Most important socioeconomically and culturally relevant results
Annual report
2014,
2015,
2016,
final report
