Biopharmaceuticals: Discovery, Design and Delivery (BDDD)

Research programme

Mission statement

The BDDD Division explores innovative approaches oriented towards the early phase of drug development up to the use of these approaches in practice. The focus is on fundamental research towards the discovery and design of biopharmaceuticals that as drugs recently have grown enormously in importance as drugs. The division uniquely combines research on drug targeting, drug delivery, biopharmacy and pharmacokinetics. Furthermore, fundamental aspects of
biotechnological production processes and dosage forms are studied.

Research area
The sub-programme Pharmaceutical Biology has as its central aim the study of the living cell as a source of pharmaceutically important products. Natural and directed diversity of micro-organisms, plants and plant cells are explored as a source of natural products, including protein therapeutics.

The growing understanding of the basic molecular mechanisms underlying diseases has expanded the number of potential targets for therapeutic intervention. Both in-depth pathophysiological investigations and the genomics and proteomics revolution have allowed identification of numerous novel receptors and cell components, for which interacting ligands are sought. Biodiversity and biotechnology are very complementary in providing complex ligand molecules that can be the start of a new therapeutic. Exploiting natural diversity, e.g. plant cells, has a long standing tradition in drug discovery. Novel techniques such as directed diversity and directed evolution are now being explored for creating new leads from secondary metabolites and (poly)peptides. This is the key research area of this programme.

• The plant biotechnology research line is concentrated on the production of bioactive compounds of natural origin using plant cell cultures and plants. Next to phytochemical analysis, molecular-biological techniques are applied to gain insight into biosynthetic routes and to control the formation of bioactive compounds (pathway engineering). Current projects that involve this work are (i) the production of cytostatic lignans in cell suspensions, organ cultures and plants from Anthriscus sylvestris (ii) the production and isolation of the antimalaria drug Artemisinin with the use of plants and plant cell cultures from Artemisia annua. One of the goals is to redesign Xanthophillum dendrohorous as minimal cell factory to maximize the production of plant-derived natural terpenoids.
• The molecular-biological research line concentrates on biotechnologically produced pharmaceutical proteins, enzymes and cell surface receptors. The efficacy of biopharmaceuticals is being improved by the application of new techniques of combinatorial biology, protein mutagenesis and ultimately, computational design. The engineering of more selective cytokine variants is at the core of this research line. New biocatalysts for stereo selective reactions are being engineered including enantioselective proline-based biocatalysts for general alkylation, Michael addition, and aldol reactions.
• The cell biology research line concentrates on the expression and especially the secretion of pharmaceutical proteins from cells. Protein ligands as potential therapeutics -being macromolecules- present special problems with respect to production. The production of complex natural products is also a huge challenge in the drug development phase, and major bottlenecks are being addressed by developing cell factories.

The sub-programme Pharmacokinetics, Toxicology and Targeting explores innovative drug delivery tools for the cell-specific targeting of drugs and therapeutic proteins. Specific peptides and protein fragments are studied as homing devices and tools for improving pharmacokinetics. This is combined with research on the in vitro prediction of drug metabolism, transport and toxicity, as well as with pharmacokinetic modelling and simulation. Research has focussed on 3 research lines

• drug targeting
• human pharmacokinetics & PKPD modelling
• drug metabolism & toxicology.
  
  Strategies are being developed for targeting drugs and biologicals such as cytokines, enzymes and prostaglandins to diseased cells in chronic inflammatory and fibrotic diseases (in liver and kidneys) and tumours. New neoglycoproteins and receptor recognizing peptides have been developed, and their therapeutic effects in animal models have been established. Future research activities will focus on the design and development of new receptor-recognizing proteins and peptides for drug targeting purposes, with the aim to design a series of effective cell-selective compounds to target
  important receptors in fibrosis and tumorgenesis.
  Another research interest is human pharmacokinetics, as well as pharmacokinetic-pharmacodynamic (PK-PD) modelling and analysis. Computer programs for PK-PD simulation and population-based data analysis are being developed, both for research on translational modelling and simulation of treatment effects in schizophrenia, and for use in the daily practice of therapeutic drug monitoring.
  Innovative in vitro models using human and animal liver and intestinal tissue have been developed to predict human drug disposition, metabolism and toxicity. They are currently applied to the development of biomarkers and elucidation of mechanisms of (idiosyncratic) toxicity, to study regulation of drug metabolism and transport, to study interorgan interactions, and for testing of anti-fibrotic drugs. In addition, studies on the mechanisms of cell damage during cold- and cryopreservation have been initiated, aimed at developing improved preservation methods for transplantation organs as well as tissue for research.

The sub-programme Pharmaceutical Gene Modulation focuses on the development of medicines for the therapeutic manipulation of genes and gene activity. Drugs and delivery forms are being developed for the specific and efficient treatment of cancer and inflammatory diseases. Two research lines can be distinguished.

• Modification of gene transcription via gene transfer vectors. This is a conceptually new strategy for drug discovery. Gene therapy suffers currently from a lack of efficiency. This research line aims to improve the efficiency by transgene transmission (efficient spread of the gene product). The transgenes encode for transcription factors or single chain antibodies capable of modulating gene
  expression of native genes.
• Modification of gene transcription using small drug-like molecules. This research line is represented by Dr. F. J Dekker, a tenure-track assistant professor, and aims to combine chemical and biological techniques to study gene transcription. Small drug-like molecules are developed using a variety of medicinal chemistry methods. The inhibitors are applied in a reverse chemical genetics approach to
  study the role of histone acetyltransferases in gene transcription. This will ultimately result in new therapeutic approaches in cancer and inflammatory diseases.

In order to guide the early stage drug research towards patient therapies a crucial contribution comes from the sub-programme Pharmaceutical Technology and Biopharmacy that performs research in the field of dosage forms and their interaction with the living organism. Basic research on the design and development of novel and improved drug delivery systems is combined with research on new processes, equipment and technologies for the production of (biopharmaceutical) dosage forms and their performance.

• The nature of modern drug compounds increasingly requires the application of advanced dosage forms to obtain optimal therapeutic efficacy. The rise of biopharmaceuticals such as therapeutic proteins, gene vectors or advanced vaccines, as well as the increase in the number of highly insoluble drugs, has rejuvenated academic research in biopharmacy and pharmaceutical technology over the past decade. This brings challenges that require new approaches in formulation science, production technology and routes of administration.
• The sub-programme Pharmaceutical Technology and Biopharmacy is dedicated to fundamental research in the field of dosage forms, their production processes and the interactions of these dosage forms with the living organism. The research objective can briefly be described as “bringing advanced technology from laboratory and production facility to bedside”, which places the group in the centre of the triangle “academic research, industrial research and application in patients”.
• The sub-programme has achieved a tremendous expertise surrounding the central theme of pharmaceutical powder technology. As a consequence of this choice, the research focuses on three topics: (1) dosage forms for pulmonary administration (mainly dry powder inhalers), (2) solid oral dosage forms, and (3) the application of sugar glass technology in the formulation of biopharmaceuticals (peptides, proteins, vaccines and gene delivery systems) and highly insoluble
  drugs (a subject closely linked to nanotechnology). These three research lines exhibit strong synergy. Research is performed on both biopharmaceutical as well as technological aspects, in order to design optimal dosage forms with respect to the technological production, therapeutic efficacy and use by the patient.

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 Contact
Programme leaders

Name: Prof.Dr. H.J. Haisma
Phone: +31 (0)50 363 7866
e-mail Prof Haisma

Name: Prof.Dr. W.J. Quax
Phone: +31 (0)50 363 2558
e-mail Prof. Quax

Secretariat
Name: Mrs. I. Uuldriks
Phone: +31 (0)50 363 7866
e-mail Mrs. I. Uuldriks