Biomedical Engineering

Our group is working on the development of novel strategies for tumour therapy. These strategies are based on the use of specific ligands to target potent cytotoxic effector mechanism to the tumour. We are focusing on three effector arms: 1) bispecific antibodies for the retargeting of effector cells of the immune system (immunotherapy), 2) targeted carrier systems (liposomes, polymers) for drug delivery (chemotherapy), and 3) targeted cytotoxic fusion proteins (biotherapy). Main targets are molecules associated with the tumour vasculature (vascular targeting), since these structures are easily accessible for circulating agents and all solid tumours are dependent on vascularisation.

The identification of suitable ligands is essential for the development of efficient targeting strategies. Besides antibodies (e.g. single-chain Fv fragments) natural receptor-binding molecules and synthetic peptides can be used as ligands. Such new or improved ligands can be obtained by combinatorial and evolutionary approaches, e.g. in combination with phage display technology. Several phage display ligand libraries have been developed in our group and applied for the isolation of specific ligands. For instance, a fully synthetic antibody library was generated, which can be employed for the isolation of human scFv fragments against virtually any antigen.

The immune system is composed of an arsenal of different and potent effector cells, e.g. cytotoxic T-lymphocytes or NK cells. Recognition and elimination of malignant cells by these effector cells is, however, often not very efficient. Bispecific antibodies are capable to redirect effector cells and to trigger killing of target cells, thus improving effector cell cytotoxicity. Our work is focused on the use of small recombinant bispecific antibody formats, which have several advantages over conventional antibody molecules (e.g. a defined structure and reduced side effects). These recombinant bispecific molecules can be easily generated and produced by genetic engineering. In the past years we have developed a novel format, so called single-chain diabodies (scDb), composed of the variable antigen-binding domains of two different antibodies. This format were successfully evaluated for a variety of applications, including retargeting of effector molecules, effector cells and viral gene vectors. Current work is focusing on the development of single-chain diabodies for the retargeting of different effector cell populations (CTLs, NK cells, macrophages, neutrophils) and their evaluation in relevant tumour models.

Many chemotherapeutics are characterized by a limited therapeutic efficacy, often due to severe side effects at higher doses and rapid elimination from the body due to their small size. Encapsulation of small therapeutic molecules into nanoparticular carrier systems, such as liposomes or polymers, can improve the pharmacokinetic and pharmacodynamic properties and protects the active compound from degradation. Furthermore, equipping these carrier systems with target cell specific ligands increases selectivity and efficacy. We have already successfully used various ligands (e.g. scFv fragments, EGF, RGD peptides) to generate such targeted liposomal carrier systems with improved properties. These approaches are currently further developed and explored.

The direct fusion of effector molecules to ligands allows for the generation of targeted cytotoxic molecules. Using different ligands against vascular structures fused to effector molecules such as toxins or cytokines we plan to develop novel vascular targeting agents and to analyse their efficacy, selectivity and safety in animal models.