Structural analysis of antibody-based profibrinolytics
Cardiovascular disease is a main cause of mortality and morbidity in the Western World. The fibrinolytic system is responsible for the removal of blood clots and plays an important role in maintaining flow in the blood vessels. The blood contains many factors required to achieve a balance between the formation of blood clots (e.g. to stop the bleeding of a wound) and the removal of blood clots (to prevent occlusion of blood vessels). TAFI is an important factor that constitutes a risk for increased thrombosis. The unique properties of monoclonal antibodies such as exceptional specificity make them an attractive basis for the design of novel drugs against a multitude of diseases. The development of other antibody-based drugs such as nanobodies, has recently gained a lot of attention. In the past we have developed a wide panel of antibodies and nanobodies that can be used to control the activity of TAFI. In particular, antibody-based products that inhibit TAFI activity have a great potential as antithrombotic drugs, while TAFI-stimulating nanobodies may help to fight haemophilia. The current project aims at the elucidation of the molecular mechanism of nanobodies and monoclonal antibodies that modify TAFI activity, by solving the structures of their complexes. Insight into these mechanisms will contribute to the development of drugs that restore the normal speed of removal of blood clots thereby decreasing the risk for thrombosis.