Targeted apoptosis induction in hemato-oncology

Promotie: dhr. B. ten Cate, 16.15 uur, Academiegebouw, Broerstraat 5, Groningen

Proefschrift: Targeted apoptosis induction in hemato-oncology

Promotor(s): prof.dr. L.F.M.H. de Leij

Faculteit: Medische Wetenschappen

Contact: via de persvoorlichters van het UMCG, tel. 050-361 2200, e-mail: voorlichting@bvl.umcg.nl

Targeted apoptosis induction in hemato-oncology

Leukemia is characterized by the uncontrolled overproduction of white blood cells. The five years survival rate for some distinct types of leukemia is only 20%. This poor prognosis is due to the lack of effective therapies as well as to therapy-related mortality. Therefore, the aim of this research was to develop novel targeted therapies which effectively eliminate leukemia cells while sparing normal cells. In this respect we have utilized antibodies, since antibodies can selectively bind to and eliminate leukemia cells. Currently, a number of antibodies are already applied in the clinic; however enhancement of their anti-leukemia activity is necessary. Using recombinant DNA technology we have fused antibody fragments with the pro-apoptotic proteins TRAIL and FasL. TRAIL and FasL are immune effector molecules involved in the elimination of cancer cells. The clinical application of TRAIL and FasL for leukemia therapy is hampered due to the wide-spread expression of their cognate receptors. Therefore, we have generated fusion proteins comprising a leukemia-selective antibody fragment genetically linked with either TRAIL or FasL. Due to the leukemia-specific antibody fragment these fusion proteins accrete at the cell surface of leukemia cells and thereby redirect TRAIL and FasL to these leukemia cells. Our studies indicate that these fusion proteins potently eliminate leukemia cells, without apparent toxicity towards normal cells. Furthermore, by applying different antibody fragments in our fusion proteins we were able to target and eliminate cells of several distinct types of leukemia. The ultimate goal is to develop these fusion proteins for clinical applications.