WIJNAND HELFRICH :  THURSDAY 30 MARCH 2006, 17:25

Tumor cell-restricted apoptosis induction; therapeutic targeting of the messengers of death

Edwin Bremer¹, Bram ten Cate¹, Douwe Samplonius¹, Georg Fey², Lou de Leij¹, Wijnand Helfrich^1
1Pathology and Laboratory Medicine, Medical Biology, Lab for Tumor Immunology, Groningen University Institute for Drug Exploration (GUIDE), 9713 GZ Groningen, The Netherlands; ²Chair of Genetics, University of Erlangen-Nuremberg, D-91058 Erlangen, Germany

Future direction in oncology strongly points to targeted therapies using MAbs, small inhibitory molecules (e.g. Iressa), and tumor-selective death ligands (e.g. TRAIL & FasL). TRAIL is a promising candidate as its agonistic death receptors TRAIL-R1 and TRAIL-R2 are expressed on a wide variety of malignant cells, rendering many of them sensitive to its pro-apoptotic action, while normal tissues are protected.
Recently, we and Wajant et al. showed that fusion proteins comprising the extracellular domain of a death ligand (TRAIL or FasL) and a tumor-selective targeting domain (e.g. scFv antibody fragment) directed against a cancer-associated cell surface antigen exert superior cancer-selective activity. We produced a large panel of fusion proteins specific for both solid tumor types and leukemia's/lymphomas. This series include those directed at EpCam, EGFR, CD7, CD19, CD20, CD33, CD38 and more. Death ligand fusion proteins show potent and target antigen-selective apoptotic activity with minimal reactivity towards normal cells. Importantly, the selective binding of fusion proteins conveys an exceptionally potent apoptotic bystander effect towards tumor cells devoid of target antigen. For some fusion proteins the anti–tumor bystander activity was detectable at target : bystander cell ratios as low as 1:100. Importantly, this bystander effect did not require internalization, enzymatic conversion, or intracellular communication between target and bystander tumor cells. The principle of target cell-restricted apoptosis induction may be of value for various human diseases.

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