BioVT-pre-2008-07 [BibTeX]
M. K. Tur, I. Neef, E. Jost, O. Galm, Gernot Jäger, M. Stöcker, M. Ribbert, A. Teubner, R. Osieka, U. Klinge, S. Barth:
Cell-specific induction of apoptosis by constitutive reconstitution of the tumorsuppressor protein DAPK2: Immunokinases, a novel class of immunotherapeutics
Antibodies Europe, Lissabon, Portugal, 22-23.10.2008
Abstract:
Death-associated protein kinase 2 (DAPK2) is a calcium/calmodulin (CaM)-regulated pro-apoptotic serine/threonine kinase that acts as a tumor suppressor. Deletion of the CaM-domain results in constitutive kinase activity and the enhanced stimulation of apoptosis. Here we show that DAPK2 is downregulated in Hodgkin lymphoma-derived tumor cells and that promoter region hypermethylation is one mechanism for DAPK2 inactivation. To determine whether selective reconstitution of DAPK2 catalytic activity in these cells could induce apoptosis, we created a fusion protein comprising a human CD30 ligand conjugated to a human DAPK2 CaM-deletion mutant. This recombinant immunokinase has a constitutive kinase activity with enhanced pro-apoptotic function. We show that DAPK2′-CD30L induces apoptotic cell death specifically in CD30+/DAPK2-negative tumor cells in vitro and significantly prolonged overall survival in a disseminated Hodgkin lymphoma xenograft SCID mouse model. This proof-of-concept study provides the first demonstration of therapeutic strategies based on the restoration of a defective, tumor-suppressing kinase activity by a novel class of recombinant immunotherapeutics.
Keywords:
DAPK, kinase, apoptosis, immunotoxin, immuntherapeutic, lymphoma, cancer