Immunokinases, a novel class of immunotherapeutics for targeted cancer therapy.
Certain characteristics of tumor cells make it possible to develop rational strategies for targeting tumors without harming normal cells. These include the presence of cell surface molecules that characterize the current state of the tumor (e.g. CD30 on Hodgkin lymphoma cells) and the genetic and epigenetic changes that activate oncogenes and inactivate tumor suppressor genes (e.g. the inactivation of tumor suppressor gene DAPK2 in Hodgkin lymphoma cells, which blocks apoptosis). We have developed a novel tumor-targeting fusion protein by combining a selective ligand (CD30L) with a constitutively active version of DAPK2 (DAPK2'-CD30L), thus increasing tumor specificity and reducing systemic toxicity. We showed that this immunokinase fusion protein induces apoptosis specifically in CD30(+)/DAPK2(-) tumor cells in vitro and significantly prolonged overall survival in a disseminated Hodgkin lymphoma xenograft SCID mouse model. Therapeutic strategies based on the cell-specific restoration of a defective, tumor-suppressing kinase demonstrate the feasibility of targeted therapy using recombinant immunokinases.
Tur
Mehmet Kemal
MK
Department of Experimental Medicine and Immunotherapy, Chair of Applied Medical Engineering, Helmholtz-Institute for Biomedical Engineering, University Hospital RWTH Aachen, Germany. tur@hia.rwth-aachen.de
Neef
Inga
I
Jäger
Gernot
G
Teubner
Andreas
A
Stöcker
Michael
M
Melmer
Georg
G
Barth
Stefan
S
D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects; D051017:Apoptosis Regulatory Proteins / Q000276:immunology / Q000502:physiology / Q000627:therapeutic use; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000276:immunology / Q000502:physiology / Q000627:therapeutic use; D045744:Cell Line, Tumor; D064550:Death-Associated Protein Kinases; D016503:Drug Delivery Systems / Q000379:methods*; D006689:Hodgkin Disease / Q000188:drug therapy*; D006801:Humans; D000922:Immunotoxins / Q000627:therapeutic use*; D017730:Ki-1 Antigen / Q000276:immunology; D051379:Mice; D016513:Mice, SCID; D008954:Models, Biological; D011993:Recombinant Fusion Proteins / Q000096:biosynthesis / Q000627:therapeutic use*
D000970:Antineoplastic Agents; D051017:Apoptosis Regulatory Proteins; D000922:Immunotoxins; D017730:Ki-1 Antigen; D011993:Recombinant Fusion Proteins; C544074:DAPK2'-CD30L fusion protein; C579104:DAPK2 protein, human; D064550:Death-Associated Protein Kinases; C579103:dapk2 protein, mouse; D017871:Calcium-Calmodulin-Dependent Protein Kinases