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Immunokinases

Most cellular processes such as proliferation, differentiation, secretion and apoptosis are tightly regulated by enzymatic activities. Protein kinases and phosphatases play a crucial role in these processes as well as signal transduction pathways and thus do affect the cellular response to a variety of hormones, cytokines and neurotransmitters. Until now, approximately 2,000 kinase and 500 protein phosphatase genes were identified within the human genome; a large number of these are oncogenes or tumor suppressor genes.

Silencing of tumor suppressor or other cancer-associated genes by aberrant hypermethylation of CpG islands within the promoter and/or 5-regions of tumor-related genes is a common feature of human cancer and has been associated with a transcriptional inactivation and loss of the relevant protein. Death-associated protein-kinase (DAP kinase) is a Ca2+/calmodulin (CaM)-regulated serine/threonine kinase that functions as a positive mediator of apoptosis. The deletion of the CaM-domain (DAP-kinase-DCaM) generates a constitutively active kinase with enhanced ability to induce apoptosis. Ectopic expression of DAP kinase induces cell death and suppresses oncogenic transformation. Thus, we speculated that receptor-specific reconstitution of DAP kinase activity by DAP-kinase-DCaM might induce cell death in DAP kinase 2 hypermethylated tumor cells. We verified this speculation by generation of novel human immunotoxins by fusing DAP-kinase-DCaM to recombinant antibody fragments (EP04/000847).