Genetic Engineering of Death Ligands for Improvement of Therapeutic Activity

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The death ligands TRAIL, FasL/CD95L, and TNF are in the focus of intense preclinical and clinical research efforts having the aim to exploit these molecules as new anticancer drugs. A common feature of these ligands is that their transmembrane form displays higher and/or broader activity than their soluble counterpart. Accordingly, the bioactivity of the soluble form of these ligands ranges from being poorly active (FasL/CD95L) to displaying a receptor type-selective signaling capacity (TNF, TRAIL). The presently approved or clinically exploited recombinant variants of TNF and TRAIL correspond to the soluble trimeric form of these proteins. In order to increase their intrinsic and tumor-selective bioactivity, we modified these ligands by genetic engineering to reach two aims: (i) stabilization of their trimeric organization and/or (ii) directing ligand action to the diseased tissue. Here, we summarize our concepts and show recent data on improving death ligand activity by intramolecular stabilization and/or membrane ligand mimicking activity through cell surface presentation.