Bi- und tri-functional IL-15 based cytokine fusion proteins for targeted cancer immunotherapy

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The antitumor potential of cytokine/ligand-receptor interactions that modulate an immune response has moved into the spotlight of cancer treatment strategies. Here, we propose an approach with multifunctional antibody-fusion proteins for target-directed delivery of different cytokines and ligands to the tumor site in order to support an efficient antitumor immune response. Targeting should reduce the risk of systemic toxicity and autoimmune effects. Furthermore, the combinatorial use of different immune-modulatory molecules should allow to overcome tumor evasion mechanisms. In the preceding project we have already successfully generated bi-functional antibody-fusion proteins with the cytokine IL-15 linked to part of the IL-15Ralpha chain, obtaining improved activity in vitro and in vivo. Additional combination with the costimulatory ligand 4-1BBL into a tri-functional fusion protein rendered enhanced immune-stimulatory capacity in targeted form in vitro. In light of these encouraging results, we aim to develop second generation tri-functional antibody-fusion proteins, meeting criteria of simple configuration, minimal size and good accessibility of all compounds in soluble and targeted form. Therefore we will focus on the combination of IL-15 with different ligands either of the 4-helix-bundle cytokine family (IL-7, IL-21), costimulatory ligands of the TNF-family (OX40L, GITRL, LIGHT) or the chemokine CCL-family (CCL16, CCL21). We will analyze the influence of the configuration of these molecules on the activity displayed in soluble and targeted form and their impact on the immune response of T cells and NK cells in vitro. Subsequently the antitumor potential of the most promising tri-functional fusion proteins will be evaluated in a lung metastasis tumor mouse model in vivo. Thus, insight into the implementation and prospect of this innovative approach is expected to be gained.