Tri-functional antibody- fusion proteins for cancer immunotherapy

• Applicant: Dr. Dafne Müller
• Subject Area: Immunology
• Term: from 2014 to 2017
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 256957568

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 tri-functional antibody-fusion proteins composed of a tumor-directed recombinant antibody and two different cytokines/chemokines. According to the concept, target-directed delivery of appropriate combinations of cytokine/ chemokine to the tumor site will support an efficient local antitumor immune response. Thereby, targeting should reduce the risk of systemic toxicity and autoimmune effects, while the combinatorial use of different immune-modulatory molecules should allow overcoming tumor evasion mechanisms. In the preceding project we have already successfully generated antibody-fusion proteins with IL-15 linked to part of the IL-15Ralpha chain and generated first tri-functional fusion proteins by the additional incorporation of the costimulatory ligand 4-1BBL. Thus, improved immune-stimulatory activity was achieved by the targeted form in vitro and antitumoral effects were reported in vivo. In light of these encouraging results, we aim to continue developing this concept by improving and expanding the generation of tri-functional antibody-fusion proteins, thereby meeting criteria of simple configuration, minimal size and good accessibility of all compounds in soluble and targeted form. Furthermore, we will focus on the combination of IL-15 with different ligands either of the TNF-superfamily (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, murine versions of the most promising tri-functional fusion proteins will be generated and their antitumor potential evaluated in an immune competent tumor mouse model. Thus, insight into the implementation and prospect of this innovative approach is expected to be gained.

• DFG Programme: Research Grants