OZR opvangmandaat post doc Federica Cappellesso

Most tumors lack specific receptors and cannot be targeted by the currently available monoclonal antibodies. Synthetic chimeric molecules that mediate ternary complex formation between cancer cells and effector immune cells, without the need for a specific receptor on target cells, would hence be of tremendous therapeutic benefit. Furthermore, specific drug delivery to the tumor microenvironment (TME) is a critical challenge to minimize off-target effects and toxicity. Here we introduce a new technology to fully exploit the therapeutic potential of tumor-targeted cell activation or degradation: Membrane Anchoring TRAfficking Chimeras (MATRACs). MATRACs use tumor acidity, a universal feature of solid tumors, to trigger TME-confined cell destruction or activation. They are recombinant fusion proteins composed of a ligand for a protein or cell of interest and the translocation domain of diphtheria toxin (td-DT), that will change conformation and anchor the cell surface in response to an acidic pH. I will investigate the mode of action and therapeutic efficacy of two different formulations: FC-MATRACs, composed of td-DT fused with the Fc portion of antibodies, enabling Fc-mediated recognition of tumor cells by innate immune cells in the TME; and CD40-MATRACs, containing td-DT and an anti-CD40 agonist, aiming at the activation of dendritic cells within the TME. This project could lead to the validation of MATRACs as innovative anti-tumoral drugs acting specifically in the TME.