Tumor Necrosis Factor (TNF) is a homotrimeric pro-inflammatory cytokine that was originally discovered based on its extraordinary antitumor activity. However, its shock-inducing properties, causing hypotension, leukopenia and multiple organ failure, prevented its systemic use in cancer treatment. With this proof-of-concept study we want to evaluate a novel class of cell-targeted TNFs with strongly reduced systemic toxicities (AcTafactors). In these engineered immuno-cytokines, single-chain TNFs that harbor mutations to reduce the affinity for its receptor(s) are fused to a cell- specific targeting domain. Whilst almost no biological activity is observed on non-targeted cells, thus preventing systemic toxicity, avidity effects at the targeted cell membrane lead to recovery of over 90% of the TNF signaling activity. In this project we propose a lead optimization program to further improve the lead AcTafactors identified in the context of the ERC Advanced Grant project and to evaluate the resulting molecules for their ability to target the tumor (neo)vasculature in clinically relevant murine tumor models. The pre-clinical proof-of-concept we aim for represents a first step towards clinical development and ultimately potential market approval of an effective AcTafactor anti-cancer therapy.
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