Our ability to treat cancer has vastly improved through immunotherapy, which taps into the ability of cytotoxic T lymphocytes (CTLs) to selectively kill cancer cells. Several strategies have been developed to stimulate CTLs, incl. use of monoclonal antibodies (mAbs) blocking inhibitory immune checkpoints. It was shown for various cancer types that treatment with these mAbs induces durable responses even in patients with advanced disease. Ever since, immune checkpoint blockade has been an intense focus of interest in research and pharmaceutical circles. We developed a novel immune checkpoint drug, nanobody K2, that targets the inhibitory ligand prgrammed death-ligand 1 (PD-L1). Preclinical data using human in vitro models show that activation of CTLs against cancer cells is stronger in the presence of nanobody K2. In this project, we will extend on these data and study nanobody K2 as well as different formats of nanobody K2 (multivalent and antibody-like) in validated in vitro and in vivo models. As protein-based immune checkpoint therapy is associated with a high expense, we will further evaluate
the feasibility of delivering nanobody K2 (or its derivatives) under the form of mRNA, thereby building on prior studies showing that mRNA can be used to deliver tumor modulating proteins. In conclusion, we propose to evaluate novel immune checkpoint drugs with a strong potential for direct translation from bench to bedside.