Targeted Repolarization of Tumor‐Associated Macrophages via Imidazoquinoline‐Linked Nanobodies
Evangelia Bolli, Maximilian Scherger, Sana M. Arnouk, Ana Rita Pombo Antunes, David Straßburger, Moritz Urschbach, Judith Stickdorn, Karen De Vlaminck, Kiavash Movahedi, Hans Joachim Räder, Sophie Hernot, Pol Besenius, Jo A. Van Ginderachter, Lutz Nuhn
Abstract
Abstract Tumor‐associated macrophages (TAMs) promote the immune suppressive microenvironment inside tumors and are, therefore, considered as a promising target for the next generation of cancer immunotherapies. To repolarize their phenotype into a tumoricidal state, the Toll‐like receptor 7/8 agonist imidazoquinoline IMDQ is site‐specifically and quantitatively coupled to single chain antibody fragments, so‐called nanobodies, targeting the macrophage mannose receptor (MMR) on TAMs. Intravenous injection of these conjugates result in a tumor‐ and cell‐specific delivery of IMDQ into MMR high TAMs, causing a significant decline in tumor growth. This is accompanied by a repolarization of TAMs towards a pro‐inflammatory phenotype and an increase in anti‐tumor T cell responses. Therefore, the therapeutic benefit of such nanobody‐drug conjugates may pave the road towards effective macrophage re‐educating cancer immunotherapies.