SureTAC Technology to Harness IGSF11 as a Treatment Target for Diffuse Midline Glioma

Diffuse midline glioma (DMG) is a highly aggressive, lethal brain tumor in children. Currently, we lack effective treatment options for these patients, resulting in a life expectancy of less than 2 years after diagnosis. To identify new immunotherapy treatment angles, we profiled both the tumor and its interaction with the immune system in DMG patient samples, considering the spatial organization of the tumor. This revealed specific tumor areas that interacted with microglia, the resident immune cells of the brain. Moreover, we could identify molecules involved in this interaction. IGSF11 expressed by tumor cells in these areas interacted with VISTA on microglia. When tumor cells were genetically altered to remove IGSF11, this induced tumor control by microglia, resulting in 100% survival in mouse models of DMG. This demonstrates that IGSF11 expressed by DMG tumors acts as an inhibitory molecule. It allows tumor cells to hide from the immune system and prevent microglia from attacking. Here, we propose to abrogate this immune evasion mechanism for the treatment of DMG, by developing SureTAC antibodies. These antibodies will bind to IGSF11 and an E3 ligase, bringing the two into close proximity. This will instruct the tumor cell’s own machinery to degrade IGSF11. We will test whether this leads to tumor control in the lab by using both human and mouse models of DMG. If successful, this might offer a new treatment option for DMG depending on the brain-resident immune compartment. These microglia might be better adapt to navigate this delicate brain environment compared to other cellular immunotherapies. Therefore, we hope that this treatment will not only be effective in controlling the tumor, but also safe with few side effects.