Tumor Immune Cell Targeting Chimeras (TICTACs) For Targeted Depletion of Macrophage-Associated Checkpoint Receptors

Abstract

Immune cells in the tumor microenvironment are not only powerful regulators of immunosuppression and tumorigenesis, but also represent a dominant cell type, with tumor-associated macrophages (TAMs) comprising up to 50% of total cell mass in solid tumors. Immunotherapies such as immune checkpoint inhibitors (ICIs) derive their efficacy from this cancer-immune cell interface, however, immune-related adverse events resulting from systemic blockade remain a significant challenge. To address this need for potent, yet highly tumor-specific immunotherapies, we developed Tumor-Immune Cell Targeting Chimeras (TICTACs), antibody conjugates that are capable of selectively depleting immune checkpoint receptors such as SIRPα from the surface of TAMs. These chimeric molecules consist of a synthetic glycan ligand that binds the C-type lectin CD206, a well-established TAM marker, conjugated to a non-blocking antibody that binds but does not inhibit the checkpoint receptor. By engaging CD206, which constitutively recycles between the plasma membrane and early endosomes, TICTACs facilitate robust removal of the checkpoint receptors from the surface of CD206highmacrophages, while having no effect on CD206lowmacrophages. By decoupling antibody selectivity from its blocking function, we present a new paradigm for developing highly tumor-specific immunotherapies.