Signal-regulatory protein α (SIRPα) expressed by myeloid cells is of particular interest for therapeutic strategies targeting the interaction between SIRPα and the "don't eat me" ligand CD47 and as a marker to monitor macrophage infiltration into tumor lesions. To address both approaches, we developed a set of novel human SIRPα (hSIRPα)-specific nanobodies (Nbs). We identified high-affinity Nbs targeting the hSIRPα/hCD47 interface, thereby enhancing antibody-dependent cellular phagocytosis. For non-invasive in vivo imaging, we chose S36 Nb as a non-modulating binder. By quantitative positron emission tomography in novel hSIRPα/hCD47 knock-in mice, we demonstrated the applicability of 64Cu-hSIRPα-S36 Nb to visualize tumor infiltration of myeloid cells. We envision that the hSIRPα-Nbs presented in this study have potential as versatile theranostic probes, including novel myeloid-specific checkpoint inhibitors for combinatorial treatment approaches and for in vivo stratification and monitoring of individual responses during cancer immunotherapies.
Keywords: PET imaging tracer; SIRPalpha; immune checkpoint inhibitor (ICI); myeloid cells; nanobodies (Nbs); theranostics.
Copyright © 2023 Wagner, Blaess, Leske, Frecot, Gramlich, Traenkle, Kaiser, Seyfried, Maier, Rezza, Sônego, Thiam, Pezzana, Zeck, Gouttefangeas, Scholz, Nueske, Maurer, Kneilling, Pichler, Sonanini and Rothbauer.