AUTHOR=Wagner Teresa R. , Blaess Simone , Leske Inga B. , Frecot Desiree I. , Gramlich Marius , Traenkle Bjoern , Kaiser Philipp D. , Seyfried Dominik , Maier Sandra , Rezza Amélie , Sônego Fabiane , Thiam Kader , Pezzana Stefania , Zeck Anne , Gouttefangeas Cécile , Scholz Armin M. , Nueske Stefan , Maurer Andreas , Kneilling Manfred , Pichler Bernd J. , Sonanini Dominik , Rothbauer Ulrich TITLE=Two birds with one stone: human SIRPα nanobodies for functional modulation and in vivo imaging of myeloid cells JOURNAL=Frontiers in Immunology VOLUME=14 YEAR=2023 URL=https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2023.1264179 DOI=10.3389/fimmu.2023.1264179 ISSN=1664-3224 ABSTRACT=

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.