Two birds with one stone: human SIRPα nanobodies for functional modulation and in vivo imaging of myeloid cells

Wagner, T. R.; Blaess, S.; Leske, I.; Frecot, D. I.; Gramlich, M.; Traenkle, B.; Kaiser, P. D.; Seyfried, D.; Maier, S.; Rezza, A.; Sonego, F.; Thiam, K.; Pezzana, S.; Zeck, A.; Gouttefangeas, C.; Scholz, A. M.; Nueske, S.; Maurer, A.; Kneilling, M.; Pichler, B. J.; Sonanini, D.; Rothbauer, U.

doi:10.1101/2023.06.27.546763

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bioRxiv · 10.1101/2023.06.27.546763

Two birds with one stone: human SIRPα nanobodies for functional modulation and in vivo imaging of myeloid cells

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Abstract

Signal-regulatory protein (SIRP) expressed by myeloid cells is of particular interest for therapeutic strategies targeting the interaction between SIRP and the "dont 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 SIRP (hSIRP)-specific nanobodies (Nbs). We identified three high-affinity Nbs targeting the hSIRP/hCD47 interface, thereby enhancing antibody-dependent cellular phagocytosis (ADCP). For non-invasive in vivo imaging, we chose S36 Nb as a non-modulating binder. By quantitative positron emission tomography (PET) in novel hSIRP/hCD47 knock-in (KI) mice, we demonstrated the applicability of 64Cu-hSIRP-S36 Nb to visualize tumor infiltration of myeloid cells. We envision that the hSIRP-Nbs presented in this study have potential as versatile probes, including novel myeloid-specific checkpoint inhibitors for combinatorial treatment approaches and for in vivo stratification and monitoring of individual responses during cancer immunotherapies.

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Wagner, T. R., Blaess, S., Leske, I., Frecot, D. I., Gramlich, M., Traenkle, B., Kaiser, P. D., Seyfried, D., Maier, S., Rezza, A., Sonego, F., Thiam, K., Pezzana, S., Zeck, A., Gouttefangeas, C., Scholz, A. M., Nueske, S., Maurer, A., Kneilling, M., Pichler, B. J., Sonanini, D., Rothbauer, U.. 2023-06-29. Two birds with one stone: human SIRPα nanobodies for functional modulation and in vivo imaging of myeloid cells. https://doi.org/10.1101/2023.06.27.546763

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