AUTHOR=Waaijer Stijn J. H. , Suurs Frans V. , Hau Cheei-Sing , Vrijland Kim , de Visser Karin E. , de Groot Derk Jan A. , de Vries Elisabeth G. E. , Lub-de Hooge Marjolijn N. , Schröder Carolina P. 

TITLE=Radiolabeled Monoclonal Antibody Against Colony-Stimulating Factor 1 Receptor Specifically Distributes to the Spleen and Liver in Immunocompetent Mice

JOURNAL=Frontiers in Oncology

VOLUME=11

YEAR=2021

URL=https://www.frontiersin.org/journals/oncology/articles/10.3389/fonc.2021.786191

DOI=10.3389/fonc.2021.786191

ISSN=2234-943X

ABSTRACT=<p>Macrophages can promote tumor development. Preclinically, targeting macrophages by colony-stimulating factor 1 (CSF1)/CSF1 receptor (CSF1R) monoclonal antibodies (mAbs) enhances conventional therapeutics in combination treatments. The physiological distribution and tumor uptake of CSF1R mAbs are unknown. Therefore, we radiolabeled a murine CSF1R mAb and preclinically visualized its biodistribution by PET. CSF1R mAb was conjugated to <italic>N</italic>-succinyl-desferrioxamine (<italic>N</italic>-suc-DFO) and subsequently radiolabeled with zirconium-89 (<sup>89</sup>Zr). Optimal protein antibody dose was first determined in non-tumor-bearing mice to assess physiological distribution. Next, biodistribution of optimal protein dose and <sup>89</sup>Zr-labeled isotype control was compared with PET and <italic>ex vivo</italic> biodistribution after 24 and 72 h in mammary tumor-bearing mice. Tissue autoradiography and immunohistochemistry determined radioactivity distribution and tissue macrophage presence, respectively. [<sup>89</sup>Zr]Zr-DFO-<italic>N</italic>-suc-CSF1R-mAb optimal protein dose was 10 mg/kg, with blood pool levels of 10 ± 2% injected dose per gram tissue (ID/g) and spleen and liver uptake of 17 ± 4 and 11 ± 4%ID/g at 72 h. In contrast, 0.4 mg/kg of [<sup>89</sup>Zr]Zr-DFO-<italic>N</italic>-suc-CSF1R mAb was eliminated from circulation within 24 h; spleen and liver uptake was 126 ± 44% and 34 ± 7%ID/g, respectively. Tumor-bearing mice showed higher uptake of [<sup>89</sup>Zr]Zr-DFO-<italic>N</italic>-suc-CSF1R-mAb in the liver, lymphoid tissues, duodenum, and ileum, but not in the tumor than did <sup>89</sup>Zr-labeled control at 72 h. Immunohistochemistry and autoradiography showed that <sup>89</sup>Zr was localized to macrophages within lymphoid tissues. Following [<sup>89</sup>Zr]Zr-DFO-<italic>N</italic>-suc-CSF1R-mAb administration, tumor macrophages were almost absent, whereas isotype-group tumors contained over 500 cells/mm<sup>2</sup>. We hypothesize that intratumoral macrophage depletion by [<sup>89</sup>Zr]Zr-DFO-<italic>N</italic>-suc-CSF1R-mAb precluded tumor uptake higher than <sup>89</sup>Zr-labeled control. Translation of molecular imaging of macrophage-targeting therapeutics to humans may support macrophage-directed therapeutic development.</p>