ImmunoPET imaging-based pharmacokinetic profiles of an antibody and its Fab targeting endothelin A receptors on glioblastoma stem cells in a preclinical orthotopic model

The resistance of glioblastoma stem cells (GSCs) to treatment is one of the causes of glioblastoma (GBM) recurrence. Endothelin A receptor (ET${}_A$) overexpression in GSCs constitutes an attractive biomarker for targeting this cell subpopulation, as illustrated by several clinical trials evaluating the therapeutic efficacy of endothelin receptor antagonists against GBM. In this context, we have designed an immunoPET radioligand combining the chimeric antibody targeting ET${}_A$, chimeric-Rendomab A63 (xiRA63), with ${}^{89}$Zr isotope and evaluated the abilities of xiRA63 and its Fab (ThioFab-xiRA63) to detect ET${}_A$${}^{+}$ tumors in a mouse model xenografted orthotopically with patient-derived Gli7 GSCs. Radioligands were intravenously injected and imaged over time by µPET-CT imaging. Tissue biodistribution and pharmacokinetic parameters were analyzed, highlighting the ability of [${}^{89}$Zr]Zr-xiRA63 to pass across the brain tumor barrier and achieve better tumor uptake than [${}^{89}$Zr]Zr-ThioFab-xiRA63. This study shows the high potential of [${}^{89}$Zr]Zr-xiRA63 in specifically targeting ET${}_A$${}^{+}$ tumors, thus raising the possibility of detecting and treating ET${}_A$${}^{+}$ GSCs, which could improve the management of GBM patients.