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

Abstract

Background: 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 ⁸⁹Zr 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.

Results: Radioligands were intravenously injected and imaged over time by µPET-CT imaging. Tissue biodistribution and pharmacokinetic parameters were analyzed, highlighting the ability of [⁸⁹Zr]Zr-xiRA63 to pass across the brain tumor barrier and achieve better tumor uptake than [⁸⁹Zr]Zr-ThioFab-xiRA63.

Conclusions: This study shows the high potential of [⁸⁹Zr]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.

Keywords: Endothelin A (ETA); Glioblastoma; Pharmacokinetics; Positron emission tomography (PET).