Biodistribution and pharmacokinetics of [89Zr]-anti-VEGF mAbs using PET in glioblastoma rat models

• Published in: International journal of pharmaceutics Vol. 652; p. 123795
• Main Authors: García-Varela, Lara, Codesido, Jessica, Perez-Pedrosa, Alberto, Muñoz-González, María, Ramos-Docampo, Emma, Rey-Bretal, David, García-Otero, Xurxo, Gómez-Lado, Noemí, Turrero, Angela, Beiroa, Daniel, Rodríguez-Perez, Ana Isabel, Vidal, Anxo, Fernández-Ferreiro, Anxo, Pubul, Virginia, Aguiar, Pablo
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 05.03.2024
• Subjects: Animals; Antibodies, Monoclonal; Anti–Vascular Endothelial Growth Factor therapy; Bevacizumab; Blood-Brain-Barrier; Cell Line, Tumor; Deferoxamine; Glioblastoma - diagnostic imaging; Glioblastoma - drug therapy; Glioblastomas; Neuro-oncology; Positron Emission Tomography; Positron-Emission Tomography - methods; Rats; Tissue Distribution; Vascular Endothelial Growth Factor A; Zirconium; Blood-Brain-Barrier; Neuro-oncology; Glioblastomas; Anti–Vascular Endothelial Growth Factor therapy; Positron Emission Tomography
• ISSN: 0378-5173; 1873-3476
• DOI: 10.1016/j.ijpharm.2024.123795

[Display omitted] •Aflibercept showed a faster blood clearance compared to bevacizumab.•Tumors were earlier targeted by bevacizumab compared to aflibercept.•Bevacizumab tumor uptake was significantly higher than aflibercept uptake.•Our data supports the limited effectiveness of aflibercept compared to bevacizumab.•PET imaging allows to study the in vivo biodistribution of novel immunotherapies. Glioblastomas present intensive angiogenesis, thus anti–Vascular Endothelial Growth Factor (VEGF) antibodies (mAbs) have been proposed as promising therapies. However, the results of clinical trials reported moderate toxicity and limited effectiveness. This study evaluates the in vivo pharmacokinetics and biodistribution of these mAbs in a growing model of glioblastoma in rats using Positron Emission Tomography (PET). &Methods: mAbs were radiolabeled with zirconium-89. Four days after the model induction, animals were injected with 2.33 ± 1.3 MBq of [89Zr]-DFO-bevacizumab (n = 8) or 2.35 ± 0.26 MBq of [89Zr]-DFO-aflibercept (n = 6). PETs were performed at 0H, 48H, 168H, 240H, and 336H post-injection. Tumor induction was confirmed using [18F]-Fluorodeoxyglucose-PET and immunohistochemistry. Radiotracer uptake was estimated in all pre-defined Volumes-of-Interest. Anti-VEGF mAbs showed 100 % Radiochemical-Purity. [89Zr]-DFO-bevacizumab showed a significantly higher bioavailability in whole-blood. A significant increase in the tumor uptake was detectable at 168H PET with [89Zr]-DFO-bevacizumab meanwhile with [89Zr]-DFO-aflibercept it was only detectable at 336H. [89Zr]-DFO-bevacizumab tumor uptake was significantly higher than that of [89Zr]-DFO-aflibercept in all the scans. Tumor induction was confirmed in all animal models. MAbs detect VEGF-expression in glioblastoma models. Tumors were earlier targeted by Bevacizumab. The lower blood availability of aflibercept resulted in a lower tumor uptake than bevacizumab in all the scans.