IL13RA2 targeted alpha particle therapy against glioblastomas

// Anirudh Sattiraju 1, 2, * , Kiran Kumar Solingapuram Sai 1, 2, * , Ang Xuan 4, * , Darpan N. Pandya 2 , Frankis G. Almaguel 1 , Thaddeus J. Wadas 1, 3 , Denise M. Herpai 2, 3 , Waldemar Debinski 2, 3 and Akiva Mintz 1, 2 1 Department of Radiology, Wake Forest School of Medicine, Winston-Salem, NC 27157, USA 2 Brain Tumor Center of Excellence, Wake Forest University Comprehensive Cancer Center, Winston-Salem, NC 27157, USA 3 Department of Cancer Biology, Wake Forest School of Medicine, Winston-Salem, NC 27157, USA 4 Department of Nuclear Medicine and Radiology, The People’s Hospital of Zhengzhou University, Zhengzhou, Henan 450003, China * These authors contributed equally to this work Correspondence to: Akiva Mintz, email: amintz@wakehealth.edu Keywords: glioblastoma, IL13RA2, alpha particle therapy, Actinium-225, Copper-64 Received: January 10, 2017 Accepted: April 15, 2017 Published: May 11, 2017 ABSTRACT Glioblastoma (GBM) is the most aggressive primary malignant brain cancer that invariably results in a dismal prognosis. Chemotherapy and radiotherapy have not been completely effective as standard treatment options for patients due to recurrent disease. We and others have therefore developed molecular strategies to specifically target interleukin 13 receptor alpha 2 (IL13RA2), a GBM restricted receptor expressed abundantly on over 75% of GBM patients. In this work, we evaluated the potential of Pep-1L, a novel IL13RA2 targeted peptide, as a platform to deliver targeted lethal therapies to GBM. To demonstrate GBM-specificity, we radiolabeled Pep-1L with Copper-64 and performed in vitro cell binding studies, which demonstrated specific binding that was blocked by unlabeled Pep-1L. Furthermore, we demonstrated real-time GBM localization of [ 64 Cu]Pep-1L to orthotopic GBMs using small animal PET imaging. Based on these targeting data, we performed an initial in vivo safety and therapeutic study using Pep-1L conjugated to Actinium-225, an alpha particle emitter that has been shown to potently and irreversibly kill targeted cells. We infused [ 225 Ac]Pep-1L into orthotopic GBMs using convection-enhanced delivery and found no significant adverse events at injected doses. Furthermore, our initial data also demonstrated significantly greater overall, median and mean survival in treated mice when compared to those in control groups ( p < 0.05). GBM tissue extracted from mice treated with [ 225 Ac]Pep-1L showed double stranded DNA breaks, lower Ki67 expression and greater propidium iodide internalization, indicating anti-GBM therapeutic effects of [ 225 Ac]Pep-1L. Based on our results, Pep-1L warrants further investigation as a potential targeted platform to deliver anti-cancer agents.