Abstract
Rationale: Glioblastoma (GBM) is characterized by an aggressive and aberrant vascular network that promotes tumor progression and hinders effective treatment; the median survival is 16 months despite standard-of-care therapies. There is a need to improve therapeutic options for this disease. We hypothesized that antibody targeting of the vascular endothelium (VE) of glioblastoma with cytotoxic short-range, high-energy alpha particles would be an effective therapeutic approach. Methods: E4G10, an antibody directed at an epitope of monomeric VE cadherin, is expressed in tumor neovasculature and on endothelial progenitor cells in the bone marrow. E4G10 was labeled with alpha particle emitting 225Actinium (225Ac). Pharmacokinetic studies investigated the tissue distribution and blood clearance of the 225Ac-E4G10 radioimmunoconstruct in a transgenic XFM mouse model of high-grade glioblastoma. Histological analysis was used to demonstrate local therapeutic effects in treated brain tumor sections. Radioimmunotherapy with 225Ac-E4G10 was performed in XFM mice to assess overall survival alone and in combination with temozolomide, the standard-of-care chemotherapeutic agent. Results: 225Ac-E4G10 was found to accumulate in tissues expressing the target antigen. Anti-vascular alpha-particle therapy of glioblastoma in the transgenic XFM model resulted in significantly improved survival compared to controls and potent control of tumor growth. Adding the chemotherapeutic temozolomide to the treatment increased survival to 30 days (versus 9 days for vehicle treated animals). Histological analyses showed a remodeled GBM vascular microenvironment. Conclusion: Targeted alpha-particle anti-vascular therapy is shown for the first time to be effective in increasing overall survival in a solid tumor in a clinically relevant transgenic GBM mouse model.
- Monoclonal Antibodies
- Radionuclide Therapy
- Vascular
- Actinium-225 (225Ac)
- Glioblastoma multiforme (GBM)
- Radioimmunotherapy (RIT)
- Vascular endothelium (VE)
- Copyright © 2016 by the Society of Nuclear Medicine and Molecular Imaging, Inc.