Abstract
Radioimmunotherapy of solid tumors using antibody-targeted radionuclides has been limited by low therapeutic indices (TI). We recently reported a novel three-step pretargeted radioimmunotherapy (PRIT) strategy based on a glycoprotein A33 (GPA33)-targeting bispecific antibody (bsAb) and a small-molecule radioactive hapten, a complex of lutetium-177 (177Lu) and S-2-(4-aminobenzyl)-1,4,7,10-tetraazacyclododecane tetraacetic acid (177Lu-DOTA-Bn) that leads to high TIs for radiosensitive tissues such as blood (TI = 73) and kidney (TI = 12). We tested our hypothesis that a fractionated anti-GPA33 DOTA-PRIT treatment regimen calibrated to deliver a radiation-absorbed dose to tumor >100 Gy would lead to a high probability of tumor cure while being well tolerated by nude mice bearing subcutaneous GPA33-postitive SW1222 xenografts. Methods: We treated groups of nude mice bearing 7-day-old SW1222 xenografts with a fractionated three-cycle anti-GPA33 DOTA-PRIT treatment regimen (total administered 177Lu-DOTA-Bn activity: 167 MBq/mouse; estimated radiation-absorbed dose to tumor: 110 Gy). In randomly selected mice undergoing treatment, serial single-photon emission computed tomography/computed tomography (SPECT/CT) imaging was used to monitor treatment response and calculate radiation-absorbed doses to tumor. Necropsy was done on surviving animals 100-200 days post-treatment to determine frequency of cure and assess select normal tissues for treatment-related histopathologies. Results: Rapid exponential tumor progression was observed in control treatment groups (i.e., no treatment or 177Lu-DOTA-Bn only), leading to euthanasia due to excessive tumor burden, while 10/10 complete responses were observed for the DOTA-PRIT treated animals within 30 days. Treatment was well tolerated and 100% histologic cure in 9/9 assessable animals without detectable radiation damage to critical organs, including bone marrow and kidney. Radiation-absorbed doses to tumor derived from SPECT/CT (102 Gy) and from biodistribution (110 Gy) agreed to within 6.9%. Of the total dose of ~100 Gy, the first dose contributes 30%, the second dose 60%, and the third dose 10%. Conclusion: In a GPA33-positive human colorectal cancer (CRC) xenograft mouse model, we validated a SPECT/CT-based theranostic PRIT regimen that led to 100% complete responses and 100% cures without any treatment-related toxicities, based on high TIs for radiosensitive tissues. These studies support the view that anti-GPA33 DOTA-PRIT will be a potent radioimmunotherapy regimen for GPA33-positive CRC tumors in man.
- Copyright © 2017 by the Society of Nuclear Medicine and Molecular Imaging, Inc.