Abstract
Affibody molecules are small proteins engineered using a non-antibody scaffold. Radiolabeled affibody molecules are excellent imaging probes, but their application for radionuclide therapy was so far prevented by high renal reabsorption. The aim of this study was to test the hypothesis that affibody-based peptide nucleic acid (PNA)-mediated pretargeted therapy of HER2-expressing cancer extends survival without accompanying renal toxicity. Methods: Human epidermal growth factor (HER2)-targeting affibody molecule ligated with AGTCGTGATGTAGTC PNA hybridization probe (ZHER2:342-SR-HP1) was used as the primary pretargeting agent. A complementary AGTCGTGATGTAGTC PNA conjugated to the chelator DOTA and labeled with the radionuclide 177Lu (177Lu-HP2) was used as the secondary agent. The influence of different factors on pretargeting was investigated. Experimental radionuclide therapy in mice bearing SKOV-3 xenografts was performed in six cycles separated by 7 days. Results: Optimal tumor targeting was achieved when 16 MBq/3.5 µg (0.65 nmol) 177Lu-HP2 was injected 16 h after injection of 100 µg (7.7 nmol) ZHER2:342-SR-HP1. The calculated absorbed dose to tumor was 1076 mGy/MBq, while the absorbed dose to the kidneys was 206 mGy/MBq and the absorbed dose to blood (surrogate of bone marrow) was 4 mGy/MBq. Survival of mice in the treatment group (66 d) was significantly (p<0.05) longer than survival of mice in control groups treated with the same amount of ZHER2:342-SR-HP1 only (37 d), the same amount and activity of 177Lu-HP2 only (32 d), or PBS (37 d). Conclusion: The studied pretargeting system can deliver an absorbed dose to tumors appreciably exceeding absorbed doses to critical organs, making affibody-based PNA-mediated pretargeted radionuclide therapy highly attractive.
- Oncology: General
- Peptides
- Radionuclide Therapy
- Radiopharmaceuticals
- HER2
- PNA
- affibody molecules
- pretargeting
- radionuclide therapy
- Copyright © 2018 by the Society of Nuclear Medicine and Molecular Imaging, Inc.