Radionuclide Therapy of HER2-Expressing Human Xenografts Using Affibody-Based Peptide Nucleic Acid-Mediated Pretargeting: In Vivo Proof of Principle.

Abstract

Affibody molecules are small proteins engineered using a nonantibody scaffold. Radiolabeled Affibody molecules are excellent imaging probes, but their application to radionuclide therapy has been 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 human epidermal growth factor receptor 2 (HER2)-expressing cancer extends survival without accompanying renal toxicity. Methods: A HER2-targeting Affibody molecule ligated with an 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 6 cycles separated by 7 d. Results: Optimal tumor targeting was achieved when 16 MBq/3.5 μg (0.65 nmol) of 177Lu-HP2 was injected 16 h after injection of 100 μg (7.7 nmol) of ZHER2:342-SR-HP1. The calculated absorbed dose to tumors was 1,075 mGy/MBq, whereas the absorbed dose to kidneys was 206 mGy/MBq and the absorbed dose to blood (surrogate of bone marrow) was 4 mGy/MBq. Survival of mice was significantly longer (P < 0.05) in the treatment group (66 d) than in the 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 phosphate-buffered saline (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.

• Authors: Kristina Westerlund, Mohamed Altai, Bogdan Mitran, Mark Konijnenberg, Maryam Oroujeni, Christina Atterby, Marion de Jong, Anna Orlova, Johanna Mattsson, Patrick Micke, Amelie Eriksson Karlström, Vladimir Tolmachev
• Journal: Journal of nuclear medicine : official publication, Society of Nuclear Medicine (J Nucl Med) Vol. 59 Issue 7 Pg. 1092-1098 (07 2018) ISSN: 1535-5667 [Electronic] United States
• PMID: 29439013 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2018 by the Society of Nuclear Medicine and Molecular Imaging.

Chemical References

• Peptide Nucleic Acids
• Proteins
• Recombinant Fusion Proteins
• ERBB2 protein, human
• Receptor, ErbB-2

Topics

• Animals
• Base Sequence
• Cell Line, Tumor
• Cell Transformation, Neoplastic
• Female
• Gene Expression Regulation, Neoplastic
• Humans
• Kidney (radiation effects)
• Mice
• Ovarian Neoplasms (metabolism, pathology, radiotherapy)
• Peptide Nucleic Acids (genetics, metabolism)
• Proteins (metabolism)
• Radiometry
• Receptor, ErbB-2 (metabolism)
• Recombinant Fusion Proteins (metabolism, pharmacokinetics)
• Survival Analysis
• Tissue Distribution