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Radionuclide Therapy of HER2-Expressing Human Xenografts Using Affibody-Based Peptide Nucleic Acid-Mediated Pretargeting: In Vivo Proof of Principle
KTH, School of Engineering Sciences in Chemistry, Biotechnology and Health (CBH), Protein Science, Protein Engineering.ORCID iD: 0000-0003-4334-9360
Uppsala Univ, Dept Immunol Genet & Pathol, SE-75181 Uppsala, Sweden..
Uppsala Univ, Div Mol Imaging, Dept Med Chem, Uppsala, Sweden..
Erasmus MC, Dept Radiol & Nucl Med, Rotterdam, Netherlands..
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2018 (English)In: Journal of Nuclear Medicine, ISSN 0161-5505, E-ISSN 1535-5667, Vol. 59, no 7, p. 1092-1098Article in journal (Refereed) Published
Abstract [en]

Affibody molecules are small proteins engineered using a nonanti-body 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 (Z(HER2:342)-SR-HP1) was used as the primary pretargeting agent. A complementary AGTCGTGATGTAGTC PNA conjugated to the chelator DOTA and labeled with the radionuclide Lu-177 (Lu-177-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 mu g (0.65 nmol) of Lu-177-HP2 was injected 16 h after injection of 100 mu g (7.7 nmol) of Z(HER2:342)-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 Z(HER2:342)-SR-HP1 only (37 d), the same amount and activity of Lu-177-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.

Place, publisher, year, edition, pages
SOC NUCLEAR MEDICINE INC , 2018. Vol. 59, no 7, p. 1092-1098
Keywords [en]
pretargeting, PNA, affibody molecules, radionuclide therapy, HER2
National Category
Radiology, Nuclear Medicine and Medical Imaging
Identifiers
URN: urn:nbn:se:kth:diva-232408DOI: 10.2967/jnumed.118.208348ISI: 000437237200028PubMedID: 29439013Scopus ID: 2-s2.0-85049158654OAI: oai:DiVA.org:kth-232408DiVA, id: diva2:1235609
Note

QC 20180726

Available from: 2018-07-26 Created: 2018-07-26 Last updated: 2018-07-26Bibliographically approved

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Westerlund, KristinaEriksson Karlström, Amelie

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