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Comparative In Vivo Evaluation of Technetium and Iodine Labels on an Anti-HER2 Affibody for Single-Photon Imaging of HER2 Expression in Tumors

¹ Affibody AB, Bromma, Sweden; ² Unit of Biomedical Radiation Sciences, Department of Oncology, Radiology, and Clinical Immunology, Rudbeck Laboratory, Uppsala University, Uppsala, Sweden; ³ Department of Biotechnology, AlbaNova University Center, Royal Institute of Technology (KTH), Stockholm, Sweden; and ⁴ Section of Hospital Physics, Department of Oncology, Uppsala University Hospital, Uppsala, Sweden

Correspondence: For correspondence or reprints contact: Vladimir Tolmachev, PhD, Unit of Biomedical Radiation Sciences, Rudbeck Laboratory, 751 85 Uppsala, Sweden. E-mail: valdimir.tolmachev{at}bms.uu.se

In vivo diagnosis with cancer-specific targeting agents that have optimal characteristics for imaging is an important development in treatment planning for cancer patients. Overexpression of the HER2 antigen is high in several types of carcinomas and has predictive and prognostic value, especially for breast cancer. A new type of targeting agent, the Affibody molecule, was described recently. An Affibody dimer, His₆-(Z_HER2:4)₂ (15.4 kDa), binds to HER2 with an affinity of 3 nmol/L and might be used for the imaging of HER2 expression. The use of ^99mTc might improve the availability of the labeled conjugate, and Tc(I)-carbonyl chemistry enables the site-specific labeling of the histidine tag on the Affibody molecule. The goals of the present study were to prepare ^99mTc-labeled His₆-(Z_HER2:4)₂ and to evaluate its targeting properties compared with the targeting properties of ¹²⁵I-4-iodobenzoate-His₆-(Z_HER2:4)₂ [¹²⁵I-His₆-(Z_HER2:4)₂]. Methods: The labeling of His₆-(Z_HER2:4)₂ with ^99mTc was performed with an IsoLink kit. The specificity of ^99mTc-His₆-(Z_HER2:4)₂ binding to HER2 was evaluated in vitro with SK-OV-3 ovarian carcinoma cells. The comparative biodistributions of ^99mTc-His₆-(Z_HER2:4)₂ and ¹²⁵I-His₆-(Z_HER2:4)₂ in tumor-bearing BALB/c nu/nu mice were determined. Results: The labeling yield for ^99mTc-His₆-(Z_HER2:4)₂ was 60% (50°C), and the radiochemical purity was greater than 97%. The conjugate was stable during storage and under histidine and cysteine challenges and demonstrated receptor-specific binding. The biodistribution study demonstrated tumor-specific uptake levels (percentage injected activity per gram of tissue [%IA/g]) of 2.6 %IA/g for ^99mTc-His₆-(Z_HER2:4)₂ and 2.3 %IA/g for ¹²⁵I-His₆-(Z_HER2:4)₂ at 4 h after injection. Both conjugates provided clear imaging of SK-OV-3 xenografts at 6 h after injection. The tumor-to-nontumor ratios were much more favorable for the radioiodinated Affibody. Conclusion: The use of Tc(I)-carbonyl chemistry enabled us to prepare a stable, site-specifically labeled ^99mTc-His₆-(Z_HER2:4)₂ conjugate that was able to bind to HER2-expressing cells in vitro and in vivo. The indirectly radioiodinated conjugate provided better tumor-to-liver ratios. The labeling of Affibody molecules with ^99mTc should be investigated further.

Key Words: Affibody • HER2 • Tc(I)-carbonyl chemistry • indirect iodination • tumor targeting

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