RT Journal Article
SR Electronic
T1 Targeting of HER2-Expressing Tumors with a Site-Specifically <sup>99m</sup>Tc-Labeled Recombinant Affibody Molecule, Z<sub>HER2:2395</sub>, with C-Terminally Engineered Cysteine
JF Journal of Nuclear Medicine
JO J Nucl Med
FD Society of Nuclear Medicine
SP 781
OP 789
DO 10.2967/jnumed.108.056929
VO 50
IS 5
A1 Ahlgren, Sara
A1 Wållberg, Helena
A1 Tran, Thuy A.
A1 Widström, Charles
A1 Hjertman, Magnus
A1 Abrahmsén, Lars
A1 Berndorff, Dietmar
A1 Dinkelborg, Ludger M.
A1 Cyr, John E.
A1 Feldwisch, Joachim
A1 Orlova, Anna
A1 Tolmachev, Vladimir
YR 2009
UL http://jnm.snmjournals.org/content/50/5/781.abstract
AB The detection of human epidermal growth factor receptor type 2 (HER2) expression in malignant tumors provides important information influencing patient management. Radionuclide in vivo imaging of HER2 may permit the detection of HER2 in both primary tumors and metastases by a single noninvasive procedure. Small (7 kDa) high-affinity anti-HER2 Affibody molecules may be suitable tracers for SPECT visualization of HER2-expressing tumors. The use of generator-produced 99mTc as a label would facilitate the prompt translation of anti-HER2 Affibody molecules into use in clinics. Methods: A C-terminal cysteine was introduced into the Affibody molecule ZHER2:342 to enable site-specific labeling with 99mTc. Two recombinant variants, His6-ZHER2:342-Cys (dissociation constant [KD], 29 pM) and ZHER2:2395-Cys, lacking a His tag (KD, 27 pM), were labeled with 99mTc in yields exceeding 90%. The binding specificity and the cellular processing of Affibody molecules were studied in vitro. Biodistribution and γ-camera imaging studies were performed in mice bearing HER2-expressing xenografts. Results: 99mTc-His6-ZHER2:342-Cys was capable of targeting HER2-expressing SKOV-3 xenografts in SCID mice, but the liver radioactivity uptake was high. A series of comparative biodistribution experiments indicated that the presence of the His tag caused elevated accumulation in the liver. 99mTc-ZHER2:2395-Cys, not containing a His tag, showed low uptake in the liver and high and specific uptake in HER2-expressing xenografts. Four hours after injection, the radioactivity uptake values (percentage of injected activity per gram of tissue [%IA/g]) were 6.9 ± 2.5 (mean ± SD) %IA/g in LS174T xenografts (moderate level of HER2 expression) and 15 ± 3 %IA/g in SKOV-3 xenografts (high level of HER2 expression). The corresponding tumor-to-blood ratios were 88 ± 24 and 121 ± 24, respectively. Both LS174T and SKOV-3 xenografts were clearly visualized with a clinical γ-camera 1 h after injection of 99mTc-ZHER2:2395-Cys. Conclusion: The Affibody molecule 99mTc-ZHER2:2395-Cys is a promising tracer for SPECT visualization of HER2-expressing tumors.