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Development and characterization of clinical-grade 89Zr-trastuzumab for HER2/neu immunoPET imaging.

Journal of nuclear medicine : official publication, Society of Nuclear Medicine (2009-05-16)
Eli C F Dijkers, Jos G W Kosterink, Anna P Rademaker, Lars R Perk, Guus A M S van Dongen, Joost Bart, Johan R de Jong, Elisabeth G E de Vries, Marjolijn N Lub-de Hooge
ABSTRACT

The anti-human epidermal growth factor receptor 2 (HER2/neu) antibody trastuzumab is administered to patients with HER2/neu-overexpressing breast cancer. Whole-body noninvasive HER2/neu scintigraphy could help to assess and quantify the HER2/neu expression of all lesions, including nonaccessible metastases. The aims of this study were to develop clinical-grade radiolabeled trastuzumab for clinical HER2/neu immunoPET scintigraphy, to improve diagnostic imaging, to guide antibody-based therapy, and to support early antibody development. The PET radiopharmaceutical (89)Zr-trastuzumab was compared with the SPECT tracer (111)In-trastuzumab, which we have tested in the clinic already. Trastuzumab was labeled with (89)Zr and (for comparison) with (111)In. The minimal dose of trastuzumab required for optimal small-animal PET imaging and biodistribution was determined with human HER2/neu-positive or -negative tumor xenograft-bearing mice. Trastuzumab was efficiently radiolabeled with (89)Zr at a high radiochemical purity and specific activity. The antigen-binding capacity was preserved, and the radiopharmaceutical proved to be stable for up to 7 d in solvent and human serum. Of the tested protein doses, the minimal dose of trastuzumab (100 microg) proved to be optimal for imaging. The comparative biodistribution study showed a higher level of (89)Zr-trastuzumab in HER2/neu-positive tumors than in HER2/neu-negative tumors, especially at day 6 (33.4 +/- 7.6 [mean +/- SEM] vs. 7.1 +/- 0.7 percentage injected dose per gram of tissue). There were good correlations between the small-animal PET images and the biodistribution data and between (89)Zr-trastuzumab and (111)In-trastuzumab uptake in tumors (R(2) = 0.972). Clinical-grade (89)Zr-trastuzumab showed high and HER2/neu-specific tumor uptake at a good resolution.

MATERIALS
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Product Description

Sigma-Aldrich
Monoclonal Anti-Human IgG (Fc specific)−FITC antibody produced in mouse, clone HP-6017, purified immunoglobulin, buffered aqueous solution

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