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Evaluation of an anti-p185HER2 (scFv-CH2-CH3)2 fragment following radioiodination using two different residualizing labels: SGMIB and IB-Mal-d-GEEEK
- Source :
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Nuclear Medicine & Biology . Aug2009, Vol. 36 Issue 6, p671-680. 10p. - Publication Year :
- 2009
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Abstract
- Abstract: Introduction: A 105-kDa double mutant single-chain Fv-Fc fragment (scFv-Fc DM) derived from the anti-p185HER2 hu4D5v8 antibody (trastuzumab; Herceptin) has been described recently. The goal of this study was to investigate whether improved tumor targeting could be achieved with this fragment through the use of residualizing radioiodination methods. Methods: The scFv-Fc DM fragment was radioiodinated using N-succinimidyl 4-guanidinomethyl 3-[131I]iodobenzoate ([131I]SGMIB) and N ɛ-(3-[131I]iodobenzoyl)-Lys5-N α- maleimido-Gly1-GEEEK ([131I]IB-Mal-d-GEEEK), two residualizing radioiodination agents that have been used successfully with intact antibodies. Paired-label internalization assays of the labeled fragments were performed in vitro using MCF7 human breast cancer cells transfected to express HER2 (MCF7-HER2); comparisons were made to scFv-Fc DM directly radioiodinated using Iodogen. The tissue distribution of the scFv-Fc DM labeled with [125I]IB-Mal-d-GEEEK and [131I]SGMIB was compared in athymic mice bearing MCF7-HER2 xenografts. Results: The scFv-Fc DM fragment was labeled with [131I]SGMIB and [131I]IB-Mal-d-GEEEK in conjugation yields of 53% and 25%, respectively, with preservation of immunoreactivity for HER2. Internalization assays indicated that labeling via SGMIB resulted in a 1.6- to 3.5-fold higher (P<.05) retention of radioactivity, compared to that from the directly labeled fragment, in HER2-expressing cells during a 24-h observation period. Likewise, the amount of radioactivity retained in cells from the IB-Mal-d-GEEEK-labeled fragment was 1.4- to 3.3-fold higher (P<.05). Tumor uptake of radioiodine activity in athymic mice bearing MCF7-HER2 xenografts in vivo was significantly higher for the [125I]IB-Mal-d-GEEEK-labeled scFv-Fc DM fragment compared with that of the [131I]SGMIB-labeled fragment, particularly at later time points. The uptake of 125I was threefold (3.6±1.1 %ID/g vs. 1.2±0.4 %ID/g) and fourfold (3.1±1.7 %ID/g vs. 0.8±0.4 %ID/g) higher than that for 131I at 24 and 48 h, respectively. However, the [125I]IB-Mal-d-GEEEK-labeled scFv-Fc DM fragment also exhibited considerably higher levels of radioiodine activity in liver, spleen and kidney. Conclusions: The overall results further demonstrate the potential utility of these two prosthetic groups for the radiohalogenation of internalizing monoclonal antibodies and their fragments. Specifically, the trastuzumab-derived double mutant fragment in combination with these residualizing agents warrants further evaluation for imaging and possibly treatment of HER2 expressing malignancies. [Copyright &y& Elsevier]
Details
- Language :
- English
- ISSN :
- 09698051
- Volume :
- 36
- Issue :
- 6
- Database :
- Academic Search Index
- Journal :
- Nuclear Medicine & Biology
- Publication Type :
- Academic Journal
- Accession number :
- 43525495
- Full Text :
- https://doi.org/10.1016/j.nucmedbio.2009.04.002