<p>Radioactive substances are used <i>in vivo</i> to localize and characterize malignant tumours, generally by scintigraphic methods. In this context positron emission tomography (PET) in combination with radiolabelled monoclonal antibodies (mAbs) may provide a sensitive and specific method for detection of cancer. Individual dose calculations, based on such PET measurements, may be carried out to predict the possible use of mAbs labelled with therapeutic nuclides. The positron emitter <sup>76</sup>Br, with a half-life of 16 h, is a well-suited candidate for radiolabelling and PET imaging. One drawback of radiobromine is that bromide, the ultimate catabolite after degradation of brominated mAb, is only tardily excreted from the body and is evenly distributed throughout the extracellular space, thereby increasing the background radioactivity. The aim of this work was to produce <sup>76</sup>Br-mAb preparations with high accumulation and retention in tumour tissue together with a quick clearance of <sup>76</sup>Br-labelled catabolites. Furthermore, the possibility to use brominated or iodinated mAbs in combination with PET to predict <sup>211</sup>At-mAb dosimetry was evaluated.</p><p>Monoclonal Abs directed against colorectal cancer were labelled with <sup>76</sup>Br using the direct Chloramine-T-method or indirectly by labelling the precursor molecule N-succinimidyl para-(tri-methylstannyl) benzoate with <sup>76</sup>Br, which was subsequently conjugated to the mAbs. Monoclonal Ab A33 labelled with <sup>76</sup>Br using the two labelling protocols was characterized in vitro and in vivo in a rat tumour xenograft model. The mAb A33 was also labelled with <sup>125</sup>I for comparison. In addition, mAb A33 was labelled with <sup>211</sup>At, <sup>125</sup>I and <sup>76</sup>Br using the indirect labelling protocol and the mAb pharmacokinetics was studied in normal rats in order to estimate if data from brominated or iodinated mAb could be used for dosimetry of <sup>211</sup>At in healthy organs and tissue.</p><p>In conclusion, both direct and indirect labelling resulted in high yields and mAbs with preserved immunoreactivity. <i>In vivo</i> characterization of <sup>76</sup>Br-brominated mAb A33 showed that the indirect labelling method makes <sup>76</sup>Br-brominated mAb A33 a promising candidate for tumour imaging with PET due to the faster excretion of radiolabelled catabolites compared with direct bromination. Finally, mAb A33 labelled with <sup>76</sup>Br and <sup>124/125</sup>I can be used to predict the <sup>211</sup>At dose of astatinated mAb A33 in most organs given that a correction factor is applied for organs with varying uptake.</p>
| Identifer | oai:union.ndltd.org:UPSALLA/oai:DiVA.org:uu-1908 |
| Date | January 2002 |
| Creators | Höglund, Johanna |
| Publisher | Uppsala University, Department of Oncology, Radiology and Clinical Immunology, Uppsala : Acta Universitatis Upsaliensis |
| Source Sets | DiVA Archive at Upsalla University |
| Language | English |
| Detected Language | English |
| Type | Doctoral thesis, comprehensive summary, text |
| Relation | Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, 0282-7476 ; 1128 |
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