<p>Targeted radionuclide therapy (TRT) holds great promise for the treatment of cancer. In TRT, radioactive nuclides are delivered specifically to tumours by molecules that recognise and bind to structures overexpressed by, or specific to, cancer cells. Human epidermal growth factor receptor like protein 2 (HER-2) is an oncogene product overexpressed in e.g. urological, breast, or ovarian cancers that have been correlated to poor prognosis and resistance to hormonal therapy. There is also evidence that tumour cells retain their HER-2 overexpression in metastases.</p><p>Trastuzumab and pertuzumab are two humanised monoclonal antibodies targeting different parts of HER-2. This thesis describes the radiolabelling of these antibodies for use in TRT and diagnostics. The thesis also investigates possible methods for modifying uptake and retention of radioactivity delivered with antibodies binding to HER-2. Modification of the cellular retention of <sup>125</sup>I by using polyhedral boron anion based linker molecules (DABI and NBI) is investigated, and it is shown that linking <sup>125</sup>I to trastuzumab using DABI increases cellular accumulation of radioactivity by 33%. It is also shown that trastuzumab can be efficiently coupled to the positron emitter <sup>76</sup>Br by using NBI. Furthermore, it is shown that cellular uptake of <sup>125</sup>I can be modified by stimulating EGFR (HER-1) with EGF.</p><p>When labelled with the alpha emitter <sup>211</sup>At, trastuzumab could specifically kill cells in vitro. This cell killing effect could be prevented by saturating the receptors of the target cells with non-radiolabelled trastuzumab.</p><p>Pertuzumab was radiolabelled with the low energy beta emitter <sup>177</sup>Lu without losing affinity or immunocompetence. [<sup>177</sup>Lu]pertuzumab was specific to HER-2 in vitro and in vivo. This targeting conjugate was shown to increase median time to tumour progression in mice bearing xenografts of the radioresistant SKOV-3 cell line. </p><p>In conclusion, antibodies against HER-2, especially pertuzumab radiolabelled with <sup>177</sup>Lu, show promise as TRT agents.</p>
| Identifer | oai:union.ndltd.org:UPSALLA/oai:DiVA.org:uu-6798 |
| Date | January 2006 |
| Creators | Persson, Mikael |
| Publisher | Uppsala University, Biomedical Radiation Sciences, Uppsala : Acta Universitatis Upsaliensis |
| Source Sets | DiVA Archive at Upsalla University |
| Language | English |
| Detected Language | English |
| Type | Doctoral thesis, comprehensive summary, text |
| Relation | Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, 1651-6206 ; 140 |
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