Persson M I, Gedda L, Jensen H J, Lundqvist H, Malmström P-U, Tolmachev V
Unit of Biomedical Radiation Sciences, Rudbeck Laboratory, Uppsala University, S-751 85 Uppsala, Sweden.
Oncol Rep. 2006 Mar;15(3):673-80. doi: 10.3892/or.15.3.673.
The anti-ErbB2 antibody trastuzumab is used for the treatment of patients with advanced breast cancer, resulting in a response rate of 40-60%. Coupling with a cytotoxic nuclide, e.g. alpha-emitting 211At, may further increase tumour response. The tumour-targeting properties of trastuzumab, astatinated using N-succinimidyl-para-(tri-n-methylstannyl)-benzoate, were evaluated and compared with those of radioiodinated trastuzumab in this study. We found that astatinated trastuzumab retains high specificity towards ErbB2. While the immunoreactive fraction of radioiodinated trastuzumab was higher than that of astatinated trastuzumab (76+/-9% versus 54+/-28%), both radioconjugates showed high affinity (KD 0.75+/-0.16 nM versus 1.8+/-0.3 nM). A growth inhibition study indicated a dose-dependent cell deactivation, in which approximately 74 cell-associated astatine decays per cell gave a survival fraction of 4.5+/-0.8x10(-4). Results of a comparative animal study on normal mice gave no indication that astatination would have any adverse effects on the biodistribution of the antibody. In conclusion, the results of the study suggest that astatinated trastuzumab is a promising candidate for treating ErbB2-expressing tumours.
抗ErbB2抗体曲妥珠单抗用于治疗晚期乳腺癌患者，有效率为40%-60%。与细胞毒性核素偶联，如发射α粒子的211At，可能会进一步提高肿瘤反应。在本研究中，评估了用N-琥珀酰亚胺基-对-(三甲基锡基)苯甲酸进行astatination修饰的曲妥珠单抗的肿瘤靶向特性，并与放射性碘化曲妥珠单抗进行了比较。我们发现astatination修饰的曲妥珠单抗对ErbB2仍具有高特异性。虽然放射性碘化曲妥珠单抗的免疫反应分数高于astatination修饰的曲妥珠单抗(76±9%对54±28%)，但两种放射性缀合物都显示出高亲和力(KD分别为0.75±0.16 nM和1.8±0.3 nM)。一项生长抑制研究表明存在剂量依赖性的细胞失活，其中每个细胞约74次与细胞相关的砹衰变产生的存活分数为4.5±0.8×10(-4)。对正常小鼠进行的比较动物研究结果表明，astatination修饰不会对抗体的生物分布产生任何不利影响。总之，研究结果表明，astatination修饰的曲妥珠单抗是治疗表达ErbB2肿瘤的有前景的候选药物。
