多塔
体内分布
化学
结合
螯合作用
曲妥珠单抗
放射化学
点击化学
放射免疫疗法
单克隆抗体
核化学
组合化学
抗体
医学
体外
有机化学
生物化学
癌症
数学分析
免疫学
乳腺癌
内科学
数学
作者
Ryota Imura,Yoshitaka Kumakura,Lin Yan,Yuki Shimoura,Hiroyuki Takahashi,Hiroyuki Ida,Youichiro Wada,Nobuyoshi Akimitsu
标识
DOI:10.1101/2022.09.08.507067
摘要
Abstract Currently, the DFO chelator is commonly used to conjugate monoclonal antibodies (mAbs) and 89 Zr, whereas the DOTA chelator is commonly used to conjugate mAbs and alpha- and beta-emitting metal radionuclides. However, if the degradation of [ 89 Zr]Zr-DFO-mAb is not negligible, the in vivo biodistribution of 89 Zr might not reflect that of metal radionuclides conjugated with DOTA-mAb. We hypothesized that [ 89 Zr]Zr-DOTA-mAb as a new imaging counterpart would accurately predict the biodistribution of therapeutic metal radionuclides delivered by DOTA-mAb. In this study, we prepared [ 89 Zr]Zr-DOTA-trastuzumab for the first time by a two-step reaction using click chemistry and then investigated the differences in biodistribution profiles between two chelating approaches for 89 Zr. Methods We prepared [ 89 Zr]Zr-DOTA-trastuzumab from DOTA-tetrazine conjugates (DOTA-Tz) and transcyclooctene-trastuzumab conjugates (TCO-trastuzumab). We first radiolabeled DOTA-Tz with 89 Zr in a reaction solution of MeOH and HEPES buffer and then used a click reaction to obtain [ 89 Zr]Zr-DOTA-Tz/TCO-trastuzumab. We performed biodistribution studies and PET imaging with [ 89 Zr]Zr-DOTA-trastuzumab in a mouse model of HER2-positive ovarian cancer, SKOV3 xenograft mice at 24, 72, and 144 hours post-injection and compared these data with those of [ 89 Zr]Zr-DFO-trastuzumab. Results TCO-trastuzumab was radiolabeled with [ 89 Zr]Zr-DOTA-Tz in the two-step reaction in good radiochemical yield (57.8 ± 17.6%). HER2-positive tumors were clearly visualized with [ 89 Zr]Zr-DOTA-trastuzumab in PET imaging studies. The temporal profile changes of 89 Zr radioactivity in SKOV3 tumors and bone marrow were sufficiently different between [ 89 Zr]Zr-DOTA-trastuzumab and [ 89 Zr]Zr-DFO-trastuzumab (P < 0.05). Conclusion: [ 89 Zr]Zr-DOTA-trastuzumab can be produced by the two-step radiolabeling reaction based on the Tz/TCO click reaction. Presumably, 89 Zr released from DFO is not negligible. In contrast, [ 89 Zr]Zr-DOTA-mAb would better predict the biodistribution of [ 177 Lu]Lu- or [ 225 Ac]Ac-DOTA-mAb than [ 89 Zr]Zr-DFO-mAb, thus avoiding the use of different chelator for 89 Zr at the expense of the click chemistry step. Graphical Abstract
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