N Tinianow Jeff, Pandya Darpan N, Pailloux Sylvie L, Ogasawara Annie, Vanderbilt Alexander N, Gill Herman S, Williams Simon-P, Wadas Thaddeus J, Magda Darren, Marik Jan
1. Department of Biomedical Imaging, Genentech, Inc. 1 DNA way, South San Francisco, CA 94080.
2. Wake Forest School of Medicine, Medical Center Boulevard, Winston-Salem, NC 27157.
Theranostics. 2016 Feb 13;6(4):511-21. doi: 10.7150/thno.14261. eCollection 2016.
A novel octadentate 3-hydroxypyridin-2-one (2,3-HOPO) based di-macrocyclic ligand was evaluated for chelation of (89)Zr; subsequently, it was used as a bi-functional chelator for preparation of (89)Zr-labeled antibodies. Quantitative chelation of (89)Zr(4+) with the octadentate ligand forming (89)ZrL complex was achieved under mild conditions within 15 minutes. The (89)Zr-complex was stable in vitro in presence of DTPA, but a slow degradation was observed in serum. In vivo, the hydrophilic (89)Zr-complex showed prevalently renal excretion; and an elevated bone uptake of radioactivity suggested a partial release of (89)Zr(4+) from the complex. The 2,3-HOPO based ligand was conjugated to the monoclonal antibodies, HER2-specific trastuzumab and an isotypic anti-gD antibody, using a p-phenylene bis-isothiocyanate linker to yield products with an average loading of less than 2 chelates per antibody. Conjugated antibodies were labeled with (89)Zr under mild conditions providing the PET tracers in 60-69% yield. Despite the limited stability in mouse serum; the PET tracers performed very well in vivo. The PET imaging in mouse model of HER2 positive ovarian carcinoma showed tumor uptake of (89)Zr-trastuzumab (29.2 ± 12.9 %ID/g) indistinguishable (p = 0.488) from the uptake of positive control (89)Zr-DFO-trastuzumab (26.1 ± 3.3 %ID/g). In conclusion, the newly developed 3-hydroxypyridin-2-one based di-macrocyclic chelator provides a viable alternative to DFO-based heterobifunctional ligands for preparation of (89)Zr-labeled monoclonal antibodies for immunoPET studies.
评估了一种新型的基于八齿3-羟基吡啶-2-酮（2,3-HOPO）的双大环配体对（89）Zr的螯合作用；随后，将其用作双功能螯合剂来制备（89）Zr标记的抗体。在温和条件下，15分钟内实现了八齿配体与（89）Zr（4+）的定量螯合，形成（89）ZrL络合物。（89）Zr络合物在存在二乙三胺五乙酸（DTPA）的情况下在体外稳定，但在血清中观察到缓慢降解。在体内，亲水性（89）Zr络合物主要通过肾脏排泄；放射性在骨骼中的摄取增加表明（89）Zr（4+）从络合物中部分释放。使用对亚苯基双异硫氰酸酯连接子将基于2,3-HOPO的配体与单克隆抗体、HER2特异性曲妥珠单抗和同型抗gD抗体偶联，得到平均每个抗体负载量少于2个螯合物的产物。在温和条件下用（89）Zr标记偶联抗体，得到正电子发射断层扫描（PET）示踪剂的产率为60 - 69%。尽管在小鼠血清中的稳定性有限；但PET示踪剂在体内表现良好。HER2阳性卵巢癌小鼠模型中的PET成像显示，（89）Zr-曲妥珠单抗的肿瘤摄取量（29.2±12.9 %ID/g）与阳性对照（89）Zr-去铁胺-曲妥珠单抗（26.1±3.3 %ID/g）的摄取量无显著差异（p = 0.488）。总之，新开发基于3-羟基吡啶-2-酮双大环螯合剂为免疫PET研究中制备（89）Zr标记单克隆抗体提供了一种可行替代基于去铁胺异双功能配体。
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