Liapis Vasilios, Tieu William, Rudd Stacey E, Donnelly Paul S, Wittwer Nicole L, Brown Michael P, Staudacher Alexander H
Translational Oncology Laboratory, Centre for Cancer Biology, SA Pathology and University of South Australia, Adelaide, SA, 5000, Australia.
School of Medicine, University of Adelaide, Adelaide, SA, 5000, Australia.
EJNMMI Radiopharm Chem. 2020 Nov 17;5(1):27. doi: 10.1186/s41181-020-00109-6.
The chimeric monoclonal antibody (mAb) chDAB4 (APOMAB®) targets the Lupus associated (La)/Sjögren Syndrome-B (SSB) antigen, which is over-expressed in tumors but only becomes available for antibody binding in dead tumor cells. Hence, chDAB4 may be used as a novel theranostic tool to distinguish between responders and nonresponders early after chemotherapy. Here, we aimed to ascertain which positron emitter, Zirconium-89 ([Zr]Zr) or Iodine-124 ([I]I), was best suited to label chDAB4 for post-chemotherapy PET imaging of tumor-bearing mice and to determine which of two different bifunctional chelators provided optimal tumor imaging by PET using [Zr]Zr-labeled chDAB4.
C57BL/6 J mice bearing subcutaneous syngeneic tumors of EL4 lymphoma were either untreated or given chemotherapy, then administered radiolabeled chDAB4 after 24 h with its biodistribution examined using PET and organ assay. We compared chDAB4 radiolabeled with [Zr] Zr or [I] I, or [Zr]Zr-chDAB4 using either DFO-NCS or DFOSq as a chelator.
After chemotherapy, [Zr]Zr-chDAB4 showed higher and prolonged mean (± SD) tumor uptake of 29.5 ± 5.9 compared to 7.8 ± 1.2 for [I] I -chDAB4. In contrast, antibody uptake in healthy tissues was not affected. Compared to DFO-NCS, DFOSq did not result in significant differences in tumor uptake of [Zr]Zr-chDAB4 but did alter the tumor:liver ratio in treated mice 3 days after injection in favour of DFOSq (8.0 ± 1.1) compared to DFO-NCS (4.2 ± 0.7).
ImmunoPET using chDAB4 radiolabeled with residualizing [Zr] Zr rather than [I] I optimized post-chemotherapy tumor uptake. Further, PET imaging characteristics were improved by DFOSq rather than DFO-NCS. Therefore, the radionuclide/chelator combination of [Zr] Zr and DFOSq is preferred for the imminent clinical evaluation of chDAB4 as a selective tumor cell death radioligand.
嵌合单克隆抗体（mAb）chDAB4（APOMAB®）靶向狼疮相关（La）/干燥综合征B（SSB）抗原，该抗原在肿瘤中过度表达，但仅在死亡肿瘤细胞中可用于抗体结合。因此，chDAB4可用作一种新型的诊疗工具，在化疗后早期区分反应者和无反应者。在此，我们旨在确定哪种正电子发射体，锆-89（[Zr]Zr）或碘-124（[I]I），最适合标记chDAB4用于荷瘤小鼠化疗后的PET成像，并确定两种不同的双功能螯合剂中哪一种使用[Zr]Zr标记的chDAB4通过PET提供最佳的肿瘤成像。
将携带EL4淋巴瘤皮下同基因肿瘤的C57BL/6 J小鼠分为未治疗组或化疗组，24小时后给予放射性标记的chDAB4，然后使用PET和器官分析检查其生物分布。我们比较了用[Zr]Zr或[I]I标记的chDAB4，或使用DFO-NCS或DFOSq作为螯合剂的[Zr]Zr-chDAB4。
化疗后，[Zr]Zr-chDAB4的平均肿瘤摄取量更高且持续时间更长，平均（±标准差）为29.5±5.9，而[I]I-chDAB4为7.8±1.2。相比之下，健康组织中的抗体摄取不受影响。与DFO-NCS相比，DFOSq在[Zr]Zr-chDAB4的肿瘤摄取方面没有导致显著差异，但在注射后3天改变了治疗小鼠的肿瘤：肝脏比值，有利于DFOSq（8.0±1.1），而DFO-NCS为（4.2±0.7）。
使用残留[Zr]Zr而非[I]I标记的chDAB4进行免疫PET可优化化疗后肿瘤摄取。此外，DFOSq而非DFO-NCS改善了PET成像特征。因此，对于即将进行的chDAB4作为选择性肿瘤细胞死亡放射性配体的临床评估，[Zr]Zr和DFOSq的放射性核素/螯合剂组合是首选。
