Chekol Rufael, Solomon Viswas Raja, Alizadeh Elahe, Bernhard Wendy, Fisher Darrell, Hill Wayne, Barreto Kris, DeCoteau John Francis, Parada Angel Casaco, Geyer Clarence Ronald, Fonge Humphrey
Department of Medical Imaging, University of Saskatchewan, College of Medicine, Saskatoon, SK, Canada.
Saskatchewan Centre for Cyclotron Sciences (SCCS), The Fedoruk Centre, Saskatoon, SK, Canada.
Oncotarget. 2018 Mar 30;9(24):17117-17132. doi: 10.18632/oncotarget.24965.
Epidermal growth factor receptor (EGFR) upregulation is associated with enhanced proliferation and drug resistance in a number of cancers. Nimotuzumab is a humanized monoclonal antibody with high affinity for EGFR. The objective of this study was to determine if Zr-DFO-nimotuzumab could be suitable for human use as a PET probe for quantifying EGFR .
To evaluate the pharmacokinetics, biodistribution, microPET imaging, radiation dosimetry, and normal tissue toxicity in tumor and non-tumor bearing mice of Zr-desferoxamine-nimotuzumab (Zr-DFO-nimotuzumab) of a product prepared under GMP conditions. Nimotuzumab was conjugated to DFO and radiolabeled with Zr. Zr-DFO-nimotuzumab was characterized by gel-electrophoresis, biolayer interferometry (BLI) and flow cytometry. Zr-DFO-nimotuzumab was evaluated by microPET and by biodistribution in healthy and EGFR-positive tumor bearing mice.
Flow cytometry with A431 cells showed no significant difference in the dissociation constant of nimotuzumab (13 ± 2 nM) compared with DFO-nimotuzumab (17 ± 4 nM). PET imaging in mice xenografts showed persistently high tumor uptake with the highest uptake obtained in DLD-1 xenograft (18.3 %IA/cc) at 168 hp.i. The projected human effective dose was low and was 0.184 mSv/MBq (0.679 rem/mCi) in females and 0.205 mSv/MBq (0.757 rem/mCi) in males. There was no apparent normal tissue toxicity as shown by cell blood counts and blood biochemistry analyses at 168-fold and 25-fold excess of the projected human radioactive and mass dose of the agent.
Zr-DFO-nimotuzumab had low organ absorbed dose and effective dose that makes it suitable for potential human use.
表皮生长因子受体（EGFR）上调与多种癌症的增殖增强和耐药性相关。尼妥珠单抗是一种对EGFR具有高亲和力的人源化单克隆抗体。本研究的目的是确定Zr-DFO-尼妥珠单抗是否适合作为定量EGFR的PET探针供人类使用。
为了评估在GMP条件下制备的产品Zr-去铁胺-尼妥珠单抗（Zr-DFO-尼妥珠单抗）在荷瘤和未荷瘤小鼠中的药代动力学、生物分布、微型PET成像、辐射剂量测定和正常组织毒性。将尼妥珠单抗与去铁胺偶联并用Zr进行放射性标记。通过凝胶电泳、生物膜干涉术（BLI）和流式细胞术对Zr-DFO-尼妥珠单抗进行表征。通过微型PET以及在健康和EGFR阳性荷瘤小鼠中的生物分布对Zr-DFO-尼妥珠单抗进行评估。
对A431细胞进行的流式细胞术显示，尼妥珠单抗的解离常数（13±2 nM）与DFO-尼妥珠单抗（17±4 nM）相比无显著差异。小鼠异种移植瘤的PET成像显示肿瘤摄取持续较高，在168小时注射后，DLD-1异种移植瘤的摄取最高（18.3%IA/cc）。预计人体有效剂量较低，女性为0.184 mSv/MBq（0.679 rem/mCi），男性为0.205 mSv/MBq（0.757 rem/mCi）。在该制剂的预计人体放射性剂量和质量剂量分别高出168倍和25倍时，血细胞计数和血液生化分析显示无明显正常组织毒性。
Zr-DFO-尼妥珠单抗的器官吸收剂量和有效剂量较低，使其适合潜在的人体使用。
