Improved Tumor Targeting of Tc-99m Fab by Chemical Modifications

通过化学修饰改进 Tc-99m Fab 的肿瘤靶向性

• 批准号: 6103629
• 负责人: JORGE A. CARRASQUILLO
• 金额: --
• 依托单位: CLINICAL CENTER
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/6103629
• 关键词: acylating agent; autoradiography; blood /lymphatic neoplasm; chemical elimination; clearance rate; kidney metabolism; laboratory mouse; monoclonal antibody; neoplasm /cancer radionuclide diagnosis; physical chemical interaction; radionuclides; radiopharmacology; technetium

This project was developed and is directed by C.H. Paik, Ph.D. We have been developing chemical methods to radiolabel monoclonal antibodies and their fragments to use them as scintigraphic imaging agents to detect hematologic malignancies that express IL-2a receptors. For FY '98 we have extended our efforts to label genetically synthesized single chain, disulfide stabilized variable-region fragment (scdsFv) of antiTac monoclonal antibody with Tc-99m. The biodistribution of scdsFv was similar to that of dsFv, with its rapid tumor uptake whereas clearing rapidly from blood and all organs except kidneys. To improve its pharmacokinetic property with respect to its high renal uptake, we lowered the isoelectric point (pI 10) of scdsFv by acylation of its amino groups with succinic anhydride. This reaction neutralizes one positive charge on an amino group of scdsFv and at the same time adds one negative charge to dsFv. The succinic acid conjugated, Tc-99m-labeled scdsFv with a pI range of 4.4-6.4 showed the renal accumulation three to four times lower than that of the control Tc-99m-labeled scdsFv in tumor-bearing nude mice whereas its tumor uptake was not affected. Similarly, the whole-body retention of the succinic acid conjugate was much lower. The IL-2 receptor-positive ATAC4 tumor to non-tumor ratios increased steadily over time with ratios of 14.0, 13.6, 7.0, 22.8, 1.5, and 0.13 at 180 minutes for blood, the receptor-negative A431 tumor, liver, spleen, intestine, and kidney. This study suggests that the renal uptake of scdsFv involves charge interactions between positively charged scdsFv and negatively charged phopholipid bilayers of renal parenchymal cell membranes and that the lowering of the pI decreases the renal uptake. In conclusion, this study indicates that the high renal uptake of scdsFv can be optimized by chemical modifications without compromising tumor uptake.

该项目由C.H. Paik博士我们一直在开发化学方法， 放射性标记的单克隆抗体及其片段，以将它们用作 用于检测血液系统恶性肿瘤的血管造影成像剂 表达IL-2a受体。在1998年财政年度， 努力标记基因合成的单链，二硫键 抗Tac单克隆抗体稳定可变区片段（scdsFv） 用Tc-99 m标记抗体。scdsFv的生物学分布类似于 dsFv的肿瘤摄取迅速，而清除迅速， 血液和除肾脏外的所有器官改进其 就其高肾摄取而言，我们 通过酰化scdsFv，降低其等电点（pI 10）， 氨基与琥珀酸酐。这个反应中和了一个 scdsFv的氨基上带正电荷，同时 给dsFv加上一个负电荷。共轭琥珀酸， Tc-99 m标记的scdsFv的pI范围为4.4-6.4，显示肾组织 积累比对照低三到四倍 Tc-99 m标记的scdsFv在荷瘤裸鼠中的表达， 肿瘤摄取不受影响。同样，全身保留 琥珀酸缀合物的量低得多。的IL-2 受体阳性ATAC 4肿瘤与非肿瘤的比率增加 随着时间的推移，比值稳定在14.0、13.6、7.0、22.8、1.5和0.13 在180分钟时，血液、受体阴性A431肿瘤、肝脏 脾肠和肾这项研究表明，肾脏 scdsFv的摄取涉及正电荷之间的电荷相互作用。 带电荷的scdsFv和带负电荷的磷脂双层 肾实质细胞膜和降低的pI 降低肾摄取。总之，这项研究表明， scdsFv的高肾摄取可以通过化学方法优化， 修饰而不影响肿瘤摄取。