Biodistributions of 177Lu- and 111In-labeled 7E11 antibodies to prostate-specific membrane antigen in xenograft model of prostate cancer and potential use of 111In-7E11 as a pre-therapeutic agent for 177Lu-7E11 radioimmunotherapy.
Biodistributions of 177Lu- and 111In-labeled 7E11 antibodies to prostate-specific membrane antigen in xenograft model of prostate cancer and potential use of 111In-7E11 as a pre-therapeutic agent for 177Lu-7E11 radioimmunotherapy.
复制标题
DOI：
10.1007/s11307-008-0185-9
复制
发表时间：
2009-05
影响因子：
3.1
通讯作者：
Franc, Benjamin L.
中科院分区：
文献类型：
--
作者：
Pan, Mei-Hsiu;Gao, Dong-Wei;Feng, Jinjin;He, Jiang;Seo, Youngho;Tedesco, John;Wolodzko, John G.;Hasegawa, Bruce H.;Franc, Benjamin L.
关键词：
前列腺特异性膜抗原（PSMA）是一种在多种前列腺癌中高度表达的跨膜糖蛋白，可作为放射标记抗体的靶标，用于前列腺癌的诊断和治疗。作为一种放射免疫治疗剂，需要一种动力学惰性偶联物，以最大限度地提高肿瘤摄取和肿瘤辐射剂量，使骨髓和其他主要器官的非特异性暴露最小。在这项研究中，我们评估了用镥-177 (177Lu) -四氮杂环十二烷四乙酸（DOTA）偶联体系（177Lu-7E11）放射标记的7E11单克隆抗体（MAb）与用铟-111 (111In) -甘氨酸酪氨酸-（N，-二乙烯三胺五乙酸）-赖氨酸盐渍（DTPA）偶联体系（111In-7E11，也称为ProstaScint®）放射标记的7E11单克隆抗体（MAb）的药代动力学和生物分布。确定111In-7E11作为177Lu-7E11放射免疫治疗前药物的可行性。分别于给药后2、8、12、24、72和168小时对177Lu-7E11在LNCaP异种移植小鼠体内的药代动力学和生物分布进行研究。对于111In-7E11，在8、24和72小时进行药代动力学和生物分布研究。177Lu-7E11在非荷瘤小鼠注射后8、24和72小时的平行研究作为对照。进行伽玛闪烁成像，随后进行放射自显像和组织计数，以证明和量化放射共轭单克隆抗体在肿瘤和正常组织中的分布。177Lu-和111In-7E11缀合物均表现出早期血池期，在此阶段主要由血液、肺、脾脏和肝脏摄取，随后在24 h时肿瘤中放射标记抗体的摄取和保留最为突出。与111In-7E11相比，177Lu-7E11在24 h时肿瘤中放射共轭单抗的总积累量更大。在整个研究过程中，177Lu-7E11和111In-7E11都在肿瘤中持续积累。肝脏是唯一的主要器官，在两种缀合物之间表现出显著的积累差异。总之，177Lu-7E11在LNCaP异种移植小鼠模型中的药代动力学和生物分布研究支持其作为针对前列腺癌的放射免疫治疗剂的潜在应用，并且111In-7E11的分布和肿瘤摄取似乎与177Lu-7E11相似，支持其作为治疗前工具评估177Lu-7E11放射免疫治疗在前列腺癌部位的潜在蓄积。然而，111In和177Lu免疫偶联物在肝脏中的不同积累模式可能会阻止111In- 7e11作为177Lu-7E11放射免疫治疗的真正剂量测定工具的使用。
Prostate-specific membrane antigen (PSMA) is a transmembrane glycoprotein highly expressed in many prostate cancers, and can be targeted with radiolabeled antibodies for diagnosis and treatment of this disease. To serve as a radioimmunotherapeutic agent, a kinetically inert conjugate is desired to maximize tumor uptake and tumor radiation dose with minimal nonspecific exposure to bone marrow and other major organs. In this study, we assessed the pharmacokinetics and biodistribution of the 7E11 monoclonal antibody (MAb) radiolabeled with the lutetium-177 (177Lu) - tetraazacyclododecanetetraacetic acid (DOTA) conjugate system (177Lu-7E11) versus those of the 7E11 MAb radiolabeled with the indium-111 (111In) – glycyl-tyrosyl-(N,-diethylenetriaminepentaacetic acid)-lysine hydrochloride (DTPA) conjugate system (111In-7E11, also known as ProstaScint®), to determine the feasibility of using 111In-7E11 as a pretherapeutic agent for 177Lu-7E11 radioimmunotherapy. Pharmacokinetic and biodistribution studies of 177Lu-7E11 in LNCaP xenograft mice were performed at 2, 8, 12, 24, 72, and 168 hours after radiopharmaceutical administration. For 111In-7E11, pharmacokinetic and biodistribution studies were performed at 8, 24, and 72 hours. Parallel studies of 177Lu-7E11 in nontumor bearing mice at 8, 24, and 72 hours postinjection served as controls. Gamma scintigraphy was performed, followed by autoradiography and tissue counting to demonstrate and quantify the distributions of radioconjugated MAb in the tumor and normal tissues. Both 177Lu- and 111In- 7E11 conjugates demonstrated an early blood pool phase in which uptake was dominated by the blood, lung, spleen and liver, followed by uptake and retention of the radiolabeled antibody in the tumor which was most prominent at 24 h. Total accumulation of radioconjugated MAb in tumor at 24 h was greater in the case of 177Lu-7E11 in comparison to that of 111In-7E11. Continued accumulation in tumor was observed for the entire time course studied for both 177Lu-7E11 and 111In-7E11. The liver was the only major organ demonstrating a significant difference in accumulation between the two conjugates. In conclusion, pharmacokinetic and biodistribution studies of 177Lu-7E11 in LNCaP xenograft mouse models support its potential application as a radioimmunotherapeutic agent targeting prostate cancer, and the distribution and tumor uptake of 111In-7E11 appear to be similar to those of 177Lu-7E11, supporting its use as a pretherapeutic tool to assess the potential accumulation of 177Lu-7E11 radioimmunotherapeutic at sites of prostate cancer. However, the different accumulation patterns of the 111In and 177 Lu immunoconjugates in liver will likely prevent the use of 111In-7E11 as a true dosimetry tool for 177Lu-7E11 radioimmunotherapy.
登录
查看更多内容
影响因子：
45.3
作者：
Milowsky, MI;Nanus, DM;Bander, NH
通讯作者：
Bander, NH
影响因子：
4.5
作者：
Nargund, V;Al Hashmi, D;Britton, KE
通讯作者：
Britton, KE
影响因子：
4.8
作者：
Feneley, MR;Jan, H;Britton, KE
通讯作者：
Britton, KE
影响因子：
5.7
作者：
Christiansen, JJ;Rajasekaran, SA;Rajasekaran, AK
通讯作者：
Rajasekaran, AK
影响因子：
5.8
作者：
Russell, PJ;Hewish, D;Kortt, AA
通讯作者：
Kortt, AA