In vivo evaluation of pretargeted 64Cu for tumor imaging and therapy.
In vivo evaluation of pretargeted 64Cu for tumor imaging and therapy.
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发表时间：
2003-08
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通讯作者：
M. Lewis;Mu Wang;D. Axworthy;L. Theodore;R. Mallet;A. Fritzberg;M. Welch;C. Anderson
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作者：
M. Lewis;Mu Wang;D. Axworthy;L. Theodore;R. Mallet;A. Fritzberg;M. Welch;C. Anderson
unlabeled预靶向涉及将肿瘤靶向单克隆抗体（mAb）共价连接到具有快速分布的放射性标记效应分子高亲和力结合位点的分子。本研究的目的是比较预靶向与传统标记的靶向中间寿命放射性核素（64）Cu的抗体，后者在PET成像和癌症放射免疫治疗中显示出前景。方法将DOTA生物素（其中DOTA为1,4,7,10-四氮杂环十二烷-N，N',N ',N '-四乙酸）和完整的免疫偶联物DOTA- nr - lu -10用（64）Cu标记为高比活性，并在体外测定各药物的血清稳定性和靶结合能力。携带SW1222人结直肠癌异种移植物的裸鼠分别给予（64）cu - dota -生物素，用单抗-链霉亲和素偶联物NR-LU-10/SA和合成清除剂生物素- galnac（16）进行预处理，或注射（64）Cu-DOTA-NR-LU-10。注射后5 min至48 h，测定两种药物的生物分布。结果（64）cu - dota -生物素和（64）Cu-DOTA-NR-LU-10在体外血清中均100%稳定。（64） cu - dota -生物素对固定化链霉亲和素的特异性结合率为98%，而（64）Cu-DOTA-NR-LU-10的免疫反应性平均接近80%。携带sw1222的小鼠体内的生物分布表明，NR-LU-10/ sa预靶向（64）cu - dota生物素在1 h时达到肿瘤摄取峰值，每克注射剂量为18.9% (%ID/g)，同时从血液和肾脏排泄中迅速消失。在没有预先靶向的情况下，（64）cu - dota -生物素具有非常相似的生物分布和清除特性，除了极低的非特异性肿瘤摄取。相比之下，（64）Cu-DOTA-NR-LU-10在48小时后在肿瘤组织中达到80.3%的ID/g，而血液清除率明显低于预先靶向的（64）cu - dota -生物素。对比预靶向（64）Cu和（64）Cu标记抗体的肿瘤摄取和血液清除率的时间-活性曲线显示，两种药物的最大放射性肿瘤累积量相似，分别为17.9% /g （%IA/g）和20.7% IA/g。然而，由于小效应分子的血液清除率大幅增加，预先靶向（64）cu - dota生物素的曲线下区域的肿瘤与血液比率高出14倍。结论与常规标记的（64）Cu-DOTA-NR-LU-10相比，预靶向（64）cu - dota -生物素极快的肿瘤摄取和血液清除率可提供明显更好的PET成像对比度和治疗效果。需要进一步比较这两种药物的治疗效果、毒性和剂量学。
UNLABELLED Pretargeting involves administration of a tumor-targeting monoclonal antibody (mAb) covalently linked to a molecule having a high-affinity binding site for a rapidly distributed radiolabeled effector molecule. The aim of this study was to compare pretargeting to a conventionally labeled antibody for tumor targeting of the intermediate-lived radionuclide (64)Cu, which has shown promise for PET imaging and radioimmunotherapy of cancer. METHODS DOTA-biotin (where DOTA is 1,4,7,10-tetraazacyclododecane-N,N',N",N"'-tetraacetic acid) and the intact immunoconjugate DOTA-NR-LU-10 were labeled to high specific activities with (64)Cu, and the serum stabilities and target binding capabilities of each agent were assayed in vitro. Nude mice bearing SW1222 human colorectal carcinoma xenografts were administered (64)Cu-DOTA-biotin, with and without pretreatment with the mAb-streptavidin conjugate NR-LU-10/SA and the synthetic clearing agent Biotin-GalNAc(16), or injected with (64)Cu-DOTA-NR-LU-10. Biodistributions of both agents were obtained from 5 min to 48 h after injection. RESULTS Both (64)Cu-DOTA-biotin and (64)Cu-DOTA-NR-LU-10 were 100% stable in serum in vitro. (64)Cu-DOTA-biotin exhibited >98% specific binding to immobilized streptavidin, whereas the immunoreactivity of (64)Cu-DOTA-NR-LU-10 averaged nearly 80%. Biodistributions in SW1222-bearing mice showed that NR-LU-10/SA-pretargeted (64)Cu-DOTA-biotin attained a peak tumor uptake of 18.9 percentage injected dose per gram (%ID/g) at 1 h, with concomitant rapid disappearance from blood and renal excretion. In the absence of pretargeting, (64)Cu-DOTA-biotin had very similar biodistribution and clearance properties, except with extremely low nonspecific tumor uptake. In contrast, (64)Cu-DOTA-NR-LU-10 reached 80.3 %ID/g in tumor tissue, after 48 h, whereas blood clearance was considerably slower than pretargeted (64)Cu-DOTA-biotin. Comparison of the time-activity curves for tumor uptake and blood clearance of pretargeted (64)Cu and the (64)Cu-labeled antibody revealed that the maximum tumor accumulations of radioactivity were similar for each agent, 17.9 percentage injected activity per gram (%IA/g) and 20.7 %IA/g, respectively. However, the tumor-to-blood ratio of areas under the curves was 14 times higher for pretargeted (64)Cu-DOTA-biotin because of the substantial increase in blood clearance of the small effector molecule. CONCLUSION The extremely rapid tumor uptake and blood clearance of pretargeted (64)Cu-DOTA-biotin should afford markedly superior PET imaging contrast and therapeutic efficacy, compared with conventionally labeled (64)Cu-DOTA-NR-LU-10. Further comparison of the therapeutic efficacy, toxicity, and dosimetry of these 2 agents is warranted.