In Vivo Evaluation of Pretargeted 64Cu for Tumor Imaging and Therapy

Journal of Nuclear Medicine

Donald B. Axworthy¹  Robert W. Mallet¹  Alan R. Fritzberg¹  Michael R. Lewis¹  Carolyn J. Anderson¹  Mu Wang¹  Michael J. Welch¹  Louis J. Theodore¹ 

关键词: ⁶⁴Cu;    pretargeting;    PET;    radioimmunotherapy;   

DOI  :  

学科分类：医学（综合）

来源: Society of Nuclear Medicine

【 摘 要 】

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 64Cu, 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 64Cu, 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 64Cu-DOTA-biotin, with and without pretreatment with the mAb-streptavidin conjugate NR-LU-10/SA and the synthetic clearing agent Biotin-GalNAc16, or injected with 64Cu-DOTA-NR-LU-10. Biodistributions of both agents were obtained from 5 min to 48 h after injection. Results: Both 64Cu-DOTA-biotin and 64Cu-DOTA-NR-LU-10 were 100% stable in serum in vitro. 64Cu-DOTA-biotin exhibited >98% specific binding to immobilized streptavidin, whereas the immunoreactivity of 64Cu-DOTA-NR-LU-10 averaged nearly 80%. Biodistributions in SW1222-bearing mice showed that NR-LU-10/SA–pretargeted 64Cu-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, 64Cu-DOTA-biotin had very similar biodistribution and clearance properties, except with extremely low nonspecific tumor uptake. In contrast, 64Cu-DOTA-NR-LU-10 reached 80.3 %ID/g in tumor tissue, after 48 h, whereas blood clearance was considerably slower than pretargeted 64Cu-DOTA-biotin. Comparison of the time–activity curves for tumor uptake and blood clearance of pretargeted 64Cu and the 64Cu-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 64Cu-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 64Cu-DOTA-biotin should afford markedly superior PET imaging contrast and therapeutic efficacy, compared with conventionally labeled 64Cu-DOTA-NR-LU-10. Further comparison of the therapeutic efficacy, toxicity, and dosimetry of these 2 agents is warranted.

【 授权许可】

Unknown