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

¹ Mallinckrodt Institute of Radiology, Washington University School of Medicine, St. Louis, Missouri
² NeoRx Corporation, Seattle, Washington

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.

Key Words: ⁶⁴Cu • pretargeting • PET • radioimmunotherapy

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