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¹²⁴I-Labeled Engineered Anti-CEA Minibodies and Diabodies Allow High-Contrast, Antigen-Specific Small-Animal PET Imaging of Xenografts in Athymic Mice

¹ Crump Institute for Molecular Imaging, Department of Molecular and Medical Pharmacology, David Geffen School of Medicine at UCLA, Los Angeles, California
² Beckman Research Institute, City of Hope National Medical Center, Duarte, California
³ City of Hope Comprehensive Cancer Center, Duarte, California
⁴ Radiopharmaceutical Chemistry Service and Nuclear Medicine Service, Department of Radiology, Memorial Sloan-Kettering Cancer Center, New York, New York
⁵ UCLA Jonsson Comprehensive Cancer Center, David Geffen School of Medicine at UCLA, Los Angeles, California
⁶ Department of Radiology and Bio-X Program, Stanford University, Stanford, California

Prolonged clearance kinetics have hampered the development of intact antibodies as imaging agents, despite their ability to effectively deliver radionuclides to tumor targets in vivo. Genetically engineered antibody fragments display rapid, high-level tumor uptake coupled with rapid clearance from the circulation in the athymic mouse/LS174T xenograft model. The anticarcinoembryonic antigen (CEA) T84.66 minibody (single-chain Fv fragment [scFv]-C_H3 dimer, 80 kDa) and T84.66 diabody (noncovalent dimer of scFv, 55 kDa) exhibit pharmacokinetics favorable for radioimmunoimaging. The present work evaluated the minibody or diabody labeled with ¹²⁴I, for imaging tumor-bearing mice using a high-resolution small-animal PET system. Methods: Labeling was conducted with 0.2–0.3 mg of protein and 65–98 MBq (1.7–2.6 mCi) of ¹²⁴I using an iodination reagent. Radiolabeling efficiencies ranged from 33% to 88%, and immunoreactivity was 42% (diabody) or >90% (minibody). In vivo distribution was evaluated in athymic mice bearing paired LS174T human colon carcinoma (CEA-positive) and C6 rat glioma (CEA-negative) xenografts. Mice were injected via the tail vein with 1.9–3.1 MBq (53–85 µCi) of ¹²⁴I-minibody or with 3.1 MBq (85 µCi) of ¹²⁴I-diabody and imaged at 4 and 18 h by PET. Some mice were also imaged using ¹⁸F-FDG 2 d before imaging with ¹²⁴I-minibody. Results: PET images using ¹²⁴I-labeled minibody or diabody showed specific localization to the CEA-positive xenografts and relatively low activity elsewhere in the mice, particularly by 18 h. Target-to-background ratios for the LS174T tumors versus soft tissues using ¹²⁴I-minibody were 3.05 at 4 h and 11.03 at 18 h. Similar values were obtained for the ¹²⁴I-diabody (3.95 at 4 h and 10.93 at 18 h). These results were confirmed by direct counting of tissues after the final imaging. Marked reduction of normal tissue activity, especially in the abdominal region, resulted in high-contrast images at 18 h for the ¹²⁴I-anti-CEA diabody. CEA-positive tumors as small as 11 mg (<3 mm in diameter) could be imaged, and ¹²⁴I-anti-CEA minibodies, compared with ¹⁸F-FDG, demonstrated highly specific localization. Conclusion: ¹²⁴I labeling of engineered antibody fragments provides a promising new class of tumor-specific probes for PET imaging of tumors and metastases.

Key Words: radioimmunoimaging • engineered antibody fragments • carcinoembryonic antigen • ¹²⁴I • PET

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