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Radioiodinated versus Radiometal-Labeled Anti–Carcinoembryonic Antigen Single-Chain Fv-Fc Antibody Fragments: Optimal Pharmacokinetics for Therapy

¹ Division of Molecular Biology and ² Division of Immunology, Beckman Research Institute of the City of Hope; ³ Department of Radioimmunotherapy, ⁴ Radiology Division, and ⁵ Department of Biostatistics, City of Hope National Medical Center, Duarte, California; and ⁶ Crump Institute for Molecular Imaging, Department of Molecular and Medical Pharmacology, David Geffen School of Medicine at University of California Los Angeles, Los Angeles, California

Requests for reprints: Anna M. Wu, Crump Institute for Molecular Imaging, Department of Molecular and Medical Pharmacology, David Geffen School of Medicine at University of California Los Angeles, 700 Westwood Plaza, Los Angeles, CA 90095. E-mail: awu{at}mednet.ucla.edu.

Antibody fragments with optimized pharmacokinetic profiles hold potential for detection and therapy of tumor malignancies. We studied the behavior of three anti–carcinoembryonic antigen (CEA) single-chain Fv-Fc (scFv-Fc) variants (I253A, H310A, and H310A/H435Q; Kabat numbering system) that exhibited differential serum persistence. Biodistribution studies done on CEA-positive tumor xenografted mice revealed that the ¹¹¹In-labeled I253A fragment with the slowest clearance kinetics (T_1/2ß, 27.7 h) achieved the highest tumor uptake (44.6% ID/g at 24 h), whereas the radiometal-labeled H310A/H435Q fragment with the most rapid elimination (T_1/2ß, 7.05 h) reached a maximum of 28.0% ID/g at 12 h postinjection. The H310A protein was characterized by both intermediate serum half-life and tumor uptake. The ¹¹¹In-based biodistribution studies showed that all three fragments were eliminated primarily through the liver, and hepatic radiometal activity correlated with the rate of fragment clearance. The ¹¹¹In-labeled H310A/H435Q protein exhibited the highest liver uptake (23.5% ID/g at 24 h). Metabolism of the ¹²⁵I-labeled scFv-Fc proteins resulted in low normal organ activity. Finally, the ¹²⁵I/¹¹¹In biodistribution data allowed for dose estimations, which suggest the ¹³¹I-labeled scFv-Fc H310A/H435Q as a promising candidate for radioimmunotherapy. [Cancer Res 2007;67(2):718–26]