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Pharmacokinetics and Biodistribution of ¹¹¹In- and ¹⁷⁷Lu-Labeled J591 Antibody Specific for Prostate-Specific Membrane Antigen: Prediction of ⁹⁰Y-J591 Radiation Dosimetry Based on ¹¹¹In or ¹⁷⁷Lu?

¹ Division of Nuclear Medicine, Department of Radiology, New York Presbyterian Hospital–Weill Medical College of Cornell University, New York, New York
² Division of Hematology and Medical Oncology, New York Presbyterian Hospital–Weill Medical College of Cornell University, New York, New York
³ Laboratory of Urological Oncology, Department of Urology, New York Presbyterian Hospital–Weill Medical College of Cornell University, New York, New York

¹¹¹In-Labeled antibodies and peptides have been routinely used as chemical and biologic surrogates for ⁹⁰Y-labeled therapeutic agents. However, recent studies have shown that there are significant differences in biodistribution between ¹¹¹In- and ⁹⁰Y-labeled agents. Yttrium and lutetium metals favor the +3 oxidation state, similar to indium, but there are minor differences in the solution and coordination chemistries among these metals. These 3 metals, however, form strong complexes with the macrocyclic chelator, 1,4,7,10-tetraazacyclododecane-N,N',N'',N'''-tetraacetic acid (DOTA). We, therefore, compared the pharmacokinetics and biodistribution of ¹¹¹In- and ¹⁷⁷Lu-labeled J591 antibody. The radiation dosimetry of ⁹⁰Y-J591 was estimated based on both ¹¹¹In and ¹⁷⁷Lu data to validate the usage of ¹¹¹In as a chemical and biologic surrogate for ⁹⁰Y. Methods: J591 is a deimmunized monoclonal antibody with specificity for the extracellular domain of prostate-specific membrane antigen. In patients with prostate cancer, phase I dose-escalation studies were conducted with ⁹⁰Y-J591 (n = 29) and ¹⁷⁷Lu-J591 (n = 25). Each patient had pharmacokinetics and imaging studies with ¹¹¹In-J591 (185 MBq/20 mg) over a period of 1 wk and before treatment with ⁹⁰Y-J591 antibody. In the ¹⁷⁷Lu trial, the pharmacokinetics and imaging studies were performed after treatment with the ¹⁷⁷Lu-J591 dose (370–2,590 MBq/m²/10 mg/m²) over a 2-wk period after treatment. Results: Blood and urinary pharmacokinetics were similar for both tracers. Based on biexponential decay, the terminal half-life was 44 ± 15 h for both tracers. In addition, the total-body retention of radioactivity over a 7-d period was also similar between the 2 isotopes. The percentage uptake in liver was about 20% greater with ¹¹¹In than with ¹⁷⁷Lu. Radiation dosimetry estimates for ⁹⁰Y-J591 calculated on the basis of ¹¹¹In or ¹⁷⁷Lu data were mostly similar and showed that liver is the critical organ, followed by spleen and kidney. Based on blood radioactivity, the radiation dose (mGy/MBq) to the bone marrow was 3 times higher with ⁹⁰Y (0.91 ± 0.43) compared with that with ¹⁷⁷Lu (0.32 ± 0.10). Conclusion: ¹¹¹In- and ¹⁷⁷Lu-labeled J591 antibodies have similar plasma and whole-body clearance kinetics. The net retention of ¹¹¹In activity by lung, liver, and spleen is slightly higher compared with that with ¹⁷⁷Lu. These results justify using ¹¹¹In as a chemical and biologic surrogate for ⁹⁰Y. However, the radiation dose to the liver may be overestimated by about 25% based on ¹¹¹In data. In addition, the data also suggest that ¹⁷⁷Lu may be a potential alternative for estimating the pharmacokinetics and biodistribution of ⁹⁰Y-labeled radiopharmaceuticals.

Key Words: antiprostate-specific membrane antigen antibody • ⁹⁰Y dosimetry • ¹⁷⁷Lu-labeled J591 monoclonal antibody

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