Biodistributions of 177Lu- and 111In- labeled 7E11 Antibodies to Prostate-Specific Membrane Antigen in Xenograft Model of Prostate Cancer and Potential Use of 111In-7E11 as a Pretherapeutic Agent for 177Lu-7E11 Radioimmunotherapy

摘要

Prostate-specific membrane antigen (PSMA) is a transmembrane glycoprotein highly expressed in many prostate cancers, and can be targeted with radiolabeled antibodies for diagnosis and treatment of this disease. To serve as a radioimmunotherapeutic agent, a kinetically inert conjugate is desired to maximize tumor uptake and tumor radiation dose with minimal nonspecific exposure to bone marrow and other major organs. In this study, we assessed the pharmacokinetics and biodistribution of the 7E11 monoclonal antibody (MAb) radiolabeled with the lutetium-177 (¹⁷⁷Lu) - tetraazacyclododecanetetraacetic acid (DOTA) conjugate system (¹⁷⁷Lu-7E11) versus those of the 7E11 MAb radiolabeled with the indium-111 (¹¹¹In) – glycyl-tyrosyl-(N,-diethylenetriaminepentaacetic acid)-lysine hydrochloride (DTPA) conjugate system (¹¹¹In-7E11, also known as ProstaScint^®), to determine the feasibility of using ¹¹¹In-7E11 as a pretherapeutic agent for ¹⁷⁷Lu-7E11 radioimmunotherapy. Pharmacokinetic and biodistribution studies of ¹⁷⁷Lu-7E11 in LNCaP xenograft mice were performed at 2, 8, 12, 24, 72, and 168 hours after radiopharmaceutical administration. For ¹¹¹In-7E11, pharmacokinetic and biodistribution studies were performed at 8, 24, and 72 hours. Parallel studies of ¹⁷⁷Lu-7E11 in nontumor bearing mice at 8, 24, and 72 hours postinjection served as controls. Gamma scintigraphy was performed, followed by autoradiography and tissue counting to demonstrate and quantify the distributions of radioconjugated MAb in the tumor and normal tissues. Both ¹⁷⁷Lu- and ¹¹¹In- 7E11 conjugates demonstrated an early blood pool phase in which uptake was dominated by the blood, lung, spleen and liver, followed by uptake and retention of the radiolabeled antibody in the tumor which was most prominent at 24 h. Total accumulation of radioconjugated MAb in tumor at 24 h was greater in the case of ¹⁷⁷Lu-7E11 in comparison to that of ¹¹¹In-7E11. Continued accumulation in tumor was observed for the entire time course studied for both ¹⁷⁷Lu-7E11 and ¹¹¹In-7E11. The liver was the only major organ demonstrating a significant difference in accumulation between the two conjugates. In conclusion, pharmacokinetic and biodistribution studies of ¹⁷⁷Lu-7E11 in LNCaP xenograft mouse models support its potential application as a radioimmunotherapeutic agent targeting prostate cancer, and the distribution and tumor uptake of ¹¹¹In-7E11 appear to be similar to those of ¹⁷⁷Lu-7E11, supporting its use as a pretherapeutic tool to assess the potential accumulation of ¹⁷⁷Lu-7E11 radioimmunotherapeutic at sites of prostate cancer. However, the different accumulation patterns of the ¹¹¹In and ¹⁷⁷ Lu immunoconjugates in liver will likely prevent the use of ¹¹¹In-7E11 as a true dosimetry tool for ¹⁷⁷Lu-7E11 radioimmunotherapy.