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Basic Science Investigations |
1 Division of Nuclear Medicine, Department of Radiology, New York Presbyterian Hospital-Weill Medical College of Cornell University, New York, New York
2 Laboratory of Urological Oncology, Department of Urology, New York Presbyterian Hospital-Weill Medical College of Cornell University, New York, New York
Prostate-specific membrane antigen (PSMA), a transmembrane glycoprotein, is highly expressed by virtually all prostate cancers. PSMA is also expressed on the tumor vascular endothelium of virtually all solid carcinomas and sarcomas but not on normal vascular endothelium. PSMA is currently the focus of several diagnostic and therapeutic strategies. We have previously reported on the radiolabeling and in vitro binding properties of monoclonal antibodies (mAbs) (J415, J533, and J591) that recognize and bind with high affinity to the extracellular domain of PSMA (PSMAext). This article reports on the in vivo behavior and tumor uptake of 131I- and 111In-labeled antiPSMAext mAbs (J415, J533, and J591) and their potential utility for radioimmunotherapy. Methods: In nude mice bearing PSMA-positive human LNCaP tumors, the pharmacokinetics, biodistribution, and tumor uptake of these antibodies was compared with 111In-7E11 mAb, specific to the intracellular domain of PSMA (PSMAint). Autoradiographic studies were done to identify intratumoral distribution of radiolabeled mAbs. Results: With 131I-labeled antibodies, the net tumor retention of radioactivity by day 6 was significantly higher with J415 (15.4% ± 1.1%) and 7E11 (14.5% ± 1.7%) than with J591 (9.58% ± 1.1%). By contrast, the tumor uptake of 111In-1,4,7,10-tetraazacyclododecane-N,N',N'', N'''-tetraacetic acid-labeled J415 and J591 gradually increased with time and was quite similar to that of 7E11. In addition, the blood clearance of 111In-labeled J415 and J591 antibodies was relatively faster than that of radiolabeled 7E11. As a consequence, the tumor-to-blood ratios with J415 and J591 were higher than that of 7E11. The localization of radiolabeled anti-PSMAext antibodies in PSMA-positive LNCaP tumors was highly specific because the tumor uptake of 131I-labeled J415 and J591 was more than twice that of a nonspecific antibody. Furthermore, the tumor uptake of 131I-J591 was almost 20 times higher in PSMA-positive LNCaP tumors than in PSMA-negative PC3 and DU145 tumor xenografts. Autoradiographic studies suggested that 7E11 (anti-PSMAint) distinctly favors localization to areas of necrosis whereas J415 and J591 (anti-PSMAext) demonstrated a distinct preferential accumulation in areas of viable tumor. Conclusion: These results clearly demonstrate that PSMA-specific internalizing antibodies such as J415 and J591 may be the ideal mAbs for the development of novel therapeutic methods to target the delivery of ß-emitting radionuclides (131I, 90Y, and 177Lu) for the treatment of PSMA-positive tumors. In addition, because J591 and J415 mAbs are specific to PSMAext, thus targeting viable tumor, these immunoconjugates are better candidates for targeted radioimmunotherapy than are antibodies targeting PSMAint.
Key Words: monoclonal antibody • prostate-specific membrane antigen • 131I-huJ591 • 111In-DOTA-huJ591 • tumor localization
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