Smith-Jones Peter M, Vallabhajosula Shankar, Navarro Vincent, Bastidas Diego, Goldsmith Stanley J, Bander Neil H
Division of Nuclear Medicine, Department of Radiology, New York Presbyterian Hospital-Weill Medical College of Cornell University, New York, NY 10021, USA.
J Nucl Med. 2003 Apr;44(4):610-7.
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 (PSMA(ext)). This article reports on the in vivo behavior and tumor uptake of (131)I- and (111)In-labeled antiPSMA(ext) mAbs (J415, J533, and J591) and their potential utility for radioimmunotherapy.
In nude mice bearing PSMA-positive human LNCaP tumors, the pharmacokinetics, biodistribution, and tumor uptake of these antibodies was compared with (111)In-7E11 mAb, specific to the intracellular domain of PSMA (PSMA(int)). Autoradiographic studies were done to identify intratumoral distribution of radiolabeled mAbs.
With (131)I-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 (111)In-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 (111)In-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-PSMA(ext) antibodies in PSMA-positive LNCaP tumors was highly specific because the tumor uptake of (131)I-labeled J415 and J591 was more than twice that of a nonspecific antibody. Furthermore, the tumor uptake of (131)I-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-PSMA(int)) distinctly favors localization to areas of necrosis whereas J415 and J591 (anti-PSMA(ext)) demonstrated a distinct preferential accumulation in areas of viable tumor.
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 beta-emitting radionuclides ((131)I, (90)Y, and (177)Lu) for the treatment of PSMA-positive tumors. In addition, because J591 and J415 mAbs are specific to PSMA(ext), thus targeting viable tumor, these immunoconjugates are better candidates for targeted radioimmunotherapy than are antibodies targeting PSMA(int).
前列腺特异性膜抗原（PSMA）是一种跨膜糖蛋白，几乎在所有前列腺癌中都高度表达。PSMA在几乎所有实体癌和肉瘤的肿瘤血管内皮上也有表达，但在正常血管内皮上不表达。PSMA目前是几种诊断和治疗策略的重点。我们之前报道了单克隆抗体（mAb）（J415、J533和J591）的放射性标记和体外结合特性，这些抗体能识别并与PSMA的细胞外结构域（PSMA(ext)）高亲和力结合。本文报道了¹³¹I和¹¹¹In标记的抗PSMA(ext) mAb（J415、J533和J591）的体内行为和肿瘤摄取情况及其在放射免疫治疗中的潜在效用。
在携带PSMA阳性人LNCaP肿瘤的裸鼠中，将这些抗体的药代动力学、生物分布和肿瘤摄取情况与特异性针对PSMA细胞内结构域（PSMA(int)）的¹¹¹In - 7E11 mAb进行比较。进行放射自显影研究以确定放射性标记mAb在肿瘤内的分布。
对于¹³¹I标记的抗体，到第6天时，J415（15.4%±1.1%）和7E11（14.5%±1.7%）的肿瘤放射性净保留率显著高于J591（9.58%±1.1%）。相比之下，¹¹¹In - 1,4,7,10 - 四氮杂环十二烷 - N,N',N",N"'-四乙酸标记的J415和J591的肿瘤摄取随时间逐渐增加，且与7E11相当。此外，¹¹¹In标记的J415和J591抗体的血液清除相对比放射性标记的7E11更快。因此，J415和J591的肿瘤与血液比值高于7E11。放射性标记的抗PSMA(ext)抗体在PSMA阳性LNCaP肿瘤中的定位具有高度特异性，因为¹³¹I标记的J415和J591的肿瘤摄取是一种非特异性抗体的两倍多。此外，¹³¹I - J591在PSMA阳性LNCaP肿瘤中的摄取几乎比PSMA阴性PC3和DU145肿瘤异种移植高20倍。放射自显影研究表明，7E11（抗PSMA(int)）明显倾向于定位到坏死区域，而J415和J591（抗PSMA(ext)）在存活肿瘤区域表现出明显的优先积累。
这些结果清楚地表明，PSMA特异性内化抗体如J415和J591可能是开发新型治疗方法的理想mAb，该方法用于靶向递送发射β射线的放射性核素（¹³¹I、⁹⁰Y和¹⁷⁷Lu）以治疗PSMA阳性肿瘤。此外，由于J591和J415 mAb对PSMA(ext)具有特异性，从而靶向存活肿瘤，这些免疫缀合物比靶向PSMA(int)的抗体更适合用于靶向放射免疫治疗。
