Prostatespecific Membrane Antigen

Just as prostate cancer seems to be an ideal target for mAb therapy in general, prostate-specific membrane antigen (PSMA), the most well-studied, highly restricted prostate cell surface antigen (6-11), seems to be an ideal specific cellular target because it is expressed by all prostate cancers (8,9,12-14). It is an integral type II cell surface transmembrane

extracellular portion

Fig. 1. Schematic representation of PSMA demonstrating extracellular, transmembrane, and intracellular portions. J591 recognizes the extracellular portion of the antigen molecule, whereas 7E11 recognizes the intracellular portion. In viable cells, the extracellular epitope is more readily exposed to circulating antibodies. After binding, the J591 and extracellular epitope are internalized.

/J591 recognizes

. ûvtfQi»û 1111 lor extracellular portion

Cell membrane

Fig. 1. Schematic representation of PSMA demonstrating extracellular, transmembrane, and intracellular portions. J591 recognizes the extracellular portion of the antigen molecule, whereas 7E11 recognizes the intracellular portion. In viable cells, the extracellular epitope is more readily exposed to circulating antibodies. After binding, the J591 and extracellular epitope are internalized.

glycoprotein (Fig. 1) (15,16), and its level of expression is increased with increased tumor dedifferentiation (9,13,17), and in metastatic and hormone-refractory cancers (8,9,13,14, 17,18). In addition to expression by prostate cells, it can be expressed also by nonprostate tissues such as small intestine, proximal renal tubules, and salivary glands (10), albeit at levels 100- to 1000-fold less than in prostate tissue (11). PSMA expression was also found on the vascular endothelium of solid tumors and sarcomas, but not of normal tissues (8, 10,13,17-22). PSMA, therefore, represents a potential target for antiangiogenic therapies.

The first PSMA-specific mAb to be developed was 7E11-C5.3 (6), which was later commercialized and used as an imaging agent (ProstaScint®; Cytogen Corporation). The finding that 7E11 bound to an epitope of PSMA located on the inner cytoplasmic surface of the cell (23,24) explains the observation that 7E11 binds to fixed cells but not intact cells, as well as the observation that 7E11 does not detect bone marrow metastases. Necrotic cells expose the intracellular components and permit 7E11 binding. Because bone marrow metastases tend to be well vascularized, few if any cells are necrotic and, hence, the intra-cellular cytosolic domain of PSMA is not exposed.

Subsequently, Liu et al. developed four murine (mu) mAbs that bind to the extracellular domain of PSMA (19): muJ591 (IgG1), muJ415 (IgG1), muJ533 (IgG1), and muE99 (IgG3). These four mAbs bind to approx 1.0-1.3 ^ 106 PSMA sites per permeabilized LNCaP cell and 0.6-0.8 ^ 106 PSMA sites per viable LNCaP cell. Two epitopes were identified on the extracellular domain of PSMA; muJ591, muJ533, and muE99 bound to one of the epitopes and muJ415 bound to the other. muJ591 and muJ415 bound to viable cultured LNCaP (PSMA-positive) prostate cancer cells with high affinity (Kd = 1.83 ± 1.21 nmol/L and Kd = 1.76 ± 0.69 nmol/L, respectively) (25). After binding, the PSMA-antibody complexes are rapidly internalized (26), increasing the potential utility of PSMA as a target for the delivery of cytotoxins or mAb-conjugated isotopes that would then be sequestered intracellularly.

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