Biodistribution in normal mice of an111in-labelled prostatic acid phosphatase-specific antibody and its F(ab?)2 fragments derivatized site-specifically or via bicyclic diethyl enetriaminepentaacetic acid anhydride

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Abstract
In this study we examined optimization of derivatization of monoclonal antibodies and their fragments intended for use as radiopharmaceutical in radioimaging and/or radioimmunotherapy of prostatic cancer. Two different principles were used to conjugate diethylene triaminepentaacetic acid (DTPA) to a monoclonal antibody (Mab, subclass IgG1) raised against human prostatic acid phosphatase (PAP). In addition, the F(ab′)2 fragments of this Mab were also derivatized. We used the cyclic anhydride of DTPA (CA-DTPA) as a chelating agent for these two protein moieties. Furthermore, the Mab and the F(ab′)2 fragments were modified site-specifically by attaching linkers,N-(p-aminobenzyl)diethylenetriaminetetraacetic acid (p-NH2-Bz-DTTA) and 1(p-aminobenzyl)diethylenetriaminepentaacetic acid (p-NH2-Bz-DTPA), to the carbohydrate components of the parent molecules. In this study, biodistribution of the111In-labelled derivatives was investigated in normal mice. All the derivatives of IgG1 demonstrated a slower blood clearance than the corresponding derivatives of the F(ab′)2 fragments. This property was particularly pronounced in the site-specifically conjugated derivatives of IgG1. All the derivatives studied accumulated in the liver, kidney, and spleen. The CA-DTPA derivatives of F(ab′)2 fragments showed the highest kidney-to-blood ratios of radioactivity compared with the other compounds studied. The derivatives of IgG1 showed a higher percentage of the injected dose in liver and spleen tissues than the derivatives of the F(ab′)2 fragments. The F(ab′)2 fragments studied also gave rise to site-specific derivatives, which demonstrated that carbohydrates were also present in this part of the molecule. They behaved similarly to the CA-DTPA F(ab′)2 derivative in other respects, but the kidney accumulation was lower at 72 and 120 h. The F(ab′)2 fragments studied would be better suited for radioimaging than the derivatives of the IgG1 studied due to the rapid blood clearance of the F(ab′)2 derivatives. In contrast, the derivatives of IgG1, especially thep-NH2-Bz-DTPA conjugate, which showed the lowest kidney uptake, might be more suitable candidates for the development of therapeutic agents.

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