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The application of intraperitoneal (i.p.) radioimmunotherapy to treat i.p. tumor loci has been limited by bonemarrow toxicity secondary to circulating radiolabeled antibodies. The generation of novel genetically engineeredmonoclonal antibodies, which can achieve high tumor uptake and rapid blood clearance, should enhancethe therapeutic index of i.p. radioimmunotherapy. In this regard, a novel humanized anti-TAG-72 monoclonalantibody with a deleted CH2 region (HuCC49ΔCH2) has been described, which localized well tosubcutaneous xenograft tumors and had a rapid plasma clearance. The aim of this study was to examine thecharacteristics of this radiolabeled reagent when administered through the i.p. route in mice bearing i.p. tumor(LS174T). The ΔCH2 molecule and intact humanized CC49 (HuCC49) monoclonal antibody were conjugatedto PA-DOTA and radiolabeled with 177Lu. Both molecules retained high-affinity binding to TAG-72positive LS174T tumor cells in vitro. The radiolabeled ΔCH2 molecule had a modest decrease in tumor localization,as compared to the intact molecule when administered i.p. to tumor-bearing mice and a dramaticallyshorter plasma disappearance T1/2 at 2.7 hours compared to 61.2 hours for the intact antibody. Theradiolabeled ΔCH2 molecule thus had very high tumor:blood ratios. Using an 131I-labeled system, the maximumtolerated dose of ΔCH2 was >3× that of intact HuCC49. Autoradiography of tumors showed low radiationdose rates at tumor centers early (1 and 4 hours), as compared to higher dose rates at tumor peripherybut a more uniform distribution by 24 hours. Dose-rate distributions were similar for both reagents.Animals bearing LS174T i.p. tumors were treated with 300 µCi of 177Lu-labeled ΔCH2 or intact HuCC49 byi.p. route daily × 3. The 177Lu-ΔCH2 molecule mediated an increase in median survival compared to controls(67.5 ± 7.5 days versus controls of 32 ± 3.3) while the same dose of 177Lu-HuCC49 produced earlytoxic deaths. These studies suggest that i.p. radioimmunotherapy using radiolabeled HuCC49ΔCH2 shouldallow higher radiation doses to be administered with less marrow toxicity and potentially improved efficacy. [ABSTRACT FROM AUTHOR]

The goal of this study was to synthesize and evaluate a novel bombesin (BN) analogue containing a polyethylene glycol (PEG) linker that can be radiolabeled with 64Cu through the DOTA bifunctional chelate. It is hypothesized that PEG linkers would improve the pharmacokinetics of radiolabeled bombesin analogues to optimize their tumor-to-normal tissue ratios for radiotherapy applications. The formation of this conjugate (DOTA-PEG-BN(7-14)) was confirmed by MALDI-TOF mass spectrometry and was radiolabeled with 64Cu at a specific activity of 2.7 MBq/nmol. DOTA-PEG-BN(7-14) bound specifically to gastrin-releasing peptide receptor (GRPR)-positive PC-3 cells with an IC50 value of 3.9 μM for displacing 125I-Tyr4-BN. Internalization of 64Cu-DOTA-PEG-BN(7-14) into PC-3 cells showed that 5.7%, 13.4%, and 21.0% was internalized at 0.5, 2, and 4 hours, respectively. Biodistribution of 64Cu-DOTA-PEGBN(7-14) was evaluated in normal, athymic nude mice 2, 4, and 24 hours after i.v. injection. This showed that most of the tissues had a similar uptake and clearance of 64Cu-DOTA-PEG-BN(7-14) compared to a control peptide with an alkyl linker (DOTA-Aoc-BN(7-14)) at the given time points. There was uptake of 10.8% ID/g of 64Cu-DOTA-PEG-BN(7-14) 4 hours after i.v. injection in the GRPR-positive pancreas that was inhibited to 2.4% upon injection of an excess of Tyr4-BN. These studies demonstrate that BN analogues can be conjugated with PEG linkers, radiolabeled with 64Cu, and bind to GRPR. Future studies will attempt to increase the affinity of these analogues for GRPR and alter the pharmacokinetics of the 64Cu-labeled conjugates through the use of various sized PEG linkers. [ABSTRACT FROM AUTHOR]