Dl D2 07

Figure 2 Anterior and posterior 111-indium whole-body images after intraperitoneal radioimmunotherapy (RIT) with 90-yttrium-humanized 3S193 (the indium was colabeled with the yttrium).

therapeutic target for a cancer refractory to chemotherapy whose five-year survival rate is less than 10%. Antibody G250, developed by Oosterwijk et al., recognizes carbonic anhydrase-IX with normal tissue cross-reactivity, limited only to biliary epithelium (82). Our initial study with murine G250 demonstrated excellent targeting to renal tumors with probably the highest absolute solid tumor uptakes documented by biopsy. Repeat treatment was obviated by HAMA (83). Multiple administrations may be crucial for the treatment of heterogeneous, bulky solid tumors. Chimeric G250 (IgGi) was therefore produced and studied in phase 1 studies with 131I.

A study has been carried out with a single large RIT dose. This has demonstrated a decrease in HACA formation (84,85), and the ability to predict HACA by carrying out "scout" dose imaging. In order to evaluate the effect of treatment dose fractionation upon safety and efficacy, we simultaneously started a single large-dose RIT study based on escalating amounts of 131I and a study of fractionated cG250 using 1110-MBq (30 mCi) 131I-cG250 doses in a whole body radiation-absorbed dose-based schema (85) (Fig. 3). In this study, the MTD of 131I was found to be 0.75 Gy, and dose-limiting toxicity was hematologic. Preliminary calculations suggest that dose-limiting whole body radiation-absorbed dose is not different in "rapidly" fractionated and single large dose treatment schema (86). However, differential distribution of radioactivity in tumor may vary following each fraction, therefore, putatively allowing better delivery of cytotoxic radiation. These data are currently being analyzed.

As the G250 antibody binds to epithelial cells of the large bile duct and gall bladder, and as biliary cancers are sensitive to radiation, RIT with WX-G250 RIT may have clinical benefits in the treatment of biliary cancer patients. These cancers are particularly difficult to treat owing to the late stage at diagnosis. The 131I-labeled antibody WX-G250 RIT is designed to identify the tumor cells and deliver doses of radiation directly to the tumor cells. Clinical phase 1/2 trials with WX-G250 RIT in biliary cancer patients appear promising. As the antigen is expressed on both normal biliary tissue and biliary cancers, the evaluation of

Figure 3 Anterior whole-body images after 131-iodine-cG250. Note the excellent targeting to metastases (arrows).

differential expression is important to the selection of an appropriate RIT model, and we are therefore evaluating differential in vivo expression of tumor antigen using quantitative positron emission tomography (PET) and 124I-cG250.

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