To evaluate the factors responsible for the accumulation of indium-111 immunoglobulin G (111In-IgG) at sites of inflammation, sequential measurements of tissue blood volume, interstitial fluid volume and accumulation of radiolabelled albumin and IgG were made in rats following Escherichia coli infection in the thigh. Compared with normal thigh muscle, there was approximately two-fold increase in interstitial fluid volume and approximately 1.5-fold increase in plasma and red blood cell volumes in infected muscle. For both proteins, there was a fivefold increase in influx rate constant (kin) in infected muscle. In normal muscle, the interstitial fluid concentration of labelled human serum albumin (111In-HSA) was significantly higher than that of 111In-IgG (P less than 0.01). In contrast, the concentrations in infected muscle were nearly identical. The concentration ratios (infected to normal muscle) were 1.7:1 for HSA and 3:1 for IgG. These data suggest that the infection imaging properties of 111In-IgG are related to expansion of the space available to macromolecules in infected tissue and increased transport into this space. At clinically important imaging times (24-48 h after injection), the higher target-to-background ratio of 111In-IgG compared with 111In-HSA is not due to the higher accumulation IgG in infected tissue but rather to the higher accumulation of HSA in normal tissue.
The poor prognosis of patients with advanced medullary thyroid carcinoma (MTC) has prompted a search for new treatment modalities. In this report we explore the characteristics of carcinoembyronic antigen (CEA) as a target for radioimmunotherapy (RAIT) of MTC, with respect to antibody processing, targeting, and experimental therapy. In vitro studies showed a high level of CEA expression on the cell surface of the MTC cell line TT. MAbs bound to the cell were predominantly retained for several days, although there was also a significant level of internalization and catabolism. Immunohistology of frozen sections of tumor xenografts demonstrated that approximately half of the cells were darkly stained, however, some cells expressed little or no CEA. In biodistribution studies in nude mice bearing TT tumors, the mean percent injected dose per gram of tumor observed at three days post injection (time of maximum uptake) of 125I-MN-14 was 19.7%. When the MAb was labeled with 88Y, a residualizing label, a much higher accretion, 50.5%, was observed at the time of maximum uptake (7 days). Significant anti-tumor effects were seen at the maximum tolerated doses of 131I- and 90Y-MN-14, compared with relatively rapid tumor growth in untreated animals or those treated with the same dose of control MAbs. Importantly, it was observed that 90Y-MN-14 yielded significantly improved therapeutic efficacy in comparison to 131I-MN-14, which may have important implications for design and conduct of future clinical trials for the treatment of MTC.
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