Radioactive antibodies for cancer detection in vivo

The noninvasive, external detection of tumors after the administration of antitumor antibodies labeled with a suitable radioisotope has been an objective of certain cancer immunologists for more than three decades (1, 2, 24, 25). Because of its convenient labeling to antibodies without affecting their immunoreactivity, its short half-life of 8 days, and a suitable energy of 364 KeV for external scintigraphy, I~I has been the radionuclide of most frequent use (see 9). However, the major limitation over the years has been the recognition and development of suitable tumor-localizing antibodies, especially since there is little evidence for the existence of truly tumor-distinct substances (4). The recognition of the carcinoembryonic antigen (CEA) of Gold and Freedman (5) as a cancerassociated marker (i.e., showing a quantitative increase with certain forms of neoplasia), suggested that antibodies to CEA may show a selective and increased localization in CEA-containing tumors as compared to adjacent normal structures, and, indeed, initial animal experiments with CEA-producing human colonic carcinomas provided evidence to support this view, first in hamsters (10, 26) and then in nude mice (21) and in monkeys (18). Since these human tumor-animal models did not have high levels of CEA circulating in the blood, a major concern was whether CEA antibodies given to humans with appreciable blood CEA levels would result in antigen-antibody complexes preventing accretion of the antibodies in the tumors. Indeed, initial clinical failures by Reif et al. (28) and by Mach et al. (22) suggested to them that circulating antigen prevented tumor accretion by the injected radioactive antibodies. Subsequently, however, we found that radioactive antibodies to CEA could prove useful for the scintigraphic demonstration of CEA tumors despite high circulating levels of CEA, and that an important technical consideration was the elimination or reduction of nonspecific background radioactivity by means of computer-assisted subtraction, with 99m-Tc components having a different energy for imaging (I40 KeV) than the 13~I conjugated to the antibody (11). The circulating CEA was not inert in this process, since we did observe the formation of circulating antigenantibody complexes (27), but these did not seem to interfere with the deposition of sufficient anti-CEA antibody for tumor radiolocalization. Surprisingly, moreover, a few patients given the go~t antibody to CEA also showed evidence of complexes between human immunoglobulin G (IgG) and the injected goat IgG (27). Despite these findings, no hypersensitivity or other untoward reactions were observed in any of the patients we have studied to date by this technique (13). We concluded from these early studies with CEA antibodies in tumor localization that a truly cancer-specific "marker" substance was not essential for the selective and increased accretion of antitumor antibodies in the appropriate carcinomas. Benign tumors only showed abnormal radioactivity when they contained elevated amounts of CEA (29), while less than 2% of nonneoplastic, benign diseases showed transiently increased radioactivity after administration of the radioactive antibody preparations (13). On the other hand, only very large tumors were usually localized by this technique when irrelevant goat IgG was given (13). Thus, a quantitatively increased tumor marker showed a high degree of tumor specificity when its antibodies were applied in vivo. This observation, and the expectation that the advent of hybridoma monoclonal antibodies might enable the recognition of truly