Therapeutic efficacy and dose-limiting toxicity of auger-electron vs. beta emitters in radioimmunotherapy with internalizing antibodies: Evaluation of ¹²⁵I- vs. ¹³¹I-labeled CO17-1A in a human colorectal cancer model

Recent clinical results suggest that higher anti-tumor efficacy may be achieved with internalizing monoclonal antibodies (MAbs) at lower toxicity when labeled with Auger-electron, as compared to conventional β-emitters. The aim of our study was to compare the toxicity and anti-tumor efficacy of the ¹²⁵I-labeled internalizing MAb, CO17-1A, with its ¹³¹I-labeled form in a human colon cancer model in nude mice. Biodistribution studies were performed in nude mice bearing s.c. human colon cancer xenografts. For therapy, the mice were injected either with unlabeled ¹²⁵I- or ¹³¹I- labeled CO17-1A at equitoxic doses. Control groups were left untreated, were given a radiolabeled isotype-matched irrelevant antibody or a tumor- specific, but noninternalizing antibody. The maximum tolerated activities (MTD) of ¹³¹I-and ¹²⁵I-CO17-1A without artificial support were 300 μCi and 3 mCi, respectively. Myelotoxicity was dose-limiting; bone marrow transplantation allowed for an increase of the MTD to 400 μCi of ¹³¹I- 17-1A, whereas the MTD of ¹²⁵I-17-1A with bone marrow support had not been reached at 5 mCi. Whereas no significant therapeutic effects were seen with unlabeled CO17-1A, tumor growth was retarded with ¹³¹I-CO17-1A. With the ¹²⁵I-label, however, therapeutic results were clearly superior. In contrast, no significant difference was observed in the therapeutic efficacy of the ¹³¹I- vs. ¹²⁵I-labeled, noninternalizing antibodies. Our data indicate a superiority of Auger-electron emitters, such as ¹²⁵I, as compared to therapy with conventional β-emitters with internalizing antibodies. The lower toxicity of Auger emitters may be due to the short path length of their low-energy electrons, which can reach the nuclear DNA only if the antibody is internalized (as is the case in antigen-expressing tumor tissue, but not in the stem cells of the red marrow).