High-linear energy transfer (LET) alpha versus low-LET beta emitters in radioimmunotherapy of solid tumors: Therapeutic efficacy and dose-limiting toxicity of Bi-213- versus Y-90-labeled CO17-1A Fab ' fragments in a human colonic cancer model

Recent studies suggest that radioimmunotherapy (RIT) with high-linear energ y transfer (LET) radiation may have therapeutic advantages over conventiona l low-LET (e.g., beta(-)) emissions. Furthermore, fragments may be more eff ective in controlling tumor growth than complete IgG. However, to the hest of our knowledge, no investigators have attempted a direct comparison of th e therapeutic efficacy and toxicity of a systemic targeted therapeutic stra tegy, using high-LET alpha versus low-LET beta emitters ill vivo. The aim o f this study was, therefore, to assess the toxicity and antitumor efficacy of RIT with the alpha emitter Bi-213/Po-213, as compared to the beta emitte r Y-90, linked to a monovalent Fab' fragment in a human colonic cancer xeno graft model in nude mice. Biodistribution studies of Bi-213- Or Y-88-labeled benzyl-diethylene-triami ne-pentaacetate-conjugated Fab' fragments of the murine monoclonal antibody CO17-1A were performed in nude mice bearing s.c. human colon cancer xenogr afts. Bi-213 was readily obtained from an "in-house" Ac-225/Bi-213 generato r. It decays by beta(-) and 440-keV gamma emission, with a t(1/2) of 45.6 m in, as compared to the ultra-short-lived alpha emitter, Po-213 (t(1/2) = 4. 2 mu s) For therapy, the mice were injected either with Bi-213- or Y-90-lab eled CO17-1A Fab', whereas control groups were left untreated or were given a radiolabeled irrelevant control antibody. The maximum tolerated dose (MT D) of each agent was determined. The mice were treated with or without inhi bition of the renal accretion of antibody fragments by D-lysine (T. M. Behr et at, Cancer Res., 55: 3825-3834, 1995), bone marrow transplantation, or combinations thereof. Myelotoxicity and potential second-organ toxicities, as well as tumor growth, were monitored at,weekly intervals. Additionally, the therapeutic efficacy of both Bi-213- and Y-90-Iabeled CO17-1A Fab' was compared in a GW-39 model metastatic to the liver of nude mice. In accordance with kidney uptake values of as high as greater than or equal to 80% of the injected dose per gram, the kidney was the first dose-limiti ng organ using both Y-90- and Bi-213-labeled Fab' fragments. Application of D-lysine decreased the renal dose by >3-fold. Accordingly, myelotoxicity b ecame dose limiting with both conjugates. By using lysine protection, the M TD of Y-90-Fab' wits 250 mu Ci and the MTD of Bi-213-Fab' was 700 mu Ci, co rresponding to blood doses of 5-8 Gy. Additional bone marrow transplantatio n allowed for an increase of the MTD of Y-90-Fab' to 400 mu Ci and for Bi-2 13-Fab' to 1100 mu Ci, respectively. At these very dose levels, no biochemi cal or histological evidence of renal damage was observed (kidney doses of <35 Gy). At equitoxic dosing, Bi-213-labeled Fab' fragments were significan tly more effective than the respective Y-90-Iabeled conjugates. In the meta static model, all untreated controls died from rapidly progressing hepatic metastases at 6-8 weeks after tumor inoculation, whereas a histologically c onfirmed cure was observed in 95% of those animals treated with 700 mu Ci o f Bi-213-Fab' 10 days after model induction, which is in contrast to an onl y 20% cure rate in mice treated with 250 mu Ci of Y-90-Fab'. These data show that RIT with alpha emitters may be therapeutically more ef fective than conventional beta emitters. Surprisingly, maximum tolerated bl ood doses were, at 5-8 Gy, very similar between high-LET alpha and low-LET beta emitters. Due to its short physical half-life, Bi-213 appears to be es pecially suitable for use in conjunction with fast-clearing fragments.