High-Linear Energy Transfer (LET) a versus Low-LET b Emitters in Radioimmunotherapy of Solid Tumors: Therapeutic Efficacy and Dose-limiting

Recent studies suggest that radioimmunotherapy (RIT) with highlinear energy transfer (LET) radiation may have therapeutic advantages over conventional low-LET (e.g., b) emissions. Furthermore, fragments may be more effective in controlling tumor growth than complete IgG. However, to the best of our knowledge, no investigators have attempted a direct comparison of the therapeutic efficacy and toxicity of a systemic targeted therapeutic strategy, using high-LET a versus low-LET b emitters in vivo. The aim of this study was, therefore, to assess the toxicity and antitumor efficacy of RIT with the a emitter Bi/Po, as compared to the b emitter Y, linked to a monovalent Fab* fragment in a human colonic cancer xenograft model in nude mice. Biodistribution studies of Bior Y-labeled benzyl-diethylene-triaminepentaacetate-conjugated Fab* fragments of the murine monoclonal antibody CO17-1A were performed in nude mice bearing s.c. human colon cancer xenografts. Bi was readily obtained from an “in-house” Ac/Bi generator. It decays by b and 440-keV g emission, with a t1/2 of 45.6 min, as compared to the ultra-short-lived a emitter, Po (t1/2 5 4.2 ms). For therapy, the mice were injected either with Bior Y-labeled CO17-1A Fab*, whereas control groups were left untreated or were given a radiolabeled irrelevant control antibody. The maximum tolerated dose (MTD) of each agent was determined. The mice were treated with or without inhibition of the renal accretion of antibody fragments by D-lysine (T. M. Behr et al., 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 Biand Y-labeled 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 >80% of the injected dose per gram, the kidney was the first dose-limiting organ using both Yand Bi-labeled Fab* fragments. Application of D-lysine decreased the renal dose by >3-fold. Accordingly, myelotoxicity became dose limiting with both conjugates. By using lysine protection, the MTD of Y-Fab* was 250 mCi and the MTD of Bi-Fab* was 700 mCi, corresponding to blood doses of 5–8 Gy. Additional bone marrow transplantation allowed for an increase of the MTD of Y-Fab* to 400 mCi and for Bi-Fab* to 1100 mCi, respectively. At these very dose levels, no biochemical or histological evidence of renal damage was observed (kidney doses of <35 Gy). At equitoxic dosing, Bi-labeled Fab* fragments were significantly more effective than the respective Y-labeled conjugates. In the metastatic model, all untreated controls died from rapidly progressing hepatic metastases at 6–8 weeks after tumor inoculation, whereas a histologically confirmed cure was observed in 95% of those animals treated with 700 mCi of Bi-Fab* 10 days after model induction, which is in contrast to an only 20% cure rate in mice treated with 250 mCi of Y-Fab*. These data show that RIT with a emitters may be therapeutically more effective than conventional b emitters. Surprisingly, maximum tolerated blood doses were, at 5–8 Gy, very similar between high-LET a and low-LET b emitters. Due to its short physical half-life, Bi appears to be especially suitable for use in conjunction with fast-clearing fragments.