Recent studies suggest that radioimmunotherapy (RIT) with high-linear energy transfer (LET) radiation may have therapeutic advantages over conventional low-LET (e.g., β⁻) 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 α versus low-LET β emitters in vivo. The aim of this study was, therefore, to assess the toxicity and antitumor efficacy of RIT with the α emitter ²¹³Bi/²¹³Po, as compared to the β emitter ⁹⁰Y, linked to a monovalent Fab′ fragment in a human colonic cancer xenograft model in nude mice.

Biodistribution studies of ²¹³Bi- or ⁸⁸Y-labeled benzyl-diethylene-triamine-pentaacetate-conjugated Fab′ fragments of the murine monoclonal antibody CO17-1A were performed in nude mice bearing s.c. human colon cancer xenografts. ²¹³Bi was readily obtained from an “in-house” ²²⁵Ac/²¹³Bi generator. It decays by β⁻ and 440-keV γ emission, with a t_1/2 of 45.6 min, as compared to the ultra-short-lived α emitter, ²¹³Po (t_1/2 = 4.2 μs). For therapy, the mice were injected either with ²¹³Bi- or ⁹⁰Y-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 ²¹³Bi- and ⁹⁰Y-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 ⁹⁰Y- and ²¹³Bi-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 ⁹⁰Y-Fab′ was 250 μCi and the MTD of ²¹³Bi-Fab′ was 700 μCi, corresponding to blood doses of 5–8 Gy. Additional bone marrow transplantation allowed for an increase of the MTD of ⁹⁰Y-Fab′ to 400 μCi and for ²¹³Bi-Fab′ to 1100 μCi, respectively. At these very dose levels, no biochemical or histological evidence of renal damage was observed (kidney doses of <35 Gy). At equitoxic dosing, ²¹³Bi-labeled Fab′ fragments were significantly more effective than the respective ⁹⁰Y-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 μCi of ²¹³Bi-Fab′ 10 days after model induction, which is in contrast to an only 20% cure rate in mice treated with 250 μCi of ⁹⁰Y-Fab′.

These data show that RIT with α emitters may be therapeutically more effective than conventional β emitters. Surprisingly, maximum tolerated blood doses were, at 5–8 Gy, very similar between high-LET α and low-LET β emitters. Due to its short physical half-life, ²¹³Bi appears to be especially suitable for use in conjunction with fast-clearing fragments.