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High-Linear Energy Transfer (LET) versus Low-LET ß Emitters in Radioimmunotherapy of Solid Tumors: Therapeutic Efficacy and Dose-limiting Toxicity of ²¹³Bi- versus ⁹⁰Y-labeled CO17-1A Fab' Fragments in a Human Colonic Cancer Model¹

Departments of Nuclear Medicine [T. M. B., M. B., E. We., S. G., W. B.], Internal Medicine (Nephrology) [F. S.], Pathology [A. F.], and Clinical Chemistry [E. Wi.], Georg-August-University, Göttingen D-37075, Germany; Oak Ridge Institute for Science and Education, Oak Ridge Associated Universities, Oak Ridge, Tennessee 37831 [M. G. S.]; Institute for Transuranium Elements, D-76125 Karlsruhe, Germany [C. A., R. M., L. K.]; and Garden State Cancer Center, Belleville, New Jersey 07109 [D. M. G.]

Recent studies suggest that radioimmunotherapy (RIT) with high-linear energy transfer (LET) radiation may have therapeutic advantages over conventional low-LET (e.g., ß^-) 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 versus low-LET ß emitters in vivo. The aim of this study was, therefore, to assess the toxicity and antitumor efficacy of RIT with the emitter ²¹³Bi/²¹³Po, as compared to the ß 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 ß^- and 440-keV emission, with a t_1/2 of 45.6 min, as compared to the ultra-short-lived 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 emitters may be therapeutically more effective than conventional ß emitters. Surprisingly, maximum tolerated blood doses were, at 5–8 Gy, very similar between high-LET and low-LET ß emitters. Due to its short physical half-life, ²¹³Bi appears to be especially suitable for use in conjunction with fast-clearing fragments.

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