The a-emitter 211 At labeled to a monoclonal antibody has proven safe and effective in treating microscopic ovarian cancer in the abdominal cavity of mice. Women in complete clinical remission after second-line chemotherapy for recurrent ovarian carcinoma were enrolled in a phase I study. The aim was to determine the pharmacokinetics for assessing absorbed dose to normal tissues and investigating toxicity. Methods: Nine patients underwent laparoscopy 2-5 d before the therapy; a peritoneal catheter was inserted, and the abdominal cavity was inspected to exclude the presence of macroscopic tumor growth or major adhesions. 211 At was labeled to MX35 F(ab9) 2 using the reagent N-succinimidyl-3-(trimethylstannyl)-benzoate. Patients were infused with 211 At-MX35 F(ab9) 2 (22.4-101 MBq/L) in dialysis solution via the peritoneal catheter. g-camera scans were acquired on 3-5 occasions after infusion, and a SPECT scan was acquired at 6 h. Samples of blood, urine, and peritoneal fluid were collected at 1-48 h. Hematology and renal and thyroid function were followed for a median of 23 mo. Results: Pharmacokinetics and dosimetric results were related to the initial activity concentration (IC) of the infused solution. The decay-corrected activity concentration decreased with time in the peritoneal fluid to 50% IC at 24 h, increased in serum to 6% IC at 45 h, and increased in the thyroid to 127% 6 63% IC at 20 h without blocking and less than 20% IC with blocking. No other organ uptakes could be detected. The cumulative urinary excretion was 40 kBq/(MBq/L) at 24 h. The estimated absorbed dose to the peritoneum was 15.6 6 1.0 mGy/(MBq/L), to red bone marrow it was 0.14 6 0.04 mGy/(MBq/L), to the urinary bladder wall it was 0.77 6 0.19 mGy/(MBq/L), to the unblocked thyroid it was 24.7 6 11.1 mGy/(MBq/L), and to the blocked thyroid it was 1.4 6 1.6 mGy/(MBq/L) (mean 6 SD). No adverse effects were observed either subjectively or in laboratory parameters. Conclusion: This study indicates that by intraperitoneal administration of 211 At-MX35 F(ab9) 2 it is possible to achieve therapeutic absorbed doses in microscopic tumor clusters without significant toxicity. The lifetime risk of ovarian cancer is 1%22% in European and U.S. women. Despite seemingly successful cytoreductive surgery, followed by systemic chemotherapy, most patients will relapse and succumb. The relapse is most frequently localized in the abdominal cavity. New systemic chemotherapy regimens have not improved the outcome over the past decade, which prompted experimental intraperitoneal treatments, including radioimmunotherapy.Radioimmunotherapy with b-emitters has displayed promising results, although an international randomized phase III study of 90 Y-HMFG1 showed no improvement in survival or time to relapse (1). This disappointing result could be partly explained by the choice of radionuclide. The long range of this b-emitter results in poor irradiation of small tumor clusters, likely insufficient to eradicate peritoneal micrometastases. Furthermore, the relativel...

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Bioconjugates used in internal radiotherapy exhibit heterogeneous distributions in organs and tumors, implying a risk of nonuniform dose distribution in therapeutic applications using a-particle emitters. Tools are required that provide data on the activity distribution for estimation of absorbed dose on a suborgan level. The a-camera is a quantitative imaging technique developed to detect a-particles in tissues ex vivo. The aim of this study was to evaluate the characteristics of this imaging system and to exemplify its potential use in the development of a-radioimmunotherapy. Methods: The a-camera combines autoradiography with a scintillating technique and optical registration by a charge-coupled device (CCD). The imaging system characteristics were evaluated by measurements of linearity, uniformity, and spatial resolution. The technique was applied for quantitative imaging of 211 At activity distribution in cryosections of tumors, kidney, and whole body. Intratumoral activity distributions of tumor-specific 211 At-MX35-F(ab9) 2 were studied at various times after injection. The postinjection activity distributions in the renal cortex and whole kidneys were compared for 211 At-F(ab9) 2 and 211 At-IgG trastuzumab. Results: Quantitative analysis of a-camera images demonstrated that the pixel intensity increased linearly with activity in the imaged specimen. The spatial resolution was 35 6 11 mm (mean 6 SD) and the uniformity better than 2%. Kidney cryosections revealed a higher cortex-to-whole kidney ratio for 211 At-F(ab9) 2 than for 211 At-IgG (1.38 6 0.03 and 0.77 6 0.04, respectively) at 2 h after injection. Nonuniform intratumoral activity distributions were found for tumor-specific 211 At-MX35-F(ab9) 2 at 10 min and 7 h after injection; after 21 h, the distribution was more uniform. Conclusion: The characteristics of the a-camera are promising, suggesting that this bioimaging system can assist the development, evaluation, and refinement of future targeted radiotherapy approaches using a-emitters. The a-camera provides quantitative data on the activity distribution in tissues on a near-cellular scale and can therefore be used for small-scale dosimetry, improving the prediction of biologic outcomes with a-particles with short path length and high linear energy transfer. Promi sing results from preclinical studies (1-6) and pilot clinical trials (7,8) have increased the interest in clinical applications using a-emitting radionuclides for the treatment of cancer. The high linear energy transfer (LET) of a-particles yields a potent method of killing cancer cells. The short path length of a-particles in tissues (50-70 mm) is an advantage if the bioconjugate can be targeted specifically to tumor cells. In combination, the high LET and the short path length can make a-particle therapy an effective treatment of micrometastases and small tumors.Because of the short range of a-particles and the heterogeneous distributions of the targeting molecules, the resulting dose distributions within organs and tumor tissues can...

and 2 Cyclotron and PET Unit, KF-3982, Rigshospitalet, Copenhagen, Denmark 211 At-labeled tumor-specific antibodies have long been considered for the treatment of disseminated cancer. However, the limited availability of the nuclide and the poor efficacy of labeling procedures at clinical activity levels present major obstacles to their use. This study evaluated a procedure for the direct astatination of antibodies for the production of clinical activity levels. Methods: The monoclonal antibody trastuzumab was conjugated with the reagent N-succinimidyl-3-(trimethylstannyl)benzoate, and the immunoconjugate was labeled with astatine. Before astatination of the conjugated antibody, the nuclide was activated with N-iodosuccinimide. The labeling reaction was evaluated in terms of reaction time, volume of reaction solvent, immunoconjugate concentration, and applied activity. The quality of the astatinated antibodies was determined by in vitro analysis and biodistribution studies in nude mice. Results: The reaction proceeded almost instantaneously, and the results indicated a low dependence on immunoconjugate concentration and applied activity. Radiochemical labeling yields were in the range of 68%281%, and a specific radioactivity of up to 1 GBq/mg could be achieved. Stability and radiochemical purity were equal to or better than those attained with a conventional 2-step procedure. Dissociation constants for directly astatinated, conventionally astatinated, and radioiodinated trastuzumab were 1.0 6 0.06 (mean 6 SD), 0.44 6 0.06, and 0.29 6 0.02 nM, respectively. The tissue distribution in non-tumor-bearing nude mice revealed only minor differences in organ uptake relative to that obtained with the conventional method. Conclusion: The direct astatination procedure enables the high-yield production of astatinated antibodies with radioactivity in the amounts required for clinical applications. Among the isotopes of the heaviest element in the halogen group, 211 At has attracted interest as a prospective candidate for endoradiotherapeutic applications because of its physicochemical characteristics (1). Unlike most commonly medically applied therapeutic radionuclides that decay through medium-to high-energy b-emission, leading to low-linear-energy-transfer radiation with particle ranges of 1-10 mm, 211 At decays through a-emission, depositing high-linear-energy-transfer radiation in a microvolume corresponding to a mean a-particle range of ;65 mm. When bound to a tumor-specific substance, this radiation can be effective in the destruction of disseminated microtumors, that is, micrometastases, as has been demonstrated in several preclinical studies (2-5). The preclinical work has resulted in 2 phase I studies, a study of the treatment of malignant gliomas at

Radioimmunotherapy (RIT) with ␣-emitting radionuclides is an attractive approach for the treatment of minimal residual disease because the short path lengths and high energies of ␣-particles produce optimal cytotoxicity at small target sites while minimizing damage to surrounding normal tissues. Pretargeted RIT (PRIT) using antibody-streptavidin (Ab-SA) constructs and radiolabeled biotin allows rapid, specific localization of radioactivity at tumor sites, making it an optimal method to target ␣-emitters with IntroductionNon-Hodgkin lymphoma (NHL) is the sixth most common type of cancer, with over 74 000 new cases diagnosed annually in the United States. 1 Following conventional treatment with chemotherapy or radiation therapy, patients with advanced stage indolent NHL inevitably relapse, with death occurring a median of 5 years after recurrence. 2 The introduction of rituximab, a monoclonal antibody against CD20, has led to improved survival in patients with NHL. [3][4][5] Despite the encouraging clinical results with anti-CD20 antibodies, however, the majority of patients with indolent NHL who respond to immunochemotherapy eventually relapse with recurrent lymphoma. 6,7 Recently, radioimmunotherapy (RIT) has emerged as a promising treatment option for lymphoma. RIT with iodine-131( 131 I) tositumomab or yttrium-90 ( 90 Y) ibritumomab tiuxetan as a single agent has yielded excellent overall response rates of 50% -80%, with complete response rates of 20% -40% in patients with relapsed or refractory indolent NHL. [8][9][10][11][12][13] Even more notable response rates have been observed when RIT is used as front-line treatment in patients with indolent NHL. 14 In a recent large phase 3 trial, the addition of 90 Y-ibritumomab tiuxetan in first remission after chemotherapy significantly improved response rates and remission durations in patients with advancedstage follicular lymphoma, 15 presumably by killing residual tumor cells that survived the induction chemotherapy. 16 Based on this data, 90 Y-ibritumomab tiuxetan has been approved by the FDA for first line consolidation therapy in follicular lymphoma. However, the ␤-emitting radionuclides used in current RIT schemes may not be ideal for irradiating microscopic tumors and isolated tumor cells present in the setting of minimal residual disease (MRD). It is estimated that the fraction of energy deposited in a tumor measuring 200 m in diameter is only 1.5% and 17% for 90 Y-labeled and 131 I-labeled antibodies (Abs), respectively. 17,18 The remainder of the ␤ energy is deposited in surrounding normal tissues, resulting in dose-limiting toxicities. Furthermore, the relatively low decay energies of ␤-particles result in suboptimal killing of tumor cells, ultimately contributing to relapse in the majority of treated patients. In contrast, ␣-emitting radionuclides impart high-linear-energytransfer radiation along densely ionized, linear tracks over relatively short distances (40 to 90 m or few cell diameters), which are highly effective in cell-killing. Alpha-particle...