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...
This article presents a general discussion on what has been achieved so far and on the possible future developments of targeted alpha (α)-particle therapy (TAT). Clinical applications and potential benefits of TAT are addressed as well as the drawbacks, such as the limited availability of relevant radionuclides. Alpha-particles have a particular advantage in targeted therapy because of their high potency and specificity. These features are due to their densely ionizing track structure and short path length. The most important consequence, and the major difference compared with the more widely used β−-particle emitters, is that single targeted cancer cells can be killed by self-irradiation with α-particles. Several clinical trials on TAT have been reported, completed, or are on-going: four using 213Bi, two with 211At, two with 225Ac, and one with 212Pb/212Bi. Important and conceptual proof-of-principle of the therapeutic advantages of α-particle therapy has come from clinical studies with 223Ra-dichloride therapy, showing clear benefits in castration-resistant prostate cancer.
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
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