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PubMed2001

Comparative cellular catabolism and retention of astatine-, bismuth-, and lead-radiolabeled internalizing monoclonal antibody.

UNLABELLED: Monoclonal antibodies (mAbs) labeled with alpha-emitting radionuclides such as (211)At, (212)Bi, (213)Bi, and (212)Pb (which decays by beta-emission to its alpha-emitting daughter, (212)Bi) are being evaluated for their potential applications for cancer therapy. The fate of these radionuclides after cells are targeted with mAbs is important in terms of dosimetry and tumor detection. METHODS: In this study, we attached various radionuclides that result in alpha-emissions to T101, a rapidly internalizing anti-CD5 mAb. We then evaluated the catabolism and cellular retention and compared them with those of (125)I- and (111)In-labeled T101. T101 was labeled with (211)At, (125)I, (205,6)Bi, (111)In, and (203)Pb. CD5 antigen-positive cells, peripheral blood mononuclear cells (PBMNC), and MOLT-4 leukemia cells were used. The labeled T101 was incubated with the cells for 1 h at 4 degrees C for surface labeling. Unbound activity was removed and 1 mL medium added. The cells were then incubated at 37 degrees C for 0, 1, 2, 4, 8, and 24 h. The activity on the cell surface that internalized and the activity on the cell surface remaining in the supernatant were determined. The protein in the supernatant was further precipitated by methanol for determining protein-bound and non-protein-bound radioactivity. Sites of internal cellular localization of radioactivity were determined by Percoll gradient centrifugation. RESULTS: All radiolabeled antibodies bound to the cells were internalized rapidly. After internalization, (205,6)Bi, (203)Pb, and (111)In radiolabels were retained in the cell, with little decrease of cell-associated radioactivity. However, (211)At and (125)I were released from cells rapidly ((211)At < (125)I) and most of the radioactivity in the supernatant was in a non-protein-bound form. Intracellular distribution of radioactivity revealed a transit of the radiolabel from the cell surface to the lysosome. The catabolism patterns of MOLT-4 cells and PBMNC were similar. CONCLUSION: (211)At catabolism and release from cells were somewhat similar to that of (125)I, whereas (205,6)Bi and (203)Pb showed prolonged cell retention similar to that of (111)In. These catabolism differences may be important in the selection of alpha-radionuclides for radioimmunotherapy.

Alpha Particles↗
PubMed2003

Astatine-211-labeled antibodies for treatment of disseminated ovarian cancer: an overview of results in an ovarian tumor model.

PURPOSE: The aim of the study was to establish and refine a preclinical model to alpha-immunoradiotherapy of ovarian cancer. EXPERIMENTAL DESIGN: At-211 was produced by cyclotron irradiation of a bismuth-209 target and isolated using a novel dry distillation procedure. Monoclonal antibodies were radiohalogenated with the intermediate reagent N-succinimidyl 3-(trimethylstannyl)benzoate and characterized in terms of radiochemical yield and in vitro binding properties. In vitro OVCAR-3 cells were irradiated using an external Cobalt-60 beam, as reference, or At-211-albumin and labeled antibody. Growth assays were used to establish cell survival. A Monte Carlo program was developed to simulate the energy imparted and the track length distribution. Nude mice were used for studies of WBC depression, with various activities of Tc-99m antibodies, as reference, and At-211 antibodies. In efficacy studies, OVCAR-3 cells were inoculated i.p., and animals were treated 2 weeks later. The animals were either dissected 6 weeks later or followed-up for long-term survival. RESULTS: A rapid distillation procedure, as well as a rapid and high-yield, single-pot labeling procedure, was achieved. From growth inhibition data, the relative biological effectiveness of the alpha-emission for OVCAR-3 cells was estimated to be approximately 5, which is in the same range as found in vivo for hematological toxicity. At-211 MOv18 was found to effectively inhibit the development of tumors and ascites, also resulting in long-term survival without significant toxic effect. CONCLUSIONS: Use of the short-range, high-linear energy transfer alpha-emitter At-211 conjugated to a surface epitope-recognizing monoclonal antibody appears to be highly efficient without significant toxicity in a mouse peritoneal tumor model, urging a Phase I clinical trial.

Animals↗
PubMed1987

Efficacy of astatine-211-labeled monoclonal antibody in treatment of murine T-cell lymphoma.

The short-lived isotope 211At (half-life, 7.2 hr), an alpha particle-emitting halogen, has been attached to a monoclonal antibody (anti-thy 1.1, IgG1, OX7) and used in mice in the treatment of a thy 1.1 T-cell lymphoma (A120). Forty-eight hours after receiving an iv injection of 10(3) or 10(5) A120 cells, mice were treated with phosphate-buffered saline, 211At-, antibody alone, or 211At conjugated to OX7. Treatment with the 211At-labeled OX7 conjugate increased the median survival time of mice and probably "cured" (survival at 200 days) 6 of the 15 mice given 10(5) cells and 21 of the 27 mice given 10(3) cells.

Animals↗
PubMed1997

Microdosimetry of astatine-211 using histological images: application to bone marrow.

A method is presented for calculating the small-scale dosimetry of 211At in red bone marrow using chord-length distributions obtained from digitized histological images. This study used histological samples of bone marrow from beagle dogs to convey morphological information about cell conglomerations within bone marrow. Two 211At activity distributions were considered within the extracellular fluid and the surface of red bone marrow cells. Results confirmed the influence of cell conglomeration and activity distribution in determining the microdosimetry of red bone marrow. Average S* values of 1.6 x 10(-9) and 1.90 x 10(-9) Gy g Bq(-1) s(-1) were calculated for activity distributions located within the extracellular fluid and the surface of red bone marrow cells, respectively. The cumulated activity required to reduce survival probability to 0.37 also was calculated as a function of cell sensitivity for both activity distributions. The activity distribution on the cell surface resulted in a higher cell-killing efficiency, requiring a lower activity concentration of approximately 25% when compared with activity located in the extracellular fluid. Of relevance to potential clinical studies with 211At, the probability for zero hits for red bone marrow cells was > 10% for cumulated activities of less than 5.5 x 10(8) Bq s g(-1) in bone marrow.

Animals↗
PubMed1998

Survival and DNA damage in Chinese hamster V79 cells exposed to alpha particles emitted by DNA-incorporated astatine-211.

Asynchronous Chinese hamster V79 lung fibroblasts were incubated at 37 degrees C for 30 min with the thymidine analog 5-[211At]astato-2'-deoxyuridine (211AtdU, exposure from DNA-incorporated activity) or with [211At]astatide (211At-, exposure from extracellular activity), and DNA-incorporated activity was determined. The 211AtdU content in cellular DNA increased as a function of extracellular concentration. Incorporation of 211At- was less than 1% of that of 211AtdU. After exposure, cells were frozen in the presence of 10% DMSO. One month later, survival was determined by the colony-forming assay, and DNA double-strand breaks (DSBs) were measured by the neutral elution method (pH 9.6). The survival curve for 211AtdU was biphasic (D37 = 2.8 decays per cell), reflecting killing of 211At-DNA-labeled cells and of unlabeled cells irradiated by 211At in neighboring labeled cells. The toxicity of 211At- decaying outside the cell (30-min exposure) was negligible. Analysis of the survival curve produced a D0 of 1.3 decays/cell for 211At-labeled cells. The yield of DSBs from the decay of DNA-incorporated 211At was compared with that from DNA-incorporated 125I. Each decay of 211At produced at least 10 times the number of DSBs as that obtained per 125I decay. The extreme radiotoxicity of DNA-incorporated 211AtdU seems to be associated with considerable damage to the mammalian cell genome.

Animals↗
PubMed2002

Comparative biodistribution of the radiohalogenated (Br, I and At) antibody A33. Implications for in vivo dosimetry.

The alpha-emitter astatine-211 (T(1/2) = 7.2 h) has great potential for use in targeted radionuclide therapy. Its potent alpha-radiation makes (211)At unsuitable for dose planning. Its x-rays can be used for gamma-camera monitoring of the radioactivity distribution during therapy but not for accurate estimation of absorbed dose in critical organs. This study was intended to establish whether the absorbed dose delivered by astatinated antibody could be accurately determined by analogue labeling with radiohalogens, better suited for quantitative measurements in vivo. PET facilitates quantitative pharmacokinetics; possible halogen labels are, e.g., (76)Br (T(1/2) = 16.2 h) and (124)I (T(1/2) = 4.18 d). Antibody A33 was labeled with (76)Br, (125)I and (211)At using N-succinimidyl-p-halobenzoates. The conjugates were co-injected into Sprague-Dawley rats. Radioactivity concentrations in different organs and tissues were measured at three time points. Pharmacokinetic data were used to calculate absorbed doses. (125)I and (76)Br reflected the biokinetics of astatine reasonably well. The absorbed doses in bladder, kidney, pancreas, liver, bone and brain were determined with 10% accuracy. The absorbed doses in stomach, spleen and thyroid were underestimated by a factor 2-3. Positron-emitting analogues can be used to predict the astatine-derived dose in critical organs. Correction factors should be used for stomach, spleen and thyroid.

Animals↗
PubMed1990

Comparative tissue distribution in mice of the alpha-emitter 211At and 131I as labels of a monoclonal antibody and F(ab')2 fragment.

Because it decays by the emission of short-range, high-energy alpha-particles, the radiohalogen 211At might be a particularly useful nuclide for some types of radioimmunotherapy. However, no suitable gamma-emitting nuclide of astatine exists which would permit either imaging prior to therapy to obtain radiation dosimetry estimates or performing experiments in paired-label format. Since iodine is the halogen above astatine in the periodic table, we investigated whether the in vivo distribution of 131I could be used to mimic the biodistribution of 211At. In this study, the N-succinimidyl 3-(trialkylstannyl)benzoate method was used to label C110 IgG, an antibody directed against carcinoembryonic antigen, and its (Fab')2 fragment with 211At and 131I. Paired-label experiments were performed in normal mice comparing the tissue distribution of 211At- versus 131I-labeled C110 IgG and F(ab')2 as well as [211At]astatide versus [131I]iodide and m-[211At]astatobenzoic acid versus m-[131I]iodobenzoic acid, potential catabolites of proteins radiohalogenated via the N-succinimidyl 3-(trialkylstannyl)benzoate method. With the exception of thyroid, retention of astatide in tissues was higher than that of iodide; and, with the halobenzoic acids, uptake of 211At was higher than 135I in thyroid, stomach, and spleen. Use of the N-succinimidyl 3-(trialkylstannyl)benzoate method to label C110 IgG with 211At and 131I resulted in similar distributions of the two nuclides. In contrast, loss of 211At from the F(ab')2 fragment was considerably more rapid than 131I, suggesting that different astatination methods may be required for use with F(ab')2 fragments.

Animals↗