| 1. |
- Andersson, Håkan, 1944, et al.
(författare)
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Astatine-211-labeled antibodies for treatment of disseminated ovarian cancer: an overview of results in an ovarian tumor model
- 2003
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Ingår i: Clin Cancer Res. - 1078-0432. ; 9:10 Pt 2
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Tidskriftsartikel (refereegranskat)abstract
- 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.
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| 2. |
- Andersson, Håkan, 1944, et al.
(författare)
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Comparison of the therapeutic efficacy of 211At- and 131I-labelled monoclonal antibody MOv18 in nude mice with intraperitoneal growth of human ovarian cancer.
- 2001
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Ingår i: Anticancer research. - 0250-7005. ; 21:1A, s. 409-12
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Tidskriftsartikel (refereegranskat)abstract
- The purpose of the present study was to compare the therapeutic efficacy of the alpha-emitter Astatine-211 with the beta-emitter Iodine-131 bound to the specific monoclonal antibody MOv18. The measurements were performed in an ovarian cancer cell line (NIH:OVCAR 3) growing intraperitoneally in nude mice. Two weeks after the intraperitoneal inoculation of 1 x 10(7) cells of the human ovarian cancer cell line NIH:OVCAR-3 twenty mice were treated intraperitoneally with the specific monoclonal antibody MOv-18 labelled with either 211At (310-400 kBq) or 131I (5100-6200 kBq). The pharmacokinetics and biodistribution of labelled antibody in tumour-free animals were studied and the resulting bone marrow dose was estimated. When the mice were treated with 211At-labelled antibody 9 out of 10 mice were free of macro- and microscopic tumour compared to 3 out of 10 when Iodine-131 was used. The equivalent dose to the bone marrow was 2.4-3.1 Sv from 211At- and 3.4-4.1 Sv from 131I-irradiation. The therapeutic efficacy of 211At-labelled specific antibody is very good and, at approximately equivalent bone marrow doses, better than that of 131I.
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| 6. |
- Lindegren, Sture, 1960, et al.
(författare)
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(211)At-labeled and biotinylated effector molecules for pretargeted radioimmunotherapy using poly-L- and poly-D-Lysine as multicarriers
- 2003
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Ingår i: Clin Cancer Res. - 1078-0432. ; 9:10 Pt 2
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Tidskriftsartikel (refereegranskat)abstract
- Poly-L- and poly-D-lysine were evaluated as carriers of astatine and biotin for prospective use as effector molecules in pretargeted radioimmunotherapy of micrometastases. The precursor polylysine was derivatized in a three-step, single-pot procedure, including biotinylation with biotin amidocaproic N-hydroxysuccinimide, astatination via the intermediate reagent N-succinimidyl 3-(trimethylstannyl)benzoate, and, finally, charge modification using succinic anhydride. The chemistry was shown to be very facile, with a biotinylation efficiency of 75 +/- 5%, and overall radiochemical yields in the range of 50-70%. After charge modification, no amines could be detected in the final product. The biotin function was unaffected by the chemistry and the radiation, as confirmed by almost complete binding of the effector molecule to avidin beads using a convenient filter tube assay. The effector molecules were evaluated in tumor-free female nude mice with regard to whole-body retention and tissue distribution after i.p. administration. The distribution of the L-isomer effector molecule showed rapid whole-body clearance with low uptake in all tissues, whereas the D-isoform showed whole-body clearance related to uptake in the kidneys. Both D-isomer and L-isomer showed faster blood clearance and generally lower tissue uptakes than labeled antibodies. The normal tissue distribution after the peritoneal administration implies that pretargeting using L-structure polylysine as the effector molecule may give a higher therapeutic index than that achieved in conventional radioimmunotherapy.
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| 7. |
- Lindegren, Sture, 1960
(författare)
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Astatine-211 and Iodine Conjugates: Radiohalogenation and Preclinical Pharmacokinetics for Targeted and Pretargeted Radioimmunotherapy
- 2002
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Endoradiotherapy using labelled tumour specific-monoclonal antibodies in the therapy of malignant disease is a therapeutic modality that is coming of age. While clearly defined tumours can be treated with surgery and/or chemotherapy, occult metastases requires adjuvant systemic treatment, e.g. chemotherapy or endoradiotherapy, to prevent or delay tumour progress. To improve the therapeutic efficiency in the treatment of disseminated occult disease, short-range, high-LET .alfa.-emitters such as 211At offers an attractive prospect together with carrier substances such as tumour specific antibodies. The aim of this work were: to establish a convenient procedure to obtain 211At in chemically useful form, to develop routes of synthesis, and the subsequent evaluation in vitro and in vivo, of radiohalogenated conjugates for targeted and pretargeted radioimmunotherapy. Methods. 211At was produced by cyclotron irradiation via the 211At(.alfa.,2n)209Bi reaction, and the astatine was isolated from the irradiated targets using a novel dry-distillation procedure. Antibodies (Mov18, ovarian-tumour-specific, and C215 colon-tumour-specific) or poly-L-lysine of different molecular weights, were radiohalogenated with 125I, 131I or 211At via the intermediate labelling reagent N-succinimidyl 3-(trimethylstannyl)benzoate (m-MeATE). Radiohalogenated products, labelled antibodies for radioimmunotherapy (RIT) and modified poly-L-lysine as effector molecule for pretargeted radioimmunotherapy (PRIT), were characterised in terms of radiochemical yields, structure, in vitro binding properties, and were subsequently evaluated in vivo with regard to biodistribution or therapeutic efficiency in athymic mice. Results. 211At was isolated at high radiochemical yields (75-85% of the original target activity) with fast kinetics. Subsequent labelling and conjugation to antibodies and polymers were highly efficient with overall labelling efficiencies of 50-70%. In vitro evaluation of labelled products showed that binding properties were retained at present reaction conditions. In short term therapy of 211At-MOv18 in mice with occult intraperitoneal human metastases (NIH:OVCAR-3 cells), 9 of 10 animals were apparently free of tumour after treatment given intraperitoneally. The distribution of modified polymers in tumour-free mice revealed fast whole-body clearance rates and tissue uptakes generally lower than that of labelled antibodies. Conclusions. 211At-labelled tumour specific antibodies are effective in therapy of intraperitoneal human ovarian micro metastases xenograft in nude mice treated intraperitoneally. Improvement of pharmacokinetics, with enhanced therapeutic index, in the treatment of minimal residual disease may be achieved utilising a pretargeting strategy based upon a biotinylated, 211At-labelled and charged modified poly-L-lysine effector molecule.
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| 8. |
- Lindegren, Sture, 1960, et al.
(författare)
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Synthesis and biodistribution of 211At-labeled, biotinylated, and charge-modified poly-L-lysine: evaluation for use as an effector molecule in pretargeted intraperitoneal tumor therapy.
- 2002
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Ingår i: Bioconjugate chemistry. - 1043-1802 .- 1520-4812. ; 13:3, s. 502-9
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Tidskriftsartikel (refereegranskat)abstract
- Poly-L-lysine (7, 21, and 204 kDa) has been evaluated as an effector carrier for use in pretargeted intraperitoneal tumor therapy. For the synthesis, the epsilon-amino groups on the poly-L-lysine were modified in three steps utilizing conjugate biotinylation with biotin amidocaproate N-hydroxysuccinimide ester (BANHS), conjugate radiolabeling with (211)At using the intermediate reagent N-succinimidyl 3-(trimethylstannyl)benzoate (m-MeATE), and charge modification using succinic anhydride, resulting in an increase in the molecular weight of approximately 80% of the final product. The labeling of the m-MeATE reagent and subsequent conjugation of the polymer were highly efficient with overall radiochemical yields in the range of 60-70%. The in vitro avidin binding ability of the modified polymer was almost complete (90-95%), as determined by binding to avidin beads using a convenient filter tube assay. Following intraperitoneal (ip) injection in athymic mice, the 13 kDa polymer product was cleared mainly via the kidneys with fast kinetics (biological half-live T(b) approximately 2 h) and with low whole-body retention. The clearance of the 38 kDa polymer was distributed between kidneys and liver, and the 363 kDa polymer was mainly sequestered by the liver with a T(b) of 8 h. Increased tissue uptake in the thyroid, lungs, stomach, and spleen following the distribution of the large effector molecules (38 and 363 kDa) suggests that degradation of the polymers by the liver may release some of the label as free astatine/astatide.
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| 9. |
- Palm, Stig, 1964, et al.
(författare)
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Cell growth kinetics of the human cell line Colo-205 irradiated with photons and astatine-211 alpha-particles
- 2000
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Ingår i: Anticancer Res. - 0250-7005. ; 20:3A, s. 1807-12
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Tidskriftsartikel (refereegranskat)abstract
- Cell growth kinetics following Astatine-211 (211At, alpha-particle emitter) and photon irradiation were studied for the human colorectal cell line Colo-205. A growth assay using 96-well plates was chosen. The growth kinetics could be simulated by assuming certain fractions of cells with various proliferative capacities, i.e. from none up to 5 cell doublings, in addition to the defined survivors with remaining unlimited clonogenic capacity. No significant difference in cell growth characteristics was seen between 211At and photon irradiation. The cell doubling time, as calculated from the increment in optical density, was compared with the results from BrdU experiments in the early phases of growth (Tpot = 18.5 +/- 0.6 h for LDR (low dose rate) photon irradiated and 20.3 +/- 0.8 hours for sham-irradiated cells 40-45 hours post-irradiation) confirming the transient accelerated growth of irradiated cells. No statistically significant difference in growth was found between LDR, MDR (medium dose rate) and HDR (high dose rate) photon irradiation.
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| 12. |
- Palm, Stig, 1964, et al.
(författare)
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In vitro effects of free 211At,211At-albumin and 211At-monoclonal antibody compared to external photon irradiation on two human cancer cell lines
- 2000
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Ingår i: Anticancer Res. - 0250-7005. ; 20:2A, s. 1005-12
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: The aim of this study was to perform various 211At irradiations of importance for the evaluation of 211At-radioimmunotherapy, and compare the effect with that of low linear energy transfer (LET) radiation. MATERIALS AND METHODS: All irradiations were performed on low-concentration single-cell suspensions. Growth assays using 96-well plates were used to estimate apparent cell survival. Centrifuge tube filters were used to estimate the cell uptake and binding of 211At. RESULTS: A relative biological effect (RBE) of 12 +/- 2 (Colo-205) and 5.3 +/- 0.7 (OVCAR-3) was found from 211At-albumin irradiations. There was a 174 +/- 28 times higher free 211At concentration in the cell fraction than in the surrounding medium. For 211At-MAb, an 8,000-30,000 times higher concentration in the cell fraction was achieved, compared to the medium. Corrected for the uptake, an average of 31 +/- 2 ([211At]-astatine) or 26 +/- 5 ([211At]-MAb) decays per cell were required for 37% survival of Colo-205 cells. An average of 19 +/- 3 decays ([211At]-astatine) were required per OVCAR-3 cell. CONCLUSIONS: Cell uptake and binding of 211At was unexpectedly high, possibly favouring its therapeutic use. The binding is probably to the cell surface. The RBE is 5.3 +/- 0.7 for OVCAR-3 and 12 +/- 2 for Colo-205 cells.
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| 13. |
- Palm, Stig, 1964, et al.
(författare)
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Single-cell irradiation from [211At] astatine-labeled C215 monoclonal antibody: improved estimates of radiosensitivity from measurements on cellular uptake and retention
- 2003
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Ingår i: Anticancer Res. - 0250-7005. ; 23:2B, s. 1219-21
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Tidskriftsartikel (refereegranskat)abstract
- New data on the biological effect of 211At-C215 monoclonal antibody in a slowly rotating, widely dispersed single-cell suspension of the human cancer cell line Colo-205 is presented. Cell growth curves of each experiment were used to calculate an apparent cell survival after irradiation. Uptake measurements provided the data needed to calculate the average number of 211At decays per cell in the cell suspension. The results from each experiment were then fit to a mono-exponential function. From the exponential fit, an average of 35 +/- 2 (SD) astatine-211 decays per cell are required for 37% apparent cell survival (D0).
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