| 1. |
- Andersson, Håkan, 1944, et al.
(författare)
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Intraperitoneal alpha-particle radioimmunotherapy of ovarian cancer patients: pharmacokinetics and dosimetry of (211)At-MX35 F(ab')2--a phase I study.
- 2009
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Ingår i: Journal of nuclear medicine : official publication, Society of Nuclear Medicine. - : Society of Nuclear Medicine. - 0161-5505. ; 50:7, s. 1153-60
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Tidskriftsartikel (refereegranskat)abstract
- The alpha-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(ab')(2) using the reagent N-succinimidyl-3-(trimethylstannyl)-benzoate. Patients were infused with (211)At-MX35 F(ab')(2) (22.4-101 MBq/L) in dialysis solution via the peritoneal catheter. gamma-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% +/- 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 +/- 1.0 mGy/(MBq/L), to red bone marrow it was 0.14 +/- 0.04 mGy/(MBq/L), to the urinary bladder wall it was 0.77 +/- 0.19 mGy/(MBq/L), to the unblocked thyroid it was 24.7 +/- 11.1 mGy/(MBq/L), and to the blocked thyroid it was 1.4 +/- 1.6 mGy/(MBq/L) (mean +/- 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(ab')(2) it is possible to achieve therapeutic absorbed doses in microscopic tumor clusters without significant toxicity.
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| 2. |
- Cederkrantz, Elin, et al.
(författare)
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Absorbed Doses and Risk Estimates of (211)At-MX35 F(ab')2 in Intraperitoneal Therapy of Ovarian Cancer Patients.
- 2015
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Ingår i: International journal of radiation oncology, biology, physics. - : Elsevier BV. - 1879-355X .- 0360-3016. ; 93:3, s. 569-76
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Tidskriftsartikel (refereegranskat)abstract
- Ovarian cancer is often diagnosed at an advanced stage with dissemination in the peritoneal cavity. Most patients achieve clinical remission after surgery and chemotherapy, but approximately 70% eventually experience recurrence, usually in the peritoneal cavity. To prevent recurrence, intraperitoneal (i.p.) targeted α therapy has been proposed as an adjuvant treatment for minimal residual disease after successful primary treatment. In the present study, we calculated absorbed and relative biological effect (RBE)-weighted (equivalent) doses in relevant normal tissues and estimated the effective dose associated with i.p. administration of (211)At-MX35F(ab')2.
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| 3. |
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| 4. |
- Cederkrantz, Elin, et al.
(författare)
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Evaluation of Effects on the Peritoneum After Intraperitoneal α-Radioimmunotherapy with (211)At.
- 2012
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Ingår i: Cancer biotherapy & radiopharmaceuticals. - : Mary Ann Liebert Inc. - 1557-8852 .- 1084-9785. ; 27:6, s. 353-364
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Tidskriftsartikel (refereegranskat)abstract
- Abstract The introduction of the short-lived α-emitter (211)At to intraperitoneal radioimmunotherapy has raised the issue of the tolerance dose of the peritoneum. The short range of the α-particles (70μm) and the short half-life (7.21h) of the nuclide yield a dose distribution in which the peritoneum is highly irradiated compared with other normal tissues. To address this issue, mice were injected with (211)At-trastuzumab to irradiate the peritoneum to absorbed doses ranging between 0 and 50 Gy and followed for up to 34 weeks. The peritoneum-to-plasma clearance of a small tracer, (51)Cr-ethylenediamine tetraacetic acid, was measured for evaluation of the small solute transport capacity of the peritoneal membrane. The macroscopic status of the peritoneum and the mesenteric windows was documented when the mice were sacrificed. Biopsies of the peritoneum were taken for morphology and immunohistochemical staining against plasminogen activator inhibitor-1 and calprotectin. Peritoneum-to-plasma clearance measurements indicated a dose-dependent decrease in peritoneal transport capacity in irradiated mice. However, macroscopic and microscopic evaluations of the peritoneal membrane showed no difference between irradiated mice versus controls. The results imply that the peritoneal membrane tolerates absorbed doses as high as 30-50 Gy from α-particle irradiation with limited response.
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| 5. |
- Cederkrantz, Elin
(författare)
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Pharmacokinetics and dosimetry in intraperitoneal radioimmunotherapy with 211At
- 2014
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The prognosis for patients diagnosed with disseminated cancer is often poor. Radioimmunotherapy (RIT) is a new approach to treat disseminated disease. The aim is to target tumor cells with monoclonal antibodies (mAbs) labeled with radionuclides which release cytotoxic particle radiation upon decay. The radionuclide 211At, with half-life 7.21h, is an interesting candidate for RIT. It emits an α-particle which leaves a short, dense ionization track along its path. The range of the α-particle (<100 μm) corresponds to a few cell diameters. Thus, with 211At in combination with a tumor-specific mAb, a high level of irradiation may be achieved in very small tumors, while, at the same time, the surrounding tissue is spared. In this thesis, the pharmacokinetics of intraperitoneal (IP) 211At-MX35 F(ab’)2 for ovarian cancer was investigated in 12 patients partaking in a phase I study. The in vivo distribution was monitored by sampling of bodily fluids and gamma camera imaging. Absorbed doses to normal organs and tissues were estimated. The peritoneum was subjected to the highest absorbed dose of all investigated tissues after the amendment of a thyroid blocking agent. The radiation tolerance of the peritoneum was unknown and was therefore studied in an animal model. The absorbed doses associated with therapeutic activity levels were found to be well tolerated in a short term perspective. Exposure to α-particles is however associated with a high risk for cancer induction. The ICRP recommends a radiation weighting factor 20 for α- particles. The effective dose provides a tool for estimating the risk associated with a procedure involving irradiation. It was estimated to < 2 Sv for a general patient undergoing IP 211At-RIT with 300 MBq in 1.5 L icodextrin.
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| 6. |
- Lindegren, Sture, 1960, et al.
(författare)
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Binding Affinity, Specificity and Comparative Biodistribution of the Parental Murine Monoclonal Antibody MX35 (Anti-NaPi2b) and Its Humanized Version Rebmab200.
- 2015
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Ingår i: PloS one. - : Public Library of Science (PLoS). - 1932-6203. ; 10:5
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Tidskriftsartikel (refereegranskat)abstract
- The aim of this preclinical study was to evaluate the characteristics of the monoclonal antibody Rebmab200, which is a humanized version of the ovarian-specific murine antibody MX35. This investigation contributes to the foundation for future clinical α-radioimmunotherapy of minimal residual ovarian cancer with 211At-Rebmab200. Here, the biodistribution of 211At-Rebmab200 was evaluated, as was the utility of 99mTc-Rebmab200 for bioimaging. Rebmab200 was directly compared with its murine counterpart MX35 in terms of its in-vitro capacity for binding the immobilized NaPi2B epitope and live cells; we also assessed its biodistribution in nude mice carrying subcutaneous OVCAR-3 tumors. Tumor antigen and cell binding were similar between Rebmab200 and murine MX35, as was biodistribution, including normal tissue uptake and in-vivo tumor binding. We also demonstrated that 99mTc-Rebmab200 can be used for single-photon emission computed tomography of subcutaneous ovarian carcinomas in tumor-bearing mice. Taken together, our data support the further development of Rebmab200 for radioimmunotherapy and diagnostics.
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