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    • Plusieurs versions

    N-[2-(maleimido)ethyl]-3-(trimethylstannyl)benzamide, a molecule for radiohalogenation of proteins and peptides

    Aneheim, Emma, Foreman, Mark R. Stj, Jensen, Holger, Lindegren, Sture
    Applied radiation and isotopes, February 2015, Vol.96, pp.1-5 [Revue évaluée par les pairs]

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    Automated astatination of biomolecules - a stepping stone towards multicenter clinical trials

    Aneheim, Emma, Albertsson, Per, Bäck, Tom, Jensen, Holger, Palm, Stig, Lindegren, Sture
    Scientific Reports (Nature Publisher Group), Jul 2015, Vol.5, p.12025 [Revue évaluée par les pairs]

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    Administered activity and metastatic cure probability during radioimmunotherapy of ovarian cancer in nude mice with {sup 211}At-MX35 F(ab'){sub 2}

    Elgqvist, Joergen, Andersson, Hakan, Bernhardt, Peter, Baeck, Tom, Claesson, Ingela, Hultborn, Ragnar, Jensen, Holger, Johansson, Bengt R, Lindegren, Sture, Olsson, Marita, Palm, Stig, Warnhammar, Elisabet, Jacobsson, Lars
    International Journal of Radiation Oncology, Biology and Physics, 15 November 2006, Vol.66(4) [Revue évaluée par les pairs]

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    Multifunctional Clickable Reagents for Rapid Bioorthogonal Astatination and Radio‐Crosslinking

    Denk, Christoph, Wilkovitsch, Martin, Aneheim, Emma, Herth, Matthias M., Jensen, Holger, Lindegren, Sture, Mikula, Hannes
    ChemPlusChem, July 2019, Vol.84(7), pp.775-778 [Revue évaluée par les pairs]

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    Direct procedure for the production of 211At-labeled antibodies with an epsilon-lysyl-3-(trimethylstannyl)benzamide immunoconjugate

    Lindegren, Sture, Frost, Sofia, Bäck, Tom, Haglund, Elin, Elgqvist, Jörgen, Jensen, Holger
    Journal of nuclear medicine : official publication, Society of Nuclear Medicine, September 2008, Vol.49(9), pp.1537-45 [Revue évaluée par les pairs]
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    Titre: Direct procedure for the production of 211At-labeled antibodies with an epsilon-lysyl-3-(trimethylstannyl)benzamide immunoconjugate
    Auteur: Lindegren, Sture; Frost, Sofia; Bäck, Tom; Haglund, Elin; Elgqvist, Jörgen; Jensen, Holger
    Sujet: Antibodies, Monoclonal -- Chemistry ; Astatine -- Chemistry ; Benzamides -- Chemistry
    Description: (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. 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. 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%-81%, 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+/-0.06 (mean+/-SD), 0.44+/-0.06, and 0.29+/-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. The direct astatination procedure enables the high-yield production of astatinated antibodies with radioactivity in the amounts required for clinical applications.
    Fait partie de: Journal of nuclear medicine : official publication, Society of Nuclear Medicine, September 2008, Vol.49(9), pp.1537-45
    Identifiant: 0161-5505 (ISSN); 18703591 Version (PMID); 10.2967/jnumed.107.049833 (DOI)

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    Combined effect of gefitinib ('Iressa', ZD1839) and targeted radiotherapy with 211 At-EGF

    Sundberg, Åsa, Almqvist, Ylva, Orlova, Anna, Blomquist, Erik, Jensen, Holger, Gedda, Lars, Tolmachev, Vladimir, Carlsson, Jörgen
    European Journal of Nuclear Medicine and Molecular Imaging, 2003, Vol.30(10), pp.1348-1356 [Revue évaluée par les pairs]

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    Myelotoxicity and RBE of 211At-conjugated monoclonal antibodies compared with 99mTc-conjugated monoclonal antibodies and 60Co irradiation in nude mice

    Elgqvist, Jörgen, Bernhardt, Peter, Hultborn, Ragnar, Jensen, Holger, Karlsson, Börje, Lindegren, Sture, Warnhammar, Elisabet, Jacobsson, Lars
    Journal of nuclear medicine : official publication, Society of Nuclear Medicine, March 2005, Vol.46(3), pp.464-71 [Revue évaluée par les pairs]
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    Titre: Myelotoxicity and RBE of 211At-conjugated monoclonal antibodies compared with 99mTc-conjugated monoclonal antibodies and 60Co irradiation in nude mice
    Auteur: Elgqvist, Jörgen; Bernhardt, Peter; Hultborn, Ragnar; Jensen, Holger; Karlsson, Börje; Lindegren, Sture; Warnhammar, Elisabet; Jacobsson, Lars
    Sujet: Relative Biological Effectiveness ; Astatine -- Adverse Effects ; Bone Marrow -- Radiation Effects ; Radiometry -- Methods ; Technetium -- Adverse Effects
    Description: The rationale of this study was to determine the myelotoxicity in nude mice of the alpha-emitter 211At conjugated to monoclonal antibodies (mAbs) and to compare the effect with an electron emitter, (99m)Tc, and external irradiation from a 60Co source, for estimation of the relative biological effectiveness (RBE). 211At and (99m)Tc were conjugated to the IgG1 mAbs MX35 and 88BV59. Nude female BALB/c mice, 8- to 12-wk old, were injected intraperitoneally or intravenously. The biodistribution was determined 3, 6, and 18 h after injection. The bone-to-blood and bone marrow-to-blood activity concentration ratios (BBLR and BMBLR, respectively) were determined for simultaneously injected 211At- and (99m)Tc-mAbs. Bone marrow samples were taken from the femur. For each mouse, the whole-body retention was measured as well as the blood activity by repeated blood samples from the tail vein (0), 1, 3, 6, 12, and 18 h after injection. External-beam irradiation from a 60Co source was also performed at 3 different dose levels. White blood cell (WBC) counts, red blood cell counts, platelet counts, and hemoglobin were determined for each mouse initially and on days 1, 4, 5, 7, 15, 22, and 27 after injection. The calculations of the absorbed dose to the bone marrow were based on the BBLR, BMBLR, the cumulated activities,... The BMBLR was 0.58 +/- 0.06 and 0.56 +/- 0.06 for the 211At- and (99m)Tc-mAbs, respectively. No significant variation in BMBLR with time was found. The absorbed fractions for alpha-particles and electrons in the bone marrow were 0.88 and 0.75, respectively. The mean absorbed fractions of the photons from (99m)Tc were 0.033 and 0.52 for 140 and 18.3 keV, respectively. When different amounts of 211At- and (99m)Tc-mAbs (0.09-1.3 and 250-1,300 MBq, respectively) were administered intraperitoneally or intravenously, corresponding to absorbed doses to the bone marrow of 0.01-0.60 and 0.39-1.92 Gy, respectively, the WBC counts was suppressed by 1%-90% and 23%-89%, respectively. When external-beam irradiation with a 60Co source was performed to absorbed doses of 1.4, 1.9, and 2.4 Gy, the WBC counts was suppressed by 47%-90%. These results indicate a myelotoxic in vivo RBE of 3.4 +/- 0.6 for alpha-particles compared with (99m)Tc and 5.0 +/- 0.9 compared with 60Co irradiation. The effect on the WBC counts from bone marrow irradiation with 211At-mAbs indicates an in vivo RBE of 3.4 +/- 0.6 in comparison with (99m)Tc-mAbs. The RBE value compared with external irradiation is 5.0 +/- 0.9.
    Fait partie de: Journal of nuclear medicine : official publication, Society of Nuclear Medicine, March 2005, Vol.46(3), pp.464-71
    Identifiant: 0161-5505 (ISSN); 15750160 Version (PMID)

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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

    Andersson, Håkan, Cederkrantz, Elin, Bäck, Tom, Divgi, Chaitanya, Elgqvist, Jörgen, Himmelman, Jakob, Horvath, György, Jacobsson, Lars, Jensen, Holger, Lindegren, Sture, Palm, Stig, Hultborn, Ragnar
    Journal of nuclear medicine : official publication, Society of Nuclear Medicine, July 2009, Vol.50(7), pp.1153-60 [Revue évaluée par les pairs]
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    Titre: Intraperitoneal alpha-particle radioimmunotherapy of ovarian cancer patients: pharmacokinetics and dosimetry of (211)At-MX35 F(ab')2--a phase I study
    Auteur: Andersson, Håkan; Cederkrantz, Elin; Bäck, Tom; Divgi, Chaitanya; Elgqvist, Jörgen; Himmelman, Jakob; Horvath, György; Jacobsson, Lars; Jensen, Holger; Lindegren, Sture; Palm, Stig; Hultborn, Ragnar
    Sujet: Body Burden ; Radiometry ; Radiotherapy Dosage ; Antibodies, Monoclonal -- Therapeutic Use ; Astatine -- Therapeutic Use ; Ovarian Neoplasms -- Metabolism
    Description: 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. 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. 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. 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.
    Fait partie de: Journal of nuclear medicine : official publication, Society of Nuclear Medicine, July 2009, Vol.50(7), pp.1153-60
    Identifiant: 0161-5505 (ISSN); 19525452 Version (PMID); 10.2967/jnumed.109.062604 (DOI)

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    Therapeutic efficacy and tumor dose estimations in radioimmunotherapy of intraperitoneally growing OVCAR-3 cells in nude mice with (211)At-labeled monoclonal antibody MX35

    Elgqvist, Jörgen, Andersson, Håkan, Bäck, Tom, Hultborn, Ragnar, Jensen, Holger, Karlsson, Börje, Lindegren, Sture, Palm, Stig, Warnhammar, Elisabet, Jacobsson, Lars
    Journal of nuclear medicine : official publication, Society of Nuclear Medicine, November 2005, Vol.46(11), pp.1907-15 [Revue évaluée par les pairs]
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    Titre: Therapeutic efficacy and tumor dose estimations in radioimmunotherapy of intraperitoneally growing OVCAR-3 cells in nude mice with (211)At-labeled monoclonal antibody MX35
    Auteur: Elgqvist, Jörgen; Andersson, Håkan; Bäck, Tom; Hultborn, Ragnar; Jensen, Holger; Karlsson, Börje; Lindegren, Sture; Palm, Stig; Warnhammar, Elisabet; Jacobsson, Lars
    Sujet: Antibodies, Monoclonal -- Pharmacokinetics ; Organometallic Compounds -- Pharmacokinetics ; Ovarian Neoplasms -- Metabolism ; Radiopharmaceuticals -- Pharmacokinetics
    Description: The purpose of this study was to investigate the therapeutic efficacy of-and to estimate the absorbed dose to-tumor cells from radioimmunotherapy (RIT) in an ovarian cancer model using the alpha-particle-emitting nuclide (211)At labeled to monoclonal antibody (mAb) MX35. Previous studies on mAb MOv18 did not allow for dosimetry because of antigen shedding in vitro. Five-week-old female nude BALB/c nu/nu mice were inoculated intraperitoneally with 1 x 10(7) cells of the human tumor cell line OVCAR-3. Three weeks later, the animals were given approximately 400, 800, or 1,200 kBq of (211)At-labeled mAb MX35 intraperitoneally. As controls, one group of animals was injected with unlabeled mAb and another group was injected with phosphate-buffered saline (PBS). Another group was given approximately 400 kBq of (211)At labeled to the previously investigated mAb MOv18 for efficacy comparison. Two months after treatment, the animals were sacrificed and the presence of macroscopic and microscopic tumors, as well as ascites, was determined. The absorbed dose to tumor cells on the peritoneal surface was estimated in terms of the sum of a specific and a nonspecific contribution. The specific contribution, arising from mAbs binding to the antigenic sites on the cell membrane, was calculated using a dynamic compartment model developed in-house and Monte Carlo software.... In the control groups given unlabeled MX35 or PBS, all 18 animals had ascites, 6 of 9 animals in each group had macroscopic tumors, and all animals had microscopic growth. In the 3 groups given different amounts of (211)At-MX35, only 3 of 25 animals developed ascites. None of these animals had any sign of macroscopic tumors, but 8 had microscopic growth. In the group given (211)At-MOv18, no animals had ascites or macroscopic tumors, but 3 of 10 animals had microscopic tumors. After injecting 400 kBq of (211)At-MX35, the absorbed dose due to specific binding, for a cell cluster with a radius of 50 microm, ranged from 413 to 223 Gy between 0- and 45-microm distance from the cluster center, assuming a homogeneous distribution of (211)At-MX35 in the cluster. The contribution from unbound (211)At-MX35 and (211)At-MX35 only distributed on the cluster surface, for this cluster size, ranged from 7 to 14 Gy and from 29 to 94 Gy, between 0- and 45-microm distance from the cluster center, respectively.... (211)At-MX35 injected intraperitoneally exhibits a high efficacy when treating micrometastatic growth of the ovarian cancer cell line OVCAR-3 on the peritoneum of nude mice.
    Fait partie de: Journal of nuclear medicine : official publication, Society of Nuclear Medicine, November 2005, Vol.46(11), pp.1907-15
    Identifiant: 0161-5505 (ISSN); 16269606 Version (PMID)