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Träfflista för sökning "WFRF:(Malmström Per Uno) ;pers:(Tolmachev Vladimir)"

Sökning: WFRF:(Malmström Per Uno) > Tolmachev Vladimir

  • Resultat 1-9 av 9
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1.
  • Carlsson, Jörgen, et al. (författare)
  • Conjugate chemistry and cellular processing of EGF-dextran
  • 1999
  • Ingår i: Acta Oncologica. - 0284-186X .- 1651-226X. ; 38:3, s. 313-321
  • Tidskriftsartikel (refereegranskat)abstract
    • Conjugates with specific binding to the epidermal growth factor receptor, EGFR, of interest for radionuclide based imaging and therapy were prepared using mouse epidermal growth factor, mEGF, and dextran. In one type of conjugate, mEGF was coupled to dextran by reductive amination in which the free amino group on the mEGF N-terminal reacted with the aldehyde group on the reductive end of dextran. The end-end coupled conjugate could be further activated by the cyanopyridinium agent CDAP, thereby introducing tyrosines to the dextran part. In the other type of conjugate, the cyanylating procedure using CDAP was applied, first to activate dextran and then allowing for the amino terminus of mEGF to randomly attach to the dextran. In the latter case, radionuclide-labelled tyrosines or glycines could be added in the same conjugation step. All types of mEGF-dextran conjugates had EGFR-specific binding since the binding could be displaced by an excess of non-radioactive mEGF. The conjugates were to a large extent internalized in the test cells and the associated radioactivity was retained intracellularly for different times depending on both the type of cells and conjugate applied. Different intracellular 'traffic routes' for the radionuclides are discussed as well as applications for both imaging and therapy.
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2.
  • Fortin, Marc-André, et al. (författare)
  • Labelling chemistry and characterization of [90Y/177Lu]-DOTA-ZHER2:342-3 Affibody molecule, a candidate agent for locoregional treatment of urinary bladder carcinoma
  • 2007
  • Ingår i: International Journal of Molecular Medicine. - 1107-3756 .- 1791-244X. ; 19:2, s. 285-291
  • Tidskriftsartikel (refereegranskat)abstract
    • The direct instillation of radiolabelled conjugates in the urinary bladder is a promising path for the treatment of bladder carcinoma. The targeting of HER2/neu receptors expressed on the surface of many bladder carcinoma cells shows potential to be developed as a therapeutic strategy, and patients identified with a high risk of progression may benefit from adjuvant targeted radionuclide therapy. A phage-display selected Affibody molecule (Z(HER2:342)) which binds to HER2/neu with picomolar affinity, can be used for targeting HER2/neu-expressing bladder carcinomas. A DOTA-derivative of Z(HER2:342), designated as DOTA-Z(HER2:342)-3, is considered as a suitable targeting agent for therapy. The DOTA chelator provides stable labelling with radiometals, and the low molecular weight (7.2 kDa) of the DOTA-Z(HER2:342)-3 compound is expected to enable efficient tumor penetration. DOTA-Z(HER2:342)-3 was radiolabelled with 90Y and 177Lu in 1 M ammonium acetate buffer, at pH 5.5, and in the presence of ascorbic acid. Nearly quantitative labelling yields were achieved for both nuclides after 15 min of incubation at 60 degrees C. After chelation, the conjugates retained their capacity to specifically bind to HER2/neu-expressing SKOV-3 cells. The radiolabelled affibody conjugate (DOTA-Z(HER2:342)-3) demonstrated high antigen-binding capacity and good cellular retention. Biodistribution in normal mice demonstrated low uptake in all organs and tissues except for kidneys.
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3.
  • Kullberg, Erika Bohl, et al. (författare)
  • An aminoacridine derivative for radionuclide therapy : DNA binding properties studied in a novel cell-free in vitro assay
  • 2005
  • Ingår i: International Journal of Oncology. - 1019-6439 .- 1791-2423. ; 27:5, s. 1355-60
  • Tidskriftsartikel (refereegranskat)abstract
    • Radiolabelled DNA-binding compounds can be used to increase the efficiency of radionuclide cancer therapy of disseminated disease. In this work, the aminoacridine compound N-[3-(acridine-9-ylamino)-propyl]-3-iodobenzamide (A3) labelled with the Auger-emitting nuclide 125I using Chloramine-T was studied. Optimal labelling conditions of 125I-A3 were investigated and the interaction with DNA was studied using a novel cell-free in vitro assay with naked human genomic DNA in agarose plugs. This novel assay showed to be simple and reliable. The results verify that 125I-A3 specifically binds DNA with low dissociation and is potent in causing double-strand breaks, yielding 1.0-1.4 breaks per decay. In conclusion, 125I-A3 is a most suitable DNA-binding compound for future therapeutic studies of Auger-electron emitters like 125I.
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4.
  • Mume, Eskender, et al. (författare)
  • Radiobromination of humanized anti-HER2 monoclonal antibody trastuzumab using N-succinimidyl 5-bromo-3-pyridinecarboxylate, a potential label for immunoPET
  • 2005
  • Ingår i: Nuclear Medicine and Biology. - : Elsevier BV. - 0969-8051 .- 1872-9614. ; 32:6, s. 613-22
  • Tidskriftsartikel (refereegranskat)abstract
    • Combining the specificity of radioimmunoscintigraphy and the high sensitivity of PET in an in vivo detection technique could improve the quality of nuclear diagnostics. Positron-emitting nuclide (76)Br (T(1/2)=16.2 h) might be a possible candidate for labeling monoclonal antibodies (mAbs) and their fragments, provided that the appropriate labeling chemistry has been established. For internalizing antibodies, such as the humanized anti-HER2 monoclonal antibody, trastuzumab, radiobromine label should be residualizing, i.e., ensuring that radiocatabolites are trapped intracellularly after the proteolytic degradation of antibody. This study evaluated the chemistry of indirect radiobromination of trastuzumab using N-succinimidyl 5-(tributylstannyl)-3-pyridinecarboxylate. Literature data indicated that the use of this method provided residualizing properties for iodine and astatine labels on some antibodies. An optimized "one-pot" procedure produced an overall labeling efficiency of 45.5+/-1.2% over 15 min. The bromine label was stable under physiological and denaturing conditions. The labeled trastuzumab retained its capacity to bind specifically to HER2-expressing SKOV-3 ovarian carcinoma cells in vitro (immunoreactivity more than 75%). However, in vitro cell test did not demonstrate that the radiobromination of trastuzumab using N-succinimidyl 5-bromo-3-pyridinecarboxylate improves cellular retention of radioactivity in comparison with the use of N-succinimidyl 4-bromobenzoate.
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5.
  • Persson, Mikael, 1975- (författare)
  • Antibody Mediated Radionuclide Targeting of HER-2 for Cancer Diagnostics and Therapy : Preclinical Studies
  • 2006
  • Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
    • Targeted radionuclide therapy (TRT) holds great promise for the treatment of cancer. In TRT, radioactive nuclides are delivered specifically to tumours by molecules that recognise and bind to structures overexpressed by, or specific to, cancer cells. Human epidermal growth factor receptor like protein 2 (HER-2) is an oncogene product overexpressed in e.g. urological, breast, or ovarian cancers that have been correlated to poor prognosis and resistance to hormonal therapy. There is also evidence that tumour cells retain their HER-2 overexpression in metastases. Trastuzumab and pertuzumab are two humanised monoclonal antibodies targeting different parts of HER-2. This thesis describes the radiolabelling of these antibodies for use in TRT and diagnostics. The thesis also investigates possible methods for modifying uptake and retention of radioactivity delivered with antibodies binding to HER-2. Modification of the cellular retention of 125I by using polyhedral boron anion based linker molecules (DABI and NBI) is investigated, and it is shown that linking 125I to trastuzumab using DABI increases cellular accumulation of radioactivity by 33%. It is also shown that trastuzumab can be efficiently coupled to the positron emitter 76Br by using NBI. Furthermore, it is shown that cellular uptake of 125I can be modified by stimulating EGFR (HER-1) with EGF. When labelled with the alpha emitter 211At, trastuzumab could specifically kill cells in vitro. This cell killing effect could be prevented by saturating the receptors of the target cells with non-radiolabelled trastuzumab. Pertuzumab was radiolabelled with the low energy beta emitter 177Lu without losing affinity or immunocompetence. [177Lu]pertuzumab was specific to HER-2 in vitro and in vivo. This targeting conjugate was shown to increase median time to tumour progression in mice bearing xenografts of the radioresistant SKOV-3 cell line. In conclusion, antibodies against HER-2, especially pertuzumab radiolabelled with 177Lu, show promise as TRT agents.
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6.
  • Persson, Mikael I., et al. (författare)
  • Astatinated trastuzumab, a putative agent for radionuclide immunotherapy of ErbB2-expressing tumours
  • 2006
  • Ingår i: Oncology Reports. - 1021-335X .- 1791-2431. ; 15:3, s. 673-80
  • Tidskriftsartikel (refereegranskat)abstract
    • The anti-ErbB2 antibody trastuzumab is used for the treatment of patients with advanced breast cancer, resulting in a response rate of 40-60%. Coupling with a cytotoxic nuclide, e.g. alpha-emitting 211At, may further increase tumour response. The tumour-targeting properties of trastuzumab, astatinated using N-succinimidyl-para-(tri-n-methylstannyl)-benzoate, were evaluated and compared with those of radioiodinated trastuzumab in this study. We found that astatinated trastuzumab retains high specificity towards ErbB2. While the immunoreactive fraction of radioiodinated trastuzumab was higher than that of astatinated trastuzumab (76+/-9% versus 54+/-28%), both radioconjugates showed high affinity (KD 0.75+/-0.16 nM versus 1.8+/-0.3 nM). A growth inhibition study indicated a dose-dependent cell deactivation, in which approximately 74 cell-associated astatine decays per cell gave a survival fraction of 4.5+/-0.8x10(-4). Results of a comparative animal study on normal mice gave no indication that astatination would have any adverse effects on the biodistribution of the antibody. In conclusion, the results of the study suggest that astatinated trastuzumab is a promising candidate for treating ErbB2-expressing tumours.
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7.
  • Persson, Mikael, et al. (författare)
  • In vitro evaluation of two polyhedral boron anion derivatives as linkers for attachment of radioiodine to the anti-HER2 monoclonal antibody trastuzumab
  • 2007
  • Ingår i: Cancer Biotherapy and Radiopharmaceuticals. - : Mary Ann Liebert Inc. - 1084-9785 .- 1557-8852. ; 22:5, s. 585-596
  • Tidskriftsartikel (refereegranskat)abstract
    • Improving intracellular retention is important for the use of radiohalogens in radionuclide therapy usinginternalizing antibodies. Two putative linkers for residualization of radioiodine labels, 7-(4-isothiocyanato-phenyl)undecahydro-7,8-dicarba-nido-undecaborate(1Ϫ) ion (NBI) and (4-isothiocyanato-benzylammo-nio)undecahydro-closo-dodecaborate(1Ϫ) (DABI), were analyzed. The anti-HER-2 antibody, trastuzumab,was labeled with iodine-125 using NBI and DABI linkers, and, for comparison, with the para-[125I]iodoben-zoate (PIB), and Chloramine-T (CAT) methods. The different labels were tested for residualizing prop-erties using the HER-2 overexpressing SKBR-3 cells. The cellular radioactivity retention showed thatDABI provided a 55% better retention than CAT and was 42% better than PIB after 20 hours. NBI didnot improve retention. Accumulation tests up to 21 hours showed that the HER-2-specific accumulationof radioactivity delivered with DABI was, on average, 33% higher than with the use of PIB. These DABI-dependent improvements could, with high probability, be attributed to the good residualizing propertiesof DABI. The affinity of DABI-labeled trastuzumab to SKBR-3 cells was not better than the affinity of thePIB labeled (3.2 Ϯ 1.9 nM and 0.77 Ϯ 0.39 nM, respectively). In conclusion, the use of the DABI linkerimproved intracellular retention in vitro in comparison with the other labeling methods.
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8.
  • Persson, Mikael, et al. (författare)
  • [Lu-177]pertuzumab : Experimental therapy of HER-2-expressing xenografts
  • 2007
  • Ingår i: Cancer Research. - 0008-5472 .- 1538-7445. ; 67:1, s. 326-331
  • Tidskriftsartikel (refereegranskat)abstract
    • Pertuzumab (Omnitarg) is a novel antibody against HER-2, domain II. HER-2 is a tyrosine kinase receptor that is overexpressed in several carcinomas, especially breast cancer. Pertuzumab, labeled with the low-energy beta emitter Lu-177, might be a candidate for targeted radiotherapy of disseminated HER-2-positive micrometastases. The radiolabeled antibody [Lu-177]pertuzumab showed favorable targeting properties in BALB/c (nu/nu) mice with HER-2-overexpressing xenografts. The absorbed dose in tumors was more than five times higher than the absorbed dose in blood and more than seven times the absorbed dose in any other normal organ. Experimental therapy showed that [Lu-177]pertuzumab delayed tumor progression compared with controls (no treatment, P < 0.0001; nonlabeled pertuzumab antibody, P < 0.0001; and Lu-177-labeled irrelevant antibody, P < 0.01). No adverse side effects of the treatment could be detected. Thus, the experimental results support the planning of clinical studies applying [Lu-177]pertuzumab for therapy.
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9.
  • Winberg, Karl Johan, et al. (författare)
  • Radiobromination of anti-HER2/neu/ErbB-2 monoclonal antibody using the p-isothiocyanatobenzene derivative of the [76Br]undecahydro-bromo-7,8-dicarba-nido-undecaborate(1-) ion
  • 2004
  • Ingår i: Nuclear Medicine and Biology. - : Elsevier BV. - 0969-8051 .- 1872-9614. ; 31:4, s. 425-33
  • Tidskriftsartikel (refereegranskat)abstract
    • The monoclonal humanized anti-HER2 antibody trastuzumab was radiolabeled with the positron emitter (76)Br (T(1/2) =16.2 h). Indirect labeling was performed using the p-isothiocyanatobenzene derivative of the [(76)Br]undecahydro-bromo-7,8-dicarba-nido-undecaborate(1-) ((76)Br-NBI) as a precursor molecule. (76)Br-NBI was prepared by bromination of the 7-(p-isothiocyanato-phenyl)dodecahydro-7,8-dicarba-nido-undecaborate(1-) ion (NBI) with a yield of 93-95% using Chloramine-T (CAT) as an oxidant. Coupling of radiobrominated NBI to antibody was performed without intermediate purification, in an "one pot" reaction. An overall labeling yield of 55.7 +/- 4.8% (mean +/- maximum error) was achieved when 300 microg of antibody was labeled. The label was stable in vitro in physiological and denaturing conditions. In a cell binding test, trastuzumab remained immunoreactive after labeling.
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  • Resultat 1-9 av 9

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