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Persson, Mikael
Publications (8 of 8) Show all publications
Persson, M., Sivaev, I., Winberg, K.-J., Gedda, L., Malmström, P.-U. & Tolmachev, V. (2007). In vitro evaluation of two polyhedral boron anion derivatives as linkers for attachment of radioiodine to the anti-HER2 monoclonal antibody trastuzumab. Cancer Biotherapy and Radiopharmaceuticals, 22(5), 585-596
Open this publication in new window or tab >>In vitro evaluation of two polyhedral boron anion derivatives as linkers for attachment of radioiodine to the anti-HER2 monoclonal antibody trastuzumab
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2007 (English)In: Cancer Biotherapy and Radiopharmaceuticals, ISSN 1084-9785, E-ISSN 1557-8852, Vol. 22, no 5, p. 585-596Article in journal (Refereed) Published
Abstract [en]

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.

Keywords
antibody, radiolabeling, polyhedral boron anion, HER-2
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-94330 (URN)10.1089/cbr.2006.338 (DOI)000250821800002 ()17979561 (PubMedID)
Available from: 2006-04-20 Created: 2006-04-20 Last updated: 2018-12-04
Persson, M., Tolmachev, V., Andersson, K., Gedda, L., Sandström, M. & Carlsson, J. (2005). [(177)Lu]pertuzumab: experimental studies on targeting of HER-2 positive tumour cells. European Journal of Nuclear Medicine and Molecular Imaging, 32(12), 1457-62
Open this publication in new window or tab >>[(177)Lu]pertuzumab: experimental studies on targeting of HER-2 positive tumour cells
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2005 (English)In: European Journal of Nuclear Medicine and Molecular Imaging, ISSN 1619-7070, E-ISSN 1619-7089, Vol. 32, no 12, p. 1457-62Article in journal (Refereed) Published
Abstract [en]

PURPOSE: The new antibody pertuzumab (Omnitarg) targets the dimerisation subdomain of HER-2. The purpose of this study was to analyse whether pertuzumab retains HER-2 targeting capacity after labelling with the therapeutically interesting beta emitter (177)Lu and to make initial characterizations in vitro and in vivo. METHODS: Pertuzumab was conjugated with isothiocyanate-benzyl-CHX-A''-DTPA and chelated to (177)Lu. Immunoreactivity, affinity, cellular retention and internalisation were analysed using SKOV-3 cells. The affinity of non-radioactive pertuzumab was measured using a surface plasmon resonance biosensor. In vivo targeting and specific binding were assessed in Balb/c (nu/nu) mice carrying SKOV-3 xenografts. The biodistribution of (177)Lu was determined 1, 3 and 7 days after [(177)Lu]pertuzumab administration. Gamma camera images were taken after 3 days. RESULTS: The immunoreactivity of [(177)Lu]pertuzumab was 85.8+/-1.3%. The affinity of non-radioactive pertuzumab was 1.8+/-1.1 nM, and that of [(177)Lu]pertuzumab, 4.1+/-0.7 nM. The cellular retention after 5 h pre-incubation was 90+/-2% at 20 h. The targeting was HER-2 specific both in vitro and in vivo, since excess amounts of non-labelled antibody inhibited the uptake of labelled antibody (p<0.0001 and p<0.01, respectively). The biodistribution and gamma camera images of (177)Lu showed extensive tumour uptake. Normal tissues had a surprisingly low uptake. CONCLUSION: Pertuzumab was efficiently labelled with (177)Lu and showed good intracellular retention and HER-2 specific binding both in vitro and in vivo. The gamma camera images and the biodistribution study gave excellent tumour targeting results. Thus, [(177)Lu]pertuzumab is of interest for further studies aimed at radionuclide therapy.

Keywords
Cancer, Tumor, Radiation, Therapy
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-104461 (URN)10.1007/s00259-005-1902-0 (DOI)16193312 (PubMedID)
Available from: 2009-05-28 Created: 2009-05-28 Last updated: 2018-12-04
Nordberg, E., Steffen, A.-C., Persson, M., Sundberg, Å. L., Carlsson, J. & Glimelius, B. (2005). Cellular uptake of radioiodine delivered by trastuzumab can be modified by the addition of epidermal growth factor.. European Journal of Nuclear Medicine and Molecular Imaging, 32(7), 771-7
Open this publication in new window or tab >>Cellular uptake of radioiodine delivered by trastuzumab can be modified by the addition of epidermal growth factor.
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2005 (English)In: European Journal of Nuclear Medicine and Molecular Imaging, ISSN 1619-7070, E-ISSN 1619-7089, Vol. 32, no 7, p. 771-7Article in journal (Refereed) Published
Abstract [en]

PURPOSE: The purpose of this study was to analyse whether non-radiolabelled epidermal growth factor (EGF) can modify the cellular uptake of 125I when delivered as [125I]trastuzumab. 125I was used as a marker for the diagnostically and therapeutically more interesting isotopes 123I (SPECT), 124I (PET) and 131I (therapy). METHODS: The cell-associated radioactivity was measured in squamous carcinoma A431 cells following addition of [125I]trastuzumab. Different concentrations of [125I]trastuzumab and unlabelled EGF were used, and the total, membrane-bound and internalised radioactivity was measured. We also analysed how EGF and trastuzumab affected the cell growth. RESULTS: It was generally found that the cellular 125I uptake was decreased by the addition of EGF when [125I]trastuzumab was added for short incubation times. However, if the incubation times were longer, EGF increased the 125I uptake. This shift came earlier when higher [125I]trastuzumab concentrations were applied. The addition of EGF also influenced cell proliferation, and concentrations above 10 ng/ml reduced cell growth by approximately 20% after 24 h of incubation. CONCLUSION: By adding unlabelled EGF, it was possible to modify the cellular uptake of [125I]trastuzumab. This points towards new approaches for the modification of radionuclide uptake in EGFR- and HER2-positive tumours.

Keywords
Antibodies; Monoclonal/*administration & dosage/chemistry, Antineoplastic Agents/*administration & dosage, Cell Line; Tumor, Cell Membrane/metabolism, Cell Proliferation, Dose-Response Relationship; Drug, Epidermal Growth Factor/*administration & dosage/metabolism, Humans, Iodine Radioisotopes/*pharmacokinetics, Ligands, Positron-Emission Tomography, Receptor; Epidermal Growth Factor/metabolism, Receptor; erbB-2/metabolism, Time Factors, Tomography; Emission-Computed; Single-Photon, Tumor Markers; Biological
National Category
Radiology, Nuclear Medicine and Medical Imaging
Identifiers
urn:nbn:se:uu:diva-80492 (URN)10.1007/s00259-005-1761-8 (DOI)15765233 (PubMedID)
Available from: 2007-02-12 Created: 2007-02-12 Last updated: 2017-12-14Bibliographically approved
Winberg, K. J., Persson, M., Malmström, P.-U., Sjöberg, S. & Tolmachev, V. (2004). 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. Nuclear Medicine and Biology, 31(4), 425-33
Open this publication in new window or tab >>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
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2004 (English)In: Nuclear Medicine and Biology, ISSN 0969-8051, E-ISSN 1872-9614, Vol. 31, no 4, p. 425-33Article in journal (Refereed) Published
Abstract [en]

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.

Keywords
Antibodies; Monoclonal/*chemistry/immunology/*pharmacokinetics, Breast Neoplasms/immunology/*metabolism/radionuclide imaging, Bromine Radioisotopes/*chemistry/immunology/*pharmacokinetics, Cell Line; Tumor, Drug Stability, Humans, Isotope Labeling/*methods, Radioimmunodetection/methods, Radiopharmaceuticals/chemical synthesis/chemistry/pharmacokinetics, Receptor; erbB-2/immunology/*metabolism, Research Support; Non-U.S. Gov't
National Category
Organic Chemistry
Identifiers
urn:nbn:se:uu:diva-72941 (URN)10.1016/j.nucmedbio.2003.11.007 (DOI)15093812 (PubMedID)
Available from: 2005-06-21 Created: 2005-06-21 Last updated: 2017-12-14Bibliographically approved
Bruskin, A., Sivaev, I., Persson, M., Lundqvist, H., Carlsson, J., Sjöberg, S. & Tolmachev, V. (2004). Radiobromination of monoclonal antibody using potassium [76Br] (4 isothiocyanatobenzyl-ammonio)-bromo-decahydro-closo-dodecaborate (Bromo-DABI). Nuclear Medicine and Biology, 31(2), 205-11
Open this publication in new window or tab >>Radiobromination of monoclonal antibody using potassium [76Br] (4 isothiocyanatobenzyl-ammonio)-bromo-decahydro-closo-dodecaborate (Bromo-DABI)
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2004 (English)In: Nuclear Medicine and Biology, ISSN 0969-8051, E-ISSN 1872-9614, Vol. 31, no 2, p. 205-11Article in journal (Refereed) Published
Abstract [en]

The use of charged linkers in attaching radiohalogens to tumor-seeking biomolecules may improve intracellular retention of the radioactive label after internalization and degradation of targeting proteins. Derivatives of polyhedral boron clusters, such as closo-dodecaborate (2-) anion, might be possible charged linkers. In this study, a bifunctional derivative of closo-dodecaborate, (4-isothiocyanatobenzyl-ammonio)-undecahydro-closo-dodecaborate (DABI) was labeled with positron-emitting nuclide (76)Br (T 1/2 = 16.2 h) and coupled to anti-HER2/neu humanized antibody Trastuzumab. The overall labeling yield at optimized conditions was 80.7 +/- 0.6%. The label was proven to be stable in vitro in physiological and a set of denaturing conditions. The labeled antibody retained its capacity to bind to HER-2/neu antigen expressing cells. The results of the study demonstrated feasibility for using derivatives of closo-dodecaborate in indirect labeling of antibodies for radioimmunoPET.

Keywords
Adenocarcinoma/*metabolism/*radionuclide imaging, Antibodies; Monoclonal/chemistry/*diagnostic use/*pharmacokinetics, Boron Compounds/chemical synthesis/*diagnostic use/*pharmacokinetics, Cell Line; Tumor, Drug Stability, Humans, Isotope Labeling/*methods, Metabolic Clearance Rate, Radiopharmaceuticals/chemical synthesis/diagnostic use/pharmacokinetics, Research Support; Non-U.S. Gov't
National Category
Organic Chemistry
Identifiers
urn:nbn:se:uu:diva-72891 (URN)15013486 (PubMedID)
Available from: 2005-06-21 Created: 2005-06-21 Last updated: 2017-12-14Bibliographically approved
Cheng, J., Persson, M., Tolmachev, V., Siavaev, I., Orlova, A., Kairemo, K. & Anniko, M. (2004). Targeting of a head and neck squamous cell carcinoma xenograft model using the chimeric monoclonal antibody U36 radioiodinated with a closo-dodecaborate-containing linker. Acta Oto-Laryngologica, 124(9), 1078-85
Open this publication in new window or tab >>Targeting of a head and neck squamous cell carcinoma xenograft model using the chimeric monoclonal antibody U36 radioiodinated with a closo-dodecaborate-containing linker
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2004 (English)In: Acta Oto-Laryngologica, ISSN 0001-6489, E-ISSN 1651-2251, Vol. 124, no 9, p. 1078-85Article in journal (Refereed) Published
Abstract [en]

OBJECTIVE: High rates of local recurrence and distant metastases following surgery of high-grade head and neck squamous cell carcinoma (HNSCC) necessitate the use of adjuvant systemic treatment. Radioimmunotargeting might be a possible treatment modality in this case. The nuclear properties of 131I make it a suitable isotope for treatment of minimal residual disease and small metastases, but the conventional radioiodine label has poor cellular retention and its radiocatabolites accumulate in the thyroid. We attempted to overcome these problems by using closo-dodecaborate derivatives for attachment of radioiodine. MATERIAL AND METHODS: We investigated the feasibility of targeting an SCC25 HNSCC xenograft in vivo using a benzylisothiocyanate derivative of closo-dodecaborate (DABI) as radioiodine linker and the chimeric anti-CD44v6 antibody U36. 125I was used in biodistribution studies. RESULTS: The use of DABI enabled tumor targeting and decreased the radioactivity uptake of the thyroid. CONCLUSION: Tumor localization of DABI-labeled U36 was similar to its para-iodobenzoate-labeled counterpart, presumably due to the strong dependence of targeting efficiency on tumor size.

Keywords
Animals, Antibodies; Monoclonal/pharmacokinetics/*therapeutic use, Area Under Curve, Boron Compounds/pharmacokinetics, Cell Line; Tumor/radiation effects, Head and Neck Neoplasms/metabolism/*radiotherapy, Humans, Iodine Radioisotopes/pharmacokinetics/*therapeutic use, Mice, Mice; Nude, Neoplasms; Squamous Cell/metabolism/*radiotherapy, Radioimmunotherapy/*methods, Research Support; Non-U.S. Gov't, Tissue Distribution, Transplantation; Heterologous
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-72820 (URN)15513553 (PubMedID)
Available from: 2007-05-04 Created: 2007-05-04 Last updated: 2017-12-14Bibliographically approved
Nestor, M., Persson, M., Cheng, J., Tolmachev, V., van Dongen, G., Anniko, M. & Kairemo, K. (2003). Biodistribution of the chimeric monoclonal antibody U36 radioiodinated with a closo-dodecaborate-containing linker: Comparison with other radioiodination methods. Bioconjugate chemistry, 14(4), 805-10
Open this publication in new window or tab >>Biodistribution of the chimeric monoclonal antibody U36 radioiodinated with a closo-dodecaborate-containing linker: Comparison with other radioiodination methods
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2003 (English)In: Bioconjugate chemistry, ISSN 1043-1802, E-ISSN 1520-4812, Vol. 14, no 4, p. 805-10Article in journal (Refereed) Published
Abstract [en]

We have evaluated the applicability of the [(4-isothiocyanatobenzylammonio)undecahydro-closo-dodecaborate (1-)] (DABI) linker molecule for antibody radiohalogenation and compared it to radiohalogenation using the linker N-succinimidyl 4-iodobenzoate (PIB) and to direct radiohalogenation using Chloramine T. These studies were performed to assess the potential of DABI conjugates and to optimize the biological properties of halogen-labeled cMAb U36. The three conjugates were evaluated in vitro for their specificity and affinity and in vivo for their biodistribution patterns in normal mice at 1.5, 6, 24, and 96 h pi. Labeling efficiencies of direct CAT labeling, indirect PIB labeling, and indirect DABI labeling were 90-95%, 60%, and 68%, respectively. This resulted in a PIB:cMAb U36 molar ratio of 1.8-2.5 and a DABI:cMAb U36 molar ratio of 4.1. The in vitro data demonstrated specific binding for all conjugates and similar affinities with values around 1 x 10(8) M(-)(1). However, the in vivo data revealed accumulation of the radioiodine uptake in thyroid for the directly labeled conjugate, with a value 10 times higher than the indirectly labeled conjugates 96 h pi. Both the (125)I-PIB-cMAb U36 and (125)I-DABI-cMAb U36 conjugates yielded a low thyroid uptake with no accumulation, indicating different catabolites for these conjugates. This may favor the use of the indirectly labeled conjugates for future studies. Apart from the specific results obtained, these findings also demonstrate how the right linker molecule will provide additional opportunities to further improve the properties of an antibody-radionuclide conjugate.

Keywords
Animals, Antibodies; Monoclonal/administration & dosage/*chemistry/pharmacokinetics, Benzoates/chemistry/pharmacokinetics, Boron Compounds/*chemistry/pharmacokinetics, Cell Line; Tumor/radiation effects, Chloramines/chemistry/pharmacokinetics, Comparative Study, In Vitro, Iodine Radioisotopes/*chemistry/pharmacokinetics, Mice, Molecular Structure, Radiopharmaceuticals/*chemistry/pharmacokinetics, Research Support; Non-U.S. Gov't, Staining and Labeling/methods, Time Factors, Tissue Distribution
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-72824 (URN)10.1021/bc034003n (DOI)12862434 (PubMedID)
Available from: 2007-05-04 Created: 2007-05-04 Last updated: 2017-12-14Bibliographically approved
Agell, A. & Persson, M. (2000). Klippanmålet och lagens ögon. Juridisk Tidsskrift, 11
Open this publication in new window or tab >>Klippanmålet och lagens ögon
2000 (Swedish)In: Juridisk Tidsskrift, p. 11-Article in journal (Other scientific) Published
Identifiers
urn:nbn:se:uu:diva-73608 (URN)
Available from: 2005-06-12 Created: 2005-06-12 Last updated: 2011-01-14
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