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Radiobromination of humanized anti-HER2 monoclonal antibody trastuzumab using N-succinimidyl 5-bromo-3-pyridinecarboxylate, a potential label for immunoPET
Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Biochemistry and Organic Chemistry.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Biomedical Radiation Sciences.ORCID iD: 0000-0001-6120-2683
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Biomedical Radiation Sciences.
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2005 (English)In: Nuclear Medicine and Biology, ISSN 0969-8051, E-ISSN 1872-9614, Vol. 32, no 6, 613-22 p.Article in journal (Refereed) Published
Abstract [en]

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.

Place, publisher, year, edition, pages
2005. Vol. 32, no 6, 613-22 p.
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:uu:diva-104548DOI: 10.1016/j.nucmedbio.2005.04.010PubMedID: 16026708OAI: oai:DiVA.org:uu-104548DiVA: diva2:219917
Available from: 2009-05-28 Created: 2009-05-28 Last updated: 2017-12-13Bibliographically approved
In thesis
1. Radiohalogenated Compounds for Tumor Targeting: Synthesis and Radiolabeling
Open this publication in new window or tab >>Radiohalogenated Compounds for Tumor Targeting: Synthesis and Radiolabeling
2005 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

This thesis describes the synthesis and radiohalogenation of compounds of potential use for tumor targeting.

The first section describes the synthesis and radioiodination of DNA intercalating compounds. The compounds are derivatives of 9-aminoacridine, and the anthracyclins daunorubicin and doxorubicin. The precursor compounds were labeled with 125I (T1/2 = 60 days), which is an Auger emitting nuclide. 125I decaying in the close vicinity of DNA is known to have a much higher cell killing effect than 125I decaying in the cytoplasm and some of the labeled compounds prepared in this thesis are currently being tested for use in targeted radionuclide therapy for cancer.

The second section describes the radiobromination of closo-carboranes by subjecting the corresponding iodinated compounds to palladium-catalyzed halogen exchange using [76Br]bromide. The 76Br isotope (T1/2 = 16.2 h) is a positron emitting nuclide that is suitable for PET studies. Via the halogen exchange reaction good to excellent radiochemical yields of radiobrominated closo-carboranes were obtained. The results of the present study may prove to be applicable to pharmacokinetic studies of carboranes and their derivatives.

The third and final section describes the indirect radiobromination of the trastuzumab anti-HER2 monoclonal antibody and of the anti-HER2 Affibody by means of an “one-pot” procedure using N-succinimidyl-5-(tributylstannyl)-3-pyridinecarboxylate (SPC) and ((4-hydroxyphenyl)ethyl))maleimide (HPEM), respectively. It was found that SPC and HPEM can be efficiently radiobrominated and thereafter coupled to the antibody and Affibody, respectively. The labeled proteins retained their capacity to bind specifically to HER2 expressing SKOV-3 cells in vitro. Application of this method to 76Br might enable the use of PET in the detection of HER2 expression in breast, ovarian, and urinary bladder carcinomas.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2005. 51 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Science and Technology, ISSN 1651-6214 ; 22
Keyword
Inorganic chemistry, 9-Aminoacridine, Daunorubicin, Doxorubicin, Carborane, Radiobromination, Radioiodination, Affibody, Monoclonal antibody, Oorganisk kemi
National Category
Inorganic Chemistry
Identifiers
urn:nbn:se:uu:diva-4817 (URN)91-554-6165-4 (ISBN)
Public defence
2005-04-25, Room B42, BMC, Husargatan 3, Uppsala, 10:15 (English)
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Supervisors
Available from: 2005-03-04 Created: 2005-03-04 Last updated: 2009-11-23Bibliographically approved

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Orlova, AnnaTolmachev, Vladimir

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