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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 universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för biokemi och organisk kemi.
Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för onkologi, radiologi och klinisk immunologi, Enheten för biomedicinsk strålningsvetenskap.ORCID-id: 0000-0001-6120-2683
Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper.
Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för onkologi, radiologi och klinisk immunologi, Enheten för biomedicinsk strålningsvetenskap.
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2005 (Engelska)Ingår i: Nuclear Medicine and Biology, ISSN 0969-8051, E-ISSN 1872-9614, Vol. 32, nr 6, s. 613-22Artikel i tidskrift (Refereegranskat) 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.

Ort, förlag, år, upplaga, sidor
2005. Vol. 32, nr 6, s. 613-22
Nationell ämneskategori
Medicin och hälsovetenskap
Identifikatorer
URN: urn:nbn:se:uu:diva-104548DOI: 10.1016/j.nucmedbio.2005.04.010PubMedID: 16026708OAI: oai:DiVA.org:uu-104548DiVA, id: diva2:219917
Tillgänglig från: 2009-05-28 Skapad: 2009-05-28 Senast uppdaterad: 2017-12-13Bibliografiskt granskad
Ingår i avhandling
1. Radiohalogenated Compounds for Tumor Targeting: Synthesis and Radiolabeling
Öppna denna publikation i ny flik eller fönster >>Radiohalogenated Compounds for Tumor Targeting: Synthesis and Radiolabeling
2005 (Engelska)Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
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.

Ort, förlag, år, upplaga, sidor
Uppsala: Acta Universitatis Upsaliensis, 2005. s. 51
Serie
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Science and Technology, ISSN 1651-6214 ; 22
Nyckelord
Inorganic chemistry, 9-Aminoacridine, Daunorubicin, Doxorubicin, Carborane, Radiobromination, Radioiodination, Affibody, Monoclonal antibody, Oorganisk kemi
Nationell ämneskategori
Oorganisk kemi
Identifikatorer
urn:nbn:se:uu:diva-4817 (URN)91-554-6165-4 (ISBN)
Disputation
2005-04-25, Room B42, BMC, Husargatan 3, Uppsala, 10:15 (Engelska)
Opponent
Handledare
Tillgänglig från: 2005-03-04 Skapad: 2005-03-04 Senast uppdaterad: 2009-11-23Bibliografiskt granskad

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