HEHEHE-Tagged Affibody Molecule May Be Purified by IMAC, Is Conveniently Labeled with [Tc-99m(CO)(3)](+), and Shows Improved Biodistribution with Reduced Hepatic Radioactivity Accumulation

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HEHEHE-Tagged Affibody Molecule May Be Purified by IMAC, Is Conveniently Labeled with [Tc-99m(CO)(3)](+), and Shows Improved Biodistribution with Reduced Hepatic Radioactivity Accumulation

Tolmachev, Vladimir (author): Uppsala universitet,Enheten för biomedicinsk strålningsvetenskap,Institutionen för medicinska vetenskaper,BMS

Hofström, Camilla (author): KTH,Molekylär Bioteknologi

Malmberg, Jennie (author): Uppsala universitet,Enheten för biomedicinsk strålningsvetenskap,BMS

Ahlgren, Sara (author): Uppsala universitet,Institutionen för medicinska vetenskaper,BMS

Hosseinimehr, Seyed Jalal (author): Uppsala universitet,Enheten för biomedicinsk strålningsvetenskap,BMS

Sandström, Mattias (author): Uppsala universitet,Enheten för onkologi

Abrahmsen, Lars (author)

Orlova, Anna (author): Uppsala universitet,Enheten för biomedicinsk strålningsvetenskap,BMS

Gräslund, Torbjorn (author): KTH,Molekylär Bioteknologi

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2010-10-22
2010
English.
In: Bioconjugate chemistry. - : American Chemical Society (ACS). - 1043-1802 .- 1520-4812. ; 21:11, s. 2013-2022

Related links:: https://urn.kb.se/re...; show more...; https://doi.org/10.1...; https://urn.kb.se/re...; show less...

Journal article (peer-reviewed)

Abstract Subject headings

Affibody molecules are a class of small (ca. 7 kDa) robust scaffold proteins suitable for radionuclide molecular imaging of therapeutic targets in vivo. A hexahistidine tag at the N-terminus streamlines development of new imaging probes by enabling facile purification using immobilized metal ion affinity chromatography (IMAC), as well as convenient [Tc-99m(CO)(3)](+)-labeling. However, previous studies in mice have demonstrated that Affibody molecules labeled by this method yield higher liver accumulation of radioactivity, compared to the same tracer lacking the hexahistidine tag and labeled by an alternative method. Two variants of the HER2-binding Affibody molecule Z(HER2:342) were made in an attempt to create a tagged tracer that could be purified by immobilized metal affinity chromatography, yet would not result in anomalous hepatic radioactivity accumulation following labeling with [Tc-99m(CO)(3)](+). In one construct, the hexahistidine tag was moved to the C-terminus. In the other construct, every second histidine residue in the hexahistidine tag was replaced by the more hydrophilic glutamate, resulting in a HEHEHE-tag. Both variants, denoted Z(HER2:342)-H-6 and (HE)(3)-Z(HER2:342), respectively, could be efficiently purified using IMAC and stably labeled with [Tc-99m(CO)(3)](+) and were subsequently compared with the parental H-6-Z(HER2:342) having an N-terminal hexahistidine tag. All three variants were demonstrated to specifically bind to HER2-expressing cells in vitro. The hepatic accumulation of radioactivity in a murine model was 2-fold lower with [Tc-99m(CO)(3)](+)-Z(HER2:342)-H-6 compared to [Tc-99m(CO)(3)](+)-H-6-Z(HER2:342), and more than 10-fold lower with [Tc-99m(CO)(3)](+)-(HE)(3)-Z(HER2:342). These differences translated into appreciably superior tumor-to-liver ratio for [Tc-99m(CO)(3)](+)-(HE)(3)-Z(HER2:342) compared to the alternative conjugates. This information might be useful for development of other scaffold-based molecular imaging probes.

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By the author/editor: Tolmachev, Vladi ...; Hofström, Camill ...; Malmberg, Jennie; Ahlgren, Sara; Hosseinimehr, Se ...; Sandström, Matti ...; show more...; Abrahmsen, Lars; Orlova, Anna; Gräslund, Torbjo ...; show less...

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By the university: Royal Institute of Technology; Uppsala University

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HEHEHE-Tagged Affibody Molecule May Be Purified by IMAC, Is Conveniently Labeled with [Tc-99m(CO)(3)](+), and Shows Improved Biodistribution with Reduced Hepatic Radioactivity Accumulation

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