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Imaging of HER3-expressing xenografts in mice using a (99m)Tc(CO) 3-HEHEHE-Z HER3:08699 affibody molecule

Orlova, Anna ; Malm, Magdalena ; Rosestedt, Maria ; Varasteh, Zohreh ; Andersson, Ken ; Selvaraju, Ram Kumar ; Altai, Mohamed LU ; Honarvar, Hadis ; Strand, Joanna LU and Ståhl, Stefan , et al. (2014) In European Journal of Nuclear Medicine and Molecular Imaging 41(7). p.9-1450
Abstract

PURPOSE: Human epidermal growth factor receptor type 3 (HER3) is a transmembrane receptor tyrosine kinase belonging to the HER (ErbB) receptor family. Membranous expression of HER3 is associated with trastuzumab resistance in breast cancer and the transition to androgen independence in prostate cancer. Imaging of HER3 expression in malignant tumors may provide important diagnostic information that can influence patient management. Affibody molecules with low picomolar affinity to HER3 were recently selected. The aim of this study was to investigate the feasibility of HER3 imaging using radiolabeled Affibody molecules.

METHODS: A HER3-binding Affibody molecule, Z08699, with a HEHEHE-tag on N-terminus was labeled with (99m)Tc(CO)3... (More)

PURPOSE: Human epidermal growth factor receptor type 3 (HER3) is a transmembrane receptor tyrosine kinase belonging to the HER (ErbB) receptor family. Membranous expression of HER3 is associated with trastuzumab resistance in breast cancer and the transition to androgen independence in prostate cancer. Imaging of HER3 expression in malignant tumors may provide important diagnostic information that can influence patient management. Affibody molecules with low picomolar affinity to HER3 were recently selected. The aim of this study was to investigate the feasibility of HER3 imaging using radiolabeled Affibody molecules.

METHODS: A HER3-binding Affibody molecule, Z08699, with a HEHEHE-tag on N-terminus was labeled with (99m)Tc(CO)3 using an IsoLink kit. In vitro and in vivo binding specificity and the cellular processing of the labeled binder were evaluated. Biodistribution of (99m)Tc(CO)3-HEHEHE-Z08699 was studied over time in mice bearing HER3-expressing xenografts.

RESULTS: HEHEHE-Z08699 was labeled with (99m)Tc(CO)3 with an isolated yield of >80 % and a purity of >99 %. Binding of (99m)Tc(CO)3-HEHEHE-Z08699 was specific to BT474 and MCF7 (breast cancer), and LS174T (colon cancer) cells. Cellular processing showed rapid binding and relatively quick internalization of the receptor/Affibody molecule complex (70 % of cell-associated radioactivity was internalized after 24 h). The tumor targeting was receptor mediated and the excretion was predominantly renal. Receptor-mediated uptake was also found in the liver, lung, stomach, intestine, and salivary glands. At 4 h pi, tumor-to-blood ratios were 7 ± 3 for BT474, and 6 ± 2 for LS174T xenografts. LS174T tumors were visualized by microSPECT 4 h pi.

CONCLUSIONS: The results of this study suggest the feasibility of HER3-imaging in malignant tumors using Affibody molecules.

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type
Contribution to journal
publication status
published
subject
keywords
Animals, Cell Line, Tumor, Cell Transformation, Neoplastic, Drug Stability, Female, Gene Expression Regulation, Neoplastic, Humans, Mice, Organotechnetium Compounds/chemistry, Receptor, ErbB-3/metabolism, Recombinant Fusion Proteins/chemistry, Tissue Distribution, Tomography, Emission-Computed, Single-Photon/methods
in
European Journal of Nuclear Medicine and Molecular Imaging
volume
41
issue
7
pages
9 - 1450
publisher
Springer
external identifiers
  • scopus:84903722742
  • pmid:24622956
ISSN
1619-7070
DOI
10.1007/s00259-014-2733-7
language
English
LU publication?
no
id
d85eaeea-80a2-433d-81d3-ae9b9e3632cf
date added to LUP
2022-11-16 13:40:18
date last changed
2024-03-06 07:47:28
@article{d85eaeea-80a2-433d-81d3-ae9b9e3632cf,
  abstract     = {{<p>PURPOSE: Human epidermal growth factor receptor type 3 (HER3) is a transmembrane receptor tyrosine kinase belonging to the HER (ErbB) receptor family. Membranous expression of HER3 is associated with trastuzumab resistance in breast cancer and the transition to androgen independence in prostate cancer. Imaging of HER3 expression in malignant tumors may provide important diagnostic information that can influence patient management. Affibody molecules with low picomolar affinity to HER3 were recently selected. The aim of this study was to investigate the feasibility of HER3 imaging using radiolabeled Affibody molecules.</p><p>METHODS: A HER3-binding Affibody molecule, Z08699, with a HEHEHE-tag on N-terminus was labeled with (99m)Tc(CO)3 using an IsoLink kit. In vitro and in vivo binding specificity and the cellular processing of the labeled binder were evaluated. Biodistribution of (99m)Tc(CO)3-HEHEHE-Z08699 was studied over time in mice bearing HER3-expressing xenografts.</p><p>RESULTS: HEHEHE-Z08699 was labeled with (99m)Tc(CO)3 with an isolated yield of &gt;80 % and a purity of &gt;99 %. Binding of (99m)Tc(CO)3-HEHEHE-Z08699 was specific to BT474 and MCF7 (breast cancer), and LS174T (colon cancer) cells. Cellular processing showed rapid binding and relatively quick internalization of the receptor/Affibody molecule complex (70 % of cell-associated radioactivity was internalized after 24 h). The tumor targeting was receptor mediated and the excretion was predominantly renal. Receptor-mediated uptake was also found in the liver, lung, stomach, intestine, and salivary glands. At 4 h pi, tumor-to-blood ratios were 7 ± 3 for BT474, and 6 ± 2 for LS174T xenografts. LS174T tumors were visualized by microSPECT 4 h pi.</p><p>CONCLUSIONS: The results of this study suggest the feasibility of HER3-imaging in malignant tumors using Affibody molecules.</p>}},
  author       = {{Orlova, Anna and Malm, Magdalena and Rosestedt, Maria and Varasteh, Zohreh and Andersson, Ken and Selvaraju, Ram Kumar and Altai, Mohamed and Honarvar, Hadis and Strand, Joanna and Ståhl, Stefan and Tolmachev, Vladimir and Löfblom, John}},
  issn         = {{1619-7070}},
  keywords     = {{Animals; Cell Line, Tumor; Cell Transformation, Neoplastic; Drug Stability; Female; Gene Expression Regulation, Neoplastic; Humans; Mice; Organotechnetium Compounds/chemistry; Receptor, ErbB-3/metabolism; Recombinant Fusion Proteins/chemistry; Tissue Distribution; Tomography, Emission-Computed, Single-Photon/methods}},
  language     = {{eng}},
  number       = {{7}},
  pages        = {{9--1450}},
  publisher    = {{Springer}},
  series       = {{European Journal of Nuclear Medicine and Molecular Imaging}},
  title        = {{Imaging of HER3-expressing xenografts in mice using a (99m)Tc(CO) 3-HEHEHE-Z HER3:08699 affibody molecule}},
  url          = {{http://dx.doi.org/10.1007/s00259-014-2733-7}},
  doi          = {{10.1007/s00259-014-2733-7}},
  volume       = {{41}},
  year         = {{2014}},
}