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188Re-ZHER2:V2, a promising affibody-based targeting agent against HER2-expressing tumors : preclinical assessment

Altai, Mohamed LU ; Wållberg, Helena ; Honarvar, Hadis ; Strand, Joanna LU ; Orlova, Anna ; Varasteh, Zohreh ; Sandström, Mattias ; Löfblom, John ; Larsson, Erik LU and Strand, Sven-Erik LU , et al. (2014) In Journal of nuclear medicine : official publication, Society of Nuclear Medicine 55(11). p.8-1842
Abstract

UNLABELLED: Affibody molecules are small (7 kDa) nonimmunoglobulin scaffold proteins with favorable tumor-targeting properties. Studies concerning the influence of chelators on biodistribution of (99m)Tc-labeled Affibody molecules demonstrated that the variant with a C-terminal glycyl-glycyl-glycyl-cysteine peptide-based chelator (designated ZHER2:V2) has the best biodistribution profile in vivo and the lowest renal retention of radioactivity. The aim of this study was to evaluate (188)Re-ZHER2:V2 as a potential candidate for radionuclide therapy of human epidermal growth factor receptor type 2 (HER2)-expressing tumors.

METHODS: ZHER2:V2 was labeled with (188)Re using a gluconate-containing kit. Targeting of HER2-overexpressing... (More)

UNLABELLED: Affibody molecules are small (7 kDa) nonimmunoglobulin scaffold proteins with favorable tumor-targeting properties. Studies concerning the influence of chelators on biodistribution of (99m)Tc-labeled Affibody molecules demonstrated that the variant with a C-terminal glycyl-glycyl-glycyl-cysteine peptide-based chelator (designated ZHER2:V2) has the best biodistribution profile in vivo and the lowest renal retention of radioactivity. The aim of this study was to evaluate (188)Re-ZHER2:V2 as a potential candidate for radionuclide therapy of human epidermal growth factor receptor type 2 (HER2)-expressing tumors.

METHODS: ZHER2:V2 was labeled with (188)Re using a gluconate-containing kit. Targeting of HER2-overexpressing SKOV-3 ovarian carcinoma xenografts in nude mice was studied for a dosimetry assessment.

RESULTS: Binding of (188)Re-ZHER2:V2 to living SKOV-3 cells was demonstrated to be specific, with an affinity of 6.4 ± 0.4 pM. The biodistribution study showed a rapid blood clearance (1.4 ± 0.1 percentage injected activity per gram [%ID/g] at 1 h after injection). The tumor uptake was 14 ± 2, 12 ± 2, 5 ± 2, and 1.8 ± 0.5 %IA/g at 1, 4, 24, and 48 h after injection, respectively. The in vivo targeting of HER2-expressing xenografts was specific. Already at 4 h after injection, tumor uptake exceeded kidney uptake (2.1 ± 0.2 %IA/g). Scintillation-camera imaging showed that tumor xenografts were the only sites with prominent accumulation of radioactivity at 4 h after injection. Based on the biokinetics, a dosimetry evaluation for humans suggests that (188)Re-ZHER2:V2 would provide an absorbed dose to tumor of 79 Gy without exceeding absorbed doses of 23 Gy to kidneys and 2 Gy to bone marrow. This indicates that future human radiotherapy studies may be feasible.

CONCLUSION: (188)Re-ZHER2:V2 can deliver high absorbed doses to tumors without exceeding kidney and bone marrow toxicity limits.

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publication status
published
subject
keywords
Animals, Antibodies/chemistry, Cell Line, Tumor, Chelating Agents/chemistry, Drug Evaluation, Preclinical, Female, Gluconates/chemistry, Humans, Mice, Mice, Nude, Oligopeptides/chemistry, Ovarian Neoplasms/drug therapy, Peptides/chemistry, Radiation Dosage, Radioisotopes/therapeutic use, Radiometry, Radiopharmaceuticals, Receptor, ErbB-2/chemistry, Rhenium/chemistry, Xenograft Model Antitumor Assays
in
Journal of nuclear medicine : official publication, Society of Nuclear Medicine
volume
55
issue
11
pages
8 - 1842
publisher
Society of Nuclear Medicine
external identifiers
  • scopus:84910602926
  • pmid:25278516
ISSN
0161-5505
DOI
10.2967/jnumed.114.140194
language
English
LU publication?
yes
additional info
© 2014 by the Society of Nuclear Medicine and Molecular Imaging, Inc.
id
61596623-f0c1-475d-9288-9fe43d45015b
date added to LUP
2022-11-16 13:40:54
date last changed
2024-02-01 22:26:05
@article{61596623-f0c1-475d-9288-9fe43d45015b,
  abstract     = {{<p>UNLABELLED: Affibody molecules are small (7 kDa) nonimmunoglobulin scaffold proteins with favorable tumor-targeting properties. Studies concerning the influence of chelators on biodistribution of (99m)Tc-labeled Affibody molecules demonstrated that the variant with a C-terminal glycyl-glycyl-glycyl-cysteine peptide-based chelator (designated ZHER2:V2) has the best biodistribution profile in vivo and the lowest renal retention of radioactivity. The aim of this study was to evaluate (188)Re-ZHER2:V2 as a potential candidate for radionuclide therapy of human epidermal growth factor receptor type 2 (HER2)-expressing tumors.</p><p>METHODS: ZHER2:V2 was labeled with (188)Re using a gluconate-containing kit. Targeting of HER2-overexpressing SKOV-3 ovarian carcinoma xenografts in nude mice was studied for a dosimetry assessment.</p><p>RESULTS: Binding of (188)Re-ZHER2:V2 to living SKOV-3 cells was demonstrated to be specific, with an affinity of 6.4 ± 0.4 pM. The biodistribution study showed a rapid blood clearance (1.4 ± 0.1 percentage injected activity per gram [%ID/g] at 1 h after injection). The tumor uptake was 14 ± 2, 12 ± 2, 5 ± 2, and 1.8 ± 0.5 %IA/g at 1, 4, 24, and 48 h after injection, respectively. The in vivo targeting of HER2-expressing xenografts was specific. Already at 4 h after injection, tumor uptake exceeded kidney uptake (2.1 ± 0.2 %IA/g). Scintillation-camera imaging showed that tumor xenografts were the only sites with prominent accumulation of radioactivity at 4 h after injection. Based on the biokinetics, a dosimetry evaluation for humans suggests that (188)Re-ZHER2:V2 would provide an absorbed dose to tumor of 79 Gy without exceeding absorbed doses of 23 Gy to kidneys and 2 Gy to bone marrow. This indicates that future human radiotherapy studies may be feasible.</p><p>CONCLUSION: (188)Re-ZHER2:V2 can deliver high absorbed doses to tumors without exceeding kidney and bone marrow toxicity limits.</p>}},
  author       = {{Altai, Mohamed and Wållberg, Helena and Honarvar, Hadis and Strand, Joanna and Orlova, Anna and Varasteh, Zohreh and Sandström, Mattias and Löfblom, John and Larsson, Erik and Strand, Sven-Erik and Lubberink, Mark and Ståhl, Stefan and Tolmachev, Vladimir}},
  issn         = {{0161-5505}},
  keywords     = {{Animals; Antibodies/chemistry; Cell Line, Tumor; Chelating Agents/chemistry; Drug Evaluation, Preclinical; Female; Gluconates/chemistry; Humans; Mice; Mice, Nude; Oligopeptides/chemistry; Ovarian Neoplasms/drug therapy; Peptides/chemistry; Radiation Dosage; Radioisotopes/therapeutic use; Radiometry; Radiopharmaceuticals; Receptor, ErbB-2/chemistry; Rhenium/chemistry; Xenograft Model Antitumor Assays}},
  language     = {{eng}},
  number       = {{11}},
  pages        = {{8--1842}},
  publisher    = {{Society of Nuclear Medicine}},
  series       = {{Journal of nuclear medicine : official publication, Society of Nuclear Medicine}},
  title        = {{188Re-ZHER2:V2, a promising affibody-based targeting agent against HER2-expressing tumors : preclinical assessment}},
  url          = {{http://dx.doi.org/10.2967/jnumed.114.140194}},
  doi          = {{10.2967/jnumed.114.140194}},
  volume       = {{55}},
  year         = {{2014}},
}