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

Mohamed Altai, Helena Wallberg, Hadis Honarvar, Joanna Strand, Anna Orlova, Zohreh Varasteh, Mattias Sandström, John Löfblom, Erik Larsson, Sven Erik Strand, Mark Lubberink, Stefan Stah, Vladimir Tolmachev

Research output: Contribution to journalArticlepeer-review

18 Citations (Scopus)

Abstract

Affibody molecules are small (7 kDa) nonimmunoglobulin scaffold proteins with favorable tumor-targeting properties. Studies concerning the influence of chelators on biodistribution of 99mTc-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 188Re-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 188Re using a gluconatecontaining kit. Targeting of HER2-overexpressing SKOV-3 ovarian carcinoma xenografts in nude mice was studied for a dosimetry assessment. Results: Binding of 188Re-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 injecte 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 188Re-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: 188Re- ZHER2:V2 can deliver high absorbed doses to tumors without exceeding kidney and bone marrow toxicity limits.

Original languageEnglish
Pages (from-to)1842-1848
Number of pages7
JournalJournal of Nuclear Medicine
Volume55
Issue number11
DOIs
Publication statusPublished - 1 Nov 2014
Externally publishedYes

Keywords

  • 188Re
  • Affibody molecule
  • Dosimetry
  • HER2

ASJC Scopus subject areas

  • Radiology Nuclear Medicine and imaging

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