Targeting of HER2-expressing tumors using 111In-ABY-025, a second-generation Affibody molecule with a fundamentally reengineered scaffold

Sara Ahlgren, Anna Orlova, Helena Wållberg, Monika Hansson, Mattias Sandström, Richard Lewsley, Anders Wennborg, Lars Abrahmsén, Vladimir Tolmachev, Joachim Feldwisch

Research output: Contribution to journalArticlepeer-review

66 Citations (Scopus)

Abstract

Overexpression of the human epidermal growth factor receptor type 2 (HER2) in breast carcinomas predicts response to trastuzumab therapy. Affibody molecules based on a nonimmunoglobulin scaffold have demonstrated a high potential for in vivo molecular imaging of HER2-expressing tumors. The reengineering of the molecular scaffold has led to a second generation of optimized Affibody molecules that have a surface distinctly different from the parental protein domain from staphylococcal protein A. Compared with the parental molecule, the new tracer showed a further increased melting point, stability, and overall hydrophilicity and was more amenable to chemical peptide synthesis. The goal of this study was to assess the potential effects of this extensive reengineering on HER2 targeting, using ABY-025, a DOTA-conjugated variant of the novel tracer. Methods: 111In-ABY-025 was compared with previously evaluated parent HER2-binding Affibody tracers in vitro and in vivo. Thein vivo behavior was further evaluated in mice bearing SKOV-3 xenografts, rats, and cynomolgus macaques (Macaca fascicularis). Results:111In-ABY-025 bound specifically to HER2 in vitro and in vivo. Direct comparison with the previous generation of HER2-binding tracers showed that ABY-025 retained excellent targeting properties. Rapid blood clearance was shown in mice, rats, and macaques. A highly specific tumor uptake of 16.7 ± 2.5 percentage injected activity per gram of tissue was seen at 4 h after injection. The tumor-to-blood ratio was 6.3 at 0.5 h and 88 at 4 h and increased up to 3 d after injection. γ-camera imaging of tumors was already possible at 0.5 h after injection. Furthermore, the repeated intravenous administration of ABY-025 did not induce antibody formation in rats. Conclusion: The biodistribution of111In-ABY-025 was in remarkably good agreement with the parent tracers, despite profound reengineering of the nonbinding surface. The molecule displayed rapid blood clearance in all species investigated and excellent targeting capacity in tumorbearing mice, leading to high tumor-to-organ-ratios and highcontrast imaging shortly after injection. COPYRIGHT

Original languageEnglish
Pages (from-to)1131-1138
Number of pages8
JournalJournal of Nuclear Medicine
Volume51
Issue number7
DOIs
Publication statusPublished - Jul 2010
Externally publishedYes

Keywords

  • Affibody molecule
  • Molecular imaging
  • Peptides
  • Radiopharmaceuticals
  • Reengineered scaffold

ASJC Scopus subject areas

  • Radiology Nuclear Medicine and imaging

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