Tumor targeting using affibody molecules: Interplay of affinity, target expression level, and binding site composition

Vladimir Tolmachev, Thuy A. Tran, Daniel Rosik, Anna Sjöberg, Lars Abrahmsén, Anna Orlova

Research output: Contribution to journalArticlepeer-review

58 Citations (Scopus)

Abstract

Radionuclide imaging of cancer-associated molecular alterations may contribute to patient stratification for targeting therapy. Scaffold high-affinity proteins, such as Affibody molecules, are a new, promising class of probes for in vivo imaging. Methods. The effects of human epidermal growth factor receptor 2 (HER2) affinity and binding site composition of HER2-binding Affibody molecules, and of the HER2 density on the tumor targeting, were studied in vivo. The tumor uptake and tumor-to-organ ratios of Affibody molecules with moderate (dissociation constant [K D] = 10 -9 M) or high (K D = 10 -10 M) affinity were compared between tumor xenografts with a high (SKOV-3) and low (LS174T) HER2 expression level in BALB/C nu/nu mice. Two Affibody molecules with similar affinity (KD = 10 -10 M) but having alternative amino acids in the binding site were compared. Results. In SKOV-3 xenografts, uptake was independent of affinity at 4 h after injection, but high-affinity binders provided 2-fold-higher tumor radioactivity retention at 24 h. In LS174T xenografts, uptake of high-affinity probes was already severalfold higher at 4 h after injection, and the difference was increased at 24 h. The clearance rate and tumor-to-organ ratios were influenced by the amino acid composition of the binding surface of the tracer protein. Conclusion. The optimal affinity of HER2-binding Affibody molecules depends on the expression of a molecular target. At a high expression level (>10 6 receptors per cell), an affinity in the low-nanomolar range is sufficient. At moderate expression, subnanomolar affinity is desirable. The binding site composition can influence the imaging contrast. This information may be useful for development of imaging agents based on scaffold affinity proteins.

Original languageEnglish
Pages (from-to)953-960
Number of pages8
JournalJournal of Nuclear Medicine
Volume53
Issue number6
DOIs
Publication statusPublished - Jun 2012
Externally publishedYes

Keywords

  • Affibody molecules
  • Affinity
  • HER2
  • Radionuclide molecular imaging
  • Scaffold proteins

ASJC Scopus subject areas

  • Radiology Nuclear Medicine and imaging

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