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Tumor Targeting Using Affibody Molecules: Interplay of Affinity, Target Expression Level, and Binding Site Composition.

Tolmachev, Vladimir; Tran, Thuy LU ; Daniel, Rosik; Anna, Sjöberg; Lars, Abrahamsén and Anna, Orlova (2012) In Journal of Nuclear Medicine 53(6). p.953-960
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... (More)
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 (K(D) = 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. (Less)
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author
organization
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type
Contribution to journal
publication status
published
subject
in
Journal of Nuclear Medicine
volume
53
issue
6
pages
953 - 960
publisher
Society of Nuclear Medicine
external identifiers
  • wos:000305040900040
  • scopus:84861861669
ISSN
0161-5505
DOI
10.2967/jnumed.111.101527
language
English
LU publication?
yes
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bc59e8a3-2bb2-4557-bcda-9443856a4685 (old id 2544816)
alternative location
http://jnm.snmjournals.org/content/early/2012/05/14/jnumed.111.101527.long
date added to LUP
2012-12-17 12:02:28
date last changed
2017-11-19 03:02:24
@article{bc59e8a3-2bb2-4557-bcda-9443856a4685,
  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 (K(D) = 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.},
  author       = {Tolmachev, Vladimir and Tran, Thuy and Daniel, Rosik and Anna, Sjöberg and Lars, Abrahamsén and Anna, Orlova},
  issn         = {0161-5505},
  language     = {eng},
  number       = {6},
  pages        = {953--960},
  publisher    = {Society of Nuclear Medicine},
  series       = {Journal of Nuclear Medicine},
  title        = {Tumor Targeting Using Affibody Molecules: Interplay of Affinity, Target Expression Level, and Binding Site Composition.},
  url          = {http://dx.doi.org/10.2967/jnumed.111.101527},
  volume       = {53},
  year         = {2012},
}