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Tumor Targeting Using Affibody Molecules: Interplay of Affinity, Target Expression Level, and Binding Site Composition
KTH, Skolan för bioteknologi (BIO), Molekylär Bioteknologi.ORCID-id: 0000-0003-4409-9236
Vise andre og tillknytning
2012 (engelsk)Inngår i: Journal of Nuclear Medicine, ISSN 0161-5505, E-ISSN 1535-5667, Vol. 53, nr 6, s. 953-960Artikkel i tidsskrift (Fagfellevurdert) Published
Abstract [en]

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.

sted, utgiver, år, opplag, sider
2012. Vol. 53, nr 6, s. 953-960
Emneord [en]
radionuclide molecular imaging, scaffold proteins, Affibody molecules, affinity, HER2
HSV kategori
Identifikatorer
URN: urn:nbn:se:kth:diva-98731DOI: 10.2967/jnumed.111.101527ISI: 000305040900040Scopus ID: 2-s2.0-84861861669OAI: oai:DiVA.org:kth-98731DiVA, id: diva2:538875
Forskningsfinansiär
Swedish Research Council
Merknad
QC 20120702Tilgjengelig fra: 2012-07-02 Laget: 2012-07-02 Sist oppdatert: 2017-12-07bibliografisk kontrollert

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