Abstract
Designed ankyrin repeat proteins (DARPins) are small engineered scaffold proteins that can be selected for binding to desirable molecular targets. High affinity and small size of DARPins render them promising probes for radionuclide molecular imaging. However, detailed knowledge on many factors influencing their imaging properties is still lacking. We have evaluated two human epidermal growth factor 2 (HER2)-specific DARPins with different size and binding properties. DARPins 9-29-H 6 and G3-H 6 were radiolabeled with iodine-125 and tricarbonyl technetium-99m and evaluated in vitro. A side-by-side comparison of biodistribution and tumor targeting was performed. HER2-specific tumor accumulation of G3-H 6 was demonstrated. A combination of smaller size and higher affinity resulted in a higher tumor uptake of G3-H 6 in comparison to 9-29-H 6 . Technetium-99m labeled G3-H 6 demonstrated a better biodistribution profile than 9-29-H 6 , with several-fold lower uptake in liver. Radioiodinated G3-H 6 showed the best tumor-to-organ ratios. The combined effect of affinity, molecular weight, scaffold composition, and nonresidualizing properties of iodine label provided radioiodinated G3-H 6 with high clinical potential for imaging of HER2.
| Original language | English |
|---|---|
| Journal | Molecular Pharmaceutics |
| DOIs | |
| Publication status | Published - 1 Jan 2019 |
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Keywords
- DARPin
- I-125
- imaging
- radionuclide
- targeting
- Tc-99m
ASJC Scopus subject areas
- Molecular Medicine
- Pharmaceutical Science
- Drug Discovery
Cite this
Comparative Evaluation of Two DARPin Variants : Effect of Affinity, Size, and Label on Tumor Targeting Properties. / Deyev, Sergey; Vorobyeva, Anzhelika; Schulga, Alexey; Proshkina, Galina; Güler, Rezan; Löfblom, John; Mitran, Bogdan; Garousi, Javad; Altai, Mohamed; Buijs, Jos; Chernov, Vladimir; Orlova, Anna; Tolmachev, Vladimir.
In: Molecular Pharmaceutics, 01.01.2019.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Comparative Evaluation of Two DARPin Variants
T2 - Effect of Affinity, Size, and Label on Tumor Targeting Properties
AU - Deyev, Sergey
AU - Vorobyeva, Anzhelika
AU - Schulga, Alexey
AU - Proshkina, Galina
AU - Güler, Rezan
AU - Löfblom, John
AU - Mitran, Bogdan
AU - Garousi, Javad
AU - Altai, Mohamed
AU - Buijs, Jos
AU - Chernov, Vladimir
AU - Orlova, Anna
AU - Tolmachev, Vladimir
PY - 2019/1/1
Y1 - 2019/1/1
N2 - Designed ankyrin repeat proteins (DARPins) are small engineered scaffold proteins that can be selected for binding to desirable molecular targets. High affinity and small size of DARPins render them promising probes for radionuclide molecular imaging. However, detailed knowledge on many factors influencing their imaging properties is still lacking. We have evaluated two human epidermal growth factor 2 (HER2)-specific DARPins with different size and binding properties. DARPins 9-29-H 6 and G3-H 6 were radiolabeled with iodine-125 and tricarbonyl technetium-99m and evaluated in vitro. A side-by-side comparison of biodistribution and tumor targeting was performed. HER2-specific tumor accumulation of G3-H 6 was demonstrated. A combination of smaller size and higher affinity resulted in a higher tumor uptake of G3-H 6 in comparison to 9-29-H 6 . Technetium-99m labeled G3-H 6 demonstrated a better biodistribution profile than 9-29-H 6 , with several-fold lower uptake in liver. Radioiodinated G3-H 6 showed the best tumor-to-organ ratios. The combined effect of affinity, molecular weight, scaffold composition, and nonresidualizing properties of iodine label provided radioiodinated G3-H 6 with high clinical potential for imaging of HER2.
AB - Designed ankyrin repeat proteins (DARPins) are small engineered scaffold proteins that can be selected for binding to desirable molecular targets. High affinity and small size of DARPins render them promising probes for radionuclide molecular imaging. However, detailed knowledge on many factors influencing their imaging properties is still lacking. We have evaluated two human epidermal growth factor 2 (HER2)-specific DARPins with different size and binding properties. DARPins 9-29-H 6 and G3-H 6 were radiolabeled with iodine-125 and tricarbonyl technetium-99m and evaluated in vitro. A side-by-side comparison of biodistribution and tumor targeting was performed. HER2-specific tumor accumulation of G3-H 6 was demonstrated. A combination of smaller size and higher affinity resulted in a higher tumor uptake of G3-H 6 in comparison to 9-29-H 6 . Technetium-99m labeled G3-H 6 demonstrated a better biodistribution profile than 9-29-H 6 , with several-fold lower uptake in liver. Radioiodinated G3-H 6 showed the best tumor-to-organ ratios. The combined effect of affinity, molecular weight, scaffold composition, and nonresidualizing properties of iodine label provided radioiodinated G3-H 6 with high clinical potential for imaging of HER2.
KW - DARPin
KW - I-125
KW - imaging
KW - radionuclide
KW - targeting
KW - Tc-99m
UR - http://www.scopus.com/inward/record.url?scp=85061542501&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85061542501&partnerID=8YFLogxK
U2 - 10.1021/acs.molpharmaceut.8b00922
DO - 10.1021/acs.molpharmaceut.8b00922
M3 - Article
AN - SCOPUS:85061542501
JO - Molecular Pharmaceutics
JF - Molecular Pharmaceutics
SN - 1543-8384
ER -