In vivo and in vitro studies on renal uptake of radiolabeled affibody molecules for imaging of HER2 expression in tumors.

Abstract

Affibody molecules (6-7 kDa) are a new class of small robust three-helical scaffold proteins. Radiolabeled subnanomolar anti-HER2 affibody ZHER2:342 was developed for imaging of HER2 expression in tumors, and a clinical study has demonstrated that the (111)In- and (68)Ga-labeled affibody molecules can efficiently detect HER2 expressing metastases in breast cancer patients. However, a significant renal accumulation of radioactivity after systemic injection of a radiolabeled anti-HER2 affibody conjugate is observed. The aim of this study was to investigate the mechanism of renal reabsorption of anti-HER2 affibody at the molecular level. Renal accumulation of radiolabeled anti-HER2 affibody molecules was studied in a murine model and in vitro using opossum-derived proximal tubule (OK) cells. It was found that kidney reabsorption of affibody molecule was not driven by megalin/cubilin. Amino acids in the target-binding side of affibody molecule were involved in binding to OK cells. On OK cells, two types of receptors for anti-HER2 affibody molecule were found: KD1=0.8 nM, Bmax1=71,500 and KD2=9.2 nM, Bmax2=367,000. The results of the present study indicate that affibody molecule and other scaffold-based targeting proteins with a relatively low kidney uptake can be selected using in vitro studies with tubular kidney cells.

• Authors: Mohamed Altai, Zohreh Varasteh, Karl Andersson, Annemarie Eek, Otto Boerman, Anna Orlova
• Journal: Cancer biotherapy & radiopharmaceuticals (Cancer Biother Radiopharm) Vol. 28 Issue 3 Pg. 187-95 (Apr 2013) ISSN: 1557-8852 [Electronic] United States
• PMID: 23461385 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Heterocyclic Compounds, 1-Ring
• Immunoconjugates
• Indium Radioisotopes
• Radiopharmaceuticals
• Recombinant Fusion Proteins
• affibody (ZHER2-342)2
• 1,4,7,10-tetraazacyclododecane- 1,4,7,10-tetraacetic acid
• Technetium
• Receptor, ErbB-2

Topics

• Animals
• Cell Line, Tumor
• Female
• Heterocyclic Compounds, 1-Ring (chemistry, pharmacokinetics)
• Humans
• Immunoconjugates (pharmacokinetics)
• Indium Radioisotopes (chemistry)
• Kidney (metabolism)
• Male
• Mice
• Molecular Imaging (methods)
• Opossums
• Ovarian Neoplasms (diagnostic imaging, metabolism)
• Radiopharmaceuticals (pharmacokinetics)
• Receptor, ErbB-2 (analysis, biosynthesis)
• Recombinant Fusion Proteins (pharmacokinetics)
• Technetium (chemistry)
• Tissue Distribution
• Tomography, Emission-Computed, Single-Photon