Evaluation of [(111/114m)In]CHX-A''-DTPA-ZHER2:342, an affibody ligand coniugate for targeting of HER2-expressing malignant tumors.

Abstract

AIM:

Radionuclide imaging of the HER2 receptor, which is a target for trastuzumab therapy, can provide important diagnostic information. Further, targeting radionuclide therapy might be an option for treatment of HER2 expressing tumors. The phage-display selected Affibody ligand Z(HER2:342), which binds to HER2 with an affinity of 22 pM, may here play an important role. The small size of the Z(HER2:342), 7.5 kDa, enables quick tumor localization and fast blood clearance. Earlier, successful targeting of HER2-expressing xenografts using Z(HER2:342) labeled using [(111)In]benzyl-DTPA was reported. By changing to the CHX-A''-DTPA chelator, the stability and labeling kinetics of the radiometal-Z(HER2:342) conjugate can be improved. The aim of this study was to evaluate the labeling of the CHX-A''-DTPA-Z(HER2:342) conjugate with (111)In for diagnostic imaging and with (114m)In for locoregional radionuclide therapy.

METHODS:

The isothiocyanate derivative of CHX-A''-DTPA was coupled to Z(HER2:342) in alkaline conditions at 37 degrees C. The conjugate was labeled with both (111)In and (114m)In and evaluated in vitro and in vivo.

RESULTS:

Labeling with (111)In and (114m)In provided >95% yield after 30 min at RT. Specific radioactivity was 0.5 and 12 MBq/nmol, for (114m)In and (111)In, respectively. The radiolabeled conjugates demonstrated specific binding to HER2 expressing SKOV-3 cells. In mice bearing SKOV-3 xenografts, the tumor uptake of [(111)In]CHX-A''-DTPA-Z(HER2:342) 4 h postinjection was 10.3+/-3.6% IA/g and tumor-to-blood ratio about 190.

CONCLUSION:

[(111)In]CHX-A''-DTPA-Z(HER2:342) is a promising candidate for the visualization of HER2 expression in malignant tumors. Labeled with (114m)In it could also be used for locoregional treatment of HER2 expressing tumors.

• Authors: A Orlova, D Rosik, M Sandström, H Lundqvist, L Einarsson, V Tolmachev
• Journal: The quarterly journal of nuclear medicine and molecular imaging : official publication of the Italian Association of Nuclear Medicine (AIMN) [and] the International Association of Radiopharmacology (IAR), [and] Section of the Society of... (Q J Nucl Med Mol Imaging) Vol. 51 Issue 4 Pg. 314-23 (Dec 2007) ISSN: 1824-4785 [Print] Italy
• PMID: 17464277 (Publication Type: Journal Article)

Chemical References

• 111In-CHX-A''-DTPA-Z(HER2;342) affibody
• Antibodies, Monoclonal
• Ligands
• Radiopharmaceuticals
• Recombinant Fusion Proteins
• Pentetic Acid
• Receptor, ErbB-2

Topics

• Animals
• Antibodies, Monoclonal (pharmacokinetics, therapeutic use)
• Cell Survival (radiation effects)
• Female
• Ligands
• Metabolic Clearance Rate
• Mice
• Organ Specificity
• Ovarian Neoplasms (diagnostic imaging, metabolism, radiotherapy)
• Pentetic Acid (analogs & derivatives, chemistry, pharmacokinetics)
• Radionuclide Imaging
• Radiopharmaceuticals (chemical synthesis, pharmacokinetics)
• Radiotherapy (methods)
• Receptor, ErbB-2 (metabolism)
• Recombinant Fusion Proteins (chemistry, pharmacokinetics)
• Tissue Distribution
• Treatment Outcome