In vivo visualization of MET tumor expression and anticalin biodistribution with the MET-specific anticalin 89Zr-PRS-110 PET tracer.

Abstract

UNLABELLED:

Anticalins are a novel class of biopharmaceuticals, displaying highly desirable attributes as imaging agents. The anticalin PRS-110 was rationally engineered to target the oncogene MET with high affinity and specificity. The aim of this study was to visualize MET expression and analyze biodistribution of (89)Zr-labeled PRS-110 in human tumor-bearing mice.

METHODS:

(89)Zr-PRS-110 was generated. For biodistribution studies (96 h after injection of tracer) 10 μg of (89)Zr-PRS-110 (with 0-490 μg of unlabeled PRS-110) were injected into BALB/c mice bearing high MET-expressing H441 non-small cell lung cancer xenografts. Further characterization with PET imaging was performed at 6, 24, 48, and 96 h after injection of 50 μg of (89)Zr-PRS-110 into mice bearing H441, primary glioblastoma U87-MG (intermediate MET), or ovarian cancer A2780 (low MET) xenografts. Drug distribution was also analyzed ex vivo using fluorescently labeled PRS-110.

RESULTS:

Biodistribution analyses showed a dose-dependent tumor uptake of (89)Zr-PRS-110, with the highest fractional tumor uptake at 10 μg of (89)Zr-PRS-110, with no unlabeled PRS-110. Small-animal PET imaging supported by biodistribution data revealed specific tumor uptake of (89)Zr-PRS-110 in the MET-expressing H441 and U87-MG tumors whereas the MET-negative A2780 tumor model showed a lower uptake similar to a non-MET binder anticalin control. Tumor uptake increased up to 24 h after tracer injection and remained high, whereas uptake in other organs decreased over time. Ex vivo fluorescence revealed intracellular presence of PRS-110.

CONCLUSION:

(89)Zr-PRS-110 specifically accumulates in MET-expressing tumors in a receptor density-dependent manner. PET imaging provides real-time noninvasive information about PRS-110 distribution and tumor accumulation in preclinical models.

• Authors: Anton G T Terwisscha van Scheltinga, Marjolijn N Lub-de Hooge, Marlon J Hinner, Remy B Verheijen, Andrea Allersdorfer, Martin Hülsmeyer, Wouter B Nagengast, Carolien P Schröder, Jos G W Kosterink, Elisabeth G E de Vries, Laurent Audoly, Shane A Olwill
• Journal: Journal of nuclear medicine : official publication, Society of Nuclear Medicine (J Nucl Med) Vol. 55 Issue 4 Pg. 665-71 (Apr 2014) ISSN: 1535-5667 [Electronic] United States
• PMID: 24614223 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antibodies, Monoclonal, Humanized
• Lipocalins
• PRS-110
• Proteins
• Radiopharmaceuticals
• Bevacizumab
• Proto-Oncogene Proteins c-met

Topics

• Animals
• Antibodies, Monoclonal, Humanized
• Bevacizumab
• Binding, Competitive
• Cell Line, Tumor
• Dose-Response Relationship, Drug
• Isotope Labeling
• Lipocalins
• Male
• Mice
• Mice, Inbred BALB C
• Mice, Nude
• Neoplasm Transplantation
• Proteins
• Proto-Oncogene Proteins c-met (biosynthesis)
• Quality Control
• Radiopharmaceuticals
• Tissue Distribution
• Xenograft Model Antitumor Assays